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Autumn 2008 | Issue #15

GENETICS:redefining diagnosis, disease

and drug therapy

PathW

ayA

utumn

2008-

Issue#15

PHARMACOGENETICS:TAILOR-MADE TREATMENTS

PCR TESTING:A REVOLUTIONARY DISCOVERY

HAEMOCHROMATOSIS:IGNORANCE IS NOT BLISS

GENETICS:redefining diagnosis, disease

and drug therapy

PathWay #15 - Cover 20/2/08 5:56 PM Page 2

PATHWAY_1

ContentsADVISORY BOARD

Dr Debra Graves (Chairman)Chief Executive, RCPA

Dr Tamsin WaterhouseDeputy CEO, RCPA

Dr Edwina DuhigDirector of Anatomical Pathology QHPS(Prince Charles Hospital)

Dr Andrew LaycockChairman Trainees Advisory Committee, RCPA

Dr David RocheNew Zealand Representative, RCPA

Wayne TregaskisS2i Communications

PUBLISHERWayne Tregaskis

EXECUTIVE EDITORDr Debra Graves

EDITORDr Linda Calabresi

ART DIRECTORJodi Webster

ADVERTISING SALES DIRECTORSue Butterworth

PUBLISHING CO-ORDINATORAndrea Plawutsky

PathWay is published quarterly for the Royal College

of Pathologists of Australasia (ABN 52 000 173 231)

by S2i Communications, Level 9,

16 Spring St Sydney 2000

Tel (02) 9251 8222 Fax (02) 9247 6544

PrintPOST approved PP60630100114

The Royal College of Pathologists of AustralasiaTel: (02) 8356 5858

Email: rcpa@rcpa.edu.au

S2i Communications Pty LtdTel: (02) 9251 8222

Email: wayne@s2i.com.au

PathWayEmail: pathway@rcpa.edu.au

http://pathway.rcpa.edu.au

COVER STORY

A perfect fit: Pharmacogentetics 8

Advances in genetics are making it possible to tailor treatmentsto the individual patient.

FEATURES

Disciplines in depth: Back to basics 12

Pathology’s newest subspecialty, genetics looks set to change thefuture of medicine’s approach to disease and treatment.

In profile: Family matters 16

Dr Graeme Suthers’ drive and vision have had a major influenceon Australia’s familial cancer services.

Testing testing: The ABC of PCR 20

Bianca Nogrady reports on how PCR testing has changed the faceof medical diagnosis.

Spotlight on disease: Metal detectors 26

Haemochromatosis: easy to diagnose and treat but still oftengoing undetected until too late.

Cutting edge: High expectations 32

Prenatal genetic screening is becoming commonplace inAustralia. Dr Kathy Kramer looks at its benefits, limitations andpotential.

Foreign correspondence: Wisdom in the Solomons 35

Australian expertise is behind the setting up of the SolomonIslands’ first anatomical pathology laboratory.

PATHWAYAutumn 2008Issue #15

FOR FURTHER INFORMATION ON THE ROYAL COLLEGE OF

PATHOLOGISTS OF AUSTRALASIA OR ANY OF THE FEATURES

IN THIS ISSUE OF PATHWAY CHECK OUT THE WEBSITE

www.rcpa.edu.au

PathWay #15 - Text 21/2/08 12:45 PM Page 1

Pathology in Australia has been a leader in accreditation and qualityassurance. Recent studies in many countries have shown that the majority of adverse patient incidents occur in the non-analytical phase of the test-request-report cycle.

To minimise the risk of errors and incidents in pathology, the pre- and post- analytical phase of testing need to be measured and monitored. KIMMS is designed to provide pathology practices with the tools for continuous measurement and monitoring of key incident indicators.

KIMMS provides the means by which laboratories can be encouraged to monitor rate of adverse incidents affecting patient safety and welfare; through benchmarking against peers and state-of-the-art, a mechanism is provided for the systematic risk management and improvement of performance in agreed key areas.

Key Incident Monitoring and Management Systems (KIMMS)

KIMMS Objectives: x To establish a national data set for pathology incidents x To develop the data set to enable participants to measure and monitor pathology incidents x Utilise the data to set achievable national benchmarks for good pathol-ogy practice in the pre- and post-analytical phase of testing x Work with participants, by ex-changing information, to educate laboratories on methods to reduce errors x Raise awareness of safe work practices which in turn will reduceerrors and increase patient safety x Set standards for best practice in the pre– and post-analytical areas of laboratory work

KIMMS offers pathology laboratories: x Data and graphical analysis, show-

ing trend analysis x Benchmarking against peers x Educational content

For further information contact: Penny Petinos

KIMMS Coordinator pennyp@rcpa.edu.au Ph: +612 8356 5814

PATHWAY_3

REGULARS

From the CEO 4

Welcome from RCPA CEO Dr DebraGraves

Under the microscope 6

News + views

6minutes news 30

Interesting news from around theworld

Finance finesse 38

Financial advisor, Greg Lomax givessome timely tips on superannuationinvestments.

Conference calendar 42

Postscript 64

Fairy tales and feral carbon: Dr PamRachootin proposes pathologists areideally placed to save the planet

LIFESTYLE

Travel: O Paradiso 44

Pangkor Laut Resort in Malaysia is a heady combination of beauty,serenity and luxury.

Travel: Images of Iran 46

Judy Myers finds a country rich in history, culture, colour andhospitality

Travel doc 49

On the trail of the tiger: Dr Harsha Sheorey has the experience of alifetime while on safari in Central India

Private passions 52

Doing the hard yards: Mike Ralston’s hankering for hiking has certainlyseen him cover some ground.

Recipe for success 54

Expelled to greatness: Carolyn Alexander meets lauded chef, AndrewMcConnell, the talent behind Melbourne’s Three, One, Two.

Dining out 57

Food with a view: Combining a spectacular view with fabulous foodmakes for a truly memorable dining experience

The good grape 61

Chic sherries: Ben Canaider explains why sherry is enjoying arenaissance around the world

Rearview 62

Racing to unravel the mystery of AIDS: Who discovered AIDS? DrGeorge Biro looks at one of the great feuds of our time

IMAGES OF IRANPAGE 46

WISDOM IN THESOLOMONSPAGE 35

4_PATHWAY

Arevolution started in medicine in 1953when Watson and Crick discovered

DNA.

Over the ensuing 55 years manyadvances have occurred in the field ofGenetics which have had profound effectson our understanding of disease and ourresponse to it.

This edition of PathWay focuses on the“Genetic Revolution” examining specificareas where genetic testing impacts onhealthcare and the challenges that layahead for countries dealing with thisphenomenon.

For many people genetic testing is abrave new world and perhaps even a littleabstract, with concepts such as “predictivetesting” and its far reaching consequences.But the reality is genetic testing is here andalready contributing significantly to theadvancement of medicine.

As a result, it is time for politicians,health care administrators and the generaland medical communities to be betterinformed about genetics and what we needto do to ensure the healthcare system iswell-equipped to deal with this revolution.

Perhaps the most widely known form ofgenetic testing is that involved with prenatalscreening, looking for conditions such asDown syndrome.

This type of testing and the issuessurrounding it are explored in the article byDr Kathy Kramer, “High Expectations”.While a very important area it must bestressed that this is only one application ofgenetic testing, and only the tip of a verylarge iceberg.

Other major areas of genetic testing thatwill be explored include predictive testing inadults for susceptibility to disease andresponsiveness to drug therapy, the geneticsof cancers and genetics of organismscausing infectious diseases.

In our article “The ABC of PCR”, the

use of Polymerase Chain Reaction (PCR) to

detect the genetic make up of organisms is

outlined. Developed in the early '90s, the

technique of PCR testing allows scientists

to produce or amplify genetic material to a

sufficient “volume” to enable the detection

of particular base pair sequences in genes

that code for particular conditions or

organisms.

In the article “Family Matters”, we

profile Dr Graeme Suthers who is the head

of the South Australian Familial Cancer

Service, which is doing remarkable work in

this important area of genetic testing.

Dr Graeme Suthers, a genetic

pathologist and Chair of the College's

Genetics Advisory Committee is one of a

number of pathologists driving the

College's push for a National Framework in

Genetics in Australia.

As is so often the case with new

technologies, the funding, workforce planning,

regulatory, ethical and quality/standards need

to be planned in a systematic way to ensure a

high quality appropriate service is delivered.

Compared to the UK, many countries

including Australia are slow in addressing

these issues. In the UK, over 300 genetic

tests are funded by the NHS, in Australia the

Medical Benefits Schedule includes only ten,

with some States funding some genetic

tests in a somewhat ad hoc manner.

The College thinks it is time for urgent

action to be taken to keep Australia at the

forefront of the medical world.

In the feature “Metal Detectors”, we

examine another area of genetic testing for

the condition known as haemochromatosis.

We talk with Professor David Ravine about

this very important genetic test and explore

the question of population screening for the

disease.

The other very exciting area of genetics

that we look at is that of predicting a

person’s responsiveness to a particular

medication. This is explored in the article “A

perfect fit: Pharmacogenetics”.

Already there are a number of genetic

tests that are being used to determine a

patient's suitability for particular treatments.

And the number of new tests becoming

available over the next few years is likely to

increase dramatically. This will have

tremendous benefits for patients as they will

receive much more targeted treatments, and

also has the potential to save considerable

amounts of money with people only being

offered a drug if it is known they will be

responsive to it.

In the pharmacogenetics article,

another major area of genetic testing - the

testing of the genetic make up of cancers

themselves - is discussed. Variations in the

genetic profile of cancer cells compared to

normal cells is a key area of research and

indeed in a number of areas is already used

in routine diagnostic practice. Greater

understanding of these differences offers

benefits in diagnosis, prognosis and

treatment of cancer.

By understanding the exact type of

tumour present more targeted therapy can

be provided, the classic example being the

effectiveness of trastuzumab (Herceptin) in

HER2 positive breast cancer.

We hope you enjoy this exciting very

important edition of PathWay.

Dr Debra Graves

CEO, RCPA

Welcometo the 15th Edition of PathWay

from the CEO

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6_PATHWAY

After a year-long review of its curriculum,

Sydney University has more than

doubled the teaching time devoted to

anatomy as part of its graduate medical

course. The four year course will now

include reportedly 1200 hours of anatomy

study, significantly more than the 500 hours

allocated in the previous curriculum.

The move is believed to be in in

response to complaints from many in the

medical community, including the students

themselves, that graduates of the course

were inadequately trained in a number of

the basic medical sciences, including

anatomy. It is believed that the revised

curriculum, the first revision in 11 years also

contains increases in the teaching time

allocated for other sciences such as

pathology.

Three Australian pathologists wereamong those recognised on this year’s

Australia Day honours list.

Dr Colin Laverty (pictured right) wasawarded a Medal of the Order of Australia(OAM) for his service to medicine,particularly gynaecological cytology andhistopathology.

He established the role of humanpapillomavirus in cervical cancer and hashelped advance cervical screeningservices in Australia. The award alsoacknowledged Dr Laverty’s contribution toart, particularly Indigenous art, both inAustralia and overseas.

Immunologist, Professor Paul Gatenby,foundation dean of ANU medical schoolwas made a Member of the Order ofAustralia (AM) for service to medicine inthe field of clinical immunology as aclinician and researcher, to theadvancement of medical education, andthrough professional organisations.

Former chief executive officer of theWA Centre for Pathology and MedicalResearch, Dr Keith Shilkin was also madea Member of the Order of Australia (AM)for his work in developing WA’s publicsector pathology services. Hiscontributions to professional organisationsas well as to the Jewish community werealso recognised.

Australia Day honours

under the microscope: news + views

Boost forHep C/HIVresearchHepatitis C and HIV research has

been given a significant boost

with the announcement of $17.7

million in funding being awarded to

the University of NSW by the

National Health and Medical

Research Council (NHMRC) to

advance understanding of the two

diseases.

The grant, the largest in

Australia’s history, was announced

last month by the Minister for Health

and Ageing, Nicola Roxon.

Professor David Cooper from the

National Centre in HIV Epidemiology

and Clinical Research (NCHECR) will

lead a nine person team from across

Australia, combining researchers in

virology and immunology with those

who have expertise in translating

findings in the laboratory into human

clinical trials.

Part of the grant has been

allocated to fund a five year project

to develop new strategies to prevent

and treat hepatitis C, which is

currently affecting more than

260,000 Australians.

Leading the project, University of

Adelaide virologists Dr Michael

Beard and Dr Karla Helbig, along

with colleagues from the University

of NSW, hope to identify antiviral

proteins that can work effectively

against the hepatitis C virus with the

aim of developing vaccines and

treatments for the disease.

More anatomy for SydneyUni med students

PATHWAY_7

GPs orderingmore pathtestsAustralian GPs are ordering significantly

more tests and investigations,particularly pathology tests than they weresix years ago, new data show.

Findings from a report released by theAustralian Institute of Health and Welfareshow GPs ordered 44% more tests (orbatteries of tests) per 100 patients in2006-07 compared with 2000-01.

Researchers suggest incentives forimproved care of people with chronicdiseases such as diabetes may, at leastpartly be responsible for the increase.

The report, General Practice Activityin Australia 2006-07, reports the resultsfrom the ‘Bettering the Evaluation andCare of Health’ (BEACH) program’snational survey of 100,000 GP-patientencounters.

Australian innovationadvances genetictechnology

A new type of RNA microarray chip developed by Australian scientists has been

licensed to one of the world’s largest life sciences technology companies, Invitrogen.

Dr Marcel Dinger and Professor John Mattick from the University of Queensland’s

Institute of Molecular Bioscience designed the proprietary technology that will help

analyse which genes are being expressed at any one time in a particular cell.

Each cell in the body contains a full set of genes, however different cells express

different subsets of these genes. Previously it was believed these genes only coded

mainly for proteins via the production of ‘messenger RNAs’. However it has been

discovered that many other genes produce non-coding RNAs, the functions of which

are yet to be determined.

The newly licensed RNA microarray chip can uniquely identify tens of thousands of

coding and non-coding RNA sequences. For the first time, one product can identify

large numbers of both types of RNAs and the new technology has the potential to

make a significant impact in the areas of cancer and stem cell research where RNAs

have been implicated.

The technology has been licensed through IMBcom, University of Queensland’s

company for the commercialisation of intellectual property arising from research

conducted at the Institute of Molecular Bioscience.

8_PATHWAY

cover story

A perfect fit

PharmacogeneticsGENETICS CAN PREDICT A PERSON’S RESPONSE TO A DRUG EVEN BEFORE THEY’VE

TAKEN IT. PPEETTEERR LLAAVVEELLLLEE LOOKS INTO THIS BRAVE NEW WORLD.

PATHWAY_9

It was a lot better to be born at the end of

last century than at the beginning. In

1900, life expectancy wasn’t much over 30

years of age. But we ended the 1900s with

a life expectancy of 77 years for men and

83 for women.

Better sanitation, hygiene and nutrition

played a big part. But it was the

emergence of the pharmaceutical industry

that gave us vaccines, antibiotics,

anaesthetics and host of other drugs, that

helped bring the killer diseases of centuries

past under control.

So we’ve a lot to be grateful for.

Still, drug treatment is a clumsy

business. It's mostly trial and error; a

doctor prescribes a certain drug, hoping it

will work, and if it doesn’t, tries another.

There’s not much certainty - one person

responds well to a drug while another is

resistant to it, or develops side effects so

the drug has to be stopped.

Why?

We’ve known since the 1950s that

people react differently to different drugs;

and that a person's age, sex, weight, and

ethnic background all influence how he or

she will react.

But what’s becoming clearer in the

beginning of the 21st century is how

important an individual's genetic makeup is

in determining a person’s reaction to a

particular drug.

Thanks to an emerging discipline called

‘pharmacogenetics’, clinicians are

increasingly using genetic testing to

identity who is suitable for a particular

treatment - enabling clinicians to tailor drug

treatments to particular individuals.

It's not a new concept - the term

pharmacogenetics was coined in 1958 -

but what is new are the advances in our

understanding of the human genome and

the technologies we now have to detect

abnormalities in individual genetic profiles.

Professor Ross McKinnon is Professor

of Pharmaceutical Biotechnology in the

School of Pharmacy and Medical Sciences

University of South Australia. “A drug is a

molecule that goes through a journey in

someone’s body, and that journey depends

on interactions with different proteins,” he

says. “Those proteins are encoded by

genes, and those genes vary from person

to person and so the journey differs in each

person. In most cases the differences

won’t mean much but in others these

differences can have a dramatic impact.”

The genetic differences themselves

seem minor on the face of it.

In most cases they are just mutations

in single bases of DNA known as single

nucleotide polymorphisms (SNPs) -

variations that occur when a single

nucleotide (A, T, C or G) in the genome

sequence is altered.

In some individuals, there may be

multiple different single base mutations, or

multiple copies of the same mutated

sequence.

Some people may have inherited the

mutations from one parent (this is called

heterozygous) or from both parents

(homozygous).

But the consequences can be

dramatic, says Professor McKinnon.

Genes that code for proteins that

affect the way a drug is metabolised may

be altered so they work differently or they

don’t work at all.

If, for example, the mutation produces

enzymes that are less effective in breaking

down a drug into its metabolites, the

person will have abnormally high levels of

that drug in the body, causing toxicity and

side effects.

If the mutation produces more of the

enzyme than normal, this may lead to

faster metabolism of the drug, and the

drug is less effective than in the normal

population.

Where there are several copies of the

same abnormal gene, or the person is

homozygous for the altered gene, then the

effect can be especially dramatic.

Fortunately, many of these mutations

can be tested for and identified, thanks to

advances in genomics and in genetic

testing.

There are two ways of testing for

genetic mutations affecting drug

metabolism, says Professor McKinnon.

One involves looking for the faulty

genes themselves; that is to do genotypic

tests to look for the abnormal DNA bases

(single nucleotide polymorphisms or SNPs)

using polymerase chain reaction (PCR)

techniques. These tests can be done on

blood samples or cheek swabs.

The other approach is to look for the

consequences of the abnormality, by doing

assays of the enzyme(s) that break the

drug down in the body, or of the

metabolites of the drug - these are blood

tests.

Professor Ross Pinkerton is a

paediatric oncologist at Royal Children's

Hospital, Brisbane.

>

10_PATHWAY

Identifying theenemyIn the world of tailored medicine there are two sides to the equation.

Isolating variations in a person’s genetic profile to see whether a treatmentwill be effective is an important component of customising therapies.

However, on the flipside it is often equally important to know the geneticmake up of the disease that is to be treated.

One area of medicine where this is particularly true is cancer.

The ‘genetic revolution’ has enabled a greater understanding of a wholerange of cancers.

In lymphoma for example, advances in genetics have led to greatlyimproved diagnostic accuracy, says Clinical Professor Dominic Spagnolo fromthe University of Western Australia.

“Being able to identify antigen receptor genes in B and T lymphocyteshas allowed us to be more definite in difficult-to-diagnose cases oflymphoma,” he says.

Advances in this discipline have also led to the identification andassessment of genes that control cell growth, differentiation and death.

“In lymphoma the inappropriate switching on or off of these genescorrelates with the progression of the disease and indicates how aggressivethe cancer is likely to be,” says Professor Spagnolo who is also consultantpathologist at PathWest Laboratory Medicine, Perth.

The presence of such genetic markers therefore has become predictive ofpatient outcomes and hopefully will enable the tailoring of future lymphomatherapies, he adds.

In other cancers the use of genetics to determine suitability of particulartreatments is already well advanced.

Breast cancer is a classic example says Dr Adrienne Morey, senior staffspecialist in anatomical pathology at St Vincent’s Hospital, Sydney.

“It is becoming increasingly apparent that breast cancer is not a singledisease but a group of diseases with different molecular profiles that arelinked to specific genetic defects.”

“New therapies are being developed which target different subgroups ofthe disease, the most widely known probably being trastuzumab (Herceptin)and lapatinib (Tykerb) which are indicated only in cancers that have an over-expression of the HER-2 protein to which the drug binds,” she says.

Only one fifth of all breast cancers have this over-expression. Genetictesting to identify this subgroup ensures these new (expensive) treatments areonly given in cases where they will be most effective, Dr Morey says.

As the genetic profiles of more and more cancers are identified, advancesin diagnosis, prognosis and effective therapies look set to follow.

In addition to breast cancer and lymphoma, cancers of the colon, prostateand ovary are just some of the many malignancies that are currently thesubject of genetic research.

Dr Morey predicts that down the track, more targeted therapies will bedeveloped and pathologists will be increasingly asked to identify the geneticprofile of individual cancers as such knowledge becomes a fundamentalcomponent of determining treatment.

One of the drugs he uses to treat

children with acute lymphoid leukaemia

(ALL) is 6-mercaptopurine, a thiopurine

drug that is usually well tolerated and

used as a maintenance drug.

Normally 6-mercaptopurine is broken

down in the body by thiopurine

methyltransferase (TMT). But some

children don’t have this enzyme.

“In these children [6-mercaptopurine]

is toxic. They get severe neutropaenia,

that is they get dangerously low white cell

counts that leave them susceptible to

infection.”

Other children have greater than

normal levels of TMT and in these

children, the drug doesn’t have the

therapeutic effect it normally should.

The faulty gene can be detected using

genotypic testing, or by testing for the

levels of metabolites of 6-mercaptopurine.

“Those kids without the enzyme have

low levels of metabolites, while those with

higher than normal levels of the enzyme

have high levels of the metabolites,” he

says.

These tests aren’t routinely done on

children commencing treatment with

6-mercaptopurine, but they will be done if

a child shows neutropaenia or isn’t

responding to treatment. If the test shows

a faulty gene and/or abnormal levels of

metabolites, the dosage of

6-mercaptopurine is adjusted.

Many of the advances in

pharmacogenetics have been in oncology

(diagnosis and treatment of cancers),

largely because of the important role

genetics plays in the genesis and

inheritance of cancers.

But it is by no means confined to

oncology.

It is now being used in the prevention

of blood clots, in inflammatory bowel

disease management, in the treatment of

high blood pressure and in viral illnesses.

Genetic testing is already being widely

used in the treatment of hepatitis and HIV,

where the genotype of the virus is being

used to predict the response to drugs,

says Professor McKinnon.

Some people have an exaggerated

response to the anti-clotting agent,

warfarin. They may not metabolise it or

they may have a gene that increases

PATHWAY_11

warfarin's effects on the clotting cascade.

These people are at risk of catastrophic

bleeding. Both types of mutations can be

identified with gene testing, and the

dosage of warfarin can be adjusted

accordingly.

Psychiatry is another area where

pharmacogenetics will play an important

role in the future, Professor McKinnon

believes. Clinicians will be able to match

differences in a person's biochemistry -

differences in their levels of chemical

neurotransmitters in their brain for

example - using genetic testing, so their

use of antidepressants and other drugs

can be customised.

It is expected that pharmacogenetics is

going to be most useful where a drug has

serious side effects at a dose not much

greater than the therapeutic dose, where a

drug is particularly expensive (so it’s

important to know the drug will work), and

where there is known to be a great deal of

variation in a drug’s effectiveness.

Nevertheless genetic testing of drugs is

still a relatively new field and isn't yet in

widespread use.

There are many issues still to be sorted

out; such as what drugs should be tested

and at what stage of treatment.

Also - does the cost justify the benefit?

Some, such as the older tests involving the

cytochrome P450 (CYP) family of liver

enzymes, (which break down many

commonly used drugs) are commercially

available from the larger pathology labs at

a cost of a few hundred dollars. But others

can cost thousands of dollars and are only

available through research centres.

Conversely, there are huge potential

cost savings in the form of fewer drugs

being prescribed that don’t work in certain

patients, and less treatment needed for

toxic side effects in others.

There are some drugs where it’s

generally accepted that it makes sense

from a cost benefit point of view to screen

individuals before giving the drug, says

Professor McKinnon.

They include mercaptopurine and

azathioprine (another thiopurine used in the

treatment of solid tumours and other

conditions such as inflammatory bowel

disease). “With these drugs there's a good

argument that we should be doing genetic

testing before we start treatment to give us

an idea of how the patient is going to react

to them,’ he says.

But for most other drugs, there isn’t yet

enough evidence that pre-treatment

screening saves money in the longer term.

“We need more studies done before we

can make those decisions,’ he says.

“We are still unravelling the genetic

differences that underlie the variation in

response from person to person. So there

are plenty of challenges” he says.

To complicate matters, most of these

tests aren’t eligible for a Medicare rebate.

“The drug itself may be subsidised by

the Pharmaceutical Benefits Scheme but

the test isn’t covered by Medicare, so there

needs to be a better alignment of funding

for the drug and the test,” he says.

Another issue is how well and how

quickly GPs and other clinicians will adapt

to using pharmacogenetics. It means more

training for GPs who’ll need to improve

their understanding of genetics to get to

the point where they become used to

ordering genetic tests for drugs as an aid

to prescribing.

Associate Professor Leslie Sheffield is

a clinical geneticist with Genetic Health

Services Australia, and at the Royal

Children's Hospital in Melbourne. He has

been interpreting genetic tests for 25

years. He says there are now tests

available for about 30 per cent of all the

drugs in a physician’s armoury (most not

yet commercially available but used in

research labs).

He predicts GPs will eventually

embrace pharmacogenetics because it will

take much of the hit-and-miss out of

prescribing.

He’s in the process of setting up a

service that will give GPs and other

clinicians access to information about what

pharmacogenetic tests are available and

for what drugs. The service will be

accessible via a web site that he hopes will

be online about April this year. The address

is www.genesfx.com.

“We are still unravelling the

genetic differences that

underlie the variation in

response from person to

person. So there are plenty

of challenges”

12_PATHWAY

Genetics is described in the RCPA

history, Pathology: Professional

Practice and Politics, as the “Cinderella of

disciplines”.

It is a surprisingly apt analogy with its

“rags to riches” connotations. Following

what Dr Ron Trent, the inaugural

Chairman of the Genetics Advisory

Committee, RCPA, describes as the

“genetics to genome revolution”, the sub-

speciality is poised to give a unique and

new focus to important health issues in

the community, becoming an integral part

of every medical discipline.

“Genetics will change the future for

inherited disease absolutely”, says Dr

Michael Buckley, chief examiner in

Genetics for the College.

Over recent years, medicalprofessionals will have noticed theincreasing interest in this area, with almostevery conference now featuring a geneticstrand. Yet this discipline has only been arecognised part of pathology and theRCPA since 1996.

The training program in laboratorygenetics is available in three differentareas - cytogenetics, biochemicalgenetics and molecular genetics. Since1996 the diversity of the training requiredin genetics has grown with the curriculumnow including the need to understandclinical genetics, which includes aspectsof genetics counselling and analysis ofgenetic information in the clinical setting.

The exponential increase in interest ingenetics can be tied intrinsically to the

success of the Human Genome Project.

This international tour de force,

coordinated by the U.S. Department of

Energy and the National Institutes of

Health, brought scientists together

between 1990 and 2003, to identify the

20,000 genes in human DNA.

It also determined the sequences of

the three billion chemical base pairs that

make up human DNA.

The information from the project has

been stored in extensive databases and

research is ongoing.

The Human Genome Project’s success

has stimulated the creation and rapid

growth of the field of genomic medicine

within pathology making the development

of an understanding of genetic material on

disciplines in depth

THE MOST RECENTLY RECOGNISED OF THE PATHOLOGY DISCIPLINES, GENETICS IS SET TO HAVE

A MAJOR IMPACT ON THE FUTURE OF MEDICINE, AS LLOOUUIISSEE MMAARRTTIINN--CCHHEEWW FINDS OUT.

Back to basics

PATHWAY_13

a large scale possible. Importantly, theProject has also resulted in thedevelopment of improved tools for dataanalysis.

In the area of molecular medicine, thenew knowledge base has already led toan improved diagnosis of disease.

Increasingly, detailed genome mapsare aiding scientists seeking genesassociated with a myriad of geneticconditions. These include, for example,myotonic dystrophy, fragile X syndrome,inherited colon cancer, Alzheimer'sdisease, and familial breast cancer.

Diagnosis based on the presence ofspecific genes heralds a new era ofmolecular medicine - characterised lessby treating symptoms and more bylooking to the most fundamental causesof disease.

Dr Buckley has a special interest inmuscular dystrophy where genetics is partof routine management.

“Parents want to know first what it is,secondly if they can stop it happeningagain and thirdly if it is a consequence oftheir actions. So far we can answerquestions one and two. We classify thedisease according to gene mutation. Ifparents are willing to go down the track offalling pregnant and having the necessaryanalysis and termination, yes we can stopit happening again.”

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Marcus Hinchcliffe4th year traineeRegistrar in Molecular Genetics,Royal Prince Alfred Hospital, Sydney

Ihave always been interested in molecular genetics and was

keen to understand the science better, so after my residency at

the Royal Brisbane Hospital I went back to university to do a

Masters in Molecular Biology. I began training in molecular

genetic pathology at the Department of Molecular and Clinical

Genetics at the Royal Prince Alfred Hospital in Sydney in 2005.

Genetic knowledge is rapidly expanding, there’s a lot to keep

up with and I find that very stimulating. Increasingly, molecular

genetics will become central to medicine. Personal genome

profiles will become standard within the next ten years. There

will be wide impacts upon diagnostics, cancer profiling and

individualised prescribing.

It still amazes me that the complexity of life can be simplified

to the combinatorics of a four letter DNA code.

The clinical side of our department consults with families

mainly on an outpatient basis. I work on the diagnostic side.

Blood/DNA is sent off to the relevant laboratory. (In Australia

each lab specialises in a number of tests). At RPA we specialise

in the haemoglobinopathies, as well as a number of other

heritable conditions.

I will complete my training in 2010. My exams are mid 2008

and then I’ll do the PhD component of the RCPA molecular

genetic course. I will be looking at non-coding RNA in the

human brain using high throughput sequencing technology.

14_PATHWAY

But diagnosis is just part of the

genetics story.

Understanding the role of certain

genes and the significance of their

presence, medical researchers will also be

able to devise therapeutic regimens based

on a person’s genetic profile. They will be

able to augment or even replace defective

genes through gene therapy. Rational

drug design, control systems for drugs

and pharmacogenomics “custom drugs”

are other benefits currently under

development.

As Dr Trent notes, the sequencing of

the human genome began with modest

ambitions but has had revolutionary by-

products, albeit more complex than

originally anticipated.

“Humans have 20,000 genes. The

pinot noir grape, just sequenced, also has

20,000 genes. Humans are obviously

more complex. We need to ascertain how

it all works, how it interacts with the

environment. We need answers to these

questions.”

Advancements in genetics have been

possible in a large part by the technology

developed to manage the bonanza of

information now available, according to DrTrent.

The trend to automate analysis andthe development of microarray analysishas allowed, researchers to identifyindividual genes, to look at any singlegene and have access to the informationfrom it concerning particular disease.

Previously this was too complicated ortime consuming. It was also vulnerable tohuman error.

In Australia, new machinery hasallowed developments in the revolutionaryareas of personalised medicine andpredictive medicine.

Personalised medicine, working withan individual’s genomes, allows thedevelopment of drugs and medicationsthat work best for that individual. Giventheir genetic profile, the practitioner mayselect which category of drugs puts themat least risk and maximum benefit.

Predictive medicine allows analysis ofan individual’s DNA to identify geneticmarkers that signal that person’spredisposition to particular diseases.Identification of such genetic mutationsprior to the disease causing anysymptoms, enables a person to take

preventative or control measures, such asis the case with women with the BRCA1and BRCA2 genes for breast and ovariancancers.

As Dr Trent suggests, “[Because ofthis technology] we can predict thepossible consequences for the individual,and this possibility, for genetics, is huge.A handful of conditions have markergenes, and as the technology improveseven bigger profiles of people’s geneticmake up will be a possibility.”

But this is far from a straightforwardprocess. Added to the difficulties inherentin identifying the genetic markers ofdisease, researchers have to alsodetermine how well that genetic markerpredicts the disease and whether anyaction can or should be taken. And thenthere is the ethical debate about the risksversus benefits of this type of testing.

While the way forward is not withoutits challenges, Dr Trent says informaticswill have an important role to play. Thesequencing of a genome and thedepositing of this information within adatabase still requires interpretation, andtoday, most of the genome information inthe databases remains unintelligible. He

“Genetics will change the future

for inherited disease

absolutely”, says Dr Michael

Buckley, chief examiner in

Genetics for the College.

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Kym Mina1st year traineeRegistrar in Molecular Genetics,PathWest, Perth

Istudied medicine at The University of Western Australia and

completed my intern year in 2000. I worked as a resident at the

Royal Perth and Sir Charles Gairdner Hospitals but then took

some time away from medicine and had two children (now two

and five years of age). At the same time I worked toward my

PhD (completed end 2006) in Public Health (epidemiologic

methods). My training and work as a registrar in Molecular

Genetics immediately followed.

I am employed by PathWest which has laboratories (for both

molecular genetics and cytogenetics) in the public hospitals here

in Perth, so I rotate through different hospitals for my training. At

the moment I am working at Sir Charles Gairdner Hospital, but I

have also worked at Royal Perth Hospital and King Edward

Memorial Hospital during 2007.

While there was no direct relationship between my PhD topic

and laboratory genetics, when the opportunity to do this job

arose I found it irresistible. I have always found molecular

biology and genetics interesting, even at school, but had not

worked in the area previously. I am naturally analytical and

methodical and hence genetics and laboratory work fit well with

both my personality and interests. Genetics is also very

appealing because of its relative newness in comparison to other

fields of pathology and its growing medical relevance and

applications.

I have now been working in this position for one year and I

am enjoying it immensely. This is a new position and as a result

we’re all learning; primarily about how best to train a genetic

pathologist, but secondly about how such a pathologist might fit

into a complex and expanding genetics workforce here in WA.

indicates that better informatics and

algorithms will make more sense of this

information in the future, and more

training in the clinical genetics area will

be required to interpret the vast amount

of data that will be generated.

While there has been a small increase

in the number of trainees in this field of

pathology, there are insufficient trainee

positions funded by governments to cope

the demand for genetic pathologists.

“The workforce will have to be

educated, to become more savvy

concerning genetic issues. Otherwise the

level of testing required and the numbers

of clinical geneticists needed will become

unsustainable. There are important

questions which need to be addressed in

terms of these workforce issues as

genetics becomes part of every medical

discipline,” Dr Trent says.

Genetics, as the Cinderella of the

pathology disciplines, has well and truly

arrived at the ball.

As a direct result of all the advances

in knowledge and technology, genetics is

playing an increasingly important role in

the diagnosis, monitoring and treatment

of diseases. Its revolutionary nature and

importance is such that genetics is

poised to become arguably the foremost

science of the 21st century.

16_PATHWAY

Originally specialising in paediatrics in

Sydney, where he grew up, Graeme

Suthers wasn’t thinking of pursuing a

career in genetics. But after a young

patient with homocystinuria (an inherited

deficit of amino acid metabolism) piqued

his interest, Dr Suthers changed track to

specialise in the field that has since

inspired a life-long interest in DNA and

gene technology.

Combining an interest in both clinical

and research work, Dr Suthers went on

to complete a PhD in Fragile X syndrome

at the Women’s and Children’s Hospital

in Adelaide and further research at

Oxford University. Returning to clinical

work, he was subsequently accredited as

a specialist clinical geneticist in 1993

and, more recently, as a genetic

pathologist in 2002.

But it’s his work in the field of familial

cancer that has clearly dominated the last

ten years of his career. In 1998 he

established the Familial Cancer Service in

South Australia where he remains

Program Director to this day.

“By the mid 1990s, there was growing

awareness that a tendency to develop

cancer could be familial,” says Dr Suthers,

explaining the reasons for establishing the

service. “And instead of clinical

geneticists always being paediatricians

dealing with children and reproductive

issues and so on, the geneticists had to

start making some linkages with the

clinicians and services operating out of

adult hospitals. And that was novel. That

really hadn't happened very much. We

also saw a growing demand from patients

saying we want to come and get our

genetic situation sorted out. In South

Australia, as elsewhere, there was a rising

tide of referrals to talk about familial

breast cancer and familial bowel cancer.”

When Dr Suthers established the

service it was one of Australia’s first and

quickly became a leader in its field - an

achievement that his peers readily

attribute to Dr Suthers’ powerful

combination of vision and drive.

“Graeme saw very quickly that clinical

genetics was becoming a sub-specialty,”

Family mattersIF YOU OR YOUR GP HAS EVER SUSPECTED THAT YOUR

DNA MIGHT INCLUDE A HEREDITARY RISK OF CANCER,

THEN YOU’VE PROBABLY BEEN REFERRED TO A

FAMILIAL CANCER SERVICE. AND EVEN IF YOU DON’T

LIVE IN THE SAME STATE, THERE’S A GOOD CHANCE THE

SERVICE YOU HAVE VISITED HAS BEEN INFLUENCED BY

THE WORK OF THE SOUTH AUSTRALIAN SERVICE,

JJUUSSTTIINNEE CCOOSSTTIIGGAANN MEETS GRAEME SUTHERS, THE

MAN BEHIND THE CUTTING EDGE APPROACH TO

FAMILIAL CANCER.

in profile

PATHWAY_17>

says Professor Eric Haan, Head of the

South Australian Clinical Genetics Service

who first met Dr Suthers when he came to

South Australia to do his PhD.

“It was Graeme’s vision that got [the

Familial Cancer Service] going and he has

worked very hard and very successfully to

bring so many different people together to

work at such a very high standard.”

“The Familial Cancer Service has been

an Australian leader,” continues Professor

Haan, “and Graeme’s delivery of an

integrated service to patients has been

one of his most important contributions

(to genetics) so far.”

At the heart of the Familial Cancer

Service is the role clinicians and

counsellors play in helping people come

to terms with the knowledge they may

have an increased risk of cancer.

For those with only a basic

understanding of science or medicine,

being confronted with the thought of a

pending serious disease can be daunting.

Not only does the idea of a potential (or

actual) health threat cause alarm, but

understanding the genetic process and

the risks to yourself or your family can be

a challenge.

One of Dr Suthers’ strategies to help

his patients understand how genetics

works is to highlight the universality of

mutations. When patients understand that

“It was Graeme’s vision that got

[the Familial Cancer Service]

going and he has worked very

hard and very successfully to

bring so many different people

together to work at such a very

high standard.”

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the corrosion of one’s individual genetic

heritage is intrinsic to every one of us, it

can help minimise the anxiety of a birth

defect or the word ‘cancer’.

As he laconically explains it, “Your

genes are becoming rusty.”

“I think that we still have a major job

to do in terms of giving cancer better

press, if I can put it that way,” says Dr

Suthers.

“Cancer is generally perceived to be

something that comes out of the blue and

strikes people at random. A more realistic

view is to recognise that cancer is the

result of a slow burning fuse, and we all

have a fuse that is burning. And the thing

that varies is the rate at which it burns, or

how long the fuse is. Cancer is an

inevitable consequence of being alive.

Cancer is one of the ‘privileges’ that

comes from living in a peaceful developed

society.”

One of the most rapidly changing

specialties, keeping up to date with

advances in technology and new

information is a necessity.

“It’s a bit scary to see how quickly

your carefully nurtured skills and

knowledge become out of date in this

field. You have to keep reinventing

yourself. Once you’re a cardiologist or a

respiratory physician, you’re always pretty

much a cardiologist or a respiratory

physician. But in genetics, you need to

reinvent how you perceive your discipline

and your skills. And it does require quite

constant footwork, I think, to maintain

your usefulness as a clinician.”

The speed of change also impacts the

challenges for the specialty as a whole.

While ethical frameworks for the medical

profession are being developed and

refined, private enterprise simply speeds

ahead.

“It hasn't taken long for the field to

explode well outside the reach of clinical

geneticists. We now have all sorts of

health care providers and laboratories and

commercial companies doing genetic

testing and they don’t necessarily know or

want to know about the sorts of ethical

concerns, training and mindset that was

being inculcated by those at the forefront

of research during the 1980s.”

The ethical considerations of DNA

testing is just one of the many reasons

why Dr Suthers is promoting the concept

of a National Genetics Framework (see

box) as part of his role as Chairman of the

RCPA Genetics Advisory Committee.

Professor of Molecular Genetics at the

University of Sydney, Ron Trent, says that

Dr Suthers has always showed leadership.

As the incoming Chairman of the

Committee, a position Professor Trent

himself occupied until retiring a year ago,

Dr Suthers “looks at the big picture and

takes on the issues with drive and

enthusiasm - which is what you need if

you are going to take on the hospital

system.”

Dr Graeme Suthers is the program director of

the South Australian Familial Cancer Service,

senior visiting consultant in clinical genetics to

a number of teaching hospitals in Adelaide,

and consultant genetic pathologist to the

State’s largest public sector laboratory (IMVS)

and is the Chairman of the RCPA Genetics

Advisory Committee.

“Cancer is generally perceived to be something that comes out of the blue and strikes

people at random. A more realistic view is to recognise that cancer is the result of a

slow burning fuse, and we all have a fuse that is burning.”

RCPA urgesNational Genetics Framework

The RCPA is calling on the federal government to develop a National

Genetics Framework to deal with urgent issues relating to the future of the

specialty including; regulation and external quality assurance for genetic

testing; the collection and interpretation of data; the development of an

appropriate framework for making ethical decisions; and the creation of a

national register of funding for genetic tests.

Also the College is concerned at the lack of long term planning for the

management and growth of genetics.

Currently there are eleven qualified Genetic Pathologists in Australia, with

few training positions available and a lack of Clinical Geneticists and Genetic

Counsellors.

Genetics is a rapidly changing specialty and the potential for it to

challenge how we look at healthcare is considerable.

Testing DNA for the degree of genetic fragility and degradation is now

possible (though still experimental) and has the potential to reduce the burden

of degenerative diseases in the community. Yet who will benefit from this

technology, and who should pay for it?

Although many of these issues are currently being addressed by the

NHMRC Human Genetics Advisory Committee, the AHMAC Clinical, Technical

and Ethical Principal Committee, the RCPA Quality Use of Pathology Project

and the PSTC/RCPA Alternative Funding Proposal, the RCPA is urging the

Government to create a National Genetics Framework to ensure consistency

of testing and ethical guidelines across Australia and to develop a national

framework for planning.

“NT-proBNP... showed the best power, compared with the other immunoassays... for separating healthy individuals from patients with mild symptoms of heart failure.” 1

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Roche Diagnostics Australia Pty. Limited ABN 29 003 001 205 PO Box 955 Castle Hill 1765 Australia Ph: (02) 9860 2222

1. Clerico et al. Clinical Chemistry 2005;51(2):445-7. 2. Januzzi JL et al. Am J Cardiol 2005;95:948–954. 3. Gustafsson F et al. Heart Drug 2003;3:141-146. 4. Kragelund C et al. New Engl J Med 2005;352:666-75. 5. Richards AM, Troughton RW. Eur J Heart Fail 2004;6(3):351-4.

COBAS and COBAS H are trademarks of Roche. ©2007 Roche Diagnostics

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PCR

testing testing

THE

OF

PATHWAY_21

Six months before the 1993 Nobel

Prizes were due to be announced,

Kary Mullis’ mentor, University of

California Berkley biochemist Joe

Neilands, suggested to him that “you’d

make it easier for the [Nobel] committee

to give it to you if you didn’t talk to the

press so much”. Not that Mullis’ work

was in any way controversial - far from it.

He had developed the polymerase chain

reaction; a technique for amplifying

segments of DNA that was soon to

revolutionise molecular biology.

What had Neilands on edge was his

protegé’s openness about his use of LSD,

and to a lesser extent, his enthusiastically

proclaimed fondness for women and

surfing. Thankfully, the Nobel Committee

saw fit to overlook these apparent

transgressions, and in 1993 awarded

Mullis the Nobel Prize in Chemistry for his

discovery of the polymerase chain

reaction.

Mullis is an intriguing character.

Raised on a farm in rural North Carolina,

he studied chemistry then completed a

PhD and lectured in biochemistry, before

joining biotechnology company Cetus

Corporation as a DNA chemist. While

working here, he made the discoveries

that led to the polymerase chain reaction.

But far more interestingly, he has also

been tabled as an expert witness in the

O.J Simpson murder case (although was

never called to the stand), has stirred

controversy with his views on climate

change and the link between HIV and

AIDS, has been quite forthcoming about

his use of LSD in Berkley during the 60s

and 70s, apparently believes in astrology,

and is a keen surfer.

Kary Mullis’ entire Nobel autobiography

is unusually dedicated to a portrayal of his

family and upbringing. At the very end of

the document, a single, brief sentence

acknowledges his momentous role in

scientific history: “I worked as a

consultant, got the Nobel Prize, and have

now turned to writing. It is 1994.”

What this sentence fails to capture is

the significance of his discovery, and why

it was judged worthy of one of science’s

greatest accolades.

“It has been absolutely

transformative,” says microbiologist Dr

David Smith, Head of the Division of

Microbiology and Infectious Diseases at

PathWest Laboratory Medicine WA.

PCR allows scientists to locate within

a mess of DNA and RNA a short

sequence of base pairs that is unique to

the organism they are trying to detect. A

reaction is then set in motion to multiply

this stretch of DNA or RNA over and over

again until it reaches a concentration high

enough to be detectable, or usable for

other purposes.

The ready identification of DNA and

RNA through PCR testing has wide-

ranging applications from prenatal

screening to testing of adults for

susceptibility to diseases such as breast

and bowel cancer. It can be used to help

predict a patient's response to a

particular drug, or provide more accurate

diagnosis of diseases such as cancer

helping with prognosis and therapeutics.

PCR testing also enables rapid genetic

identification of infective micro-organisms,

a process that is now standard for a

range of infections from chlamydia to

pertussis.

DISCOVERED BY ONE OF SCIENCE’S MORE COLOURFUL

CHARACTERS, POLYMERASE CHAIN REACTION HAS CHANGED

THE FACE OF MEDICAL DIAGNOSIS AND DNA DETECTION.

BBIIAANNCCAA NNOOGGRRAADDYY REPORTS..

>

22_PATHWAY

As simple as it may sound, thisapproach has enabled a quantum leap inprogress. Compared to conventionaldetection methods, PCR enablesdetection of organisms that are dead ordegraded, difficult to culture, present inlevels too low to detect with conventionalmethods, in a wide range of samples, andcan now be done within a matter of hours.

The PCR process consists of twostages (see box). In the first stage, theDNA of the sample is heated to separateit into single strands, then the mix iscooled and special DNA primers areadded to seek out a short sequence ofDNA that is unique to the organism beingtested for. Once those primers find andlock onto their target, an enzyme is addedto create multiple copies of that particulartarget. By repeating this entire process ofthermal cycling again and again, scientistscan amplify that unique DNA sequence toa level where it becomes detectable.

The second stage involves addingDNA probes that will bind to thatsequence, and which are tagged to allowtheir concentration to be assessed.

When PCR was in its early days, eachof these steps was done separately andwould take several days to complete.

“You used to have to put them intothe thermal cycler, then leave it to run for30-40 cycles and then you took them outof that machine and put them onto gels toread them,” Dr Smith says. “With real-time PCR machines it’s actuallymonitoring as it goes through.” Thismeans the machine is calculating levels ofyour target sequence as it replicates it,and can alert you as soon as a target levelhas been reached. Cycling times havealso improved considerably, so now eachthermal cycle to denature and anneal theDNA strands and primers takes aroundone minute. Within just a few hours, theoriginal target sequence of DNA can becopied several million times.

This not only enables detection oforganisms or features of those organisms,

it can also provide a valuable source ofgenetic material for use in otherexperiments - DNA cloning. “PCR canalso be used to generate material whichyou can use to further characterise thatorganism,” Dr Smith says.

In pathology, PCR has a number ofapplications. It can be used to detect awide variety of genetic diseases, theamplification enabling pathologists torecognise insertions, deletions ormutations that characterise certainhereditary diseases such as Duchennemuscular dystrophy.

“It’s very useful for detecting bacteriaor DNA viruses, because you can amplifythe small amount of signal material there isto give you a measurable piece of DNA,”says microbiologist Professor Peter Coloe,head of Applied Sciences and professor ofbiotechnology at Melbourne’s RMIT.

Even when that signal material isthousands or even millions of years old,PCR can still be used. In a Jurassic Park-style scenario, DNA has been extractedfrom insects preserved in amber morethan 20 million years ago, and amplifiedup into useable quantities by PCR.Ancient Egyptian mummies have alsobeen probed for the DNA remains of thepathogens that plagued them, and PCRused to diagnose their ailments severalthousand years after they died. Using thistechnique, scientists have been able toposthumously diagnose tuberculosis froma tiny fragment of lung tissue taken from amummy.

Unfortunately for this Egyptian, thediagnosis may have come a little too late,but the diagnosis of tuberculosis inmodern times has also benefited fromPCR. Mycobacterium tuberculosis - thebacteria that causes the disease - isparticularly slow growing, which meansdiagnosis by conventional means cantake a long time. In contrast, PCR doesn’trequire the bacteria to be cultured, so adiagnosis using nucleic acid detectiontakes just a few hours.

While Mycobacterium tuberculosismight be slow growing, at least it can becultured. Other pathogens, such ashepatitis C, have proven extremelydifficult to culture. However PCR’s abilityto detect even the tiniest amount ofbacterial or viral DNA without requiringculture means it has become essential fordiagnosis of diseases such as hepatitis C.

It is also enabling researchers to, notonly diagnose, but learn more about apathogen, providing information that mayaffect management of the infection. Drugresistance is a particular concern whentreating diseases such as HIV. Theprevalence of drug-resistant HIV is currentlyestimated at around 10% of new infections,so detecting that resistance early can makea significant difference to the choice andefficacy of antiretroviral medication.

“Researchers can do a virtualphenotype to work out the likelyresistance to antiretrovirals,” Dr Smithsays. “They use PCR methods to amplifyup the viral RNA and then from thesequence of that RNA they can tellwhether it’s likely to be resistant or not.”The same technique has also been usedto determine whether a particular strain ofthe H5N1 influenza virus is likely to beresistant to a particular neuraminidaseinhibitor - a class of drugs that includesoseltamivir (Tamiflu) and zanamivir(Relenza).

PCR is also extremely sensitive andextremely specific, meaning that it willdetect even the smallest amounts of aDNA sequence, and will only detect thatexact sequence.

“In pathology, it’s going to give youways of detecting very low levels oforganisms and you’ve got a level ofspecificity that you might not have had byconventional microscopy or culture,” saysProfessor Coloe. “It gives you a high levelof specificity because you’re usingprimers that will only bind to specificregions where the DNA is a perfectmatch.”

PCR is also extremely sensitive and extremely specific,

meaning that it will detect even the smallest amounts of a

DNA sequence, and will only detect that exact sequence.

PATHWAY_23

However that extreme sensitivity canalso be a problem. “You can occasionallydetect levels of organisms… in such lowconcentrations that they might notconstitute a disease problem,” ProfessorColoe says. “That becomes an issuewhen you’re dealing with things likewater and looking for the presence ofthings like Giardia - there might beextremely low levels, you pick them upbut whether it constitutes a clinicalproblem is questionable.”

It also means PCR may detect thepresence of a dead organism that is longpast being a biological threat. “If theorganism is still there in the sense that ithasn’t been degraded, the DNA is stillthere but the organism is not alive, but youcan still get a positive response,” he says.

But, there is an upshot to this - PCR isparticularly useful in situations wheresamples haven’t always been kept inoptimum conditions, according to Dr Smith.

“The organism doesn’t have to bealive, which means it’s particularly goodfor samples where there are difficulties instorage or transport,” Dr Smith says. “Thisis a big advantage in testing in remoteareas where it’s very difficult to get liveorganisms, particularly things like viruseswhich tend to be fragile.”

So what is the future for PCR testing?

Dr Smith believes the next step willlikely be to make the test moretransportable. “How do we make thesetests more accessible?” he asks. “At themoment, they’re confined to relatively largelaboratories, so how do we make themeasier to deliver in small laboratories?”Making the test more transportable will alsoenable its use in very remote areas or evenin scenarios such as on the battlefield.

However Professor Coloe says PCR isnot likely to reach the stage of being abedside test any time soon because ofthe need for the amplification process.“Remember that PCR still relies on thetemperature cycling,” he says. “In thepathology laboratory that’s easy to do but

at the bedside you’re not going to go

through a PCR amplification process.”

However PCR may be used to produce

the material that might be used in a hand-

held device, for example to detect the

presence of herpes simplex virus in a cold

sore.”

PCR has come a long way in terms of

speed and efficiency since its invention,

thanks to improvements in technology

and biochemistry. It’s hard to know

whether the man who is credited with

developing PCR could fully appreciate the

impact his discovery has since had on

biological research and medicine.

His reaction to the announcement that

he had won the Nobel Prize gives some

indication - he went surfing.

What is PCR?“PCR is one of the techniques used for what we call nucleic acid detectiontest,” says Dr David Smith. “What that means is that we detect the RNA orDNA of the nucleic acid rather than, in the case of infectious diseases, theorganisms.”

The technique has a variety of applications. As well as diagnosinghereditary and infectious diseases, PCR can also be used for DNA cloningfor sequencing, identification of genetic ‘fingerprints’ used in forensics andpaternity testing including, as well as the functional analysis of genes.

But how is it done?To start with, you need to know the genetic sequence of the particular

organism you are looking for in a sample. That information is easilyobtainable from public ‘libraries’ of DNA and RNA sequence data, such asGenBank in the US, European Molecular Biology Laboratory's EuropeanBioinformatics Institute and the DNA Data Bank of Japan. “You’re lookingfor parts of the sequence of the organism which are found in all strands ofthat organism and which are only found in that organism; usually an areabetween 80-200 base pairs in length,” Dr Smith says. The next step is tocreate smaller fragments of DNA about 20 base pairs in length that aredesigned to pair with either end of your larger sequence - these are calledprimers.

These two ingredients, plus the enzyme DNA polymerase, are thencombined in a thermal cycler, which first raises the temperature highenough so that the double-stranded DNA and primers denature, or peelapart into single strands. The cycler then lowers the temperature to allowthe strands of primer to anneal, or bond, to their target at one or the otherend of the target sequence on the larger DNA strands, creating a collectionof single stranded DNA with a primer attached.

Now the DNA polymerase comes into play. Starting from one end ofeach primer, this enzyme reads back along the single strand of DNA,copying as it goes. After repeating this process several times, the endresult is two double-stranded copies of the target DNA sequence. Thewhole process is then repeated again, and each time it is repeated, thetarget sequence is copied.

“Commonly you’d use anywhere between 30-50 cycles, so you end upwith a lot of material… but once you amplify it you have to know you’veamplified the product you’re interested in,” says Dr Smith. This is done byadding in a probe that binds to a specific section of the DNA and is taggedwith a particular enzyme label or fluorescent tag that can be easilydetected and measured.

close up

Human chromosomes. Coloured

scanning electron micrograph (SEM) of

a group of human chromosomes.

These structures occur in the nucleus of

every cell in the body, carrying genetic

information in the form of DNA

(deoxyribonucleic acid), arranged in

discrete segments known as genes.

Apart from the sex cells, every human

cell contains 46 chromosomes, 23

inherited from the father and 23 from

the mother. The chromosomes shown

here have replicated themselves during

cell division and so consist of two

identical strands (chromatids) linked at

their centre by a structure known as a

centromere.

PH

OTO

CR

ED

IT:

AN

DR

EW

SY

RE

D /

SC

IEN

CE

PH

OTO

LIB

RA

RY

26_PATHWAY

Think of seven friends to whom you arenot related. The odds are one of you

is carrying a single mutation of C282Y.

C282Y is a common mutation of theHFE gene which, until the 1990s, layundiscovered on chromosome six, buthas, for millions of years, been controllinghow much iron is absorbed from food.

Individuals without the mutationabsorb only about 10% of the ironcontained in the food they eat: asufficiently wasteful process thatcombined with a nutritionally poor dietputs many people at risk of irondeficiency.

In contrast, those with the C282Ymutation absorb up to three times that

amount and, with no natural way to

excrete that much iron, it can accumulate

to levels more than 20 times what the

body needs.

There are now two known mutations

of the HFE gene: C282Y and H63D, and

while a single mutation of either may

increase your iron absorption and storage,

it probably won’t accumulate sufficiently

to develop haemochromatosis, the

disease associated with too much iron.

But if you are homozygous - that is

you have two copies of the mutation,

one inherited from each parent - then

it’s likely you will be struck with

symptoms that can range from barely

noticeable to debilitating and perhapseven eventually fatal.

The most common cause of ironoverload, hereditary haemochromatosis, isalso the most common genetic disorder inAustralia, affecting an estimated one inevery 200 to 300 of the population.Because of its genetic nature, as many as25% of the siblings of haemochromatosissufferers will also develop the disorder.

The symptoms of haemochromatosisare both common and vague, and don’tusually present in men until their mid 30s,a decade or two before women who arepartially protected by the iron lost duringmenstruation and pregnancy in theirreproductive years. The most frequent

Metaldetectors

spotlight on disease

SO WHY THEN, DESPITE A KNOWN CAUSE, A RELATIVELY STRAIGHTFORWARD TESTING

PROCEDURE AND A SIMPLE TREATMENT, ARE THERE PEOPLE WITH THE DISEASE REMAINING

UNDETECTED UNTIL THEIR ORGANS ARE IRREVERSIBLY DAMAGED, AND WHY ARE MILLIONS OF

DOLLARS BEING WASTED ON THE INAPPROPRIATE TESTS? MMAATTTT JJOOHHNNSSOONN INVESTIGATES.

THERE ARE DISEASES WHERE THE

CAUSE IS UNKNOWN, WHERE THE

DIAGNOSIS IS DIFFICULT, AND

WHERE THE TREATMENT IS

COMPLEX AND EXPENSIVE.

HAEMOCHROMATOSIS

IS NOT ONE OF THESE

DISEASES.

PATHWAY_27

symptoms of haemochromatosis are jointpain and fatigue, but they can alsoinclude abdominal pain, loss of sex drive,and shortness of breath.

Because there are few characteristicor reliable symptoms that differentiatehaemochromatosis from other conditions,diagnosing the disease is notoriouslydifficult.

One North American study found onein three people with iron overload had metwith more than 11 doctors beforereceiving the correct diagnosis.

With so many of the initial symptomsbeing attributable to other conditions, andbecause excess iron damages organsslowly, the disease was often wellestablished with irreversible organdamage having already occurred beforethe diagnosis was made.

Not surprisingly the discovery of thegenetic cause of the disease and theestablishment of an accurate test for theHFE mutations was expected to radicallyimprove the management of the disease.

But a misunderstanding about thetest’s ability to link non-specificsymptoms to a definitive diagnosis hasled to widespread inappropriate use of thegenetic test according to David Ravine,Professor of Medical Genetics at theUniversity of WA and genetic pathologistat PathWest at the Royal Perth Hospital.

Professor Ravine and his teamrecently conducted an audit of requestsfor HFE testing submitted to theirlaboratory.

The audit took 187 HFE test requestsand, by referring to hospital notes orconferring directly with the doctor whorequested the tests, the audit tried todetermine if the tests were appropriateand could therefore provide accurateresults.

The audit found that up to 57% ofHFE test requests are made forinappropriate reasons. And in more than athird of cases there was not enough

clinical detail in the requests for his team

to provide an accurate interpretation of

the result.

“When it was created the HFE test

was assigned a Medicare item number

and laboratories set themselves up to

conduct the test, so it very quickly

became routine,” Professor Ravine

explained. “It became like a routine

sodium test, but it’s actually a very

different type of test.”

“The interpretation of this test is totally

dependent on the clinical indication that

prompted the test. You can have a very

different report on the same result

depending on why the test was ordered,”

he said.

The problem, according to Dr Ravine

is that the link between the gene mutation

and the disease is far less perfect than

people appreciate.

“When the genetics of

haemochromatosis were first discovered

the basic view was that it was one gene,

one mutation, and you’ve got iron

overload,” he explained. >

Organs affected byhaemochromatosis

LiverAs the major site of iron storage, the liver is often the firstorgan to display the effects of haemochromatosis. Pain,swelling and cirrhosis can all develop and the diseaseincreases the risk of liver cancer.

HeartCardiac failure can occur with very little tissue irondeposition but it can also occur suddenly once the ironlevels have reached extremely high values. Once itappears, heart function tends to rapidly deteriorate.

HormonalDiabetes is common in people with haemochromatosis asiron accumulates in the pancreas. People develop overtdiabetes mellitus requiring insulin therapy. Excess iron canalso cause pituitary dysfunction and reduced sex hormoneproduction that can lead to infertility.

One North American study found one in three people with iron overload had met with more

than 11 doctors before receiving the correct diagnosis.

With so many of the initial symptoms being attributable to other conditions, and because

excess iron damages organs slowly, the disease was often well established with irreversible

organ damage having already occurred before the diagnosis was made.

28_PATHWAY

“That’s not the case. The link between

genotype and iron overload is not

perfect,” he said. “There are actually

several genes involved and since that first

discovery our awareness of the nuances

that go with that are increasing.”

Interestingly, the message coming

from Dr Ravine’s and similar studies is for

doctors to use older tests to identify

patients with iron overload before they

search for the cause of the accumulation.

“Serious iron overload is pretty

uncommon when compared with the

number of people with HFE mutations,” Dr

Ravine said. “One in four of us are carriers

of the various mutations, so just testing

for that will identify a lot people who don’t

actually have the disease.”

Dr Ravine’s position aligns with the

Medical Benefits Scheme indications for

requesting a HFE test, with the return of

at least two positive tests for elevated iron

result before requesting genotype testing.

“If you’re thinking haemochromatosis,

measure the iron first, then if that comes

back positive, then test for the gene,”

reinforced Professor Ravine.

The serum transferrin saturation test

and serum ferritin concentration tests

used to assess iron levels in the blood are

both sensitive and reliable tests that

geneticists described as phenotypic - that

is, they show patients who actually have

the disease rather than just having the

genes that can cause it.

But the dilemma faced by Dr Ravineand his associates is to not create asituation where the prevalence of thedisease is underestimated.

“Significant iron overload may beuncommon, but it’s still beingunderdiagnosed, so we still want to getdoctors thinking about it,” he said. Thebest chance patients have for a diagnosisis when they build a relationship with asingle doctor who can conduct tests in alogical order.

Professor Ravine has beenencouraged by the response of doctors tohis study but is concerned there is nosystem in place to change the way thetest is ordered.

“We identified a misunderstandingabout the clinical utility of the genotypetest,” he said, “and having spotted that,the solution is to educate doctors. Butthat’s a long term, major undertaking - agenerational change and in the meantimewe’re spending millions inappropriately.”

Massachusetts General Hospital in theUSA also identified this problem and,according to Professor Ravine, hasinstituted a better system.

“They make sure someone talks to thedoctor so we know why the test wasrequested,” he explained.

“This allows the pathologists tointegrate the genotype results with theclinical indications. It’s been hugelysuccessful,” he said, adding that the

program had also proved very popular

with physicians.

“It’s a collaborative approach that

helps the doctor understand what are the

best tests for the condition they are

seeking.” But he is pessimistic about it

being introduced in Australia.

“The system doesn’t permit this sort

of interaction here, and while it would be

expensive it’s probably not as expensive

as what we’re currently doing.”

Compared with the complexity of

interpreting genotype test results, treating

haemochromatosis is startlingly

straightforward and effective.

Ridding the body of excess iron

simply requires removing blood the same

way it is drawn from donors at blood

banks.

Based on the severity of the iron

overload, 500ml of blood is to be taken

once or twice a week for several months.

Blood ferritin tests conducted periodically

monitor iron levels and when they reach

the low end of normal the withdrawals are

reduced in frequency. The treatment

needs to continue indefinitely but it will

usually prevent further organ damage.

Because early detection and treatment

are so effective, a number of researchers

have proposed widespread screening for

haemochromatosis would be cost-

effective depending on the type of testing

conducted.

Haemochromatosisbefore Chronic Fatigue

Researchers have called for doctors to exclude

haemochromatosis before diagnosing and

commencing treatment of Chronic Fatigue Syndrome

(CFS). Although also a symptom of liver failure and

cirrhosis, fatigue has proved the most common

symptom present at diagnosis of haemochromatosis.

PATHWAY_29

Testing for blood iron is relatively

inexpensive but it has to be done twice to

confirm a diagnosis while, as has already

been shown, HFE gene testing will

capture a large number of people who

don’t have the disease.

Associate Professor Martin Delatycki,

Director of the Bruce Lefroy Centre at the

Murdoch Children’s Research Institute

and also Clinical Geneticist at Genetic

Health Services Victoria, is one of the

many researchers trying to find the most

effective screening plan for

haemochromatosis.

“One of the first issues raised in any

form of genetic screening is the stress of

knowing you have a predisposition to a

condition that you may never develop,

and that it might impact on your ability to

get insurance,” he explained.

But the results of the Haemscreen

study conducted by Professor Delatycki in

which 11,000 participants were assessed

for anxiety and health perception before

and after genetic testing found a genetic

predisposition to haemochromatosis ,

indicated those who tested positive were

not anxious about the result.

In a difficult process Professor

Delatycki was also able to reach an

agreement with the health insurers to not

discriminate against these individuals.

“In the end it’s in everyone’s interest

to prevent the disease,” he said.

Since that study Professor Delatycki

has also been involved in a study which

found 28 per cent of men in their 60s who

were homozygous had very significant

disease.

This, according the Professor

Delatycki contradicted earlier studies that

had predicted only 1% would by severely

affected.

“It’s a strong indicator for genetic

screening,” says Professor Delatycki who

wants to take advantage of the fact

haemochromatosis is rare before 30 years

of age.

“Young males traditionally don’t go to

GPs, so screening them in high school

may be feasible as it virtually captures the

entire population.”

The greatest impediment to screening

remains cost.

Professor Delatycki has recently been

granted funding to conducted a health

economic study into the cost benefit

relationship of testing just such a group.

But those results are years away and

until then, Professor Delatycki is reinforcing

the need for early detection by GPs.

“There’s good evidence GPs are

thinking more and more about

haemochromatosis, but we’d like to pick

up more people earlier so we need to

keep reminding doctors to have a very

low threshold for requesting iron studies,”

he said.

“Until screening starts that’s still our

best way of helping these patients.”

GPs NOTE: This article is available for

patients at http://pathway.rcpa.edu.au

YourPartner inClinical Genomics

Drug Metabolism / Pharmacogenomics

Microbial Identi�cation

Cancer- Chromosome Copy Number- Linkage Analysis- Array CGH- Loss of Heterozygosity

Enabling Clinical Genomics

Email: appliedgenomics@agrf.org.au

WORLD RECOGNISEDACCREDITATION

30_PATHWAY

While for many, the Renaissance

masterpieces are the epitome of

fine art, for some scientists, the works

represent a hidden fascination with the

anatomy of the human brain.

Writing in the Journal of the Royal

Society of Medicine (2007;100:540-543),

four UK scientists describe examples of

hidden symbolism in Renaissance

paintings by artists such as Rafael,

Michelangelo and David. The theory is

that the artists used the imagery to

conceal their fascination with the

anatomical discoveries being made at

the time, as such interest was often

branded as sacrilegious by the clergy

who were likely to have commissioned

the artwork.

The artistic anatomical representation

was first suggested by another scientist,

FL Mershberger, who believed the cloth

and figures behind God in Michelangelo’s

Creation of Adam resembled the sagittal

section of the human brain.

Heart diseaseon the riseThe decline in coronary artery disease

seen in western countries in recent

times may have come to an end, trends

seen in autopsy findings suggest.

In a US study of 425 autopsies of

people who died of unnatural causes

between 1981 and 2004, researchers

found that the temporal decline observed

in the grade of coronary disease ended

after 1995 “and possibly reversed after

2000.”

The findings are based on data from

death certificates and pathology reports

among Olmsted County residents aged

16 through to 64 years. Writing in the

Archives of Internal Medicine (2008;168:

264-270) the study authors say their

findings provide “some of the first data to

support increasing concerns that

declines in heart disease mortality may

not continue.... The extent to which

recent trends are attributable to the

epidemics of obesity and diabetes

mellitus awaits further investigation.”

In the eye of the beholder

ASpam-fuelled epidemic of diabetes

and cardiovascular disease is

rampaging through the South Pacific, the

UK’s Daily Telegraph reports.

The Telegraph notes the tragedy of a

region once famed for its lithe inhabitants

driven to health crisis by a luncheon meat

“lampooned by Monty Python and

spurned by British shoppers.”

“Where once islanders ate fish,

vegetables and coconuts, burning off

excess calories by casting nets from

canoes and farming small plots of land,

now they eat tinned, processed food and

drive to the nearest shop,” the article

says.

"Even if you go into a store in a

remote village you'll find shelves of Spam

and corned beef," the piece quotes Dr

Jan Pryor, the director of research at the

Fiji School of Medicine, as saying.

World Health Organisation figures

show that eight of the world’s 10 most

obese nations are in the region.

Nauru, former home to Australia’s

“Pacific Solution” detention centre, tops

the table with 94.5% of adults defined as

obese. Similar problems are repeated

across the South Pacific.

Epidemic of diabetes andcardiovascular disease

PATHWAY_31

GlucosamineinteractionRegulatory authorities are warning

doctors of an interaction between the

alternative arthritis remedy glucosamine

and warfarin.

In its recent bulletin (Volume 27,

February 2008), the Adverse Drug

Reactions Advisory Committee (ADRAC),

says it has received 10 reports of patients

showing an increase in their INR after

starting glucosamine.

The mechanism behind this interaction

is still unknown, but the effect of

glucosamine on warfarin activity is

consistent with reports received by other

drug monitoring bodies overseas,

including the WHO Collaborating Centre

for Drug Monitoring.

ADRAC recommends patients on

warfarin should have their INR checked

within a few days and no later than two

weeks after they start or increase their

dose of glucosamine.

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For all the information you need and to join visit www.doctorshealthfund.com.au. Contact us at info@doctorshealthfund.com.au or call 1800 226 126.

ProstatepredictorAgenetic test for hereditary prostate

cancer appears to be around the

corner, with the successful identification

of an array of gene markers for the

disease.

In a study of over 4000 Swedish men,

researchers from the Karolinska Institute

and their American colleagues found the

presence of a number of genetic

variations, along with family history of

prostate cancer increased the likelihood

of the cancer more than nine-fold.

They found 16 single nucleotide

polymorphisms, in five different regions of

chromosomes 8 and 17 were common to

men with prostate cancer.

While the findings published in NEJM

online (Jan 16, 2008) need to be

validated and refined, efforts to develop a

genetic test are underway, say the study

authors.

MagnesiumpreventsgallstonesMagnesium-rich foods such as nuts

may help prevent gallstones, USresearchers say.

In a prospective study of more than42,000 men over a 17 year period,researchers at the University of Kentuckyfound that men with higher intakes ofmagnesium-containing foods had asignificantly lower rate of symptomaticgallstone formation.

The findings, published in theAmerican Journal of Gastroenterology(103:375-82), were supported by otherevidence that magnesium deficiencycauses dyslipidaemia and insulinhypersecretion, which may promotegallstone formation, said the studyauthors.

6minutes is a daily online newsletter andwebsite for Australian doctors, includinggeneral and specialist practitioners, publishedby Reed Business Information.

Highexpectations

DDRR KKAATTHHYY KKRRAAMMEERR LOOKS AT THE ROLE OF

GENETIC TESTING IN PRENATAL SCREENING FOR

FETAL ABNORMALITIES - ITS BENEFITS,

LIMITATIONS AND POTENTIAL.

Many pregnant women worry about whether the

baby is okay, and now doctors can offer so

much more than soothing words.

There aren’t tests for all the potential problems,

but general screening for some serious conditions -

and special testing for families with particular risks -

have become a routine part of Australian prenatal care. In

fact, the Human Genetics Society of Australia and the

Royal College of Obstetricians and Gynaecologists both

recommend that screening be offered to every woman.

Professor Eric Haan is a clinical geneticist at the Women's

and Children's Hospital in Adelaide and an expert on prenatal

genetic testing. “There are basically two time points when

screening is offered for Down syndrome, and the screening picks

up some other abnormalities, such as trisomy 18.”

“First trimester screening involves an ultrasound at 11 to 13 weeks

looking at nuchal translucency (the width of a fluid-filled space at the

back of the fetal neck) plus a blood test at nine to 13 weeks.”

It picks up about 90% of Down syndrome pregnancies but

falsely suggests one in twenty pregnancies is affected when really

it is fine.

The screening calls for a skilled ultrasonographer but also

relies on the expertise of biochemists, like Dr Michael Sinosich,

Scientific Director of Prenatal Testing at Sydney’s Sonic Health

Care.

“We really need both diagnostic modalities, biochemistry

and ultrasound, monitoring different parameters to get an

optimal performance in assessment of feto-placental

wellbeing,” he says.

32_PATHWAY

cutting edge

PATHWAY_33

In the laboratory, pathologists look

at a range of different chemicals -

known as markers - which are produced

by the placenta or fetus, and are

detectable in the mother’s blood.

Marker levels can change when there is

an abnormality such as Down

syndrome. The results are used to build

a picture of how likely it is that a

pregnancy is affected by the condition

for which it is being screened.

There’s nothing magic about the

number produced by screening, he

says, and different labs can produce

slightly different numbers depending on

how many biochemical markers they

test for, what machines they use and

the software they employ. “For example,

we use four markers but other units

may use two,” he says.

Second trimester screening involves

a blood test at 14 to 20 weeks (ideally

15 to 17 weeks). It picks up only about

75% of Down syndrome pregnancies

and wrongly identifies about 7% of

normal pregnancies as being at

increased risk.

“Being told about an increased risk

often causes anxiety in women at the

time and during the pregnancy and

even after the birth, and they often

remember it very vividly as something

that had a big emotional impact,”

Professor Haan says.

About 80% of women found to have

an increased risk choose to go on to

invasive diagnostic testing, he says, and

most decide not to continue with the

pregnancy if the baby is affected.

An ultrasound is also recommended

for all women at 19 to 20 weeks. This is

not part of Down syndrome screening; it

checks the well-being of the pregnancy

and can detect physical malformations

in the baby, some of which may be due

to underlying genetic problems.

“Once you know your risk is high,

you have to decide, ‘am I going to sort

this out or not?’ And the main way to

sort out whether the baby does or does

not have the condition after first

Fetal genetic testing can also helpwomen who have recurrent early

miscarriages or a late miscarriage orstillbirth.

Fetal pathologists have a particularrole in diagnosing lethal inheriteddisorders. In these conditions, there is a1-in-2 to 1-in-4 chance of futurepregnancies being affected. It’simportant to distinguish these fromchromosomal disorders, where therecurrence rate varies from 1-in-3 to 1-in-100, and environmental, sporadic anduterine disorders which don’t tend torecur.

Dr Adrian Charles is a perinatal andpaediatric pathologist at the KingEdward Memorial Hospital in Perth.There are two scenarios that typicallycall for his services.

The first is where an apparentlynormal pregnancy ends in miscarriage orstillbirth and the parents consent to anautopsy. “We say, this fetus has a rangeof abnormalities that amount to this typeof syndrome and then we ask for thattest to confirm the diagnosis. Sometimesthe parents are tested and/or futurepregnancies are tested early in thepregnancy with possibility of interruptingthe pregnancy if it’s abnormal,” DrCharles says.

A question arises over whetherchromosomal testing should be offeredafter all pregnancy losses. “A largenumber of the first and early secondtrimester miscarriages are due tochromosomal abnormalities, so we couldcheck for these but the test costs a fewhundred dollars and most of these willnot recur, so is not indicated on everycase,” he says.

“There is growing pressure fromparents to try to find an answer: youhave to be thoughtful of the health dollarbut it does ease the parents’ minds toidentify a cause.”

The second scenario is whereprenatal screening has identified anabnormality and the pregnancy has been

terminated. Often there is little doubtabout the diagnosis, and a post-mortemexamination merely confirms, forexample, that the fetus has featuresconsistent with Down syndrome.

However, anatomical pathologycomes into its own when the diagnosiscan only be made by examining specifictissues. For example, an ultrasound mayidentify cystic kidney disease but only apathologist can determine which of themany disease types is involved. “Welook at the fetal tissues under themicroscope and this can give us a veryclear idea, even though we don’t have aspecific genetic test, about what therecurrence rate is, whether it’s 1-in-4 or1-in-2 or pretty low.”

“We try to get the abnormality clearlydetermined so the parents can becounselled.”

Dr Diane Payton, an anatomicalpathologist, does similar work at theRoyal Brisbane Hospital.

“If we can recognise an intact fetus,we do an autopsy,” says. “If it is verytiny, we look at the external appearanceand may attempt an internal examinationand certainly examine the cells. Fromaround ten to twelve weeks, we can doan excision and check the internalorgans.”

She takes tissue for basic genetictesting in most cases. When she has aspecific diagnosis in mind - for example,such as cystic fibrosis - she may takeadditional cells from relevant organs.However, careful thought is required,because there isn’t a screening test forall the potential different geneticproblems. “Unless I can suggest what Iwant them tested for, there’s not muchwe can do.”

“This is a specialised area in which Iusually seek advice from clinicalgeneticists,” she says. “Many of theinvestigations are highly specialised andare only performed in selectedlaboratories in the country.”

Another side of the story

>

34_PATHWAY

trimester screening is chorionic villous sampling

[CVS] at the end of the first trimester or

amniocentesis at the beginning of the second

trimester, or amniocentesis after screening in

the second trimester.”

If there is an increased risk of a

chromosome problem - say, because the

woman is more than 35 years old or because a

previous pregnancy has had a chromosome

abnormality - women can skip screening and

go straight to a definitive (rather than screening)

chromosome test. This is either CVS from 10 to

11 weeks or amniocentesis at 15 to 16 weeks.

Many couples choose CVS because the result

is available at a much earlier stage in the

pregnancy.

The most commonly performed genetic test

is a chromosome test using cells taken from

the placenta (via CVS) or shed from the baby

and floating in the amniotic fluid (via

amniocentesis). “The chromosomes can be

seen and counted, so it is a very reliable test

for Down syndrome because they can see the

extra chromosome,” Professor Haan explains.

DNA tests for literally hundreds of different

heritable genetic conditions can also be done.

The first such test was performed in 1978 for

sickle cell anaemia, Professor Haan says.

The most common tests these days are for

thalassaemia, fragile X syndrome, cystic

fibrosis, Duchenne muscular dystrophy and

infantile spinal muscular dystrophy. If doctors

don’t know which gene is causing a problem,

there may be other ways to test for the disease;

for example, if the disease involved a specific

enzyme, a chemical pathologist may be able to

measure enzyme levels.

However, prenatal genetic testing is not

without risk. CVS and amniocentesis can

trigger a miscarriage, although the risk is small.

An occasional problem with CVS occurs

when some, but not all, of the placental cells

contain a genetic mutation. This is called

‘mosaicism’. It usually affects only the placenta,

not the baby, so amniocentesis is

recommended to check the baby’s cells.

However, even a normal amniocentesis does

not definitely exclude mosaicism.

“Also, some abnormalities may not be

detected because they are too small to be seen

reliably with a light microscope,” Professor

Haan points out.

So, women and their partners need to know

that chromosomal testing is not foolproof.

Goodbye to invasive testing?

Both chorionic villous sample and amniocentesis can trigger a

miscarriage, albeit very rarely, so researchers are looking for safer

ways to perform fetal genetic testing.

“It is known that there are a small number of fetal cells, shed by the

placenta, that circulate in the mother’s blood,” geneticist Professor Eric

Haan says. “And for many years attempts have been made to isolate

these cells for genetic testing. It is clearly possible to do so, but so far

reliable, universally applicable and cost-effective testing in early

pregnancy has not been developed.”

Preimplantation genetic testing, performed on cells removed three

day after fertilisation, is an evolving field which may allow couples to

implant only embryos free of a particular gene.

IVF Australia, on its website, points out that this is really only

appropriate for couples where there are already family members with

serious inherited genetic disorders. “Worldwide researchers are

questioning whether the same technology will allow improved embryo

selection prior to embryo transfer, and hence improve pregnancy rates

per cycle for all couples having IVF treatment. The small studies

performed so far have not been of a large enough size or been designed

to answer this question accurately.”

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PATHWAY_35

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The appointment of the SolomonIslands’ first indigenous pathologist

last year brought an unexpected bonus. Agroup of top Australian pathologists andmedical scientists travelled fromQueensland to the South Pacificarchipelago to establish an anatomicalpathology laboratory.

For more than 20 years, PathologyQueensland (a branch of QueenslandHealth’s clinical and statewide services)has been the Solomon Islands’ majorreferral centre for pathology support.Services have included general pathologyas well as diagnosis of surgicalhistopathology and cytology specimens.

However, with the appointment of DrRoger Maraka to Honiara’s NationalReferral Hospital (NRH), it seemed logicalto the group that a laboratory beestablished, in which the pathologistcould practise.

The five experts who traveled to thenation’s capital Honiara last September

for the mission included Dr MichaelWhiley, director of Pathology Queensland,Professor Konrad Muller, state director ofanatomical pathology, Bob Partridge,regional coordinator and Leigh Owensupervising scientist at PathologyQueensland Central Laboratory, and DrStephen Weinstein, director of pathologyat the Gold Coast Laboratory Group.

Dr Weinstein, who has worked onsimilar projects in East Timor andVanuatu, said the team operated as a“well-oiled machine”. Tasks undertakenincluded installation of histologyequipment and communication software,staff training and the development of aquality assurance program and supportframework for Dr Maraka’s ongoingprofessional development.

“For the first time ever the surgeonsand doctors can get the results then andthere, and view their own tumours andcancers without having to have them sentto Brisbane,” Dr Weinstein said.

The Solomons is made up of almost1,000 mountainous islands and coralatolls divided by nine provinces spreadacross 28,000 square kilometres. It has apopulation of just over 500,000 with about40 per cent aged less than 15 years.

The NRH has about 280 beds andabout 20 medical staff. The NRHlaboratory has haematology, biochemistryand microbiology with a separate malarialaboratory. Apart from Honiara, there aretwo small laboratories in the provincialcapitals of Auki (Malaita province) andGizo (Western province).

Dr Weinstein said the 750 annualhistology cases that are produced in theSolomons are likely to rise with theoperation of the local service. Dr Marakaalso conducts about two forensicautopsies a month and runs a fine needleaspiration clinic.

Pathology Queensland donatedequipment to fit out the histology unit,which was freighted with the support of

SOLOMON ISLANDS PATHOLOGY IS SET TO COME INTO ITS OWN WITH A LITTLE HELP

FROM SOME AUSTRALIAN FRIENDS. KKIIMM CCOOTTTTOONN REPORTS.

Wisdom in the Solomons

foreign correspondence

36_PATHWAY

“Just the fact that the

pathologist can function as an

important member of the

clinical team… that makes a

difference for the hospital and

the medical staff”

the Lions Club. The donation was made

possible by the Ipswich lab and Mr Owen

was instrumental in organising the

logistics of moving the equipment,

including a processor, microtome and

embedding station to the Solomons. Two

local Solomons technicians who had been

previously trained in Brisbane were

reskilled in operating the equipment as

well as correct specimen handling and

packaging, Dr Weinstein said.

“At the end of the week they were

producing diagnostic-quality histology

slides to the delight of Dr Maraka. This

will mean that the majority of histology

from the Solomons - all of which was

previously sent to Brisbane will be

reported locally in the future,” he said.

Oral cancer, including cancer of the

buccal mucosa, tongue and gums, is one

of the most common malignancies in the

Solomon Islands - due to the popularity of

chewing the carcinogenic betel nut. Liver

cancer is also common courtesy of the

high prevalence of hepatitis.

Cervical cancer, still common due to

poor screening practices, will continue to

be diagnosed in Brisbane - in part

because of the absence of a local

cytoscreener and the issue of quality

assurance in Pap smear reporting

procedures.

With the greatest morbidity in the

Solomons being caused by infectious

diseases, namely malaria and

tuberculosis, the unit was unlikely to have

an “immediate earth shattering” effect on

the nation’s health, Dr Weinstein said.

Also the benefit of having a local

pathology service was hampered by the

lack of radiotherapy and chemotherapy,

limiting the ability to treat diagnosed

malignancies beyond surgical excision.

However, the fact that a resident

pathologist can now discuss with

colleagues diagnostic reports - and

receive results much faster - will have a

major impact on staff professional

development and morale, he said.

“For medical staff in the National

Referral Hospital it’s important that they’re

not isolated, they feel they are not

stranded without support,” Dr Weinstein

said. “Now they can come down and ask

if they can see the tumour or have Dr

Maraka point out an interesting feature

and discuss whether surgical margins are

clear, did they excise it completely… they

can interact with the pathologist in the

laboratory and the pathologist can also

present these [findings] in clinicalmeetings.

“Just the fact that the pathologist canfunction as an important member of theclinical team… that makes a difference forthe hospital and the medical staff,” hesaid.

Another tenet of the project was thedevelopment of a strong continuingeducation model for Dr Maraka to ensurehis professional development remainscurrent and that he also feels supportedcollegially.

“Continuing education for thepathologist himself is a major problem in aplace like the Solomons becausepathologists should ideally not practisealone. They should have a colleague towhom they can show interesting cases,bounce them off and also cover for themwhen they go on leave,” Dr Weinsteinsaid.

The pathologist will continue to sendto Brisbane all cases requiring secondopinions and special stains, and inaddition send a randomly selected fiveper cent of his work for quality assurancepurposes. Twice a year, with the supportof the Pathology Queensland SERTF TrustFund, Dr Maraka will also visit Brisbane torefresh his skills.

PATHWAY_37

Fact fileThe majority of Solomon Islanders (80 per cent) relyon subsistence agriculture and fishing.

There were 90,606 reported malaria cases in 2003with 71 deaths.

TB rates in 2005 were 142 per 100,000.

The prevalence of betel quid chewers is 76.8 percent.

Life expectancy for Solomon Islanders is 63 years(at 2004).

Sources: AusAID, World Malaria Report 2005, WHO Global Health Atlas TBCountry Profile, American Journal of Tropical Medicine and Hygiene, HumanDevelopment Report 2006.

During the visit, Dr Whiley gave apresentation to the medical staff grandrounds on the relevance of point of caretesting and the Istat instrument to remotelocations. Dr Weinstein presented recentSolomons’ histology cases reported inBrisbane and also breast cancer andscreening.

Such an experience for the Australiancontingent brought an insight into thehealth problems and health system of asmall developing country and “a greatsense of satisfaction to help out there”,Dr Weinstein said.

“Even be it in a very limited way and ithelps set up long term relationshipswhich are valued greatly.”

Dr Weinstein suggested opportunitiesare available for Australian pathologists totake on unpaid locums in the SolomonIslands as a means of experiencing adifferent health system as well asaffording them a break from the normalroutine.

Meanwhile, Dr Maraka reports thenew lab is going well.

Dr Weinstein said. “He is able torepair any equipment locally; he is inemail contact when he needs advice andis energetically getting down to work.”

Previous page: Young Solomon Islanders in traditional dressBlood sample being taken by a Pathology staff member.

Left to right this page:Selling taro at the market in Honiara

Mr Michael Aiko, histotechnologist preparing diagnostic slides;Dr Roger Maraka, Solomon Islands first Indigenous pathologist with

Professor Konrad Muller, Pathology Queensland's Directorof Anatomical Pathology

$$$$$$

38_PATHWAY

finance finesse

STEADY AS YOU GO

- Super Planning

Greg Lomax

Greg Lomax is the CEO of Huthnance Lomax

Accountants and Financial Advisors in

Chatswood NSW. He is a regular columnist for

the Sydney Morning Herald and Melbourne

Age and other professional magazines.

It has been a roller coaster ride for investors in the

share market this financial year. Not only has the

year seen the start of the biggest changes to our

superannuation system in 20 years but the share

market has reached its highest levels in history and

then tumbled by more than 20 per cent.

This much anticipated correction to the share

market had been expected for some time but the

magnitude of the fall surprised many. Consequently

because of various international influences the ride

in the short term future looks anything but steady.

However for superannuation investors it is perhaps

not as alarming, as the effect of these corrections

have been felt more by those investing money in a

relatively short term volatile market. As

superannuation is a longer term investment these

fluctuations are expected in the overall investment

cycle and with a well chosen portfolio of

investments, the magnitude of any fall can be

cushioned by diversification.

It is important to remain calm and focused on the

underlying benefits that can be gained from

choosing super as the number one investment

strategy in today’s uncertain and volatile markets.

PATHWAY_39

1. ACHIEVE MAXIMUM TAXBREAKS VIA SUPER

The new superannuation rules changedthe maximum deductible contribution to$50,000 per annum. However if you are50 or over the maximum contribution is$100,000 per annum until 2012.

This provides special opportunitiesparticularly for those employing theirspouses in their business where taxdeductions for super contributions can beup to $200,000 per annum.

Also self employed practitioners cannow enjoy full deductibility on theircontributions compared to the old rulewhere only 75% of the contribution wastax deductible.

Some careful planning needs to takeplace if you also receive a salary as wellas self employed income. If the salaryincome exceeds 10% of the overall grossincome of the practitioner then taxdeductible contributions cannot be made.This can usually be avoided by a salarysacrifice arrangement or restructuring ofthe employment income.

Additional contributions can be madeto super without claiming a tax deduction.The limits on these contributions are$150,000 or $450,000 averaged over threeyears. There is no contributions tax onthese undeducted contributions.

2. REVIEW YOUR CURRENTSUPER ARRANGEMENTS

Now that most people are making supertheir main retirement vehicle, it isimportant to be aware of the manner ofinvestment and type of fund you have. Inparticular you need to be well aware ofyour own risk profile and match this to theclass of investments you use in your fund.Many people are not aware of thecommissions and fees attached to everycontribution. A statement of advice mustbe provided by an advisor when making arecommendation so be sure to read itclosely as it must clearly state the way inwhich the advisor is paid and how theinvestment is managed.

Self managed superannuation fundsare growing rapidly in popularity for goodreason especially since the introduction ofthe new super rules.

The advantages of considering a selfmanaged fund strategy include:

• The flexibility of controlling the typeof investments you have in super.

• The ability to move into a pensionmode, tax free without disposing ofany of the fund’s assets. (i.e. nocapital gains tax to pay).

• The ability to both receive an incomestream from your super fund andcontinue to make tax deductiblecontributions to the same account(i.e. no need to have separate superfunds or accounts)

• The tax benefits from receivingincome from fully franked investmentsand offset the resulting tax creditsthereby reducing the tax rate in thefund.

• Delay of tax payments until thelodgement of the funds tax returnsrather than paying 15% contributiontax on the day you make acontribution.

• Ability to access new products thatwill allow borrowing by self managedsuper funds. These are calledinstallment warrants and are allowedunder new Government legislationthat now extends the allowableborrowings to any assets includingproperty.

While self managed super isn’t foreveryone, it is certainly worth looking atthe pros and cons as it affects individualpractitioner circumstances.

3. ACCESS TO SUPER ANDRESULTING STRATEGIES

You can access your super from 55 yearsof age while you are still working. Thebenefits you withdraw are taxable at yourmarginal tax rate less a 15% rebate. Onceyou turn 60 the benefits are tax free onwithdrawal.

The advantage in considering this isthat the underlying super benefits in yourfund are placed into a tax free state. Thismeans there is no tax on capital gains orearnings of the fund whilst it is in thispension mode. If you have a self managedfund in pension mode you can even get arefund of the value of any franking creditsthe fund has received.

For a practitioner over 60 this is a“must do” and presents some top taxstrategy opportunities. An example is bycontributing up to $100,000 per annum,you receive a tax deduction against yourincome and also have the ability to assistthe funding for further contributions ifneeded by access to your super benefits.This is certainly a hot strategy as it allowsa tax saving on the $100,000 of incomereducing the tax rate from 46.5% to lessthan 15 per cent.

4. REVIEW ESTATE PLANNINGISSUES

The new super rules allow for super to bewithdrawn tax free when you are over 60.But if you die and do not have a survivingspouse or financial dependents, the fundswill be taxed at 16.5% when passed toyour estate.

It does not apply to after tax orundeducted contributions you made tothe fund. This is an unfair and inequitabletreatment and one that may well bechanged in the future. In the meantime itis prudent to speak to your advisor aboutthe best way for you to deal with this.Most lawyers and financial advisorsrecommend you not only have an up-to-date trust deed, but an enduring power ofattorney together with a death benefitnomination in place to assist in the taxfree release of super benefits in cases ofterminal illness. Once released from super,the funds can be gifted to children,relatives or other intended beneficiariesdirectly or via an individual’s estatewithout tax implications.

The following four steps will help

you utilise superannuation as your

main investment choice:

1. Achieve your maximum tax

breaks via super for this and

future years.

2. Review your current super

arrangements to ensure you are

in the right fund and determine

if a self managed fund is right

for you

3. Understand the impact of

accessing your super benefits

and the hot tax strategies this

creates for over 60’s.

4. Review the basic estate

planning issues involved with

the increased financial

resources now in super.

40_PATHWAY

Innovation andTrainees Program- Friday 14 March 2008Innovations explores professional issuesconcerning pathology now and in the future.The program starts with the RCPA QualityAssurance Program Symposium, which willprofile a range of important developments inquality assurance, and culminates with apresentation by the eminent Dr Stephen Raabon practice redesign for patient safety. Theafternoon will showcase the inestimable DrChris Smith, sponsored by the AustralasianAssociation of Clinical Biochemists (AACB),who is speaking on the naked pathologist(though he will be clothed as far as weknow!). The afternoon continues with thetheme of patient safety in microbiology withProf David Paterson and genetics with DrGraeme Suthers.

Trainees Day is a great opportunity toaddress aspects of the curriculum thattrainees might otherwise find difficult, as wellas providing practical, exam-orientedsessions and workshops in the afternoon.Talks include critical appraisal, issues aroundthe handling and control of laboratory-generated data and ethics and patientadvocacy – all by prominent pathologists withextensive experience in these areas. There isalso a session on using mindlfulness to helpdeal with the stresses of being a trainee byCraig Hassed, from Monash University who isinternationally recognised for his work on theapplications of meditation in medicine. Theafternoon includes workshops on electronand light microscopy as well as the AP examreview and the mock exam for part IMicrobiology candidates.

Snapshot of

Pathology Update 200814- 16 March 2008Sydney Convention and Exhibition Centre,Darling Harbour

PATHOLOGY UPDATE IS TRULY A UNIQUE CONFERENCE,

WHICH BRINGS TOGETHER EIGHT DIFFERENT

DISCIPLINES OF PATHOLOGY OVER A THREE DAY

SCIENTIFIC MEETING, OFFERING SOMETHING FOR

EVERYONE.

Highlights of the 2008 programinclude:

• Innovations Program on PatientSafety

• Trainees Program

• Seven international speakers

• Six cross discipline sessions

• ‘Meet the Chief Examiner’ sessions

• General Poster Display and acombined discipline AbstractPublication.

www.rcpa.edu.au/pathologyupdate

RCPA update

Anatomical Pathology has worked hardto put together a varied and interestingprogram that will have “something foreveryone”. Dr Neil Lambie, fromChristchurch, will present this year’s “AnApproach To…” lecture, on lung biopsyfor non-neoplastic lesions. The combinedAnatomic and Paediatric Pathologyseminar will feature Dr Adrian Charlesfrom Perth, and Prof Yee Khong and DrNicholas Manton from Adelaide. TheAnatomical Pathology stream will alsoinclude one of a number of cross-discipline sessions this year, in jointpresentations with Genetics and with OralPathology.

Chemical Pathology The program willinclude a joint session withMicrobiologists to update attendees onthe latest advances in all aspects of viralhepatitis, including a lecture on bloodtests for liver fibrosis, as well as drugtoxicity of the liver. There will also beupdates from working parties on cardiacmarkers, serum urate, creatinine andeGFR, as well as from the AustralianPathology Lipid Interest Group. A wholesession is devoted to the ChemicalPathology of pregnancy, and experts onPSA and vitamin D will be bringing thecurrent thinking in their areas of expertise.

Forensic Pathology will include how todistinguish real injuries from post-mortemand decomposition artefacts, presentingevidence in court, pros and cons of theexpert witness by two eminent lawyers,sudden death due to alcohol, the problemof drowning, sudden death inschizophrenia, the toxicology of the newanti-psychotics and the documentation ofsexual assault.

Genetics The genetic code acts as aresource for building and maintaining thehuman body, and also dictates the body'sresponse to a variety of externalchallenges, such as infection. For thisreason, genetics is pervasive and hasrelevance in every discipline of pathology.The genetic program in Pathology Update2008 is closely integrated with otherdisciplines, including anatomicalpathology (genetics of tumours),haematology (genetics of leukaemia), and

microbiology (genetics of susceptibility toinfection). But the novelty and broadapplication of genetics also raisesparticular challenges in developing andmaintaining quality assurance acrossmultiple disciplines, and this is the focusof later sessions in the program.

Haematology has a program thatencompasses updates on malignanthaematological disorders with reviews ofsome practical day-to-day issues ofassessing haemostasis and managingalloimmunisation in pregnancy. Overseasspeaker Dr Wendy Erber opens theUpdate with Acute Leukaemia; sub-classification and markers of prognosis,local speakers follow with topics onindividualizing therapies for childhoodleukemia. There will be a combinedsession with Immunopathology onlymphoma.

Immunopathology has a range ofhighlights, including some of the topAustralian B cell biologists discuss theapplication of recent advances in B cellbiology to clinical practice. There are alsotalks on clinical application of some thenewer autoantibodies including antibodiesagainst water channels and nucleosomesand a joint session with haematology onlymphoma diagnosis. In addition asession has been devoted to neweraspects of allergy epidemiology anddiagnosis. In all a varied but veryinteresting program.

Microbiology has internationallyrecognised experts presenting in the areasof hepatitis, meningococcal infections,and new ways of preventing theseinfections. Aboriginal health remains anenormous public health issue for allAustralians, and speakers from researchinstitutes in the Northern Territory, and theUK, will discuss their personal experienceand research. Microbiology impingesupon all parts of pathology, so we havedesigned the program around the needsof all pathologists, trainees, and cliniciansfrom a wide variety of subspecialties.

Oral Pathology is a specialised area ofAnatomical Pathology, dealing with themouth, teeth, and jaws. The OralPathology program commences with areview of the Oral Pathology QualityAssurance Program module, followed by aseries of case reports. There will be a jointOral Pathology and Anatomical Pathologyplenary session featuring Dr JocelynShand, an Oral and Maxillofacial Surgeonwho will talk about surgicalmanagement of headand neck pathology. Thispresentation will enablepathologists to betterunderstand thetreatment ofthe variousconditionsthey report inpatients.

PATHWAY_41

Last but not least…

Network and Relax atPathology Update

As well as an important professional event, Pathology Update 2008 has a funand relaxing social program that gives attendees the chance to meet with otherlocal and international colleagues in a relaxed and informal environment. TheUpdate will kick-off with the Welcome Cocktail Party, ‘Jive at Five’, on FridayMarch 14 with a special cocktail. The Industry dinner of the year is always onethat’s not to be missed – at Doltone House, nestled on the upper deck of thehistoric Finger Wharf at the newly restored Jones Bay Wharf, Pyrmont Point.

Scientific Programs- Saturday 15 & Sunday 16 March

2008Conference CalendarMARCH 2008

513th Ottawa International Conferenceon Clinical Competence

5 - 8 March

Melbourne, Australia

14Pathology Update

14 - 16 March

Sydney, Australiawww.rcpa.edu.au/pathologyupdate

17Focus Cytology Tutorial forPathologists

17 - 19 MarchSydney, AustraliaJoanne.clarke@symbionhealth.com

MAY 2008

30Cytopathology Course Singapore

30 May - 1 June

Singaporewww.med.nus.edu.sg/path/teach/cytopath2008.htm

JUNE 2008

22American Academy of OralMaxillofacial Pathology

22 - 26 June

California, USAwww.iaop.com

JULY 2008

20World Summit of Antivirals - WSA 2008

20 July 2008 to 26 July 2008Kunming, Chinawww.bitlifesciences.com/wsa2008

SEPTEMBER 2008

25College of American Pathologists

25-28 September 2008

San Diegohttp://www.cap.org

OCTOBER 2008

6The 19th International Symposiumon the Forensic Sciences

6 - 9 October

Melbourne, Australiawww.anzfss2008.org.au

16American Society of Clinical Pathology

October 16-19 2008

Baltimore MD, USAhttp://www.ascp.org

29The National Forum on Safety andQuality in Health Care

29 - 31 October

Adelaide, Australiawww.achs.org.au/nationalfiorum08

MARCH 2009

13The XXV WASPaLM Congress inconjunction with Pathology Update

13 - 15 March

Sydney, Australiawww.rcpa.edu.au/pathologyupdate

42_PATHWAY

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