Conquering Kinabalu

Medical Tribune April 2009 P18
David Brill

Mount Kinabalu is widely promoted as a straightforward climb for the everyday tourist. David Brill wonders whether Superman has been writing travel books in his spare time.

Pulling myself up a sheer cliff face in the pitch black at 4 a.m. I realized I’d been misled. With my hands slipping on the wet rope, the cramp aching in my legs and the insidious cold penetrating four layers of clothing, it began to dawn on me that climbing Mount Kinabalu was not going to be as simple as I’d been led to believe. When I saw a grown adult burst into tears, my worst suspicions were confirmed.

Rising to 4,095 meters above sea level, Mount Kinabalu is the highest mountain in Borneo although not, as often claimed, the highest in Southeast Asia (Myanmar and Indonesia boast loftier peaks). With 47,848 climbers in 2008 alone –26,595 of them non-Malaysians –it is considered to be one of the world’s most accessible mountains, and no specialist climbing skills are required.

Armed with a personal assurance that conquering the peak would be “easy,” we had arrived in the town of Kota Kinabalu on Friday night and travelled straight to the Kinabalu National Park, the UNESCO World Heritage site where the mountain is located. The drive usually takes around 2 hours but with heavy rain, thick fog and herds of cows mysteriously crossing the road, our progress was a little slower than might be expected. We arrived in the small hours of Saturday and, 5 hours sleep in a freezing dormitory later, were ready to begin the climb.

Only the bravest attempt to ascend and descend Mount Kinabalu in a single day, and the majority of tourists spend a night at Laban Rata –an accommodation compound situated around 3,000 meters up. With the mountain entirely shrouded in mist, it was left to our imaginations as to how high this might actually be, and we set off with the blissful optimism that accompanies blind ignorance.

Stage one of the climb is straightforward but cannot be described as easy. Five hours on a steep, meandering path, clambering over boulders and slipping in the mud, was achievable but not an experience I’d wish to repeat. When cramp set in it became genuinely challenging, and the need for effective hydration was a lesson learned the hard way. Cramp does not seem to be a problem for the porters, however, who regularly ferry supplies and equipment back and forth up the slopes, hardly breaking a sweat as they do so. There can be few experiences in life more demoralizing than struggling your way up a mountain, only to be overtaken by a man running full pelt with a dishwasher strapped to his back.

The relief upon arriving at Laban Rata was palpable. Accommodation here must be reserved before beginning the climb and is often booked up as far as 6 months in advance. There are a few different options within the compound, which can hold a total of 146 climbers on any single night, but the Laban Rata Rest House is promised as offering the greatest level of luxury. However with ice-cold showers and an electric radiator that struggled to generate heat but succeeded in unleashing a torrent of sparks during the night, I can only imagine what comforts await in the other buildings. The wisdom of reserving early was firmly reinforced.

Any last lingering hopes of a relaxing weekend break were finally shattered by the 2:30 a.m. wake up on the Sunday morning. Half an hour later we were on our way to Low’s Peak –an ironic title dedicated to British Explorer Sir Hugh Low who in 1851 became the first documented person to reach the summit. The warmth that was enjoyed at 3,000 meters quickly plummets along this stretch, and it is here that the rewards of a sensible packing list are reaped. A good pair of waterproof gloves and a head torch are extremely useful for sections where a rope is required, and a warm, windproof jacket will come in handy throughout. As the temperature drops so too does the vegetation –the lush greenery of the lower slopes giving way to sweeping expanses of bare rock that offer little shelter from the wind.

With altitude sickness, fatigue and depression setting in, we finally reached the peak around 2 hours after leaving Laban Rata. We did not have to wait long for the mood to lift, however. As the sun crept up over the horizon sometime after 5 a.m. the misery of all that had gone before was forgotten, replaced with a delirium-heightened wave of elation which swiftly swept through
the group. Aches and pains were put on hold as we reveled in the collective sense of achievement – 13 members of our motley crew had set off from Singapore and 13 were now sitting at the peak of Mount Kinabalu.

The view, as expected, is breathtaking. And as the sun began to provide some warmth, so the urgency to descend diminished. For the first time on the trip we were able to take in our surroundings without the sense of impending dread at what was to follow, leaving us free to return to Laban Rata in a more relaxed fashion than that in which we left. The rocks are significantly easier to traverse with the benefit of daylight, and we were breakfasting at the hostel around an hour after leaving the peak.

The rest of the descent is no simple task, and is considered by some to be the hardest part of the journey. Stiffness sets into the muscles and the height of the steps places considerable strain on the knees and calves. Buoyed by the knowledge that the worst was over, however, the pain became bearable and personally I came dangerously close to enjoying myself. Descending at a leisurely pace brought us back to base camp within 4 hours, while quicker members of the group made it inside 3. The porters, needless to say, sprinted past like Olympic mountain goats.

Climbing Mount Kinabalu is a physical and emotional rollercoaster. It took me a week to regain the full use of my legs, but it’s a small price to pay to know that I made it. Easy? No. Worth every second? Undoubtedly.

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For details of accommodation and climbing fees for Mount Kinabalu, see: www.suterasanctuarylodges.com.my/climbing_mt_kinabalu.php

Urine test shows promise for prostate cancer detection

Medical Tribune April 2009 P4

David Brill

A prototype urine test has been shown to be highly specific for detecting prostate cancer and could even help to reduce the number of unnecessary biopsies, US researchers suggest.

Moreover the results showed some correlation to disease severity markers, suggesting that the test could be used to distinguish between mild and aggressive forms of cancer.

The urine test detects the presence of a fusion between the TMPRSS2 (T2) and ERG genes, which is found in around 50 percent of prostate cancers.

“Many cancers detected at biopsy are low volume, low grade. There is a real need for tests that can help determine which of those men should receive aggressive treatment such as prostatectomy, and which could potentially be monitored more conservatively,” said lead researcher Dr. Jack Groskopf, who presented the results at the recent Genitourinary Cancers Symposium in Orlando, US.

“The key next steps here are to follow up and confirm the results that we have generated to date and, perhaps more importantly, to start looking at the correlation between the urine test and pathologic features in prostatectomy tissues, such as tumor volume stage and grade,” he said.

Commenting on the results, Dr. Howard Sandler, chair of radiation oncology at Cedars-Sinai Medical Center, Los Angeles, said: “The fact that this gene fusion is related to the progression and development of prostate cancer in half of all men who develop prostate cancer has major implications for diagnosis but hopefully for therapy as well. This unique fusion protein might become a therapeutic target at some point in the future.”

In a preliminary study of 556 men due to undergo prostate biopsy the urine test was 84 percent specific, reported Groskopf, a senior research scientist at Gen-Probe Incorporated, the San Diego-based company which is developing the test. For serum prostate-specific antigen (PSA) testing this figure is just 27 percent, he said, adding that the other current screening method – digital rectal exam – is also hampered by its low specificity.

“As a result the majority of prostate biopsies are negative, and you could argue that we are doing too many biopsies,” he said.

The sensitivity of the urine test was 42 percent – a favorable result considering that with only half of cancers containing the T2:ERG gene fusion, the theoretical maximum would be 50 percent, Groskopf added.

The urine test showed significant correlations to aggressiveness indicators such as the Gleason Score, the percentage positive prostate cores and the Epstein criteria.

Researchers from the University of Michigan, who are collaborating with Gen-Probe on the test, recently published another research paper linking sarcosine, a glycine derivative, to more aggressive forms of prostate cancer. This metabolite and its pathways could not only serve as a disease severity marker but also as a target for therapeutic intervention in future, they suggest. [Nature 2009 Feb 12;457:910-4]

CRT holds promise for atrial fibrillation in heart failure

Medical Tribune April 2009 P9
David Brill

The benefits of cardiac resynchronization therapy (CRT) for heart failure could extend to those sicker patients who have atrial fibrillation (AF), according to a leading Hong Kong cardiologist.

Although more randomized controlled studies are needed, observational data so far appear to support the use of CRT for these patients said Dr. Jeffrey WH Fung, director of cardiac electrophysiology and pacing services at the Prince of Wales Hospital, Chinese University of Hong Kong.

Fung estimated that up to 30 percent of heart failure patients have AF, but noted that guidelines currently exclude this group from the class I indications for CRT. This top-level recommendation is presently reserved for those who are in sinus rhythm, while AF patients are grouped under class IIa indications – reflecting a lower level of evidence in support of the treatment.

Fung, however, pointed to a recent paper from the Multicentre Longitudinal Observational Study (MILOS) group – the largest study so far to address the use of CRT in AF patients. After a median of 34 months following CRT, all-cause and cardiac mortality were similar between the 243 AF patients and the 1,042 sinus rhythm patients. [Eur Heart J 2008 Jul;29(13):1644-52]

Further support for these findings comes from a meta-analysis of 5 observational studies involving 1,164 patients, which showed that AF and sinus rhythm patients had similar mortality 1 year after CRT initiation. Improvements in New York Heart Association functional class were also comparable for the two groups. [J Am Coll Cardiol 2008 Oct 7;52(15):1239-46]

“It seems that sinus rhythm and AF patients behave similarly after receiving CRT,” Fung summarized. He noted that sinus rhythm patients appear to fare better on quality of life measurements, but said that this finding is “consistent with other heart failure studies which show that AF patients are much sicker than those who remain in sinus rhythm, no matter what therapies they receive.”

Besides the clinical benefits, CRT also seems to offer comparable improvements between the two patient groups when it comes to echocardiographic parameters, he added.

The jury is still out, however, on whether AF patients should undergo atrio-ventricular junction (AVJ) ablation alongside CRT, said Fung. The MILOS study found that ablation improved survival compared to CRT alone but other studies have produced inconsistent results, he said, cautioning that AVJ ablation renders patients device-dependent for the rest of their lives and should not be done unless necessary.

“I think we need a properly randomized study to try to ascertain the merits of ablation or pharmacological rate control and understand which one is really preferred in patients with heart failure and permanent AF,” he said.

“We should try to maximize drugs and sometimes maybe if there is a very low percentage of pacing you may ask the patient to undergo AVJ ablation. But looking in our database it seems that most of the patients are doing fine with more than 90 percent pacing just with drugs,” he concluded.

Healthcare technology saves lives, boosts care

Medical Tribune April 2009 SFI

David Brill

Adopting the latest healthcare information technologies can save lives, reduce complications and cut costs, a new report from 41 US hospitals shows.

It is one of the first studies to provide generalizable, empirical evidence that technology actually improves outcomes, the researchers say.

Inpatient mortality dropped by 15 percent in hospitals with the most highly automated notes and record systems. Complication rates were reduced by 16 percent in those with the highest levels of electronic decision support. [Arch Intern Med 2009;169:108-14]

Lead author Dr. Ruben Amarasingham, assistant professor of medicine at the University of Texas Southwestern Medical Center, said that the study “provides good news and caution” as governments worldwide debate healthcare stimulus packages.

The findings were welcomed in Singapore, where the upgrading of electronic systems across the healthcare clusters continues apace (inset).

Dr. Chong Yoke Sin, group chief information officer at SingHealth, said: “This study is reassuring for the people who invest in information technology for hospitals. There is now evidence to prove that it is indeed useful.”

Although happy with progress so far Chong stressed the importance of performing “meticulous” checks to ensure the integrity of new systems.

“When you use any kind of technology you have got to do it right, otherwise you are propagating the wrong faster and more pervasively. If a human being writes a wrong prescription you have only got that one wrong prescription, whereas if technology is not performing correctly it’s systemic,” she said. “At SingHealth we are always improving with constant feedback from clinical staff on the ground, which enables us to review workflow for better efficiency.”

Amarasingham agrees. “Our results suggest that investment in information technology is a necessary part to improving healthcare. But it’s clearly not sufficient – there needs to be a lot of other action taken.

“It has to be done carefully and thoughtfully over a prolonged period of time with careful outcome measures. If [investment] is not accompanied by a deliberative, strategic approach within hospitals and clinics then you may end up with worse systems, or at least a waste of money,” he said.

Over at the National Healthcare Group Mr. Ho Khai Leng, information technology director, said that new technology “improves care” by giving clinicians quicker and more accurate access to medical information. New systems also “facilitate the seamless transfer of patient information between care providers,” he said.

The digitization of x-rays has been particularly successful – cutting turnaround time from 2 or 3 days down to an hour or less, and saving “significant costs” for NHG and patients alike, he said. Tan Tock Seng Hospital alone saved $16,000 on films and chemicals between January and March 2006, following implementation of the project.

Amarasingham and colleagues reviewed data from 167,233 over-50s who were admitted to urban Texas hospitals between December 1 2005 and May 30 2006. They graded hospitals using the Clinical Information Technology Assessment Tool (CITAT), which measures the level of computerization in four clinical areas.

Average patient costs were reduced by US$538 ($816), US$132 ($200) and US$110 ($167) in hospitals with high scores on decision support, CPOE and test results, respectively. Costs were not significantly different within the notes and records domain.

Amarasingham acknowledged a “generational gap” with technology use, but said that all opinions must be considered when implementing new systems.

“If there are physicians who are reluctant or scared of using it then we need to reach out to them and involve them in the process. They are sometimes our best physicians with enormous experience that they can bring to the table,” he said.

Singapore center set to tackle childhood cancer in Asia

Medical Tribune April 2009 SFIV

David Brill

A new Singapore center could help raise childhood cancer survival rates across Asia, thanks to a recent $24 million funding boost.

The money will expand treatment facilities and strengthen research at the Viva-University Children’s Cancer Centre, which has already treated some 40 overseas children and begun training visiting specialists.

Around four out of five children with leukemia are cured in Singapore but in nearby countries this figure can be as low as one in 20.

“There is an urgent need for us to respond to the cries of children with cancer in Singapore and the whole region,” said Mrs. Jennifer Yeo, director and secretary of Singapore-based Viva Foundation for Children with Cancer.

“We are confident that with the support of all our donors, volunteers and strategic partners we can save many young lives,” she said.

The center, known as VUC3, has been operational for a year but was officially opened last month. Two specialists from the Philippines have already trained there, and one each from Myanmar and Brunei are currently in training.

The new funding comprises a $12 million gift from the Goh Foundation – a nonprofit private group – matched like-for-like by the Singapore government.

Four main research programs will be established, comprising bone marrow transplantation, childhood leukemia, bone cancer and ‘after completion of therapy,’ which focuses on the long-term impact of cancer treatment. This research will have a strong translational clinical focus with a view to raising cure rates, lowering treatment costs and minimizing side effects, said Associate Professor Allen Yeoh, medical director of VUC3.

“This will provide us with a quantum leap in the care of childhood cancer in Singapore, and help ensure that no child dies in the dawn of life. In the current severe recessionary climate, we are truly grateful to the Goh Foundation for their generosity,” said Yeoh, also a consultant at the University Children’s Medical Institute, National University Hospital, which houses VUC3.

Pediatric cancer survival is “dismal” in low-income countries, according to a study published last year. Five-year survival in the Philippines was estimated at 10 percent and in Vietnam just 5 percent. [Lancet Oncol 2008 Aug;9:721-9]

Between 120 and 140 new pediatric cancer cases are diagnosed in Singapore each year – some 40 percent of which are leukemia. Around 40 local children have been treated at VUC3 so far.

The center has already installed five new bone marrow transplant rooms and raised the number of inpatient beds from 12 to 17. The funding has also helped establish the Viva-Goh Foundation Professorship in Pediatric Oncology.

VUC3, built at a cost of $5 million from the Singapore Tote Board and Viva Foundation, is working closely with the St. Jude Children’s Research Hospital in Memphis, US – one of the world’s leading childhood cancer centers.

Statin-associated adverse events under-appreciated, experts say

Medical Tribune April 2009 P11

David Brill

The potential hazards of taking statins may be under-appreciated by the medical community, with adverse reactions often overlooked and sometimes even dismissed, according to US researchers.

Attention has largely focused on the most commonly-reported issue of muscle problems but the full side effect profile is wider than typically thought, they warn.

Cognitive problems are the second most common reaction to statins, followed by peripheral neuropathy-type symptoms, such as numbness and burning, said Dr. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego (UCSD).

Rarer reports have also linked statins to a range of other conditions including sexual dysfunction, glucose elevation and vision problems.

Golomb is head of the Statin Study Group at UCSD, which is currently conducting an observational study looking at the adverse effects of the drugs. She also recently co-authored a literature review which, with almost 900 references, she believes to be the most comprehensive look at the subject to date. [Am J Cardiovasc Drugs 2008;8(6):373-418]

“In clinical trials, adverse events look rare. But for those of us who see real-world patients they’re a really big problem,” she told Medical Tribune.

Golomb highlighted a French observational study reporting that 10.5 percent of patients experienced muscle symptoms, and a Danish population-based study which showed that current statin users had a roughly 16-fold increased risk of polyneuropathy compared to non-users. [Cardiovasc Drugs Ther 2005 Dec;19(6):403-14; Neurology 2002 May 14;58(9):1333-7] She noted, however, that adverse event rates vary between different studies and populations, making it difficult to provide definitive overall figures.

Meta-analyses, meanwhile, have yielded significant odds ratios of 1.4 and 1.44 for any adverse event on statins (the latter with intensive therapy), although both also recorded substantial clinical benefits. [Clin Ther 2006 Jan;28(1):26-35; Clin Ther 2007 Feb;29(2):253-60]

“I think there is a lack of awareness of these problems from physicians,” added Golomb, pointing to an earlier survey of 650 patients which found that doctors were “more likely to deny than affirm a connection” in cases of adverse statin reactions. [Drug Saf 2007;30(8):669-75]

“Even for patients who met literature criteria for probable or definite causality of their problems, the physicians denied the possibility of a connection about 50 percent of the time for each of the top three best known and most reported symptoms. And when we asked who initiated the conversation it was overwhelmingly the patients, even though it should be the physician who is aware of the connection of those specific symptoms to statins,” said Golomb.

Golomb believes that the most of the problems are class effects, and largely relate to the dose and potency of the statin rather than to any particular brand. Her literature review also notes that mitochondrial mechanisms are implicated in several adverse effects and proposes that this may be a common underlying factor behind a wide range of the problems.

She added that muscle problems occurring with statins are not always associated with a rise in creatine kinase levels, and that this can sometimes cause them to be overlooked.

Other academic authors have reached different conclusions about the risk profile of statins. The most recent such review paper in The Lancet, for example, concluded that statins are “a well-tolerated and extensively studied group of drugs.” [2007; 370:1781-90]

“With a few caveats, and while awaiting good-quality randomized data for the newer drugs, statins seem to be a remarkably safe group of drugs when used at their usual doses,” wrote Dr. Jane Armitage, of the University of Oxford, UK.

Golomb added, however, that the side effects reported so far could be just “the tip of the iceberg,” cautioning that even more problems could ultimately be shown to be related to statins.

“We’ve had reports from patients who have developed accelerated hearing loss or tinnitus with onset of statins. We don’t have data to demonstrate an association but that’s one of the domains in which I predict an association will likely be found in future,” she said.

Orbit of JUPITER extends to stroke prevention

Medical Tribune April 2009 P12
David Brill

The benefits of rosuvastatin for patients with elevated high sensitivity C-reactive protein (hsCRP) could include a reduction in the risk of stroke, according to new data from the JUPITER* trial.

The relative risk of any stroke was reduced by 48 percent among patients taking the drug, the study’s investigators reported recently at the International Stroke Conference in San Diego, US.

This finding appears to have been driven largely by a reduction in ischemic stroke rates – just 23 of the 8,901 patients in the treatment group experienced this outcome compared to 47 in the equally-sized placebo group (hazard ratio 0.49; P=0.004). Rates of hemorrhagic stroke, conversely, were not significantly different – six events occurred in the intervention group and nine in the placebo group (hazard ratio 0.67; P=0.44).

The new stroke data bring fresh fuel to the debate about the role of hsCRP in risk stratification and the use of statins for primary prevention – questions that have risen to prominence since the presentation of the original JUPITER study at the American Heart Association’s annual Scientific Sessions in November last year. [N Engl J Med 2008 Nov 20;359(21):2195-207]

“The bottom line is that we now have conclusive evidence for the efficacy of statins specifically for primary prevention of stroke,” said Dr. Robert Glynn of Brigham and Women’s Hospital in Boston, US, one of the JUPITER investigators who presented the latest findings.

LDL cholesterol is not typically considered as a risk factor for stroke in patients without established vascular disease, said Glynn, noting that CRP, however, has been shown to be a valid predictor of stroke risk. Statin therapy, which lowers levels of both biomarkers, could therefore be particularly beneficial for stroke prevention in patients with elevated CRP, he added.

The ARIC** study implicated hsCRP as a risk marker for stroke. The study, which involved 12,762 middle-aged men and women followed up for around 6 years, showed that those with an hsCRP level above 3 mg/L had an adjusted hazard ratio for ischemic stroke of 2.7 when compared to those with an hsCRP level below 1 mg/L. [Arch Intern Med 2005 Nov 28;165(21):2479-84]

The SPARCL*** study, meanwhile, demonstrated the benefits of atorvastatin (80 mg daily) for secondary stroke prevention in a population of 4,731 patients with a recent history of stroke or transient ischemic attack. After a median follow up of 4.9 years, overall stroke risk was reduced by 16 percent in the statin group compared to placebo (adjusted hazard ratio 0.84; P=0.03) with comparable mortality between the two groups. There was, however, an increase in the number of hemorrhagic strokes: 55 events occurred in the atorvastatin group and 33 in the placebo group. [N Engl J Med 2006 Aug 10;355(6):549-59]

The original JUPITER trial found that after a median of 1.9 years of follow up rosuvastatin (20 mg daily), as compared to placebo, reduced the relative risk of major cardiovascular events by 44 percent in a cohort of 17,802 overtly healthy subjects with baseline hsCRP levels above 2 mg/L and LDL cholesterol levels below 130 mg/dL (hazard ratio 0.56; P<0.00001). Over the course of the study hsCRP levels were reduced by 37 percent and LDL cholesterol levels by 50 percent. *JUPITER: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin **ARIC: Atherosclerosis Risk in Communities *** SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels