NHS Choices

Depression blood test could lead to personalised treatments

NHS Choices - Behind the Headlines - Tue, 07/06/2016 - 18:30

"UK scientists have developed a blood test to help doctors pick the best drug for patients with depression," BBC News reports, somewhat prematurely.

It is currently unproven whether such a test, based on measuring inflammation, would improve treatment outcomes.

Previous research has suggested high levels of inflammation – which is not just a reaction to infection, but can also be caused by stress – may impair the beneficial effects of antidepressants.

Researchers screened blood samples from people with depression who had, and had not, responded well to antidepressant medicines in the hope of identifying molecules associated with inflammation and drug response.

They then used this information for a second group to see if they could predict who would and wouldn't respond to treatment with antidepressants.

A significant proportion of people were correctly identified as responders and non-responders, which is a big step forward compared with current practices.

But the test also missed 39-43% of non-responders, meaning they would continue to receive antidepressant treatment that is unlikely to work for them.

One of the study's limitations is its size. It was based on less than 200 people with depression, not nearly enough to draw any concrete conclusions about whether it works well in most people with depression.

The study also only looked at drug treatments, and did not assess talking therapies such as cognitive behavioural therapy.

This approach certainly seems to be a step in the right direction, but it needs refinement before personalised treatments for depression can be practised with confidence.

Where did the story come from?

The study was led by researchers from King's College London in the UK.

It was funded by the Medical Research Council, South London and Maudsley NHS Foundation Trust, King's College London, and the European Commission.

One of the study authors declared a potential conflict of interest, having received funding from Johnson & Johnson for research into depression and inflammation, as well as speaker fees for Lundbeck.

They have also received research funding from a large consortia, which included Johnson & Johnson, GSK, Pfizer and Lundbeck.

The study was published in the peer-reviewed International Journal of Neuropsychopharmacology.

The research is open access, so it is free to read online or download as a PDF.

The UK media's coverage was generally accurate, but there was some room for improvement.

Describing current depression treatment as "trial and error" (The Daily Telegraph and BBC News) is perhaps unfair on doctors and patients, who are attempting to jointly work out the best way to treat a serious condition with the options at their disposal.

For example, doctors usually prescribe the least powerful antidepressant available that is the least likely to lead to troublesome side effects, given the person's current and past medical history.

However, the reporting does touch on the uncertainty this treatment approach currently involves, which the new approach hopes to improve.

Also, some of the tone of the BBC's reporting could give the impression that this blood test had led to proven successes in terms of improved outcomes, which is currently not the case.

What kind of research was this?

This laboratory study looked to develop a way of classifying people with depression into those likely or unlikely to respond to commonly used antidepressant medicines.

The research team says higher inflammation levels have been linked to poorer responses to antidepressants in several studies.

But researchers hadn't yet developed accurate or reliable ways to predict who would benefit from antidepressants, and who wouldn't, so they could try a different type of drug or a non-drug treatment.

Part of the problem is we don't fully understand the biology of depression, making it difficult to know which molecules or processes to target to develop a predictive test.

What did the research involve?

Researchers screened blood samples from people with depression who had, and had not, responded well to antidepressant medicines in the hope of identifying molecules that could distinguish the two groups.

The researchers didn't measure these molecules directly. Instead, they counted up the number of messenger RNA (mRNA) molecules in the blood – small strands of genetic material that carry instructions to build many biological molecules.

This, they said, gave a reliable and accurate measure of the levels of the immune messengers, and had the added benefit of being able to be detected accurately and reliably by a simple blood test sent to the lab.

Seventy-four people with major depression (at least moderate severity), most of whom were in their second episode of depression, had their mRNA analysed to identify potential predictive molecules, as well as cut-off points for responders and non-responders.

These people came from a randomised controlled trial comparing 12 weeks of treatment with the antidepressants escitalopram (a selective serotonin reuptake inhibitor, usually the first choice class of antidepressant) and nortriptyline (a tricyclic antidepressant, or TCA, an older class of antidepressant), so their response to these medicines was known.

Response was defined as a greater than 50% reduction in score on a standard depression rating scale (the Montgomery-Åsberg Depression Rating Scale, MADRS).

To make sure these initial test cut-offs were accurate, the researchers tested them in a second validation sample of 68 people with depression using the same methods to detect responders.

This group had only recently started to take antidepressants and took a wider range, including:

  • escitalopram (SSRI)
  • paroxetine (SSRI)
  • duloxetine (serotonin and noradrenaline reuptake inhibitors, SNRI)
  • venlafaxine (SNRI)
  • amitriptyline (TCA)
  • desipramine (a TCA not licensed in the UK)

Patients were excluded from this part of the investigation if they were taking antipsychotics or mood stabilising medication.

The main analysis quantified the accuracy of the newly developed test to identify responders and non-responders to antidepressant medicines.

This included taking into account background differences in mRNA expression, which varies naturally from person to person.

What were the basic results?

Across the two studies, between 66% and 69% of patients responded to antidepressants.

Researchers identified mRNA linked to macrophage migration inhibitory factor and interleukin-1ß as the most useful to identify responders and non-responders.

Using their first group of patients, the test found:

  • 100% of those classified as non-responders were true non-responders (positive predictive value 100%, 14 of 14) – in other words a positive test result is 100% accurate
  • 100% of responders were correctly identified as being responders (specificity 100%, 51 of 51), meaning nobody on effective treatment would be unnecessarily "stepped up" to more advanced treatment
  • about 22% of the group were identified as "intermediates", meaning they weren't responders or non-responders – they fell in the middle
  • the test missed 39% of non-responders, falsely categorising them as responders (negative predictive value 85%) – a negative test result is only 85% accurate; this group would continue to receive standard antidepressant treatment that is unlikely to work for them

Results were very similar in the second group. The top two measures remained at 100% and the test missed 43% of non-responders, falsely categorising them as responders (negative predictive value 82%). Around 38% were classified as intermediates.

The researchers found background levels of mRNA made little difference to the test accuracy. All that mattered was the absolute amount of mRNA for macrophage migration inhibitory factor and interleukin-1ß.

How did the researchers interpret the results?

The researchers concluded that, "The absolute numbers of MIF [macrophage migration inhibitory factor] and IL-1β [interleukin-1ß] mRNA molecules are both accurate and reliable predictors of antidepressant response, identifying, for the first time, an mRNA-based biomarker approach that is independent from local experimental settings and does not require 'relative' quantification using housekeeping genes."

Conclusion

This study shows how a new blood test in development can help identify people with depression who are most and least likely to benefit from antidepressants.

While promising, the test is far from perfect. For example, it missed 39-43% of non-responders, meaning these people would continue to receive standard antidepressant treatment that is unlikely to work for them.

A large proportion of patients (22-38%) also fell into the "intermediate" group who were neither responders nor non-responders, so the test wasn't too useful here.

This means there is a significant proportion of people with depression who would not necessarily benefit from this test.

However, we shouldn't be overly negative. A significant proportion of people were identified correctly as responders and non-responders, which is a big step forward on what happens today.

The study was based on less than 200 people with depression, far too few to conclude whether it works well in most people with depression.

Larger studies involving many hundreds, perhaps thousands, of people will be needed to establish this, and is the natural next step for this research.  

Links To The Headlines

New blood test targets depression. BBC News, June 7 2016

Blood test could identify people who will respond to antidepressants. The Guardian, June 7 2016

Simple blood test could stop doctors using 'trial and error' to prescribe antidepressants, scientists claim. The Daily Telegraph, June 7 2016

Depression patients 'could get personalised treatment thanks to new blood test'. Mail Online, June 7 2016

Links To Science

Cattaneo A, Ferrari C, Uher R, et al. Absolute Measurements of Macrophage Migration Inhibitory Factor and Interleukin-1-β mRNA Levels Accurately Predict Treatment Response in Depressed Patients. International Journal of Neuropsychopharmacology. Published online May 11 2016

Categories: NHS Choices

Women are more likely to suffer from anxiety than men

NHS Choices - Behind the Headlines - Tue, 07/06/2016 - 16:40

"Women twice as likely as men to experience anxiety, research finds," The Guardian reports. A new review that attempts to get a global snapshot of the prevalence of anxiety disorders identifies a number of vulnerable groups.

There are various types of anxiety disorder, but generally they involve feelings of unease, such as worry or fear, that can be mild or severe and affect daily life. Having an overwhelming sense of anxiety that "takes over your life" is described as having a generalised anxiety disorder.

There are many factors that can trigger an anxiety disorder, such as stress, physical conditions, genetic background and hormonal imbalances.

The researchers found that women, young people and those with other chronic diseases were disproportionally affected. Across countries, women were found to be twice as likely to be affected as men.
 
The researchers call for further research to be carried out on the illness, as well as investigating which type of interventions have the greatest benefit. There is also a need for further study of anxiety prevalence in developing and under-developed parts of the world, as there was a lack of representation.

Although feelings of anxiety at certain times are completely normal, you should see your GP if anxiety is affecting your daily life or causing you distress.

 

Where did the story come from?

The study was carried out by researchers from the University of Cambridge and Westminster City Council. It was funded by the UK National Institute for Health Research. The study was published in the peer-reviewed clinical journal Brain and Behavior. It is available on an open-access basis and is free to read online.

While the media coverage was generally accurate, both the Mail Online and The Times claimed that the reasons why younger women had higher levels of anxiety were down to many of them being working mothers. This claim seems to be based on opinions, rather than any hard evidence presented in the study.

 

What kind of research was this?

This was a systematic review that aimed to collate evidence from other systematic reviews which had explored the prevalence of anxiety, to describe the burden of disease across population subgroups.

As the researchers mention, anxiety disorders contribute to significant disability and impairment to quality of life, and are the most prevalent mental health conditions in Europe. They place increasing demand upon health services across the globe, and are recognised as important determinants of poor health. This is the first reported study to attempt to provide a comprehensive synthesis of the findings from reviews undertaken on the global burden of anxiety.

Systematic reviews are one of the highest levels of evidence, but they are only as good as the studies they contain. The included reviews varied widely in their methods, the studies they had included and populations examined. Due to this variation, the researchers did not attempt to carry out a meta-analysis of their findings. Instead, they report the findings across the individual reviews.

 

What did the research involve?

The researchers searched three literature databases up to May 2015 to identify systematic reviews and meta-analyses that had reported the burden of anxiety across the globe.

Reviews could have looked at any anxiety disorder, including generalised, social anxiety or obsessive compulsive disorder, and use any method to assess anxiety. The researchers specifically searched for reviews including individuals suffering from other medical or mental health conditions (chronic or infectious disease, psychiatric conditions, and addiction) as well as those from vulnerable populations. Reviews on the treatment of anxiety were excluded.

Two researchers assessed the quality of the reviews and eligibility for inclusion, and extracted data.

The reviews included studies of people of all ages, from young children to people of old age, with the overall number of studies and individual study sample sizes varying. The method of anxiety assessment also varied between studies, from structured and unstructured interviews to self-reported questionnaires.

 

What were the basic results?

Results from the 48 studies were gathered to describe the global distribution of anxiety disorders. The main results were as follows:

  • The general prevalence of anxiety disorders in healthy populations ranged from 3% to 25%.
  • Women were found to be twice as likely to be affected as men (female: male ratio of 1.9:1). This was consistently the case across different countries and co-existing health conditions.
  • Young adults under the age of 35 were also more often affected (2.5% to 9.1%).
  • Prevalence was found to be highest in North America (7.7%, 95% confidence interval [CI] 6.8 to 8.8) and in North Africa/Middle East (7.7%, 95% CI 6.0 to 10.0).
  • The lowest prevalence was found in East Asia (2.8%, 95% CI 2.2 to 3.4).

The prevalence was then described according to five common themes:

  • addiction
  • other mental and neurological disorders
  • chronic physical diseases
  • trauma
  • vulnerable population subgroups

They found that, compared to healthy populations, the prevalence was higher in individuals with chronic conditions, who had a prevalence ranging from 1.4% to 70%.

 

How did the researchers interpret the results?

The researchers concluded: "Despite epidemiologic advances in this field, important areas of research remain under- or unexplored. There is a need for further studies on the prevalence of anxiety disorders. These recommendations can serve to guide the research agenda, and most importantly, help develop tailored and timely interventions."

 

Conclusion

This systematic review of previously gathered data compiled evidence from 48 studies to describe the global prevalence of anxiety disorders, which are placing increasingly high demand upon health services across the globe. The review gives us a general picture of the prevalence of these conditions worldwide and notes several themes.

It found that anxiety disorders are common across all population groups, but women and young people seem to be disproportionally affected. Anxiety prevalence was also higher in individuals with chronic conditions, though it is not possible to say whether mental health problems could be a contributing factor or a consequence.

Reviews were assessed for eligibility against a validated quality assessment tool. However, the researchers highlight the large variability in the methods of the reviews and the studies they included, which makes comparison of prevalence figures between the studies difficult.

For example, there was wide variation between reviews in:

  • the overall number of studies they included and their sample sizes
  • the ages of participants, with some reviews looking at older individuals and some looking at children (aged 6+)
  • whether they were general population samples or those with specific physical or mental health conditions
  • the tools used to assess anxiety
  • whether they took account of other health, environmental or lifestyle factors

While this review is a useful indicator of the prevalence of anxiety disorders, it is unable to suggest causation – for example, why prevalence may be higher in women or younger adults. It is possible that this could be down to a complex interaction of biological and lifestyle factors. However, the direction of effect or the extent of influence of different factors remains unknown.

The researchers call for further research to be carried out on the course of the illness, as well as anxiety levels pre- and post-treatment. They also note the need for further study into developing and under-developed parts of the world, as there was a lack of representation of those areas, and for specific study into vulnerable subgroups of society.

Visit the NHS Choices Moodzone for more information about stress, anxiety and depression, and methods you can try to cope with and combat these feelings.  

Links To The Headlines

Women twice as likely as men to experience anxiety, research finds. The Guardian, June 6 2016

Women 'nearly twice as likely to have anxiety' as men. BBC News, June 6 2016

Women twice as likely to worry than men. The Independent, June 6 2016

Women are almost TWICE as likely to suffer from anxiety as men. Daily Mirror, June 6 2016

Modern life is leaving women twice as likely to be stressed as men as they juggle work, family and children. Mail Online, June 6 2016

Women under 35 have it all — including anxiety disorders. The Times, June 6 2016 (subscription required)

Links To Science

Remes O, Brayne C, van der Linde R, Lafortune L. A systematic review of reviews on the prevalence of anxiety disorders in adult populations. Brain and Behavior. Published online June 5 2016

Categories: NHS Choices

Ten years of hormone breast cancer drugs 'may benefit some'

NHS Choices - Behind the Headlines - Mon, 06/06/2016 - 13:30

"Taking hormonal drugs for up to 15 years reduces the risk of breast cancers coming back," BBC News reports.

A new study looked at 1,918 postmenopausal women with what is known as oestrogen receptor-positive (or ER+) breast cancers – where cancer growth is stimulated by the hormone oestrogen.

A class of drugs known as aromatase inhibitors are often used in such cases, as they are able to reduce the production of oestrogen.

The women had previously responded well to a five-year course of hormone treatments.

They were randomised into two groups: either they took an aromatase inhibitor called letrozole for another five years, or they were given a dummy treatment (placebo).

Disease-free survival after five years was 95% in the treatment group and 91% in the placebo group.

Extended aromatase inhibitor treatment cut the risk of recurrent or new breast cancer development by about a third. 

Osteoporosis was the most significant side effect from extended treatment with letrozole.

However, there was no effect on overall survival, and no effect on disease-free survival when taking into account baseline differences between the participants.

It is hoped further evidence will be forthcoming to identify which women – in terms of characteristics, stage of breast cancer and prior treatment – may be most suited to this treatment, and for whom the benefits of prolonged treatment would outweigh the side effects.

Where did the story come from?

The study was carried out by researchers from the Avon International Breast Cancer Research Program at Massachusetts General Hospital Cancer Center and other institutions in the US.

Funding was provided by the Canadian Cancer Society Research Institute, the National Cancer Institute, the Canadian Cancer Trials Group, the ECOG-ACRIN Cancer Research Group, and Novartis Pharmaceuticals.

Several researchers declared conflicts of interest for serving on advisory boards for various pharmaceutical companies.

The study was published in the peer-reviewed journal, The New England Journal of Medicine, on an open access basis, so you can read it for free online.

The UK media reported on the study accurately, but many of the headlines included the phrase "women should stay on hormonal drugs for 10 years", or variations on it.

The researchers actually went out of their way to make the point that this study should not be taken as some sort of blanket recommendation for all women with ER+ breast cancer.

There was also apparent headline confusion on the BBC website over whether women should continue treatment for 10 or 15 years. This seems to come from the fact that most women had taken 5 years of tamoxifen prior to 10 years of an aromatase inhibitor.  

What kind of research was this?

This was a placebo-controlled randomised controlled trial that aimed to investigate the effects of extended treatment with an aromatase inhibitor (letrozole) in women with ER+ breast cancer.

ER+ means that the breast cancer cells have oestrogen receptors and the body's natural hormone is stimulating the cancer to grow. These cancers can be treated by hormone treatments, which can block this.

There are two types of hormone treatment – aromatase inhibitors, which are only given to postmenopausal women, and tamoxifen, which is most often used in premenopausal women, but can also be used in the treatment of postmenopausal women.

The problem is that even after treatment, there is always a risk the cancer will relapse or recur.

Hormone therapy regimens vary, depending on what treatment the person is having alongside it.

They can involve giving just an aromatase inhibitor for five years, or a combination of tamoxifen for five years and then an aromatase inhibitor for five years.

This placebo-controlled trial specifically aimed to look at the effect of giving an aromatase inhibitor for 10 years rather than 5, after any duration of previous treatment with tamoxifen.

What did the research involve?

The trial involved postmenopausal women with ER+ breast cancer who had received 4.5 to 6 years of treatment with an aromatase inhibitor.

In most women (two-thirds) this had been preceded by about five years of tamoxifen treatment.

A total of 1,918 women who were still disease-free after using aromatase inhibitor treatment were randomised to then receive the aromatase inhibitor letrozole or placebo for a further five years. Treatment started within six months of stopping their previous treatment.

Participants received yearly clinical assessments, including blood tests, mammography, bone scans, and assessment of drug side effects and quality of life.

The main outcome of interest was disease-free survival, defined as time from randomisation to breast cancer recurrence.

Other outcomes included overall survival, cancer development in the other breast, quality of life and long-term safety.

After five years, as the number of recurrence events in the placebo group was less than expected, the trial design was amended to look at the time that events occurred, rather than just looking at the number of events over continued follow-up time.

The duration of the study was five years, and the average follow-up period was 6.3 years.

What were the basic results?

The rate of cancer recurrence or new cancer development in the opposite breast was lower in the letrozole group, at 7%, compared with 10.2% of the placebo group.

The rate of disease recurrence specifically was 5.7% in the letrozole group versus 7.1% in the placebo group. Each year, around 0.21% of the letrozole group and 0.49% of the placebo group developed a new cancer in the other breast.

Five-year disease-free survival was higher in the letrozole group, at 95%, compared with 91% in the placebo group.

Letrozole reduced the risk of recurrence or development of cancer in the other breast by a third (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.48 to 0.91). 

There was no statistically significant difference when looking at overall survival, which was 90% in the letrozole group and 88% in the placebo group. Deaths were due to breast cancer, other primary cancers and cardiovascular disease.

Loss of bone density was a significantly more common side effect in the letrozole group, though few people in either group stopped treatment because of side effects. There was no difference between groups in terms of quality of life.

There was no significant difference between groups when adjusting for baseline characteristics and duration of prior aromatase inhibitor treatment.

How did the researchers interpret the results?

The researchers concluded that, "Extension of treatment with an aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of [opposite] breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo." 

Conclusion

This trial suggests that extending the duration of aromatase inhibitor treatment for postmenopausal women to 10 years, rather than five, may reduce the risk of the cancer recurring or new cancer developing in the other breast.

The trial has many strengths, including:

  • a double-blind design, with neither participants nor the research team aware of allocation to treatment or placebo groups – this is regarded as the gold standard of assessing the effect of an intervention; adherence rates to five years were equivalent in both groups (62% in each), suggesting that participants were unaware of treatment 
  • stratified randomisation – this ensured baseline characteristics were balanced between the groups
  • a large sample size and prior power calculation – this ensured the researchers enrolled a sufficient number of people to detect a difference in survival between the groups 

However, there are points to bear in mind. There was no difference between groups when including the outcome of overall survival – this was seen only when comparing new or recurrent breast cancer rates.

There was also no significant difference between groups when taking into account baseline characteristics.

This suggests some women may be better suited to, or would gain more benefit from, prolonged aromatase inhibitor treatment than others.

The trial has only looked at disease-free survival up to five years. Though this was better in the treatment group, this is comparing women who had just stopped 10 years of treatment with an aromatase inhibitor with women who took an aromatase inhibitor for five years, and stopped five years ago.

We don't know the outcomes for the extended treatment group another 5 or 10 years down the line.

Extended treatment with an aromatase inhibitor may prolong disease-free survival, but this doesn't necessarily mean it would definitely prevent breast cancer ever coming back.

These were also a select group of postmenopausal women with ER+ breast cancer, the majority of whom had received about five years of tamoxifen before taking an aromatase inhibitor.

The results cannot be applied to all women with breast cancer, who may have different characteristics, types and stages of breast cancer, as well as different treatment regimens.

Overall, the results of this large and well-designed randomised controlled trial suggest that extended treatment with an aromatase inhibitor to 10 years may be suitable for some women.

However, the potential side effects should be balanced with the quality of life that could be had from this treatment.

The manufacturers of letrozole report menopausal-like side effects, such as hot flushes, increased sweating and fatigue, are very common, affecting more than 1 in 10 women.

It needs to be determined which women would be most suited to this regimen, and for whom the benefits would outweigh the side effects. Such information would allow women to make an informed choice about their treatment. 

Links To The Headlines

Breast cancer: Taking hormonal drugs for up to 15 years can reduce risk – study. BBC News, June 5 2016

Breast cancer drugs should be given for 10 years, study shows. The Guardian, June 5 2016

Breast cancer patients should continue taking drugs for longer to prevent it returning, experts say. Daily Mirror, June 5 2016

Breast cancer patients 'should stay on hormonal drugs for 10 years to slash risk of the disease returning'. Mail Online, June 5 2016

Links To Science

Goss PE, Ingle JN, Pritchard KI, et al. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. The New England Journal of Medicine. Published online June 5 2016

Categories: NHS Choices

'Friendly' virus repairs damaged liver cells (but only in mice)

NHS Choices - Behind the Headlines - Fri, 03/06/2016 - 14:30

"Have scientists found a cure for alcoholism?," the Mail Online asks, missing the point of the research entirely.

Researchers were able to improve liver damage in mice, but this does not amount to curing an addiction to alcohol.

The study showed it was possible to create "bespoke friendly" viruses to infect cells known as myofibroblasts, which are cells associated with tissue repair. The virus passed on instructions that transformed the myofibroblasts into healthy liver cells in mice who had fibrosis (scarring) of the liver, known as cirrhosis.

Not all the experiments in the mice worked, but in those that did, the transformed liver cells looked and behaved normally, replaced some of the diseased liver cells, and led to less liver scarring.

Researchers will now attempt to refine this technique before seeing if it works in humans.  

Right now, this technique is not available as a new treatment. It represents one of the earliest stages of treatment discovery and development, which can take decades from start to finish.

If you do have a lifestyle that increases your risk of liver disease, such as heavy alcohol consumption, being obese, or injecting drugs, you should ask your GP for a liver function test. The symptoms of liver disease often only occur once it is too late to undo the damage.

Taking action to reduce your risk before this happens could restore your liver back to good health.

 

Where did the story come from?

The study was carried out by researchers from The University of California and funded by grants from the US National Institutes of Health.

The study was published in the peer-reviewed science journal Cell – Stem Cell.

The Mail Online's reporting was poor, failing on three main points.

Firstly, it asked an inappropriate question in its headline – "Have scientists found a cure for alcoholism?". A cure, or at least a partial repair, of liver damage would not amount to a cure for alcohol addiction. The headline confused alcohol with its main health consequence – alcoholic liver disease. There are many other consequences of chronic alcohol misuse – be it social, financial or mental health-related.

Secondly, nowhere in the article (let alone in the headline) did it mention that the study was on mice, so readers might naturally assume it involved people.

Thirdly, there are other causes of liver disease aside from alcohol, such as obesity (non-alcoholic fatty liver disease) or infection with the hepatitis C virus. The mice studied didn't have alcohol-induced liver disease.

 

What kind of research was this?

This was a laboratory study investigating a potential new treatment approach for liver fibrosis.

Liver fibrosis is the scarring and demise of your liver, following repeated cell damage and inflammation. Fibrosis can have many causes, including viruses (like hepatitis B and C), alcohol misuse, and fatty liver disease.

Despite the liver's somewhat unique ability to recover and regenerate, when liver cells are repeatedly damaged, such as through sustained heavy alcohol use, they gradually die and the organ stops working. Part of the damage is the build-up of collagen, which causes scarring and restricts blood flow.

The poorly functioning liver and restricted blood flow causes symptoms including jaundice, weight loss, swelling of the abdomen, vomiting blood and, ultimately, death.

The only cure for severe liver scarring, where the liver loses most of its functioning ability (liver failure), is a liver transplant. But there are not enough organs to meet demand, so medical researchers are always looking for alternatives.

 

What did the research involve?

The researchers reprogrammed types of cells called myofibroblasts into liver cells by injecting reprogramming instructions, via a "designer virus", into mice with liver disease.

Myofibroblasts were chosen as the target, as they produce the excess collagen which causes scarring.

The researchers carefully analysed whether the reprogrammed cells behaved like normal liver cells in the lab and had similar DNA and protein profiles. They also tested whether once injected they were able to grow, repair and replace some or all of the liver damage.

Part of the challenge was devising a safe and effective way to deliver the reprogramming instructions to the mice myofibroblast cells. They used adeno-associated virus 6 (AAV6) vectors to act as delivery vehicles.

This involved taking the packaging of a virus and modifying it, so instead of infecting a mouse and causing disease, it infects the mouse and makes the modifications they wanted – in this case, turning myofibroblasts into liver cells. This involves replacing and modifying the virus DNA – that instructs the virus cell – with DNA encoding instructions you want.

 

What were the basic results?

The researchers overcame the delivery and reprogramming challenges to influence some cells to change from myofibroblasts into liver cells by injecting the reprogramming instructions into the bloodstreams of the mice using different AAV vectors.

Not all of the vectors worked. But in those that did, not only did some cells change, they appeared to function like normal liver cells, were able to grow and multiply, and reduced the amount of problematic collagen.

This partially alleviated two of the main causes of liver fibrosis – liver cell death and collagen build up – in mice with liver disease.

 

How did the researchers interpret the results?

The researchers concluded: "Our study establishes the feasibility of in vivo reprogramming of myofibroblasts into fully functional hepatocytes [liver cells] using AAV vectors, a gene delivery tool that proved to be safe and effective in clinical trials of liver-directed gene therapy".

 

Conclusion

This study showed it was possible to engineer and inject instructions that transform myofibroblasts into liver cells in mice with liver disease, which is quite a feat. Not all delivery mechanisms, called vectors, worked, but in those that did, the new liver cells looked normal, replaced some of the dying cells, and led to less damage due to collagen build up.

Despite the alcoholism-related headline, the mice did not have alcohol-induced liver damage – although this is a major cause of liver damage in people.

This study serves to prove this approach is feasible, and was successful in doing this. Researchers will now need to refine the technique before testing to see if it works in human trials.  

The good news is the vector delivery system has been used in human trials before – although not containing the same liver cell transformation message – so has a better chance than normal of working in people.

Right now this technique is not available as a new treatment. It represents one of the earliest types of treatment development, which can take decades from start to finish.

Currently the only cure for severe liver scarring is an organ transplant, but many die while waiting for a transplant as need far outstrips supply. If you are not on the register, you could save lives by joining the NHS Organ Donor Register today.

The liver is tough and can regenerate itself, but it can only take so much damage. Moderating your alcohol consumption, maintaining a healthy weight, and reducing your risk of contracting hepatitis C (mainly spread by injecting drugs), will do much to keep your liver healthy. 

Links To The Headlines

Have scientists found a CURE for alcoholism? New virus can 'repair the liver damage caused by drinking'. Mail Online, June 3 2016

Links To Science

Rezvani M, Español-Suñer R, Malato Y, et al. In Vivo Hepatic Reprogramming of Myofibroblasts with AAV Vectors as a Therapeutic Strategy for Liver Fibrosis. Cell Stem Cell. Published online June 2 2016

Categories: NHS Choices

Research raises hope of a 'Holy Grail' universal cancer vaccine

NHS Choices - Behind the Headlines - Thu, 02/06/2016 - 18:00

"'Universal cancer vaccine' breakthrough claimed by experts," The Independent reports.

Researchers extracted genetic code called RNA from cancer cells, embedded them in nanoparticles to make them appear like viruses or bacteria, and injected them into mice to "teach" immune cells to attack cancer cells.

In most cancer cases, the immune system ignores cancer cells as it cannot tell the difference between these and healthy cells. This makes it vital to give the immune system the ability to recognise and target cancer cells.

Researchers developed the vaccine after a series of experiments on mice, using different types of RNA-containing nanoparticles (tiny particles that can be as small as a billionth of a metre) disguised in fatty acid (lipid) coatings. They discovered the type that worked best to reach the relevant parts of the immune system.

After showing that the vaccines worked on mice with artificially induced tumours, the researchers began early human trials.

They used a low dose of the vaccine in three people with malignant melanoma, a type of skin cancer.

All three responded by producing T cells to target the cancer cells, in the same way as if their body had detected a virus or bacteria. Side effects were reported to be brief flu-like symptoms.

We now need to see the results of larger trials in many people with different types of cancer to assess whether a "universal" cancer vaccine could be made based on these techniques.

Where did the story come from?

The study was carried out by researchers from Johannes Gutenberg University, Biopharmaceutical New Technologies, Heidelberg University Hospital and the Cluster for Individualized Immune Intervention, all in Germany.

It was funded by the technology innovation programme of the Rhineland Palatinate government, the InnoTop programme, the CI3 Cutting Edge Cluster Funding of the German Ministry of Technology (BMBF), and the Collaborative Research Group 1066 of Deutsche Forschungsgemeinschaft.

The study was published in the peer-reviewed journal Nature.

Most of the UK media covered the story responsibly and accurately, making it clear that these are very early-stage trials and much work remains to be done. The Guardian and the Daily Mail did a good job of explaining the science.

What kind of research was this?

The study in humans was a phase 1 trial, which is aimed at checking the safety and initial effects of the vaccine.

It followed a series of studies in mice, where researchers tested which type of nanoparticle was best taken up by the relevant cells of the body.

They then investigated the effects of nanoparticles containing cancer RNA, both as a protective vaccine and then in mice that had already been given cancer.

This combination of animal studies and very small-scale studies in humans is typical of the early stages of drug or vaccine development. These studies help researchers work out whether a treatment is worth testing in proper clinical trials.

What did the research involve?

Researchers began with a series of tests on mice to identify types of nanoparticle that can deliver a fragment of RNA to dendritic cells, which flag up viruses and bacteria to the immune system.

They did this using RNA that causes cells to emit light (fluoresce), so they could see where in the mice's bodies the particles ended up. They then tested nanoparticles containing cancer RNA on a series of genetically engineered mice to see what effect they had.

Finally, the researchers injected three people who had malignant melanoma with small doses of nanoparticles containing RNA that encodes four proteins usually produced by malignant melanoma cancer. They measured the immune response mounted by the patients' bodies.

The first part of the research showed that adjusting the proportions of fatty acids to RNA in the nanoparticles affected their electrical charge, which allowed them to be directed to the areas of the body where dendritic cells are most common, such as the spleen.

The following experiments used RNA from mouse cancers in the nanoparticles. The researchers wanted to see whether giving mice a vaccine before injecting them with cancer cells would prevent the growth of tumours.

They then looked at the effects of giving the mice a vaccine several weeks after they had been injected with cancer cells. They compared vaccinated mice with non-vaccinated mice.

They also looked at the effects of the vaccine on mice genetically engineered without certain working parts of the immune system to see which parts of the immune system were important for the vaccine to work.

Finally, the researchers recruited three skin cancer patients with advanced disease and gave them first a very low dose, then four weekly doses at a higher level (but still proportionately lower than that given to the mice) of the RNA nanoparticles.

They monitored the patients for side effects and tested their blood for antibodies to the cancer, as well as for signs of production of the immune system signalling protein, interferon alpha, and T-cells. 

What were the basic results?

In the mouse studies, all mice given the vaccine before being injected with cancer cells remained cancer-free, while all untreated mice died within 30 days.

Mice vaccinated after being given cancer cleared the tumours within 20 days of vaccination, while untreated mice continued to grow tumours.

The three people treated with vaccine all released alpha-interferon in response to the vaccine and produced T-cells against the antigens in the vaccine.

They all had a short flu-like illness after vaccination – similar to the reaction you get when your body is fighting off a virus.

The study was not designed to find out whether the vaccine cured the cancer. However, the researchers say that in one patient, scans before and after the vaccine showed a tumour had shrunk.

One patient who had their tumours removed surgically before vaccination remained tumour-free seven months later.

The third, who had eight tumours that had spread to their lungs, had no growth in those tumours, although the researchers do not say what the time period was for this. 

How did the researchers interpret the results?

The researchers say that this type of vaccine is "fast and inexpensive to produce" and "virtually any tumour antigen can be encoded by RNA" – meaning that this type of vaccine could be potentially used against any type of cancer.

Their approach "may be regarded as a universally applicable novel vaccine class for cancer immunotherapy", they say.

Conclusion

It's important to keep a sense of proportion when researchers make sweeping claims, such as stating that they have developed a vaccine that can work against all cancers.

While the scientific advances are important and could lead to future treatments, we don't yet know whether this approach is safe, effective or practical in humans.

Early studies like this create an enormous amount of interest. But studies in animals often don't work out so well when they're carried out in humans.

And dose-escalation studies are primarily done to make sure the treatment in question doesn't have obvious, catastrophic effects – they aren't designed to show whether the treatment actually works.

In a comment on the study, also published in Nature, experts say the new approach "may give a strong boost" to the cancer vaccine field, and that "the results of forthcoming clinical studies will be of great interest".

The key point is that we need to wait for the results of those studies. Early results in three patients, all with the same type of cancer, do not tell us whether researchers have indeed hit on the "Holy Grail" of a universal cancer vaccine. 

Links To The Headlines

'Universal cancer vaccine' breakthrough claimed by experts. The Independent, June 2 2016

'Trojan horse' cancer-fighting injection sparks hope in human trials. The Guardian, June 2 2016

Universal cancer vaccine on horizon after genetic breakthrough. The Daily Telegraph, June 1 2016

One step closer to the Holy Grail of a universal cancer vaccine: Therapy masks the disease as an invading virus - prompting the body to mount an attack. Daily Mail, June 2 2016

Immune system tricked into combating cancer. The Times, June 2 2016 (subscription required)

Links To Science

Kranz LM, Diken M, Haas H, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. Published online June 1 2016

Categories: NHS Choices

Could statins prevent breast cancer returning?

NHS Choices - Behind the Headlines - Thu, 02/06/2016 - 16:28

"Statins could be used in the treatment of breast cancer," Sky News report. Findings from a new study suggest the potential involvement of cholesterol in the recurrence of breast cancer following treatment.

The researchers hope their discovery could pave the way towards new treatment targets, and say that the effect of cholesterol-lowering drugs (such as statins) now needs to be examined. 

The research centred on what is known as oestrogen receptor-positive (or "ER+") breast cancers – where cancer growth is stimulated by the hormone oestrogen; these account for the majority of cases. Hormonal treatments such as tamoxifen can be used to block the effects of oestrogen. However, in some cases, these cancers build up resistance to the lack of oestrogen and can return. This study aimed to investigate why this happens and suggests that one of the answers may lie in cholesterol.

The findings suggest that specific cholesterol molecules (25-HC and 27-HC) are produced in the absence of oestrogen, which may stimulate further tumour growth. This may be one of the reasons behind cancer resistance.

Current evidence suggests the most effective method for reducing your risk of breast cancer reoccurrence is to follow standard healthy living advice: stop smoking, exercise regularly, eat a healthy dietmaintain a healthy weight and moderate your alcohol consumption.

 

Where did the story come from?

The study was carried out by researchers from a number of institutions, including the London Institute of Cancer Research, University of Oslo and the Department of Biochemistry, Royal Marsden Hospital in London. It was funded by the Breast Cancer Now Toby Robins Research Centre and NHS Trust funding.

The study was published in the peer-reviewed scientific journal Breast Cancer Research. It is available on an open-access basis and is free to read online here.

The UK media's headlines are slightly premature by suggesting that the study has already assessed the effect of statins on breast cancer recurrence, which isn't the case. However, the main body of the news articles were more accurate, with the papers acknowledging that most of the research was in the lab, and therefore has not yet been tested on humans.

 

What kind of research was this?

This was a laboratory study, which aimed to identify the biological pathways that could be responsible for some oestrogen receptor-positive (ER+) breast cancers becoming resistant to hormone treatments. ("ER" is used due to the American spelling of oestrogen: estrogen).

Eighty percent of breast cancers are reported to carry oestrogen receptors and, while current hormone treatments such as aromatase inhibitors are effective at blocking the action of oestrogen, many patients relapse. Previous research had indicated that cholesterol-producing pathways may be involved. 

Laboratory studies like this are useful early stage research for getting an indication of biological processes and how things work at a cellular level. They can pave the way towards the development of new treatments, or using existing treatments in new ways to treat different diseases. However, clinical trials would need to be conducted to understand whether proposed treatments are firstly safe, and then effective, for this purpose in humans.

 

What did the research involve?

The researchers aimed to identify novel mechanisms of resistance to oestrogen deprivation. They first cultured five different types of ER+ breast cancer cells. These were grown in the absence of oestrogen until their growth rate was no longer dependent on the hormone.

They then analysed the changes in gene activity and protein production that occurred in this setting of oestrogen deprivation.

On finding increased activity of the cholesterol-producing pathway, they assessed the effect that the cholesterol molecules 25-HC and 27-HC had on cancer cell growth, and also looked at what happened when they interrupted the genes needed to produce them.

They then verified their findings in two cohorts of people with ER+ breast cancer who had been treated with aromatase inhibitors or tamoxifen.

 

What were the basic results?

Overall, the researchers found that ER+ breast cancer cells grown in the absence of oestrogen show increased activity of cholesterol-producing pathways. The cholesterol molecules 25-HC and 27-HC can mimic oestrogen and stimulate cancer growth instead.

When they interfered with the genes needed to produce these cholesterol molecules using small interfering RNAs (siRNAs – artificially made packets of genetic material), they observed a 30-50% drop in cancer cell growth.

Gene analysis of samples from the cohort of people with ER+ patients who had been treated with aromatase inhibitors showed that poor response to treatment was associated with increased expression of four enzymes that are required to make cholesterol molecules.

 

How did the researchers interpret the results?

The researchers concluded: "Our observations suggest that enzymes within the cholesterol biosynthesis pathway may be associated with acquired resistance to AI [aromatase inhibitors] therapy. Our study highlights the need to evaluate the lowering of cholesterol on the impact of endocrine therapy."

 

Conclusion

The study aimed to identify biological pathways that could be the reason why some ER+ breast cancers relapse after oestrogen-blocking treatment.

It seems that one of the answers for treatment resistance lies in increased activity of cholesterol-producing pathways in the absence of oestrogen. The cholesterol molecules mimic oestrogen and stimulate further tumour growth.

The researchers hope that their research could potentially highlight a new pathway, which could be used as a target for therapeutic treatment in the future. Dr Lesley-Ann Martin from the research team told the media, "This is hugely significant. Testing the patient's tumour for 25-HC or the enzymes that make it may allow us to predict which patients are likely to develop resistance to hormone therapy, and tailor their treatment accordingly."

While this may be an important discovery, and could hopefully pave the way to more targeted treatments, the research has so far only been performed in cells in the lab. Cholesterol-blocking treatments such as statins may have new potential in the management of some people with ER+  breast cancers, but they have not yet been tested for this use.

Further laboratory studies are likely to be needed to test the effect of statins upon cancer growth. If these results are positive, this may lead to clinical trials to test whether statins have the same effect in people as they do on cancer cell growth in the lab. This will identify which women could benefit from statin involvement in their breast cancer treatment, and to see if there are any long-term side effects.

Current evidence suggests that the most effective methods to reduce your risk of breast cancer reoccurrence is to follow standard healthy living advice: stop smoking, exercise regularly, eat a healthy dietmaintain a healthy weight and moderate your alcohol consumption.

Links To The Headlines

Statins Could Stop Breast Cancer Return – Study. Sky News, June 1 2016

Statins 'could be valuable addition to breast cancer treatment'. The Guardian, June 1 2016

Statins could prevent breast cancer returning, study suggests. The Daily Telegraph, June 1 2016

Statins could provide hope for millions of breast cancer sufferers. Daily Mirror, June 1 2016

Statins offer new way to beat breast cancer – for good. The Times, June 1 2016 (subscription required)

Links To Science

Simigdala N, Gao Q, Pancholi S, Roberg-Larsen H, et al. Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. Breast Cancer Research. Published online June 1 2016

Categories: NHS Choices

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