Scientists warn about future flu strains

reposted from: http://www.nhs.uk/news/2011/03March/Pages/call-for-vaccination-against-h2n2-flu.aspx

crabsallover highlights, key points, comments / links.

Governments should start vaccinations against a lethal strain of the influenza virus circulating in birds and pigs, The Independent has reported.

The news is based on an article written by US vaccine researchers, who said that an old flu strain known as H2N2, which caused a pandemic in the 1950s and 60s, could easily start circulating again in humans. The researchers also conducted a small test of 90 people, which showed that people under the age of 50 have little or no immunity to the strain. They argue that creating a new vaccination programme to deal with this strain of flu could save lives by preventing a potential pandemic.

The emergence of different flu strains and the question of whether vaccines are needed against them is an important public health issue, particularly in light of the rapid spread of swine flu in 2009. However, it can be hard to initially tell how widely a new or re-emergent strain of flu will spread or how severely it will affect people. In the case of H2N2, the disease does not currently circulate in humans and any pre-emptive vaccine programme will need further investigation before it can be justified.

Where did the story come from?

The report was written by researchers working at the Vaccine Research Centre of the US National Institutes of Health. The researchers did not report any sources of external funding. The report was published in the peer-reviewed journal Nature.

The research article was faithfully reported by both the BBC andThe Independent. The BBC included comments from an independent UK expert, who questioned whether the public would want another vaccine against a disease that does not presently exist. The Independent’s headline, which stated that we should “vaccinate against killer flu virus now”, does not reflect the conclusion of the research article, which suggested we should examine the issue rather than begin vaccinations. In addition, it is not possible to tell whether the H2N2 flu virus would be likely to kill if it began circulating in a modern population.

What kind of report was this?

This commentary, written by vaccine researchers, argued that government regulatory authorities should plan for a vaccination programme against an old flu strain called H2N2. They warned that this strain is circulating in birds and pigs and could jump to humans, as the H1N1 swine flu strain did in 2009.

In their comment article, the researchers reported details of a small study they conducted, in which they tested 90 US residents for antibodies against the H2N2 flu strain. Their results suggested that people under the age of 50 have little or no immunity to the strain, while resistance dramatically increases in people older than 50. They say this pattern of immunity is similar to that found in H1N1.

What does the report say?

The researchers point out that the emergence of a new strain of the H1N1 virus in 2009 took the world by surprise. The public health community had assumed that any future pandemic flu strain would arise from a “major genetic reshuffling” of existing flu viruses to produce a new virus that had never circulated in humans before. As it turned out, the virus that emerged bore a remarkable resemblance to one that had already caused a pandemic 90 years earlier: H1N1 Spanish flu, which killed about 50 million people worldwide. A version of this virus had circulated in pigs for nearly a century and was able to eventually transfer back to humans and cause a new pandemic at a time when immunity levels had waned.

The authors of this comment article say that the unexpected origin of the H1N1 pandemic provides a “cautionary tale” for the public health community, and that the H2N2 strain constitutes a possible public health threat as it could re-emerge in a similar way. They argue that government regulatory agencies should develop a pre-emptive vaccine programme against H2N2.

The researchers draw a number of parallels between the H1N1 and H2N2 viruses. For example, they have both caused pandemics: from 1957 to 1968, an H2N2 strain caused 1–4 million deaths worldwide. Like the 1918 strain, the H2N2 virus has not circulated in humans for several decades but continues to do so among birds and pigs.

To examine people’s levels of immunity to this class of virus, between 2003 and 2007 the researchers tested stored blood samples for antibodies against H2N2 strains in a small cohort of 90 people in the US. The researchers admit that ideally the test needs to be repeated in several thousand individuals, but say their study suggests that people under the age of 50 have little or no immunity to H2N2, and immunity is far stronger in people over 50 (as was also the case for H1N1).

The researchers argue that governments should plan a pre-emptive vaccination programme to prevent the re-emergence of H2N2 in humans, perhaps based on the vaccine against H2N2 licensed for use against the 1957-68 pandemic. They suggest several possible strategies for doing this:

• Manufacture the vaccine licensed in 1957 and immunise enough of the world’s population to provide “herd immunity” to the rest (i.e. vaccinate a large enough proportion of people so that the virus cannot easily spread to non-vaccinated individuals).
• Stockpile the vaccine so supplies are ready in the event of an outbreak (which they point out would be more expensive and less effective than routine vaccination).
• Make “master lots” of H2N2 vaccine and increase production as soon as signs of an outbreak occur (they argue this would be cheaper but less effective than either of the above methods).

What do these researchers conclude?

The researchers looked at the pros and cons of developing a pre-pandemic vaccine, including cost, the obstacles to distributing vaccines internationally, potential public distrust of vaccines and the limitations that are placed on public health resources. However, they finally concluded that another major flu pandemic is likely to cost far more and create a far greater health burden than a pre-emptive vaccination programme.  Such a strategy would save lives and “spare the world a major public-health crisis”, they concluded.

Conclusion

The researchers raise important questions about the possibility of a future flu pandemic caused by the H2N2 virus, and about whether vaccination programme planning could be used to prevent it. However, many issues need further consideration, including a detailed assessment of the probability of the H2N2 strain jumping to humans, whether it would pose a serious health threat, how long it would take to emerge and which groups of people would be vulnerable. It is important to note that infection with the H1N1 virus, although dangerous for some population groups, did not make most people seriously ill.

As the researchers point out, there are concerns over whether it makes sense to expose individuals to vaccines for a virus that is not currently circulating in humans, although they say the previously licensed H2N2 vaccine has a proven safety and efficacy record. Also, the virus that might emerge in humans may have evolved or mutated to the point where the current H2N2 vaccine no longer provides immunity, although the researchers argue that this is unlikely. As the researchers note, more studies of the existing H2N2 vaccine would be required to confirm its safety and efficacy and to establish who to immunise and when.

The question of whether vaccines should be prepared against the possibility of new, emergent and sometimes dangerous strains of flu is an important public health issue, particularly given the nature of the 2009 swine flu pandemic, in which a new strain of the H1N1 virus emerged and spread quickly.

With new or re-emergent strains of flu, immunity levels are often low, and it can be difficult to initially tell how widely a new strain will spread, or how severely it will affect people. In the case of H2N2, the disease does not currently circulate in humans, so there is still uncertainty over whether it is necessary to plan a vaccine programme and whether existing vaccines would work against an emerging strain. It is also not clear whether the public would find it acceptable to receive or have the government fund a vaccine against a non-circulating disease.

While this research paper rightly argues that an H2N2 vaccination should be investigated, such an examination will need to be informed by evidence on the medical and logistic issues involved, particularly whether available vaccines would be likely to provide protection against future strains.

Links to the headlines

Call to vaccinate against possible H2N2 flu pandemic. BBC News, March 10
2011

Vaccinate against killer flu virus now, say experts. The Independent, March 10 2011

Links to the science

Nabel GJ, Wei CJ, Ledgerwood JE. Vaccinate for the next H2N2 pandemic now. Nature, 10 March 2011, volume: 471, Pages: 157–158

Mediterranean diet - high in fruit & veg & olive oil, low in meat

reposted from: http://www.nhs.uk/news/2011/03March/Pages/mediterranean-diet-obesity-blood-pressure-diabetes.aspx

crabsallover highlights, key points, comments / links.

Eating a Mediterranean diet “can reduce the risk of developing conditions such as diabetes, obesity and high blood pressure”, The Daily Telegraphhas today reported. Mediterranean diets are typically high in fruit and vegetables, low in meat and use olive oil in place of dairy fats.

The news comes from a new review of research on the Mediterranean diet that combined and analysed the results of 50 studies in more than 500,000 people. Among the most notable findings were that those eating the diet had lower blood pressure, lower blood sugar and higher levels of ‘good’ cholesterol. The study also found an overall reduction in symptoms of metabolic syndrome, which is a combination of risk factors that increase the likelihood of cardiovascular disease.

This new review did not assess the development of heart disease and diabetes, but it has demonstrated that the Mediterranean diet reduces the development of metabolic syndrome and its components, which are often precursors to the development of these conditions. There were some differences between the gathered studies that suggest that the results should be interpreted somewhat cautiously, although the trends seen do support other research about this dietary pattern.

Where did the story come from?

The study was carried out by researchers from universities in Athens and Ioannina in Greece and in Naples, Italy. The authors do not specify whether they received external funding. The study was published in the peer-reviewed Journal of the American College of Cardiology.

The press has covered this study well, although headlines stating that the Mediterranean diet “cuts risk of heart disease” may incorrectly imply that the study directly measured outcomes of heart disease. The study was concerned with a range of risk factors that are likely to precede heart disease, such as high blood pressure.

What kind of research was this?

This is certainly not the first time that research on the Mediterranean diet has made headlines, with numerous individual studies on the diet having received press coverage. However, this systematic review and meta-analysis provides the most up-to-date assessment of the evidence for the diet as a way to reduce the risk of developing cardiovascular disease in adults.

Specifically, the authors combined the results from 50 previous studies that had measured the effects of the diet on metabolic syndrome, a cluster of risk factors in adults that together can considerably raise the likelihood that a person will develop diabetes or heart disease. Metabolic syndrome is defined formally as the presence of any three of the following:

• high blood pressure (greater than 130/85mmHg or active treatment for hypertension)
• high blood sugar (fasting plasma glucose >5.6mmol/L or active treatment for hyperglycaemia)
• high blood fat (triglycerides ≥1.7mmol/L)
• low levels of ‘good cholesterol’ (<1.03mmol/L for men or <1.29mmol/L for women)
• a large waist circumference (≥102cm in men and ≥88cm in women or ≥90cm in Asian men and ≥80cm in Asian women)

Lifestyle interventions, particularly changes in diet and increases in physical activity, are established ways to prevent metabolic syndrome and, consequently, to reduce the likelihood of cardiovascular disease and diabetes. The Mediterranean diet is generally considered to consist of a high concentration of good oils (monosaturated fatty acids), usually from olives and olive oil; daily consumption of fruit, vegetables, wholegrains and low-fat dairy; weekly fish, poultry, nuts and legumes; low red meat consumption and moderate alcohol consumption. It has been linked to reduced risk of cardiovascular disease, cancer and diabetes.

This study takes a new angle by specifically looking at the effects diet has on the risk factors that often precede the development of cardiovascular diseases.

What did the research involve?

The researchers set out to identify all English language research studies published up to April 30 2010, that assessed the effects of a Mediterranean diet on the development of metabolic syndrome or its components. They searched well known medical databases including PubMed, Embase and the Cochrane Central Register of Controlled Trials. They did not exclude studies on the basis of study design at this stage.

Their search initially identified 474 studies, but after excluding those that did not meet specific inclusion criteria (such as those that failed to be randomised if they were trials, those that failed to compare the Mediterranean diet against another diet or those that missed some of the key components of the Mediterranean diet) they were left with 50 studies that were eligible for analysis. There were 2 cohort studies, 35 randomised controlled trials and 13 cross-sectional studies. They provided a total study population of 534,906 individuals.

The researchers extracted the results data from each study, specifically the reports of changes in or progression of metabolic syndrome or any of the main components (waist circumference, blood pressure, blood cholesterol, blood fat or blood glucose). The results were then pooled using the statistical techniques of meta-analysis. The researchers differed the techniques according to whether they were combining the results from the randomised controlled trials, the cohort studies or the cross-sectional studies. The researchers also rated the quality of each study to help provide a measure of their confidence in the results obtained from the pooling.

From their analyses, the researchers then reported how a Mediterranean diet affects the risk of metabolic syndrome and some of its separate components. Although 50 studies were included overall, the different outcomes they each addressed meant that fewer studies could be included in the meta-analyses relating to each specific outcome. For example, in total, only eight studies assessed the effect of Mediterranean diet on the development or progression of the entire set of metabolic syndrome risk factors. Only two of these were randomised controlled trials, two were cohort studies and four were cross-sectional studies.

What were the basic results?

The Mediterranean diet was found to protect against the development or progression of metabolic syndrome, reducing the risk by about 50%. The Mediterranean diet was also protective against some of the individual components of the syndrome, with people who consumed it having, on average, a 42cm smaller waist circumference, higher levels of good cholesterol (1.17mg more), lower blood triglycerides (-6.14mg lower), lower blood pressure and lower blood glucose.

How did the researchers interpret the results?

The researchers conclude that their results “are of considerable public health importance” because the dietary pattern can be easily adopted by all population groups and is a cost-effective approach to the primary and secondary prevention of metabolic syndrome and its individual components.

Conclusion

This was a well conducted systematic review and meta-analysis, although the interpretation of some of its extensive results is not straightforward. The researchers have performed different sub-analyses, each separately pooling all cross-sectional studies, all cohort studies and all controlled trials. They then reported the results of these groups separately and also combined the results from cohort studies and trials in some cases.

The most noteworthy results are probably those obtained from pooling randomised controlled trials. Randomised controlled trials have the most appropriate study design for assessing the effects of receiving an intervention compared with not receiving it. Pooling just those results from randomised controlled trials showed Mediterranean diet reduced the risk of developing or progressing metabolic syndrome overall, as well as all of the individual components that make up the syndrome. These are the important results of the study, as combining the results of cohort studies and cross-sectional studies has limitations. Neither cohort studies nor cross-sectional studies can prove cause and effect.

There are some other points to keep in mind when interpreting the results:

• Although the researchers excluded studies that did not describe the full Mediterranean diet, the precise pattern of food was likely to vary across the included studies as was the way it was administered and the recommendations given. There were also differences in the diets consumed by the control groups and in whether dietary change was being recommended as part of wider lifestyle changes or not.
• Importantly, some of the analyses combined studies that were very different from one another in terms of the sample size, study duration, trial quality and context of intervention. These analyses had a high ‘statistical heterogeneity’, which is a way of measuring whether it is appropriate to pool them or not (higher heterogeneity means pooling is less appropriate). The researchers say that this “introduces a warning about the generalisation of the present results”.
• The outcomes were related to risk factors for cardiovascular disease, not the disease itself. It is, therefore, an extrapolation, although perhaps not an unrealistic one, to claim that this study proves that the Mediterranean diet has an effect on cardiovascular disease outcomes.

Overall, this research provides further evidence of the benefits of eating a Mediterranean-style diet and quantifies the benefit in terms of the individual risk components of metabolic syndrome.

Links to the headlines

Mediterranean diet 'cuts risk of heart disease'. The Daily Telegraph, March 8 2011

Links to the science

Kastorini CM, Milionis HJ, Esposito K et al. The Effect of Mediterranean Diet on Metabolic Syndrome and its Components: A Meta-Analysis of 50 Studies and 534,906 Individuals. Journal of the American College of Cardiology, 2011; 57:1299-1313

Can ibruprofen ward off Parkinson's?

reposted from: http://www.nhs.uk/news/2011/03March/Pages/ibruprofen-reduced-risk-parkinsons-disease.aspx

crabsallover highlights, key points, comments / links.

Taking ibuprofen just a few times a week could cut the risk of developing Parkinson's disease by a third, according to The Daily Telegraph.

The news is based on the publication of a large study that followed 136,197 middle-aged to elderly people over six years. It looked at whether regular use of the painkiller ibruprofen had any association with the risk of developing Parkinson’s disease. The study found that 291 people developed Parkinson’s, with those who regularly took ibuprofen having an approximately 30% lower risk of developing the disorder than those who did not. Other painkillers were also examined but were not associated with a reduced risk.

The study was well-designed but has some limitations, which mean it cannot prove that ibuprofen can help to protect against Parkinson’s. For example, only 28 people who developed Parkinson’s had used ibuprofen, making it hard to perform statistical comparisons of their behaviour. Also, early (pre-clinical) Parkinson’s may be present many years before obvious symptoms, so it is possible that participants may have already had undiagnosed Parkinson’s before their ibruprofen use was assessed.

Regular use of ibuprofen can have side effects, including a raised risk of stomach bleeds. Given the potential risks, people should not attempt to take ibuprofen as a preventative treatment against Parkinson’s disease at the current time.

Where did the story come from?

This US study was carried out by researchers from Brigham and Women’s Hospital, Harvard medical School, Harvard University School of Public Health, the National Institute of Environmental Health Sciences, and Massachusetts General Hospital. The research paper featured no information about external funding. The study was published in the peer-reviewed medical journal,Neurology.

In general, the study was reported accurately by the newspapers, although reports tended to be over-optimistic and did not mention the study’s limitations.

What kind of research was this?

This research was based on data from two prospective cohort studies, and it involved more than 136,000 participants. It looked at whether use of ibuprofen, other NSAIDs or paracetamol was associated with a lower risk of developing Parkinson’s disease: a progressive neurological disorder characterised by muscle tremor, stiffness and weakness.

This type of study, which can follow large groups of people for many years, is useful to assess the possible relationship between an intervention (in this case, use of ibuprofen and other painkillers) and an outcome (in this case, development of Parkinson’s disease). However, on its own it cannot prove a causal association between the two. Prospective cohort studies, which follow people in real time, are also considered to be more reliable than retrospective studies, which often ask people to recall events that have happened several years in the past.

The authors also pooled the results of their study with other previously-published trials to perform a meta-analysis of the relationship between NSAIDS, other painkillers and Parkinson’s.

The researchers discuss how neuroinflammation, a chronic, inflammation-like response in the central nervous system) may contribute to the development of Parkinson’s Disease. They point out that previous epidemiological studies suggest that use of NSAIDs in general, and ibuprofen in particular, may be related to a lower risk of developing Parkinson’s.

What did the research involve?

The researchers used data from two very large, long-term studies of health professionals. One was based in the US (the Health Professionals Follow-up Study, which began in 1986) and one was from the UK (the Nurses’ Health Study, which began in 1976). Both studies are based on participants completing questionnaires regarding the medical history and lifestyle of participants at the start of each study, with follow-up questionnaires mailed every two years.

The authors have already published earlier research from these groups, which found an association between non-aspirin NSAID use and a lower risk of PD. This new research was restricted to the years after the original study, using the 2000 US survey and the 1998 UK survey as their starting point. The total number of participants in these studies was 136,197.

The researchers established that participants were not diagnosed with Parkinson’s at the start of their study. They assessed the use of NSAIDs by questionnaire, with participants being asked if they regularly took (two or more times weekly) the painkillers aspirin, ibuprofen, other NSAIDs or paracetamol. Information on the participants’ use of these painkillers was updated every two years for both study groups. The questionnaires also recorded information on age, ethnicity, body weight, height and smoking status.

Participants were followed for six years. Those diagnosed with Parkinson’s over this period were identified using self-reports and diagnostic confirmation from relevant doctors.

The researchers used standard statistical techniques to assess the possible relationship between use of NSAIDs and Parkinson’s. They adjusted their findings to take account of possible “confounders” which might have affected results, including age, smoking and caffeine intake. Researchers also excluded patients with gout, since high uric acid levels also lower PD risk. They excluded PD cases identified in the first two years of follow-up, to avoid the possibility of reverse causation, i.e. people not taking NSAIDs because of their PD.

What were the basic results?

During six years of follow-up, the researchers identified 291 people who had developed PD. They found that:

• After adjusting for age, smoking, caffeine use and other possible confounders, people using ibuprofen had a significantly lower PD risk than non-users (relative risk [RR], 0.62, 95% confidence interval [CI] 0.42 to 0.93).
• The higher the dose of ibuprofen taken each week, the lower the risk. This is called a dose–response relationship.
• Use of other painkillers, including aspirin, paracetamol and other NSAIDs, had no significant association with risk of PD.
• When researchers combined their results with other published studies in a meta-analysis, they again saw a reduced incidence of Parkinson’s disease with ibuprofen use (pooled RR of Parkinson’s 0.73, 95% CI 63 to 0.85).
• In the meta-analysis, other types of analgesics were once again not found to be associated with lower Parkinson’s disease risk.

How did the researchers interpret the results?

The researchers say their results suggest that ibuprofen should be investigated further as a “potential neuroprotective agent” against Parkinson’s disease. They add that there is some evidence that “inflammatory mechanisms” may contribute to the progressive damage to nerve cells. They argue that ibuprofen therefore possibly has protective properties against this process. They suggest that these protective properties are not shared by other NSAIDs.

Conclusion

The strengths of this study lie in its large sample size and high follow-up rate (95% and 94% in the UK and US studies, respectively). Because the study was prospective, following people in real time, there was also less chance of “recall bias” (where participants inaccurately recall the use of painkillers). In addition, the researchers controlled for important confounding factors, such as age, smoking, body mass index, caffeine and alcohol intake. The way they assessed NSAID use, intended to cover both prescription and over-the-counter use, is also thought to be reliable.

However, as the authors note, it does have some limitations:

• NSAID use was self-reported and therefore potentially subject to error.
• The studies involved US and UK health professionals rather than random samples of men and women. Their use of NSAIDs would not necessarily reflect the pattern of use seen in the general population. The authors point out that the biological effects of ibuprofen on Parkinson’s disease would be the same, however.
• It is possible that ibuprofen was used to treat conditions that are themselves associated with a lower risk of PD. That said, the primary use of ibuprofen was for muscle and joint pain, which is not associated with PD risk.
• Although they adjusted for confounders, other factors that might influence the results cannot be ruled out.

Importantly, although this was a large study, it should be noted that the number of people who developed Parkinson’s disease was small (28 Ibruprofen users and 263 non-users). Carrying out statistical comparisons in such few participants can be problematic as it increases the possibility of presenting inaccurate risk associations. The potential for inaccuracy is even greater when subdividing them by dose taken. For example, only nine people with Parkinson’s had taken ibuprofen once or twice a week; four people used it three to five times a week; and 10 people, more than six times. Though they observed a trend for higher dose to be associated with lower risk, this may therefore be inaccurate. 

A further limitation that might have affected results is the study’s short follow-up period: as an accompanying editorial points out, early signs of “preclinical” PD may be present up to 20 years before obvious symptoms. It is possible that gastrointestinal symptoms, for example, could cause a person with very early Parkinson’s to be less likely to take ibuprofen regularly (because it would be contraindicated).

In conclusion, this study is of interest but it cannot show a causative association between ibuprofen use and the development of Parkinson’s. Further research is required to investigate whether ibuprofen could be “neuroprotective”. 

Regular use of ibuprofen and other NSAIDs can have side effects, including stomach bleeds, particularly in the elderly, and a slightly increased risk of heart attack and stroke. Given these risks, and the uncertainy over whether it is associated with a lower risk of Parkinson’s disease the use of ibuprofen as a preventative treatment against Parkinson’s cannot be recommended at the current time.

Links to the headlines

Ibuprofen could help fight off Parkinson's Disease. The Daily Telegraph, March 3 2011

Parkinson's disease risk 'could be cut by a third' through ibuprofen use. Daily Mail, March 3 2011

Ibuprofen may reduce risk of getting Parkinson's disease by a third.The Guardian, March 3 2011

Ibuprofen 'cuts Parkinson's risk'. BBC News, March 3 2011

Links to the science

Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology, [Published online before print] March 2, 2011

Dedicated to John Head, aged 80+, who is being treated for Prostate Cancer.

reposted from: http://www.nhs.uk/news/2011/03March/Pages/new-prostate-cancer-test-studied.aspx

crabsallover highlights, key points, comments / links.

“Thousands of lives could be saved by a new cancer test,” the Daily Express reported today. It said that the new test for prostate cancer “detects twice as many cases as the current method”.

This story is based on a study in 288 men with and without prostate cancer, which assessed whether a urine test that measures levels of a protein called EN2 could detect the disease. Cases of prostate cancer had been confirmed through biopsy. The study found that testing for the protein could accurately identify 66% of men with prostate cancer, and correctly rule out the disease in almost 90% of men without the disease.

This study has identified a potential new marker for prostate cancer. The results are promising, but the research is at an early stage, and much further study is needed. The performance of the test will need to be confirmed in larger samples of men from the general population. After this, studies would need to examine how the test affects outcomes such as the numbers of men dying from prostate cancer, and those having unnecessary biopsies. Newspaper estimates that the test will be ready within months are probably overly optimistic.

Where did the story come from?

The study was carried out by researchers from the University of Surrey and other research centres in the UK. It was funded by Cancer Research UK and the Prostate Project Foundation. The authors were also supported by The University of Cambridge, Hutchison Whampoa Limited, the NIHR Cambridge Biomedical Research Center, the Department of Health, and the Medical Research Council.

The study was published in the peer-reviewed medical journal Clinical Cancer Research.

The Daily Express, Daily Mail, Mirror, and The Daily Telegraph covered this research. The papers vary in their predictions of how soon the test might be available; the Mail suggests it could be in general use within months, while the Telegraph claims “within 18 months”. The Express suggests that the test could cost less than £100. However, the test’s performance is still being assessed in the laboratory. It is too early to say if it is reliable and accurate enough to be put into general use, when that may be, or how much it might cost. It is much too early to know whether the test “could save thousands of lives” as some papers suggest.

What kind of research was this?

This laboratory research investigated whether testing for a protein called engrailed-2 (EN2) might detect prostate cancer. This protein belongs to a family of proteins that are usually produced in cells in the embryo but are also switched back on in cancerous cells. The researchers wanted to test whether this protein was produced by prostate cancer cells, and whether it might be a good marker for prostate cancer.

Currently, prostate cancer is detected by measuring the levels of prostate specific antigen (PSA) in the blood. PSA levels are also used to monitor the effects of treatment. PSA is made by normal prostate cells as well as cancerous prostate cells, and men vary in their natural levels of PSA. Raised PSA levels may indicate the presence of prostate cancer, but can also occur in men with non-cancerous enlargement of the prostate. This means that the PSA test misses some cancers (false negatives), and it may suggest that cancer is present in some men who do not have the disease (false positives). The performance of the test depends on the level of PSA selected as the “threshold” for indicating the possible presence of cancer. It also depends on the population tested. Different studies have reported that the PSA test detects between 15% and 44% of prostate cancers.

Therefore, researchers are looking into whether they can develop a better test for prostate cancer. This study aimed to test the diagnostic accuracy of the EN2 urine test (its sensitivity and specificity) and to define a useful threshold for the test, i.e. what a ‘normal’ and ‘abnormal’ level for the protein might be.

What did the research involve?

The researchers first tested whether the EN2 protein was produced by prostate cancer cells and non-cancerous prostate cells grown in the laboratory. They also tested for EN2 in normal and cancerous prostate tissue samples from men with prostate cancers. Prostate tissue samples from men with the non-cancerous condition “benign prostatic hyperplasia” were also tested, as were tissue samples from men with the pre-cancerous condition “high-grade prostatic intraepithelial neoplasia”.

In the next part of their study, the researchers compared the levels of EN2 in urine samples from 82 men with biopsy-confirmed prostate cancer, with 102 men without the disease.

Some of the urine samples were collected from men who had been referred to their specialist Uro-Oncology clinic. These men were referred because they had urinary symptoms that could be a sign of prostate cancer, or had no symptoms but were concerned that they might have prostate cancer (due to a family history of prostate cancer, for example) or had an abnormal PSA test. These men had been referred for testing to determine whether they did or did not have prostate cancer. Of these men, 82 had prostate cancer confirmed on biopsy. Fifty-eight had negative biopsies and were included in the control group of men without prostate cancer.

The researchers also collected urine samples from additional control men aged over 40, who had normal levels of PSA (below 2.5 nanogrammes per mL). These men either had blood in their urine but had no malignancies in their urinary system (urothelial malignancy) detected on testing (17 men), or they had no symptoms or family history of prostate cancer (27 men). The researchers also had urine samples from 10 men with the pre-cancerous condition “high grade prostatic intraepithelial neoplasia”.

Men already being treated for known prostate cancer, or with any known cancer in the past 10 years, or with a urinary tract infection, were not eligible to take part in the study. Urine samples were collected from the first passage of urine of the day. They were taken before any biopsies were performed or any hormone therapy received, and at least 24 hours after any digital rectal examination.

The researchers testing the urine samples did not know which men had cancer. Blood samples for PSA testing were also collected before the urine samples were collected. The researchers looked at whether the levels of EN2 in a man’s urine were related to the levels of PSA in his blood.

To confirm their results, another research centre tested urine from a further 81 patients with prostate cancer and 13 men without prostate cancer.

What were the basic results?

The researchers found that the EN2 protein was being made and secreted by prostate cancer cells grown in the laboratory, but not in normal prostate cells.

They also found EN2 protein in 92% of 184 prostate cancer tissue samples, but in none of the 20 normal prostate tissue samples. The EN2 protein was not detected in prostate tissue samples from men with “benign prostatic hyperplasia”, nor in prostate tissue samples from men with “high grade prostatic intraepithelial neoplasia”.

The urine tests showed that 66% of the men with prostate cancer had EN2 protein in their urine. About 12% of men without prostate cancer had EN2 protein in their urine. The researchers report that using a cut-off value of 42.5 ng/mL of EN2 protein in the urine appeared to be optimal, giving a sensitivity of 66% and specificity of almost 90%. This suggests that in combination with other tests it may be useful at ruling out disease in normal men and confirming disease in those with cancer.

On average, levels of EN2 protein in the urine of men with prostate cancer were 10.4 times higher than those in men without prostate cancer. Independent testing of urine samples from another 94 men at another laboratory found that 58% of the prostate cancer patients in this sample had EN protein in their urine, compared with 15% of control men without the disease.

Of the 10 men with the pre-cancerous condition “high grade prostatic intraepithelial neoplasia”, three had EN2 protein in their urine. A second biopsy taken within six months of the first found that two of these three men had prostate cancer.

The level of EN2 in the men’s urine was not related to the level of PSA in their blood.

How did the researchers interpret the results?

The researchers concluded that EN2 protein in the urine is a good candidate marker for the presence of prostate cancer. They say that a larger study across multiple centres “to further evaluate the diagnostic potential of EN2 is justified”.

Conclusion

This study has identified a potential new marker for prostate cancer. This research is at an early stage, and much further research is needed. The test’s accuracy will need to be confirmed in larger samples of men from non-specialist settings to show how effective it is at screening for prostate cancer in the general population. After this, studies would need to examine how the test affects outcomes such as the numbers of men dying from prostate cancer, and those having unnecessary biopsies.

Though promising, these findings also need to be considered with some pragmatism. Even if the EN2 test performs well in larger scale testing, the test would not necessarily replace PSA testing. The authors suggest that the tests could be used together in prostate cancer diagnosis. Also, if the combined tests did indicate that cancer might be present, the results would still need confirmation by prostate biopsy.

There is a need for improved prostate cancer tests, particularly those that can detect early prostate cancer accurately. There is a lot of research going on in this area. More research will be needed to determine how well these newer tests perform when compared with current tests, and which of them performs the best.

Links to the headlines

Thousands of lives could be saved by a new cancer test. Daily Express, March 2 2011

Prostate cancer test is 'twice as good', say researchers. BBC News, March 2
2011

Accurate new prostate cancer test could save thousands of lives. Daily Mirror, March 2 2011

Urine test for prostate cancer 'in 18 months'. The Daily Telegraph, March 2 2011

New test to spot prostate cancer could be in use in surgeries within months. Daily Mail, March 2 2011

Links to the science

Morgan R, Boxall A, Bhatt A,et al.Engrailed-2 (EN2): A Tumor Specific Urinary Biomarker for the Early Diagnosis of Prostate Cancer.Clinical Cancer Research 2011, Published OnlineFirst March 1

Further reading

Ilic D, O'Connor D, Green S, Wilt TJ. Screening for prostate cancer.Cochrane Database of Systematic Reviews 2006, Issue 3