NUS to receive $3.5 million oncology funding boost

Medical Tribune December 2008 SFIII
David Brill

Singapore’s rapidly-expanding cancer research field has received a further boost with the recent signing of a $3.5 million deal for translational research.

The agreement will see the National University of Singapore’s (NUS) Yong Loo Lin School of Medicine embark on three joint projects with Bayer Schering Pharma, the Germany-based pharmaceutical company.

One of the aims is to profile new cancer drugs within Asian populations, where certain types dominate in comparison to the West.

The deal with NUS is just the first stage of a larger project for Bayer, which intends to invest S$20 million over the next 6 years in research and development in Singapore.

The focus of the present deal is on gastric, liver and lung cancer, but future projects could extend to other cancer types, said Associate Professor Manuel Salto-Tellez, assistant dean of research at NUS.

"We are very proud of this collaboration and believe that the partnership will have significant benefits for patients, academia and industry alike," he said.

"Some of the drugs that are currently with patients have taken up to 20 years to
be developed. By linking with industry in this way we’ll be able to make this process faster. What we are doing is at the core of what our institution is supposed to do, which is to serve patients better."

The project also seeks to identify new predictive biomarkers and to study new clinically-relevant tumor models.

Oncology research in Singapore is booming, with collaborations between academia and industry apparently on the rise. Another deal, signed in August, will see AstraZeneca provide promising new compounds for clinical and preclinical trials at National University Hospital and the National Cancer Centre Singapore.

"We are facing a big problem because cancer is one of the biggest killers in Singapore and the incidence continues to rise," said Salto-Tellez.

"Soon it’s going to develop into an extraordinary contradiction where the majority of cancer patients will come from Asian countries, yet the knowledge of the patients and how to treat them will be based on the results from other parts of the world and other ethnicities. Thus we cannot overemphasize how important it is to build clinical and scientific knowledge in Asia that will be directly and immediately applicable to Asians," he said.

Routine NT-proBNP screening could tackle heart failure burden

Medical Tribune December 2008 SFVI
David Brill

The incidence of heart failure could be reduced by adopting routine screening for N terminal pro-B-type natriuretic peptide (NT–proBNP), an international group of experts has advised.

The biomarker offers important information on both diagnosis and prognosis, and "holds great promise" for screening high-risk populations, the panel wrote in a consensus statement published earlier this year.

"We need to shift from a reactive to a proactive mode," the
group’s co-chairman Dr. James Januzzi told Medical Tribune.

"Rather than just waiting for the disease to show itself we’re now shifting our focus upstream in the process to better recognize the earliest changes in the heart prior to this very high-risk situation developing."

Januzzi, who spoke recently on the topic at the 17th ASEAN Congress of Cardiology in Hanoi, Vietnam, said that patients with diabetes, hypertension, left ventricular hypertrophy and men aged over 65 would benefit most from routine screening.

He added that NT-proBNP testing is more cost-effective than echocardiography which, although a useful tool for detecting heart failure, is not widely available and requires extensive training to operate. Chest X-ray and physical examination are neither sensitive nor specific for the condition, he said.

The International Collaborative of NT-proBNP (ICON) study showed that when using age-related cut-off points, NT-proBNP testing was 90 percent sensitive and 84 percent specific for detecting acute heart failure. Using a standard cut-point of 300 pg/mL, the test had a 98 percent negative predictive value for ruling out the condition. [Eur Heart J 2006 Feb;27(3):330-7]

NT-proBNP testing is particularly relevant for primary care doctors, Januzzi said, since the majority of the at-risk population falls into their hands.

"Having an objective means to say that their patient is at high risk and thus, despite their adjustments in medication, should probably be sent to a specialist, is yet another example of where the value of this marker is going to be heading," he said.

NT-proBNP, which is primarily released by the cardiac ventricles in response to the stretching of myocytes, has been studied extensively as a prognostic indicator for patients with established heart failure and acute coronary syndromes but is not yet widely accepted as a diagnostic screening tool.

The consensus statement, which comprises a series of reviews on the different applications for NT-proBNP, was published in The American Journal of Cardiology.

Heart failure is responsible for around 1 million hospital admissions each year in the US alone, and is thought to cost the health-care system there around US$60 billion.

The Massachusetts General Hospital, Boston, US, has already begun implementing NT-proBNP screening said Januzzi, who is director of the cardiac intensive care unit and an associate professor of medicine at Harvard Medical School.

"We need to have a much, much higher level of suspicion for this very common diagnosis, which is only going to get more common as the population ages. Testing for natriuretic peptide – contrary to many other diagnostics that seem to come and go – is here to stay," he said.

Beating childhood eating disorders: Mum’s the word

Medical Tribune December 2008 SFX

David Brill

Physicians can help children overcome eating disorders by taking a tactful, measured approach to worried mothers, an international expert said on a recent visit to Singapore.

Some 25 percent of children are thought to have a feeding disorder, the long-term consequences of which can include growth problems and an increased susceptibility to chronic diseases. [J Clin Gastroenterol 2000 Jan;30(1):34-46]

The majority of children, left to their own devices, will simply grow out of it, according to Dr. Benny Kerzner, a professor of pediatrics at the George Washington University School of Medicine, US. The problem, however, can be worsened if the parents’ minds are not put at ease.

"The trouble is the anxiety effect. These parents, even if their kids are doing nutritionally well, bring an intensity to their feeding which becomes a problem. The mothers are fearful and the resulting meal conflict has negative consequences."

It is common for mothers to be concerned about their child’s eating habits: a study by Abbott Nutrition shows that two in five consider their child to be a fussy eater, with 55 percent coaxing or enticing them to eat certain foods.

This anxiety is typically borne out of a fear that if the child is undernourished their development will be stunted, Kerzner said. Research shows, however, that psychosocial factors such as mother-child interactions actually have a greater impact than nutritional status on the cognitive development of toddlers with eating disorders. [Pediatrics 2004 May;113(5):e440-7]

Concerned mothers will often consult their GP or pediatrician, which provides the ideal opportunity to allay their fears, Kerzner said.

"The doctor needs to be empathetic, and needs to be certain that he’s not slighting the issue. You don’t want to make too much of a big deal out of it but you want to be knowledgeable enough to tell her why she can relax."

The doctor should begin by taking a thorough history in order to rule out genuine medical explanations such as allergies, pain with swallowing, or gastroesophageal reflux, Kerzner said.

"You’ll then be left with a large number of children where the mother is still concerned. Those I divide into two: the children who primarily have an appetite issue and, at the other end of the spectrum, the kids with sensory issues."

For children in the first group the doctor can teach some basic appetite-enhancing techniques or "food rules," such as stopping snacking between meals, limiting the size of meals, avoiding distractions at mealtimes and adopting a neutral attitude so that the child does not feel pressured to eat.

Sensory issues such as neophobia – the fear of new things – can be overcome by introducing new foods slowly and gradually, Kerzner said, adding that parents need to show genuine persistence and not lose heart if the child rejects a new food two or three times.

Doctors can also use growth charts to demonstrate to parents that their child is developing normally. In some cases they may also wish to recommend a dietary supplement or, if the problem persists, refer the child to a dietician, he said.

"In order to put them at ease you can’t fool them. What we need to have is a genuine discussion explaining the attitude that we have and why we’re not worried," Kerzner concluded. He was speaking at a press conference organized by Abbott Nutrition.

Sleep apnea could trigger heart attacks at night

Medical Tribune December 2008 SFXI
David Brill

Treating obstructive sleep apnea (OSA) could help to prevent nighttime heart attacks, according to new research.

Professor Virend Somers and colleagues found that patients who had a myocardial infarction (MI) between midnight and 6 a.m. were six times more likely to have OSA than those whose attack happened at other times.

Although definitive evidence of cause and effect is presently lacking, the study suggests that OSA could be a trigger for nighttime MI.

"If your patient has a heart attack waking them from sleep you might want to get them checked out for sleep apnea, then individualize decisions regarding treatment," said Somers, a cardiologist at the Mayo Clinic in Rochester, Minnesota, US.

Randomized controlled trials are now needed to prove whether treating OSA can actually prevent MI and strokes, he said, adding that the observational data so far is "strongly suggestive" of a causative link.

The study involved 92 patients with a recent MI. Twenty out of 22 patients whose attack occurred at night were subsequently found to have OSA when assessed by overnight polysomnography. [J Am Coll Cardiol 2008 Jul 29;52(5):343-6]

Dr. Anne Hsu, a senior consultant in the sleep disorders unit at Singapore General Hospital, agreed that patients with nocturnal MI should be evaluated for OSA in light of the study.
She also recommended that patients with coronary artery disease with or without myocardial ischemia or infarction be screened for OSA.

"Ask for a history of habitual loud snoring and excessive daytime sleepiness, and
examine for habitus of OSA such as narrowed oropharynx, receding or small lower jaw or short and obese neck," she said.

OSA can be treated with continuous positive airway pressure therapy, surgery and oral appliances. Patients should also be encouraged to cut down on cigarettes and alcohol, maintain an ideal body weight and sleep lying on their side, Hsu said.

She added that GPs can refer their patients to specialist medical centers and sleep disorder clinics for treatment of OSA.

The research adds to a growing volume of literature linking OSA to cardiovascular
disease. A joint statement on the subject was released recently by the American Heart Association and the American College of Cardiology. [Circulation 2008 Jul 28 Epub ahead of print]

Somers, who is also lead author of the statement, estimates that around 20 percent of MIs occur at night.

Patients with OSA effectively stop breathing at certain times while sleeping, causing their oxygen levels to drop, he said. This could prompt a reflex increase in sympathetic activity which sends the adrenaline system into overdrive, causing blood vessels to tighten and blood pressure to increase as a result.

These conditions are stressful for the cardiovascular system and could explain how OSA leads to MI, Somers said.

A limitation of the present study is that only patients who survived their MI and came to hospital were included, so the data may not be applicable to fatal events he added.

Study stirs debate on PCI for stable coronary artery disease

Medical Tribune November 2008 SFXI
David Brill

A recent meta-analysis has reignited the debate over whether to employ an invasive strategy for patients with stable coronary artery disease (CAD).

The study by Professor Albert Schömig and colleagues concluded that percutaneous coronary intervention (PCI) reduced the risk of all-cause death by 20 percent compared with medical therapy alone.

The findings appear at odds with the pivotal COURAGE* trial which, to the consternation of interventional cardiologists the world over, found that PCI offered no benefits on a composite endpoint of death, myocardial infarction and stroke.

"The take-home message of this metaanalysis is that patients with stable CAD might benefit from PCI not only in terms of symptom alleviation but also of prognosis," said Schömig, who is based at the German Heart Centre Munich, Germany.

"PCI should not be seen as a substitute for effective pharmacological therapies that are available for patients with atherosclerotic CAD but as a treatment option on top of those therapies," he said.

The study comprised 7,513 patients with symptoms of myocardial ischemia but no acute coronary syndrome, drawn from 17 trials, including COURAGE. After an average of 51 months of follow up 335 patients died in the medical therapy group compared to 271 in the PCI group. [J Am Coll Cardiol 2008 Sep 9;52(11):894-904]

Schömig added that despite the apparently different conclusions, the results of the meta-analysis should not be seen as contradicting those of COURAGE since the trial alone was underpowered to assess mortality. He noted that COURAGE reported a 13 percent reduction in overall mortality with PCI but this did not reach significance.

Dr. Paul Chiam, a consultant cardiologist at the National Heart Centre, Singapore, said that the meta-analysis would be useful for informing treatment decisions in future.

"Cardiologists may be able to advise patients that PCI is more effective than medical therapy in relieving symptoms and may reduce events in those with moderate to severe ischemia on functional testing. In addition PCI may even reduce all cause mortality, or at the very least does not worsen mortality outcomes," he said.

Chiam noted, however, that the methodological limitations inherent to meta-analyses mean that the study does not carry the same weight as a large-scale trial.

COURAGE randomized 2,287 patients at 50 centers to PCI or optimal medical therapy. After a median of 4.6 years the rates of the composite end point were 20 percent and 19.5 percent, respectively, in the two groups (hazard ratio 1.05; P=0.62). [N Engl J Med 2007;356(15):1503-16]

One of the co-principal investigators for COURAGE, writing in a commentary accompanying the meta-analysis, said that the study had several limitations, such as the fact that some trials included patients with recent myocardial infarction whereas others did not.

"The difference between the findings of the meta-analysis and the COURAGE trial may be attributable to a difference in the accuracy of the data being analyzed, with pa-tient-level data from a large randomized controlled trial being superior," wrote Dr. Robert O’Rourke of the University of Texas Health Science Center at San Antonio, US. [J Am Coll Cardiol 2008 Sep 9;52(11):905-7] – DB

Unhealthy diet raises heart attack risk by 35 percent

Medical Tribune December 2008 SFXIV

David Brill

Eating a diet high in salt and fried foods can increase the risk of acute myocardial infarction (AMI) by as much as 35 percent, according to a large-scale study conducted across 52 countries worldwide.

The analysis of 5,761 AMI cases and 10,646 controls from the INTERHEART study also highlighted the benefits of eating fruit and vegetables – a dietary pattern that reduced AMI risk by 30 percent.

The chairman of the Singapore Heart Foundation, Dr. Terrance Chua, said that the findings should serve as a warning to Singaporeans, who are increasingly moving towards the unhealthy diet described in the paper.

"This is a message that all the various health promotion bodies in Singapore have been advocating all along, but knowledge is one thing and actual practice is another. Changing behavior is a real challenge," he said.

Chua hailed the global scale of the study as "very significant" since most previous research in this area had been limited to Western countries.

"This allows us to extend those results to different populations and different ethnic groups," he said.

"In a way it’s confirmed our understanding that high fat, salty snacks and dairy products are associated with an increased risk. Unfortunately that’s the diet that everyone in the world is tending to develop because it’s seen as the diet of successful societies."

The National Nutrition Survey of 2004 showed that although Singaporeans are eating more fruit and vegetables they are also consuming more fat, an increasingly high proportion of which is saturated.

Dr. Seow Swee Chong, a consultant cardiologist at National University Hospital, agreed that the findings from the INTERHEART study are a concern for Singaporeans but was more cautious in his appraisal of the research.

"This study is hypothesis-generating but not conclusive," he said, adding that the exact extent to which diet influences risk remains unclear since there are several limitations to the paper.

"The type of diet is undoubtedly influenced by the region that the study subject is from and also his ethnicity. Thus the findings may reflect more of a difference in propensity towards AMI due to genetic, racial or geographical factors rather than the diet. Indeed, there was a significant interaction between diet and region in the study," he said.

Participants in the case-control study were enrolled at 262 centers between February 1999 and March 2003. Dietary patterns were assessed using a 19-item food frequency questionnaire. [Circulation 2008 Nov 4;118(19):1929-37]

The international research team, led by McMaster University and Hamilton Health Sciences, Ontario, Canada, divided diet into three types: ‘prudent’ – high in fruit and vegetables, ‘Western’ – rich in fats, meat and salt, and ‘Oriental’ – high in tofu, soy and other sauces.

The adjusted odds ratios for AMI were 1.35 and 0.70 for those in the highest quartile
of adherence to the Western and prudent diets, respectively, compared to those in the lowest quartile (P for trend <0.001).>

Chua and Seow, however, both expressed reservations about the arbitrary classification system employed by the authors, preferring instead to focus on the components of the diet.

"It’s important not to be confused by the labeling and think that a Western diet is unsafe but it’s fine to eat nasi lemak and chicken rice," said Chua, noting that Asian food often contains just as much fat as Western food.

Managing chronic obstructive pulmonary disease in primary care

Medical Tribune December 2008 P14 & 15

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide, affecting some 210 million people. It is expected to become the third leading cause of death by 2030, according to WHO estimates.

COPD is characterized by airflow limitation, which unlike asthma, is not fully reversible. The airflow limitation is progressive and is associated with an abnormal inflammatory response to noxious particles or gases. It is a preventable disease, primarily caused by tobacco smoke. In some countries, where there is exposure to indoor air pollution, the use of biomass fuels for cooking and heating can cause COPD.

The disease has a chronic progressive course. As lung function declines the patient’s symptoms worsen and they become increasingly dependent on the healthcare system for medical care, which may include hospitalization. Although not curable, treatment is available which helps relieve symptoms and improve quality of life.

GPs can play an important role in the management of COPD in the community: in addition to providing treatment to stable patients, they can also help to educate patients and identify those who are at risk and should be screened.

Diagnosis

A diagnosis of COPD should be considered in any patient who has breathlessness, chronic cough, sputum production and a history of smoking. COPD can sometimes go unrecognized as the symptoms are commonly attributed to smoking and ignored.

Patients often seek medical attention for breathlessness. This may occur only on exertion or strenuous activity in patients with mild disease, but as the condition progresses and lung function deteriorates the breathlessness can become persistent and can be disabling and frustrating to the patient. Cough is a common symptom in COPD but its significance may not be appreciated by smokers, who may consider it to be a consequence of the habit and not seek further attention or assessment. The amount of sputum brought up is variable, and might be purulent during an infective exacerbation.

The diagnosis of COPD should be confirmed by spirometry. This is presently the gold standard for establishing the diagnosis, providing reproducible and objective results. The presence of a post-bronchodilator Forced Expiratory Volume (FEV)1 / Forced Vital Capacity (FVC) less than 70 percent, and an FEV1 above 80 percent of predicted values confirms the presence of airflow limitation that is not fully reversible. Spirometry also permits COPD to be classified into four stages of severity: stage 1, mild; stage 2, moderate; stage 3, severe, and stage 4, very severe, according to the FEV1 predicted.

Spirometry is not typically available in primary care practices but can be ordered at most hospitals and some polyclinics. GPs can facilitate an early diagnosis of COPD by identifying patients who are at risk and referring them for further testing.

Screening studies have shown that many patients who have been diagnosed with COPD are unaware of it, even when they have advanced disease. Subjects aged over 40 who have any smoking history and breathlessness, chronic cough and sputum production, are at risk of COPD and should be identified and encouraged to undergo spirometry. This represents
an opportunity for GPs to diagnose the disease and initiate treatment which may slow its progression.

Practice Guidelines

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides helpful, informative guidelines on the diagnosis, management and prevention of COPD. These were most recently updated in 2007, and are easily accessible from the GOLD website. International
guidelines are also available from a range of other sources including the American Thoracic
Society, the European Respiratory Society and the National Institute for Health and Clinical Excellence (NICE), UK.

Locally, the Ministry of Health, Singapore, published COPD guidelines in 2006.

Treatment

The goals of management in COPD are the relief of symptoms, prevention of disease progression, improvement of exercise tolerance, improvement of health status, prevention
and treatment of complications, prevention and treatment of exacerbations, and reduction of
mortality.

All patients with COPD should be educated on the disease. This can be time-consuming in the busy practice schedule of a GP but a good understanding of the disease helps the patient to better participate in the management of his disease. Patients should be advised to stop smoking and provided with the necessary support to facilitate this. Education should also address coping skills and the use of medications and inhalers.

The majority of patients encountered by GPs will have mild (FEV1 > 80 percent predicted) or
moderate (FEV1 50 – 80 percent predicted) COPD and are usually in a stable condition. Bronchodilators are central to the management of symptomatic COPD. Many patients seek treatment because of breathlessness which restricts their activities and can be disabling. A short-acting bronchodilator – either a beta2-agonist (e.g. salbutamol) or an anticholinergic (e.g. ipratropium) – can be prescribed on an as-needed basis for relief of symptoms or on a
regular basis to prevent or reduce symptoms. The preferred route of delivery is by inhaler.

For persistent symptoms, a combination inhaler containing both a beta2-agonist and an anticholinergic can be used. If patients are still symptomatic, regular treatment with a long-acting bronchodilator is more effective and convenient than the short-acting bronchodilators. Tiotropium is a long acting anticholinergic agent which was shown in the recently-published Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study to improve lung function, reduce the risk of exacerbations and hospitalization and improve quality of life. [N Engl J Med 2008 Oct 9;359(15):1543-54] Two recent publications (a meta-analysis and a nested case-control study) suggested an increased risk of cardiovascular events in patients using inhaled anticholinergic drugs but in the UPLIFT study there was a reduction of cardiac adverse events associated with tiotropium. [JAMA 2008 Sep 24;300(12):1439-50; Ann Intern Med 2008 Sep 16;149(6):380-90]

Inhaled corticosteroids are indicated in patients with severe and very severe COPD with an FEV1 ≤50 percent of predicted, and at least 2 exacerbations in the preceding 12 months. An inhaled corticosteroid combined with a long-acting beta2-agonist is more effective than the individual components. The Towards a Revolution in COPD Health (TORCH) study, published in 2007, showed that a combination regimen of salmeterol 50 mcg and fluticasone propionate 500 mcg twice daily reduced the rate of exacerbations and improved lung function and health
status. Patients taking fluticasone were also noted to have a higher incidence of pneumonia. [N Engl J Med 2007 Feb 22;356(8):775-89]

The long-term use of oral corticosteroids should be avoided as it is associated with unwanted adverse effects. The widespread use of mucolytic agents and regular use of antitussives is not recommended.

Exacerbations are defined as a sustained worsening of the patient’s symptoms from his usual stable state which is beyond the usual day-to-day variation and is acute in onset. The common symptoms are a worsening of breathlessness, cough, increased sputum production and a change in sputum color. The change of symptoms usually necessitates a change in medication,
comprising an increase in the frequency of bronchodilators, a course of antibiotics and prednisolone for a week. Mild exacerbations can usually be treated by the GP but patients who are very breathless, unable to cope at home and in poor general condition should be referred to the hospital for management.

Exacerbations are more common in patients with advanced disease, and are a major cause of
morbidity and mortality in COPD. The use of inhaled corticosteroids (alone or in combination with a long-acting beta2-agonist) and long-acting anticholinergics, as well as influenza and pneumococcal vaccination, can reduce the incidence of exacerbations. Patients should also be taught to recognize the development of an exacerbation so that immediate measures can be
taken to control it.

COPD patients should be encouraged to participate in physical activity. Many of those with breathlessness are often apprehensive to exercise for fear of worsening the dyspnea, owing to dynamic hyperinflation of the lungs. This can be overcome with the regular use of bronchodilators which help empty the lungs and improve effort tolerance. Deconditioning will occur if they remain sedentary and passive, resulting in muscle atrophy and weakness. Patients may also be referred to the hospital for pulmonary rehabilitation programs where an exercise regime tailored to the patient can be developed to help improve their exercise capacity and their ability to cope.

Disease management tools

Singapore’s National Healthcare Group Integrated Chronic Obstructive Pulmonary Disease
(NICE) program is a hospital-based initiative aimed at reducing hospitalization and readmissions from COPD, reducing emergency room visits and improving patient quality
of life. Team members include respiratory physicians, case managers and physiotherapists. The
physicians focus on the medical aspects of care, while dedicated case managers provide a more holistic approach by helping to educate patients and encouraging them to make lifestyle changes. Subsidized medications are also available through the program. There are currently over 500 COPD patients in the program.

At present the NICE program is solely hospital-based but this represents just an early step in a continuing journey to engage primary healthcare. In the long term we hope to share the ongoing management of our patients with the GPs and polyclinics, such that care during stable periods can be administered in the community with the hospitals on standby in the event of acute exacerbations. As well as facilitating our processes of care we hope that implementing this vision will improve awareness of COPD in the community and help primary care
practitioners to become more confident with handling the disease.

Conclusion

GPs and primary healthcare doctors play a major role in the management of COPD in the community and have a real opportunity to make an impact in the management of the disease. Smokers can be identified and advised on smoking cessation in order to prevent the development of COPD, while other high-risk patients can be sent for spirometry in order to
diagnose the condition. Patients with established COPD can be educated on the disease and the
effective treatments for symptom control. GPs can work in partnership with hospital physicians to help improve the framework of care for COPD patients in the community.

Online Resources:

The Global Initiative for Chronic Obstructive Lung Disease:
http://www.goldcopd.com/

The American Thoracic Society COPD guidelines:
www.thoracic.org/sections/copd/

The European Respiratory Society COPD guidelines:
www.ersnet.org/ers/default.aspx?id=1418

The National Institute for Health and Clinical Excellence, UK, COPD guidelines:
www.nice.org.uk/guidance/CG12