Thursday, February 5, 2009

Mixed fortunes for ultrasound breast cancer screening

Medical Tribune July 2008 SFIV
David Brill

Adding ultrasound to standard mammography for breast screening will identify more cancers but also lead to more false alarms, according to research published in the Journal of the American Medical Association.

The study, conducted by the American College of Radiology Imaging Network, found that a combined protocol would yield an extra 4.2 cancers for every 1,000 women screened compared to mammography alone (95 percent confidence interval 1.1 – 7.2; P=0.003). Combining ultrasound with mammography, however, increased the false positive rate from 4.4 percent to 10.4 percent. [JAMA 2008 May 14;299(18):2151-63]

Dr. James Khoo, head of the department of oncologic imaging at the National Cancer Centre Singapore, said that this increase was a concern.

“From mammography alone you would be doing a certain number of biopsies, but if you add ultrasound the number of biopsies would increase significantly and the vast majority would be benign results,” he said.

Khoo added that being recalled for extra tests is “a very fearful experience” for most women, and that feelings of anxiety can persist for a long time even once a lesion is identified as benign.

The study analysis comprised 2,637 women at high risk for breast cancer, who were followed up for 12 months. Of these 275 were recommended for an unnecessary biopsy after combined screening, compared to 116 who were screened with mammography alone.

Although combined screening increased the diagnostic yield in the study it did not detect all cancers: eight women out of 40 who were ultimately diagnosed with cancer had lesions that were not detected on either modality.

Previous research suggested that women at high risk for breast cancer should be monitored using mammography and magnetic resonance imaging (MRI). [J Clin Oncol 2005 Nov 20;23(33):8469-76]

Although unlikely to replace MRI in these patients, ultrasound could be used in addition or as an alternative when MRI is contraindicated, said Khoo.

Ultrasound is well tolerated, relatively inexpensive and widely available, and has the potential to detect small node-negative cancers which can be missed by mammography. However the technology is hindered by high inter-observer variability and a low sensitivity for detecting microcalcifications, such as those seen in ductal carcinoma in situ.

In an accompanying comment in the journal, Christiane Kuhl from the University of Bonn in Germany wrote that: “Individualized screening schemes tailored to the individual risk and to the personal preferences of a woman may be the way to consider how to screen for breast cancer.

“Whether in the long run, ultrasound or breast MRI will be more appropriate for this purpose remains to be seen,” she concluded

Brain tumor removed using robotic arm

Medical Tribune July 2008 SFVIII
David Brill

Doctors in Canada have become the first in the world to successfully remove a brain tumor using robotic surgery – a procedure hailed as a “breakthrough.”

The team at The University of Calgary took 8 hours to remove a subfrontal meningioma from the brain of a 21-year-old woman using the neuroArm – a magnetic resonance imaging (MRI)-compatible system which is capable of extremely fine movements.

Dr. Garnette Sutherland, the team leader, said that the system had “exceptional capabilities.”

“This is a turning point in the performance and teaching of neurosurgery. neuroArm will improve surgical outcomes as it is less invasive and more delicate in its touch,” he said.

neuroArm combines real-time image guidance with the option to do MRI on demand, providing the operator with superior spatial orientation to that offered by earlier systems. Surgeons using the system can work at a resolution of 50 – 100 μm.

The arm, which can be used to perform both surgery and biopsies, is operated from an external room using a state-of-the-art control panel which offers tremor filtering and motion scaling.

Dr. Tang Kok Kee, a neurosurgeon at Mount Elizabeth Medical Centre in Singapore, described the surgery as “a very good breakthrough.” He added that neuroArm offered good dexterity, and that the removal of operator tremors would allow for great precision.

The patient had a tumor of the olfactory groove which was affecting her sense of smell. She was discharged 2 days after the procedure.

Since completing its first operation neuroArm has continued to perform surgery, including the removal of a very deep-seated tumor located anterior to the brain stem.

“I suspect neuroArm and other robotic systems will have an increasing role to play not only in neurosurgery but in all surgical specialties,” said Sutherland.

Singapore splashes the cash to boost pool of clinician-scientists

Medical Tribune July 2008 SFXII
David Brill

Around S$180 million is to be invested in medical research in Singapore over the next five years in a joint initiative by the Ministry of Health (MOH) and the Agency for Science, Technology and Research (A*STAR).

Oncology, retinal imaging and cognitive neuroscience are the main fields to benefit from the creation of two new award schemes, which are intended to bridge the gap between scientific research and clinicalpractice.

Speaking at a recent award ceremony, MOH permanent secretary Yong Ying-I described the program as “an important phase in our efforts to nurture a core group of clinician-scientists who will take our biomedical sciences initiative to the next level.”

The Singapore Translational Research Investigator Award (STaR) is the top award in the program. Recipients receive a research grant of up to S$1 million each year for 5 years, as well as complete salary funding and a one-off start-up sum.

Professor David Virshup, director of the Program in Cancer and Stem Cell Biology at the Duke-NUS graduate medical school, is one of four inaugural STaR awardees. His laboratory has been awarded the full S$1 million-a-year, and will be focusing on studying the signaling pathways that are involved in the proliferation of cancer stem cells.

“Having this award allows us to lure back to Singapore people who were getting funded elsewhere. Now that the funding is good here, people like to do their research here,” he said, noting that his research group includes recently-returned Singaporeans who had trained in the US and Canada.

Virshup added that the awards are important for helping practicing physicians to further their research careers.

“If they’re working too hard in the clinic they can’t get any research done. This sort of funding is designed to free-up their time and [help them] to recognize the importance of turning off the beeper, going into the lab and thinking differently for a while, and to take that clinical experience and turn it into a knowledge advance,” he said.

The second type of award is the Clinician Scientist Award (CSA) – a revamped version of the Clinician Scientist Investigator Award that was launched in 2004. The new scheme provides full salary support through the recipient’s institution, whereas the previous system only funded 70 percent of their salary.

Chng Wee Joo, a CSA winner, was working at the Mayo Clinic, US, until last year. He was offered a position to stay on but chose instead to pursue his research in Singapore, feeling that the opportunity to return was “equally attractive.”

“This is a really exciting time for a young researcher like me to come back,” said Chng, who is currently a consultant in the hematology and oncology department at National University Hospital and an associate professor in the Yong Loo Lin School of Medicine at the National University of Singapore, where he is researching multiple myeloma and the role of genes that cause the condition to become malignant.

Applications for the new awards were invited around a year ago. The proposals underwent an international peer review process before being reviewed by a biomedical sciences executive committee, which assessed the projects on both their scientific merit and their relevance to Singapore.

World expert leads Singapore’s gamma knife center

Medical Tribune July 2008 SFXIII
David Brill

Singapore’s new gamma knife radiosurgery center, due to open in early July, is to be headed by one of the world’s leading experts on the technology.

Dr. Bengt Karlsson, who has been working with gamma knife technology since 1986, will be present at the opening ceremony and expects to relocate permanently to Singapore by late autumn. His exact role at the center was still to be confirmed at the time of writing but it appears likely that he will be the center’s new director or co-director.

“I believe that we can enhance the reputation of the gamma knife center to be one of the very best in the world,” said Karlsson, who is currently based at West Virginia University in the US.

“Our aim is to have a treatment quality that meets the highest expectations, and I am thrilled to have been given the opportunity to participate in this.”

Karlsson has used gamma knife treatment for more than 4,000 patients, having previously served as director of the centers at the Karolinska Institutet in Stockholm, Sweden and Goethe University in Frankfurt, Germany. He has also been involved with developing the technology in Singapore and has helped train local doctors to become proficient with the system.

“He’s a mentor for most of the neurosurgeons here for gamma knife radiosurgery,” said Dr. Yeo Tseng Tsai, medical director of the new center, adding that he was looking forward to working with Karlsson in future.

The new center was built by ParkwayHealth at a cost of around S$1.7 million. Singapore has been without a gamma knife machine since the closure of the previous center at Singapore General Hospital in August 2007.

“When the gamma knife was down and some of the neurosurgeons had to use the other systems it was obvious that they were not happy,” said Yeo.

“This gives us access to gold standard radiosurgery again, which has been missing for the last year or so.”

Yeo expects the center to treat around 100 patients a year – primarily those with benign well-defined brain tumors but also some cases of arteriovenous malformations, trigeminal neuralgia and rarer types of tumor.

Private patients will typically pay around S$23,000 to S$25,000 per procedure.

Gamma knife surgery uses converging beams of radiation to target tumor cells while sparing the surrounding healthy brain tissue. The technique is attractive for patients as it is quick and non-invasive, and does not require hospitalization.

Identifying causes of hospitalization could optimize heart failure care

Medical Tribune July 2008 P11
David Brill

The factors that precipitate hospitalization for heart failure (HF) are independent predictors of clinical outcomes, a large multicenter study from the US has found.

HF patients who were hospitalized with pneumonia, worsening renal function or ischemia had the highest in-hospital mortality, whereas those with uncontrolled hypertension had the lowest. Ischemia and worsening renal function were also most strongly associated with mortality following discharge.

“Identifying these precipitating factors can be helpful for clinicians and give us targets for therapy addressing some of these precipitating factors, which are preventable,” said Professor Gregg Fonarow, principal investigator for the study and associate chief of the division of cardiology at the University of California, Los Angeles.

“This can help improve clinical outcomes, improve care and avoid future hospitalizations, and be important in optimizing the management of this high-risk, high-morbidity and high-mortality patient population.”

The study, part of the ongoing Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF), included data on 48,612 patients from 259 US hospitals with 60 to 90 days of follow-up for each case. Almost two-thirds of patients (61.3 percent) were identified as having at least one factor that had led to hospitalization. [Arch Intern Med 2008 Apr 28;168(8):847-54]

The risk-adjusted odds ratios (ORs) for in-hospital mortality were 1.6 for patients hospitalized
with pneumonia, 1.48 for worsening renal function, 1.2 for ischemia, and .74 for uncontrolled hypertension – a factor which was also linked to a lower overall risk of death or rehospitalization following discharge (hazard ratio .71). ORs for mortality during followup were 1.52 for ischemia and 1.46 for worsening renal function.

In light of these findings, Fonarow advised hospital doctors who are treating HF patients to read through the history, determine which factors may have contributed to their worsening in symptoms and take steps to rectify them.

Dr. Kenneth Ng from the Novena Heart Centre in Singapore agreed that identifying and addressing precipitating factors is important for preventing a recurrence of hospitalization for HF.

“In (Singapore’s) National Healthcare Group hospitals we have a built-in protocol to vaccinate
all our HF patients against influenza and pneumonia,” Ng said. He added that: “every effort
should be made to monitor renal function closely, especially when starting and titrating angiotensinconverting enzyme inhibitors and angiotensin receptor blockers”.

Ng admitted, however, that he was “a little disappointed” with the modest nature of the study’s results – when the researchers compared all patients with one or more precipitating factors against those with none, the adjusted OR for inhospital mortality was .88 (95 percent
CI .78 – 1.00) with a borderline P-value of .046. There was no significant difference in follow-up mortality when comparing these patient groups.

Doctors sacrifice honoraria in quest for objectivity



Medical Tribune July 2008 P12-13
David Brill

Feeling their integrity questioned, some doctors are beginning to reject money
from the pharmaceutical industry. David Brill reports.

Professor Kelly Brownell
was once offered US$50,000
to join the advisory board
of a pharmaceutical company. He
turned it down and “feels good
about the decision.”
Brownell, director of the Rudd
Center for Food Policy and Obesity
at Yale, is one of several highprofile
US academics who have decided
to stop taking any payments
from the industry. He gradually
settled on the decision around 10
years ago, having begun to question
the influence that financial
reimbursement was having on his
professional judgment.
“Scientists pride themselves
on objectivity as their cardinal virtue,
but it’s remarkable how nonobjective
scientists can be when
conflicts of interest are involved,”
he said, citing the literature published
around the subject as the
main factor in his decision.
“The studies suggest that
when industry pays for research
or pays people as consultants they
get something in return. And in
addition, the studies show that
industry-funded science typically
finds results favorable to the industry,”
said Brownell. In his own
experience, he added, he felt “a
natural tendency to want to help
the companies.”
“The money really comes in a
lot of different forms but the two
main ones are funding for one’s research,
and then the other is money
that you get as an individual,” he
explained.
“People become reliant on
these things. For some the money
can be considerable, and it pushes
them up the social and economic
ladder. And for a lot of people
they don’t want to go down a rung
or two.”
Brownell’s move has recently
been followed by two doctors at
Harvard – Peter Libby, the chief of
cardiovascular medicine, and Eric
Winer, the director of the Breast
Oncology Center at the Dana-Farber
Cancer Institute. How many
more doctors in the US will follow
their lead remains to be seen.
Conflicts of interest are presently
a hot topic in the US. A recent
high-profile editorial in the
New England Journal of Medicine
called for greater transparency in
the declaration of funding sources,
concluding that: “The public’s
trust in biomedical research depends
on it.” [N Engl J Med 2008
Apr 24;358(17):1850-1] The murky
nature of the relationships between
doctors and pharmaceutical
companies has also prompted
two senators – Chuck Grassley of
Iowa and Herb Kohl of Wisconsin – to propose new legislation
that would make it mandatory
for pharmaceutical companies to
publicly declare how much money
is given to doctors. The proposal,
known as the Physician Payments
Sunshine Act, has received the
public backing of the Association
of American Medical Colleges,
and was also recently endorsed by
Eli Lily.
In Southeast Asia, doctors are
largely governed by guidelines
and codes of ethics issued by the
various medical associations, and
these issues have yet to reach the
mainstream legal agenda. Dr. Ravindran
Jegasothy, former chairman
of the ethics committee at the
Malaysian Medical Association,
believes nonetheless that it remains
very important to educate
medical professionals about how
to handle their relationships with
the industry. He called the decision
by Brownell, Libby and Winer to
distance themselves financially a
“commendable move” in drawing
attention to some of the issues at
hand.
“It sets people thinking: ‘where
is it that we should draw the line?’”
he said. “My personal view is that
if possible, doctors should not be
sponsored by drug companies. I
feel there is always an ethical dilemma
when a pharmaceutical
company sponsors you.
“Senior people should be role
models in how they conduct their
relationships,” explained Jegasothy,
who is also head of the department
of obstetrics and gynecology
at Hospital Kuala Lumpur.
“I feel that an individual who’s
in a leadership position should as
far as possible diverge himself
from the pharmaceutical industry
… In some cases, in our country
we have had bad examples being
set by senior people taking part in
private excursions or golf tournaments
and so on, which you hear
about being sponsored by pharmaceutical
companies. I think that
does not set a good example for
the juniors.”
Jegasothy would encourage
more doctors take a similar stance
to Brownell. Not everyone, however,
is quite so supportive of the
move.
“I think the action in this case
is a bit extreme, quite frankly,” said
Professor Brian Tomlinson, who is
head of clinical pharmacology at
the Chinese University of Hong
Kong. “I think it’s a sort of noble
idea but in practice it’s not easy for
everyone to do that. If everyone
did it the whole progress of clinical
and medical research would grind
to a halt.
“It just isn’t viable for the majority
of doctors doing clinical
research, especially within Asia.
There isn’t that much funding
readily available and if you want
to do any substantial research it’s
necessary to collaborate with the
industry.”
As both a clinician and an academic
researcher, Tomlinson is
used to dealing with patients while
also liaising with pharmaceutical
companies over the development
of clinical trials. He feels that doctors
should keep a balanced view
and avoid aligning themselves with
any one company more than the
others, but should not be encouraged
to renounce pharmaceutical
money entirely. And if they have
to give up their time to advise, he
says, it is reasonable to expect payment
for it.
In Singapore, the academic
research community is not in the
same sort of quandary as Brownell
and his colleagues, according to
Dr. Thiru Thirumoorthy, a former
director of the Singapore Medical
Association’s Centre for Medical
Ethics and Professionalism. Fewer
phase I and II trials are conducted
in Asia than in the US and Europe
so it’s less of a problem at present,
he said.
Thirumoorthy warned, however,
that conflicts of interest will
inevitably arise as more research
is done in the region. He believes
that ethics committees should be
given greater financial support
and resources in order to monitor
research closely and avoid the situation
where doctors feel the need
to distance themselves from the industry,
as their counterparts in the
US have done.
“The lesson to learn is for us
not to reach this point. If you don’t
moderate, beginning early, and if
we don’t have the infrastructure
then we will end up like this,” he
said.
Brownell has his own suggestions
for limiting the potential for
future conflicts of interest involving
doctors and pharmaceutical
companies.
“The problem is pretty obvious.
If an industry does research
on their own products they have
a strong interest in positive outcomes.
One solution would be for
the industry to take some of the
money they’re spending on these
studies, pool it, and let some objective
outside group commission the
study,” he said.
Acknowledging that it could
be harder for more junior doctors
to say no to pharmaceutical sponsorship,
he added that: “The fact
that young people are vulnerable
to the money because they need it
speaks to the sad state of government
funding for research.”
Brownell agreed with Jegasothy’s
point that senior academics
should act as role models for
younger doctors but, not wishing
to sound as though he was
preaching, was reluctant to directly
encourage others to follow his
example.
“I did it because of my own
principles but if it serves as a model
for others then so be it.”

Dementia in the primary care setting

Medical Tribune July 2008 P14-15

Diagnosis
Patients with dementia typically
present with some general
symptoms that should alert the
doctor to their condition. The major
symptom is memory deterioration,
which usually begins with difficulty
in recalling recent events. As a
result patients may misplace items,
fail to recognize people, become
disorientated to time, forget that
they have eaten and become confused
in unfamiliar surroundings.
Longer-term memory, conversely,
can often remain intact during the
early stages of the condition. Behavioral
and psychiatric symptoms
can also be suggestive of dementia,
such as agitation, aggression, hallucinations
and delusions – particularly
of people wanting to harm
them or steal from them. Sleeplessness
and nighttime wandering are
also common symptoms.
Recognizing dementia in its
early stages can be challenging
as elderly people are often quite
forgetful and these warning signs
can be dismissed as normal aging.
The condition can also be confused
with depression, as depressed patients
may also present with forgetfulness
and poor attention and
concentration. Furthermore the
diagnosis is often missed in cases
where the patient visits a doctor for
other reasons and neglects to mention
that he or she is becoming forgetful,
so it is important that physicians
remain aware of the condition
in order to recognize it early.
A full psychiatric and medical
history should be taken, and
any problems with daily functioning
and aspects of self-care such
as bathing and feeding should be
noted. A mental state examination
should be performed to look for
depressed and irritable mood, hallucinations
and delusions. It is also
important to perform a full cognitive
assessment using tests, such as
the Mini Mental State Examination
and the Elderly Cognitive Assessment
Questionnaire. These can be
time-consuming, however, and
busy general practitioners (GPs)
may prefer to use quicker tests
such as the Abbreviated Mental
Test, and then refer the patient to
a geriatrician or psychologist for
more detailed assessment. The
doctor should also take the time
to perform a complete physical examination
to rule out other medical
problems.
There are a number of tests
that general practitioners should
perform to establish whether a
patient with forgetfulness has dementia.
The initial objective is to
exclude other potential causes for
the problem, many of which may
be reversible with the appropriate
treatment. Blood testing should be
used to rule out anemia, hypoglycemia,
syphilis, and vitamin B12
and folate deficiencies. Liver, kidney
and thyroid function should
be tested, and urine analysis
should be performed to exclude
infections. Suspected cases should
also receive a chest x-ray and a
computed tomography scan, and
in some cases the radiologist will
also recommend magnetic resonance
imaging.
Once the diagnosis is established
the doctor should assess
which type of dementia is present
in the patient. The most common
forms are Alzheimer’s disease,
which is caused by the formation
of amyloid plaques and neurofibrillary
tangles, and vascular dementia,
which is caused by stroke.
Physicians can make the distinction
using specific diagnostic criteria,
such as those contained in
the International Classification of
Diseases or the Diagnostic and the
Statistical Manual of Mental Disorders.
A family history for Alzheimer’s
disease should arouse suspicion
for this diagnosis, whereas a
recent history of stroke or the presence
of multiple risk factors (such
as diabetes, hypertension, high
cholesterol and smoking) would
be clues for a diagnosis of vascular
dementia.
Practice Guidelines
Internationally-recognized
guidelines for treating patients
with dementia have been published
by the American Psychiatric
Association (APA), most
recently in October 2007. These
can be downloaded from the APA
website, along with a quick reference
guide. This document contains
a wide range of information
about all aspects of the condition
and should be relevant to doctors
in most countries.
The Ministry of Health in Singapore
published its own comprehensive
dementia guidelines in
March 2007 along with an 8-page
summary card. Dementia management
guidelines are also available
from the Academy of Medicine of
Malaysia, published in July 2003.
Treatment
Alzheimer’s disease and vascular dementia are progressive
non-reversible conditions and the
overall aim of treatment is to slow
down the functional deterioration
and to reduce the severity of associated
psychiatric symptoms.
It is important that GPs explain
these facts to the patient’s family
so that they have realistic expectations
and do not expect the patient
to make a full recovery. The family
should be educated about the
nature of dementia and its symptoms,
and should be prepared to
expect the worst.
Pharmacological treatment can
be employed in order to slow the
rate of cognitive decline in dementia
patients. The use of an acetylcholinesterase
inhibitor should
be considered for this purpose in
most patients. Donepezil, rivastigmine
and galantamine are all effective
drugs from this class. Memantine,
an N-methyl D-aspartate
antagonist, can also be used – either
alone or in conjunction with
an acetylcholinesterase inhibitor.
Other pharmacological agents
such as anti-inflammatories, prednisolone
and estrogen are not recommended
for preventing cognitive
decline in dementia patients.
Drug therapy can also be used
to target the specific symptoms
that may accompany dementia
such as depression, hallucinations
and psychosis. The use of these
drugs should be decided on a caseby-
case basis.
Doctors must also give careful
consideration to the non-pharmacological
aspects of dementia
management, and should try to
improve the quality of life for
both patients and their families
wherever possible. Depression,
psychiatric symptoms and sleep
disorders can all be distressing for
the family and should be taken
into consideration. GPs should
look out for carer stress and burnout,
which can lead to frustration
and sometimes elder abuse. They
should try to assess stress levels
by asking indirectly, but this can
be challenging as carers are unlikely
to volunteer such information
readily and may be sensitive
to questioning.
Dementia patients may benefit
from being referred to a day center
in order to keep them occupied.
This may also help the patient to
sleep better at night and reduce
carer stress levels.
In patients with VaD it is important
to prevent further strokes,
and risk factors such as hypertension
and diabetes should be addressed.
These patients should also
be given aspirin to reduce the risk
of recurrence.
Disease management tools
GPs who wish to further their
understanding of dementia can
often sign up for specialist training.
Programs such as these can
increase doctors’ knowledge of
the available resources and treatment
options and help them to
feel more confident about handling
their patients.
The Institute of Mental Health
(IMH) in Singapore, for example,
has a partnership program with
GPs – offering training comprised
of lectures and workshops. Upon
completion of training the GPs
can sign up for the IMH-GP partnership
program, where they can
participate in the management of
psychiatric and dementia patients
in their own clinics.
Conclusion
Dementia is distinct from normal
aging and needs to be carefully
distinguished from other causes
of forgetfulness. Early detection
is beneficial so that the patient
can be managed appropriately in
order to delay the progression of
symptoms and prevent further
complications.