Dr Bert-Jan de Boer speaking at the EAU Annual Congress in Paris

BPH can be accurately diagnosed using a set of simple tests that can be easily implemented in the primary care setting, attendees at the EAU Congress heard.

It is estimated that as many as 24 million European men aged 50 and older experience bothersome urinary symptoms. Yet, despite experiencing symptoms, men typically wait nearly two years before speaking to their doctor.

Benign prostatic hyperplasia (BPH) is one of the 10 most commonly-diagnosed diseases in men over the age of 65.

The challenge is that despite some of the troubling symptoms of BPH, men are not seeking medical treatment. These symptoms, which are known as lower urinary tract symptoms (LUTS), include: an urgent and frequent need to urinate; frequently getting up in the night to urinate (nocturia); a feeling of incomplete bladder emptying; and a weak urine stream. Men are instead living with these very treatable conditions and experiencing a lower quality of life due to inconvenient and often embarrassing symptoms.

During the recent European Association of Urology (EAU) Annual Congress in Paris, a key discussion took place on how to proactively engage men in BPH communications with their GP. These discussions were led by two distinguished guest speakers: Prof Mark Emberton, Professor in Interventional Oncology, University College London and Associate Professor, Middlesex University, London, and Dr Bert-Jan de Boer, Primary Care Physician, Utrecht, The Netherlands.

The discussions included how to increase the understanding of BPH, the chronic nature of the condition and its impact on the lives of older men, and emphasised how proactive GP-led discussions are important for positive patient outcomes, including what role the GP and patient play in initiating the discussion. The benefit of this dialogue can be an earlier diagnosis and better quality of life for the patient.

Prof Mark Emberton stated: “We face one key challenge: why do men choose to wait to seek help, especially if it’s available? The answer is that men don’t see their doctor.” Based on a recent survey, he mentioned that about one-third of men don’t go to their doctor and about 30 per cent go once a year.

Greater communication

To help with the communication and understanding of BPH, first there needs to be increased general awareness within the public about BPH, the symptoms, and that it is a treatable and manageable condition. Secondly, there is the need for greater communication between healthcare professionals and patients, with GPs being ideally suited to be a first-line point of contact for men.

In agreement with this approach was Mr Syed Jaffry from the Galway Clinic, who says that more than half of hospital referrals for BPH could be handled in the primary care setting. GPs do need greater understanding of a BPH diagnosis; however, they are best placed to treat these patients, he said. Primary care teams can treat BPH patients very effectively by putting together a preliminary BPH treatment strategy, which would include: taking symptom history; digital rectal exam (DRE); PSA check; and examining flow rates.

GPs can seize the opportunity to help improve the management of this disease.

The management of LUTS associated with BPH should now focus on risk stratification as a means of identifying men who will benefit most from treatment to reduce the risk of long-term complications. The following are suggestions from Prof Emberton regarding what can be done to help BPH diagnosis and treatment within the GP community: a diagnostic algorithm, which will include four simple objective tests, including a medical history, I-PSS, DRE and PSA. The benefits of these tests are they are easily implemented in any GP surgery and they allow GPs to accurately diagnose BPH in approximately three-quarters of patients spontaneously reporting LUTS.

In conclusion, Prof Emberton stressed that help was available and that men needed to know this. He also said that BPH was “not cancer”, so men could do something now to improve their quality of life, and that clinicians should be ready for this.

Emberton’s key messages:

• BPH can be accurately diagnosed using a set of simple tests that can be easily implemented in the primary care setting.

• Early diagnosis and effective management of BPH has multiple benefits.

• Clinicians need to initiate conversations about bothersome urinary symptoms with men and GPs are well placed to have these conversations.

Dr Bert-Jan de Boer presented a case study, entitled ‘Achieving effective LUTS/BPH management in primary care: What is the GP view? A project from The Netherlands’. The Dutch have developed guidelines which were supported by evidence-based medicine, literature reviews and clinical experience. These guidelines involve treating BPH at a primary care level and patients are only referred to a consultant if the symptoms worsen. This would include a rising I-PSS score, AUR, signs of tumour activity, or if further treatment or surgery were required.

Similar to Ireland, the BPH diagnosis pathway includes the GP taking a full medical history and symptom discussion. Then the I-PSS score is calculated and a physical examination performed, including a DRE with urine and blood tests (Urinalysis and PSA test).

Within these guidelines, the GP’s role includes monitoring the patient regularly (three monthly/twice yearly/yearly, depending on changes in symptom severity) and using the I-PSS score to see if the symptoms are improving.

Dr Bert-Jan de Boer’s key messages:

• In order to get men talking, GPs need to “just ask” about certain symptoms such as urination trends, overall feelings and common BPH symptoms.

• Men will open up if given the right environment and given the opportunity.

• GPs can help men to overcome their embarrassment on the topic.

Take-home messages:

• Proactive, GP-initiated conversations about bothersome urinary symptoms in older men may result in symptoms and/or suspected cases of BPH being identified and managed at the earliest opportunity.

• Early identification and assessment of BPH in older men may lead to timely interventions that reduce the negative impact of symptoms and the potential risk of long-term health complications.

• Improving the diagnosis and management of BPH in older men is appropriate and achievable for primary care physicians.

• There is a need to raise awareness about BPH, the symptoms and the fact that these are not life-threatening and are treatable, thus improving their quality of life.

• Patient-empowerment via online education is one route for enabling men and their clinicians to have better dialogue about conditions such as BPH: www.yourprostate.eu provides a positive example.

Article courtesy of Irish Medical Information (IMI).

References on request.

Researchers are suggesting a negative single ultrasound scan may safely rule out a diagnosis of deep vein thrombosis (DVT) in women during pregnancy or in the first few weeks after giving birth.

French researchers said the diagnosis of DVT during pregnancy was a diagnostic challenge. The low prevalence of the condition and the need for a non-radiating diagnostic strategy in these women renders non-invasive diagnostic tools — such as compression ultrasonography — highly appealing.

Because pregnancy is known to be a risk factor for venous thromboembolism and pregnant women often experience symptoms compatible with deep vein thrombosis — such as pain, tenderness and swelling of the legs — the threshold for clinical suspicion and the accuracy of clinical examination are reduced.

Study limitations prevented the authors from drawing firm conclusions. They added that further studies were needed to confirm their findings.

The study, published in the British Medical Journal, included 210 pregnant and post-partum women referred for suspected DVT from medical practices in France and Switzerland.

BMJ 2012 doi: 10.1136/bmj.e2635

An obesity prevention programme designed to prevent unhealthy weight gain in adolescent girls living in low-income communities did not result in statistically significant differences in body mass index (BMI), but researchers said their results have potential clinical importance.

The amount of time girls spent at “screen-based activities” per day was reduced by 30 minutes compared to control group peers.

”High levels of screen time are associated with a range of adverse health consequences, and our findings have important implications that may help address the increasing burden of paediatric and adolescent obesity observed in areas of social and economic disadvantage,” according to the authors.

“The intervention effects on body composition were small and not statistically significant but have potential clinical importance,” they add.

Results from the Australian school-based obesity prevention programme for adolescent girls were published in JAMA’s Online First Archives of Pediatrics & Adolescent Medicine.

The 12-month Nutrition and Enjoyable Activity for Teen Girls (NEAT Girls) programme was a group, randomised, controlled trial designed to prevent unhealthy weight gain in adolescent girls living in low-income communities.

The study included 357 adolescent girls between the ages of 12 and 14 years, and 148 girls received the intervention. The intervention programme included enhanced school sport sessions, nutrition workshops, lunchtime physical activity sessions and text messaging for social support.

Arch Pediatr Adolesc Med doi:10.1001/archpediatrics.2012.41.

Children are three times more likely to self-harm up to the age of 12 if bullied, according to a new study carried out in the UK.

Bullying during early years can have damaging consequences by adolescence, especially if children are also exposed to family adversity or have mental health difficulties said the authors, who suggested that schools and healthcare professionals should aim to further “reduce bullying and introduce self-harm risk-reduction programmes” in order to prevent the risk of bullied children hurting themselves in later life.

Bullying was defined as when another child: says mean or hurtful things; completely ignores or excludes the victim; hits, kicks or shoves the victim; tells lies or spreads rumours and/or does other hurtful things, all on a frequent basis. Examples of self-harm included: cutting and biting arms; pulling out clumps of hair; banging the head against walls; and attempted suicides by strangulation.

‘Bullying, Victimisation and Risk of Self-Harm in Early Adolescence: Longitudinal Cohort Study’ was published in the BMJ.

The authors from King’s College London carried out a study on just over a 1,000 pairs of twins at five, seven, 10 and 12 years of age. All children were born in 1994-1995 in England and Wales.

The children were assessed on the risks of self-harm in the six months prior to their 12th birthday. Self-harm data were available for 2,141 children.

A total of 237 children were victims of frequent bullying: 18 or 8 per cent of them self-harmed. Of the 1,904 who had not been bullied, 44 — or 2 per cent — had self-harmed.

The authors found that several factors increased the risk of self-harm amongst children who were bullied, including: a family history of self-harming; maltreatment; and behavioural and emotional problems.

Although the likelihood was slightly higher for girls (1.6 per cent), the association was evident amongst both sexes.

BMJ doi/10.1136/bmj.e2683

Consuming probiotics in foods such as yogurt can reduce the risk of antibiotic-associated diarrhoea (AAD), says a new a review and meta-analysis of previous studies.

“There is an increasing interest in probiotic interventions, and evidence for the effectiveness of probiotics in preventing or treating AAD is also increasing,” said the authors, who assessed the available evidence on probiotic use for the prevention or treatment of diarrhoea associated with antibiotic use, which can affect up to 30 per cent of patients.

Across 63 randomised, controlled trials (n=11,811 participants), probiotic use was associated with a 42 per cent lower risk of developing diarrhoea compared with a control group not using probiotics. The result was consistent across a number of subgroup and sensitivity analyses.

“Symptoms range from mild and self-limiting to severe, particularly in Clostridium difficile infections, and antibiotic-associated diarrhoea is an important reason for non-adherence with antibiotic treatment,” according to background information in the article published in JAMA.

The reviewers searched through randomised, controlled-trial databases to identify involvement of antibiotic-associated diarrhoea and probiotics (Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus).

While the researchers said their review found sufficient evidence to conclude that adjunct probiotic administration was associated with a reduced risk of AAD, this generalised conclusion likely obscured heterogeneity. Future studies should assess significant differences in effectiveness among the patients, the antibiotics, and the probiotic strains or blends, they noted.

JAMA: doi: 10.1001/jama.2012.3507

Lloyd Mudiwa reports that some 50 deaths every year are attributable to asthma and poor control is still a concern for 60 per cent of asthmatics.

Asthma is tragically still claiming one life a week in the Republic, the Asthma Society of Ireland, which is carrying out an awareness campaign this month, has said.

According to the Society, some 400 people attend emergency departments every week because of the lung condition.

As part of the campaign, the Society will launch its new asthma emergency information pack.

Dr Jean Holohan, CEO, Asthma Society of Ireland, said: “Fifty asthma-related deaths a year is too high. These deaths are so tragic and affect families, friends and entire communities.” She urged asthma sufferers to speak to their healthcare practitioner about ways to improve their asthma control and to download the new Asthma Attack Card from www.asthmasociety.ie or by calling 1850 44 54 64.”

Dr Dermot Nolan, Tramore Medical Centre, Co Waterford, added: “The death of a young person is tragic but to die from an asthma attack, a very common and manageable condition, can send ripple effects throughout a community. Extensive research is needed into these sudden, unexpected asthma deaths.”

With one-in-10 people in Ireland affected, everyone should know how to respond in an emergency situation, the Society added, advising that the card is available free of charge to patients, healthcare professionals, schools and sporting organisations.

With poor control a concern for 60 per cent of asthmatics, the Society wants to ensure everyone knows the five key steps outlined in the card to follow in the event they, or someone they are with, experience an attack.

The steps are: take two puffs of reliever inhaler (usually blue) immediately; sit upright and stay calm; take slow, steady breaths; and if there is no improvement, take a puff of reliever inhaler every minute — patients can take up to 10 puffs in 10 minutes and children under six years of age can take up to six puffs in the same period.

The final step is to call 999 or 112 if symptoms do not improve after following steps 1 to 4 or if worried, the campaign stresses.

The work of Prof Joseph Scandura suggests drugs that interfere with the way genes work may reduce the side-effects of chemotherapy, reports Gary Culliton.

US-based cancer research pioneer Prof Joseph Scandura of Weill Cornell Medical College in New York visited Cork recently to discuss results of a clinical study aimed at improving treatment of acute leukaemias and bone marrow cancers.

Physician-scientist Prof Scandura presented the results of his Phase 1 study, which indicated that adding the drug Decitabine (an epigenetic modifier) in conjunction with standard chemotherapy, aided remission rates. Currently, the most effective treatments for acute myelogenous leukaemia (AML) involve a combination of cytotoxic chemotherapeutics, but some subtypes of AML are resistant to this standard approach. The new therapy makes more cancer cells vulnerable to chemotherapy, Prof Scandura reported.

One way that the leukaemia cells escape is by turning off the genes that make them sensitive to chemotherapy; they essentially repackage their genes so that they cannot be turned on. This repackaging doesn’t change the genetic code like a mutation, but simply makes the gene inaccessible, IMT was informed. This is called epigenetic regulation, Prof Scandura said. “This offers a potential for getting more people into a remission, which is the first milestone which has to be reached if one is to survive acute leukaemia,” he explained.

Resistance
One of the ways cancer cells become resistant to chemotherapy is that they dispense with genes that are involved in the chemotherapy response.

There are a number of ways that tumour cells can get rid of genes that are interfering with their function or making them sensitive to chemotherapy. One way is to have this capacity deleted from the genome — to have a mutation that gets rid of the gene. The other is to turn it off in such a way that the cells can no longer express that gene. This process is called epigenetic — or around the gene. Epigenetic modifiers interfere with the mechanisms leukaemia cells use to ‘turn off’ genes which they do not want expressed any more.

“One way of looking at it is that the code of the genome itself is the computer, whereas the epigenetic regulation of this is the software. The latter is what allows the genome to be useful and do things,” said Prof Scandura.

In order for that to be ‘read’ and made into a protein, genetic information has to be accessible to the transcriptional machinery proteins that make DNA into RNA. These genes are wrapped around proteins and the proteins in turn are coiled around each other. That coiling and packaging of genes within chromosomes is very highly regulated, Prof Scandura explained.

Modifications of either the DNA itself or of the proteins around which the DNA is wrapped control how easily the gene can be turned on when it needs to be. “There are some modifications that make it extraordinarily difficult for a cell to turn on that gene. They silence it, turn it off in a way that is relatively permanent,” said Prof Scandura.

This field is attractive to cancer researchers. Unlike mutations, epigenetic modifications are reversible and it is possible to design drugs which interfere with enzyme functions.

Dr Sharon McKenna, Principal Investigator at Cork Cancer Research Centre (CCRC); Prof Joseph Scandura, Assistant Professor of Medicine at Weill Cornell Medical College in New York; and Nina Orfali, Researcher at CCRC

A Phase 1 trial of decitabine — a DNA hypomethylating agent — finished last year. The aim then was to select a dose and ensure the approach was safe. Currently, a Phase 2 trial is underway to gauge effectiveness. The basis of this trial is an attempt to demonstrate that epigenetic priming is superior to the standard approach — chemotherapy alone. The trial, involving 200 leukaemia patients in multiple centres, is being run through the Cancer Therapy Evaluation Program (CTEP) branch of the National Cancer Institute.

Though it appeared in the Phase 1 study that epigenetic priming might be more effective — as there was some benefit in terms of killing cancer cells — the toxicity was no greater than it was with the standard therapy. “Cancer cells get rid of genes that interfere with their function or make it hard for them to survive the damage that they already have done to their genome,” Prof Scandura told IMT. “A lot of the genes which might be got rid of also contribute to sensitivity to chemotherapy. If an epigenetic modifier is given to a normal cell, it is not necessarily sensitised to chemotherapy.  If epigenetic modifiers are given to cancer cells, they are much more likely to be sensitised.”

Many of the doses used for treating cancer are chosen so that they minimise bone marrow suppression (myelosuppression). Lowering blood counts can be dangerous for patients and may leave them fatigued and vulnerable to infections.

Bone marrow
Prof Scandura’s group is also investigating how bone marrow recovers from exposure to stresses such as chemotherapy. In a separate project, his group has looked at how the bone marrow recovers from chemotherapy — in effect, a toxic assault — in animal models. One of the reasons chemotherapy drug doses are restricted to avoid low blood counts is because infections can be life-threatening. In such cases, hospital stays can last longer than a week.

When chemotherapy is given, the goal is to kill cancer cells and to minimise interference with normal cell functions. Many of the chemotherapy agents used in any tumour — breast or colon cancer, for example — can have effects on normal cells, and one of the places where this is seen most is in (blood-forming) bone marrow cells.

Prof Scandura’s group has looked at treatments that affect the haematopoietic stem cells and the regulation that normally starts slowing them down during bone marrow recovery. When blood counts start recovering, a system kicks in that tells the stem cells to return to the niche and again become quiescent.

A remarkable aspect of blood cell production is that a small number of highly-specialised cells are ultimately responsible for the production of all of the blood cells that a person makes. Once chemotherapy is given, the “haematopoietic stem cells” become stimulated and attempt to replenish the blood supply. These haematopoietic stem cells are highly regulated by specialised compartments or “niches” in the bone marrow, he added.

Prof Scandura’s group has considered how the process of recovery ‘winds-down’ and normal homeostatic blood cell production resumes. Current thinking suggests that as the stress is relieved, blood cell numbers passively drift back to normal. “This is a little like driving a car using only the gas pedal; if you want to go faster, you press the gas but when you want to slow down, you can only drift back to your prior speed,” said Prof Scandura.

His research group looked for a braking mechanism and found that a specific chemical signal was induced following recovery from stress. Thus, using targeted drugs it may be possible to help blood cells to recover much more quickly, he suggested.

“The process is highly orchestrated and very fascinating,” said Prof Scandura. “We only understand the beginning part of that. Ordinarily, a good portion of stem cells are ‘mothered’ by other cells (the niche), which tell the stem cell to be quiescent. This protects them from chemotherapy and other toxins and allows them to survive. After chemotherapy, those stem cells get ejected from the niche. They undergo a rapid round of proliferation and cell division.

“They start differentiating into other cells to replenish the bone marrow. This process is driven by stress. When the stress is relieved, things go back to normal.”

Stem cells
One drug, G-CSF, currently helps recovery of infection-fighting neutrophil cells, he added, and this shortens the period when blood counts are low. However, such drugs do not affect the other blood lineages. “It is a braking mechanism and it happens very quickly once there is enough blood count recovery,” said Prof Scandura.

“The bone marrow returns to the quiescent state in a highly-regulated way. If we interfere with the braking mechanism, we can have a tremendous effect on the blood count recovery — in all types of blood counts, as the process is acting on the stem cells which give rise to them.

“In mice, at any rate, this allows us to give more chemotherapy at a higher dose. Chemotherapy can be given more quickly or in more repeated cycles. The animals survive this better. By allowing them to recover their bone marrow and blood count more quickly, we have minimised the toxicity — while still giving the same dose of chemotherapy.”

Over half the drugs included in the US electronic Physicians’ Desk Reference (ePDR) had no information about paediatric use in the labelling.

“Our estimate of the true percentage of products with paediatric labelling information is probably an underestimate because many commonly-used products were excluded from the analysis and not all products are listed in the ePDR,” said researchers from the FDA.

“Labelling with paediatric information in only 46 per cent of products is still insufficient. Legislation to increase paediatric clinical trials and require the resulting information to be added to labelling is necessary. The current legislation expires in 2012 without reauthorisation,” the authors wrote in a recent issue of JAMA.

“Progress has been made since 1975, when only 22 percent were labelled. Of new molecular entities with paediatric labelling, the increase from 20 per cent in 1999 to 41 per cent in 2009 is also an improvement,” they said.

Aaron N Sachs of the University of Maryland, Baltimore, US, and colleagues conducted a study to determine whether in the decade since that report there had been an increase in the percentage of drug labelling that contained information on use in children.

The researchers evaluated labelling in the June 2009 ePDR, and identified 560 products that met the study’s inclusion criteria.

JAMA doi: 10.1001/jama.2012.3435

The size and methodology of clinical trials registered on the US National Institutes of Health website, ClinicalTrials.gov between 2007 and 2010, has been highlighted by researchers who say they are dominated by small trials and contain significant heterogeneity in methodological approaches.

Irish clinical trials are among the studies listed from 179 countries on ClinicalTrials.gov. Studies listed in the database are conducted in all US 50 States and in 179 countries.

The US researchers examined the characteristics of interventional clinical trials registered in the ClinicalTrials.gov database from 2007 to 2010, focusing on study characteristics appropriate for generating reliable evidence from clinical trials.

The authors said recent reports highlight gaps between guidelines-based treatment recommendations and evidence from clinical trials that supports those recommendations. Strengthened reporting requirements for studies registered with ClinicalTrials.gov enable a comprehensive evaluation of the national trials portfolio, they said.

The researchers added that the fact that 50 per cent of interventional studies registered from October 2007 to September 2010 by design included fewer than 70 participants may have important policy implications.

“Small trials may be appropriate in many cases. However, small trials are unlikely to be informative in many other settings, such as establishing the effectiveness of treatments with modest effects and comparing effective treatments to enable better decisions in practice,” according to the authors.

“Our analysis raises questions about the best methods for generating evidence, as well as the capacity of the clinical trials enterprise to supply sufficient amounts of high-quality evidence needed to ensure confidence in guideline recommendations,” they added.

JAMA 2012 ;307(17):1838-1847:doi: 10.1001/jama.2012.3424

Current anticoagulant therapy to prevent stroke might not be sufficient for older women diagnosed with atrial fibrillation, according to a new study.

Women, especially those aged 75 years or older, were found to have a higher risk of stroke than men, regardless of their risk profile and use of warfarin; the analysis by Canadian researchers indicated that women had a 14 per cent higher risk of stroke than men, after adjusting for various factors.

The researchers found that crude stroke rates were significantly higher in women compared with men (5.8 per cent vs. 4.3 per cent). The difference between sexes was mainly driven by the rates in the older (75 years and older) patients.

“Furthermore, older women had significantly higher rates of stroke than older men, regardless of warfarin use, and women had higher rates of stroke compared with men, regardless of adherence level,” according to the researchers.

“Atrial fibrillation (AF) is the most common cardiac arrhythmia, accounting for approximately one-third of hospitalisations for cardiac rhythm disturbances. It has been estimated that 2.2 million people in the United States and 4.5 million in the European Union have paroxysmal or persistent AF. Patients with AF have a five-fold increase in the risk of stroke compared with the general population; therefore, antithrombotic agents are prescribed to reduce this risk. Sex-based differences related to AF have been identified, the most concerning being that women with AF have an increased risk for cardiovascular events, including stroke,” according to background information in the article.

It has been suggested that underutilisation of oral anticoagulation treatment among women has been a contributing factor to this increased risk.

“Although epidemiologic studies have investigated sex differences in stroke occurrence, little is known about warfarin effectiveness between men and women in the real-world clinical setting. Our results suggest that elderly women with AF may need to be targeted for more effective stroke prevention therapy. Clinicians should be aware of the elevated stroke risk in older women with AF, and new strategies should be applied to effectively prevent stroke equally in men and women.

“The increased risk may be attributable to physiology, vascular biology, genetic factors, hormonal or thromboembolic factors, or psychosocial factors that differ between men and women. We were not able to identify these factors with our database,” they suggested.

JAMA May 9 2012