End-of-life care in the region received a boost with the recent founding of Asia’s first research center for palliative care. Medical Tribune's Glenn Omanio reports how doctors are trying to change public perception on death and dying.

Many Asians who die every year of cancer and other chronic fatal diseases receive inadequate palliative care as the region grapples with the need for doctors and families to understand end-of-life care and comfort, palliative care experts say.

While some Asian nations have conducted pioneering work in Western-dominated palliative medicine, research efforts in palliative medicine remain relatively undeveloped in the region, especially when it comes to cultural differences in attitudes and beliefs towards dying, end-of-life experts told Medical Tribune.

“We need to improve care by getting basic facts right about our community. All our ideas about establishing palliative care evolved in the West. We have very little local and regional data on which to base our work,” said Dr. Cynthia Goh, senior consultant and head of the department of palliative medicine, National Cancer Centre Singapore (NCCS).

Central to the issues faced by palliative medicine in Asia is the lack of awareness among medical professionals and families about end-of-life care. “There’s a huge amount of ignorance in Singapore and Asia in general,” Goh said.

Twenty years after the first hospice opened in this small city-state of 4.5 million people, a recent survey showed that only one-third of Singaporeans have actually heard about palliative care services, Goh said, adding that the prospect is even bleaker in many parts of the region.

Perhaps, the diversity of culture and religion in Asia has something to do with why Asia lags behind its Western counterparts but experts cannot say how much of these factors really affect public perceptions because of the lack of formal studies.

Generally, death, which is often linked with bad luck, remains taboo in Asian cultures. Different religions also offer diverging concepts of death, making death and dying complicated to discuss.

“It’s hard for anyone, including physicians, to work with people who are going to die. You have to feel comfortable with yourself to recognize death as part of life,” said Dr. K. Ranga Rama Krishnan, executive vice dean of the Duke-NUS Graduate Medical School, Singapore.

Doctors are reluctant to discuss death while most terminally ill patients seem to not fully grasp the severity of their disease or are unwilling to admit that they are dying.

In a small study of seriously ill cancer patients published recently, Swedish researchers found that most doctors did not explicitly discuss death and dying with their patients. [BMC Palliat Care 2008 Feb 28;7(1):2]

“One of the reasons why we can’t respond to our patients is that we are afraid of our own emotions. We need to teach doctors to be comfortable with their own emotions and how to communicate well with patients,” Goh said.

Across countries and cultures, the “fear of the unknown” and ignorance of what the dying process involves makes suffering worse, with many patients fearing the pain associated with chronic illnesses.

“One of the first things that we do in palliative care is to reassure patients that dying need not be painful. We tell them that we can take away some of their pain,” Goh said.

However, she lamented that despite the discovery of powerful painkillers, national laws make it hard for pharmacists to stock morphine while doctors lack training to administer the right dosages and patients’ fear addiction to drugs.

According to the World Health Organization (WHO), more than 4.8 million dying patients who suffer from moderate to severe pain caused by cancer do not have access to palliative care services.

Millions more with other debilitating illnesses need palliative care, especially in less developed countries where a high proportion of patients are diagnosed in advanced stages of their illnesses when treatment is no longer effective.

In Asia, more than 600 institutions offer palliative care services, mostly through hospice care. However, they vary greatly in the level of service provided because of diversity in population, religion and uneven economic development.

Countries like Singapore, Hong Kong, Japan, South Korea and Taiwan have fairly well established palliative care services while such services are under development in Malaysia, the Philippines, Indonesia and India. Most Asian countries are just starting to offer this kind of service.

“Palliative care is not a wholly medical [field]. That’s why doctors do not take it as a specialty, thinking this is not for them but for volunteers and social workers. We lack doctors with specializations in palliative medicine,” Goh said.

In response, the Duke University School of Medicine and the National University of Singapore recently established Asia’s first research center for palliative care. Called the Lien Centre for Palliative Care, it will examine the clinical, social and cultural aspects of palliative care in Asia.

The center, which will be funded through a S$7.5 million dollar donation and matching funds from the Singaporean government, is housed at NCCS, the first cancer center in Southeast Asia to establish a department of palliative medicine.

“This is a dream come true for the palliative care community,” said Goh, who will be the center’s first director. “For the first time, real resources have been set aside for [palliative medicine] research and education.”

A relatively new medical specialization with a history of about 40 years, palliative medicine has only recently been granted “subspecialty” status in Singapore by the Singapore Academy of Medicine and the Specialists Accreditation Board. Subspecialty training in palliative medicine only officially started in May 2007, Goh said.

“We hope to address pressing quality of life and death issues, and sharpen the focus of resources and efforts towards the enhancement of human dignity and quality of life in the end-of-life experience,” said Krishnan, who is also chairman, department of psychiatry and behavioral sciences, Duke University Medical Center, USA.

The new center counts among its education programs a diploma course in palliative medicine developed by the NCCS and the Asia-Pacific Hospice Palliative Care Network, which is aimed at ensuring a pipeline of young doctors in the region.

“Singapore is aging very fast and 2030 is the crunch. It is quite worrying for the government to plan how to take care of its people who will be old and dying by then,”
Goh said.

For now, the center is working double-time to change public perception to regard death as a natural process rather than a failure of the medical system.

“When you are young, death is always troublesome but as you get older, you come to terms with what it means to live and die,” Krishnan said. “If you look at death as inevitable at some point, then the attitude changes somewhat.”

By GLENN OMANIO
Medical Reporter

The Singapore Health Sciences Authority (HSA) recently approved the first new anti-smoking drug in almost a decade.

The new drug, called varenicline, is a selective nicotinic acetylcholine receptor partial agonist. It works by partially stimulating nicotine receptors in the brain to reduce craving and withdrawal, while at the same time blocking the reinforcing effects of nicotine.

“While Singapore enjoys one of the lowest smoking prevalence rates in the world, we still hope to see a further reduction of the number of smokers in Singapore to decrease the number of smoking-related deaths and chronic ailments in the population,” said Dr. Ong Kian Chung, consultant respiratory physician, Mount Elizabeth Medical Centre. Ong was speaking at the launch of the new drug.

A survey of 200 smokers in Singapore, recently released by Pfizer, found that 62 percent of smokers were heavily addicted to nicotine, said Ong. He added that 49 percent of smokers, who have tried to quit before, found it difficult to do so due to psychological dependence on smoking.

The survey showed that Singaporean smokers rarely seek medical help to quit smoking – only 11 percent asked their family doctors for help, 3 percent approached smoking cessation clinics and 1 percent consulted specialists.

“Smokers who are addicted to nicotine basically cannot function properly unless they take in the substance through cigarettes. Smokers need to take this condition seriously and seek medical help as soon as possible, to help them overcome their dependency on nicotine,” said Professor Karl Fagerstrom, Fagerstrom Consulting and the Smokers Information Center, Sweden, who also spoke at the launch.

Pfizer-sponsored clinical trials of over 2,000 smokers showed that patients taking varenicline twice daily were four times more likely to quit smoking compared with patients without any pharmacological assistance. [JAMA. 2006 Jul 5;296(1):47-55; JAMA. 2006 Jul 5;296(1):56-63]

In the same double-blind, placebo-controlled phase III studies, patients on varenicline were two times more likely to quit smoking compared with those on bupriopion, an antidepressant that is also used for smoking cessation.

Patients who successfully quit smoking using varenicline were given another 12-weeks’ therapy and results showed varenicline increased the odds of three out of four patients being continuously cigarette-free after 6 months.

Varenicline is Singapore’s first new anti-nicotine treatment since the HSA approved bupropion in 1999 and nicotine replacement therapy in 1991.

By GLENN OMANIO
Medical Reporter

A miniature laboratory chip the size of a fingernail, which can identify all major types of influenza, including the deadly avian flu, was recently launched in Singapore.

The portable lab-on-chip, called VereFlu™, combines two cutting-edge technologies – polymerase chain reaction and a microarray – for rapid detection and differentiation of all human strains of influenza A and B viruses, including the H5N1 strain, in a single test.

Developed by Singapore’s Veredus Laboratories and the Geneva-based chip-maker STMicroelectronics, VereFlu is intended to be deployed at clinics, airports and seaports and in areas outside the traditional laboratory environment, such as farms caught in a flu pandemic, developers said.

“VereFlu will enable healthcare professionals to effectively monitor mutations of flu viruses and quickly identify the main strain of the season,” said Dr. Rosemary Tan, chief executive officer of Veredus Laboratories.

“This unique capability can significantly increase the effectiveness of flu vaccination and reduce public health risks associated with the emergence of a new flu virus,” Tan said.

The VereFlu chip targets hemagglutinin, neuraminidase and matrix genes to identify specific strains of influenza. For example, if a person is infected by H5N1, most of these genes will “light up” in the microarray panel of the test kit, Tan said.

The chip is the key component of the silicon-based test kit called the ST In-Check platform developed by STMicroelectronics. The kit combines various applications of common laboratory instruments into a single self-contained unit, which significantly reduces the risk of cross-contamination common in conventional analysis methods.

The kit’s micro-electro-mechanical solutions in a disposable cartridge amplify tiny DNA samples by precisely controlled heating and cooling and it quickly runs biological protocols that evaluate the analyzed samples.

The test kit generates sample-to-result reports with complete analysis in less than 2 hours, twice as fast as traditional test kits, which often look for just one virus. Clinical samples that can be used include human blood, serum and respiratory swabs.

VereFlu’s microarray panel can be constantly updated within a short period of time to detect new strains of influenza and current outbreaks, Tan said.

The commercial launching of VereFlu came after a successful 6-month evaluation trial last year at Singapore’s National University Hospital (NUH) aimed to ensure that other non-flu viruses do not give positive results and different variations of flu strains give specific results, said Dr. Raymond Lin, head of the microbiology division, NUH.

Lin said his team conducted 129 tests to evaluate the chip’s performance on real samples of various flu strains – H1N1, H3N2, H5N1, H7N1, H9N2 and influenza B – and found a 99 percent diagnostic specificity.

The same result holds true for non-flu viruses tested during the trial for cross-reactivity, including respiratory synctial virus, human coronavirus, human parainfluenza virus, metapneumovirus, adenovirus and rhinovirus, he added.

“We are pleased to report that our evaluation trials show the suitability of the VereFlu diagnostic application for field testing and deployment. The diagnostic reliability of this novel device makes it a powerful weapon against future influenza pandemics,” Lin said.

By GLENN OMANIO
Medical Reporter

Conference Coverage: 2nd Congress of the Asia-Pacific Initiative on Reproduction (ASPIRE), 11-13 April, Singapore

Three decades since the birth of the word’s first test-tube baby, Louise Brown, scientific progress in assisted reproductive technology (ART) continues to make great strides in giving people a chance at parenthood, a leading fertility scientist said recently.

From the subtle changes in the culture scientists use to grow embryos in the lab to experiments testing new combinations and doses of fertility drugs, the world of reproductive medicine has been trying to produce various permutations of human life through in-vitro fertilization (IVF) for the last 30 years.

“The advent of IVF and other associated assisted reproductive technologies has not only provided critical clinical tools to treat infertility, it has also given us the opportunity to directly observe and study human reproductive processes,” said Dr. Zev Rosenwaks, director of the Weill Medical College of Cornell University, US.

“We have witnessed a virtual revolution in our ability to successfully tackle many hitherto insurmountable impediments to human reproduction,” Rosenwaks said.

Brown’s rather conventional conception by today’s standards has given birth to more than 1.5 million IVF babies at present as dozens of leading IVF experts at the congress revealed breakthroughs to perfect and expand the technology and boost success rates in the region.

For the first time, scientists are able to examine the consequences of ovarian exposure to gonadotrophins from early folliculogenesis to oocyte maturation and ovulation, Rosenwaks said, noting that direct observation of ovulation in IVF’s early days “allowed for the precise assessment of necessary elements and temporal events surrounding ovulation.”

Similarly, research on ovarian stimulation for IVF has led to a better understanding of the mechanisms underlying ovarian hyperstimulation syndrome, leading to the introduction of several potentially preventive strategies, he added.

In addition, quantitative assessment of ovarian reserve is now possible through identification of specific markers associated with ovarian response, number of oocytes retrieved and pregnancy outcome.

The introduction of preimplantation genetic diagnosis among women has successfully eliminated chromosomal abnormalities, which may lead to unsuccessful pregnancy or devastating illnesses such as Down syndrome, cystic fibrosis and inherited blood disorders.

Another addition to IVF is intracytoplasmic sperm injection (ICSI) – in use since 1992 – which made it possible for men with few sperm to become fathers.

“ICSI has provided insight into the critical genetic and functional requirements necessary for normal fertilization and subsequent embryo development while elucidating the genetic underpinnings required for spermatogenesis,” Rosenwaks said.

Scientists have been constantly working to improve cryopreservation techniques for embryos, oocytes, spermatozoa and other reproductive tissues to preserve the fertility potential of people facing sterilizing treatments for malignant diseases.

Yet Rosenwaks said the field of ART is “still facing great challenges.”

For one, fertility scientists are still studying how to optimize embryo and gamete growth media, improve cryopreservation techniques and identify embryo viability markers, which could lead to a reduction in multiple pregnancy rates.

Rosenwaks added that much work needs to be done in stem cell research and nuclear transfer technology, which he said holds promise for gamete manufacturing and may soon wipe out infertility.

By GLENN OMANIO
Medical Reporter

Conference Coverage: 18th Singapore National Eye Centre Anniversary International Meeting, 14-17 March, Singapore

A partial thickness graft or deep anterior lamellar keratoplasty (DALK) may be the way to reduce to zero the risk of potentially blinding graft rejection that can occur with penetrating keratoplasty, the world’s most commonly performed corneal transplantation procedure.

“By retaining the inner layer of the cornea, the risk of graft rejection and long-term graft failure is significantly lowered to almost zero,” Tan said, adding that graft rejection happens to one out of 10 cases of full-thickness penetrating keratoplasty.

DALK is ideal in treating scars on the surface of the cornea like keratoconus but doctors at the SNEC have also applied the procedure in active corneal infections and ulcers related to contact lens wear and eyes that have corneal perforations, he said.

The procedure involves dissecting the cornea and removing the top layer. A donor corneal button is prepared by removing Descemet’s membrane and donor endothelium.
The donor graft is secured with fine sutures.
The SNEC has performed DALK in more than 150 eyes in the past few years, said Tan, adding that researchers have found better visual outcomes in patients who underwent this procedure for both corneal scars and active infection.

“One does not enter the eye in this procedure and therefore all complications related to intra-ocular entry, such as glaucoma and cataract, are avoided,” Tan said.

“There is a significantly lowered risk of graft rejection and this translates into better graft survival in the long-term.”

By GLENN OMANIO
Medical Reporter

18th Singapore National Eye Centre Anniversary International Meeting, 14-17 March, Singapore

An ultra-fast laser pulse of one quadrillionth of a second, otherwise known as one femtosecond, is transforming treatment on human corneas at the Singapore National
Eye Centre (SNEC), giving patients sharper vision, fewer side effects and a quicker recovery time, the eye center announced recently.

The femtosecond laser-assisted endothelial keratoplasty (FLEK) has produced smoother surfaces far better than the traditional microkeratome cut and with little damage to the endothelial cells, said Professor Donald Tan, deputy director, and head of cornea and external eye disease, SNEC.

He said femtosecond laser can cut both the donor’s posterior lamellar and the recipient’s posterior corneal surface with precision, making it an essential tool in surgery to replace back layers of the cornea as performed in endothelial keratoplasty.

“Our studies show that with new nomograms and algorithms, the laser is able to create surfaces smoother and more reliably than those created by bladed microkeratomes, even with deep corneal dissections,” Tan said.

Femtosecond lasers have been widely used in creating laser assisted in situ keratomileusis (LASIK) flaps with very smooth cuts in the front of the cornea but eye surgeons have found it difficult to produce the same quality in cutting deeper tissues, Tan said.

Corneal transplant surgery has involved circular blades called trephines. Although good outcomes were common, irregularity in the cuts is not unusual because of lack of precision in the cut angles and the pressure on the blade, which distorts tissues.

At SNEC, researchers have been focusing on how to optimize the use of Femtosecond lasers for all forms of corneal surgery, which would allow greater precision, improved surgical dissection and faster operating times, he added.

“The potential of femtosecond lasers in corneal dissection is huge, and they may also help in future with surgery for artificial corneas,” Tan said.

By GLENN OMANIO
Medical Reporter

Conference Coverage: 18th Singapore National Eye Centre Anniversary International Meeting, 14-17 March, Singapore

Researchers in Singapore recently developed a new technique for corneal transplantation, which may reduce graft failure and improve rehabilitation times. The technique is a new insertion method used in Descemet’s stripping automated endothelial keratoplasty (DSAEK) and it is designed to work on Asian eyes.

The so-called “sheet glide technique” developed by Professor Donald Tan, deputy director, and head of cornea and external eye disease, Singapore National Eye Centre (SNEC), and his colleagues, has been shown to reduce the amount of endothelial damage caused by the folding and compression in standard corneal transplant techniques and has improved graft survival rates.

The most common approach used worldwide to insert the donor lamella into the patient’s eye in DSAEK is by folding it like a taco. But scanning electron microscopy and dye staining has shown extensive endothelial cell damage, which leads to a significant loss of endothelial cells and higher rates of primary graft failure, said Tan.

Moreover, this procedure is difficult to perform in Asian eyes, which tend to have shallower anterior chambers and smaller corneal diameters as compared to Caucasian eyes, posing difficulties when unfolding the donor tissue, Tan said.

“The majority of studies pertaining to folding technique had been reported in Caucasian eyes, hence we felt the need to modify the technique for Chinese eyes, which will be better suited to our local population,” Tan said.

Tan and his colleagues developed the glide insertion technique in which the donor tissue, protected by abundant viscoelastic material, is placed on a modified intraocular lens glide.

An anterior chamber maintainer is used to keep a deep chamber. Insertion of the glide through the wound prevents iris prolapse as the glide protects the iris and keeps it in place, Tan said.

Intraocular forceps, specially designed by Tan, are introduced through a 5 mm scleral incision opposite to the main wound. The donor tissue is pulled through the wound without folding, gliding on a layer of viscoelastic material, through a deep anterior chamber, a video demonstration showed.

Tan said his team had performed 20 cases of DSAEK using the standard “taco technique” with an “unacceptably high” graft failure of 25 percent. His team then switched to the “glide technique” for the next 50 cases and produced better clinical outcomes.

Tan said the glide insertion technique has an average endothelial cell loss of 26 percent after a mean follow-up of 6 months as compared to 34 percent cell loss reported recently by two U.S. surgeons using the folding technique. [Ophthalmology 2008:115;488-496]

The overall visual acuities were also equivalent to those reported in other DSAEK studies. Visual rehabilitation for the patient is faster with the new procedure compared to standard corneal transplantation, Tan said.

He added that while DSAEK remains at the cutting edge of current keratoplasty techniques, endothelial cell loss remains a major issue that needs to be addressed.

Further long-term endothelial cell count studies should be done to confirm initial findings, Tan concluded, noting that his team is still working towards perfecting the new procedure.

By GLENN OMANIO
Medical Reporter

The National University of Singapore (NUS) will open its new Centre for Translational Medicine come 2010, in its bid to boost research on various diseases and healthcare issues relevant to Singapore and the Asian region.

Prime Minister Lee Hsien Loong led the recent ground-breaking ceremony at the Kent Ridge campus, urging clinicians and basic science researchers to collaborate on a national scale to strengthen the life sciences industry and raise the country’s stature as a regional medical hub.

“Clinical research will help us grow our medical capabilities, stay ahead of our competitors, and maintain our status as a regional medical hub,” Lee said. “Our competitive edge in healthcare has to be based on better knowledge and stronger skills, grounded on scientific research, rather than being the cheapest.”

The S$180-million center will house a full range of facilities, such as a medical library, a simulated hospital and various translational research programs, including cancer, cardiovascular and infectious diseases, imaging research, as well as the recently unveiled NUS Cancer Research Centre of Excellence (RCE).

The RCE, which will focus on cancer stem cells, biology, epigenetics, genomics and experimental therapeutics, is aimed at becoming one of the top cancer research centers in the world, said Professor Tan Chorh Chuan, chief executive of the National University Health System.

The 41,000 m2, 15-storey center will devote four levels to teaching while nine floors will be turned into research facilities, such as the new Clinical Imaging Research Centre, which will be one of the first research sites in the world to use Siemens’ MR-PET system, a hybrid imaging technology that can simultaneously locate diseases and identify underlying molecular causes.

It will also accommodate a clinical research facility that will look into biomarker and epidemiological studies, and drug development studies involving clinical pharmacology.
The topmost floor will be reserved for scientists who will study infectious agents endemic to the region, such as malaria, tuberculosis, dengue, human immunodeficiency virus and the deadly avian influenza viruses.

“The center will be a key national resource for education and translational medical research. By focusing on translational medicine, we will provide a home for Singapore and the world’s talent to help shape the practice of medicine in Singapore and the region,” said Professor John Wong, dean of the Yong Loo Lin School of Medicine.

These facilities will be shared by some 500 doctors, scientists and teaching faculty from NUS, as well as foreign researchers, and even those at the Massachusetts Institute of Technology and the Duke University Graduate Medical School, Wong said.

By GLENN OMANIO
Medical Reporter

Conference Converage: 18th Conference of the Asian Pacific Association for the Study of the Liver (APASL), 23-26 March, Seoul, Korea

The prevalence of non-alcoholic fatty liver disease (NAFLD) in Japan, China and several key urban centers in Asia has more than doubled in the past decade, affecting up to one-third of the general population, according to population and hospital-based studies released recently.

Across the Asia-Pacific region, the West’s most common liver disorder posted higher-than-expected prevalence rates of two to 37 percent, while large surveys in China, Japan and Korea recorded 12 to 29 percent prevalence rates, which are comparable with Western industrialized countries.

Several large scale surveys in the US and Europe have shown that the prevalence of
NAFLD in the general population ranges from at least 20 percent to as high as 30 percent. [Hepatology 2004 Dec;40(6):1387-95]

NAFLD covers a wide range of liver disorders characterized by macrovesicular hepatic fat accumulation or steatosis. It is indistinguishable from alcoholic liver disease but a typical patient is likely to have one or more metabolic disorders associated with insulin resistance. [J Gastroenterol Hepatol 2007 Jun;22(6):775-7]

Three longitudinal studies noted an increase in the prevalence of NAFLD in Japan from 13 percent in 1989 to 30 percent in 2004. Similar trends were documented in China and the rest of Asia, particularly in key urban centers. [J Gastroenterol. 2003;38(10):1022-3; J Gastroenterol Hepatol. 2007 Jun;22(6):788-93]

“Lifestyle changes in an increasingly wealthy Asian population and the epidemic of childhood and adult obesity sweeping the Asia-Pacific are key factors which may contribute to the rising prevalence of NAFLD,” said Dr. Jose Sollano, head of gastroenterology, Santo Thomas University Hospital, Manila, Philippines.

Sollano noted that the strong prevalence of NAFLD has increased recently in parallel with the rising trends in obesity, type 2 diabetes and metabolic syndrome in Asia, which become more visible when regional definitions of anthropometry are used.

The World Health Organization has defined obesity in Asians as a body mass index (BMI) of at least 25 kg/m2. The mean BMI for Asian men and women in most NAFLD studies is below 27.5 kg/m2, in contrast to studies outside Asia, where mean BMI levels often exceed 32 kg/m2.

“NAFLD is a clear and present danger. It could be a future shock to the Asia Pacific,”
Sollano said.

Meanwhile, large community-based studies indicate a bi-modal age distribution for NAFLD within the region, where peak prevalence occurs between 40-49 years in men and over 50 years in Asian women, he said.

While it is generally believed that most asymptomatic individuals with NAFLD are unlikely to develop to more severe hepatic disorder, a Japanese study reported otherwise, Sollano pointed out.

Of 247 NAFLD patients at Tokyo Women’s Medical University from 1990-2004, 36 percent had stage 3 and stage 4 hepatic fibrosis. Over a mean follow up period of
44 months, six developed variceal bleeding, four had ascites, two had hepatic encephalopathy and five developed liver cancer. [Hepatol Res 2005 Oct;33(2):72-6]

Experts, however, are still unable to recommend any present pharmacologic agent for treatment of NAFLD though they have seen some promising results in small, randomized controlled trials, Sollano said.

At present, doctors advocate not simply weight reduction but evidence-based recommendations for lifestyle intervention, which involves dietary modification based on one’s metabolic profile and increased levels of physical activity, he added.

“NAFLD will most likely increase further in the Asia Pacific because there is an increasing number of patient populations at risk for the development of the disorder. Greater awareness by both the general population and the physicians towards its prevention is imperative,” Sollano said.

By GLENN OMANIO
Medical Reporter

Conference Coverage: 18th Conference of the Asian Pacific Association for the Study of the Liver (APASL), 23-26 March, Seoul, Korea

The APASL recently released new guidelines for the management of hepatitis B, in light of global approvals of new drugs and research findings aimed at improving treatment and prevention of the liver disease.

Sixteen recommendations were agreed upon by the group following a two-day expert meeting held to review and assess new data, revising the earlier APASL consensus statement on the management of chronic hepatitis B. [Liver Int 2005 Jun;25(3):472-89]

For the first time, the guidelines included female patients of child-bearing age, stating that interferon (IFN)-based therapy is preferred or non-pregnant women and pregnancy is discouraged during IFN-therapy, said Dr. Yun-Fan Liaw of the Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University, Taiwan.

Since the third version of the Asian-Pacific consensus statement on the management of hepatitis B was published in June 2005, pegylated IFN alpha 2a, entecavir and telbivudine have been approved globally and several updated guidelines on chronic hepatitis B have been published, Liaw said.

He added that a large volume of new data on the natural history and treatment of chronic hepatitis B has become available, including long-term follow-up studies in large community-based cohorts of asymptomatic subjects with chronic hepatitis B virus (HBV) infection, studies on the role of HBV genotype and naturally-occurring HBV mutations, treatment of drug resistance, and new therapies.

The guidelines mandated thorough evaluation and counseling of patients before considering drug therapy or liver biopsy, and prohibited the treatment of patients with viral replication, except those with advanced fibrosis or cirrhosis.

Patients can be treated with conventional IFN 5-10 million units 3x/week or pegylated IFN-alpha 2a 90-180 μg weekly, entecavir 0.5 mg daily, adefovir 10 mg daily, telbivudine 600 mg daily, or lamivudine 100 mg daily, the guidelines stated.

Liaw said the current recommended duration of therapy for conventional IFN is 4-6 months for hepatitis B e antigen (HBeAg)-positive patients and at least a year for HBeAg-negative patients.

Meanwhile, the recommended duration for pegylated IFN-alpha 2a therapy is at least 6 months for HBeAg-positive patients and 12 months for HBeAg-negative patients.

For thymosin-alpha 1, the recommended duration of therapy is 6 months for both HBeAg-positive and HBeAg-negative patients, Liaw said.

Before receiving immunosuppression or chemotherapy, the APASL recommends that patients should be screened for the surface antigen of HBV called HBsAg.

If HBsAg is positive, prophylactic therapy with a direct antiviral agent before the start and up to at least 12 weeks after the end of immunosuppression or chemotherapy is recommended, Liaw said.

He added that patients who developed drug resistance while on lamivudine may receive add-on adefovir therapy while lamivudine-naïve patients resistant to adefovir may add or switch to lamivudine, telbivudine or entecavir. Add-on adefovir therapy is indicated for telbivudine-resistant patients.

Liaw also pointed out some unresolved issues and areas for study in the treatment of hepatitis B, including HBV genotyping in designing treatment plans, optimal combination therapy to enhance efficacy and the cost-effectiveness of each therapeutic strategy.

He said the final guidelines will be published in the September 2008 issue of Hepatology International.

By GLENN OMANIO
Medical Reporter

Conference Coverage: American College of Cardiology (ACC), 57th Annual Scientific Session, 29 March – 1 April, Chicago, US

A single-pill combination of the calcium-channel blocker (CCB) amlodipine and angiotensin-converting enzyme (ACE) inhibitor benazepril reduced cardiovascular morbidity and mortality by one-fifth compared with conventional therapy and significantly lowered the blood pressure of hypertensive patients to ideal levels, results of an international blood pressure study showed.

The Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial is the first to evaluate cardiovascular outcomes using a single pill that may challenge current guidelines for blood-pressure control worldwide, according to researchers.

“These results demonstrate the superiority of an ACE/CCB fix-dose combination treatment strategy for reducing cardiovascular morbidity and mortality, and provides evidence that should modify future guidelines for the treatment of hypertension,” said lead investigator Dr. Kenneth Jamerson, a professor of internal medicine at the University of Michigan Medical School and lead investigator in the trial.

Currently, blood pressure treatment guidelines provide for a single medicine to be tried first in people with Stage 1 hypertension, followed by combination therapy when needed.

However, studies have found that most patients often have trouble taking multiple medications, which has prompted drug companies to develop combination pills.

ACCOMPLISH compared the effects of amlodipine – Benazepril antihypertensive combination therapy against the conventional benazepril-hydrochlorothiazide combination on major fatal and nonfatal cardiovascular events. The trial was stopped early because of the overwhelmingly significant results gained by the new therapy.

More than 11,400 men and women aged at least 55 years joined the trial. All of them had either a systolic blood pressure of greater than 160 mmHg or were on antihypertensive therapy and had evidence of cardiovascular or renal disease or target-organ damage.

Almost all of the patients enrolled in the trial had been treated previously for hypertension, 60 percent had diabetes mellitus and half of them were obese. Three out of four patients were treated with at least two antihypertensive agents. Only a 37.5 percent of patients had blood pressure controlled to <140/90 mmHg at baseline.

The study protocol required participants to stop medication at the beginning of the trial. They were then randomized to receive benazepril plus hydrochlorothiazide or amlodipine plus benazepril combination therapies.

Results from the ACCOMPLISH trial show that after 30 months, blood-pressure levels were significantly improved in both treatments arms. However the ACE/CCB combination arm fared better with 81.7 percent of patients achieving blood pressure of <140/90 mmHg, compared to 78.5 percent in the control group (P=.001).

Moreover, investigators found that the ACE/CCB combination treatment reduced cardiovascular morbidity and mortality – defined as cardiovascular death, fatal or non-fatal myocardial infarction, fatal or nonfatal stroke, hospitalization for unstable angina and coronary revascularization – by 20 percent, compared with those treated with benazepril plus a diuretic (P=.0002).

“ACCOMPLISH achieved exceptional (blood pressure) control with combination therapy providing a new option for cardiovascular risk reduction to millions of patients with hypertension,” Jamerson said.

Participants in the study all received no more than 40 mg of benazepril in each dose and the amlodipine dose of 5 mg could be increased to 10 mg. Hydrochlorothiazide doses began at 12.5 mg and could be increased to 25 mg.

By GLENN OMANIO
Medical Reporter

Needy medical students at the National University of Singapore (NUS) will receive new funding from the Singapore Medical Association (SMA) to help them meet the cost of basic living expenses that are not covered by government subsidies and scholarships.

Professor John Wong, dean, Yong Loo Lin School of Medicine, NUS, received the cheque amounting to about S$187,000 from SMA President Dr. Wong Chiang Yin at a recent ceremony.

The SMA set up the SMA Medical Students’ Assistance Fund, which matches dollar-for-dollar donations from SMA members and other donors, up to a maximum of S$20,000 a year. All donations collected go directly to the students, the SMA said.

A recent survey by the NUS Medical Society showed that one in five undergraduate medical students at NUS have a monthly household income of less than S$3,000. The highly-subsidized 5-year program costs more than S$100,000 and students need at least S$4,410 a year for basic living expenses, the survey said.

By GLENN OMANIO
Medical Reporter

The fasting plasma glucose (FPG) concentration of 7 mmol/L – the widely used yardstick to diagnose diabetes mellitus – has seemingly failed to predict which patients have or will likely have retinopathy, according to a recent study. [Lancet 2008:371;736-743]

The overall prevalence of retinopathy ranged from 9.6 percent to 15.8 percent across the different populations, and the study found “inconsistent evidence of a uniform glycemic threshold” for prevalent and incident retinopathy, say researchers at the Centre for Eye Research Australia, University of Melbourne.

This calls into question the current approach, advocated by the World Health Organization and the American Diabetes Association, of using retinopathy to derive
FPG thresholds for diagnosing diabetes, authors say.

“These findings could help unify the understanding of the risk of complications from diabetes, suggesting that both macrovascular and microvascular complications do not seem to respect a glycemic threshold,” the authors said in the report.

The FPG cutoff of 7 mmol/L or higher had sensitivity ranging from 14.8 percent to 39.1 percent for detecting retinopathy, the report said. The area under receiver operating characteristic curves for FPG and retinopathy was low and ranged from .56 to .61.

The results came from the analysis of multiple field retinal photographs of about 11,400 subjects in three population-based cross-sectional studies — two in Australia and one in the US.

But a vitreo-retinal surgeon, who specializes in diabetic retinopathy, at the Singapore
National Eye Centre said larger prospective studies looking into glycemic control and its various complications are needed before modifying the popular FPG benchmark.

He added that while the current diagnostic criteria may be limited, it is still an important tool for patients to personally monitor their fasting sugar in lieu of more sophisticated tests like glycosylated hemoglobin (HbA1c) that can only be done in specialized clinics.

Drs. Quresh Mohamed and Alison Evans, Cheltenham General Hospital, Cheltenham,
United Kingdom, wrote in an accompanying editorial in the Lancet that the current FPG threshold is able to distinguish a set of patients with a much greater risk of harm.

“We perhaps should focus less on a single universal cut-off and instead target resources on the basis of standardized evidence-based individual risk scores in which measures of glycemia are combined with other risk factors,” they said.

“But what would we tell our patients when they asked if they had diabetes? We are probably best sticking with what we know until a better alternative diagnostic tool becomes available,” they concluded.

By GLENN OMANIO
Medical Reporter

A tiny device working on the simple optical phenomenon of “pinhole effect” may soon eliminate the need for reading glasses brought by the normal age-related loss of near-focusing ability, researchers from the Singapore National Eye Centre (SNEC) announced recently.

At least 35 presbyopic patients in Singapore have received corneal implants of a tiny device called the AcuFocus ACI 7000 corneal inlay, which is currently awaiting approval from the US FDA, said Dr. Chan Wing Kwong, head of refractive surgery at the SNEC.

Chan said Singapore is the only test site in Asia and is one of 30 other locations abroad, mainly in the United States and Europe, running a 3-year prospective study to test the effectiveness of the ultra-thin circular plastic disc. The implant is designed to treat presbyopia in all patients, including those who have had cataract surgery.

“This exciting and groundbreaking technique to treat presbyopia will be a tremendous boon to adults who find it increasingly difficult to read small print and have to turn to the aid of reading glasses,” Chan said.

The corneal inlay, which is made of polyvinylidine fluoride polymer, measures 3.8 mm in diameter, is 5 microns thick and has a central aperture of 1.6 mm. It has tiny laser-etched holes throughout its surface to allow oxygen and other corneal nutrients to pass through, Chan explained.

The 5-minute surgical procedure involves implanting the corneal inlay in the cornea under a LASIK flap, placing it directly in front of the pupil and thereby, reducing the size of the pupil, he added.

Chan said decreasing the effective pupil diameter increases depth of field, and has proven to have improved functional near-vision almost immediately.

“The trial has shown it to be effective and safe with high patient satisfaction. It may prove to be the best and most effective surgical option for the correction of presbyopia,” he added.

All patients have achieved J2 or better distance-corrected near visual acuity in the third month following implantation while others achieve J1 in 6 months, according to Chan.

The implant is placed in one non-dominant eye. It is removable and the process is reversible, he said.

By GLENN OMANIO
Medical Reporter

Increased psychological distress, rather than depression, is associated with elevated stroke risk while major depressive disorder does not increase the risk, findings from a large prospective cohort study in the UK suggested.

People who reported the most psychological distress at baseline assessment had an increased risk of incident stroke compared to those who were least psychologically distressed, researchers at the University of Cambridge revealed in a recently published study. [Neurology 2008 Mar 4;70(10):788-94]

The study also showed that for each standard deviation decrease in the respondents score on the five-question Mental Health Inventory, the odds of stroke increased by 11 percent, after adjusting for smoking, blood pressure, diabetes and several other factors. The relationship was even more pronounced for those with fatal strokes.

“This study gives us more information on potential additional risk factors. We thus need to address these new factors if there is evidence that intervention will reduce stroke risk,” said Dr. N. V. Ramani, senior consultant neurologist, National Neuroscience Institute,
Singapore.

Meanwhile, the risk of stroke was not increased for people who had experienced an episode of major depression in the past year or for people who had experienced major depression at any point in their lifetime, it added.

Researchers examined 20,627 people, aged 41 to 80 years, who had never suffered a stroke, in the United Kingdom European Prospective Investigation into Cancer – Norfolk study, where participants answered questions concerning their psychological distress, based on a scale measuring wellbeing, and their history of major depressive disorder.

After an average follow-up period of 8.5 years, 595 patients had suffered a stroke, and nearly one-third proved to be fatal, researchers say.

“A person’s emotional health is affected by his physical and mental status, as well as the physical and social environment he is in, balanced against the innate ability of the person to respond to these challenges,” said

Ramani, who is with the Faculty of Medicine, National University of Singapore.
Worldwide, 3 million women and 2.5 million men die from stroke every year, making stroke the second leading cause of death above the age of 60 years, and the fifth leading cause in people aged 15 to 59 years old, according to the World Health Organization.

Many studies have identified depression as a consequence of stroke but evidence is mixed whether depression could lead to stroke.

“Knowing the emotional health will help us to better appreciate the patient’s medical risk profile, response to illness, health-seeking behavior. We can then provide more holistic care,” Ramani said.

By GLENN OMANIO
Medical Reporter

Two of the world’s largest breast cancer research networks are joining together in a worldwide clinical trial that investigators hope will provide a new model for global cancer research.

The Breast Cancer Intergroup of North America (TBCI) in the United States and the
Breast International Group (BIG) in Belgium recently launched the joint Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) study, which will gather 8,000 participants from more than 50 countries, including Singapore, Hong Kong, Malaysia, Thailand and the Philippines.

There is a need for “more collaboration with laboratories that perform translational work and to incorporate these correlative works in wide-scale clinical trials,” said Dr. Lee Soo Chin, senior consultant at the department of hematology-oncology, National University Hospital (NUH), Singapore.

“The advantages of studies involving many countries and sites include more rapid accrual of patients, so that the study can be completed more quickly, and the inclusion of patients from different geographical and ethnic backgrounds, so that results are more generalizable,” he said.

NUH is one of the participating sites for the ALTTO study and has so far enrolled four patients, Lee said, adding that its oncology department participates in 10 to 15 of such new studies every year.

For a study to be carried out in several hundred sites around the world, its treatment procedures are usually simplified enough to be adhered to by community hospitals, and not just high-end, tertiary hospitals, “making the results more applicable,” he added.

However, certain correlative work, such as tissue and blood collection, cannot be done at all sites in large-scale trials, Lee said, adding that centralization of certain study procedures may be necessary to ensure validity of results.

The ALTTO study is testing the effectiveness and safety of trastuzumab and lapatinib among randomly selected women with early stage HER2-positive tumors, an aggressive form of cancer that affects up to a quarter of breast cancer patients.

Over a 52-week period, the study will administer trastuzumab and lapatinib to participants to determine what would be the most effective treatment – either trastuzumab or lapatinib alone, trastuzumab followed by lapatinib or the two treatments in combination, investigators say.

Researchers say the ALTTO study is the first to make a head-to-head comparison of the FDA-approved trastuzumab and lapatinib in the most treatable stages of cancer and is also the first large-scale study to evaluate lapatinib’s effectiveness in treating early-stage breast cancer.

Trastuzumab latches on to the portion of the HER2 protein that sits on the outer surface of the cancer cell while lapatinib acts by entering a cancer cell and binding to the part of the HER2 protein that lies beneath the surface of the cell.

“It may be that using two treatments that work in different ways against HER2-positive breast cancer offers a complementary strategy that is more powerful than either drug alone,” said Dr. Edith Perez, an oncologist at the Mayo Clinic’s North Central Cancer Treatment Group in Jacksonville, US, who will lead the study for TBCI.

Biological material will be collected from participants to determine a tumor profile that responds best to the drugs, investigators say, adding that the information culled from the study may lead to the discovery of next-generation agents and individualized patient care.

They will evaluate molecules in tumor samples such as c-Myc oncogene and PTEN tumor suppressor gene, and collect blood samples from all participants to look for molecular markers that may predict clinical outcome.

Tissue samples from participants in North America will be tested and stored at the Mayo Clinic in Rochester, US, while samples from Europe and the rest of the world will be studied at the European Institute of Oncology in Milan, Italy.

Additional blood and frozen tumor samples will be gathered from a subset of 2,000 patients that will be kept in Rochester, US, and Brussels, Belgium for future studies on circulating tumor cells and proteomics, investigators say.

By GLENN OMANIO
Medical Reporter

Multi-drug-resistant tuberculosis (MDR-TB) has soared to the highest rates ever recorded globally, with more than 110,000 deaths and about half a million cases emerging yearly, according to a World Health Organization (WHO) report.

In the 37-country Western Pacific region – which includes most countries in the Asia Pacific region – the spread of the potentially fatal disease is “heterogeneous” with most of the burden focused on China, the Philippines and to a lesser extent Vietnam, said Dr.
Philippe Glaziou, who directs the WHO’s tuberculosis program in the region.

Seven countries and China’s two special administrative regions of Hong Kong and Macau reported drug resistance data from the Western Pacific region, which includes economically disparate areas such as the Inner Mongolia region in China, Singapore, Japan and the Pacific islands.

MDR-TB among new TB cases in the Western Pacific region ranged from less than one percent in Hong Kong, Japan, New Zealand and Singapore, to 7.2 percent in China’s Inner Mongolia and Heilongjiang regions, according to the WHO report, which involved 90,000 patients in 81 countries.

The highest recorded rates were in Baku, Azerbaijan, where 22.3 percent of new tuberculosis cases were found to be resistant to the standard anti-TB drug regimen, along with several parts of the former Soviet Union, the 2008 Anti-Tuberculosis Drug Resistance in the World report showed.

MDR-TB is a form of TB that does not respond to the standard 6-month treatment using first-line drugs, such as ionized and rifampicin. MDR-TB can take 2 years to treat. The drugs used are more toxic, and can be up to 100 times more expensive, the WHO said.

In some parts of the world, HIV and AIDS are fueling the spread of tuberculosis, the report said. For example, HIV infection was significantly associated with MDR-TB and any anti-TB drug resistance in Cuba, Honduras, Spain and Uruguay.

TB patients in Latvia and Donetsk, who were also HIV-infected, were almost twice as likely to have a drug-resistant strain of TB as compared to TB patients who were not HIV-infected, the report said.

“The problem relates to human practices. It is man-made. Tuberculosis control is poor and patients taking only a limited number of drugs, or an incomplete regimen, have fueled a generation of multidrug-resistant tuberculosis,” Glaziou told Medical Tribune in a phone interview.

For the first time, the survey, which is the fourth since 1997, included an analysis of extensively drug-resistant tuberculosis (XDRTB), but because only 35 countries participated, the data were limited, Glaziou said.
Based on the data, the WHO estimates around 40,000 XDR-TB cases emerge globally every year, mostly in former Soviet Union countries. The proportions of XDRTB among MDR-TB range from four percent in Armenia to almost 24 percent in Estonia.

XDR-TB is a form of TB caused by bacteria resistant to all the most effective drugs, fluoroquinolones and the second-line anti-TB injectable drugs, such as amikacin, kanamycin or capreomycin.

The rise in MDR-TB underscores the need to scale-up treatment services, including rigid monitoring of patients to ensure they complete the full drug regimen, and for governments to invest more in building laboratories and training personnel to detect the disease, Glaziou said.

“With the new report, the thinking now is that something must be done urgently. It is an important document because it maintains awareness of the problem,” Glaziou said.

By GLENN OMANIO
Medical Reporter

Many physicians may not be getting enough sleep to function at their best because of their work schedules, according to a new survey released recently by the American College of Chest Physicians Sleep Institute (ACCPSI).

About three out of four doctors reported they need at least 7 hours of sleep every night yet they only get 6.5 hours on average during their work week, as nearly half of them believe their work schedules do not allow for adequate sleep, according to the internet-based survey.

“Call hours during training and in the practice of medicine desensitize physicians to the importance of sleep. The pervasive message is that sleep is optional or dispensable,” ACCPSI chairperson Dr. Barbara Phillips said in a statement.

The doctors reported that the sleep they lost because of work is made up for by sleeping an average of 7.5 hours a night on weekends or days off, the survey said.
The ACCPSI sent the random questionnaire to 5,000 US physicians and 581 of them reported their current sleep habits and how sleep affects their work performance.

“Our performance in tasks that require close attention is impaired if we are deprived of sleep. We make more mistakes in our work and overall tend to be less productive,” said Dr. Lim Li Ling, medical director, Singapore Neurology and Sleep Centre.

Lim, who is also the deputy director of Singapore General Hospital’s sleep disorders unit, said doctors must get enough sleep every night as looking after patients requires mental sharpness, clarity and good judgment.

“When we do not get enough sleep we become very sleepy in the daytime. This can result in embarrassing situations such as falling asleep during meetings, and can
be even dangerous if we fall asleep while driving,” Lim added.

Doctors rarely report insomnia but 21.8 percent report not feeling refreshed a few times per week, when they wake up in the morning, the survey said.

Most doctors claim that lack of sleep did not adversely affect their work performance but one out of five physicians reported it caused them to miss family or leisure activities, it added.

Moreover, the survey results were compared to the findings of the 2008 National Sleep Foundation “Sleep in America” poll and found that caffeine use is more common
among physicians than the general population.

The survey revealed that 93 percent of physicians have at least one caffeinated beverage per day, compared with 81 percent of the general population.

However, the survey also showed that an overwhelming majority of physicians claim to take caffeine out of habit rather than to help boost wakefulness.

The survey also found that 83.6 percent of physicians reported being in very good or excellent health as opposed to 56 percent of the general population.

By GLENN OMANIO
Staff Reporter

Note: Here's my last piece with Kyodo News, my home for almost five years, where I covered the Philippine country beat. Since March 3rd of this year, I have been working on a new post as a medical journalist with Medical Tribune, the only regional medical newspaper in Asia. The Medical Tribune is a monthly newspaper for doctors and healthcare experts in the Asia-Pacific region published by CMPMedica, a divison of United Business Media Plc, an international media and business information company employing more than 5,000 people in over 30 countries around the world.

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MANILA, Feb. 29 Kyodo - Tens of thousands of Filipinos joined by two former presidents called for President Gloria Macapagal-Arroyo to resign on Friday amid a corruption scandal involving her husband and a close political ally.

A steady stream of people, estimated by organizers at 85,000 but downplayed by police to 15,000, carried colorful banners, chanted and prayed while marching along a half-kilometer stretch of the main thoroughfare in Manila's Makati financial district.

United by their calls for Arroyo to step down, democracy icon and former President Corazon Aquino shared the stage for the first time with her once bitter foe, deposed President Joseph Estrada, before a huge crowd of people who included university students, left-wing activists and office-goers.

Aquino, once a staunch ally of Arroyo, chanted before a cheering crowd, ''Gloria resign!'' while Estrada chided Arroyo for ''overstaying'' in office to the applause of his loyalists.

Arroyo, whose term ends in 2010, inherited the remaining years in office of Estrada's two-and-a-half year presidency and was reelected for a six-year term in 2004 in an election that was marred by vote-rigging allegations.

While Aquino was catapulted to power by a so-called ''people power revolution'' in 1986 that ousted the late strongman Ferdinand Marcos, Estrada was forced to resign by the second ''people power'' uprising in 2001 amid allegations of massive corruption.

The loudest cheer was given to Rodolfo Noel Lozada Jr., a key witness in the Senate inquiry into the $329-million telecommunications deal between the government and Chinese company ZTE.

''This movement should not be spurred by anger or loathing because once the object of loathing is gone, everyone stops again,'' the former government electronics communications engineer said, stressing the system of corruption should be gotten rid of and not just the leaders.

The latest wave of anti-Arroyo protests were triggered by Lozada's testimony before the Senate that Arroyo's husband Jose Miguel Arroyo and her close political ally Benjamin Abalos, a former Elections Commission chief, were at one time about to receive $130 million in kickbacks from the National Broadband Network project.

Arroyo, who has survived three impeachment bids and three coup plots in the last seven years of her tumultuous presidency, scrapped the contract when the scandal broke late last year and has rejected allegations her family has pocketed money from the national budget.

Arroyo aides believe the recent turmoil will not weaken her, saying she still enjoys the loyalty of the top brass in the military and her allies continue to dominate the House of Representatives, which is the frontline of any impeachment attempts against the president.