July to September 2014
Médico
A quarterly publication of GP Liaison Centre, National University Hospital, Singapore.
MCI(P) 151/07/2014
Medical Sp
tlight
Approaches to
Refractory Cancers
SILS in HPB
Surgeries in NUH
Surgical Treatment
in Bone Metastases
- A Changing Paradigm
Associate Professor
Quek Swee Tian
02-03 Medical Notes • 04-06 Medical Spotlight • 07-14 Insight • 15-17 Treatment Room • 18-21 Doctor’s Heartbeat • 22-23 Medical Notes
M EDIC AL N O TES
NCIS Yong Siew
Yoon (YSY) Wing
at the NUH Medical Centre
The National University Cancer Institute, Singapore (NCIS) has come a long way since its first ambulatory
oncology centre was set up in Singapore at the National University Hospital (NUH) in September 1988.
Today, NCIS boasts a broad spectrum of substantial capabilities and facilities spanning over three floors
from Level 8 to 10 of the all-new NUH Medical Centre, providing one-stop holistic and comprehensive
care, management and treatment for both adult and paediatric oncology patients. NCIS moved most of its
outpatient facilities, e.g., Breast Care Centre, Viva-University Children’s Cancer Centre, Stem Cell Therapy
Centre, Chemotherapy Centre, as well as the Cancer Centre, into its current premises in the Yong Siew Yoon
wing of the NUH Medical Centre in August 2013. The relocation of the Radiation Therapy Centre (RTC)
from the Main Building of NUH to its new location at the new wing in February 2014 completed the move.
2 • MED ICO
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Figure 1. Resource Library @ Health Resource Centre
Figure 2. Patient Care at Chemotherapy Centre
Housed alongside other outpatient
medical specialisations at the Medical
Centre, NCIS brings together the expertise
of multiple clinical departments to
provide multidisciplinary cancer care via
a convenient and accessible one-stop
platform to allow for more efficient
consultations and treatment processes to
be carried out under one-roof.
Located at high level above ground (Level
8 of the NUH Medical Centre) and with
its expanded floor space of 2,500 square
metres, NCIS’ relocated Radiation Therapy
Centre now has an increased capacity
for six linear accelerators, outpatient
consultation rooms, teaching hubs, as well
as CT simulation and treatment planning
rooms while its new Breast Care Centre
provides a comprehensive diagnosis
and treatment platform for patients
with various breast conditions, including
imaging, surgery, preservation and
reconstruction.
Figure 3. Viva-University Children’s Cancer Centre
Having undergone an expansion to 550
square metres (from 320 square metres),
the Viva-University Children’s Cancer
Centre is now able to accommodate
increased capacity for oncology and
bone marrow transplant therapy. Patients
are also able to relax in comfort while
receiving chemotherapy as the paediatric
infusion bays come with inbuilt television
monitors where beds are provided to the
children for resting.
Designed with patients’ convenience
in mind, the Stem Cell Therapy Centre,
Chemotherapy Centre, as well as the
Pharmacy @ NCIS have also been
consolidated into dedicated one-stop
centres. The Cancer Centre is also
strategically located on the same floor as
the surgical oncology area so as to reduce
travelling time on the patient front.
As NCIS understands the emotional
distress faced by cancer patients, a
holistic approach is adopted for its
treatment processes, with its new Health
Resource Centre (HRC) offering support
programmes and services for both
adult and paediatric patients and their
caregivers. Both patients and caregivers
can visit its resource library stocked with
over 900 titles of fiction and non-fiction
books of different genres.
Now, the Health Resource Centre on the
10th floor of Yong Siew Yoon wing of
the NUH Medical Centre is also home
to a number of cancer support groups.
Lifestyle, support and educational
programmes are conducted on a regular
basis to promote well-being and enhance
quality of life for patients and caregivers.
2 014 JULY - S E P T E M B E R
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M EDIC AL S PO TLIGHT
A/Prof Chng Wee Joo
Director,
National University Cancer Institute,
Singapore (NCIS)
Head and Senior Consultant, Division of Haematology,
Department of Haematology-Oncology,
National University Cancer Institute, Singapore (NCIS)
Associate Professor Chng Wee Joo was appointed
Director of NCIS on 1 September 2014. He is the
Head of the Division of Haematology and a Senior
Consultant at NCIS. He is also the Deputy Director
of the Cancer Science Institute of Singapore at the
National University of Singapore (NUS). He obtained
his medical degree from the University of Leeds, UK,
and did his internal medicine residency in the United
Kingdom.
His fellowship training in haematology was completed
in Singapore before he obtained an A*STAR
international fellowship in 2004 to go to the Mayo
Clinic for a research fellowship in multiple myeloma
genetics. His current research is very translational and
involves the use of high-resolution global genomic
technique to understand biology, identify drug targets,
understand drug resistance and improve disease
prognosis in haematological malignancies, with the
ultimate aim of improving patient’s outcome and
personalising treatment.
Most cancers are not curable. One of
the common terminal events in these
incurable cancers is the refractoriness to
treatment. Tumours become refractory
when they become resistant to treatment.
Current treatment for cancers utilises the
following modalities either alone or in
combination:
1) Chemotherapy which kills both cancer
cells and normal cells by interfering
with DNA synthesis and relying on the
resulting activation of DNA damage
checkpoint to kill the damage cells.
2) Radiotherapy which similarly damages
DNA and affects both cancer and
normal cells.
3) Targeted therapy which comes in two
general forms:
a. Small molecules that target enzymes
and signalling molecules which are
critical for the malignant potential
as well as the survival of cancer cells.
These molecules may be mutated
or function abnormally in cancer
4 • MED ICO
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Approaches to
Refractory Cancers
cells, but not in normal cells where
the cancer cells become critically
dependent on them. Therefore,
their inhibition by drugs will result
in preferential killing of cancer cells.
b. Therapeutic antibodies that bind
specifically to proteins expressed
on cancer cells. In most instances,
these proteins are expressed at
much higher level on cancer cells
than normal cells. These antibodies
either can directly kill the cancer
cells, activate the patient’s immune
system to kill the cells, or can be
bound to drugs and act as a conduit
to deliver the drug into the cells
that they bind to.
Tumours become resistant to treatment
through a number of different
mechanisms:
1) The tumour cells express drug
transporters that pump out toxic
chemotherapy so that it cannot
damage the cancer cells.
2) The tumour cells develop mutations
in the genes being targeted by the
treatment such that the treatment is
no longer able to inhibit the gene.
3) The tumour cells increase expression
of the gene and protein targeted by
the drugs so that the dose of drug
used will not be able to inhibit all
the abnormal gene or protein that is
driving the cancer.
4) The tumour cells develop mutations in
alternative signalling pathways such
that the original target becomes no
longer relevant.
5) The tumour cells develop mutations in
genes that result in an ability for the
tumour cells to avoid death.
a tumour becomes refractory. Once we
understand the mechanisms, we can
design therapeutic strategies to resensitise the tumour to treatment.
Another approach is to identify potential
new genes, proteins or pathways in the
tumour that may be important for the
survival of the tumour. As these are not
currently targeted by existing treatment,
the tumour can escape from the effects
of the existing therapy. However, if these
critical pathways are targeted, the cells
can still be killed.
The next possible approach is to utilise
different modality of treatment that is not
dependent on conventional mechanisms
of killing the tumour cells. Chemotherapy
and radiotherapy utilise DNA damage
to trigger death pathways. This requires
an intact p53 protein which acts as the
guardian of our genome and triggers
death pathways to remove cells where
the genome is damaged. The p53 gene
is often mutated and not functioning
in refractory cancer. For small molecular
targeted therapy, the tumour cells can
become refractory through a variety of
mechanisms as highlighted above. Hence,
using an approach that does not require
p53 or signalling targets may overcome
these problems. One such approach is
by using immunotherapy which utilises
our immune system or antibodies to kill
tumour cells by specifically recognising
proteins that are expressed on cancer
cells. As the killing mechanisms and
targets are different from chemotherapy
and targeted drugs, this therapeutic
modality may provide an alternative
method to eradicate the cancer cells.
Ways to overcome refractoriness
NCIS’s approaches to refractory
cancer
One way to approach the problem is to
identify the mechanisms through which
At NCIS, we adopted the following
strategies to tackle refractory tumours:
1) Expanding our Portfolio of Phase 1
Trials
Over the years, we have expanded on our
ability to do early phase clinical trials by
building the appropriate infrastructure
and clinical trial teams. Now, we have
a dedicated Phase 1 clinic as well as an
inpatient set-up for patients on Phase 1
clinical trials. We have also established
useful partnerships and track records with
some pharmaceutical companies and have
an increasing portfolio of Phase 1 clinical
trials (Table 1 and 2). This is an important
way in providing novel therapeutic agents
against new targets for patients with
refractory tumours where conventional
therapies have failed.
2) Genomic profiling of tumours
For a better understanding of the
pathways and mutations that are present
in a refractory tumour, we have initiated
a study where all patients with refractory
cancers suitable for Phase 1 studies will
have their tumours profiled using genetic
sequencing (Figure 1). This will help us
identify the gene mutations that may be
present in these tumours. These gene
mutations can potentially be targeted by
new drugs being tested in Phase 1 studies
and we can then match these patients to
the trials.
3) Immunotherapy
This area encompasses a number of
different strategies that harness the
patient’s own immune system to kill
cancer cells. As the approach is novel
and utilises non-conventional therapeutic
pathways, there is a potential to overcome
resistance to conventional therapy. NCIS
has been active in these areas and has
been developing a number of different
strategies.
a) Therapeutic antibodies (Figure 2)
These molecules are able to recognise
specific targets on cells as well as
home-in to and engage with the
targeted cells. Upon engagement,
they can be designed to do several
things. First, they can block the
binding of key signalling molecule
so that the pathway cannot be
activated. Second, they can activate
Study Title
Company
Total
recruited
A Phase 1 pharmacokinetic study of oral MLN9708 plus Lenalidomide and
Dexamethasone in adult Asian patients with relapsed and/or refractory multiple
myeloma
Millennium
6
Phase 1 dose escalation study of oral administration of Pan-Histone Deacetylase
(HDAC) inhibitor S 78454 given in combination with a fixed dose infusion of
cisplatin in patients with advanced non-keratinising nasopharyngeal carcinoma
Servier
3
A Phase 1b, open-label study evaluating the safety, tolerability, and
pharmacokinetics of onartuzumab given as a single agent and in combination
with sorafenib in patients with advanced hepatocellular carcinoma (HCC)
Roche
0
An open-label Phase 1 dose-escalation study to characterise the safety,
tolerability, pharmacokinetics, and maximum tolerated dose of BAY 1143572
given in a once-daily or an intermittent dosing schedule in subjects with
advanced malignancies
Bayer
4
Phase 1, open-label, dose escalation study of Anti-CD98 monoclonal antibody
KHK2898 as monotherapy in subjects with advanced solid tumours who no
longer respond to standard therapy or for whom no standard therapy is
available
Kyowa
Hakko Kirin
Co
0
An open label Phase 1 dose-escalation study to characterise the safety,
tolerability, pharmacokinetics, and maximum tolerated dose of BAY 1082439
given once daily in subjects with advanced malignancies
Bayer
9
Lead-In Phase 1 dose-escalating, open-label, non-randomised study of a weekly
regimen OPB-51602 in advanced refractory solid tumours with enrichment
cohorts of nasopharyngeal carcinoma followed by a biomarker study
evaluating OPB-51602 in locally advanced nasopharyngeal carcinoma prior to
definitive chemoradiotherapy
NUH
2
A multi-centre, open-label study to assess pharmacokinetics of TK1258 in adult
cancer patients with normal and impaired hepatic function
Novartis
0
Prospective study of UDP-gluconoryltransferase (UGT) 2B17 genotype as a
predictive marker of exemestane pharmacokinetics and pharmacodynamics in
Asian women with hormone receptor-positive advanced breast cancer
NUH
15
An investigator sponsored Phase 1 study of the saety, pharmacokinetics and
pharmacodynamics of escalating doses followed by dose expansion of the
Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) in Asian patients
with advanced or metastatic solid tumour malignancies
NUH
3
42
Total
Table 1. Current Phase 1 studies and recruitment
Drug
Class
Company
Type
Start Date
End Date
Total
recruited
Status
ABT869
VEGFR TKI
Abbott
First-inman
Oct-06
Sep-07
45
Completed
SB939
Histone
deacetylase
inhibitor
S*Bio
First-inman
Apr-07
Sep-08
25
Completed
OPB51602
Stat3
inhibitor
Otsuka
First-inman
Oct-09
Jan-13
45
Completed
Table 2. Completed First-in-man and First-in-class Phase 1 programs
Figure 1. Schema of the IMAC
study initiated at NCIS
2 014 JULY - S E P T E M B E R
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Figure 2. Different ways a therapeutic
antibody can be modified
From a specific antibody, the sequence
can be used to generate chimeric
antigen receptors. Antisense gene can
be encapsulated in nanoparticle that is
conjugated to the antibody to achieve
dual specific of targeting specific gene
in specific cells that express proteins
targeted by the antibody on the cell
membrane. Lastly, drugs can be
conjugated to the antibody which will
kill the tumour cell when the antibody
drug conjugate is internalised into the
cells after binding.
the immune system to destroy cells
that they tag. Third, they can directly
trigger cell death. Fourth, for some
antibodies, drugs or radio-isotypes
can be attached to them so that
when they are internalised into
the cells after engagement with
the target, the target cells will be
destroyed by the drug or radiation.
NCIS has been working with different
A*STAR research institutes - namely
the Singapore Immunology Network
and the Bioprocessing Technology
Institute - to generate antibodies that
specifically recognise cancer cells, in
particular, cancer stem cells that are
the source of disease relapse and
usually resistant to treatment. These
studies are producing exciting results
when tested in cell lines and will
hopefully reach the stage of human
studies in the coming few years.
b) Chimeric antigen receptors (CARs)
These are molecular constructs that
specifically recognise a target at one
end and activate the immune system
on the other end. These are used to
modify T-cell or natural killer cells
which are potent effector cells of
the immune system that carry out
killing functions. After modification,
the T-cells or NK-cells act like armed
missiles targeting cells that express
the protein specifically targeted by
the receptor. These CAR-T cells have
been shown to have remarkable
therapeutic effects in refractory acute
lymphoblastic leukaemia and chronic
lymphocytic leukaemia.
6 • MED ICO
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At NCIS, through our collaboration
with one of the experts in this
area, Professor Dario Campana,
a professor in the Department of
Paediatrics, NUS, we have initiated a
clinical trial using these constructs in
acute lymphoblastic leukaemia with
residual disease after conventional
chemotherapy. At the same time,
with any promising antibodies we
identify, we can use the specific
recognition sequence to generate
CARs. The parallel development of
CARs and therapeutic antibodies
allow us to quickly build a menu
of therapeutics products against
refractory tumours.
c) Expanded natural killer (NK) cells
As previously mentioned, NK cells
are potent at killing certain types of
tumour cells but limited by their low
levels and difficulty in expanding
them. Through the work of Professor
Campana who has developed an
effective method of expanding these
NK cells, we now have a number
of clinical trials using expanded
NK cells against different cancers
including acute myeloid leukaemia,
T-cell acute lymphoblastic leukaemia,
myelodysplastic, paediatric Ewing
Sarcoma, and rhabdomyosarcoma.
In addition, NK cells can recognise
antibody bound cells and kill them.
In this way, they can potentially
increase the therapeutic effect
of therapeutic antibodies. With
the expanded NK cells, we also
have other clinical trials in gastric
and breast cancer, which utilise
expanded NK cells together
with trastuzumab, an
antibody against HER2 that
is overexpressed in subsets of
breast and gastric cancer.
These different immunotherapeutic
strategies can also be used in
combinations, for example,
therapeutic antibodies with
expanded NK cells. Targets of
therapeutic antibodies can be used
to generate CARs. They represent
the real cutting edge of cancer
therapeutics. Immunotherapy has
been voted as the therapeutic
breakthrough for year 2013 by
Science magazine, one of the top
scientific journals. And, NCIS is right
at the forefront of this field with
five clinical trials currently on-going.
4) Understanding mechanism
of drug resistance
While offering the different novel
therapeutic options, we also seek to
identify the mechanisms by which
tumours become refractory. In
particular, we studied the molecular
differences between cancer stem
cells, which are often refractory
to cancer treatment and lead to
disease relapse. Through this work,
we have identified proteins that we
are developing antibodies against
to as well as intracellular signalling
that could be targeted. In addition,
we are studying the drug resistant
pathways that are activated in
refractory tumours and can be
targeted by either existing drugs or
drugs in developmental stage. We
hope that these studies will lead to
subsequent clinical trials that may
overcome drug resistance in some
types of cancers.
Conclusions
Tumour becomes refractory when
conventional treatment fails. NCIS
has developed a series of strategies
and portfolio of clinical trials to
target these tumours, and bring
hope to patients where there is
normally none.
Insight
A/Prof Chang Kin Yong
Stephen
Senior Consultant,
Division of Hepatobiliary and
Pancreatic Surgery,
University Surgical Cluster
Associate Professor Stephen Chang is currently a
Senior Consultant in the Division of Hepatobiliary and
Pancreatic Surgery at the National University Hospital
(NUH). He is also part of the Surgical Oncology team
in the National University Cancer Institute, Singapore
(NCIS). He graduated with MBBS in 1994 and obtained
his Master of Medicine in Surgery in 2000 from the
National University of Singapore and obtained
his Fellowship in Surgery from the Royal College of
Surgeons of Edinburgh in 2003. He went on to
further his training in Laparoscopic Hepatobiliary
and Pancreatic Surgery and Liver Transplantation in
Paris, France under the mentorship of Professor Daniel
Cherqui before returning to Singapore in 2005.
He is a key developer of the laparoscopic approach to
Hepatobiliary and Pancreatic Surgery in this region
and eagerly shares his skills with the other surgeons
in Singapore and regionally through courses and
telecommunication. He is also active in developing the
Living Donor Liver Transplant Programme in Singapore.
In addition, he is the pioneer of the Single Incision
Laparoscopic Surgery in the region. In addition to his
surgical practice, A/Prof Chang holds the appointment
of Research Director in his Division and has several
research interests.
A/Prof Chang has also been appointed as Associate
Professor at his Alumni University, NUS under the
Clinician Investigator track. A/Prof Chang is actively
involved in both undergraduate and postgraduate
teaching and is serving as core faculty in the
postgraduate General Surgery training programme.
Administratively, he sits on the board of the Chapter
of General Surgeons in the Academy of Medicine of
Singapore. He is also the Joint Commission International
Champion for the Department of General Surgery and
has keen interest in improving the quality of patient
care.
A/Prof Chang is the current President of the
Hepatopancreatobiliary Association of Singapore which
is organising this year’s Liver Disease Awareness Week
from 21st to 28th September 2014.
The opening ceremony will be held on 21st September
at the NUHS Tower Block in conjunction with NCIS’s
Liver Cancer Awareness Campaign. For further details
regarding the public symposium in this campaign,
please visit www.ncis.com.sg or call 6772 3443.
SILS in HPB
Surgeries in NUH
Minimally invasive surgery has
revolutionised surgical techniques, and
has made a huge impact in surgery. Its
benefits over traditional open surgery
include improved cosmesis, decreased
post-operative pain, shortened length
of hospital stay, and faster return to
function.
Surgeons all over the world have not
stopped extending its application to
various surgeries previously thought
to be only approachable via the open
surgery approach. Such boundaries have
progressively been broken.
More recently, the quest for minimising
the abdominal wall intrusion has led
to the development of single incision
laparoscopic surgery (SILS). The initial
interest was met with various technical
difficulties. However, with adoption of
new ways in handling the instruments
and improved surgical techniques, interest
of this potentially ‘scarless’ approach is
on the rise. Since 2008, there has been
increasing number of publications using
this approach, and its application began
to extend from the less complicated
appendicectomy and cholecystectomy
to the more complex colorectal and
urological procedures.
In NUH, since 2008, we have started
performing single incision laparoscopic
cholecystectomies. By early 2013, we have
gained more than 300 case experiences
and have since published widely in this
topic, which contribute to the scientific
value of this approach, including a
randomised control trial on post-operative
pain experience.
Traditionally, hepatopancreatobiliary
surgery has been the ‘holy grail’ of
all abdominal surgery. But, in the last
decade, many major hepatobiliary
surgeries have been performed with
the laparoscopic approach. In NUH, we
have started performing some of these
complex hepatobiliary surgeries through
the laparoscopic approach since 2005.
By 2011, we have gained more than
100 case experiences in laparoscopic
hepatectomies, distal pancreatectomies,
and cystogastrostomy. Combining the
skills gained through these laparoscopic
procedures and SILS cholecystectomies,
we are among the first in the world to
perform complex hepatopancreatobiliary
procedures via the SILS approach.
SILS cholecystectomy
SILS cholecystectomy was first performed
in NUH in 2008. After having performed
the first 30 cases, we conducted a casecontrol analysis with the conventional
4-port approach and found encouraging
results1. We went on to confirm its safety
and feasibility via a prospective study of
the first 100 patients. The outcome of
these patients was encouraging and the
result was published in 20122.
Subsequent to that, with funding from
Covidien, we embarked on a randomised
control trial, to study the pain experience
in detail. We have since completed
the study, and the interim report was
published in September 20123.
Much progress has been made in the
technique of SILS cholecystectomy. In
the beginning, three reusable ports were
inserted through three separate fascia
punctures within a single incision in the
umbilicus. This technique allows the scars
to be hidden within the umbilicus but
the closure of these fascia openings was
challenging. In early 2009, we use the
first commercially fabricated SILS port
device. With such device, we could then
2 014 JULY - S E P T E M B E R
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References
1) Chang S, Tay CW, Bicol R, Lee YY, Madhavan K. A
Case-control Study of Single-incision vs Standard
Laparoscopic Cholecystectomy. World J Surg.
2011 Feb; 35(2):289-93.Chang SKY, Tan SSY, Kok
YO. Early experience in single-site laparoscopic
cholecystectomy. Singapore Med J 2012;53(6):377
2) Chang SK, Wang YL, Shen L, Iyer SG, Shaik AB,
Lomanto D. Interim report: A randomized controlled
trial comparing postoperative pain in single-incision
laparoscopic cholecystectomy and conventional
laparoscopic cholecystectomy. Asian J Endosc Surg.
2012 Sep 14. doi: 10.1111/j.1758-5910.2012.00154.x
3) Chang SK, Mayasari M, Ganpathi lS, Wen VL,
Madhavan K. Single Port Laparoscopic Liver Resection
for Hepatocellular Carcinoma: A Preliminary
Report. International Journal of Hepatology.
2011;2011:579203. doi:10.4061/2011/579203
Figure 1. SILS surgery device
perform the surgery through a single
fascia opening which can be closed easily.
Further experience in this procedure
allows us to innovate in the way the
tools are handled to ensure safety of the
procedure.
By early 2013, we have gained more
than 300 case experiences in SILS
cholecystectomy. Furthermore, we have
been among the forerunners in sharing
this experience with other surgeons
at various regional and international
conferences. This large experience
provides us with the confidence to
pioneer single incision laparoscopic
surgery in other HPB surgeries, such as
for liver resection and pancreas resection.
SILS hepatectomy
Our first SILS hepatectomy was
performed in early 2010. In 2011,
we reported our first three cases of
SILS hepatectomies in patients with
hepatocellular carcinoma in the
International Journal of Hepatology4.
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J ULY - se ptemb er 2 014
SILS spleen preserving distal
pancreatectomy
In 2011, we performed our first
case of SILS spleen preserving distal
pancreatectomy, and the technique was
published in 20125. We find the approach
to this type of surgery particularly
attractive as the pancreatic specimen can
be delivered through the umbilical incision
fully due to its slender long shape. This
leaves behind a scar well hidden in the
umbilicus which in essence, no obvious
scar is seen on the abdomen.
Conclusion
As an academic health system, we
continue to strive to improve how we
manage our patients and aim to be at the
forefront of surgical advancement. We
are thankful to be among the first few
centres in the world to adopt the single
incision laparoscopic approach to various
hepatobiliary procedures, and we aspire to
seek greater heights in the future.
4) Stephen K. Y. Chang, Davide Lomanto, Maria
Mayasari. Single-Port Laparoscopic Spleen Preserving
Distal Pancreatectomy. Minim Invasive Surg,
2012;2012:197429. Epub 2012 Feb 26
Insight
Dr Johann Tang
Senior Consultant,
Department of Radiation Oncology,
National University Cancer
Institute, Singapore (NCIS)
Dr Johann Tang, MBBS, FRANZCR, is currently a Senior
Consultant at the Department of Radiation Oncology
at the National University Cancer Institute Singapore
(NCIS). He is also an Assistant Professor at the National
University Hospital as well as Assistant Professor
at the Yong Loo Lin School of Medicine, National
University Singapore. After obtaining his fellowship
from the Royal Australian College of Radiologist
(FRANZCR), Dr Tang underwent breast brachytherapy
fellowship at University of Wisconsin as well as prostate
brachytherapy and paediatric fellowships at Peter
Maccallum Cancer Institute, Australia.
Dr Tang’s subspecialty and main research interest
include breast, gynaecological, paediatrics and CNS
tumours. Dr Tang set up and currently heads the
breast brachytherapy and paediatric radiotherapy
service. He is passionately involved in education
and is currently the co-chair of the Euro Asia Breast
Brachytherapy School, part of the teaching faculty of
the Australian Paediatric Radiation Oncology Group and
was an external examiner in radiation oncology to the
Bangladesh College of Physicians and Surgeons.
Besides being the Research Director for his department,
Dr Tang actively mentors residents, publishes medical
journals and is a referee for several international
journals. Dr Tang has won several research prizes
and is currently holding several research grants. He
currently serves on national committees such as the
Vice President of the Chapter of Radiation Oncologist,
Academy of Medicine Singapore and Executive Member
of the Singapore Society of Oncology.
Accelerated Partial
Breast Irradiation:
Treating Less is Better
- A New Paradigm
Shift for Early
Stage Breast Cancer
Treatment
In patients with early stage breast cancer
and post breast conserving surgery cases,
adjuvant radiotherapy remains as the
standard of care resulting in local control
as well as overall survival benefit 1 2 3 .
The use of mammographic screening has
enabled identification of patients with
early stage breast cancer earlier, thus
increasing the breast conservation rates in
this group of patients4. However, the use
of conventional fractionation radiotherapy
which was usually given over 5 to 6
weeks may pose a barrier to patients
who are receiving adjuvant radiotherapy,
which later may lead to some patients
opting for total mastectomy instead5.To
avoid unnecessary total mastectomies,
Accelerated Partial Breast Irradiation (APBI)
presents a viable alternative radiotherapy
modality to patients with early stage,
node negative breast cancer, considering
its shorter overall treatment duration.
BRACHYTHERAPY COMPARED TO EXTERNAL BEAM RADIOTHERAPY
Features
HDR Brachytherapy
External Beam Therapy
Treatment areas
Tumour site with margins only
Entire breast
Number of treatments
10 treatments over 1 week
25-30 treatments over 5-6
weeks
Convenience
More convenient for those
with busy work schedules or
long commutes
Great time commitment
required. May be disruptive to
work schedules
Radiation to adjacent organs
Less radiation to lung, heart,
rib and lymphatic
Acceptable radiation to lung,
heart, ribs and lymphatic
Skin care
Requires bandaging and care
of catheter sites
Daily application of creams
during radiotherapy and
about 3 months after
radiotherapy
Cure rates
Comparable long term results
to external beam radiotherapy
Currently the gold standard
for breast treatment
Appearance
Favourable cosmesis, minimal
scarring
Acceptable and favourable in
most instances
Invasive
Yes, requires insertion of
catheters into the breast
No. External X-rays only
Table 1. Pros and cons of multi-catheter APBI if being compared with a standard external beam radiotherapy
2 014 JULY - S E P T E M B E R
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Insight
Dr Shaik Buhari
Senior Consultant,
Department of General Surgery,
University Surgical Cluster
Type of APBI Modality
His main area of expertise is breast surgery and
surgical oncology, with special interest in oncoplastic
and reconstructive surgery. He has had numerous
presentations, at both local and international meetings,
as well as publications. He has been an invited speaker
at many local and regional congresses.
- Recent clinical phase 3 data shows that multi-catheter APBI is
equivalent to a standard EBRT treatment.
- Most versatile of all the APBI modalities.
- Suitable for patients of all cup sizes.
- Can be used in patients with augmented breast implants.
-Invasive.
- Operator dependent procedure.
MammoSite
- Phase 2 registry data shows no inferiority to standard EBRT
treatment.
- Simple to insert and can be done in the surgical rooms.
- Higher toxicity rates compared to multi-catheter interstitial.
- Restricted to breasts with cup C size and above as the
smallest diameter of the balloon catheter is 5cm. Thus, it is
not suitable for majority of the Asian patients.
Intra-operative radiotherapy
with electrons (ELIOT)
Dr Shaik Buhari is also involved in several research
projects in collaboration with radiation and medical
oncology. On the teaching front, he is a lecturer at
the Yong Loo Lin School of Medicine, NUS and School
of Nursing, NYP. He is also an examiner at the MBBS
Examination in NUS.
At the national level, he was in the Panel of Complaint
Committee (SMC) and Reviewer for the Combined
Surgical Meeting (CSM). He sits on the JCI Steering
Committee, Tissue Audit Committee and Blood
Bank Committee for NUH. Apart from his academic
achievements, he has also been nominated for the Star
Award and National Excellent Service Award (Gold).
Cons
Multi-catheter APBI
Senior Consultant,
Division of Surgical Oncology,
National University Cancer Institute,
Singapore (NCIS)
Dr Shaik Buhari graduated from NUS in 1988. He
obtained FRCSEd and M.Med (Surgery) in 1993 and was
appointed as a consultant at the Department of Surgery
in 2000. He worked in Nottingham Breast Institute from
2002 to 2004, where he received advanced training in
breast surgery and oncoplastic surgery.
Pros
- Treatment is done at the time of breast conserving surgery.
- Phase 3 clinical data shows higher recurrence rates compared
with standard EBRT treatment.
- IORT ELIOT has fallen out of favour.
Targeted intra-operative
radiotherapy (TARGIT)
- Treatment is done at the time of breast conserving surgery.
- Phase 3 clinical data shows higher recurrence rates compared
with standard EBRT treatment.
- IORT TARGIT has fallen out of favour.
- In addition, 1 in 4 post TARGIT patients will require standard
EBRT due to poor pathological features.
- Not suitable for Asians due to the large electron sphere that
needs to be inserted into the breasts, similar to MammoSite.
APBI – External Beam
- Non invasive
- Suitable for any breast size.
- Clinical studies have shown APBI External Beam to have
higher long-term toxicity rates.
Table 2. Various types of APBI modalities available
This would reduce the logistic barriers,
especially for those who are active in the
workforce and find it difficult to take
time off from work or need to travel
long distances for their radiotherapy
treatments.
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Thus, APBI serves as a viable alternative
breast conservation treatment for patients
who would otherwise have opted for
total mastectomies. Furthermore, where
acute and late toxicities such as radiation
dermatitis, acute pneumonitis and skin
fibrosis are common with conventional
external beam treatment, APBI offers
better toxicity outcome leading to
favourable cosmesis with lesser acute and
late toxicity. Table 1 summarises the pros
and cons of APBI versus a standard 6-week
external beam treatment.
Types of APBI modalities
There are many different APBI modalities,
e.g., intraoperative, MammoSite,
multi-catheter, and external beam 6 7 8
(Figure 1). Each of these different APBI
modalities has its pros and cons. Given
the recent published data for various
APBI techniques, it has emerged that
multi-catheter APBI offers the best clinical
evidence for efficacy with better toxicity
profile if being compared with a standard
conventional external beam radiotherapy
treatment. Table 2 summarises the various
types of APBI modalities available.
APBI%
Conventional EBRT%
Figure 1. APBI versus conventional EBRT
Criteria
ABS
ESTRO+
ASTRO+
What is multi-catheter APBI?
Age
≥ 50 years old
≥ 40 years old
≥ 50 years old
Amongst all the APBI modalities, multicatheter interstitial APBI is the oldest
method, hence has the longest clinical
follow-up and experience. Given that the
area of highest risk of local recurrence
involves the tumour cavity plus a 1.5 to
2-cm margin, targeting and delivering
high doses of radiation to this high risk
volume decreases the chance of a local
recurrence. Radiation delivery is achieved
by placing plastic catheters surrounding
the tumour cavity. This allows the dose
delivery to be highly conformal to the
high risk volume, concentrating the high
dose to this region, whilst sparing the
surrounding organs at risk such as the
normal breast tissue, ribs, lungs, and
heart. This would lead to lower long-term
toxicity on these organs at risk. Contrast
to EBRT treatment where the dose enters
the breast externally and penetrates all
tissues in its path before exiting on the
opposite side, all the normal tissues
irradiated would be subjected to longterm toxicity. These EBRT side effects
include radiation dermatitis, cardiac
toxicity and pulmonary fibrosis, whereas
these side effects are seldom seen in
patients who have undergone multicatheter APBI.
Size
≤ 3 cm
≤ 3 cm
≤ 3 cm
All invasive subtypes
and DCIS*
All invasive subtypes
and DCIS*
All invasive subtypes
and DCIS*
Positive/Negative
Positive/Negative
Positive/Negative
Surgical Margins
Negative
Negative/Close
< 2 mm)
Negative/Close
< 2 mm)
Lymphovascular Space
Invasion
Negative
Negative
Negative/Focal
Nodal Status
Negative
< 4 Lymph Nodes
Involved
Negative
Histology
Estrogen Receptor
Table 3. Summary of the study results published by the American Society for Therapeutic Radiation Oncology (ASTRO), American
Brachytherapy Society (ABS), and European Society for Therapeutic Radiation Oncology (ESTRO)
Who are the eligible patients?
Whilst older studies using multicatheter interstitial APBI did not achieve
good results which might be due to
poor patient selection, recent studies
have demonstrated that with careful
patient selection, good clinical results
and local control can be achieved
with this technique9. The results of
the recent studies form the basis of
consensus guidelines published by
the American Society for Therapeutic
Radiation Oncology (ASTRO)10, American
Brachytherapy Society (ABS)11, and
European Society for Therapeutic
Radiation Oncology (ESTRO)12, indicating
which patients are suitable for multicatheter APBI, which group of the
patients shall be offered with caution,
and which ones of them are not
suitable for the procedure. In general,
the suitable and cautionary patients
can be offered this procedure. At the
National University Cancer Institute
Singapore (NCIS), these two groups of
patients make up about 80% of the
total cases seen. Our experience at NCIS
have shown that post breast conserving
surgery patients who are above 40 years
old and diagnosed with early stage
breast cancer have shown to be suitable
candidates for APBI.
2 014 JULY - S E P T E MB E R
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Friday
9:00 – 10:00
am
Catheter
placement
with local
anaesthetic
10:30 am
Breast CT
stimulation
Break
Weekend
The
Following
Monday to
Friday
Bid fractions
HDR
treatments,
6 hours apart
No CT
required
before each
fraction
Table 4. Sample of APBI planning & treatment schedule
Figure 2. Tumour cavity shown by seroma and clips
Multi-catheter APBI treatment
schedule
location of the tumour in respect to
the nipple and the depth of the normal
breast tissue so as to avoid the risk of
a pneumothorax by puncturing the
underlying ipsilateral lung.
Under local anaesthesia, implantation
of the catheters usually takes place on a
Friday morning and lasts for one hour.
Immediately post implantation, the
patient will undergo a planning CT scan
and then be discharged. The treatment
commences from Monday to Friday on
the following week, 2 sessions a day (i.e.
morning and afternoon). After the Friday
treatment session, the catheters are
removed.
Multi-catheter APBI technique
Target localisation
Ultrasound guided localisation of the
target is essential to a successful implant.
Under ultrasound guidance, about
0.5-1 cc of omnipaque is injected into
the tumour cavity. This is to allow the
tumour cavity to be easily identifiable on
the pre-procedure CT scan. In addition,
instead of using a skin surface marker
pen, the outline of the cavity is marked
by imprinting the straw on the breast
skin surface as the marker pen can be
accidentally washed off easily when the
area is cleaned with chlorhexidine solution
before the procedure. By imprinting the
straw marks on the skin, the impression
of the cavity outline remains even after
the cleaning of the ipsilateral breast preprocedure.
By placing contrast into the seroma cavity,
it is easier to see on the pre-procedure
CT scan. Pre-procedure CT scan is then
acquired to gain information on the
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Before the procedure, it is advisable to
mark out the outline of medial borders
of the brassiere against the bra. This is
to ensure that no catheters are placed
medially to this line such that it may be
seen when the patient wears a low cut
revealing dress. By doing this, it also
ensures that patients are more confident
of continuing their activities of daily living
by having the freedom of what to wear
and yet able to continue treatment.
Figure 3. Marking out the bra line such that no catheters
are placed superiorly to achieve favourable cosmesis
outcomes
Anaesthesia
Moderate sedation is usually the mode of
anaesthesia. A cocktail of Oxycodone 5 mg
capsule, Valium 5 mg and Synflex 550 mg
is given to the patient 45 minutes before
the commencement of the procedure.
Tumescence anaesthesia made up of 2%
lignocaine, 1:80,000 adrenaline, sodium
bicarbonate mixed in 250 ml of normal
saline is used as a breast local anaesthetic
agent. Other equipment includes a
pair of 20 ml syringes with 11 G spinal
needle attached for the delivery of the
tumescence anaesthesia.
Procedure
The template approach is most suitable
for patients with B to D cup size breast
due to the use of Kuske Template size.
Once the cavity is localised, the ipsilateral
breast area is surgically prepped under
sterile conditions. To avoid injury of the
underlying chest wall structures or causing
a pneumothorax, the overlying breast is
pinched and gently lifted off the chest
wall before applying the template and
securing it. Also to note is that the C12
grid position ideally should be in the
centre of the tumour cavity to ensure
that adequate grid space is available on
either side of the template for catheter
insertion. Usually, four anchoring needles
are then placed in an asymmetric pattern
at C8, 12, 14 and A13. The purpose of
the asymmetric pattern is to aid easy
orientation of the template in reference to
the patient’s anatomy as well as to secure
and prevent slipping of the template from
the breast.
In general, any catheter within the
PTV-Eval needs to be inserted. For
the catheters out of the PTV-Eval,
if they are within 1 cm of the PTVEval contour, they would need to be
inserted as well. By using this method,
one can easily determine the exact
number of catheters required to cover
the PTV-Eval volume and avoid under
or over insertion of catheters. For
cosmetic reason, it is worthwhile to
avoid placing catheters outside of the
patient’s low cut dress neckline so that
the catheters cannot be seen when a
low cut dress is worn. If the catheters
protrude out into the neckline area,
the best recommended measure is to
manually reside the entry point of the
catheter to below the neckline without
compromising the dosimetric coverage.
Figure 4. Diagram showing the various volumes
A CT scan is then obtained with the
anchoring catheters in-situ. These images
are then reconstructed on the Oncentra
planning system (Nucletron Elekta,
Netherlands).
The images are then reoriented in
Oncentra to depict the “template
view”. This template view is crucial
in determining where the rest of the
catheters should be placed. Next, an
overlying photocopy of the template on a
transparency is placed on the top of the
screen and the “template view” template
magnification is matched 1:1 to the
overlaid template transparency.
The corresponding anchoring needle
positions are then marked on the overlaid
transparency. Similar to the previous
step, PTV-Eval contour and the chest
wall contour are also outlined to the
transparency. Once done, the rest of
the catheter placement can be easily
determined.
Once the catheters are placed, they are
then replaced with plastic catheters to
ensure patient’s comfort. The blind end
is flushed to the skin while the other end
is trimmed to size. A numbered button is
then heat-sealed to secure the other end
of the catheter.
Treatment delivery of the radioactive
192-Iridium source is via an after-loader
machine which is remotely controlled.
On the day of the treatment, the
patient’s catheters are connected to the
after-loader using special tubes. This is
a safety mechanism to ensure that there
is no chance that the radioactive source
may be left in the patient.
Contrary to popular belief, as the
radioactive source is never in the
patient, the patient is not radioactive
and is free to carry babies or be around
pregnant women.
Figure 5. Overlaying a transparency and tracing out the various important structures to Figure 6. Kuske Template with the anchoring catheter needles in-situ
aid catheter placement
2 014 JULY - S E P T E MB E R
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References
1) Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG). Effect of radiotherapy after breast-conserving
surgery on 10-year recurrence and 15-year breast cancer
death: meta-analysis of individual patient data for
10,801 women in 17 randomised trials. Lancet. 2011
Nov 12;378(9804):1707-16.
Figure 7. Replacing the needle catheters with plastic comfort
catheters
Figure 8. Final appearance of the implanted breast catheters
Multi-catheter APBI offers favourable longterm cosmetic results with little residual
evidence of catheter implantation. Unlike
EBRT treatment where there is about 5%
chance of long-term skin pigmentation
and fibrosis from radiation skin fibrosis,
patients with multi-catheter APBI do not
experience this, which may result in higher
patient satisfaction.
Conclusion
Special advantages
of multi-catheter APBI
Augmented breast implant patients
For patients with augmented breast
implants and are diagnosed with
early stage breast cancer, mastectomy
is currently the only option. Having
mastectomy would defeat their purpose
of undergoing augmentation in the first
place as majority of the patients would
want to retain their breasts for various
reasons. Multi-catheter APBI now offers
this group of patients the chance of
breast conserving treatment, allowing
them to undergo adjuvant radiotherapy,
conserving their breast, and avoiding
a mastectomy. Done under image
guidance, the chance of puncturing the
breast implants using the multi-catheter
APBI template technique will be low.
In contrast, EBRT cannot achieve such
conformal dose distribution, leading to
contracture of the silicone capsule and
skin fibrosis from the radiation dermatitis.
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There is a new paradigm shift for a
shorter yet effective radiotherapy
treatment for early stage breast cancer.
In selected patients, multi-catheter APBI
is an effective alternative to conventional
EBRT treatment, offering shorter overall
treatment duration of five days, equivalent
efficacy, and yet offering better toxicity
profile. Increasing both physicians’ and
patients’ awareness of such treatment
options would thus lead to more informed
decisions and better patient overall
satisfaction about their treatment choice
without compromising on treatment
outcomes.
At NCIS, multi-catheter APBI has been
offered to selected patients with early
stage breast cancer since 2007 with
favourable clinical outcomes comparable
to major American and European centres.
What the physician can expect
As a referring physician, you can be rest
assured that NCIS will work closely with
you in providing your patients with the
finest treatment and continuing care
possible. We will keep you well informed
on the patients’ investigation results and
treatment progress. Last but not least,
we respect and value your knowledge of
and relationship with the patients, and
treasure your partnership in caring for the
patients.
2)Recht A, Solin LJ. Breast -conserving surgery and
radiotherapy in early-stage breast cancer: the
importance of local control. Semin Radiat Oncol. 2011
Jan;21(1):3-9
3) CVinh-Hung V, Verschraegen C. Breast-conserving surgery
with or without radiotherapy: pooled-analysis for risks
of ipsilateral breast tumor recurrence and mortality. J
Natl Cancer Inst. 2004 Jan 21;96(2):115-21
4) Olsen O, Gøtzsche PC. Screening for breast cancer
with mammography. Cochrane Database Syst Rev.
2001;(4):CD001877
5) Boscoe FP, Johnson CJ, Henry KA, et al. Geographic
proximity to treatment for early stage breast cancer and
likelihood of mastectomy. Breast. 2011 Aug;20(4):324-8
6) Vicini FA, Arthur DW. Breast brachytherapy: North
American experience. Semin Radiat Oncol. 2005
Apr;15(2):108-15. Review
7)Polgár C, Major T. Current status and perspectives of
brachytherapy for breast cancer. Int J Clin Oncol. 2009
Feb;14(1):7-24
8) Skowronek J, Wawrzyniak-Hojczyk M, Ambrochowicz K.
Brachytherapy in accelerated partial breast irradiation
(APBI) - review of treatment methods. J Contemp
Brachytherapy. 2012 Sep;4(3):152-64
9) David E. Wazer, Douglas W. Arthur, Frank A. Vicini.
Accelerated Partial Breast Irradiation. 2nd Ed. Springer,
2006. p207-345
10) Smith BD, Arthur DW, Buchholz TA, et al. Accelerated
partial breast irradiation consensus statement from the
American Society for Radiation Oncology (ASTRO). Int J
Radiat Oncol Biol Phys. 2009;74:987–1001
11) Shah C, Vicini F, Wazer DE, et al. The American
Brachytherapy Society consensus statement for
accelerated partial breast irradiation. Brachytherapy.
2013 Jul-Aug;12(4):267-77
12) Polgar C, Van Limbergen E, Potter R, et al. Patient
selection for accelerated partial-breast irradiation (APBI)
after breast conserving surgery: Recommendations of
the Groupe Europeen de Curietherapie-European Society
for Therapeutic Radiology and Oncology (GEC-ESTRO)
breast cancer working group based on clinical evidence
(2009). Radiother Oncol. 2010;94:264–273
Treatment Room
Dr Gurpal Singh
Consultant,
Division of Musculoskeletal
Oncology & Division of Hip
& Knee Surgery,
University Orthopaedics, Hand and
Reconstructive Microsurgery Cluster
Dr Gurpal Singh is a fellowship-trained Orthopaedic
surgeon specialising in musculoskeletal oncology
and total joint replacement in the National University
Hospital (NUH). He is also part of the Musculoskeletal
Cancer Group in the National University Cancer Institute,
Singapore (NCIS). Dr Singh’s clinical practice consists
of musculoskeletal tumours (benign, malignant and
metastatic bone disease) with a focus on endoprosthetic
reconstruction and limb salvage surgery, as well as
primary and revision joint replacement.
His academic interests include osteolysis, periprosthetic
tissue responses to wear debris from failed joint
replacements, infections and biomaterials in joint
replacement. Dr Singh collaborates internationally with
a team of musculoskeletal oncologists, arthroplasty
surgeons and material scientists from Germany in
an effort to continuously improve biomaterials and
increase the lifespan of artificial joint prostheses, reduce
infection rates and minimise adverse tissue responses
from the patient’s body.
Surgical Treatment of
Bone Metastases –
A Changing Paradigm
this article is to review the principles of
treatment of bone metastases and the
philosophies of surgical treatment in these
patients.
Mechanism of cancer spread to bone
Tumour cells from the primary organ
site travel through the blood stream
and lymphatic system to the axial and
appendicular skeleton. Roodman et
al. have reviewed the biology of the
osteoclast and the pathophysiology of
bone metastases3. The hypothesis for
development of bone metastases is an
interaction between tumour and bone
cells causing increased bone destruction
and proliferation of tumour cells within
the bone marrow. Bone marrow secretes
cytokines that can attract tumour cells.
Introduction
Bone metastasis may be defined as cancer
that spreads from a primary organ site to
the axial and/or appendicular skeleton.
With increasing survival of cancer patients
and advancement in treatment modalities,
bone metastases are contributing to
significant morbidity. In a recent report,
it was estimated that
280,000 adults in the
United States were
living with metastatic
bone disease with
68% of cases occurring
in patients with primary
breast, prostate, or lung
cancer1, 2. Current decisionmaking in surgical treatment
of bone metastases needs to
consider both survivorship
and quality of life. The main
aim of the surgery is a longlasting reconstruction which
outlives the patient. The aim of
Figure 1. A “vicious, self-perpetuating cycle” between tumour
cells and bone marrow leading to development of extensive bone
metastases
Local production of osteolytic factors
by cancer cells in the bone stimulates
osteoclast-mediated bone resorption.
A “vicious, self-perpetuating cycle”
between tumour cells and bone marrow
leads to development of extensive bone
metastases4-7. (Figure 1)
Clinical presentation
Patients generally present with severe
bone pain; this pain is present at rest
and is non-mechanical in nature. There
may be night pain and poor response to
conventional first-line analgesics. Patients
may present with pathologic fractures
(fractures occurring with trivial or no
injury) or impending pathologic fractures,
particularly in the lower limb. Patients
may also present with neurological
weakness in the lower limb and loss
of bowel and bladder control due to
metastases to the spine and consequent
spinal cord or cauda equina compression.
Spinal cord compression due to vertebral
collapse caused by bone metastases is an
emergency that can lead to permanent
damage to the spinal cord and paralysis.
Bone metastases may also present as
hypercalcemia of malignancy. Table 1
shows the percentage of bone metastases
from common primary organ sites1-8.
Cancer of Primary
organ site
Bone Metastatic
involvement (%)
Lung
4%
Gastric
9%
Colorectal
13%
Prostate
25%
Pancreas
28%
Liver
31%
Breast
33%
Renal
66%
Table 1. The percentage of bone metastases from common primary organ sites
2 014 JULY - S E P T E MB E R
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Investigations
The following investigations may be
performed:
1. Plain radiograph of affected bone: May
show osteolytic lesions, osteoblastic
lesions, and/or pathological fracture.
2. Bone scan: May show increased uptake
in areas of bone metastasis. It helps to
detect extent of cancer spread to the
entire skeleton.
3. MRI of affected bone: To determine
intramedullary extent of bone
metastases and “skip” lesions.
4. CT scan of thorax, abdomen and pelvis:
Helps to detect the primary organ of
cancer, and may be useful in staging of
disease.
5. Blood investigations: Alkaline
phosphatase, calcium levels, and
tumour markers where necessary.
6. Biopsy: For histopathological diagnosis.
This may sometimes be performed at
the time of surgical fixation.
Management of bone metastasis
Treatment is best undertaken in a tertiary
centre involving a multi-disciplinary
approach comprising the musculoskeletal
oncology surgeon, medical oncologist,
radiation oncologist, radiologist, advanced
practice nurse, and individual specialist’s
inputs depending on the nature of
primary cancer. The treatment depends on
whether the skeletal metastasis is solitary
or multiple, the presence of visceral
involvement and type of primary cancer,
as well as the prognosis and general
condition of the patient. Metastatic
destruction of bone reduces its weight
bearing capabilities, resulting initially in
trabecular disruption and microfractures,
and subsequently total loss of bone
integrity. Principles of treatment of bone
metastases include (Figure 2):
I. Diagnosis and treatment of the primary
cancer : In conjunction with oncologist.
II.Treatment of:
1.Pain: Analgesics in conjunction with
palliative medicine specialist/pain
specialist, radiation therapy where
appropriate.
2.Pathological fractures: Fracture
fixation and/or joint replacement
surgery.
16 • MED ICO
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3.Spinal cord compression: Spine
decompression and stabilisation.
4.Impending pathological fracture:
Prophylactic fracture fixation surgery
where indicated.
5. Hypercalcemia.
Medical management
Medical treatment options for
patients with bone metastases include
chemotherapy, endocrine therapy,
bisphosphonates, radiotherapy and
pain management4-8. Chemotherapy
uses combinations of drugs to destroy
cancer cells. Endocrine therapy or
hormone therapy is used for treatment
of breast cancer and prostate cancer.
Bisphosphonates may prevent or delay the
development of skeletal metastases and
retard bone resorption. Pain management
may be difficult and best undertaken in
conjunction with a palliative care physician
and pain specialist.
Radiotherapy is an effective modality
for treatment of bone metastases 4-6, 8 in
certain types of cancers. The probable
mechanism of radiotherapy is radiationinduced hypoxia and death of tumour
cells. This leads to local control of bone
metastases and pain relief.
Figure 2. Pelvic bone and hip metastases (impending fracture)
Surgical management
In general, surgical treatment for bone
metastases consists of fracture fixation
and/or resection of metastases and
reconstruction of the affected bone
segmental in combination with joint
replacement surgeries4. These procedures
help with pain relief, ambulation of the
patient, and ease to carry activities of
daily living. The indications of prophylactic
fracture fixation include impending
fracture, severe pain, and involvement
of one-half or more of the cortex of the
bone. Spinal cord compression from
tumour metastasis to the spine and
epidural space may result in permanent
neurological damage unless emergency
measures are undertaken to decompress
the neurological structures. These patients
are treated with surgical decompression
of spine and stabilisation of the spine with
plates and screws.
Options for surgical management of
metastases to the appendicular skeleton
include osteosynthesis (fixation with
an intramedullary nail or strong plate,
in combination with adjuvants such as
bone cement), endoprostheses (joint
replacement prostheses), or tumour
endoprostheses (modular or non-modular
References
Figure 3. Pelvic bone reconstruction and hip replacement
components). Conventional orthopedic
teaching has advocated osteosynthesis
for surgical palliation of the cancer
patient with bone metastases. But, recent
advances in musculoskeletal oncology
question the validity of this statement in
today’s context of multimodal cancer care
and increased survival.
tumour resection (particularly for solitary
metastases) and reconstruction with
longer-lasting options10,11.
The line between palliative and curative
intent has also shifted, and the approach
to a patient with a visceral malignancy
and solitary metastases is often curative.
Surgical palliation in metastatic bone
disease has conventionally been
osteosynthesis with a strong construct
such as an intramedullary nail. Ideally,
the construct should outlive the patient;
surgery should provide effective and fast
pain relief and ambulation and there
should be an improvement in survival
after surgery, particularly for solitary
metastases9.
Perhaps, the final issue that deserves to
be mentioned is the cost-effectiveness of
surgical treatment of bone metastases,
and as a subset, the justification of
increased cost of treating bone metastases
with tumour endoprostheses. Skeletal
related events (SRE’s) from bone
metastatic disease result in significant
health resource utilisation and impose
a substantial financial burden on health
systems. Treatments that delay or prevent
SRE’s therefore result in considerable
cost-savings12. We have shown that
it is more cost-effective to surgically
reconstruct metastases around the hip
joint in appropriately selected patients, as
compared to the costs of conservatively
managing these patients in a step-down
care facility in the Singapore context13.
With increased survival of patients
with long bone metastases, tumour
recurrence, failure of the osteosynthesis
construct and continuing pain are
increasing in incidence. Thus, the
idea of the osteosynthetic construct
surviving the patient may not be able
to keep up with the rapid advances in
multimodal treatments which allow
patients with bone metastases to live
much longer. There has been a frameshift
in thinking with regards to optimal
surgical management of patients with
metastases, with a greater emphasis on
Ashford et al, 2010,14 reviewed the
financial implications of using proximal
femoral replacements for metastatic
bone disease and reported that in their
setting, endoprosthetic replacements
were found as an effective treatment but
poorly reimbursed under their funding
arrangements. Thus, cost remains a
concern, and funding arrangements differ
from country to country. In appropriately
selected patients, the benefits of resection
of bone metastases and appropriate
reconstruction probably outweigh the
increased cost.
1) Shuling Li, Yi Peng, Eric D Weinhandl, Anne H
Blaes,Karynsa Cetin, Victoria M Chia, et al, Estimated
number of prevalent cases of metastatic bone disease in
the US adult population
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5) Yazawa Y, Frassica FJ, Chao EY, et al. Metastatic bone
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2 014 JULY - S E P T E MB E R
M EDICO • 17
D OCT OR’S H EAR TBEAT
A/Prof Quek Swee Tian is the Head and Senior Consultant of the
Department of Diagnostic Imaging at the National University
Hospital. Apart from being the Clinical Director of BreastScreen
Singapore Programme of the National University Health System, he
is also sitting on the Executive Committee of the National University
Cancer Institute, Singapore (NCIS). A/Prof Quek graduated from
the National University of Singapore (NUS) and embarked on
his Radiology training, by obtaining the Fellowship of the Royal
College of Radiologists in 1995. He underwent further training in
musculoskeletal radiology at several centres in the UK.
His areas of interest are in Musculoskeletal, Oncologic/Body and
Breast Imaging. A/Prof Quek was previously a Senior Consultant
in the Department of Oncologic Imaging, National Cancer Centre
Singapore and held concurrent appointments as Visiting Consultant
to the Department of Surgical Oncology at the National Cancer
Centre, Department of Diagnostic Radiology at the Singapore
General Hospital and the Ministry of Defence, Singapore.
He is also a Council member of the College of Radiology of
Singapore and sits on the College’s Steering Committee on
Professional Standards and the Teleradiology Audit Committee in
the Ministry of Health, Singapore. He has published on various
topics in oncologic, musculoskeletal and breast imaging. Specialist in Focus
A/Prof Quek Swee Tian
Head and Senior Consultant, Department of Diagnostic Imaging
1
Could you share with us about the
Department of Diagnostic Imaging’s role
in shaping clinical care delivery in NUH?
Imaging is an important aspect of the
diagnostic process and has changed
clinical care delivery in various ways. For
example, the availability of a CT scanner in
the Emergency Department has facilitated
faster and more accurate assessment
of the extent of injury in polytrauma
patients, allowing for quicker and better
surgical management. It is also commonly
18 • MED I CO
J ULY - se ptemb er 2 014
used to assess patients with acute
stroke for suitability for thrombolytic
treatment, leading to a more personalised
treatment with better outcome. Even in
conditions like suspected appendicitis or
pancreatitis, there is increasing reliance
on imaging to confirm the diagnosis and
look for possible complications to avoid
unnecessary surgery and/or provide for a
better pre-operative roadmap.
In cancer treatment, imaging is crucial
for staging the extent of disease and
determining the optimal type of treatment
(i.e. surgery, chemotherapy, or radiation
therapy). As such, a review of the patient’s
scans forms an important component in
multidisciplinary tumour board discussions
where patient management is deliberated.
It is also used to assess treatment
response and optimise treatment by
switching to a different chemotherapeutic
regime if there is poor response to firstline chemotherapy.
Besides the diagnostic aspect, the
therapeutic aspect of radiology has also
changed clinical care delivery in some
ways. Radiologists are able to offer
patients and referring physicians a host
of treatment options ranging from simple
image-guided biopsies and drainages to
more complex procedures like coiling or
stenting of aneurysms. These treatment
options are less invasive and may obviate
the need for open surgery, resulting in
shorter hospital stays and less severe/
fewer post-procedure complications.
So, not surprisingly, we are seeing an
increasing number of requests for such
treatments in lieu of more conventional
open surgery.
2
How will it support the primary
healthcare/GPs in Singapore?
Although we are a hospital-based
practice, we have always been supportive
of the primary healthcare sector. We
provide reporting services for radiographs,
ultrasound, and mammograms done at
some polyclinics. GPs are also welcome
to use our imaging services, be it simple
screening chest X-rays, mammograms, or
more complex examinations such as CT
scan. In addition, we have also organised
talks for GPs on various aspects of
imaging such as screening CT colonoscopy
and low dose CT for lung cancer screening
to keep them updated on these topics.
3
How do you see the transformation
of the Diagnostic study – in the past,
present, and future?
In the past, there was a lot of emphasis
on the plain film (X-rays). While this is
still important and will stay with us,
going forward, there will be an increase
in reliance and use of more complex
cross-sectional imaging modalities like
ultrasound, CT and MRI. These techniques
require more detailed anatomical
knowledge and more time to interpret as
they may run into hundreds of images,
particularly with reconstructed images or
additional sequences performed. However,
it is well worth the while as they provide
us with important additional information
Figure 1. Prof Quek and his children
that can aid diagnosis and patient
management.
A good example is the imaging of head
injuries. In the past, we usually obtain
two or three different radiographs
to assess patients with head injury.
Nowadays, we would perform a CT for
such patients. Although there are more
images to review, it is a faster examination
to perform and provides a much better
assessment of the extent of head injury
(e.g. intracranial haematoma, midline
shift, skull fracture) if any. The information
gained is much more comprehensive than
with plain radiographs and thus results in
better patient management. Some of the
changes that have come about are due to
changes in technology in other areas. For
example, we are performing fewer Barium
studies nowadays as improvements in
fibre-optic technology have resulted
in Bariums being partly replaced by
gastroscopy and colonoscopy.
There is certainly much more reliance on
information technology. While the films
in the past were physically cumbersome
to transport and required large film
archives to store, many institutions
now have a digital picture archiving
and communication system (PACS).
This enables easy retrieval and review
of images by both the radiologists and
clinicians and has also allowed for teleradiology services.
Crystal ball gazing is an imperfect art,
but looking at the future, I believe the
trend will be towards more hybrid and
molecular imaging which may provide a
more personalised patient diagnosis and
treatment, and further development and
use of interventional radiology services.
4
You have particular interests in
Musculoskeletal, Oncologic/Breast
Imaging. What inspired you to specialise
in these areas?
When I graduated in Radiology, MRI was
in vogue then. So, it was a toss between
Neuroradiology and Musculoskeletal
(MSK) Imaging. I found MSK more
stimulating as it involves multiple joints
and body regions. We also had a very
good working relationship with the
Orthopaedics Department whom we met
weekly to review interesting cases, so I
decided on MSK with a slant towards MSK
tumours and sports imaging.
2 014 JULY - S E P T E MB E R
M EDICO • 19
Oncologic and breast imaging was
something I stumbled into by accident
rather than by design. I worked at the
National Cancer Centre for some years
and found oncologic and breast imaging
challenging and interesting, in particular,
the participation in the multidisciplinary
tumour boards, where I could interact
and work closely with colleagues in other
disciplines, was intellectually stimulating
and academically satisfying. And as
a member of BreastScreen Singapore
since its inception, it was great to see
the growth and development of the
programme. When we first started,
some of the breast tumours were quite
large at detection, but with time, we are
now detecting more of the smaller and
earlier stage tumours that carry a better
prognosis. It is quite gratifying to know
that the programme has done some good
and that I have a chance to be part of it.
5
Could you share with us the more recent
developments and breakthroughs in
these areas that may result in better
patient care?
Advances in imaging have revolutionised
many aspects of clinical practice in the last
decade but I will only highlight a few.
In breast imaging, the development of
digital mammography is a significant step
forward. It is easier and faster to perform
and gives a higher level of detail than
conventional film-screen technology.
This means the patient spends less time
in an uncomfortable position and is less
likely to have to return for a repeat scan
due to over or under-exposure. And
being digital, it is easy for the images to
be sent to a hospital for reading if the
mammograms are done elsewhere, e.g.,
in the polyclinics, thus facilitating breast
screening.
There is also a newer technology known
as breast tomosynthesis. This takes
multiple X-ray images of the breast from
different angles. The early results seem
quite promising as the procedure is more
comfortable and appears to enable us
20 • ME D ICO
J ULY - se ptemb er 2 014
Figure 2. Prof Quek (fourth from left) during NUS Commencement 2014
to detect breast cancers more easily in
women with dense breasts.
With CT, many of the recent technological
advances have resulted in dose reduction,
reduction in scan time, as well as scan
results with greater detail (thinner slices).
CT also provides better depiction of both
the anatomy and pathology, allowing for
more accurate diagnosis. A good example
is CT angiography. In the past, patients
with suspected pulmonary embolism
were investigated with a lung ventilation/
perfusion (V/Q) scan which took about 30
minutes to an hour to perform, and was
difficult to be interpreted, particularly in
sick patients who could not ventilate well.
Nowadays, this can be easily assessed
with a contrast CT which takes only a few
minutes to perform and gives exquisite
images that are easier and more accurate
to read. Likewise, patients with suspected
clot or aneurysm causing a stroke can be
assessed first with a CT angiogram instead
of a conventional catheter angiogram
(which takes longer to organise and
perform and is a more invasive procedure
that carries a higher risk of complications).
CT angiography can also be performed for
non-invasive assessment of the coronary
arteries.
Improvement in MR technology has also
allowed for some of these angiographic
procedures to be performed by MRI.
The widespread use and acceptance of
MRI in clinical practice is a reflection of
its place in providing for better patient
care ranging from early detection of
stroke to accurate assessment of internal
derangements of joints (without having to
resort to more invasive arthroscopy) and
pre-surgical assessment of the extent of
disease (e.g. rectal, cervical, and prostate
cancer) to guide management for a better
outcome.
In nuclear medicine, a major
technological breakthrough was the
integration of PET (Positron Emission
Tomography) with CT, a process in which
one of my colleagues, David Townsend,
played a key role. The place of PET-CT in
the staging of certain tumours is now
firmly established and it has helped to
optimise treatment for these cancers and
obviate unnecessary surgery.
I have also mentioned earlier that the
advances in Interventional Radiology
allow us to treat patients with a wide
variety of disorders using techniques
that are less invasive than open surgery,
so that patients will have a faster
recovery period and fewer associated
complications.
6
What other responsibilities do you
have?
I am quite involved in the national breast
screening programme and sit in a few
of the committees there, namely the
Advisory, the Quality Assurance & Training
as well as the Audit Committees. The
roles include planning the direction of the
BreastScreen Singapore (BSS) programme
as well as auditing the programme to
ensure a high level of quality assurance.
I also chair a committee organising the
Breast Screen Singapore Seminar in
October this year which will coincide with
the Breast Cancer Awareness Month.
As an extension of my interest in
oncologic work, I am an EXCO member of
the National University Cancer Institute,
Singapore (NCIS) and a member of the
Working Committee of the Western
Cancer Action Network (WCAN).
On the NUH front, I am part of a
group of Senior Advisors to the NUHS
Medico-Legal Team and also sit in the
Singapore Medical Council Complaints
and Disciplinary Committee. Some
of my other responsibilities include
Figure 3. Prof Quek with colleagues at NUHS Tower Block
being an Editorial Board member for
the Journal of Radiology and helping to
plan for Radiology training in Singapore
as a member of the Specialist Training
Committee for Diagnostic Radiology in the
Ministry of Health.
7
What areas do you hope to focus on
in your future career? Any particular
reasons?
I hope to be able to spend more time
in the field of Medical Education and
Training. Medicine has traditionally been
taught by apprenticeship, but it is good to
make it a more structured process. IT has
also changed the way things are taught,
in particular in Radiology. For example,
our trainees are given practice sets to do
online at their own convenience and we
then meet to discuss the findings.
Training and education are important as
they help us to maintain and improve on
our professional competency and ensure
that we produce better doctors with each
succeeding generation. Of course, as one
of my colleagues pointed out, the selfish
side to it is that we will all grow old and
be looked after by the current younger
generation of doctors one day, so it pays
for us to train them well now!
8
Where do you see yourself in the next 5
years in terms of career, personal, social
and family life?
I hope to have built a good team of
younger radiologists who can take over
the running of the Department and carry
it to greater heights. That will leave me
more time to spend with my family and
for myself.
2 014 JULY - S E P T E MB E R
M EDICO • 21
M EDIC AL N O TES
A/Prof Thomas Choudary
Putti
Senior Consultant and Clinical
Director,
Department of Pathology
Associate Professor Thomas Choudary Putti graduated
from the Osmania University, Hyderabad, India in 1985
with MBBS. His initial training in Histopathology was at
the Department of Pathology, Osmania Medical College
and he obtained his specialist degree in pathology from
the Osmania University, India in 1989. Subsequently,
he did his anatomic pathology residency from Long
Island Jewish Medical Centre, New York and obtained
his American Board Certification in 1997.
He did a year of fellowship in Immunopathology from
Bronx-Lebanon Hospital, New York from 1997 - 1998.
He had a six-month stint as clinical fellow (breast
pathology) at Nottingham City Hospital, UK under the
guidance of Prof. Ian Ellis.
He is currently a Senior Consultant and Clinical Director
in the Department of Pathology at NUH and has been
with the department for the last 15 years. He is also
an affiliated member and Senior Consultant with the
National University Cancer Institute, Singapore (NCIS).
Pathology and NCIS
The Department of Pathology at the
National University Hospital (NUH)
provides a comprehensive range of
diagnostic services using innovative
technology and highly-trained personnel.
It services the diagnostic requests of
numerous medical specialties and plays
a critical role in the process of patient
diagnosis, treatment, and monitoring. The
department performs in excess of 40,000
histopathology and cytology tests per
year.
Our specialist surgical pathologists play
a definitive role in tumour diagnosis.
Despite a high index of clinical suspicion
and radiological support, the diagnosis of
cancer is not conclusively established in
the absence of tissue diagnosis. Surgical
pathologists provide an accurate and
sufficiently comprehensive diagnosis that
enables the clinician to develop an optimal
treatment plan and provide prognostic
indicators.
Figure 1. Diagnostic Molecular Oncology Centre team
22 • ME D ICO
J ULY - se ptemb er 2 014
The tremendous advances in all
fields of oncology require a great
deal of additional information
to allow the most appropriate
classification for research,
prognosis and therapeutic
intervention. Our pathologists
actively contribute to several
multi-disciplinary tumour boards.
A comprehensive range of
diagnostic services provided by
our department include:
• Routine and specialised surgical
pathology work
• Intra-operative/frozen section
consultation
• Expert consultation for
subspecialty
• Gynaecological and nongynaecological cytology
Figure 2. Interpretation of Fluorescence in-situ hybridisation by Molecular pathologist and technologist
The Diagnostic Molecular Oncology Centre (DMOC) is a
laboratory section of the NUH Department of Pathology,
which is accredited by the College of American Pathologists
(CAP). DMOC focuses on the molecular diagnosis of solid
tumours involving the integrated molecular analysis of
routine clinical samples reported by surgical pathologists
and cytopathologists.
Diagnostic Molecular
Oncology Centre
The Diagnostic Molecular Oncology Centre
(DMOC) is a laboratory section of the
NUH Department of Pathology, which is
accredited by the College of American
Pathologists (CAP). DMOC focuses on
the molecular diagnosis of solid tumours
involving the integrated molecular analysis
of routine clinical samples reported by
surgical pathologists and cytopathologists.
This collaborative paradigm is at the
core of stratified oncology or therapeutic
pathology.
The laboratory specialises in tissuebased molecular diagnosis and, in
particular, in the interfacing among tissue
morphology, immunohistochemistry,
in-situ hybridisation (ISH) techniques,
polymerase chain reaction (PCR) based
sequencing, and fragment analysis
technology, providing a one stop
laboratory for integrated pathology tissue
diagnosis.
Figure 3. FNA clinic; FNA procedure (above) and Interpretation of FNA smears by cytology
team (below)
DMOC is currently a reference laboratory
for the development of high-quality
molecular testing in the area of
personalised/stratified oncology, and
is also involved in sample logistics for
several on-going clinical trials in the
National University Cancer Institute,
Singapore (NCIS) involving next
generation sequencing (NGS) analysis
of archival clinical materials for the
panelled oncogene profiling of solid
tumours for drug-able targets, in a
collaborative partnership with the Centre
for Translational Research and Diagnostics
(CTRAD) and clinician scientists from the
NCIS.
Fine needle aspiration (FNA) service
FNA is a quick, minimally invasive test to
obtain diagnostic material from a tumour
or lump. It is an effective rapid test in
determining adequacy of the sample and
providing immediate preliminary results.
It is also extremely useful in the diagnosis
and treatment of cysts.
Fine needle aspiration is a type of
biopsy in which cells are removed
from a lump either with only a
needle or with a needle and syringe.
The cells are evaluated under a
microscope to determine the nature
of the lump. Special tests can be
applied to these small samples to
aid in the diagnosis and treatment
of cancer, including tumours of the
breast, lymph nodes and thyroid. An
immediate provisional diagnosis is
provided followed by a final report
within two days of the procedure.
At the NUH Medical Centre FNA Clinic
(Level 15), specialised pathologists
called cytopathologists who diagnose
diseases at the cellular level offer
consultation services. They perform
the procedure and provide immediate
provisional diagnosis, thereby
allowing the clinicians to plan
management of the disease in the
same visit.
2 014 JULY - S E P T E MB E R
M EDICO • 23
UPCOMING
EVENTS
NUH GP CME Programme 2014
Please refer to our GPLC website for online registration.
September
SATURDAY
October
20
National University Heart Centre, Singapore
NUHCS Cardiology Updates
Living and Managing Heart Disease:
Adult Congenital and Structural Heart Disease
SATURDAY
18
University Medicine Cluster
NUH Gastroenterology Updates
Event information listed is correct at time of print.
While every attempt will be made to ensure that all events will take place as scheduled, the organisers reserve the rights to make appropriate changes should the need arises.
Please refer to our events calendar at www.nuh.com.sg/nuh_gplc for more updates and information.
A Publication of NUH GP Liaison Centre (GPLC)
Advisor A/Prof Goh Lee Gan
Editors Jaime Raniwaty Chiah and Davin Wangsa
Editorial Member Lisa Ang
We will love to hear your feedback on Médico.
Please direct all feedback to:
The Editor, Médico
GP Liaison Centre, National University Hospital
1E Kent Ridge Road, NUHS Tower Block, Level 6, Singapore 119228
Tel: 6772 5079 Fax: 6777 8065
Email: [email protected] Website: www.nuh.com.sg/nuh_gplc
Co. Reg. No. 198500843R
The information in this publication is meant purely for educational purposes and may not be used as a substitute for medical diagnosis or treatment. You should seek the advice of your doctor
or a qualified healthcare provider before starting any treatment, or, if you have any questions related to your health, physical fitness or medical condition(s).
Copyright (2014). National University Hospital, Singapore
All rights reserved. No part of this publication may be reproduced without permission in writing from National University Hospital.
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