Medical Tribune February 2012 HK

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February 2012
Autumn in Kyoto 53rd Annual Meetng of
the American Society of
Hematology
Management of CHF in
primary care
Some contraceptves may
exacerbate seizures
AFTER HOURS
IN PRACTICE
CONFERENCE
CONTRACEPTION
Protectng our children from
HIV
FORUM
Thalassemia study: Severe
iron overload common in
South China
HONG KONG FOCUS
Early antiretroviral treatment cuts HIV transmission
2
February 2012
Early antiretroviral treatment cuts HIV
transmission
Rajesh Kumar
P
eople infected with human immu-
nodefciency virus (HIV) are 96 per-
cent less likely to transmit the disease to
their healthy partners if they start taking
antretroviral drugs (ARVs) early, accord-
ing to a study hailed as a scientfc break-
through of 2011.
The fndings end a long-standing debate
over whether ARVs can provide a double
beneft by treatng the virus in individual
patents while simultaneously cutng
transmission rates, said researchers from
the University of North Carolinas school
of medicine in Chapel Hill, North Carolina,
US. [N Engl J Med 2011; 365:493-505]
The HPTN* 052 study enrolled 1,763
heterosexual couples in 2007 from Brazil,
India, Thailand, the US, Botswana, Kenya,
Malawi, South Africa and Zimbabwe. Each
partcipatng couple included one HIV-
positve partner.
Half of the HIV-positve individuals
were put on ARVs immediately while the
other half were made to wait untl their
CD4 counts fell below 250 indicatve
of severe immune damage before
A US trial suggests that ARVs not only treat HIV infection, they also reduce transmission rates.
3
February 2012
ofering treatment to see if this made any
diference in HIV transmission to healthy
partners or to HIV-related clinical events
in HIV-positve group.
In early 2011, 39 HIV transmissions
to healthy partners were observed (inci-
dence rate, 1.2 per 100 person-years;
95% confdence interval [CI], 0.9 to 1.7),
of which 28 were virologically linked to
the infected partner (incidence rate,
0.9 per 100 person-years, 95% CI, 0.6 to
1.3). Of the 28 linked transmissions, only
one occurred in the early-therapy group
(hazard rato, 0.04; 95% CI, 0.01 to 0.27;
P<0.001).
Also, 105 partcipants had at least one
HIV-related clinical event: 40 of them in
the early-therapy group and 65 in the
delayed-therapy group, a reducton of
nearly 40 percent. Extra-pulmonary tuber-
culosis dominated the clinical events, with
three cases in the early therapy group
versus 17 cases in the other.
Seeing these results, an independent
monitoring board decided all study par-
tcipants should be given ARVs 4 years
before the studys closure. The board also
recommended that the trials fndings be
made public as soon as possible.
Professor Roy Chan, head of Singapores
natonal sexually transmited infectons
control program, called it an important
study for Asia and the rest of the world
due to its signifcance for the war on HIV/
AIDS.
Treatment with ARVs is already known
to reduce the viral load in an infected indi-
vidual. Many HIV/AIDS researchers had
reasoned that treated individuals should
also be less infectous. But skeptcs con-
tended that such a theory was unproven
and that the viral load might not refect
levels of virus in genital secretons.
The new studys fndings help promote
ongoing treatment of HIV to reduce viral
loads in communites and could possibly
eliminate HIV/AIDS epidemics in some
countries, said the researchers.
But ARV therapy is by no means a
magic bullet for controlling or ending
the HIV epidemic, said Dr. Scot Hammer
from the division of infectous diseases at
Columbia University Medical Center, New
YorkPresbyterian Hospital, New York,
US, in an accompanying editorial. [N Engl
J Med 2011; 365:561-562]
Adverse events, emergence of drug-
resistant viral strains, maintenance of
adherence, sustainability, and cost are
just some of the concerns, said Hammer.
However, this is precisely the wrong
tme to limit access to antretroviral ther-
apy in resource-limited setngs, since
we have the tools in hand to maintain or
restore health in infected persons and
reduce transmission to their sexual part-
ners, he said.
Dr. James D. Shelton of the US Agency
for Internatonal Development (USAID)s
bureau for global health, in another com-
ment, said ARV resistance mutatons are
already found in untreated patents and
providing ARVs on a more massive scale
for many years opens the doors for more
resistance, especially when use would
be long and adherence possibly lower.
[Science 2011; 334:1645-1646]
ARVs as preventon must not jeopardize
already precariously low funding for com-
plementary preventon interventons such
as male circumcision, condoms and behav-
ior change, said Shelton.
* HPTN: HIV Preventon Trials Network

because your patient's
long-term mental health matters
Higher CPE ranks are
strongly associated
with lower prevalence
of HAND
1
KALETRA has effective
CNS penetration and
viral load reduction
1-5
Without disturbing CNS
side-effects
Good toIerabiIity proIe
6-8
Can be co-prescribed with
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*Please see full prescribing information for potential drug interactions
More information is available upon request
CNS, central nervous system; CPE, CNS penetration-effectiveness; HAND, HIV-associated neurocognitive disorders
References
1. Starace F, et al. Presented at: The 17th Conference on Retroviruses and Opportunistic Infections 2010; February 1619, 2010; San Francisco, California. Poster 433.
2. Letendre S, et al. Top HIV Med 2010;18:45-55. 3. Letendre S, et al. Arch Neurol 2008;65:65-70. 4. Capparelli EV, et al. AIDS 2005;19:949-952. 5. Letendre SL, et al.
Clin Infect Dis 2007;45:1511-1517. 6. Sustiva. Summary of Product Characteristics. Available at: http://www.medicines.org.uk/EMC/medicine/11284/SPC/Sustiva+600+
mg+Film-Coated+Tablets/. Accessed 7 February 2011. 7. Kaletra. Summary of Product Characteristics. Available at: http://www.medicines.org.uk/EMC/medicine/
18442/SPC/Kalotra+200+mg+50+mg+hlm-ooatod+tablots/. Aooossod 31 Maron 2011. 8. Sprinz E, et al. HIV Clin Trials 2006;7:291-308. 6
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5
February 2012 For um
Protecting our children from HIV
W
orld AIDS Day is a day of remembrance,
and 2011 was more somber and less
hopeful than I would have predicted.
Although the latest progress report on
the global HIV/AIDS response shows that
the incidence of HIV contnues to decline
and fewer people are dying from AIDS-
related causes, new money for the cause is
drying up.
Following the recent cancellaton of the
11th funding round by the Global Fund to
fght AIDS, Tuberculosis and Malaria due
to a lack of donor country support, chil-
dren living with HIV across Asia and Africa
will be amongst those hardest hit as sup-
port for preventon of mother-to-child HIV
transmission programs and pediatric drug
formulatons will be ratoned even further.
The fund is one of the largest fnancial
supporters of programs ofering educaton,
support and treatment to those living with
HIV and AIDS. However, underfunding has
led to the replacement of round 11 with a
transitonal funding mechanism to provide
just enough for the contnuaton of essen-
tal preventon, treatment and care ser-
vices of the three diseases.
There are critcal programs around the
world that were relying on the opportu-
nity to apply for round 11 funding. Without
the opportunity to apply to round 11, crit-
cal HIV programs around the world will be
forced to make painful choices to sacrifce
actvites or close their doors. The overall
consequence will be to end access to life-
saving treatment for some of the poorest
among us. Afer achieving so much as a
global community to improve HIV treat-
ment coverage, preventon, educaton, and
community mobilizaton, funding cuts pose
a real risk of taking us back to a disastrous
situaton.
We do need to become more strategic in
our investments and more efcient in how
we implement programs, but this is the
wrong tme to slow down.
Asian children and HIV
The pediatric HIV epidemic in Asia faces
new challenges that are in some sense a
consequence of having earlier access to
antretroviral drugs. Children born with HIV
in places like Thailand were given treatment
early on in the epidemic, before we had
potent triple-drug regimens. This kept them
Dr. Annete Sohn, Director, TREAT Asia (Therapeutcs Research, Educaton and AIDS
Training in Asia), The Foundaton for AIDS Research, Bangkok, Thailand.
6
February 2012 For um
alive, but has led to fewer optons to man-
age their increasingly resistant HIV virus.
Being born with HIV infecton afects
the immune and other organ systems of
the body diferently from someone who
acquires infecton as an adult. The conse-
quences of this are apparently early on in
life in terms of brain development and later
in life in terms of bone and cardiovascular
toxicites. We do not fully appreciate what
it means to grow up with HIV and have to
deal with the virus for a lifetme.
We now have a growing cohort of older
adolescents. Within the TREAT Asia cohort
(a network of pediatric clinical sites in low
to middle income countries in SE Asia and
India), about 40 percent of the children
are already 12 years or older. These HIV-
positve adolescents, who have had the
virus all their lives, present a range of clini-
cal management challenges. At a tme when
they are growing up, trying to explore the
world and fnd a way for themselves within
it, they are also dealing with HIV and related
health problems, medicaton adherence,
drug resistance, and frequently doing this
as orphans.
Beter diagnosis needed
We also need to beter identfy the chil-
dren who have HIV infecton, because we
dont really know the true incidence of HIV
among children in Asia. That our preventon
of mother-to-child transmission program
coverage is worse than sub-Saharan Africa
should be a cause for shame among the
countries of the region, and too few infants
can access the PCR testng needed to diag-
nose HIV.
Children do not know whether they have
HIV or not. They cannot complain. They rely
on adults around them to take care of them,
to diagnose their illnesses. If we are able to
diagnose them early on and start them on
antretroviral drugs, they will survive and
hope to live to adulthood.
As we watch HIV funding shrinking more
and more, I wonder how it is that we are
able to spend so much on saving ques-
tonable elements of our fnancial systems
and so litle on saving the lives of our worlds
children.
Mother-child HIV transmission can be reduced
A
ntretroviral drugs may prevent
mother-to-child HIV transmission by
about 50 percent if they are administered
within the frst 6 months of life or untl
breasteeding stops.
South African researchers adminis-
tered the antretroviral drug nevirapine
once daily to 1,527 infants at risk for HIV
transmission for 6 weeks, as is standard
practce. Infants were randomized to con-
tnue receiving nevirapine or a placebo
for up to 6 months or untl they stopped
breasteeding. [Lancet 2011. DOI:10.1016/
S0140-6736(11)61653-X]
The trial showed that 1.1 percent of
infants randomized to receive nevirapine
became HIV-positve between the ages of
6 weeks and 6 months compared with 2.4
percent of those receiving placebo a 54
percent transmission reducton. Mortality
was comparable between the two groups,
1.2 percent in the nevirapine group and
1.1 percent in the placebo group, as was
the frequency of adverse events.
7
February 2012 Hong Kong Focus
Thalassemia study: Severe iron overload
common in South China
Christna Lau
I
ron overload in the heart, liver, pan-
creas and pituitary is a serious problem
among patents with thalassemia major
(TM) in South China, according to a recent
study by the Chinese University of Hong
Kong (CUHK).
Of the 153 TM patents we scanned,
nearly a quarter had severe cardiac
iron overload, putng them at immedi-
ate risk of death, said Professor Winnie
Chu of CUHKs Department of Imaging
and Interventonal Radiology at a press
conference. The youngest patent with
severe cardiac iron overload was only 9
years old.
In 2010, Chu and colleagues provided
free MRI assessments to 153 young TM
patents (median age, 13 years) from six
hospitals in Shenzhen, Guangzhou and
Nanning to investgate the prevalence
and severity of iron overload in various
organs.
Results showed that 36 percent of
TM patents had cardiac iron overload,
as measured by a T2* value below 20 ms.
Severe cardiac iron overload [T2* <10 ms]
was found in 24 percent of the patents,
reported Chu.
Iron overload was also prevalent in the
liver (95 percent), pancreas (85 percent)
and pituitary (23 percent). In the cohort,
55 percent of patents had severe hepatc
iron overload, as measured by a T2* value
<1.4 ms.
South China is home to the worlds
largest TM populaton, where the number
of patents is estmated to exceed a mil-
lion. However, blood transfusion and iron
chelaton therapy are not widely avail-
able in the region, and MRI assessment
for iron overload is unavailable, said
Chu. A high percentage of undiagnosed
iron overload means that ratonal iron
chelaton strategies cannot be imple-
mented. If the iron overload is not cor-
rected, premature cardiac failure and
death is inevitable in those patents in
5 to 10 years.
Based on the experience in Hong
Kong, Chu said those premature deaths
can be prevented by early MRI scan-
ning and subsequent triage of treat-
ment. A structured MRI program will
be useful and cost-efectve for chil-
dren and teenagers with TM in China.
The MRI data will help mainland col-
leagues risk-stratfy TM cases by iron load,
so that treatment of proper intensity can
be provided, she suggested.
In Hong Kong, the crude incidence
of death in TM patents has declined
8
steadily since cardiac iron assessment by
T2* MRI became available in 2006. In the
past, cardiac iron overload was the main
cause of death in TM patents, with few
surviving beyond the age of 45 years,
said Dr. Chi-Kong Li of the Department
of Pediatrics, Prince of Wales Hospital.
With T2* MRI assessment to direct iron
chelaton therapy, the prevalence of
heart failure and cardiac hemosiderosis is
reduced, which should reduce mortality
and improve life expectancy. Today, 78
percent of TM patents in Hong Kong are
in their adulthood. [Hong Kong Med J
2011;17:261-266]
With support from the Childrens
Thalassemia Foundaton, cardiac iron
assessment by T2* MRI has become avail-
able to all thalassemia patents in Hong
Kong since 2006. The MRI scanner at
CUHK is the only scanner validated for T2*
assessment in Hong Kong, said Chu.
Aerobic exercise improves cognition in early
psychosis
Christna Lau
A
erobic exercise improves learning ability
and long-term memory of patents with
early psychosis, a study by the University of
Hong Kong (HKU) has shown.
The study included 35 patents with early
psychosis who were randomized to receive a
12-week exercise interventon in additon to
their current treatment or to contnue with
their current treatment for 12 weeks. The
exercise interventon consists of three ses-
sions of aerobic exercise training (walking on
a treadmill plus statonary cycling) per week,
with each session lastng 40 to 50 minutes.
Preliminary results showed that patents
receiving exercise interventon had signif-
cantly improved verbal acquisiton and long-
term memory, as assessed by the Hong Kong
List Learning Test, said principal investgator
Professor Eric Chen of the Department of
Psychiatry. Afer the 12-week study period,
patents in the exercise group had a 26 per-
cent increase in mean score in the learning
test [from 23.8 at baseline to 30] and a 27
percent increase in mean score in the mem-
ory test [from 8.8 to 11.2], vs increases of 6
percent and 8 percent, respectvely, in the
control group.
The mean scores in healthy individu-
als are 36 and 13.4, respectvely, for verbal
acquisiton and long-term memory.
According to Chen, the preliminary data
indicate that aerobic exercise can reverse
some cognitve defcits in early psychosis.
The cognitve improvement associated with
aerobic exercise may be mediated by neural
plastcity in the brain, he suggested. Based
on the study, we developed a series of exer-
cise named FitMind movements in collabo-
raton with the Hong Kong Early Psychosis
Interventon Society. The exercise is designed
according to the specifc needs and ability of
psychosis patents.
A series of actvites, including publicity
campaigns and an exercise coaching sys-
tem, will be organized in the coming months
to promote exercise and motvate patents
with early psychosis. (htp://www.episo.org/
FitMind.html)

10
Candidate driver genes identified in gastric
cancer
Naomi Rodrig
A
team of researchers from the
University of Hong Kong and Pfzer
Inc. discovered 20 gene mutatons impli-
cated in stomach cancer. [Nature Genetcs
2011;43:1219-1223] According to the
investgators, this research could lead to
the development of new drugs and test-
ing of existng drugs that may be used to
treat this cancer.
Previous studies showed that apart
from mutatons in the TP53 gene, altera-
tons in other genes or pathways account
for only small subsets of gastric cancer.
The majority of cancer-causing muta-
tons occur in exons, regions that con-
sttute about 2 percent of the human
genome and are responsible for protein
synthesis, explained lead investgator
Professor Suet-Yi Leung.
Using exome sequencing a technol-
ogy that can signifcantly speed up the
sequencing process the team analyzed
over 160,000 exons in 22 stomach cancer
samples and in normal controls.
We identfed previously unreported
mutated genes and pathway alteratons;
in partcular, we found genes involved in
chromatn modifcaton to be commonly
mutated, the investgators reported.
Specifcally, a downstream validaton
study confrmed frequent inactvatng
mutatons in the ARID1A gene, which
encodes a member of the SWI-SNF chro-
matn remodeling family. These muta-
tons were found in 83 percent of gastric
cancers with microsatellite instability, 73
percent of those with Epstein-Barr virus
(EBV) infecton and 11 percent of those
that were not infected with EBV and
microsatellite stable.
Chromatn, which functons to support
the delicate DNA strand and compact
its volume to ft in the cell, also controls
DNA replicaton and gene expression.
Chromatn modifcaton genes consttute
an emerging group of cancer driver genes
with lots of interest by the pharmaceut-
cal industry to pursue as drug targets,
said Leung. New drugs that change the
chromatn architecture are being devel-
oped. Other such drugs have been previ-
ously intended for the treatment of other
diseases. With our fndings of frequent
mutatons of the chromatn modifcaton
genes in stomach cancer, these drugs may
now be explored to treat it.
The data also showed that the muta-
ton spectrum for ARID1A difers between
molecular subtypes of gastric cancer, and
mutaton prevalence is negatvely asso-
ciated with mutatons in TP53. Clinically,
ARID1A alteratons were associated
with beter prognosis in a stage-inde-
pendent manner. These results reveal
the genomic landscape, and highlight
the importance of chromatn remod-
eling, in the molecular taxonomy of
gastric cancer, wrote the authors.
Deciphering all the mutatons asso-
ciated with gastric cancer improves our
understanding of how this cancer devel-
ops and may provide ways for early detec-
ton and personalized treatment, added
Leung.
11
Intracranial stenting prevents stroke in
high-risk patients
Christna Lau
I
ntracranial stentng may ofer hope for
patents with severe intracranial steno-
sis who have symptomatc minor ischemic
stroke or TIA despite medical therapy. A
study by the Chinese University of Hong
Kong (CUHK) showed that the procedure is
safe and efectve for stroke preventon in
these patents.
For patents with severe intracranial
stenosis of over 70 percent, the annual
risk of stroke is high at 23 percent despite
medical therapy, said Professor Simon
Yu of the Department of Imaging and
Interventonal Radiology. Bypass sur-
gery is feasible in only 20 percent of
cases, and its not beter than medical
therapy in stroke preventon.
In 2006, Yu and colleagues from the
Vascular and Interventonal Radiology
Foundaton Clinical Science Center and
the Division of Neurology started evalu-
atng the safety and efectveness of the
Wingspan intracranial stent (Boston
Scientfc) for stroke preventon in patents
with severe intracranial stenosis (70
percent) who presented with sympto-
matc ischemic stroke or TIA despite drug
therapy.
We need local data because the etol-
ogy of ischemic stroke in Asians is difer-
ent from that in Caucasians, said Yu. In
Asians, intracranial stenosis accounts for
30 to 40 percent of ischemic stroke cases,
whereas in Caucasians this accounts for
only 8 to 10 percent of cases.
In the study, 93 patents (male, n=69;
female, n=24) aged 34 to 84 years received
intracranial stentng with the Wingspan
stent and were followed up for an average
of 36 months.
The success rate of the stentng pro-
cedure was 95.7 percent, reported Yu.
As for safety, the rate of death or stroke
within 30 days of the procedure was 5.4
percent, compared with 9.6 percent in
internatonal studies.
Importantly, the risk of stroke afer
intracranial stentng was 6.1 percent per
year much lower than the annual rate of
23 percent in patents treated with drug
therapy alone.
At 12 months, the rate of in-stent reste-
nosis was 13.6 percent, indicatng that the
intracranial stent kept blood vessels open
and blood supply normal in 86.4 percent
of patents, said Yu. Our study shows
that intracranial stentng with Wingspan is
safe and efectve for stroke preventon in
high-risk patents. The risk associated with
the procedure is stll relatvely much more
acceptable compared with the annual
stroke risk if these patents are treated
with medical therapy alone.
Based on these fndings, the researchers
recommended that patents at high risk of
12
ischemic stroke should consider intracra-
nial stentng for stroke preventon. These
patents should be referred to experienced
centers for treatment as the procedure is
stll risky and its safety is closely related
to the experience of the operatng team,
said Yu.
Furthermore, the government should
consider subsidizing the treatment cost,
he contnued. Currently, patents in most
public hospitals have to bear the cost of
the stent and related consumables, which
amounts to HKD 45,000. Successful preven-
ton of stroke will allow signifcant saving
of resources in hospitalizaton, rehabilita-
ton and disability care.
Free AMD drug for needy patients
Christna Lau
T
he Hospital Authority (HA) will launch a
3-year program in February to provide
needy patents sufering from neovascular
age-related macular degeneraton (AMD)
with the drug ranibizumab, which was previ-
ously prescribed as a self-fnanced item.
Eligible for the program are patents with
visual impairment of one eye matching pre-
defned clinical criteria and the other eye
with neovascular AMD, and recipients of
Comprehensive Social Security Assistance
with neovascular AMD in one eye. These
patents will enter the special program for 2
years, and receive ranibizumab injectons at
designated ophthalmology centers.
According to a HA press release, the pro-
gram will provide treatment for 250 patent-
eyes a year. During the treatment period,
each patent or each eye is enttled to a maxi-
mum of 10 ranibizumab injectons, including
three inital injectons and as clinically indi-
cated thereafer. The HA will provide the frst
three injectons for each recruited eye, while
Novarts will provide the remaining injec-
tons for clinically indicated patents.
Although ranibizumab was US FDA-
approved in 2006, there is no consensus
regarding the frequency and duraton of
injectons in long-term treatment. In addi-
ton, its long-term efcacy in treatng wet
AMD requires the accumulaton of more
established clinical data, said HA Director
(Cluster Services), Dr. Wai-Lun Cheung.
Ranibizumab is licensed in Hong Kong for
treatment of neovascular AMD. However,
its high cost makes it inaccessible for some
patents. While 70 percent of ophthalmolo-
gists in Hong Kong and the US reported using
bevacizumab as a lower-cost alternatve, such
use is of-label since bevacizumab is not for-
mulated for intraocular injecton. [American
Society of Retna Specialists and College of
Ophthalmologists of Hong Kong surveys; N
Engl J Med 2006;355:1409-1412]
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14
Targeting LDL-C may curb Asias CVD epidemic
Naomi Rodrig
T
o control the upward trend in cardio-
vascular disease (CVD) in Asia, doc-
tors in the region should focus on more
aggressive lowering of low-density lipo-
protein-cholesterol (LDL-C), which is a
well-recognized and easily treatable risk
factor, advised Dr. David Waters, Emeritus
Professor of Medicine at the University of
California at San Francisco, USA.
The big change in paradigm is that a
lot of physicians regard statns as drugs
to treat high cholesterol, but I would
urge them to think of statns as drugs to
treat total CV risk. Even for people with
normal cholesterol but other CV risk fac-
tors such as smoking, overweight, diabe-
tes or hypertension, reducing their LDL-C
levels cuts their CV risk, said Waters,
who addressed the Pfzer-sponsored Asia
CardioCare Summit held recently in Hong
Kong. When we think about risk reduc-
ton, we want to treat a lot more people
with statns than we would have if it was
just about the LDL-C.
For example, the Anglo-Scandinavian
Cardiac Outcomes Trial-Lipid Lowering Arm
(ASCOT-LLA) has shown that lowering LDL-C
in hypertensive patents reduced their risk
of death from heart disease and stroke by
36 and 26 percent, respectvely. [Drugs
2004;64:43-60] In diabetcs, the CARDS
study [Collaboratve Atorvastatn Diabetes
Study] demonstrated a 37 percent reduc-
ton in major cardiovascular events and a
48 percent reducton in stroke, he added.
Importantly, treatng hypertension or dia-
betes to target is much more challenging
than treatng LDL-C.
He atributed the Asian CVD epidemic
to greater prosperity and changing lifestyle
paterns that lead to obesity and diabetes.
One of the problems is that Asians develop
diabetes before Caucasians will develop it
for the same level of obesity. Its predicted
that between 2000 and 2030, the number
of people with diabetes in Southeast Asia
is going to increase from 22 to 158 million.
Given that 70 to 80 percent of people with
diabetes will eventually die from CVD, its
not difcult to foresee that the focus on
CVD will shif to Asia, partcularly China and
India, he told Medical Tribune.
According to WHO data, CVD causes
some 3.6 million deaths each year in
Southeast Asia. Furthermore, younger
people are afected, with 27 percent of all
CVD deaths in this region occurring in peo-
ple <60 years old.
Waters also stressed the role of public
educaton in reducing CV risk by healthy
lifestyle choices. Theres an opportu-
nity in Asia to provide more educaton to
15
people so that they can make their own
choices, he said. Secondly, we need to
educate the physicians that CVD is really
an epidemic, and that preventon on an
individual patent level and beter treat-
ment is important.
Physicians can treat LDL-C more aggres-
sively and earlier, he suggested. The
guidelines in most countries suggest tailor-
ing the statn dose to the level of risk, so
that somebody with a higher risk should
get a higher dose to reach the target level. I
personally think that if youre going to treat
and youve got a statn thats well tolerated
at higher doses, why not give a high dose
and lower the risk a lot?
While statn treatment has been associ-
ated with side efects such as liver enzyme
elevatons and muscle damage, according to
Waters these are uncommon. For instance,
increased liver enzymes were detected in
only 1.43 percent of 18,000 clinical trial
subjects who took the highest dose of ator-
vastatn for up to 5 years. Only four patents
had elevated CPK [creatne phosphokinase]
levels indicatve of serious muscle damage,
he noted.
As for treatment cost, the patents for
several statns will expire in the next few
years, making treatment more afordable.
Personally I think its a good thing that
branded statns are losing their exclusiv-
ity. Asian countries are fast developing and
getng more prosperous, and there are
lots of wealthy people in the region, he
remarked.In general, we need to assess
the individual patents risk and the beneft
they would get from statn treatment in
terms of reducing CV morbidity, and then
see how they can aford it.
BBiomedSc program at HKU
Naomi Rodrig
S
tartng in the academic year 2012-2013,
the University of Hong Kong (HKU) will
launch a new undergraduate program,
awarding a degree of Bachelor of Biomedical
Sciences (BBiomed Sc).
According to Dr. Mai-Har Sham, who is
Head of the Department of Biochemistry
and one of the programs leaders, the ini-
tatve was designed to meet the growing
demand for well-trained biomedical scien-
tsts antcipated in the near future.
The undergraduate curriculum will be
based on three interlinking areas that form
the biomedical sciences: understanding life
sciences and health; understanding dis-
ease mechanisms; and the applicaton of
technologies in biomedicine, she explained.
Students will be able to choose from a
wide selecton of basic science courses,
including courses in cutng-edge areas such
as stem-cell biology and regeneratve medi-
cine, genomic science, cancer biology and
neuroscience. In additon, practcal courses
on healthcare fnancing and policy, and epi-
demiology, will be on ofer to provide stu-
dents with a compettve edge in the real
world.
While some of the BBiomedSc graduates
may contnue with basic research or pursue
higher academic degrees, it is expected that
the majority will join the commercial or pub-
lic sectors to apply their skills in the health-
care services, pharmaceutcal industry and
medical technology.
16
Restoring vision to more Chinese patients
Christna Lau
L
ow-cost cataract surgery will be avail-
able to more patents in China this year
as a charitable organizaton in Hong Kong
expands their services to more provinces
across the country.
We will start providing low-cost cata-
ract surgery to patents in Gansu and Henan
Provinces in the frst quarter this year.
Surgery will be free for the poor, said Dr.
Dennis Lam, Chairman of the Project Vision
Charitable Foundaton. We are currently in
talks with authorites in Guangxi, Guizhou
and Shanxi Provinces, and hope to expand
our services to 10 more provinces in 2012
and 2013.
In support of the WHOs VISION 2020
global initatve to eliminate avoidable
blindness by 2020, Project Vision plans to
establish 100 charity eye centers across
China by 2020. This will enable the organi-
zaton to train 1,000 mainland doctors for
cataract surgery and perform 1 million
operatons.
This goal is of to a good start in 2012. In
the frst 10 days of the year alone, Project
Vision has already raised more than HKD 5
million to support its work.
Social life and drinking may help preserve
cognitive function
Christna Lau
A
ctve partcipaton in cognitve leisure
actvites and moderate drinking may
help preserve cognitve functon in late
life, as a local study found that they are
associated with beter cognitve functon
in elderly persons.
According to the authors, the fndings
illustrate the importance of a mult-faceted
lifestyle as a potental strategy for prevent-
ing dementa. [East Asian Arch Psychiatry
2011;21:152-156]
The 2-year prospectve study included 476
cognitvely healthy community-dwelling
individuals aged 60 to 92 years. Researchers
from the Department of Psychiatry,
Chinese University of Hong Kong (CUHK)
and Tai Po Hospital assessed them using
a batery of cognitve tests and queston-
naires on their leisure actvites and sense
of loneliness.
Results showed that a high level of cog-
nitve actvity partcipaton and a low level
of loneliness were associated with beter
cognitve test performance.
17
In multvariate logistc regression anal-
yses, high cognitve functon was sig-
nifcantly associated with more years of
educaton (odds rato [OR]=1.27), a higher
frequency of alcohol drinking (OR=1.17),
and lower levels of overall loneliness
(OR=0.79).
The subjects reported in this study were
primarily social drinkers who consumed
in moderaton. The majority drank only a
few tmes per month, wrote the authors.
Recent studies supported some gains in
terms cogniton from moderate drink-
ing. However, many of these studies were
inconclusive, as they depended on cross-
sectonal surveys based on self-reportng.
While the current study suggests
that actve and frequent partcipaton in
cognitve actvites, accompanied by physi-
cal actvites, may be related to sustainment
of high intellectual functon into old age, the
authors noted that further studies should
explore interactons between social factors
and cognitve ability in older adults without
signifcant cognitve impairment.
www.neuropainhk.org
Get the latest recommendations on the diagnosis and treatment of
various neuropathic pain states from the rst Hong Kong Web site
dedicated to education on neuropathic pain.
19
Case Study
An elderly patient with severe rheumatoid
arthritis treated with tocilizumab
Dr. Ronald Man-Lung Yip
Specialist in Rheumatology
Associate Consultant
Department of Medicine and Geriatrics
Kwong Wah Hospital
Hong Kong
Case history
A 71-year-old lady with a history of mild
pulmonary fbrosis presented with severe
symmetrical polyarthrits since 2008. She
had positve rheumatoid factor and a high
tter of ant-cyclic citrullinated protein (ant-
CCP) antbody, and was diagnosed to have
rheumatoid arthrits (RA).
She had been treated with combinatons
of several disease modifying ant-rheumatc
drugs (DMARDs), including sulphasalazine,
azathioprine, hydroxychloroquine and meth-
otrexate. However, these treatments were
inefectve and she contnued to have mult-
ple tender and swollen joints.
In 2009, she was put on prednisolone up
to 7.5 mg daily and lefunomide 20 mg daily,
but her disease actvity remained high. Her
erythrocyte sedimentaton rate (ESR) was
90 mm/hr, C-reactve protein (CRP) was 60
mg/L, and disease actvity score (DAS 28)
was up to 6.6. Bony erosions over carpal
bones were already present afer 1 year since
diagnosis, despite treatment with DMARDs.
She had to stop most of her actvity, includ-
ing basic household work, and had to rely
on hypnotcs for sleep due to the pain and
mood disturbance.
Treatment
She was started on a combinaton of toci-
lizumab (8 mg/kg monthly infusion) and
methotrexate in June 2010. Her disease
actvity rapidly improved afer the frst infu-
sion, with the DAS 28 score dropping from
6.6 to 4.1. Normalizaton of ESR and CRP
was notced afer 2 months. DAS 28 dropped
down to 1.82 afer 18 months of treatment.
Serial CXRs did not show any progression of
the pulmonary fbrosis, and the patent has
not sufered from any signifcant side efects.
She resumed her usual actvity and work as a
part-tme cleaner. Hypnotcs were no longer
required.
Discussion
RA is a chronic disease that results in severe
pain and disability. It is common among the
elderly, and approximately one third of RA
patents are >65 years at onset.
1
Elderly RA patents may also sufer from
intense joint pain, which warrants treat-
ment similar to that for younger adults.
Carpal bone erosions over wrists and small hand
joints in the patient
20
However, older patents are less likely to
receive DMARDs or biologic therapy when
compared with younger patents.
2
This
has been atributed to concerns about
the side efects of the drugs and the lack
of efcacy in older subjects due to their
concomitant comorbidites and drug
interactons.
Biologic therapy is a breakthrough
in treatment of RA. Previous studies
have shown that biologics such as ant-
tumor necrosis factor (ant-TNF) thera-
pies are as efectve and tolerable in older
persons as in younger patents.
3

Tocilizumab is a recombinant monoclonal
antbody against the interleukin (IL)-6 recep-
tor. It binds to both soluble and membrane-
expressed IL-6 receptors selectvely and
compettvely, thus damping down the pro-
infammatory actvites mediated by IL-6.
In the OPTION trial (Efect of Interleukin-6
Receptor Inhibiton with Tocilizumab in
Patents with RA), patents who had inad-
equate response to methotrexate were
randomized to receive a combinaton of
tocilizumab and methotrexate or placebo
plus methotrexate. The ACR response was
superior in the tocilizumab group vs pla-
cebo (ACR 20 response, 59 vs 26 percent;
p<0.001). DAS 28 < 2.6 was reported in 27
percent of patents receiving tocilizumab vs
0.8 percent in the placebo group.
4

In the TOWARD trial (Tocilizumab in
Combinaton with Traditonal DMARD
Therapy), patents on stable doses of
DMARDs with poor response and high dis-
ease actvity were randomized to receive
tocilizumab or placebo on top of the current
treatment. The data also showed a more
favorable response with tocilizumab (DAS 28
<2.6, 30.0 vs 3.0 percent).
5
A subgroup analysis of the pooled results
of these two trials that compared the efec-
tveness of tocilizumab vs control in elderly
subjects (>65 years ) vs younger subjects
(<65 years) showed statstcally signifcant
and similar improvements with tocilizumab
in ACR response, DAS 28 score and other
outcome measures compared with controls
in both older and younger individuals. Some
30 percent of elderly patents can actually
achieve disease remission (defned as DAS
28 <2.6) afer 24 weeks of treatment with
tocilizumab.
6
Tocilizumab is generally well tolerated in
elderly patents. Most of the adverse events
such as neutropenia, deranged liver functon
and lipid abnormalites are mild and generally
reversible. Based on the above analysis, their
occurrence was similar regardless of age,
although the rate of serious infectons such as
pneumonia was slightly increased in elderly
persons (3.4 vs 2.6 percent).
6
Post-marketng
surveillance data also suggest that concomi-
tant use of steroids and underlying respiratory
disease are signifcant risk factors for clini-
cally important serious infectons, requiring
careful monitoring.
7

This case illustrates the importance of
optmal and adequate treatment in elderly
RA patents, who can present with similar, if
not more, aggressive arthrits than younger
patents, resultng in great physical and men-
tal disability. Biologic treatment such as toci-
lizumab can result in marked improvement
in elderly RA patents who failed conven-
tonal DMARDs, and should be considered
regardless of the patents chronological age.
In older patents, who may have a higher risk
of infecton, vigilant monitoring is essental
during the course of therapy.
References:
1. Arthrits Rheum 2003;48:917-926. 2. Arthrits Rheum 2007;57:928-934. 3. J Rheum
2003;30:691-696. 4. Lancet 2008;371:987-997. 5. Arthrits Rheum 2008;58:2968-
2980. 6. Ann Rheum Dis 2008;67(Suppl II):338. 7. Ann Rheum Dis 2011;70:2148-2151.
22
February 2012 News
Cardiac denervation may correct abnormal heart
rhythms
Rajesh Kumar
B
ilateral cardiac sympathetc denerva-
ton (BCSD) may be a useful last resort
in stopping irregular ventricular arrhyth-
mias, according to US cardiologists.
The procedure involves snipping nerves
related to the sympathetc nervous system
on both lef and right sides of the chest.
These nerves are responsible for the bodys
fght or fight response and cutng them
may interrupt pro-arrhythmic signaling
within the heart tssue or stellate ganglion,
thus stopping irregular heart rhythms.
Researchers at the University of California
Los Angeles (UCLA) reviewed records from
six patents presentng with ventricular
arrhythmias in a small pilot study to assess
the impact of BCSD. [JACC 2012; 59:91-92]
The patents average age was 60 years
and they were all poor candidates for
a heart transplant. Afer conventonal
treatments such as medicatons, catheter
ablaton and an implantable cardiac def-
brillator (ICD) had failed, the patents were
operated upon to snip the cardiac sympa-
thetc nerves leading to both sides of the
heart.
Afer the surgery, four out of the six
study patents completely responded with
no more arrhythmias. One patent had a
partal response and one had no response
at all. With their heart rhythms stabilized,
three of the responding patents received
no more shocks from their ICDs, which
would previously occur when the devices
tried to normalize irregular rhythms, said
the researchers. One of these patents had
been experiencing 11 shocks a day.
The patent who partally responded to
treatment had a shock reducton of more
than 50 percent. Two of the responding
patents passed away afer discharge due
to health issues not related to arrhythmias.
No major operatve complicatons occurred
in the patents studied, the researchers
added. Typical side efects related to this
procedure such as alteratons in sweat-
ing or temperature regulaton were not
signifcant.
We are encouraged by this small studys
results, and plan to further examine the role
of this procedure in suppressing arrhyth-
mias in a larger patent populaton, said
lead author Dr. Olujimi Ajijola, a cardiology
fellow at UCLA, Los Angeles, California, US.
We plan to further examine the role of this procedure in
suppressing arrhythmias in a larger patent populaton
23
February 2012 News
Dr. Ching Chi Keong, senior consultant
in the department of cardiology and direc-
tor of the electrophysiology and pacing at
Natonal Heart Centre Singapore, said for-
tunately there are not too many patents
who may require such an aggressive treat-
ment that could play an adjuvant role to
conventonal therapy, including catheter
ablaton.
Commentng on the fndings rele-
vance, Ching said such advances in treat-
ment modalites enable doctors to prolong
survival and improve quality of life for
patents, and suggested GPs should iden-
tfy and refer those who may beneft from
these therapies.
The study builds on the previous work
wherein the procedure was done only on
the lef side. But some patents may need
the procedure performed bilaterally to get
relief. The fndings add to a growing feld of
research into the sympathetc nervous sys-
tems impact on stress and possible role in
disease.
Rajesh Kumar
T
aking at least one anthypertensive
medicaton at bedtme improves con-
trol of blood pressure and reduces the risk
for cardiovascular events in those with
chronic kidney disease (CKD) and hyper-
tension, a study has shown.
While the tme of taking hypertension
medicatons can afect circadian paterns
of BP, the researchers sought to fnd out
whether this impacts clinical outcomes.
They randomly assigned 661 patents with
CKD to either take all prescribed hyper-
tension medicatons on waking up or to
take at least one of them at bedtme. They
then measured 48-hour ambulatory BP at
baseline and 3 months afer any adjust-
ment in treatment or annually. [J Am Soc
Nephrol 2011; 24 October. DOI:10.1681/
ASN.2011040361]
Afer a median follow-up of 5.4 years,
patents who took at least one BP-lowering
medicaton at bedtme had an adjusted
risk for total cardiovascular events that
was approximately one-third that of
patents who took all medicatons upon
awakening (adjusted hazard rato 0.31;
95% CI 0.21 to 0.46; P<0.001), according to
the research. Total cardiovascular events
were a composite of death, myocardial
infarcton, angina pectoris, revasculariza-
ton, heart failure, arterial occlusion of
lower extremites, occlusion of the retnal
artery, and stroke.
Bedtme dosing also demonstrated a
signifcant reducton in risk for cardiovas-
cular death, myocardial infarcton, and
stroke (adjusted HR 0.28; 95% CI 0.13 to
0.61; P<0.001). The patents on bedtme
medicaton also had a signifcantly lower
mean sleep-tme BP and a greater control
of their ambulatory BP (56 percent ver-
sus 45 percent, P=0.003). Each 5-mmHg
decrease in mean sleep-tme systolic BP
was associated with a 14 percent reduc-
ton in the risk for cardiovascular events
during follow-up (P<0.001).
Better BP control with bedtime drug
dose
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25
February 2012 News
Endometriosis increases risk of IBD
Radha Chitale
A
n analysis of over 37,000 Danish women
showed that infammatory bowel dis-
ease (IBD) is 50 percent more common
among women with endometriosis.
Prior to this study, the potental risk rela-
tonship between IBD, which encompasses
Crohns disease [CD] and ulceratve colits,
and the infammatory gynecological disor-
der had not been explored.
Researchers suggested that evident
shared symptoms and localizaton may
point to possible prognostc value.
Importantly, endometriosis and IBD are
sometmes used as diferental diagnoses
which could lead to a missed diagnosis.
The two diseases (IBS, endometriosis)
have been discussed as potentally dif-
ferental diagnoses and have therefore
been described in case reports of one dis-
ease mimicking the other, the research-
ers said. An inital diagnostc mistake
between endometriosis and IBD is possi-
ble However, the diferental diagnostc
problem [between atypical CD and endo-
metriosis] does not explain the observed
increased risk of IBD decades afer a diag-
nosis of endometriosis.
The analysis identfed 320 women with
IBD 228 with ulceratve colits and 92
with CD from a natonal registry of 37,661
Danish women hospitalized between 1977
and 2007. [Gut 2011 Dec 19. Epub ahead of
print]
The women were monitored for a mean
13.1 years.
Based on these data, the risk of develop-
ing IBD was 50 percent greater in women
with endometriosis compared to the gen-
eral populaton. The risk of developing
ulceratve colits or CD increased 50 percent
and 60 percent, respectvely.
Restrictng analysis to women with
surgically verifed endometriosis resulted
in even stronger risk associatons, the
researchers said.
They acknowledged that the cohort was
biased against women who were diagnosed
in an ambulatory care setng as opposed to
a hospital or outpatent clinic.
However, surgically verifed endome-
triosis represents the most valid diagno-
sis, and such cases were all included in this
study, the researchers said.
Endometriosis involves endometrial cells
implantng outside the uterus without being
cleared by the immune system. The condi-
ton can afect up to 10 percent of repro-
ductve-age women and ofen presents as
raised cytokine levels, decreased cell death
and B- and T-cell abnormalites similar to
The risk of developing IBD was 50 percent
greater in women with endometriosis vs. the
general population.
26
February 2012 News
those observed in autoimmune diseases.
Endometriosis is caused by retrograde
menstruaton, which is thought to be more
common in women with impaired immune
systems.
In additon to underlying autoimmuno-
logical similarites between endometriosis
and IBD, the researchers suggested that oral
contraceptves used to treat endometriosis
may increase the risk of developing IBD.
One possibility would be to treat
endometriosis as an autoimmune disease
similar to the way in which IBD and rheuma-
toid arthrits are already treated, to avoid
further disease progression with oral con-
traceptves in women with both diseases.
It is also of both immunological and clin-
ical interest to know whether patents with
IBD with endometriosis have a diferent
prognosis from that of other IBD patents,
which warrants further study, the research-
ers concluded.
Celiac disease can lead to depression, stress
Radha Chitale
P
eople with celiac disease are more likely
to sufer depression and eatng disorders,
according to a survey of 177 women over age
18.
People with celiac disease are unable to
process gluten, leading to stomach pain,
constpaton, diarrhea, nausea and vomitng.
Ofen a tghtly controlled diet in which foods
like wheat, barley and rye are avoided is the
only recourse.
Researchers from the US used an online
survey to collect informaton about celiac
symptoms, dietary habits, management of
stressful situatons, depression symptoms,
and concerns about eatng and body image
from women with diagnosed celiac disease.
[Chronic Illn 2011 Sep 20. Epub ahead of
print]
We found that most partcipants fre-
quently adhered to a gluten-free diet, and
this greater compliance with diet was related
to increased vitality, lower stress, decreased
depressive symptoms and greater overall
emotonal health, the researchers said.
However, even those people who were
managing their illness very well reported
higher rates of stress, depression and a
range of issues clustered around body image,
weight and shape when compared to the
general populaton.
The researchers recommended beter
educaton about the psychological, social
and behavioral aspects of celiac disease to
prepare patents for potental difcultes
associated with celiac disease and possibly
improve well being.
Even those who manage their illness well
reported high rates of stress, depression and
body image issues.
San Franci sco
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February 2012 News
Study supports HPV testing in all cervical screens
Rajesh Kumar
H
uman papillomavirus (HPV) DNA test-
ing is the best cervical cancer screen-
ing opton for women over the age of 30
as it detects earlier high-grade lesions and
prevents more cervical cancers than cytol-
ogy alone.
These are the fndings of the
POBASCAM* trial that provide the strong-
est evidence so far in favor of using HPV
testng in natonal cervical cancer screen-
ing programs. [Lancet Oncology 2011;
DOI:10.1016/S1470-2045(11)70296-0]
The study, which involved nearly 45,000
women aged 29 to 56 years atending rou-
tne cervical screening in the Netherlands
between January 1999 and September
2002, equally randomized women to
receive either HPV DNA testng and cytol-
ogy or cytology alone.
The researchers wanted to see if HPV
testng resulted in fewer high-grade cer-
vical lesions and cervical cancer in the
second round of screening 5 years later
because of earlier detecton and treat-
ment of lesions afer the frst round. They
then assessed the most appropriate age
for startng HPV testng. In the second
screening round, HPV and cytology testng
were done on all women.
In the frst screen, HPV testng ident-
fed signifcantly more cancer precursors
(cervical intraepithelial neoplasia grade
2 or worse (CIN2+) than cytology alone.
[267/19999 vs. 215/20106; P=0.015]. Five
years later, signifcantly fewer women
had CIN grade 3 or worse (CIN3+) lesions
[88/19579 vs. 122/19731; Relatve Risk
0.73, 95% CI 0.55-0.96; P=0.023] and cer-
vical cancer [4/19579 vs. 14/19731; RR
0.29, 95% CI 0.10-0.87, P=0.031] in the
HPV group, compared with women given
cytology alone.
The trial shows that HPV testng can be
implemented as a primary cervical screen-
ing test, said lead researcher Professor
Chris Meijer of the department of pathol-
ogy at the VU University Medical Center,
Amsterdam, The Netherlands.
Afer 5 years, signifcantly less cervical
cancers and 50 percent (less) CIN3 were
found in the HPV arm than in the cytol-
ogy arm. This is due to the fact that in
the frst screening round for HPV detects
more CIN2+ than cytology, which results
in beter protecton against CIN3 and cer-
vical cancer in the second round, said
Meijer. The long screening interval also
allowed the assessment of whether cervi-
cal lesions were persistent or regressive.
The study reinforces fndings from
cohort studies, clinical trials, and routne
clinical practce by providing overwhelm-
ing evidence of the benefts of inclusion
of HPV testng in screening programs,
said Drs. Hormuzd Katki and Nicolas
Wentzensen from the Natonal Cancer
Insttute, Bethesda, US, in an accompany-
ing comment.
HPV testng is already known to be
more sensitve than cytology at detectng
prectancerous high-grade cervical lesions,
but whether this testng ofers beter
protecton in two screening rounds over
a 5-year screening interval had not been
investgated before.
Primary preventon with the HPV
29
February 2012 News
vaccine would take many years to show
its efect. However, with the use of HPV
testng as an adjunct to pap smears,
the incidence of cervical cancer can be
reduced further by earlier detecton and
treatment of cervical pre-cancers, said
Dr. Timothy Lim Yong Kuei, consultant in
the department of gynaecological oncol-
ogy at KK Womens & Childrens Hospital,
Singapore.
But the implementaton of HPV DNA
testng into the natonal screening pro-
grams needs further evaluaton by rele-
vant authorites, said Lim.
How this studys protocol of 5-yearly
screening with HPV testng/pap smear
would perform in our populaton is unclear
because diferent populatons have a dif-
ferent baseline cancer rates, compliance
to follow-up, and management infrastruc-
ture. Furthermore, some studies have also
shown that inappropriate uses of HPV test-
ing may lead to unnecessary follow-up,
interventons and increased medical costs
without added benefts.
*POBASCAM: Populaton Based Screening
Study Amsterdam
Vaginal progesterone reduces preterm birth
Rajesh Kumar
P
regnant women with a short cervix
should be treated with vaginal proges-
terone to reduce the risk of preterm birth,
recommends a landmark study by leading
obstetricians.
The meta-analysis pooled results of fve
clinical trials involving 775 women and 827
infants. It found that treatment with vagi-
nal progesterone in pregnant women with
a sonographic short cervix of 25 mm in
the mid-trimester was associated with a
42 percent reduced rate of preterm birth,
52 percent reduced rate of respiratory dis-
tress syndrome and the need for mechani-
cal ventlaton and fewer complicatons
of premature newborns eg, infecton,
necrotzing enterocolits and intracranial
hemorrhage. [AJOG 2011; DOI: 10.1016/j.
ajog.2011.12.003]
Our analysis provides compelling evi-
dence that vaginal progesterone pre-
vents preterm birth and reduces neonatal
morbidity/mortality in (asymptomatc)
women with a short cervix, said lead
investgator Dr. Roberto Romero, chief of
the perinatology research branch of the
Natonal Insttutes of Health at Wayne
State University in Detroit, Michigan, US.
Dr. Thomas J. Garite, co-editor-in-chief
of the American Journal of Obstetrics &
Gynecology, has hailed the fndings saying
they have the potental to [cause] a sea
change in obstetrical practce in the US and
Europe, and eventually in the rest of the
world.
All pregnant women in the middle
months of pregnancy should now be
ofered routne vaginal ultrasound and
treated with vaginal progesterone if
short cervix was found, commented Dr. C.
Andrew Combs of the Obstetrix Medical
Group in San Jose, California, US, in an
accompanying editorial.
The study authors said this strategy
allowed identfcaton of women at risk
for preterm delivery during their frst
30
February 2012 News
pregnancy, whereas the current strategy
based on treatng women with a previous
preterm birth did not address the chal-
lenge of preventon in women with their
frst pregnancy.
Whether all asymptomatc women
in Asia could be routnely screened for a
shortened cervical length, regardless of
any risk factors, really would depend on
whether we have the necessary resources
to do this, added Dr. Christopher Ng of the
GynaeMD, Singapore.
Ultrasound scans would have to be
made available and gynecologists would
have to be trained to perform these tests,
which will require additonal tme and
money, said Ng.
Since a majority of premature births
occur in women with no risk factors, the
approach has real potental to make an
impact in the overall premature birth rate.
The fndings also have practcal implica-
tons because vaginal progesterone is a
less expensive and less invasive alterna-
tve than the placement of a cervical cer-
clage in patents who have had a previous
preterm birth and have a short cervix, the
study authors added.
Preterm birth is the leading cause of
perinatal morbidity and mortality world-
wide and the main cause of infant mor-
tality. Approximately 12.9 million births
worldwide are preterm, of which 92.3 per-
cent occur in Africa, Asia, Latn America,
and the Caribbean.
A decline in progesterone acton is con-
sidered to be important for the onset of
labor. If such a decline occurs in the mid-
trimester, cervical shortening may lead to
the onset of preterm labor. The adminis-
traton of progesterone is believed to work
by maintaining a high concentraton of the
hormone in the uterine cervix, the study
authors said.
A study of vaginal progesterone in twin
pregnancies with a short cervix is now
urgently needed to confrm these fndings
in such pregnancies as well, said Romero.
In the current study, adverse events were
no diferent in the treatment and placebo
groups, and follow-up studies of babies
exposed to progesterone in utero to the age
of 18 or 24 months showed no evidence of
any behavioral or physical problems.
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1.Poon RT et al. Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a
randomized trial. Aliment Pharmacol Ther 2004; 19: 779-788.
2.The San-in Group of Liver Surgery. Long-term oral administration of branched chain amino acids after curative resection of hepatocellular carcinoma: a
prospective randomized trial. Br J Surg 1997; 84: 1525-1531.
3.Poon RT et al. A prospective longitudinal study of quality of life after resection of hepatocellular carcinoma. Arch Surg 2001; 136: 693-699.
4.Ichida T et al. Clinical study of an enteral branched-chain amino acid solution in decompensated liver cirrhosis with hepatic encephalopathy. Nutrition 1995; 11: 238-244.
5.Meng WCS et al. Prospective randomized control study on the effect of branched-chain amino acids in patients with liver resection for hepa tocellular carcinoma. Aust N
Z J Surg 1999; 69: 811-815.
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0.1875g, L-tryptophan 73.5mg, Gelatin hydrolysate 6.5g, Rice oil 3.5g, Dextrin 31.05g, Retinol palmitate 466IU, Ergocalciferol 46.6IU, Bisbentiamine 0.1450mg, Riboflavin 0.1550mg,
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32
February 2012 News
Statin use linked to lower death rate in flu
patients
Elvira Manzano
T
he use of statns cholesterol-lowering
drugs may reduce the risk of death in
patents hospitalized for infuenza.
In a large US study, the administraton
of statns to fu patents before or afer
hospitalizaton reduced mortality rates by
41 percent (odds rato=0.59; 95% CI 0.38-
0.92) afer adjustng for age, race, cardio-
vascular, lung and renal disease, infuenza
vaccinaton and antviral administraton. [J
Infect Dis 2012; 205:13-19]
Our fndings suggest that statns are a
promising area of exploraton and could
provide a useful adjunct to antviral medi-
catons and vaccine, partcularly in setngs
where circulatng infuenza virus strains
are not susceptble to antviral medica-
tons or vaccine is in short supply or not
well matched to circulatng viruses, said
study author Dr. William Schafer, pro-
fessor and chair of preventve medicine
at Vanderbilt University Medical Center,
Nashville, Tennessee, US.
In the study, patents who received
statns were more likely to be older, male
and white, to sufer from cardiovascu-
lar, metabolic, renal and chronic lung dis-
ease, and to have been vaccinated against
infuenza.
The researchers examined the 30-day
mortality fgures from 3,043 patents with
laboratory-confrmed infuenza who were
admited to US hospitals during the infu-
enza season in 2007 and 2008. The median
age of the patents was 70.4 years and 56
percent were women.
Among the hospitalized patents, 1,013
(33.3 percent) received statns and 151 (5
percent) died within 30 days of an infu-
enza test. Most of the deaths, however,
occurred shortly afer hospital discharge.
Previous research has suggested that
statns might have a protectve efect
against infuenza, providing ant-infamma-
tory and immunomodulatory efects that
could help cut infuenza-related deaths,
but none of those studies limited inclu-
sion to patents with laboratory-confrmed
disease.
To our knowledge, this is the frst pub-
lished observatonal study that evaluates
the relatonship between statn use among
patents hospitalized with infuenza, the
researchers said. Future studies should
examine underlying functonal status, dose
and duraton of statn therapy, use of statns
in younger age groups, and identfcaton
of the most efectve class of statns.
They suggested that randomized con-
trolled trials (RCTs) would allow for exami-
naton of such issues and assess whether
long-term prophylaxis with statns would
be a worthwhile strategy in reducing mor-
bidity and mortality from infuenza.
In an accompanying editorial, Dr. Edward
Walsh, from the Infectous Diseases
Division, Rochester General Hospital in
New York, US, said the fndings add signif-
cantly to the slowly accumulatng evidence
that statns may reduce the substantal
annual morbidity and mortality from infu-
enza. However, he echoed the researchers
call for defnitve RCTs to accurately assess
how statns may afect infuenza.

34
February 2012 Conference Coverage
53rd Annual Meeting of the American Society of Hematology, 10-13 December 2011,
San Diego, California, US
Aspirin reduces the risk of blood clots in VTE
patients
Radha Chitale
A
spirin alone reduced the incidence of
recurrent blood clots in patents who suf-
fered their frst venous thromboembolism
(VTE), according to a recently reported trial.
In the double-blind, randomized, placebo-
controlled event-driven Warfasa study, which
involved patents with a frst-ever VTE, a 100
mg daily dose of aspirin, administered fol-
lowing a 6- to 18-month period of antcoagu-
lant therapy with warfarin, reduced the risk
of another event by 40 percent compared to
placebo over 2 years (P=0.02).
This was the frst observed beneft of
aspirin in this applicaton, said Dr. Cecilia
Becatni, assistant professor of internal
medicine at the University of Perugia in Italy.
She noted that VTE occurs in 800,000
people in North America alone. Emboli
fragments may separate and enter pulmo-
nary circulaton. This sequence occurs in
up to 60 percent of VTE patents and can
be fatal in 20 percent of those cases.
Aspirin is known to prevent DVT in high
risk patents, those with hip fractures and
in post-menopausal women on estropro-
gestn therapy.
Warfarin is a common, efectve antco-
agulant for use in VTE patents. However
it needs frequent dose adjustment and is
associated with bleeding risk, the worst
outcome of which could be fatal intrac-
ranial embolism, making it a challenging
treatment opton for patents in need of
long-term antthrombotc therapy.
By contrast, bleeding risk associated with
aspirin is lower than 1 percent per year.
For its safety, practcality and low cost,
aspirin is a valid alternatve to oral antco-
agulants in the extended treatment of VTE,
Becatni said.
VTE recurrence occurred in 27 of 205
patents randomized to aspirin and in 42 out
of 197 patents randomized to placebo (6.3
percent versus 11 percent patent-years).
During the study treatment period, VTE
occurred in 23 and 39 patents taking aspi-
rin or placebo, respectvely (5.9 percent
and 11 percent patent-years).
One fatal event occurred in each group
and bleeding events were similar between
both.
This preliminary, unpublished trial will
have clinical impacts but is unlikely to change
practce in the near future, Becatni said, as
further studies are necessary to confrm the
benefts of aspirin in patents at risk for VTEs.
Prior reports on the antcoagulant ef-
cacy of aspirin in patents who already suf-
fered a VTE event have been confictng.
The researchers excluded patents with
high bleeding risk, actve bleeding or indica-
tons for indefnite antcoagulant therapy.
For its safety, practcality and low cost, aspirin is a valid alternatve
to oral antcoagulants in the extended treatment of VTE
35
Promising gene therapy cure for hemophilia
Rajesh Kumar
R
esearchers have successfully tested a
potental cure for severe hemophilia B in
six patents using gene therapy.
Hemophilia is a genetc bleeding dis-
order that is caused by defectve or miss-
ing recombinant factor IX (FIX). Insufcient
amount of this protein prevents blood from
clotng normally, causing prolonged bleed-
ing afer an injury or surgery or, in case of
severe hemophilia, even fatal spontaneous
bleeding without trauma. It afects one in
30,000 men who require regular infusions
of the protein.
The researchers used as a vector the
adeno-associated virus (AAV) that is endemic
to humans but does not cause a disease
and inserted in it a normal copy of the FIX
gene before infusing the virus into severe
hemophilia B patents. This gene transfer
approach replaced the defectve gene that
causes the disorder with a correct version in
the patents liver cells, the normal site of FIX
synthesis, so patents could make their own
FIX, said co-researcher Dr. Andrew Davidof,
chairman of the department of surgery
at St. Jude Childrens Research Hospital in
Memphis, Tennessee, US.
Six patents were equally divided to
receive low, intermediate and high doses
of the vector carrying a normal copy of the
FIX gene through an intravenous infusion in
the arm, without prior immune suppressant
therapy. At a follow up for 6 to 16 months
post-treatment, the patents vector-medi-
ated levels of FIX rose from <1 percent of
normal levels before the therapy to between
2 and 12 percent of normal levels.
Such moderate increases in FIX levels can
signifcantly impact patents symptoms and
quality of life. Four of the 6 study patents,
for instance, stopped prophylactc treatment
and remained free of spontaneous bleed-
ing, while the remaining two increased tme
interval between their FIX infusions, said the
researchers.
We have developed a vector for gene
transfer that is more efcient and efectve
than traditonal treatment for patents with
severe hemophilia B by preventng spon-
taneous bleeding in this high risk patent
populaton, said lead researcher Dr. Amit
Nathwani of the department of hematol-
ogy at the UCL Cancer Insttute in London,
UK. Our novel approach shows promise for
improved gene therapy for hemophilia B
and other protein defciencies.
The AAV has proved to be a promising
vector for FIX gene delivery. It can transduce
liver very efciently and is less likely to stmu-
late an immune response to transduced cells
than other vectors since no viral proteins are
expressed, Nathwani later added, saying this
facilitates long-term expression of the FIX
transgene following a single administraton.
Immune-mediated clearance of the AAV-
transduced liver cells appeared as a con-
cern, but researchers said this process could
be controlled with a short course of steroids
without loss of transgene expression. They
now plan to treat more patents at the high
dose of vector without giving them immu-
nosuppression.
36
Novel BTK inhibitor holds potential in CLL
Michael Kaufman
U
pdated fndings from a multcenter
phase Ib/II clinical trial, presented at
the 2011 American Society of Hematology
(ASH) Annual Meetng and Expositon,
suggest that the novel Brutons tyrosine
kinase (BTK) inhibitor PCI-32765 may be
an important new targeted treatment for
patents with chronic lymphocytc leuke-
mia (CLL).
BTK is a central mediator of B-cell
receptor signaling essental for normal
B-cell development, explained lead
author Professor Susan OBrien of the
Department of Leukemia, University
of Texas MD Anderson Cancer Center,
Houston. This makes it a primary target
for research on B-cell malignancies such
as non-Hodgkins lymphoma (NHL).
PCI-32765, an orally-administered irre-
versible inhibitor of BTK, induces apop-
tosis and inhibits cellular migraton and
adhesion in malignant B-cells. An early
analysis of the phase Ib/II study showed
PCI-32765 to be highly actve and toler-
able in patents with CLL. Longer term
follow-up was presented by OBrien.
Two cohorts of patents with relapsed
or refractory (R/R) CLL/small lymphocytc
lymphoma (SLL) were treated with PCI-
32765 at daily doses of either 420 mg
(n=27) or 840 mg (n=34) for 28-day cycles
untl disease progression. Patents in the
420 mg arm had a median of three prior
treatment regimens vs a median of fve
in the 840 mg arm. Seventy-two percent
of partcipatng patents had at least one
poor-risk molecular feature.
In the current analysis, researchers
concluded that PCI-32765 was associ-
ated with high rates of 6-month pro-
gression-free survival (PFS) in patents
with relapsed CLL. At 10-month follow-
up, 70 percent of patents in the 420 mg
treatment group achieved an objectve
response (OR) to therapy (previously
reported as 48 percent), and 44 percent
of patents in the 840 mg cohort achieved
an OR at 6-month follow-up.
An additonal 19 percent of the 420
mg cohort and 35 percent of the 840 mg
cohort had a nodal partal response,
represented by a 50 percent reducton
in lymph node size but with some lymph
nodules persistng. The researchers
emphasized that 82 percent of patents
remain on treatment, whereas 8 percent
have experienced progressive disease.
Two patents discontnued the trial
because of adverse events, and six
required dose reducton. The most fre-
quently reported adverse events were
mild and included diarrhea, fatgue, nau-
sea, and skin bruising.
Serious adverse events (SAEs), which
are common among this immune-com-
promised patent populaton, occurred
in 38 percent of patents, with 10 per-
cent considered potentally related to
treatment. The majority of patents also
experienced a transient high lymphocyte
count during the frst 2 months of treat-
ment that resolved over tme, which is
37
another typical characteristc of treat-
ment in this patent group.
Our results suggest that PC-32765
has the potental to be highly efectve
and tolerable, and, more importantly,
appears to be working well in patents
with poor prognoses, said OBrien. As
we become beter equipped to target
specifc cellular functons, it is our hope
that therapies like PCI-32765 will become
efectve interventons to manage disease
in patents with CLL.
The investgators concluded that PCI-
32765 is well tolerated with high rates of
6-month PFS in R/R CLL/ SLL. Phase III tri-
als of PCI-32765 in CLL/ SLL are planned.
One of the most excitng things about
agents like PCI-32765 is that they are not
myelosuppressive, said OBrien. This
is a big deal in CLL because one of the
biggest problems we have with treat-
ment is that all the treatments we have
are chemo-based, and the biggest com-
plicaton with practcally every agent we
have is myelosuppression and infecton,
which are of special concern in patents
with CLL who are already immunocom-
promised.
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38
Gemtuzumab: Potential new use for old drug
Anna Azvolinsky
A
phase III trial comparing the use of gem-
tuzumab ozogamicin combined with
chemotherapy vs chemotherapy alone in
newly diagnosed acute myeloid leukemia
(AML) patents provides evidence that the
combinaton treatment may be promis-
ing in this patent populaton. Using rela-
tvely low and frequently repeated doses
together with standard chemotherapy
may be a viable opton for the treatment
of older adults aged 50 to 70 years.
In the presented study, gemtuzumab
was used upfront in newly diagnosed AML
patents. The results showed a beneft in
this inital treatment and a survival beneft,
suggestng that this drug was not studied
in the correct patent populaton and at
the appropriate dose previously.
Gemtuzumab was originally approved
by the US FDA through an accelerated
process in 2000 for patents older than 60
years afer a frst relapse in AML. Further
clinical trials and post-marketng data that
did not show any evidence of a clinical
beneft in patents with AML compared to
conventonal chemotherapy partcularly,
the SWOG S0106 trial led to the with-
drawal of the treatment. There were also
toxicites increasing mortality partcularly
in younger patents.
Gemtuzumab ozogamicin is a mono-
clonal antbody to CD33 that is linked to a
calicheamicin, a cytotoxic agent. It binds
to CD33, which is expressed on AML cells,
but not on normal, mature hematopoietc
stem cells.
Because a phase II trial determined that
the 9 mg/m
2
BID dose could not be safely
combined with chemotherapy, the cur-
rent phase III trial utlized a 3, 3, 3 regimen
based on in vitro observatons and valida-
ton in two subsequent phase II trials. A
dose of 3 mg/m
2
gemtuzumab ozogamicin
was given on days 1, 4, and 7 of treatment
in conjuncton with chemotherapy, arab-
inofuranosyl cytdine, and daunorubicin.
At 2-year follow up, event-free survival
(EFS) was 15.6 percent in the chemother-
apy arm compared to 41.4 percent in the
combinaton arm. Median EFS was 11.9
months compared with 19.6 months, in
the chemotherapy and combinaton arms,
respectvely. The beneft was seen in all age
groups and translated into a longer overall
survival (OS) for patents treated with the
combinaton. Average OS was 19 months
in the chemotherapy arm and 34 months
in the combinaton therapy arm.
First-line treatment with gemtuzumab
ozogamicin was shown to improve survival in
newly-diagnosed AML patients.
39
Treatment with the combination
increased toxicities. The rate of fatal
adverse events potentially attributed to
treatment was 2 percent higher in the
gemtuzumab ozogamicin plus chemo-
therapy arm compared with chemother-
apy alone. Safety was a major issue,
stated Professor Sylvie Castaigne of the
Department of Hematology, Hpital de
Versailles in Versailles, France, who pre-
sented the study. Thrombocytopenia was
greater with gemtuzumab ozogamicin,
as was persistent thrombocytopenia.
Three episodes of veno-occlusive dis-
ease or sinusoidal obstructive syndrome
(liver vein blockages) were observed in
the arabinofuranosyl cytidine, daunoru-
bicin plus gemtuzumab ozogamicin arm,
two noted as fatal. There was no differ-
ence in non-hematologic events includ-
ing sepsis, bleeding, cardiac events, and
liver events.
New therapy improves ORR in relapsed indolent
NHL
Christna Lau
O
binutuzumab may provide a new
treatment opton for patents with
relapsed, CD20-positve indolent B-cell
non-Hodgkins lymphoma (NHL) as a phase
II study showed a slightly higher overall
response rate (ORR) in inducton therapy
than the currently available ant-CD20
antbody rituximab.
Obinutuzumab (GA101, Genentech) is
the frst type II glycoengineered CD20 mon-
oclonal antbody in phase II/III clinical trials
for chronic lymphocytc leukemia and non-
Hodgkins lymphoma. In preclinical studies,
it showed a beter ability than rituximab to
cause cell death and invoke cellular immune
response, with lower complement-depend-
ent cytotoxicity.
In the ongoing, open-label GAUSS study
(Randomized Phase II Trial Comparing
GA101 [Obinutuzumab] With Rituximab
in Patents With Relapsed CD20+
Indolent B-Cell Non-Hodgkin Lymphoma),
obinutuzumab showed higher response
rates than rituximab in patents with folli-
cular lymphoma (FL).
The study included 175 patents with
relapsed CD20-positve NHL (FL, N=149;
non-follicular indolent NHL, N=26) who had
a prior response to a rituximab-containing
regimen lastng 6 months. The patents
were randomly assigned to receive rituxi-
mab 375 mg/m
2
IV weekly or obinutu-
zumab 1 g IV weekly, for 4 weeks. At the
end of the inducton phase, patents with-
out disease progression contnued with
maintenance therapy on the same drug
and dose every 2 months for up to 2 years.
At the end of inducton, ORR by central
blinded radiology review was 44.6 per-
cent in obinutuzumab-treated FL patents
vs 26.7 percent in rituximab-treated FL
patents [p=0.01], reported Dr. Laurie
Sehn of the University of Britsh Columbia
in Vancouver, Canada.
However, ORR by investgator assess-
ment in the FL populaton showed no
40
statstcally signifcant diference between
treatments (obinutuzumab, 44.6 percent
vs rituximab, 33.3 percent; P=0.08).
The results also showed no diference in
progression-free survival in the FL popula-
ton, with 39.2 percent of obinutuzumab-
treated patents having an event at a
median tme to event of 17.3 months, vs
34.7 percent of rituximab-treated patents
at a median tme to event of 17.4 months.
Obinutuzumab was well tolerated in the
overall populaton of GAUSS, with no signif-
icant diferences in treatment discontnua-
ton due to adverse events (obinutuzumab,
8 percent vs rituximab, 10 percent).
GAUSS is the frst head-to-head trial to
compare the safety and efcacy of the two
ant-CD20 antbodies, said Sehn. Phase III
trials are underway to test obinutuzumab
in combinaton with chemotherapy.
Chemo alone tops radiation in Hodgkins
lymphoma
Christna Lau
F
or patents with limited-stage non-bulky
Hodgkins lymphoma, chemotherapy
alone is more efectve than radiaton ther-
apy in improving overall survival (OS) in
the long run, according to fnal results of a
phase III CanadianUS study.
The Natonal Cancer Insttute of Canada
(NCIC) Clinical Trials Group and Eastern
Cooperatve Oncology Group study included
405 patents with previously untreated
stage IA or IIA non-bulky disease to receive
ABVD chemotherapy (doxorubicin, bleomy-
cin, vinblastne and dacarbazine) or subtotal
nodal irradiaton (STNI). Those in the STNI
group with a favorable risk profle received
STNI only, while those with an unfavorable
risk profle received two cycles of ABVD plus
STNI. The primary endpoint was 12-year OS.
At a median follow-up of 11.3 years, OS
was superior in patents receiving chem-
otherapy alone (hazard rato [HR]=0.5;
P=0.04; 12-year OS estmates, 94 percent
for chemotherapy alone vs 87 percent for
STNI).
According to Dr. Ralph Meyer of the NCIC
Clinical Trials Group, the survival advantage
with chemotherapy resulted from fewer
deaths from causes other than Hodgkins
lymphoma. Although 5-year data showed
that patents treated with STNI experienced
greater disease control, more patents died
due to a second cancer vs those treated
with chemotherapy alone, he said.
At 12 years, 92 percent of patents
initally treated with STNI were disease
free (vs 87 percent in the chemotherapy
alone group; HR=1.91; P=0.05). Event-free
survival was similar, at 80 percent for STNI
vs 85 percent for chemotherapy alone
(HR=0.88; P=0.06).
There are limitatons in using freedom
from disease progression as a proxy meas-
ure for OS when late treatment efects may
occur, noted Meyer. New proxies that pre-
dict for the risks of late treatment efects
are needed.
41
Protein offers clues to drug treatment response
in multiple myeloma
Elvira Manzano
A
n absence of the protein cereblon
may be associated with poor response
to immunomodulatory drugs (IMiDs) in
patents with multple myeloma, research
has shown.
A new study of myeloma patents resist-
ant to the iMiD lenalidomide showed
that they had lower levels of or no cer-
eblon compared to control lines. [Blood
2011;118: 4771-4779]
These fndings help us understand
which patents may be more or less likely
to respond to therapy, said study author
Professor Keith Stewart, dean for research
in the hematology-oncology division of
the Mayo Clinic in Scotsdale, Arizona, US.
[It] will allow us to focus on other ways
we can target cereblon as a possible bio-
marker to improve treatment and patent
outcomes in multple myeloma.
Last year, Japanese researchers were
able to identfy cereblon as the molecu-
lar target of lenalidomides parent drug
thalidomide.
The discovery prompted Stewart and
colleagues to test if cereblon may be
responsible for IMiD response or resist-
ance, or if thalidomide and its analogs
lenalidomide and pomalidomide exert
clinical benefts on multple myeloma
patents through the cereblon.
By analyzing gene expression of mye-
loma cell lines, they were able to fnd
that patents who do not respond to
immunomodulators had low or zero cer-
eblon expression.
Knocking down CRBN in IMiD-sensitve
cell lines was initally cytotoxic to myeloma
cells, with 65 to 78 percent reducton in
viability. However, the surviving myeloma
cells became highly resistant to lenalido-
mide and pomalidomide, but not to other
ant-myeloma drugs such as bortezomib,
dexamethasone and melphalan.
Scientists have discovered that MM patients
with low/no cereblon expression do not respond
to immunomodulators.
42
Gene expression changes induced
by lenalidomide were dramatcally sup-
pressed in the presence of CRBN deple-
ton, further demonstratng that CRBN
is essental for lenalidomide actvity,
Stewart said.
Interestngly, some patents who did not
respond to lenalidomide had low levels of
CRBN, suggestng that there are other fac-
tors that create resistance. Our data sug-
gest that CRBN is a critcal molecule, but
not the unique source of IMiD resistance
in this patent populaton, Stewart said.
Treatment with lenalidomide and CRBN
depleton also reduced interferon regula-
tory factor 4 (IRF4) expression in myeloma
cells, suggestng a common link between
IMiDs and cereblon functon.
This work suggests that we can begin to
isolate the cause of birth defects from the
ant-cancer propertes in order to develop
safer drugs in the future, Stewart said.
The authors also suggest that IMiDs be
renamed cereblon-binding molecules to
more accurately refect their mechanism
of acton.
Dr. Jane Winter, professor of medicine
at Northwestern University in Chicago,
Illinois, US, commented that these devel-
opments are important clues that will lay
the groundwork for the development of
new agents and provided new insights
as to what mechanisms are at work in
patents who do not respond to therapy.
Rituximab retreatment promising in lymphoma
sub-type
Radha Chitale
A
rituximab retreatment strategy was
as efectve as maintenance therapy
for managing patents with low tumor
burden follicular lymphoma, researchers
reported.
Maintenance required four tmes as
much rituximab over the course of the
trial period before treatment failure com-
pared to the retreatment strategy.
Lead researcher Professor Brad Kahl,
of the University of Wisconsin School of
Medicine and Public Health in Madison,
Wisconsin, US, said retreatment could
be a very favorable therapy from the
patents point of view because it is very
safe and tolerable compared with other
chemotherapy.
The trial compared the two strategies in
384 patents with low tumor burden fol-
licular lymphoma. Following weekly 375
mg/m2 doses of rituximab for 1 month,
responders were randomized to mainte-
nance therapy, a single dose of rituximab
every 3 months, or retreatment, in which
patents were given four weekly doses at
disease progression.
Treatment contnued untl failure,
defned as disease progression within 6
months of the last rituximab dose, non-
response to therapy, initaton of alterna-
tve therapy or the inability to complete
the treatment protocol.
43
The primary endpoint was tme to treat-
ment failure. Over a median follow up of
3.8 years, tme to treatment failure in the
maintenance arm was 3.9 years and 3.6
years in the rituximab retreatment arm
(P=0.80).
Both arms ofered beter results than
the historical watch-and-wait approach,
which the researchers said is associated
with an average of 3 years before further
chemotherapy treatment.
Secondary endpoints were tme to frst
chemotherapy, quality of life and safety.
At 3 years, 95 percent of patents on main-
tenance rituximab and 86 percent of ritux-
imab retreatment patents had avoided
chemotherapy (P=0.027).
However, the small improvement in
chemotherapy represented signifcantly
more medicaton in the maintenance arm
compared to the retreatment arm, an
average of 15.8 doses versus 4.5 doses,
respectvely.
Both regimens were well tolerated with
minimal toxicity. One death was reported
in each arm.
There was litle diference in quality of
life between the two arms.
What we were really trying to get at
was whether there was a psychological
advantage to being placed in remission
and maintained there does that help
lessen anxiety relatve to going in and
out of remission, Kahl said. Our analysis
so far shows there is no quality of life ben-
eft for the maintenance strategy relatve
to retreatment.
Though retreatment is their recom-
mended strategy over maintenance in
patents with low tumor burden follicu-
lar lymphoma, Kahl said this may not be
appropriate in patents with a high tumor
burden as monotherapy is unlikely to con-
trol their disease.
It is stll unclear whether watchful wait-
ing, rituximab or chemotherapy is best
for overall survival in follicular lymphoma
patents.
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44
Elvira Manzano
T
he American Society of Hematology (ASH) is bringing the 2012 Highlights of ASH
in
Asia to Singapore next month to showcase the latest research and clinical advances
in hematology.
At the meetng, experts will present their analysis of hematology news and research
presented at the 53rd Annual Meetng of ASH held in the US recently. Topics to be cov-
ered during the 2-day event, from 3 to 4 March at the Rafes City Conventon Centre,
Singapore, will include evolving therapies in hematology, the latest treatment optons,
and their clinical implicatons.
Highlights of ASH
in Asia will also feature lectures, panel discussions, lunch with the
experts, and exhibits. Discussions will focus on blood diseases, including acute leukemias,
myeloproliferatve diseases, Hodgkin and non-Hodgkin lymphomas, disorders of hemosta-
sis, thrombosis and ant-coagulaton and hematopoietc stem cell transplantaton. Atendees
can also look forward to excitng lectures on thalassemia, novel treatments for relapsed/
refractory chronic immune thrombocytopenia, bone marrow failure and myeloma.
Highlights of ASH
in Asia program co-chair Associate Professor Chng Wee Joo, from the Yong
Loo Lin School of Medicine, Natonal University of Singapore (NUS), senior principal invest-
gator at the Cancer Science Insttute (CSI) of Singapore, and consultant at the Department of
Haematology-Oncology, Natonal University Cancer Insttute, Singapore, described the event
as a unique educatonal opportunity for partcipants to exchange informaton and ideas.
Fellows and trainees can also discuss patent cases with leaders in the feld and gain
knowledge applicable to Asian context, said Chng [The nominated experts have gone]
through all the abstracts presented at ASH and [selected those] that are more relevant to
Asia. They will present some of these abstracts and bring forward the relevance of what
these abstracts will do in terms of change of practce using illustratve case examples.
Chng said the goal is to bring ASH to diferent countries in Asia and use it as an oppor-
tunity to foster interacton and collaboraton among physicians and researchers at the
Asian level. Overall, its going to be benefcial in all levels, he concluded.
Sponsored by ASH, the meetng is presented in partnership with the CSI, NUS, Chinese
Society of Hematology (CSH), Hematology Society of Australia and New Zealand (HSANZ),
Hematology Society of Taiwan, Indian Society of Hematology and Blood Transfusion
(ISHBT), Japanese Society of Hematology (JSH), Korean Society of Hematology (KSH),
Natonal University Cancer Insttute, Singapore (NCIS), Singapore Society of Hematology
(SSH) and Thai Society of Hematology (TSH).
Highlights of ASH coming to Asia
in March
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46
February 2012
46
Oncol ogy February 2012
Novel therapies offer hope to patients with
multiple myeloma
Radha Chitale
N
ew drugs and therapeutc regimes may
slow the rate of disease progression
and improve overall survival in patents with
multple myeloma (MM), even those who
are exquisitely vulnerable, according to
experts who presented at the annual meet-
ing of the American Society of Hematology,
held recently in San Diego, California, US.
Patents with MM, a cancer of plasma
cells that create tumors in bone marrow
and damages blood cell and platelet pro-
ducton, have a poor track record when it
comes to survival typically 2 to 3 years
following diagnosis.
In the US, the annual incidence of MM is
over 20,000 cases. Though treatable, MM
is an incurable blood cancer and each year
it causes about 10,500 deaths. However, in
the last decade, novel agents such as thalid-
omide, lenalidomide (Revlimid, Celgene)
and bortezomib (Velcade, Janssen) have
improved survival rates. Meanwhile, clini-
cians contnue to explore new ways of using
these and other drugs to beneft patents
with this form of blood cancer.
Weve seen the use of these drugs mov-
ing as part of the treatment paradigm but
[now are] used in conjuncton with other
treatment modalites with the added ben-
eft of novel combinatons said Dr. Brian
Durie of Cedars-Sinai Medical Center in
Los Angeles, California, US and co-founder
of the Internatonal Myeloma Foundaton,
who moderated an MM panel workshop.

Long-term maintenance therapies
Two landmark trials described the use
of long-term maintenance treatment with
the novel agents lenalidomide, an immu-
nomodulatory compound, and bortezomib,
a proteasome inhibitor, in MM patents.
The ratonale for maintenance therapy is
to prevent residual cancer cells from prolif-
eratng following treatment completon or
during a break in actve therapy, which is
when many patents are vulnerable to dis-
ease recurrence and progression.
A phase III study involving 459 patents
with newly diagnosed MM ineligible for
Patients with multiple myeloma, a blood cancer
associated with a typically poor prognosis,
are increasingly benefting from longer term
treatment regimens and novel agents.
47
February 2012
47
stem cell transplant has reported that main-
tenance therapy improved progression-free
survival (PFS), the primary endpoint, in a
pre-specifed subgroup of patents younger
than 75.
Led by Dr. Antonio Palumbo of the
Italian Multple Myeloma Study Group and
the University of Turin in Italy, the study
researchers randomized patents to receive
either a combinaton of lenalidomide, mel-
phalan and prednisone followed by contn-
uous lenalidomide (MPR-R), MPR followed
by placebo, or melphalan and prednisone
plus placebo followed by contnuous pla-
cebo (MP).
MPR-R was associated with a median
PFS of 31 months versus 12 months for MP
(P<0.001), the former being associated with
a 70 percent reducton in risk of disease pro-
gression compared with the later. There
was also a trend towards extended overall
survival (OS) over 4 years with the contnu-
ous lenalidomide-based regimen (69 per-
cent versus 58 percent with MP, P=0.133).
PFS was 15 months among those in the
MPR inducton group compared with 12
months in the MP group (P=0.006).
MPR inducton resulted in some adverse
events including neutropenia, thrombocy-
topenia, anemia, infectons and bone pain,
as well as some second primary malignan-
cies, though these were below normal
incidence rates, which occurred more fre-
quently compared to the MP group, but
with an acceptable safety profle to allow
most patents to proceed to maintenance
therapy. The researchers did not report
evidence of toxicity in patents on lenalido-
mide alone.
In another phase III study, the benefts
of maintenance therapy with bortezomib
in conjuncton with thalidomide (VT) or
prednisone (VP) were evaluated in elderly
MM patents.
A total of 260 patents, median age 73
years, with untreated MM were rand-
omized to receive an inducton phase with
six cycles of bortezomib, melphalan and
prednisone (VcMP) or bortezomib, thalid-
omide and prednisone (VTP) followed by
maintenance with either VT or VP for up
to 3 years. Adverse events included some
peripheral neuropathy in both groups with
slightly more in the VT group.
Over a median 20 months of mainte-
nance therapy, VT or VP improved the com-
plete response rate to 42 percent, up from
24 percent afer inducton.
Afer a median 46 months of follow up,
median PFS was 39 months in the VT arm
and 32 months in the VP arm.
OS was not signifcantly diferent between
the maintenance therapy groups, though
there was a trend towards prolonged OS in
the VT maintenance arm. Median OS was
60 months in the VP arm and has not yet
been reached in the VT arm.
This bortezomib-based maintenance
regime represents an atractve platorm
for further optmizaton of the treatment of
elderly myeloma patents, using probably
novel agents, by reducing the adverse events
and potentally improving the efcacy and
especially the overall mortality, said lead
researcher Dr. Maria-Victoria Mateos of the
University Hospital of Salamanca in Spain.
Previously, treatment of MM involved
a fxed number of cycles of these novel
agents (lenalidomide or bortezomib) plus
chemotherapy to reduce the tumor bur-
den. Patents were followed to see how
long remission might last.
Now there is a new paradigm which
includes potental and reality of beneft
48
February 2012
48
from contnuous therapy, Durie said. This
contnuous therapy is possible because the
therapy we have is quite tolerable.
One of the drawbacks of prolonged ther-
apy with early myeloma drugs was intense
nerve pain due to peripheral neuropathy, a
serious side efect which is less commonly
associated with the newer drugs.
New generaton therapies
Among the cohort of MM patents who
already have high mortality rates within a
few years, those with recurrent refractve
myeloma that do not respond to therapies
are at even greater risk and may require
novel drugs for subsequent treatment
courses.
Median survival in this populaton is about
9 months with normal therapy, said Dr.
Paul Richardson of the Dana Farber Cancer
Insttute in Boston, Massachusets, US.
A phase II trial of the third generaton
immunomodulatory drug pomalidomide
in combinaton with low-dose dexametha-
sone demonstrated an improvement in sur-
vival to nearly 17 months in patents with
relapsed and refractory MM.
[Pomalidomide] combines the best
of lenalidomide and puts it together
with thalidomide, said Richardson in his
presentaton.
The drug had actvity in patents who
demonstrated prior resistance to lenalido-
mide and bortezomib.
The study populaton included 221
patents who had undergone at least two
prior treatment regimes that included at
least two cycles of lenalidomide or bort-
ezomib separately or together. Patents
were randomized to receive pomalido-
mide alone or pomalidomide plus low-dose
dexamethasone.
Median PFS, the primary end point, was
4.6 months in the pomalidomide plus low-
dose dexamethasone arm compared with
2.6 months in the pomalidomide only arm.
In the pomalidomide plus low-dose dex-
amethasone and pomalidomide arms, par-
tal response was seen in 34 percent and 13
percent of patents, respectvely, and minor
response was 45 percent and 29 percent,
respectvely. Both arms showed a 1 percent
complete response to therapy. Median
duraton of response was similar between
the arms about 8 months. Median OS
was also similar: 14.4 months in the poma-
lidomide plus low-dose dexamethasone
arm and 13.6 months in those treated with
pomalidomide alone. Therapy discontnu-
aton was mainly the result of progressive
disease.
The good news is that because this is
not only a very actve combinaton but also
a well tolerated one, we saw encouraging
progression through survival and, most
importantly for our patents, we saw very
atractve overall survival, Richardson
said, adding that given the high quality
response in highly vulnerable patents, he
hopes comparatve trials on pomalidomide
will help to get it approved for treatng
patents soon.
A second new drug, carflzomib, prom-
ises another proteasome inhibitor to add
to the cache of therapies for MM, said
Dr. Robert Orlowski of the MD Anderson
Cancer Center in Houston, Texas, US.
This new therapy binds and holds its pro-
teasome target longer than bortezomib,
which makes it more actve against multple
myeloma.
Previous studies showed the drug to be
well tolerated and had about a 25 percent
response rate among those with relapsed
49
February 2012
49
and refractory MM. And unlike other drugs,
carflzomib appears to be less prone to
causing peripheral neuropathy.
Carflzomib appears to be a drug that
has much less ability to induce these symp-
toms, meaning that not only will patents
have a beter response but they may also
have a beter quality of life afer treat-
ment, Orlowski said, reviewing the data
during the ASH. And anytme we can
improve responses and quality of life, I
think thats a big win for patents with mul-
tple myeloma.
In a small study, carflzomib was deliv-
ered to patents via a 30-minute infusion.
Compared to shorter intravenous infusions,
patents were able to receive higher doses
of carflzomib without increased side efects
and a beter overall response rate 60
percent in 2,930 patents with relapsed
disease.
In bortezomib-nave patents with
relapsed, refractory MM, the overall
response rate for single-agent carflzomib
was between 42 and 52 percent.
If the results of this type of 30-minute
infusion can be confrmed in larger, com-
paratve studies, Orlowski said clinicians
may be able to achieve greater than 100
percent partal remission up front.
Wed like to be able to have no patents
relapse with myeloma eventually. Wed like
to have everybody achieve remission right
at the beginning, Orlowski said.
Associate Professor Chng Wee Joo
Yong Loo Lin School of Medicine, National University of Singapore
Cancer Science Institute of Singapore
Department of Haematology-Oncology, National University Cancer Institute, Singapore
I
n Asia, we know the incidence of multple myeloma is lower than in the US and that
important disease abnormalites appear to be the same. But that is about it.
Groups like the Asia Myeloma Network are pioneering epidemiological research to
understand whether certain genetc subtypes or those with high-risk disease are more or
less common here compared to the US.
As the thinking behind treatment has evolved, we are also looking into maintenance
therapy with novel and emerging therapies and there may be trials in this area, in the
Asia Pacifc region, as well.
The beauty about treatng MM is that the novel agents keep coming even more will
come in the next 5 years. The challenge will be to understand how to use them, what
combinatons or sequences to try and which patents will beneft the most.
The nice thing about therapies like lenalidomide and bortezomib, which are not truly
novel now, is that they have clear benefts to patent survival as well as being well toler-
ated, non-toxic and can be given in outpatent setngs, which improves quality of life.
Perspectives on Myeloma
Nexium promo ad output (290x 406mm) new3.pdf 1 11/01/2012 3:33 PM
51
February 2012 Cont r acept i on
Combined oral contraceptive pill helps ease
painful periods
Elvira Manzano
T
aking birth control pills may ofer extra
beneft for women who sufer from men-
strual pain, according to a longitudinal, case-
control study conducted in Sweden.
In the study, which involved 2,102 women
aged 19 at baseline, those who received a
combined oral contraceptve (COC) pill had
signifcantly lower severity of dysmenorrhea
at 5-year follow-up, with a mean 0.3-unit
reducton on the verbal multdimensional
scoring (VMS) system for ratng pain com-
pared with non-users (P<0.0001). [Hum
Reprod 2012; DOI:10.1093/humrep/der417]
[This] means that every third woman
went one step down on the VMS scale, for
instance from severe pain to moderate pain,
which meant that they sufered less pain,
improved walking ability with a decrease
in the need for analgesics, said lead study
author Dr. Ingela Lindh from Gothenburg
University in Sweden.
COC use was also associated with a 9-mm
reducton in pain as measured on a 10-cm
visual analogs scale (VAS). [P<0.0001]
We found that there was a signifcant
diference in the severity of dysmenorrhea
depending on whether or not the women
used oral contraceptves, said Lindh, who is
a nurse and a midwife.
Increasing age was also associated with
decreased severity of symptoms (reducton
of 0.1 units in VMS score, 5 mm in VAS score
for 5 years, both P<0.0001). However,these
efects were small compared to those seen
with the pill. Childbirth was another factor
that infuenced severity of menstrual pain
(with a reducton of 7 mm in VAS, P<0.01)
but this was not fully analyzed as very few
women had given birth between the ages
of 19 and 24 in this study.
In this study, use of COC and increas-
ing age, independent of each other,
reduced the severity of dysmenorrhea,
the authors said.
COCs have long been used of-label for
dysmenorrhea but a Cochrane review found
only small evidence for efcacy.
Its good for women to know that there
are some benefts of the pill, Lindh said.
Informaton about the efects of COC use
on painful periods should be included in
contraceptve counseling Women who
experience a benefcial efect other than
contracepton, such as reducton in dysmen-
orrhea, are more likely to contnue with the
pill.
She did however admit that the study
should be confrmed by a placebo-controlled
randomized trial to assess the efcacy of
COCs as a primary outcome measure.
Fify to 75 percent of young women suf-
fer from dysmenorrhea. In the US, it has
been estmated to account for 600 million
lost working hours and a cost to the econ-
omy of around US$2 billion due to lost pro-
ductvity a year.
Informaton about the efects of COC use on painful periods should
be included in contraceptve counseling
52
Some contraceptives may exacerbate seizures
Radha Chitale
H
ormonal contraceptves may result
in more seizures in epileptc women
compared with non-hormonal contracep-
ton methods, new research shows.
Data from 300 women aged 18-47 years
who completed the Epilepsy Birth Control
Registry survey showed that hormonal
contraceptves, which can include con-
traceptve pills, vaginal rings, patches and
injectables, increased seizure frequency by
17.8 percent, while non-hormonal contra-
ceptves, which can include male and female
condoms, intrauterine devices (IUDs), sper-
micides and diaphragms, increased seizure
frequency by 2.9 percent (P<0.0001).
Although contracepton is an impor-
tant consideraton for women of reproduc-
tve age, there has been litle investgaton
of contraceptve practces in women with
epilepsy, the researchers said in a presen-
taton during a meetng of the American
Epilepsy Society, held recently in San Diego,
California, US.
Seizure exacerbaton occurred when
hormonal contraceptves were used in con-
juncton with ant-epileptc drugs (AEDs),
although the extent of exacerbaton dif-
fered depending on the drug.
Valproate users experienced the most
exacerbatons if they also used hormonal
contraceptves (43.6 percent), instead of
non-hormonal contraceptves (7.7 percent)
[P=0.0007].
The researchers observed a similar
though less signifcant efect with car-
bamazepine, which was associated with
more seizures when respondents were also
taking hormonal contraceptves. The pat-
tern was consistent with glucuronidated,
enzyme-inducing AEDs and non-enzyme-
inducing AEDs.
The researchers theorized that elevated
estrogen levels in the presence of valproate
could lower the seizure threshold and so
increase their frequency.
In the absence of AED use, hormonal
contraceptves were associated with a
24.4 percent increased seizure frequency.
In comparison, non-hormonal contracep-
tves increased seizure frequency by 6.67
Hormonal contraceptive drugs were shown to
increase the rate of seizures in a survey of 300
women with epilepsy.
53
percent (P=0.0463).
Among the survey cohort, 72 percent of
the women reported using contracepton
in a parallel survey, most ofen an oral con-
traceptve (23 percent), male condom (23
percent, IUDs (12 percent) and withdrawal
(10 percent).
Of a group of 178 high-risk women sur-
veyed classifed because of their potental
fertlity and sexual actvity most were
found to use highly efectve contraceptve
methods including hormonal contracep-
tves, IUDs, tubal ligatons and vasectomy.
Prospectve investgatons are needed
to determine whether these fndings rep-
resent important seizure safety issues or
reportng biases, the researchers con-
cluded.
Text reminders improve pill compliance
Rajesh Kumar
D
aily text messages have been shown
to markedly improve womens adher-
ence to an oral contraceptve pill (OCP)
regimen over a 6-month period.
In a randomized controlled trial, research-
ers assigned sexually actve women <25
years of age, who sought contracepton to
prevent unwanted pregnancies, to either
routne care (N=482) or routne care plus
daily educatonal text messages for 180
days (N=480) and obtained contnuaton
data on 683 of them (337 and 346, respec-
tvely). [Obstet Gynecol 2012; 119:1420]
Routne care included counseling by staf
at a family planning clinic and educatonal
handouts detailing the use, efectveness,
benefts and risks of oral contracepton.
The endpoint was self-reported OCP con-
tnuaton at 5 to 8 months.
At the 6-month follow-up, 64 percent of
women receiving daily text messages were
stll using the pill, compared to 54 per-
cent of the routne care group (P=0.005).
Adherence was the highest among the
group if the follow-up took place while
the text messages were stll being sent
(75 percent, compared with 54 percent;
P=0.003). The efect of the interventon
on adherence became less obvious when
the text messages stopped (60 percent in
those who had previously received texts,
compared with 54 percent in those who
never did; P=0.16).
In analyses adjusted for age, race or
ethnicity, age at frst sexual experience,
pregnancy history, and OCP experience,
the study showed women receiving daily
text reminders were more likely to con-
tnue taking the pill compared to oth-
ers at 6 months (odds rato 1.44, 95% CI
1.032.00).
Unlike programs that seek to change
the behavior of an individual woman to
increase OCP contnuaton (eg, through
enhanced counseling), the text messag-
ing interventon used in the study instead
adapts the health system to improve out-
come, said the researchers.
Such a strategy enables health care
providers to enhance the contraceptve
success of their patents simply by aug-
mentng their clinical practce.
Young women are most likely to choose
OCP as the preferred method for prevent-
ing unwanted pregnancies, but improper
use and discontnuaton are common.
54
Six-month OCP contnuaton rates in young
women range anywhere from 12 to 58 per-
cent and failure to establish a routne of
taking the pill is cited as a common reason
for OCP discontnuaton.
Professor P.C. Wong, gynecologist and
senior consultant at the Natonal University
Hospital Womens Centre in Singapore, said
that under the circumstances, it is important
for all involved in womens health to chip
in with their eforts to improve adherence.
be it the gynecologist who writes the
prescripton, the pharmacist who dis-
penses it, or the family planning clinic that
works for their welfare.
While text messages can indeed be
useful, Wong said many tools are already
available. For example, a pill reminder
smart phone applicaton recently launched
by the pharmaceutcal company, Bayer
Healthcare. The app can send daily push
reminders to those on the pill and includes
features such as customizable reminder
tme, countng remaining pills, considering
of days and 21 or 28 pill packs.
Physicians also need to establish if the
OCP is suitable for a partcular woman. If
someone is habitually forgetul and misses
more than three pills in a month, it is
important to recommend another method
of contracepton, said Wong.
Limitatons of the study included
researchers reliance on partcipant self-
report of ongoing OCP use, inadvertent
variable tme to follow up and lack of tai-
lored text message content.

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PressAd_NAN HA_Print_290x406_OP.pdf 2012/1/5 10:19:48 AM
56
February 2012 I n Pr act i ce
Management of CHF in primary care
Dr. David Sim
Consultant, Department of Cardiology
Co-Director, Heart Failure Programme
Natonal Heart Centre Singapore
Impaired pumping ability
Congestve heart failure (CHF) the
inability of the heart to pump oxygen-
rich blood sufcient to meet the bodys
metabolic needs is a clinical syndrome
accompanied by derangement in the neu-
rohormonal system, the renin-angioten-
sin-aldosterone system and sympathetc
system.
Common causes of heart failure include
ischemic heart disease, cardiomyopa-
thy and hypertension. Other causes are
alcoholic cardiomyopathy, valvular heart
disease, thyrocardiac disease, chemother-
apy-induced cardiomyopathy and viral
myocardits and in rare cases, hemochro-
matosis and amyloidosis.
When cardiac muscles are damaged, it
makes the heart less able to pump blood.
Fluid accumulates in the lungs, in the
abdomen, or in the peripheral tssues, a
conditon called fuid overload.
Diagnosing CHF
With proper history taking coupled with
comprehensive physical exam, physicians
are able to get a diagnosis. Echocardiogram
may be useful but not essental for CHF
diagnosis. A simple chest X-ray can detect
congeston in the lung. Jugular venous
pressure is ofen assessed as a marker of
fuid status. Blood tests performed include
electrolytes, renal functon and liver
CHF is the end result of a variety of insults
to the heart which in some cases may be
irreversible.
57
functon tests. The serum level of B-type
natriuretc peptde (BNP) or N-terminal pro
b-type natriuretc peptde or (NT-proBNP)
is related to the severity of heart failure.
Higher levels of BNP or NT-proBNP are
associated with bad prognosis.
Symptoms of CHF depend on the side
of the heart involved. In lef-sided fail-
ure, congeston of pulmonary vascula-
ture causes respiratory symptoms such as
dyspnea on exerton or at rest, orthopnea
increasing breathlessness on lying fat
and paroxysmal nocturnal dyspnea. Easy
fatgue and hypotension are signs of poor
cardiac output.
In right-sided failure, there is venous
congeston leading to fuid accumulaton
in the feet and ankles. Ascites and hepa-
tomegaly may also occur in progressively
severe cases. Liver congeston may result
in liver functon impairment. Jaundice and
deranged clotng may also occur.
Patents with biventricular failure ofen
present with both lef and right-sided
symptoms.
Clinical Guidelines
Physicians can refer to the American
Heart Associaton (AHA), the American
College of Cardiology (ACC) and the
European Society of Cardiology (ESC)
guidelines for managing heart failure.
Angiotensin-convertng enzyme inhibi-
tors (ACE inhibitors)/angiotensin recep-
tor blockers (ARBs) and beta-adrenergic
blockers (beta-blockers) are the corner-
stone of treatment in patents with heart
failure and a reduced lef ventricular
ejecton fracton (LVEF). Use of aldoster-
one antagonists is recommended in New
York Heart Associaton (NYHA) Class III/IV
patents with LVEF of <35 percent.
The SEATTLE Heart Failure Model which
is available online predicts mortality risk
in CHF patents. It includes medicatons
and devices used to treat heart failure
and how altering these afect survival. A
new mobile applicaton, the Seatle Heart
Failure Risk Calc, also provides an estmate
of survival rates and average years of sur-
vival for patents with heart failure.
Management approaches
Treatment of CHF focuses on dietary
changes and pharmacological modalites,
the primary objectve of which is to restrict
fuid. A liter or up to 1.2L a day is recom-
mended depending on the patents size.
Sodium intake is also restricted. Some
patents need to be put on diuretcs when
there is evidence of fuid overload. Digoxin
is useful in patents with atrial fbrilla-
ton. ACE inhibitors and beta-blockers, if
not contraindicated, are part of standard
therapy. Besides initatng the evidence-
based drugs, GPs should note the dosage.
They should see the patent in 2 weeks
to recheck electrolytes and renal func-
ton. If the patent is stable, upttraton of
ACE inhibitors and betablockers is recom-
mended untl the maximum dose is toler-
ated. Clinical trials have shown that the
higher the doses, the beter the prognosis.
Exercise is also encouraged if tolerated.
New alternatves to ACE, beta-blockers
GPs and non-cardiologists should
look beyond ACE inhibitors and beta-
blockers. New drugs are available. One is
eplerenone, a selectve aldosterone antag-
onist. In the EMPHASIS-HF trial, treatment
with eplerenone reduced the risk of car-
diovascular deaths by 24 percent and the
risk of hospitalizaton for heart failure by
58
42 percent in patents with mild symptoms
(Class II). The incidence of gynecomasta
seen with spironolactone is also lower.
For Class III or IV patents, we use spirono-
lactone based on the RALES trial.
Another drug available is ivabradine,
which in the SHIFT-HF trial was shown to
decrease mortality when added to stand-
ard therapy of ACE inhibitors/ARB and
beta-blockers. Ivabradine is recommended
in patents with sinus rhythm with a heart
rate of >70 beats per minute.
Challenge to GPs
CHF is the end result of various insults
to the heart which in some cases may be
irreversible.
The key message for GPs is not just to
treat CHF as a simple fuid overload issue.
Patents ofen have other co-morbidites
such as renal impairment, anemia, sleep
apnea and depression. All patents with
newly diagnosed heart failure should be
referred for further evaluaton. Once sta-
ble, patents can be managed in the pri-
mary care setng.
Some patents may present without
symptoms (NYHA Class I) but succumb to
sudden cardiac death. The most common
reasons for this are ventricular tachycar-
dia (VT) and ventricular fbrillaton (VF) in
patents with poor ejecton fracton. In this
case, implantable cardioverter defbrilla-
tor (ICD) improves survival.
Patents younger than 60 years old,
with symptoms that do not improve
despite optmal medical therapy, should
be referred to us for transplant.
New advances in CHF treatment
Recently, the lack of good, healthy
heart transplant donors has seen the
need to improve the current generaton
of mechanical heart devices. The widen-
ing gap in the number of patents await-
ing transplantaton and hearts available
for transplant has prompted eforts to
make the current generaton of ventricu-
lar assist devices (VAD) smaller, more con-
venient and totally implantable. Device
therapy has started to play in selected
patents with CHF. The challenge now for
cardiologists is how to get rid of the drive-
line to eliminate potental source of infec-
ton. If the pump technology improves to a
stage that survival with VAD is equivalent
to heart transplantaton, then transplanta-
ton may be replaced by VAD.
Stem cell therapy is also being tested.
This and other signifcant advances in drug
therapy have sparked an unprecedented
optmism in the treatment of CHF. We, at
the Natonal Heart Centre, Singapore, are
actvely taking part in clinical trials and are
awaitng eagerly the results of other big-
ger studies.
CHF is a debilitatng if not fatal condi-
ton with lots of burden on the patent, the
family, livelihood and the health care sys-
tem. We need a mult-approach to tackle
this problem.
Online Resources:
American Heart Associaton
www.american heart.org/heart failure
Heart Failure Maters
www.heartailurematers.org
European Society of Cardiology
www.escardio.org/communites/HFA/Pages/
welcome.aspx
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February 2012 Cal endar
February
22nd Conference of the Asia Pacifc
Associaton for the Study of Liver
Diseases
16/2/2012 to 19/2/2012
Locaton: Taipei, Taiwan
Info: Asia Pacifc Associaton for the
Study of Liver Diseases
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2/3/2012 to 6/3/2012
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3/3/2012 to 4/3/2012
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20th Annual Meetng of the Asian
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8/3/2012 to 11/3/2012
Locaton: Bali, Indonesia
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Surgery
Tel: (1) 62-21-566-5993
62
February 2012 Cal endar
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61st American College of Cardiology
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24/3/2012 to 27/3/2012
Locaton: Chicago, Illinois, US
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15th World Congress of
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25/3/2012 to 30/3/2012
Locaton: Buenos Aires, Argentna
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in Medicine and Biology
22/4/2012 to 24/4/2012
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III NWAC World Anesthesia Conventon
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24/4/2012 to 28/4/2012
Locaton: Istanbul, Turkey
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Fax: (41) 22 906 9140
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American Thoracic Society Internatonal
Conference 2012 (ATS 2012)
18/5/2012 to 23/5/2012
Locaton: San Francisco, California, US
Tel: (1) 212 315 8652
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tonal-conference
15th Biennial Meetng of the European
Society for Immunodefciencies (ESID
2012)
03/10/2012 to 06/10/2012
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Tel: (41) 22 908 0488
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42nd Annual Meetng of the
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15/10/2012 to 19/10/2012
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January 2012
63
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64
February 2012 Af t er Hour s
Autumn in
Kyoto
Christna Lau discovers autumn colors
in Kyoto, Japan, when maple leaves were
turning red in mid-November.
T
he Japanese term momijigari (,
red-leaf hunting) vividly describes the
character of the
countrys maple leaves in
autumn. Despite meticu-
lous forecasts of when the
leaves are going to turn red
in diferent parts of Japan,
whether you catch them
65
February 2012 Af t er Hour s
Autumn in
Kyoto
in their most vibrant colors is a matter of
luck.
With the forecast that Kyoto leaves
were going to start turning red in early
November, we set of hoping to see stun-
ning seas of red at scenic spots across the
city by the middle of the month. But the
maple leaves were just starting to turn
red when we were in Kyoto.
The late arrival of autumn colors did
not hamper peoples spirits, as focks of
local and overseas tourists could be seen
snapping pictures of any red leaf in sight.
At popular attractions such as the Kiyo-
mizu Temple () and the nearby
Jishu Shrine (), young women
came in kimono (traditional Japanese
full-length robes) to celebrate the oc-
casion and pray to the deity of love and
matchmaking said to reside in the latter.
For a break from the crowd, Sagano
() in the northwestern part of the
city ofers tranquility at temples built
more than 1,000 years ago. Many of the
temples house sculptures and scriptures
ofcially classifed as National Treasures
and Important Cultural Properties of Ja-
pan. These temples are also fabulous
spots for red-leaf viewing, where autumn
colors complement the beauty of the ar-
chitecture and traditional Japanese gar-
dens.
If you want to see autumn colors in
Kyoto, it is not too early to book a few
months in advance. With the large num-
ber of visitors focking to the city in No-
vember, most hotels and inns were full
when we booked in September.
66
February 2012 Humor
Lets go in and see what happens!
I should warn you that insurance fraud is a very
serious offence.
Pill time Mr. Helmholtz.
Lets hope its not contagious!
The transplant was a tremendous success.
Would you like to keep your old heart as a
souvenir?
Your husband has a great sense of humor. We
couldnt stop laughing throughout the whole
operation!
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