Medical practices

Defining Moments in Medicine Pathology MJA 2001; 174: 11-12 College of Pathologists of Australia: The College of Pathologists of Australia was established in 1956, and from 1980 became the Royal College of Pathologists of Australasia. The College has established the internationally recognised journal Pathology, and from about 1983 the College has spread its influence to several countries, including Singapore, Malaysia, Hong Kong and Saudi Arabia, as well as Australia and New Zealand. Automated cell counters: These were initially used in haematology in the 1960s and subsequently applied more generally in flow cytometry. The principle of the Coulter counter, with blood cells counted as they pass in single file across a light or other energy source, has been applied in many aspects of clinical and research pathology. Automated clinical chemistry: Initially, in the early 1970s, multichannel analysers were used, then sequential analysis and dry chemistry techniques were introduced and, more recently, "near-patient" testing. Introduction of Medicare: Medicare's introduction in 1975 profoundly affected many aspects of clinical care, and has been partly responsible for a great increase in private pathology practices. Improved standards of forensic pathology and science: The debacle of the forensic investigation for the prosecution of the Azaria Chamberlain case in the 1980s showed up the appalling state of forensic pathology and forensic science in Australia, and was an impetus for the development of excellent forensic institutes and facilities in many Australian centres, with much-improved training programs and standards of practice. Frozen-section techniques and biopsies: Frozen-section techniques, percutaneous biopsies of kidney, liver and heart and, more recently, fine-needle aspiration and endoscopic biopsies have greatly improved knowledge of many disease processes, as well as provided accurate pathological diagnoses from very small samples. Medical laboratory accreditation: Nationwide medical laboratory accreditation in the early 1980s, together with quality control and quality assurance programs under the aegis of unique cooperative arrangements between the National Association of Testing Authorities and the Royal College of Pathologists of Australasia (NATA/RCPA) began in the late 1970s and continue to operate to a large extent as peer-review systems. Decline in hospital autopsies: The progressive decline in numbers of hospital autopsies during the latter part of the 20th century has resulted in the inevitable loss of clinicopathological correlations and valuable learning resources. Surveys of hospital deaths have shown large discrepancies between the clinical opinion of cause of death and comorbidities, and findings at autopsy. Advances in microscopy and staining: In both research and diagnostic pathology, the application of transmission and scanning electron microscopy and fluorescent and immunohistochemical techniques has contributed significantly to understanding the pathogenesis of many diseases, and to their accurate diagnosis. Advances in cytological techniques: Exfoliative cytology was initially used largely in gynaecology and pulmonary medicine, but subsequently in many other circumstances. More recently, cytology has been vastly expanded with the widespread use of fine-needle aspiration, and automated techniques for screening are coming into use, increasing overall diagnostic accuracy. Molecular pathology: Application of techniques of molecular biology and genetic analysis to diagnosis in pathology has had profound effects in all disciplines of pathology. Role of Helicobacter pylori: After the initial observations by pathologist Robin Warren and gastroenterologist Barry Marshall, in Perth in the early 1980s, the aetiological role of this organism in gastric and duodenal ulceration and cancer is now accepted by gastroenterologists and pathologists worldwide. Elucidation of aspects of viral infections: Elucidation of many aspects of viral infections, including the hepatitis viruses and HIV, is having profound effects on blood donations and blood transfusion technology, and patterns of behaviour in the community. Importance of apoptosis: The role of apoptosis (certain cells are programmed to die at a particular time) in embryological development has been known for 100 years or so. Its importance in normal adult physiology and in a large number of disease processes only became apparent after pioneering work undertaken by Brisbane pathologist John Kerr in the late 1960s. Corporatisation of private pathology practices: The increasing corporatisation of private pathology practices in Australia, with ownership going from practising pathologists to other individuals or companies, and public laboratories becoming business units, is cause for concern. More and more individual practices are controlled by fewer and fewer people. Peter B Herdson Forensic Pathologist, Canberra, ACT Richard A Scolyer Anatomical Pathologist Royal Prince Alfred Hospital, Sydney, NSW Alistair R McGregor Director, Microbiology and Infectious Diseases Royal Hobart Hospital, Hobart, TAS Above photograph courtesy Alfred Hospital Heritage Committee, Melbourne. Make a comment

Peter B Herdson · Richard A Scolyer · Alistair R McGregor

Defining Moments In Medicine Radiology MJA 2001; 174: 14-15

David A Lisle

Forensic Medicine Homicide or suicide? A jigsaw puzzle of incinerated human remains Alanah M Buck, Clive Cooke, Peter de la Motte and Stephen Knott Between 800 and 900 skeletal fragments were recovered and reassembled MJA 2000; 173: 606-607 The scene - Recovery - Analysis of the remains - Interpretation of the scene - Acknowledgement - References - Authors' details - - More articles on Pathology While hunting feral goats, the caretaker of a disused gold mine discovered a burnt-out car about 100 m from a service road. The vehicle was in previously burnt bushland. Licence plates were still attached to the car and identified it as belonging to a missing person. An investigation of the scene by local police officers revealed a set of charred and fragmented human remains a small distance from the vehicle. The suspected victim was in his mid-thirties; he had gone missing from a nearby town about four years before. He was alleged to have been an associate of known criminals and had accrued considerable gambling debts. In view of this history and the remoteness of the location, the circumstances of the death were considered suspicious. The scene The area in which the remains were found consisted of low scrub bush with a scattering of medium-sized trees. A small creek bounded the furthest edge of the demarcated area of interest. The creek was dry during the period of investigation (January); however, the area was known to flood during winter months. The immediate area where the remains were found was clear of vegetation, but several trees were growing in the surrounding area (Box 1). A large area of interest was identified using natural boundaries (eg, the creek bed) and police conducted a systematic grid search. An examination of the scene showed a series of burnt trees in the immediate vicinity; local shire information confirmed that a bushfire had passed through the area two years before. Branches from badly incinerated tree trunks were observed to have fallen in "ring-like" patterns around the charred stumps. A number of trees had silt build-up at the base of the trunks as a result of flooding. The direction of the water flow was towards the skeletal remains along an east-west axis. The skeletal remains were found in a clear area, removed from any trees. However, a series of charred tree branches were noted in the immediate vicinity of the skeletal scatter. Considering the ring-like branch patterns found around burnt trees, it was determined that a tree had in fact been located near the remains and had burnt down below the surface of the ground. Its stump was later uncovered. Recovery The skeletal elements were severely fragmented and scattered around an area about 3 x 2 m. The severe thermal damage and scattered appearance of the remains initially suggested that the body may have been deliberately cremated and the fragments dispersed. After photographic and video recording of the area of interest, a datum point was established and the skeletal elements were mapped using an x,y coordinate system. Each fragment was assigned an x,y coordinate and assessed in situ. This information was recorded both on the collection bag and independently on a police inventory list. Fragile material was packed in padded bags and taken to the State Mortuary. A metal detector was used to locate metal objects in the area of interest. A ring, several coins and the remnants of a gas lighter were recovered at the scene. An amalgam dental filling was later detected at the mortuary after careful sifting of associated soil. Analysis of the remains Between 800 and 900 skeletal fragments were recovered and reassembled in the State Mortuary (Box 2). The fragments of bone had been subject to varying degrees of fire damage, which was reflected in the range of colours observed (Box 2). Fewer than half the fragments could be placed back into their anatomical position. Portions of the right pelvic bone (including sciatic notch), left and right distal ends of the femora, the left clavicle and much of the left humerus were identifiable. The cranium was so fragmented that only 3-4 main regions could be identified -- these appeared to be male. Several teeth were also recovered; however, they were fractured as a result of extreme heat damage (Box 3). To determine the original position of the body on the ground, the location of the major fragments was plotted on an x,y graph in anatomical groupings. The distribution of the skeletal elements appeared to be random. Interpretation of the scene It appeared that the body had been initially cremated while it retained some or all of the soft tissue elements. This was confirmed by the type of intense fire damage sustained, similar to that seen in motor vehicle incinerations. This type of damage usually occurs in the presence of fat. The body appeared to have been originally in association with a large tree, which had burnt to the ground. The presence of the tree would also have added to the intensity and duration of the fire. An accelerant may have been used, although no evidence of this was found. This scenario would have accounted for the extreme calcination and fragmentation of the skeleton. After incineration, the remains became scattered over the ground and probably experienced a second scorching (at much reduced temperatures) by a scrub fire, hence the wide range of colour changes on the bones. Local flooding appears to have washed the remains along a narrow channel (along an east-west axis), causing the skeletal elements to be scattered indiscriminately out of anatomical context. Dental identification was difficult, as almost all records of the suspected victim had been disposed of owing to the long period (eight years) since his last dental visit. Fortuitously, the only remaining dental radiograph contained an image of the amalgam filling recovered from the scene (Box 4). Thus, a positive identification was made. Owing to the lack of sufficient and conclusive evidence regarding the cause of death, the Coroner returned an open verdict. Acknowledgement We would like to thank the Western Australian Coroner's Office. References Shipman P, Foster G, Schoeninger M. Burnt bones and teeth; an experimental study of color morphology, crystal structure and shrinkage. J Arch Sci 1984; 11: 307-325. White T. Prehistoric cannibalism. Princeton, New Jersey: Princeton University Press; 1992. Authors' details Department of Forensic Pathology, WA Centre for Pathology and Medical Research (PathCentre), Perth, WA. Alanah M Buck, PhD, Forensic Anthropologist; Clive Cooke, BMedSci, FRCPA, Chief Forensic Pathologist; Stephen Knott, BDSc, DipForensicOdont, Forensic Dentist. Major Crime Division, Western Australian Police Service, Perth, WA. Peter de la Motte, Detective Sergeant. Reprints will not be available from the authors. Correspondence: Dr A M Buck, Department of Forensic Pathology, WA Centre for Pathology and Medical Research, Locked Bag 2009, Nedlands, WA 6009. Alanah. BuckAThealth.wa.gov.au Make a comment 1: The location of the remains, in the centre of the photograph, and the surrounding area Back to text 2: Reconstruction of the remains in the mortuary The inset shows an example of the colour variation in bone brought about by differing temperatures. Bone passes through a series of colours in accord with temperature.1 Examples of calcination, which occurs at high temperatures (600ºC-700ºC)2 and exfoliation of bone surfaces indicate that portions of the body were subjected to very high temperatures. Other sections of the bone were black-brown in colour, indicating that it burnt at a much lower temperature. Back to text 3: Fragmented remains of the teeth, with the amalgam filling at the bottom right of the picture Back to text 4: Dental identification of the body The dental x-ray of the missing man's jaw complete with filling. The amalgam filling recovered from the scene. Small changes on the occlusal surface of the filling are due to wear over the eight-year period. Back to text

Alanah M Buck · Clive Cooke · Stephen Knott

The Research Enterprise John Kerr and apoptosis Michael G E O'Rourke and Kay A O Ellem MJA 2000; 173: 616-617 On 14 March 2000, John Foxton Ross Kerr, Emeritus Professor of Pathology at the University of Queensland, received the Paul Ehrlich and Ludwig Darmstaedter Prize for his description of apoptosis, a form of cell death. The prize, which he shared with Boston biologist Robert Horvitz, is considered to be one of the most prestigious European awards in science, second only to the Nobel Prize. John Kerr's discovery, initially called "shrinkage necrosis" but which he later renamed "apoptosis", came about in the late 1960s, when his attention was caught by a curious form of liver cell death during his studies of acute liver injury in rats. The findings of this seminal study were first published in 1965.1 Subsequently, Kerr and his co-authors (including Jeffrey Searle) described the unique morphological changes of this type of cell death, compared with those of necrosis, in a series of articles published during the 1970s and 1980s.2-4 These studies extended the range of pathological and physiological states in which apoptosis is known to occur. Further studies with other collaborators (who later included Alastair Currie and Andrew Wyllie)5 led to an increase in the understanding of the role of apoptosis in embryogenesis, spermatogenesis, cancer growth, and tissue remodelling during healing or functional regression. At first thought to be somewhat arcane as a topic, the literature on apoptosis initially grew slowly. However, recognition of the significance of this "protected" form of cell death on immune function and regulation was followed by an explosion of related publications in immunology. Biochemists now recite a mantra of enzymes involved in apoptosis, and chant a list of factors capable of modulating or regulating its expression. It has become de rigueur to adorn seminars and lectures with charts of the increasingly complex interactions which occur between signalling pathways as they are traversed by the informing reactions (which either trigger or defuse the suicidal steps leading to apoptotic cell death). The astonishing total number of publications on apoptosis is now over 35 539, including some of the world's leading scientific journals, such as Nature6-8 and Science.9-11 Apoptosis is now a growth industry, the clinical implications of which can be applied to chemotherapy, the endocrine treatment of cancer, autoimmune disease and neurodegenerative disease. This body of evidence is a tribute to the catalytic influence that John Kerr's insights have had in so many disparate disciplines and areas of biological study. These insights revealed the importance of this process as a universal microphenomenon in the macroevents of tissue and organismal function, and in disease. References Kerr JF. A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J Path Bact 1965; 90: 419-435. Kerr JF, Cooksley WG, Searle J, et al. The nature of piecemeal necrosis in chronic active hepatitis. Lancet 1979; 20: 827-828. Searle J, Lawson TA, Abbott PJ, et al. An electron-microscope study of the mode of cell death induced by cancer-chemotherapeutic agents in populations of proliferating normal and neoplastic cells. J Pathol 1975; 116: 129-138. Weedon D, Searle J, Kerr JF. Apoptosis. Its nature and implications for dermatopathology. Am J Dermatopathol 1979; 2: 133-144. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-257. Wallach D. Apoptosis: Placing death under control. Nature 1977; 388: 123-126. Hengartner MO. Apoptosis: death cycle and Swiss army knives. Nature 1998; 391: 441-442. Martinou JC. Apoptosis: key to the mitochondrial gate. Nature 1999: 399; 411-412. Barinaga M. Apoptosis: forging a path to cell death. Science 1996; 273: 735-737. Barinaga M. Apoptosis: death by dozens of cuts. Science 1998; 280: 32-34. Brenner C, Kroener G. Apoptosis: Mitochondria -- the death cell integrators. Science 2000; 289: 1150-1151. Cotran R, Kumar V, Collins T, editors. Pathological basis of disease. 6th ed. Philadelphia: W. B Saunders, 1997: 18-24. Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer 1994; 73: 2013-2026. Walker NI, Harmon BV, Gobe GC, et al. Patterns of cell death. Methods Achiev Exp Pathol 1988; 13: 18-32. Sandford N, Searle JW, Kerr JF. Sucessive waves of apoptosis in the rat prostate after repeated withdrawal of testosterone stimulation. Pathology 1984; 16: 406-410. Soubrane C, Mouawad R, Antoine EC, et al. A comparative study of Fas and Fas-ligand expression during melanoma progression. Br J Dermatol 2000; 143: 307-312. Andrane F, Casciola-Rosen L, Rosen A. Apoptosis in systemic lupus erthymatosus. Clinical implications. Rheum Dis Clin North Am 2000; 26: 215-227. Make a comment John Kerr (right) with Roland Koch, Prime Minister of Hesse, Germany, and Honorary Chairman of the Board of Trustees of the Paul Ehrlich Foundation, at a dinner for award recipients. 1: Other awards and lectures recognising John Kerr's achievements Keynote opening addresses at the Cold Spring Harbor, New York, Symposia, 1990. Opening lecture, The cell and molecular biology of apoptosis, at the Queensland Institute of Medical Research Cell and Molecular Biology Symposium, 1992. Opening lecture at the conference Apoptosis in AIDS, Paris, 1993. 12th Mildford D. Schultz Lecture, Harvard Medical School, Boston, 1993. Bancroft Medal (Queensland AMA), 1993. John Earnshaw Memorial Lecture, International Melanoma Conference, Brisbane, 1994. Fred W Stewart Award, Memorial Sloane-Kettering Cancer Center, New York, for contribution to cancer research, 1995. Doctor of Science honoris causa, University of Queensland, 1998. Fellowship of the Australian Academy of Science, 1998. Back to text 2: Apoptosis: programmed cell death The term "apoptosis" is derived from the Greek for "falling off" and describes a distinct form of cell death whereby cells die in a tightly regulated and morphologically uniform fashion.12 Morphologically, there is condensation of the nucleus and cytoplasm, membrane blebbing, and the formation of discrete, packaged apoptotic bodies which are phagocytosed by nearby cells, without provoking an inflammatory reaction.13 In contrast to necrosis, a degenerative process in which cells swell and lyse after irreversible tissue injury, apoptosis appears to be an active process14 which is subject to genetic regulation. Apoptosis can be triggered either from within the cell, or from outside the cell (mediated by binding of surface membrane receptors to "death activators" such as Fas-ligand and tumour necrosis factor). Electron micrograph showing apoptosis occurring spontaneously in cell culture. Note the discrete, membrane-enclosed nuclear fragments, with characteristic segregation of uniformly compacted chromatin, the crowding of well preserved cytoplasmic organelles and the marked convolution of the cellular surface, which is a prelude to conversion of the cell into a number of membrane-bound fragments or apoptotic bodies. N = nucleus, O = organelles. Apoptosis may occur in several different physiological, adaptive and pathological settings. For example, apoptosis acts as a homoeostatic mechanism for controlling cell populations, and in hormone-dependent tissue involution such as endometrial breakdown during menstruation, prostatic atrophy after castration,15 and cessation of lactation after weaning.12 Localised apoptosis plays a role in embryonic development, such as formation of interdigital clefts and involution of phylogenetic vestiges.5 In malignant tumours, apoptosis may occur spontaneously, or may increase in response to cytotoxic chemotherapy or irradiation.13 Impaired regulation of apoptosis is known to be associated with the development of various types of cancer,16 and with the pathogenesis of some autoimmune diseases such as systemic lupus erythematosus.17 Back to text

Power of One A clinician with a passion for pathology Priscilla Kincaid-Smith MJA 2000; 173: 639-642 As a woman in medicine and as a scientist, Professor Kincaid-Smith has met and overcome some determined obstructionists Hammersmith and the research focus - No place for women - Analgesic nephropathy - The achievements of pathology - References - Author's details Make a comment - - - More articles on History Introduction The early 1950s, when I graduated, were an exciting time in clinical medicine. Penicillin had only just become generally available and it revolutionised the treatment of infectious disease, particularly in a hospital like Baragwanath Hospital, where I spent my early years as a doctor. This 2000-bed hospital across the road from the now-infamous Soweto township outside Johannesburg was to absorb my full attention for the next two years. It was a very exciting place for the residents and registrars, as the wards were full of very ill patients many of whom could now be cured. A dose of penicillin which we would now consider homoeopathic transformed pneumonia into an illness lasting a few days and its mortality fell dramatically. In the same years chloramphenicol did for typhoid fever what penicillin had done for pneumonia, and chloroquine cured most patients with malignant cerebral malaria. The ward balconies were full of patients with advanced tuberculosis and this too became a curable disease after streptomycin became available. Hammersmith and the research focus After three years of working like a galley slave but gaining a huge experience in clinical medicine, I was lucky enough to be accepted at Hammersmith Hospital, London. At that time Hammersmith Hospital was a leader in many fields, notably in cardiology, where McMichael and Sharply-Schafer had pioneered cardiac catheterisation and the Australian, Paul Wood, certainly one of the world's top clinical cardiologists, worked for a time. At Hammersmith the whole attitude was to do research, and improve medical knowledge. It didn't give me the same satisfaction of saving lives, but it was certainly the academic centre of London in the 1950s. At that time the ancient traditions of the London teaching hospitals were a handicap to doing new things and research. Hammersmith was frowned upon as "that hospital next to HMP Wormwood Scrubs, that hospital where they did all those experiments!". I came into contact with some of the most famous names in medicine. Each day seemed more exciting than the last and the rate of learning was exponential. I spent two and a half years in anatomical pathology, but my research interest in hypertension and the kidney stood me in good stead for my future career in the then non-existent field of nephrology. Renal biopsy was in its infancy and Robert Heptinstall, perhaps the world's best renal pathologist, came over regularly from Mary's Hospital to look at renal biopsies with our expert in this field, "Do" Doniach, who was senior pathologist at Hammersmith Hospital. This exposure to living pathology has had a great influence on my career in nephrology, which, although unequivocally clinical, has always kept me close to a microscope and involved in pathology. As a pathology registrar, I spent the mornings doing autopsies, the highlights of which were the attendance at lunchtime of all the top clinicians for a presentation of the findings. This was a no-holds-barred school, with people like John McMichael (Head of Medicine at Hammersmith) and Sheila Sherlock (who published the first major book on hepatology and became a world leader in the field). Nothing was taken for granted: the questioners were a very erudite and exacting bunch of clinicians. Histological analyses of biopsies and surgical specimens were reported on the day they became available. This necessitated many late nights to prepare for the consultant pathologist's overview the next morning, but this one-on-one learning process was excellent. As an early riser I found that I could easily start work about two hours before anyone else arrived, which allowed me to do some research. My first "kidney" paper was published in The Lancet in 1955,1 and I managed quite a lot more in those extra two hours each day. Although I was fully immersed in pathology, I couldn't drag myself away from the wards. After attending ward rounds two or three times a week, my envy of the doctors looking after patients finally drew me back to clinical medicine in 1956. My training was in cardiology -- there was no specialty of nephrology --but, as hypertension was my main research interest and most of my previous research had involved hypertension and the kidney, I became a de facto nephrologist. Another great advantage was that Malcolm Milne was second in charge in the McMichael cardiology unit in which I worked, and he was truly one of the founding fathers of nephrology. Not only did I learn a lot from Malcolm, but we ran the dialysis service for southern England and collaborated with a string of clinical fellows with renal interests, among them Bob Muehrcke (who established renal biopsy as a safe procedure) and Belding Scribner (of dialysis fame). In 1958 Sir John McMichael called me into his office to offer me a junior consultant post at Hammersmith. I was overwhelmed and greatly honoured, but had that week become engaged to Ken Fairley (from Melbourne, who spent four years training at the National Heart Hospital in cardiology with Paul Wood), and neither of us really wanted to bring up a family in England. I sometimes wonder if, had I known what awaited me in Australia, I might not have tried to persuade Ken to stay in England after all. No place for women I had assumed that I would be eligible for a similar post in Melbourne to that offered in what I regarded as the UK's top hospital, but I was very wrong. In the 1950s, in Australia, when a woman married she automatically lost her job. I was not considered for any significant post in a hospital or university in Melbourne. My curriculum vitae was not wanting: I had published several respectable articles, held a postgraduate qualification in pathology, was a member of the Royal College of Physicians, London, and had eight years of first class postgraduate training. I had excellent references. But I was the wrong sex! I was devastated. It seemed that almost all doors were closed to married women. After doing general practice locums to help pay the bills, Sir John McMichael arranged a part-time research position for me at the Baker Institute at the Alfred Hospital, Melbourne. However, Ken and I decided that if I was not wanted in Melbourne perhaps we could be of service in New Guinea, which had almost no specialists in its health service. We applied for and were offered appointments, Ken as a physician and I as a pathologist. We went up to New Guinea to inspect the new hospital in Rabaul and were thrilled with the facilities, but soon discovered that, as a married woman, my appointment could only be temporary. If any man, irrespective of qualifications, applied, he would get the position, and permanent to boot! So it was back to Melbourne, where I was appointed as an honorary physician at the Queen Victoria Hospital, a hospital run by women for women. I also had a part time research position at the Baker Institute and a part time research and teaching appointment in the University of Melbourne, Department of Medicine, at the Alfred Hospital. Eventually, in 1967, I was appointed as first Assistant in Medicine in the University of Melbourne. That was the year in which barriers to employing married women in universities were removed. Analgesic nephropathy It was on my very first day at the Alfred that I encountered my first case of what was later called analgesic nephropathy. I went, as I always had at Hammersmith Hospital, to review that day's postmortem findings. There was no formal presentation and the pathologist seemed somewhat surprised to see me. Demonstrated were the kidneys from three patients. All showed the same lesion, a kind which I had never encountered at the Hammersmith. These had very obvious features: black necrotic papillae with overlying atrophy and with striking hypertrophy in adjacent columns of Bertin (Box 1). On asking the pathologist what this lesion was he replied that it was papillary necrosis, a common complication of renal infection. "Well, it doesn't occur in renal infection in London", I replied, but I don't think he believed me. Although I recognised the lesion as the sign of a specific disease process at that first-ever autopsy attendance in Melbourne early in 1959, it took a bit longer to connect it to analgesic abuse. I had, of course, seen acute renal papillary necrosis in an occasional kidney in England, but the Alfred cases were quite different and more chronic lesions. Phenacetin nephritis had been described in Switzerland as chronic interstitial nephritis in 1953, but there was almost no mention of papillary necrosis in the description, certainly none of pigmented papillae. When I was finally able to get a photograph of one of the Swiss kidneys it was clearly different: the kidney was small and there was a moth-eaten appearance of the papillae, which presumably represented areas from which necrotic tissue had been lost (Box 2). Ken Fairley was working in Bill King's unit at the Royal Melbourne Hospital and it was he who made the connection between the kidneys seen so frequently on the autopsy table in Melbourne and analgesics. Bill King was a busy gastroenterologist and when he encountered patients with renal disease he consulted Ken. Over a relatively short period of time Ken gathered a series of patients with peptic ulcers and impaired renal function who also had a history of a phenomenally high intake of analgesics. When one of these patients passed a small fragment of pigmented material which was processed and turned out to be a piece of renal papilla the puzzle was solved. These patients had analgesic nephropathy, even if the lesions were quite different from those described by Spühler and Zollinger in Switzerland.2 In 1963, at the International Society of Nephrology meeting in Prague, we had great difficulty in persuading our European colleagues to accept our evidence for this new form of analgesic nephropathy. They particularly did not like the large kidneys, which we demonstrated to reduce in size on radiological imaging as papillae were sloughed, with resulting cortical atrophy. This always seemed to me to be the likely pathogenesis of the so-called "chronic interstitial nephritis". They objected even more strenuously to the demonstration that this shrinkage in our cases was often followed by remarkable hypertrophy in Bertin's columns. They stressed the rarity of pigmented papillae and papillary necrosis, both major features of our cases. They argued that what we were describing was certainly not "phenacetin nephritis". We were already calling it "analgesic nephropathy" by then, because it continued unabated if patients ceased taking phenacetin and replaced it with paracetamol. There was strong opposition to this view and almost a denial of any connection between our Australian variety of analgesic nephropathy and their "phenacetin nephritis" with chronic interstitial nephritis. Later, years of careful clinical documentation and animal experimentation showed that it was not the phenacetin but the mixed analgesics that caused the renal papillary necrosis. Phenacetin alone or its immediate metabolite, paracetamol, could be fed to rats in huge quantities without causing apparent damage. But when we fed rats the analgesic powders and tablets then being sold in huge quantities in Australia we quickly reproduced the lesion of renal papillary necrosis, which closely resembled analgesic nephropathy in man, even to the detail of pigmented papillae. The stories of analgesic abuse extracted from patients at that time were incredible. The patients were truly addicted to the analgesics. They appeared to be seeking the mood-altering effects, not the analgesic effects, and it seemed that it was the phenacetin which they missed when taking different combinations. The patients were commonly heavy smokers and found it easier to give up cigarettes than analgesics! In the first group of patients that we studied, as many died of coronary artery disease as of renal failure.3 Extensive premature atheroma was a prominent feature, but we could never quite prove that it was the analgesic abuse and not the smoking that was linked to the atheroma. Renal artery stenosis was another common feature, perhaps also due to smoking, but we did postulate that the huge quantities of aspirin which these patients took may have destroyed the "good" as well as the "bad" prostaglandins and predisposed to severe atheroma. Our wards were full of patients with the analgesic syndrome. In addition to the characteristic renal disease, peptic ulceration, anaemia, premature atheroma and premature ageing, dementia was a frequent finding. Some blamed phenacetin for the impaired cognitive function. Severe and often malignant hypertension was another characteristic feature. Renal failure was of course a major cause of death, but if the patient could be persuaded to give up the analgesic abuse a remarkable degree of recovery could be expected. Nonetheless, when this condition started to feature on dialysis and transplant registries 10 years later, it was indeed a major cause of end-stage renal failure -- most common in Queensland and New South Wales and least common in Victoria, where our studies had been carried out. Gradually the message got across. Long before government regulations were introduced to control sales, people became aware of the dangers of analgesic abuse and the prevalence gradually declined. Analgesic powders and tablets, which were then available free in factories and other places, also disappeared, as did the cardboard boxes in which a gross of analgesic powders or tablets were sold. They had once been a very prominent item in the weekly family supermarket trolley. Over the next 10 years or so, the pharmaceutical companies lobbied long and hard against the evidence that analgesic abuse was a major cause of renal failure. In the late 1970s I happened to be flying interstate, seated in front of two senior executives from one of the many companies whose fortunes were founded on APC sales. From this vantage point, I overheard them vigorously attacking me and what I had said about analgesic nephropathy. I was of course delighted that they thought that I had had such an influence on analgesic sales. Later, the tenor of their discussion was that Australia was a lost cause for advertisement and sale of mixed analgesics, and they began to discuss plans to invade the markets of South East Asia, where there were no controls over either advertising or sales. They were targeting Malaysia in the first instance, and reports of analgesic nephropathy from Malaysia 10-20 years later confirm that their plans succeeded. Advertising had been one of the secrets of the success of analgesic sales and this dated back to the 1920s, when Nicholas in Melbourne commenced manufacture of aspirin after the defeat of Germany in World War I and the collapse of Bayer. History relates that a new manager from the United States had predicted that there were millions to be made from aggressive advertising of analgesics. Thirty years later one would still hear on television programs that "You will need Aspro today". It was not uncommon even in the 1960s and 1970s to see shop windows devoted to advertising a particular variety of analgesics (Box 3). Between 1979 and 1982 all Australian States legislated to control over-the-counter sales of mixed analgesics. This was 20 years after most nephrologists were convinced of the need to do this. The final success came from joint activities by the Australian Kidney Foundation and the Australasian Society of Nephrology, which managed to convince the National Health and Medical Research Council and, in turn, the Government. Progress was painfully slow to those of us struggling with the very common disease which resulted from analgesic abuse. The controls were sensible and effective. Regulations controlled the number of analgesics that could be sold in one pack and did not permit the sale of combinations of aspirin, phenacetin, paracetamol and caffeine. Analgesic nephropathy, which had been such a common clinical condition, gradually faded away. The achievements of pathology Although I now rarely visit the autopsy room, I still look down the microscope every day, peering at all the fascinating things which appear in the urine of patients with renal disease, or examining renal biopsies. I now have a collection of some 20 000 renal biopsies; in many I have known the clinical story as well as the pathology. Nephrology was at first dominated by physiologists and pathology was a very poor relation, but, in my view, pathology has contributed far more to clinical nephrology than physiology. Now pathology, in combination with various immunological techniques applied to biopsy tissue, is certainly at the forefront of advancing knowledge in nephrology. References Kincaid-Smith P. Vascular obstruction in chronic pyelonephritic kidneys and its relation to hypertension. Lancet 1955; 2: 1263-1269. Spühler O, Zollinger HV. Die Chronische Interstitielle Nephritis. S Klin Med 1953; 151: 1-50. Dawborn JK, Fairley KF, Kincaid-Smith P, King WE. The association of peptic ulceration and chronic renal disease and analgesic abuse. Quart J Med 1966; 35: 69-83. Author's details Epworth Hospital, Melbourne, VIC. Priscilla Kincaid-Smith, AC, MD, FRACP, FRCPA, Medical Director and Director of Nephrology; Emeritus Professor, University of Melbourne. Reprints will not be available from the author. Correspondence: Professor P Kincaid-Smith, Epworth Medical Centre, 185-187 Hoddle Street, Richmond, VIC 3121. priscillkATepworth.org.au 1: Autopsy specimen of both kidneys and the aorta in a 43-year-old man The kidneys show bars of hypertrophy on the outer aspect of the right kidney representing hypertrophy in columns of Bertin. The cut surface of the left kidney shows typical features of analgesic nephropathy, with black pigmented papillae, atrophy of cortex over nephrotic papillae and pale areas of hypertrophy in Bertin's columns. The aorta shows extensive atheroma. Return to text 2: Cut section of a kidney with typical features of the "Swiss" variety of analgesic nephropathy The cortex is atrophic. The papillae show small cavities from which necrotic material has been lost. No hypertrophy is seen in Bertin's columns. Return to text 3: A typical 1960s shop window display advertising a popular analgesic Return to text

Priscilla Kincaid-Smith

Snapshots Triple vision MJA 2000; 173: 646 Axial T2-weighted magnetic resonance image of the orbits. The "third eye" is a (histologically-proven) dermoid cyst in the superolateral aspect of the left orbit. David C Wong, FRANZCR Gail Durbridge, MSc Radiology Department The Wesley Hospital Auchenflower, QLD

David C Wong · Gail Durbridge

Snapshots Biting back pain MJA 2000; 173: 658 The patient's vertebral osteophytes appear to be about to bite the calcified abdominal aorta. Geoffrey J Coltheart, FRACS Sawyers Gully, NSW

Geoffrey J Coltheart

Editorial Breast cancer guidelines in action The challenge is to develop and sustain audit programs on an ongoing basis MJA 2000; 172: 196-197 In 1995, when the National Health and Medical Research Council (NHMRC) released Clinical practice guidelines for the management of early breast cancer,1 the first of their evidence-based recommendations, the initial response by clinicians was very positive: 97% regarded them as a good summary of recent evidence and 85% believed they would be useful in improving management.2This was encouraging, but the more important question was whether the guidelines would result in evidence-based care for women with breast cancer. Until recently, there has been little national information about breast cancer management in Australia, a lack noted by the House of Representatives in 1995, whose response was to recommend a comprehensive national monitoring system.3 However, it was not until 1999 that an accurate national picture of breast cancer management emerged. A report by the NHMRC National Breast Cancer Centre,4 analysing the surgical management of 4237 women with breast cancer in 1995 (ie, 88% of all women in Australia diagnosed with breast cancer in the six months before release of the guidelines), showed that, at that time, most women were receiving care in accord with most of the recommendations. However, some aspects of care were not in line with the guidelines: for example, the report highlighted the need to encourage the use of tamoxifen in women with oestrogen receptor positive tumours (particularly in women less than 50 years); to decrease rates of testing for distant metastases at the time of diagnosis of early breast cancer; and to increase participation in clinical trials. Progress will occur only if other local groups also see value in promoting evidence as their mast-head and recognising the fundamental role of audit in evidence-based treatment Information about current practice plays a key role in supporting evidence-based care. It enables the best use of scarce resources, as costly implementation strategies can be targeted at aspects of care not in accord with the recommendations. The process of audit itself is also effective in changing practice, particularly if individual clinicians can compare their own practice with evidence-based recommendations or with the practice of their peers.5,6 In this context, the article in this issue of the Journal by Craft et al 7 is of considerable significance, as it demonstrates the feasibility of a community-based audit of breast cancer management by a multidisciplinary team (the Australian Capital Territory and South Eastern New South Wales [ACT and SE NSW] Breast Cancer Treatment Group). The Group is to be commended both for its meticulous approach to encouraging evidence-based care through local audit and for the high standards of care provided. The results presented by Craft et al7 suggest that more women than in the national survey were managed in accordance with the NHMRC guidelines. For example, in the national data, 85% of women with breast-conserving therapy received radiotherapy, compared with 98% of the sample studied by Craft et al, and all women in the sample aged under 50 with axillary node involvement received adjuvant chemotherapy. We do not know, of course, to what extent these results can be generalised to the 21% of cases occurring in the region and not included in the audit. Although these differences may show an embracing of the guidelines since their release, it is unclear whether these changes would be apparent across Australia or whether they are due to intensive efforts within the ACT and SE NSW region. However, an audit conducted in a surgical practice in Echuca, a rural town in Victoria, also demonstrated patterns of care generally in accordance with the guidelines.8 The report by Craft et al also shows the role of local ownership of guidelines and a multidisciplinary team approach to management. The ACT and SE NSW Breast Cancer Treatment Group was formed to consider priorities within the region and to select indicators of local significance for inclusion in their audit. Consumer input was included. Further, the audit was not limited to one institution, but attempted to include all clinicians, including potentially more isolated clinicians in the region, making it more likely to have an impact on outcomes. The strategies used by the Group appear to have been successful, with 23 of 24 clinicians participating and the identification of an estimated 79% of all cases of breast cancer occurring in the region. There is some evidence that a multidisciplinary team approach is more likely to result in evidence-based care and better patient outcomes than clinicians working in isolation.9,10 Recent initiatives within Australia are designed to foster multidisciplinary care, including Victoria's Breast Care Enhancement Program and the federally funded National Multidisciplinary Care Demonstration Project coordinated by the National Breast Cancer Centre. After Craft et al's conclusive demonstration of the value of local audit, the challenge now is to develop and sustain other audit programs on a continuing basis. There is a real danger that the evidence-based approach will founder from a lack of resources for guideline implementation at the local level and for support of audit programs. A commitment from State and local health services to resourcing these programs is vital. The recent initiative by the Royal Australasian College of Surgeons in developing an audit system for breast cancer should prove particularly valuable in future assessment of guideline adherence. The audit is national and provides contributing surgeons with feedback about their practice compared with that of their peers. There are also benefits to daily clinical practice: the audit provides a standardised record, which can be used in patient notes or to inform general practitioners or patients. Apart from surgery, other disciplines are also considering developing similar approaches to audit in breast cancer, notably the Royal Australian and New Zealand College of Radiologists (Faculty of Radiation Oncology) and the Medical Oncology Group, all in association with the National Breast Cancer Centre. Progress will occur only if other local groups also see value in promoting evidence as their masthead and recognising the fundamental role of audit in evidence-based treatment. In demonstrating the feasibility of this approach, the achievement of the ACT and SE NSW Breast Cancer Treatment Group could serve as a model for other regions. Sally Redman Director, NHMRC National Breast Cancer Centre, Sydney, NSW Tom S Reeve Executive Officer, Australian Cancer Network, Sydney, NSW National Health and Medical Research Council. The management of early breast cancer. Clinical Practice Guidelines. Canberra: NHMRC/AGPS, 1995. Carrick S, Bonevski B, Redman S, et al. Surgeons' opinion about the NHMRC clinical practice guidelines for the management of early breast cancer. Med J Aust 1998; 169: 300-305. House of Representatives Standing Committee on Community Affairs. Report on the management and treatment of breast cancer in Australia. Canberra: AGPS, 1995. Hill D, Jamrozik K, White V, et al. Surgical management of breast cancer in Australia in 1995. Sydney: NHMRC National Breast Cancer Centre; 1999. Thomson MA, Oxman AD, Davis DA, et al. Audit and feedback to improve health professional practice and health care outcomes (Parts I and II) (Cochrane Review). Oxford: The Cochrane Library 1999: Issue 1. NHS Centre for Reviews and Dissemination, University of York. Getting evidence into practice. Effective Health Care 1999; 5(1). Craft PS, Zhang Y, Brogan J, et al, and the Australian Capital Territory and South Eastern New South Wales Breast Cancer Treatment Group. Implementing clinical practice guidelines: a community-based audit of breast cancer treatment. Med J Aust 1999; 172: 213-216. Tulloh BR, Goldworthy ME. Breast cancer management: a rural perspective. Med J Aust 1997; 166: 26-29. Sainsbury R, Haward B, Rider L, et al. Influence of clinician workload and patterns of treatment on survival from breast cancer. Lancet 1995; 345: 1251-1252. Gillis CR, Hole DJ. Survival outcome of care by specialist surgeons in breast cancer: a study of 3786 patients in the west of Scotland. BMJ 1996; 312: 145-148. Make a comment

True Story A riposte for a fencer The residency appointment of Alfred Edmund Finckh to Sydney Hospital in 1905. Was it just a matter of male chauvinism? Alfred Finckh gained a residency at Sydney Hospital in 1905 in preference to a more academically successful female medical graduate, amid some controversy over the place of female doctors in hospitals. Here, two of his descendants argue his cause: that he was an experienced scientist with qualities that merited his selection for the post. MJA 1999; 171: 679-680

Ernest S Finckh · Andrew S Finckh

Snapshot! Happy Valentine's baby A 30-year-old man presented with abdominal pain. A computerised tomography scan of the abdomen and pelvis was performed. Contrast defines a heart in the anal canal. Perhaps this case should have been reserved for the MJA's February issue... John Rouse Radiology registrar St Vincent's Hospital, Darlinghurst, NSW Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

John Rouse

Snapshot! Bottom of my heart Have you ever wondered how to tell that special person in your life just how much you love them? Radiology can provide a unique way. This patient displayed her heart on her buttocks. Could this be where Stevie Wonder found the inspiration to write the song: "I just called to say I love you I just called to say how much I care I just called to say I love you And I mean it from the BOTTOM of my HEART"? Rodney Strahan Radiology Registrar Concord Hospital, Concord NSW Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Rodney Strahan

Snapshot! Smiley face This computed tomography (CT) scan shows a "smiley face" on the first sacral vertebra of an 80-year-old man with sclerotic vertebrae resulting from extensive prostate metastases. The patient had his prostate cancer diagnosed in 1993, and was initially treated with zoladex and androcur. Bone metastases were detected in 1998 and palliative therapies over the past two years have included various analgesics, localised external beam radiotherapy to the lumbar spine and sacrum, and strontium (89Sr) treatment. When this CT scan was taken he was taking morphine (20 mg twice daily), and was free of pain most of the time. His bone scan showed extensive diffuse uptake throughout the skeleton, and his prostate-specific antigen level was 4400 micrograms/L (normal range, <4 micrograms/L). Malcolm Feigen Radiology Registrar The New Children's Hospital, Westmead, NSW Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Malcolm Feigen

Snapshot! "The fish will eat your eyes" A young Australian surfer visiting Bali did not heed the warning of local villagers who told him not to stay out on the lagoon at dusk or the "fish will eat your eyes". One evening, while paddling back to shore from a day's surfing, he was suddenly hit in the face by an unknown object. This produced instant and intense pain in the right orbit with subsequent periorbital cellulitis and cervical lymphadenopathy, although his vision was maintained. Oral antibiotics given by local doctors had no effect, so he flew back to Australia for medical consultation. A computed tomography scan showed a 6cm foreign body passing along the right inferoloateral orbital floor, missing the globe and the optic nerve, but penetrating the inferior orbital fissure to terminate approximately 5mm anterior to the internal carotid artery (Figures a and b). It was surgically removed and proved to be the broken-off snout of a "javelin" or "needle" fish (Figure c). It comprised the upper and lower jaws, complete with multiple small teeth. The patient made an excellent recovery. Christopher J O'Donnell Radiologist, Victorian Imaging Group Elsternwick, VIC Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Christopher J O'Donnell

Diagnosis The stage is set for the diffusion of positron emission tomography (PET) in oncology A large body of evidence now attests to the diagnostic accuracy and cost-effectiveness of PET in oncology MJA 1999; 171: 527-528 Positron emission tomography (PET) is an exact, non-invasive technique for studying the body's biochemistry. The patient is injected with a positron-emitting radioisotope of a biologically active substance -- for oncological investigations, fluorodeoxyglucose (FDG) (2-deoxyglucose labelled with the positron emitter fluorine 18) is used.1,2 FDG is actively concentrated in cancer cells, and the PET camera detects the location of the FDG by registering the ejection of positrons from the nuclei of fluorine 18 atoms. As the positrons are ejected they collide with electrons; both particles annihilate and emit two 511 keV gamma rays at 180º to each other. Rings of detectors in PET cameras register these signals and the resulting images of particular organs, or the whole body, are displayed in three dimensions. Thus, PET can reveal the presence of cancer by recording an increased rate of glucose metabolism before any of the structural changes detectable by ultrasound, radiography, computed tomography (CT) and magnetic resonance imaging (MRI) have occurred. The history of PET in Australia is given in Box 1. Recognition of the utility of PET, particularly in cancer management, is reflected in its expanding applications around the world, and in the proportion of papers on PET (rising from 10% to 36%) presented at annual meetings of the US Society of Nuclear Medicine.3 The majority of these papers relate to its applications in oncology. Similarly, most clinical PET studies performed in Australia (over 80%) have been for cancer management.4 Box 2 gives a summary (adapted from Valk5) of the current role of PET in cancer management. Although these overseas studies demonstrate the superior diagnostic accuracy of PET in a wide range of applications in oncology, the article in this issue of the Journal by Hicks et al6 is the first extensive Australian report of the use of PET. The contributions of PET to patient management in oncology reported by Hicks and colleagues are similar to those recorded in the international literature. Hicks and colleagues did not assess cost-effectiveness as part of their audit of PET studies, but studies in other countries have provided a large body of evidence of the cost-effectiveness of PET in oncology. However, Valk emphasises that, while there are adequate cost-effectiveness data on diagnosis of pulmonary nodules and mediastinal staging of lung cancer, cost-effectiveness data for the use of PET in other conditions are incomplete.7 Cost-effectiveness studies have demonstrated that the benefits of PET include avoidance of unnecessary imaging procedures (radiography, CT, and MRI) and biopsies, as well as prevention of unnecessary surgery and hospitalisation.7-9 Influenced by the findings of diagnostic accuracy and cost-effectiveness, the US government has now included the oncology applications for PET studies detailed below among its Medicare reimbursement categories: Characterisation of solitary pulmonary nodule; and initial staging of non-small-cell carcinoma of the lung (since January 1998); and Colorectal cancer recurrence or metastasis; lymphoma staging and characterisation; melanoma recurrence or metastasis (since July 1999).10 In Australia, it is time to consider making PET available at additional sites, both to improve medical outcomes for a greater number of patients and to obtain our own cost-effectiveness data. Essential to this process are: A reliable supply of FDG; Acceptable instrumentation; Accredited PET staff (physicians, scientists and technologists); Appropriate locations for PET services; and Provision for ongoing evaluation. The current situation in Australia in relation to these critical factors is as follows. Fluorine-18 deoxyglucose (FDG) supply: In the past decade, Australia has made a multimillion dollar investment in cyclotrons -- the National Medical Cyclotron (NMC) in Sydney, operated by the Australian Nuclear Science and Technology Organisation (ANSTO), and two small cyclotrons in Melbourne. These cyclotrons can supply enough FDG to meet the present and immediate future needs of all capital cities except Perth and Darwin. If PET continues to expand, it may be necessary to install further regional cyclotrons. Acceptable instrumentation: The bulk of the evidence used by expert committees in the United States and Australia to determine existing reimbursement policies in PET in oncology came from PET studies using scanners equipped with bismuth germanate crystals (BGO). PET centres at Royal Prince Alfred Hospital and the Austin and Repatriation Medical Centre are equipped with BGO cameras, which remain the reference standard for FDG PET oncology studies. Further studies on cost-effectiveness need to be based on data obtained using comparable instruments. A range of instruments claiming similar performance exists, and there is an ongoing need for these to be evaluated. Accredited PET staff (physicians, scientists,11,12 technologists): Australia has a number of PET-trained physicians, scientists and technologists. This pool of expertise will need to be expanded and appropriate accreditation guidelines defined and implemented. Appropriate location of PET services: Delivery of advanced oncology therapy is centred predominantly in major hospitals which have comprehensive diagnostic services (eg, radiography, CT, MRI, nuclear medicine), a range of other specialties and radiation oncology planning and treatment services. The oncological dominance of clinical PET usage patterns automatically proposes centres such as these as logical sites for the diffusion of PET. Ongoing evaluation: Diffusion of PET services should be carried out in conjunction with the established, transparent evaluation processes. The oncology stakeholders, including patient advocacy groups, should be involved in the formulation and implementation of protocols. Liaison with the Medical Services Advisory Committee, the federal Department of Health and Aged Care and State and Territory health departments is essential. The Federal Department of Health and Aged Care is currently conducting a review of PET with input from a Medical Services Advisory Committee PET working party and involving existing PET providers. In addition, NSW and Victoria are conducting their own reviews of PET services. As well as demonstrating clinical utility, the study of Hicks et al shows the advantages that flow from locating PET facilities in major oncology referral centres. The model for the role of PET suggested here proposes the collocation of PET services in the nuclear medicine departments of comprehensive refer ral hospitals which have existing regional oncology services. The advantages of this proposal are that PET is located where the greatest number of oncology patients can benefit from its clinical accuracy, and further large-scale evaluations of its cost effectiveness can be undertaken. John G Morris, AO Professor of Clinical Medicine Australian Nuclear Medicine and PET Consultants, Sydney, NSW Sokoloff L, Reivich M, Kennedy C, et al. The [14C] deoxyglucose method of local cerebral glucose utilisation: Theory, procedure, and normal values in the conscious and anaethestised albino rat. J Neurochem 1977; 28: 897-916. Som P, Atkins HL, Bandoypadhyay D, et al. A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): non-toxic tracer for rapid tumor detection. J Nucl Med 1980; 21: 670-675. Proceedings of the 46th Annual Meeting of the Society of Nuclear Medicine, Los Angeles, California, 1999. J Nucl Med 1999; 40 (Suppl): 5. Commonwealth Department of Health and Aged Care (Diagnostics and Technology Branch). Review of positron emission tomography (PET). Canberra: The Department, July 1999. Valk PE. Effect of FDG-PET on patient management and cost. Handout book. Reston, Va (USA): Society of Nuclear Medicine, 1999: 200-204. Hicks RJ, Binns DS, Fawcett ME, et al. Positron emission tomography (PET): experience with a large-field-of-view three-dimensional PET scanner. Med J Aust 1999; 171: 529-532. Valk PE, Pounds TR, Tesar TD, et al. Cost-effectiveness of PET in clinical oncology. Nucl Med Biol 1996; 23: 737-743. Lowe VJ, Fletcher JW, Gobar L, et al. Prospective evaluation of positron emission tomography in lung nodules. J Clin Oncol 1998; 16: 1075-1084. Gambhir SS, Hoh CK, et al. Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 1996; 37: 1428-1436. HCFA expands Medicare coverage of PET. J Nucl Med 1999; 50: 23N. Bailey DL, Miller MP, Spinks TJ, et al. Experience with fully 3D PET and implications for future high-resolution 3D tomographs. Phys Med Biol 1998; 43: 777-786. Hutton B. Emerging clinical applications of quantitative emission computed tomography. In: Pham B, Braun M, Maeder AJ, Eckert MP, editors. New approaches in medical image analysis, 1999. Proceedings of SPIE (International Society of Optical Engineering) 1999; 3747: 57-76. (ISBN 0-8194-3229-6.) 1: History of positron emission tomography in Australia In Australia, PET was first used in 1992 at the Royal Prince Alfred Hospital (RPAH), Sydney, and the Austin Hospital, in Melbourne (now the Austin and Repatriation Medical Centre). In 1993, the Federal Government, in conjunction with the New South Wales and Victorian governments, funded a five-year evaluation project involving PET units at these two sites. The intention was to undertake a rigorous evaluation of the effectiveness of PET as a diagnostic tool in Australian clinical practice and provide information on which to base decisions about future resource allocation. This project had difficulties in establishing appropriate protocols, and in October 1997 a modified evaluation strategy was adopted. This involved limited Medical Benefits Schedule (MBS) funding of the RPAH and Austin PET centres to develop evidence on the clinical role, value and cost effectiveness of PET. MBS reimbursement for oncology covered breast, gastrointestinal, genitourinary, head and neck, haematological, hepatobiliary, soft tissue and thoracic cancer. In 1996 and 1998, respectively, unfunded PET centres began operating at the Peter MacCallum Cancer Institute in Melbourne and the Wesley Hospital in Brisbane. Back to text2: Uses of positron emission tomography (PET) in oncology4 1. Primary tumour diagnosis Solitary pulmonary nodule Unknown primary tumour 2. Primary tumour staging Non-small-cell lung cancer Hodgkin's disease Breast cancer Oesophageal cancer 3. Recurrent tumour - diagnosis and staging Recurrent colorectal cancer Metastatic melanoma Recurrent head and neck cancer Other tumours: lymphoma, ovarian cancer, breast cancer, non-small-cell lung cancer 4. Treatment evaluation (surgical, chemotherapy, radiation therapy) Non-small-cell lung cancer Non-Hodgkin's lymphoma Recurrent head and neck cancer Hepatic recurrence of colorectal cancer Metastatic breast cancer Adapted from Society of Nuclear Medicine 1999 Handout Book, June 1999. Back to text

John G Morris

Diagnosis Positron emission tomography (PET): experience with a large-field-of-view three-dimensional PET scanner Positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) is an accurate technique for staging and therapeutic monitoring in oncology. We evaluated our use of FDG PET in an oncology centre after our first 2500 studies, and summarise our experience of PET for the major referral indications. Optimised for clinical service, PET offers lower scanning costs and therefore improved cost-effectiveness. Rodney J Hicks, David S Binns, Meagan E Fawcett, Robert E Ware, Victor Kalff, Allan F McKenzie, John P Zalcberg and Lester J Peters MJA 1999; 171: 529-532 For related articles see Morris Introduction - Major referral indications - Providing cost-effective PET in oncology - Conclusion - Acknowledgements - References - Authors' details - - More articles on Oncology Introduction There is increasing recognition of the role of positron emission tomography (PET) in oncology, supplementing its established roles in the evaluation of myocardial viability1 and epilepsy.2 The radiopharmaceutical fluorine-18 fluorodeoxyglucose (FDG), an analogue of glucose, has high uptake in a wide range of tumours. FDG PET has been shown to be an accurate technique for tumour staging3 and for therapeutic monitoring.4However, the high establishment and operating costs of conventional PET facilities make economic justification more difficult than for cheaper imaging methods. Before funding new technologies, government and third-party payers increasingly require evidence of cost-effectiveness as well as diagnostic accuracy. High unit scanning costs demand substantially greater effectiveness. The development of lower-cost positron imaging systems over the past 10 years offers a realistic opportunity to expand the clinical availability of PET by improving this balance. Our PET facility, which uses such a system and is optimised for clinical service provision, was commissioned in September 1996. Our aim was to summarise our experience of PET scanning after the first 2500 FDG PET studies performed at our centre (Figure 1). Major referral indications Lung cancer The most common referral indication was known or suspected lung cancer -- 522 studies (20%). Our preliminary, prospective evaluation of the impact of PET scans on the management of 47 consecutive lung cancer patients found that, in over 60% of cases, management was significantly influenced by the scan result (Figure 2).16 In particular, in 32% of patients being considered for treatment with curative intent, management was changed to palliative therapy after documentation of previously unrecognised extrathoracic disease. In a more recent review limited to 140 consecutive patients being staged before definitive treatment of non-small-cell lung cancer, we found that PET changed treatment intent or modality in 47 patients (33%), altered delivery of the intended therapy in 39 patients (28%), and confirmed that the intended therapy was appropriate in only 39 patients (28%). In 15 patients (11%), an abnormality on PET, subsequently confirmed at follow-up, was ignored, with adverse outcome in all but two patients. Melanoma Assessing resectability of clinically localised metastatic disease in melanoma and staging of high-risk primary malignant melanoma have also been frequent indications -- 386 studies (14%) (possibly reflecting the presence of a dedicated melanoma unit at our institution). Based on data suggesting excellent accuracy of FDG PET for staging malignant melanoma,8 we have recently performed a comparison of this technique with high-dose gallium-67 (Ga-67) scanning, previously the standard functional imaging technique for high risk melanoma at our institution. This prospective comparison in 108 patients demonstrated concordance between these investigations in over 80% of cases.17 However, in a limited number of patients, absence of gallium avidity in metastatic melanoma deposits led to striking discordance between FDG PET and Ga-67 results (Figure 3). As FDG PET is a much more convenient study for patients, being completed in less than three hours (whereas Ga-67 requires scanning up to a week after injection), we have largely replaced Ga-67 scanning with PET for this indication at our institution. Head and neck cancer After surgery or radiotherapy, normal tissue planes can be scarred and disrupted. This complicates structural imaging or clinical examination for evaluation of residual or recurrent head and neck cancer. Thus, restaging was the most frequent indication for PET among the 318 studies (13%) in this subgroup. A preliminary review of our experience with FDG PET in 72 patients with head and neck cancer showed a positive predictive accuracy of 92% and a negative predictive accuracy of 100% for restaging.18Gastrointestinal malignancy Referrals of patients with gastrointestinal malignancy (251 studies --10%) have mainly been after primary management. Confirmation of resectability of apparently localised metastatic disease or suitability for local radiotherapy have been the major clinical indications. In a preliminary review of our experience in 41 patients,19 PET altered clinical management in 21 patients (52%), including 14 patients whose management was converted from aggressive locoregional therapy to palliative treatment based on demonstration of previously occult metastases (Figure 4). Breast cancer Evaluation of suspected recurrent or residual disease after treatment of breast cancer (190 studies -- 8%) has been the most common reason for referral of patients with breast cancer. Epilepsy Of the non-oncological indications, localisation of epileptogenic foci of complex partial seizures (88 studies -- 4%) was the most common reason for FDG PET studies. A recent review of our experience in epilepsy involving 52 patients demonstrated a sensitivity for localisation of a seizure focus of 83% versus only 49% by volumetric magnetic resonance imaging (MRI) in the same patient cohort.20 Of 20 patients with localising PET studies who have undergone surgery, 18 are currently seizure free and the other two have had a single seizure associated with drug withdrawal (unpublished data). Providing cost-effective PET in oncology Cost-effectiveness Despite an increasing body of evidence supporting the accuracy of FDG PET in oncology,5-7,9-15,21 its high cost and limited cost-effectiveness data have militated against funding for routine clinical use. In the United States, FDG PET scanning has been shown to be a cost-effective alternative to conventional diagnostic methods of assessing solitary pulmonary nodules22 and staging non-small-cell lung cancer,23 and now attracts reimbursement for these indications. US government funding of PET scans has recently been extended (on the basis of as yet unpublished cost-effectiveness analyses) to evaluation of suspected recurrent colorectal cancer and staging of melanoma and lymphoma (in place of high-dose gallium-67 scanning). In the United Kingdom, because of a reduction in surgical procedures, cost-effectiveness of PET for lung cancer staging has been reported.24 Our own preliminary data suggest a significant management impact of PET on lung cancer.16 Cost-benefit analyses to justify the use of FDG PET have shown significant savings even when based on costs derived from conventional PET facilities (quoted at US$1200, which includes technical and reporting costs).23 The ultimate cost of clinical PET scans depends on throughput of patients, availability and cost of radiopharmaceutical supplies, and the case mix of PET studies. Further evolution of lower-cost positron imaging devices and the development of production and distribution facilities to supply FDG to sites remote from a cyclotron have the potential to further reduce costs. If the cost of PET scans becomes more competitive, the merit of funding of PET for clinical use could be argued not on the basis of cost, but on its proven diagnostic and prognostic accuracy compared with standard investigations. A clinical service model As clinical service provision has been the major focus at our facility, our equipment and staffing reflect this orientation. Most other PET centres have focused on performing basic research as well as clinical studies. The capital and human establishment costs needed to perform the complex investigative studies that advance and validate PET technology increase the overall operational costs of such centres. The PET scanner at Peter McCallum Cancer Institute (GE Quest-300H, UGM Medical Systems Inc, Philadelphia, Pennsylvania, USA) uses scintillation crystals similar to those used in standard nuclear medicine gamma cameras. This significantly reduces the purchase price compared with conventional PET scanners. However, the documented spatial resolution and sensitivity are similar to current generation three-dimensional PET scanners.25 The larger axial field-of-view (25 cm v 16 cm) allows higher patient throughput. For example, whole-body imaging studies can be completed in less than an hour. The scanner characteristics limit administered radioacitivity to around 111 MBq (3 mCi) of F-18 FDG, compared with the typical dose of 300-555 MBq (8-15 mCi) with conventional PET scanners. This reduces operating costs, but limits the potential use of more short-lived PET tracers. Unlike amortisation costs, which fall, radioisotope costs increase as the number of patients studied per day increases. Because of radioactive decay, patients studied late in the day require far more isotope to be dispensed at the time of production. Decay also occurs during transport, and therefore proximity of the end-user to the cyclotron also influences daily isotope requirements and costs. A more sensitive scanner has particular advantages when used at a site remote from the production cyclotron. We believe that the relatively low start-up costs, high throughput and reduced operating expenses enable our facility to offer clinical PET studies at a cost that is significantly less than that generally quoted in the literature. Even with the lower cost of our model of practice, PET is likely to remain more expensive than other tomographic diagnostic procedures commonly used in cancer staging and therapeutic monitoring. However, the relatively poor diagnostic accuracy of these tests, when used alone, means that multiple investigations are often used or tests are supplemented by invasive staging procedures, making overall costs considerably higher. The advantages to patient quality of life of more accurate staging, particularly that which spares futile surgical intervention or reduces patient anxiety by timely assessment of therapeutic response, although more difficult to express in economic terms, can not be underestimated. Conclusion PET scanning has been available at our institution for three years. During this time it has been readily adopted by clinicians for planning of cancer management and for therapeutic monitoring. The high proportion of referrals from outside our institution suggests that there is growing awareness and high clinical acceptance of this technology among the medical community. Our own preliminary data support its utility in a wide range of oncological settings. More detailed prospective evaluation of the diagnostic accuracy and impact of PET in our institution is in progress and will help to further define the role of F-18 FDG PET in clinical oncology. By reducing scanning costs, the model of practice proposed offers the potential for PET to be become more widely available to the Australian community as a clinical rather than a research investigation. Acknowledgements Thanks to the staff of the cyclotron facilities at the Austin and Repatriation Medical Centre and the National Medical Cyclotron for providing timely supply of isotopes for clinical studies. We also thank the staff of our Department of Nuclear Medicine for taking on significantly increased work-loads with only a minimal increase in staffing levels, and Dr John Morris, the Chief Executive Officer of Peter McCallum Cancer Institute, for his ongoing support of the PET Program. References Tillisch J, Brunken R, Marshall R, et al. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med 1986; 314: 884-888. Engel J, Henry TR, Risinger MW, et al. Presurgical evaluation for partial epilepsy: relative contributions of chronic depth-electrode recordings versus FDG-PET and scalp-sphenoidal ictal EEG. Neurology 1990; 40: 1670-1677. Rigo P, Paulus P, Kaschten BJ, et al. Oncological applications of positron emission tomography with fluorine-18 fluorodeoxyglucose. Eur J Nucl Med 1996; 23: 1641-1674. Price P, Jones T. Can positron emission tomography (PET) be used to detect subclinical response to cancer therapy? Eur J Cancer 1995; 31A: 1924-1927. Valk P, Pounds TR, Hopkins DM, et al. Staging non-small cell lung cancer by whole-body positron emission tomographic imaging. Ann Thorac Surg 1995; 60: 1573-1582. Coleman RE. PET in lung cancer. J Nucl Med 1999; 40: 814-820. Steinert HC, Hauser M, Allemann F, et al. Non-small cell lung cancer: nodal staging with FDG PET versus CT with correlative lymph node sampling. Radiology 1997; 202: 441-446. Steinert HC, Huch BÖni RA, Buck A, et al. Malignant melanoma: staging with whole-body positron emission tomography and 2-[F-18]-fluoro-2-deoxy-D-glucose. Radiology 1995; 195: 705-709. Delbeke D. Oncological application of FDG PET imaging; brain tumors, colorectal cancer, lymphoma and melanoma. J Nucl Med 1999; 40: 591-603. Benchaou M, Lehman W, Slosman DO, et al. The role of FDG-PET in the preoperative assessment of N-staging in head and neck cancer. Acta Otolaryngol 1996; 116: 332-335. Newman JS, Francis IR, Kaminski MS, Wahl RL. Imaging of lymphoma with PET with 2-[F-18]-fluoro-2-deoxy-D-glucose: correlation with CT. Radiology 1994; 190: 111-116. Hoh CK, Glaspy J, Rosen P, et al. Whole-body FDG-PET imaging for staging of Hodgkin's disease and lymphoma. J Nucl Med 1997; 38: 343-348. Tse NY, Hoh CK, Hawkins RA, et al. The application of positron emission tomographic imaging with fluorodeoxyglucose to the evaluation of breast disease. Ann Surg 1992; 216: 27-34. Utech CI, Young CS, Winter PF. Prospective evaluation of fluorine-18 fluorodeoxyglucose positron emission tomography in breast cancer for staging of the axilla related to surgery and immunocytochemistry. Eur J Nucl Med 1996; 23: 1588-1593. Avril N, Bense S, Ziegler SI, et al. Breast imaging with fluorine-18-FDG PET: quantitative image analysis. J Nucl Med 1997; 38: 1186-1191. Kalff V, Hicks RJ, MacManus M, et al. The clinical impact of PET scanning in patients with lung cancer: a prospective study [Abstract]. J Nucl Med 1998; 39: 249. Hicks RJ, Kalff V, Binns DS, et al. Are high dose Ga-67 scans as good as FDG PET in staging melanoma? [Abstract] J Nucl Med 1998; 39: 11. Porceddu S, Hicks RJ, Rischin D, Peters L. Impact of PET on head and neck cancer. Proceedings of the 49th Annual Scientific Meeting of the Royal Australasian College of Radiology, 1998 Oct; Brisbane, Australia. [Abstract]: 290-291. Kalff V, Binns DS, Fawcett ME, Hicks RJ. Clinical impact of FDG PET scanning in colon cancer: a prospective study. Nucl Med Commun 1999; 20: 381. Murphy M, O'Brien TJ, Hicks RJ, et al. Experience of a 3-D, large-field-of-view PET scanner for the localisation of partial epilepsy. Annual Meeting of the American Epilepsy Society, 1999. Epilepsia (Suppl). In press. Strauss LG, Conti PS. The applications of PET in oncology. J Nucl Med 1991; 32: 623-648. Dewan NA, Reeb SD, Gupta N, et al. PET-FDG imaging and transthoracic needle lung aspiration biopsy in evaluation of pulmonary lesions: a comparative risk- benefit analysis. Chest 1995; 108: 441-446. Gambhir SS, Hoh CK, Phelps ME, et al. Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 1996; 37: 1428-1436. Lewis P, Griffin S, Marsden P, et al. Whole body 18F-fluorodeoxyglucose positron emission tomography in preoperative evaluation of lung cancer. Lancet 1994; 344: 1265-1266. Karp JS, Muehllehner G, Mankoff DA, et al. Continuous-slice PENN-PET: a positron tomograph with volume imaging capability. J Nucl Med 1990; 31: 617-627. (Received 1 Jul, accepted 5 Oct, 1999) Authors' details The Peter MacCallum Cancer Institute, Melbourne, VIC. Rodney J Hicks, MD, FRACP, Director of Diagnostic Imaging. David S Binns, DipAppSci, ANMT, Chief Nuclear Medicine Technologist. Meagan E Fawcett, BAppSci, ANMT, Nuclear Medicine Technologist. Robert E Ware, MB BS, FCP(South Africa), Honorary Physician in Nuclear Medicine; currently, Director, Hobart Isotope Imaging, Hobart, TAS. Victor Kalff, MB BS, FRACP, Honorary Physician in Nuclear Medicine; currently, Deputy Director, Alfred Hospital, Melbourne, VIC. Allan F McKenzie, MB BS, FRACR, Director of Radiology. John R Zalcberg, PhD, FRACP, Professor, and Director of Medical Oncology. Lester J Peters, MD, FRACR, Professor, and Director of Radiation Oncology. Reprints: Dr R J Hicks, Director of Diagnostic Imaging, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, Melbourne, VIC 3000. rhicksATpetermac.unimelb.edu.au The primary referral diagnosis was that prospectively assigned at the time of the PET study. Oncological indications were grouped by system (eg, "lung cancer" primarily comprised patients with non-small-cell tumours, but also included small-cell lung cancer and solitary pulmonary nodule). All imaging performed on a given day was counted as a single study. Almost all oncology patients had screening of areas remote from the known or suspected site of the primary tumour. The referral indication was known or suspected cancer in 2390/2500 cases (95.6%); 1881 individual patients had scans, with 619 follow-up studies in 379 patients for therapeutic monitoring or restaging after treatment. More than a third of our referrals were from clinicians without formal affiliation with our institution, including referrals from all States and Territories. The main referral indications at our facility reflect those cancers which have been shown to be accurately evaluated by PET - including lung cancer,5-7 melanoma,8,9 head and neck cancer,10 colorectal cancer,9 lymphoma,9,11,12 and breast cancer.13-15Back to text Figure 2. Non-small-cell lung cancer was diagnosed at bronchoscopy. A computed tomography scan was equivocal for mediastinal disease. FDG PET scanning of the thorax and abdomen was performed to assess suitability for surgical resection. The primary tumour (large arrows) and mediastinal nodal metastasis (small arrows) are clearly identified in transaxial (upper panel), sagittal (middle panel) and coronal (lower panel) projections. The patient was offered chemoradiotherapy rather than surgery. Back to text Figure 3: After resection of a melanoma of the left cheek, a palpable lymph node was shown (by fine-needle aspiration biopsy) to be a metastasis. A high-dose gallium-67 scan (left panel), which included tomographic imaging, did not demonstrate significant abnormality, so radical neck dissection was considered. Whole body FDG PET scanning (right panel) demonstrated disseminated metastases (arrows). The patient was spared unnecessary neck dissection and offered systemic therapy. Back to text Figure 4. After resection of a Duke C rectal carcinoma, this patient had rising carcinoembryonic antigen (CEA) levels and an apparently solitary hepatic metastasis (found at laparotomy - large arrow in left panel). At operation, a small bowel obstruction was thought to be related to postsurgical adhesions. FDG PET, performed to evaluate the patient's suitability for subsequent hepatic resection (right panel), demonstrated previously unrecognised widespread metastases (small arrows) and the patient was spared further futile surgery. Chemotherapy was commenced. Back to text

Rodney J Hicks · David S Binns · Meagan E Fawcett · Robert E Ware · Victor Kalff · Allan F McKenzie · John P Zalcberg · Lester J Peters

Research Evaluation of the PAPNET system in a general pathology service Annabelle Farnsworth, Fay M Chambers and Colin S Goldschmidt MJA 1996; 165: 429-431 Abstract - Introduction - Methods - Results - Discussion - References - Disclaimer of conflict of interest - Authors' details - - More articles on Obstetrics & gynaecology and women's health Abstract Objective: To compare the results of an automated rescreening device (PAPNET) with manual screening of Papanicolaou (Pap) smears. Design: All normal or technically unsatisfactory smears and a random sample of abnormal smears on manual screening were submitted for PAPNET rescreening. Setting: Large general pathology laboratory in Sydney between January and September 1995. Results: Of 54 658 PAP smears classified on manual screening as normal, 266 were reclassified as abnormal after PAPNET screening (32 atypical squamous cells of uncertain significance, 217 low-grade squamous intraepithelial lesions and 17 high-grade intraepithelial lesions). Of the random sample of 1022 smears classified on manual screening as abnormal, all high-grade intraepithelial lesions (122 smears) and squamous cell carcinomas (2 smears) were also detected by PAPNET, and 112 were reclassified as normal by PAPNET (14 atypical squamous cells of uncertain significance and 98 low-grade squamous intraepithelial lesions). Histological follow-up confirmed 15 of the 17 smears classified as high-grade intraepithelial lesions on PAPNET screening and detected a further seven that had been classified by PAPNET as either atypical squamous cells of uncertain significance or low-grade squamous intraepithelial lesions. Conclusions: When used as a quality-control measure in a general pathology laboratory, the PAPNET automated screening system detects higher numbers of abnormal PAP smears than manual screening. Introduction Papanicolaou (Pap)-smear examination has been shown to lower mortality and morbidity from cervical cancer,1 but the screening test itself is imperfect. False negative results (when a smear is reported as normal but has been taken from a woman with a high-grade lesion in her cervix) have been reported to be between 10%-20%.2The failure of Pap smears to detect some high-grade abnormalities is the result of either sampling or laboratory error.2 Sampling error occurs when the person taking the smear fails to collect the abnormal cervical cells because of either poor technique or the small size or localised nature of the lesion.3 Laboratory error is usually caused by the screening cytologist failing to detect the abnormal cells on the slide. Screening of Pap smears is a labour-intensive task requiring a high degree of skill and concentration. Even in laboratories using well-recognised quality control measures and staffed by highly trained cytologists, many high-grade abnormalities remain undetected by routine manual screening. These may also be missed on a manual rescreen.3 PAPNET is an automated interactive system for analysis of Pap smears which has been shown to detect abnormalities that were repeatedly missed on manual screening.4,5 We introduced the PAPNET system into our laboratory in January 1995 as a quality-control measure for rescreening of all negative (normal) smears. Here, we compare the detection of abnormalities by PAPNET with those detected by manual screening in our laboratory, and report on the histological follow-up of the PAPNET cytopredictions and the work practices of cytologists using this system. Methods Our laboratory is a large general practice in Sydney with a referral base covering metropolitan and country areas of New South Wales. During the period of our survey (23 January to 30 September 1995), all Pap smears were screened manually using routine methods. Quality assurance measures used in the study (e.g., rescreening and follow-up of abnormal smears) were routine procedures used in our laboratory. All smears considered "normal" (negative) and "technically unsatisfactory" on routine manual screening, together with a random sample of smears considered "abnormal" on routine screening during the same period, were submitted for PAPNET analysis. Smears were considered technically unsatisfactory when a confident report could not be given because of scanty material, or obscuring of cellular detail by blood, inflammation, cellular degeneration or air drying. The abnormal smears were randomly selected from the recent file of atypical smears. The PAPNET rescreening was undertaken blind to the results of manual screening. (See Box 1 for a description of the PAPNET technology.) Interim reports were generated for smears considered normal and technically unsatisfactory, and, after the slide review was completed in the laboratory, a final report was issued incorporating the PAPNET findings. Reporting terminology was based on the Bethesda system of reporting cervical/vaginal cytological diagnoses.6 A record was kept of the number of cases each cytologist was able to review per day with PAPNET. The number of slides that required manual rechecking and complete rescreening was also recorded. This involved the cytologists using the light microscope to recheck individual abnormal cells that were tagged on the PAPNET monitor. If these cells were considered to be significantly atypical, the whole slide was rescreened. If any degree of abnormality was found after rescreening, the slide was submitted to the cytopathologist for checking. To test the specificity of PAPNET, histological follow-up was performed for all patients who had an additional lesion predicted by PAPNET and were recommended to have colposcopy for this lesion. As follow-up of cytological predictions can take many months, the process was expedited and, where possible, histology results are given. In some cases, follow-up was still pending or the referring doctor had decided to follow-up by repeated observation and Pap smears. These are designated as "follow-up to come". In some cases, follow-up was unavailable; the referring doctor had been unable to contact the patient, the patient had moved or had decided to proceed no further with management. These cases are designated as "lost to follow-up". Results During the 10-month period of this survey, 60 317 Pap smears were submitted to the laboratory for examination. These smears are categorised in Box 2 (cytopredictions). The results fall within suggested National Cervical Screening Programme standards for reporting categories of technically satisfactory smears. PAPNET screening was performed on 54 658 smears classified on manual screening as negative (or within normal limits) and 1819 smears classified as technically unsatisfactory. Of the 3840 smears classified on manual screening as abnormal, 1022 smears (27%) were randomly selected and submitted for PAPNET screening: 807 low-grade squamous intraepithelial lesions, 122 high-grade squamous intraepithelial lesions, 91 atypical squamous cells of uncertain significance, and two cases of squamous cell carcinoma. Manual screening compared to PAPNET screening Of the smears classified as negative on manual screening, 266 were reclassified as abnormal after PAPNET rescreening, including 17 reported as high-grade squamous intraepithelial lesions (Box 3). This represents a 7% increase in abnormal smears after PAPNET rescreening. All of the 122 smears reported as high-grade squamous intraepithelial lesions and both squamous cell carcinomas detected on manual screening were also detected by PAPNET (Box 3). Fourteen (15%) of the 91 smears reported as atypical squamous cells of uncertain significance and 98 (12%) of the 807 reported as low-grade squamous intraepithelial lesions were reclassified as negative on PAPNET rescreening (Box 3). Histological follow-up of PAPNET cytopredictions Histology confirmed an abnormality in 28% of smears reported as atypical squamous cells of uncertain significance and 61% reported as low-grade squamous intraepithelial lesions (Box 4). Of the 17 smears reported as high-grade squamous intraepithelial lesions on PAPNET rescreening, 15 (88%) were confirmed on histology (Box 4). Three of the 32 cases reported as atypical squamous cells of uncertain significance and four of the 31 reported as low-grade squamous intraepithelial lesions (where colposcopy was recommended) were also shown to have a high-grade lesion on histological biopsy. In total, there were an extra 22 histologically confirmed high-grade lesions not detected on manual screening, of which 15 were detected by PAPNET. Cytologists' work practices In our laboratory, cytologists manually screened between 25 and 50 slides (mean, 42; standard deviation [SD], 6) per day. The large SD reflected the range of experience among the laboratory's cytologists, who alternate between gynaecological and non-gynaecological cytology. PAPNET rescreening was included in this rotation. After training, cytologists performing PAPNET rescreening were able to screen between 100 and 160 slides (mean, 126; SD, 15) per day. This included loading and unloading the tapes, viewing and assessing the images on the PAPNET screen, documentation and generating patient reports. The number of cases submitted for limited rechecking varied between 10%-90%, depending on the cytologist. The number requiring complete rescreening by a senior cytologist varied between 0 to 10 per cytologist per day and averaged five per day. The number of cases submitted to a cytopathologist by each cytologist averaged one per day. Discussion Pap smears remain the highest-volume pathology test that is not automated. Attempts have been made to automate this complex process for nearly 40 years, but it is only recently that advances in the development of automated systems have occurred which offer practical advantages in a laboratory. Although the detection rate of abnormalities on manual screening was well within normal standards in our study, PAPNET rescreening was able to detect an increased number of abnormal Pap smears. This increase was not associated with a loss of specificity, as often occurs with increased detection by manual screening.3 Many studies have shown the ability of PAPNET rescreening to detect a significant number of abnormal Pap smears when compared with manual screening, but these have been predominantly smaller studies using archived material.8,9 Our study was undertaken as part of the routine workflow in a laboratory processing a large number of smears and is the first Australian study to compare the two screening systems. The reported increase in detection of abnormalities in other studies has been as high as 16%,10 and the company which developed PAPNET (Neuromedical Systems Inc., New York, USA) claims increases of up to 30%. The increase in our study was much smaller (7%), with most detected abnormalities being low-grade lesions. However, we believe this increase was worthwhile given the reasonably high rate of detection on manual screening and the large volume of routine smears processed. Boon et al. reported the results of a large series of smears that were not double-screened, but had been either manually screened or PAPNET screened. Higher detection rates of abnormalities were found in the PAPNET group. Our study is the first report of a large series in which all negative smears were screened both manually and by PAPNET. Our study showed that the PAPNET system could be feasibly integrated into a routine working laboratory situation. It was a valuable educational and quality assurance tool. Cytologists found it easy to use and were able to review slides at three to four times their manual-screening rate. From our experience, cytologists did not become complacent in their manual screening, but rather became more cautious knowing that all the negative smears would be examined by a computerised device. The additional work for cytopathologists and senior cytologists was not great. PAPNET is only one of a number of automated cytology systems currently available as an additional test for routine Pap-smear screening. We did not undertake a comparison of other automated systems or their cost-effectiveness. Further studies on the cost-effectiveness of PAPNET testing and its efficacy for use in public health screening programs are needed. It may be that automated testing technology will replace current screening methods in the future. Disclaimer of conflict of interest This work was conducted independently. Neither Douglass Hanly Moir Pathology nor any of the individual authors has any financial or other association with the suppliers of the PAPNET service, Neuromedical Systems Inc. References Mitchell HS, Giles GG. Cancer diagnosis after a report of negative cervical cytology. Med J Aust 1996; 164: 270-273. Koss LG. The Papanicolaou test for cervical cancer detection. A triumph and a tragedy. JAMA 1989; 261: 737-743. Boscha MC, Rietveld-Scheffers PEM, Boon ME. Characteristics of false negative smears tested in the normal screening situation. Acta Cytol 1992; 36: 711-716. Koss LG, Hin E, Schreiber K, et al. Evaluation of the PAPNET cytologic screening system for quality control of cervical smears. Am J Clin Pathol 1994; 101: 220-229. Boon M, Kok CP. Neural network processing can provide means to catch errors that slip through human screening of Pap smears. Diagn Cytopathol 1993; 9: 411-416. The Bethesda system of reporting cervical/vaginal cytologic diagnoses: revised after the second National Cancer Institute Workshop, April 29-30, 1991. Acta Cytol 1993; 37: 115-124. Royal College of Pathologists of Australasia. Performance Standards for Australian Laboratories Reporting Cervical Cytology. Sydney: RCPA Quality Assurance Programs, 1995. Rosenthal DL, Acosta D, Peters RK. Computer-assisted re-screening of clinically important false negative cervical smears using the PAPNET testing system. Acta Cytol 1996; 40: 120-126. Sherman ME, Mango LJ, Kelly D, et al. PAPNET analysis of reportedly negative smears preceding the diagnosis of a high grade squamous intraepithelial lesion or carcinoma. Mod Pathol 1994; 7: 578-581. Elgert PA, Suhrland MJ, Re E, et al. Prospective quality control of cervical smears using the PAPNET system [abstract No. 5]. In: Abstracts of the Scientific Session of the 42nd Annual Scientific Meeting of the American Society of Cytology; 1994 Nov 1-6; Chicago. Acta Cytol 1994; 38: 793-805. Boon ME, Kok LP, Beck S. Histologic validation of neural network assisted cervical screening: comparison with the conventional procedure. Cell Vision 1995; 2: 23-27. (Received 10 Jan, accepted 14 Aug 1996) Authors' details Douglass Hanly Moir Pathology, 95 Epping Road, North Ryde, NSW. Annabelle Farnsworth, MB BS, FRCPA, Cytopathologist. Fay M Chambers, MB BS, FRCPA, Cytopathologist. Colin S Goldschmidt, MB BCh, FRCPA, Cytopathologist. Reprints: Dr A Farnsworth, Douglass Hanly Moir Pathology, 95 Epping Road, North Ryde 2113. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> We appreciate your comments. 1: The PAPNET system. PAPNET consists of a scanning apparatus and a review station.4 In Australia, the cervical slides are sent to Hong Kong for the initial scanning. The scanning apparatus includes an automated microscope with an attached video camera which transmits images to a primary classifier. Selected images are then passed into a neural net computing unit which chooses the 128 highest-ranking images for storage on an optical disk or digital tape, which is sent back to Australia for display at the review station. The review station is located in the cytology laboratory where manual screening takes place. The 128 recorded images are displayed in panels on a high-resolution colour monitor and are reviewed by a cytologist. If an abnormality is suspected, the original slide is manually checked and, if necessary, manually rescreened. Back to text 2: Categories of Pap smears on manual screening (23 January to 30 September 1995). CytopredictionNumber of smearsNegative*54 658 (90.6%)Low-grade squamous intraepithelial lesions 2974 (4.9%)High-grade squamous intraepithelial lesions 432 (0.7%)Atypical squamous cells of uncertain significance434 (0.7%)Technically unsatisfactory1819 (3%)Total60 317 (100%)* Cellular appearance was within normal limits. Back to text 3: PAPNET rescreening of PAP smears classified as normal and abnormal on manual screening. CytopredictionNormal smears: manual screeningPAPNET rescreeningAbnormal smears: manual screeningPAPNET rescreeningNegative*54 65854 359--112Atypical squamous cells of uncertain significance--329177Low-grade squamous intraepithelial lesions--217807709High-grade squamous intraepithelial lesions--17122122Squamous cell carcinoma--022Technically unsatisfactory18191852---- * Cellular appearance was within normal limits. The 112 negative smears on PAPNET screening had been classified on manual screening as atypical squamous cells of uncertain significance (14 smears) and low-grade squamous intraepithelial lesions (98 smears). Back to text 4: Histological follow-up of PAPNET cytopredictions. Histological follow-up PAPNET-detected abnormalitiesNegative/inflammation*Low-grade squamous intraepithelial lesionsHigh-grade squamous intraepithelial lesionsFollow-up to comeLost to follow-upTotalAtypical squamous cells of unknown significance66371032Low-grade squamous intraepithelial lesions21544631High-grade squamous intraepithelial lesions 01150117 *Cellular appearance was within normal limits. Back to text

Annabelle Farnsworth · Fay M Chambers · Colin S Goldschmidt

Position Statement New classification and criteria for diagnosis of diabetes mellitus Position Statement from the Australian Diabetes Society,* New Zealand Society for the Study of Diabetes, Royal College of Pathologists of Australasia and Australasian Association of Clinical Biochemists Peter G Colman,* David W Thomas, Paul Z Zimmet,* Timothy A Welborn, * Peter Garcia-Webb and M Peter Moore MJA 1999; 170: 375-378 Introduction - What are the new diagnostic criteria? - What about the oral glucose tolerance test? - Diabetes in pregnancy - How has the classification of diabetes changed? - Impaired glucose tolerance and impaired fasting glycaemia - References - Authors' details - - More articles on Endocrinology Introduction Recently, there has been major growth in knowledge about the aetiology and pathogenesis of different types of diabetes and about the predictive value of different blood glucose levels for development of complications. In response, both the American Diabetes Association (ADA) and the World Health Organization (WHO) have re-examined, redefined and updated the classification of and criteria for diabetes, which have been unchanged since 1985. While the two working parties had cross-representation, they met separately, and differences have emerged between their recommendations. The ADA published its final recommendations in 1997,1 while the WHO group published its provisional conclusions for consultation and comment in June 1998.2 The WHO process called for comments on the proposal by the end of September 1998, with the intention of finalising definitive classification and criteria by the end of December 1998 and of publishing these soon thereafter. However, WHO publications need to go through an internal approval process and it may be up to 12 months before the final WHO document appears. A combined working party of the Australian Diabetes Society, New Zealand Society for the Study of Diabetes, Royal College of Pathologists of Australasia and Australasian Association of Clinical Biochemists was formed to formulate an Australasian position on the two sets of recommendations and, in particular, on the differences between them. This is an interim statement pending the final WHO report, which will include recommendations on diabetes classification as well as criteria for diagnosis. We see it as very important to inform Australasian health professionals treating patients with diabetes about these changes. Position Statement key messages What are the new diagnostic criteria? The new WHO criteria for diagnosis of diabetes mellitus and hyperglycaemia are shown in Box 1. The major change from the previous WHO recommendation3 is the lowering of the diagnostic level of fasting plasma glucose to 7.0 mmol/L, from the former level of 7.8 mmol/L. For whole blood, the proposed new level is 6.1 mmol/L, from the former 6.7 mmol/L. This change is based primarily on cross-sectional studies demonstrating the presence of microvascular4 and macrovascular complications5 at these lower glucose concentrations. In addition, the 1985 WHO diagnostic criterion for diabetes based on fasting plasma glucose level ( 7.8 mmol/L) represents a greater degree of hyperglycaemia than the criterion based on plasma glucose level two hours after a 75 g glucose load ( 11.1 mmol/L).6 A fasting plasma glucose level of 7 mmol/L accords more closely with this 2 h post-glucose level. Recommendation: The ADA and the WHO committee are unanimous in adopting the changed diagnostic level, and the Australasian Working Party on Diagnostic Criteria recommends that healthcare providers in Australia and New Zealand should adopt it immediately. Clinicians should note that the diagnostic criteria differ between clinical and epidemiological settings. In clinical practice, when symptoms are typical of diabetes, a single fasting plasma glucose level of 7.0 mmol/L or 2 h post-glucose or casual postprandial plasma glucose level of 11.1 mmol/L suffices for diagnosis. If there are no symptoms, or symptoms are equivocal, at least one additional glucose measurement (preferably fasting) on a different day with a value in the diabetic range is necessary to confirm the diagnosis. Furthermore, severe hyperglycaemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not be regarded as diagnostic of diabetes. The situation should be reviewed when the primary condition has stabilised. In epidemiological settings, for study of high-prevalence populations or selective screening of high-risk individuals, a single measure -- the glucose-level 2 h post-glucose load -- will suffice to describe prevalence of impaired glucose tolerance (IGT). What about the oral glucose tolerance test? Previously, the oral glucose tolerance test (OGTT) was recommended in people with a fasting plasma glucose level of 5.5-7.7 mmol/L or random plasma glucose level of 7.8-11.0 mmol/L. After a 75 g glucose load, those with a 2 h plasma glucose level of < 7.8 mmol/L were classified as normoglycaemic, of 7.8-11.0 mmol/L as having IGT and of 11.1 mmol/L as having diabetes. The new diagnostic criteria proposed by the ADA and WHO differ in their recommendations on use of the OGTT. The ADA makes a strong recommendation that fasting plasma glucose level can be used on its own and that, in general, the OGTT need not be used.1 The WHO group2 argues strongly for the retention of the OGTT and suggests using fasting plasma glucose level alone only when circumstances prevent the performance of the OGTT. There are concerns that many people with a fasting plasma glucose level < 7.0 mmol/L will have manifestly abnormal results on the OGTT and are at risk of microvascular and macrovascular complications. This has major ramifications for the approach to diabetes screening, particularly when the Australian National Diabetes Strategy proposal,7 launched in June 1998 by Dr Michael Wooldridge, Federal Minister for Health and Aged Care, has early detection of type 2 diabetes as a key priority. Recommendation: The Australasian Working Party on Diagnostic Criteria has major concerns about discontinuing use of the OGTT and recommends that a formal recommendation on its use in diabetes screening be withheld until the final WHO recommendation is made. However, in the interim, the OGTT should continue to be used. Diabetes in pregnancy The ADA has retained its old criteria for diagnosis of gestational diabetes.1 These differ from those recommended by both WHO2 and the Australian Working Party on Diabetes in Pregnancy8 and are generally not recognised outside the United States. The new WHO statement retains the 1985 WHO recommendation that both IGT and diabetes should be classified as gestational diabetes. This is consistent with the recommendations of the Australasian Diabetes in Pregnancy Society, which recommended a diagnostic 2 h venous plasma glucose level on the OGTT of 8.0 mmol/L. In New Zealand, a cut-off level of 9.0 mmol/L has been applied.8 How has the classification of diabetes changed? The proposed new classification encompasses both clinical stages and aetiological types of hyperglycaemia and is supported by numerous epidemiological studies. The classification by aetiological type (Box 2) results from new knowledge of the causes of hyperglycaemia, including diabetes. The terms insulin-dependent and non-insulin-dependent diabetes (IDDM and NIDDM) are eliminated and the terms type 1 and type 2 diabetes retained. Other aetiological types, such as diabetes arising from genetic defects of -cell function or insulin action, are grouped as "other specific types", with gestational diabetes as a fourth category. The proposed staging (Box 3) reflects the fact that any aetiological type of diabetes can pass or progress through several clinical phases (both asymptomatic and symptomatic) during its natural history. Moreover, individuals may move in either direction between stages. Impaired glucose tolerance and impaired fasting glycaemia Impaired glucose tolerance (IGT), a discrete class in the previous classification, is now categorised as a stage in the natural history of disordered carbohydrate metabolism. Individuals with IGT are at increased risk of cardiovascular disease, and not all will be identified by fasting glucose level. In reducing the use of the OGTT, the ADA recommended a new category -- impaired fasting glycaemia (IFG) -- when fasting plasma glucose level is lower than that required to diagnose diabetes but higher than the reference range (< 7.0 mmol/L but 6.1 mmol/L). Limited data on this category show that it increases both risk of progressing to diabetes9 and cardiovascular risk.5 However, data are as yet insufficient to determine whether IFG has the same status as IGT as a risk factor for developing diabetes and cardiovascular disease and as strong an association with the metabolic syndrome (insulin resistance syndrome). IFG can be diagnosed by fasting glucose level alone, but if 2 h glucose level is also measured some individuals with IFG will have IGT and some may have diabetes. In addition, the number of people with OGTT results indicating diabetes but fasting plasma glucose level < 7.0 mmol/L is unknown, but early data suggest there may be major variation across different populations.10 A number of studies, including the DECODE initiative of the European Diabetes Epidemiology Group, have reported that individuals classified with IFG are not the same as the IGT group.11-15 The European Group believes that, on available European evidence, the ADA decision to rely solely on fasting glucose level would be unwise. Recommendation: The Australasian Working Party on Diagnostic Criteria recommends immediate adoption of the new classification. However, clinicians should be aware that some cases of diabetes will be missed unless an OGTT is performed. Thus, if there is any suspicion or other risk factor suggesting glucose intolerance, the working party continues to recommend use of an OGTT pending the final WHO recommendation. References Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183-1197. Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. World Health Organization. Diabetes mellitus. Report of a WHO study group. Technical report series 727. Geneva: WHO, 1985. McCance DR, Hanson RL, Charles MA, et al. Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes. BMJ 1994; 308: 1323-1328. Charles MA, Balkau B, Vauzelle-Kervoeden F, et al. Revision of diagnostic criteria for diabetes [letter]. Lancet 1996; 348: 1657-1658. Finch CF, Zimmet PZ, Alberti KGMM. Determining diabetes prevalence: a rational basis for the use of fasting plasma glucose concentrations? Diabet Med 1990; 7: 603-610. Colagiuri S, Colagiuri R, Ward J. National diabetes strategy and implementation plan. Canberra: Diabetes Australia, 1998. Hoffman L, Nolan C, Wilson D, et al. Gestational diabetes mellitus -- management guidelines. The Australasian Diabetes in Pregnancy Society. Med J Aust 1998; 169: 93-97. Charles MA, Fontbonne A, Thibult N, et al. Risk factors for NIDDM in white population. Diabetes 1991; 40: 796-799. Keen H. Impact of new criteria for diabetes on pattern of disease. Lancet 1998; 352: 1000-1001. DECODE Study Group on behalf of the European Diabetes Epidemiology Study Group. Will new diagnostic criteria for diabetes mellitus change phenotype of patients with diabetes? Reanalysis of European epidemiological data. BMJ 1998; 317: 371-375. De Vegt F, Dekker JM, Stehouwer CDA, et al. The 1997 American Diabetes Association criteria versus the 1985 World Health Organization criteria for the diagnosis of abnormal glucose tolerance. Diabetes Care 1998; 21: 1686-1690. Harris MI, Eastman RC, Cowie CC, et al. Comparison of diabetes diagnostic categories in the US population according to 1997 American Diabetes Association and 1980-1985 World Health Organization diagnostic criteria. Diabetes Care 1997; 20: 1859-1862. Unwin N, Alberti KGMM, Bhopal R, et al. Comparison of the current WHO and new ADA criteria for the diagnosis of diabetes mellitus in three ethnic groups in the UK. Diabet Med 1998; 15: 554-557. Chang C-J, Wu J-S, Lu F-H, Lee H-L, et al. Fasting plasma glucose in screening for diabetes in the Taiwanese population. Diabetes Care 1998; 21: 1856-1860. Authors' details Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, VIC. Peter G Colman, FRACP, MD, Director. Chemical Pathology Services, Women's and Children's Hospital, Adelaide, SA. David W Thomas, FRACP, FRCPA, Head. International Diabetes Institute, Melbourne, VIC. Paul Z Zimmet, FRACP, MD, Director. Diabetes Centre, Sir Charles Gairdner Hospital, Perth, WA. Timothy A Welborn, FRACP, PhD, Head. St John of God Pathology, Perth, WA. Peter Garcia-Webb, MD, FRCPA, Chemical Pathologist. Diabetes Centre, Christchurch Hospital, Christchurch, NZ. M Peter Moore, FRACP, Clinical Director. Reprints will not be available from the authors. Correspondence: Dr P G Colman, Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, VIC 3050. Email: peter.colmanATnwhcn.org.au Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> Key messages Diagnosis of diabetes is not in doubt when there are classical symptoms of thirst and polyuria and a random venous plasma glucose level 11.1 mmol/L. The Australasian Working Party on Diagnostic Criteria for Diabetes Mellitus recommends: Immediate adoption of the new criterion for diagnosis of diabetes as proposed by the American Diabetes Association (ADA) and the World Health Organization (WHO) - fasting venous plasma glucose level 7.0 mmol/L; Immediate adoption of the new classification for diabetes mellitus proposed by the ADA and WHO, which comprises four aetiological types - type 1, type 2, other specific types, and gestational diabetes - with impaired glucose tolerance and impaired fasting glycaemia as stages in the natural history of disordered carbohydrate metabolism. Awareness that some cases of diabetes will be missed unless an oral glucose tolerance test (OGTT) is performed. If there is any suspicion or other risk factor suggesting glucose intolerance, the OGTT should continue to be used pending the final WHO recommendation. Back to text 1: Values for diagnosis of diabetes mellitus and other categories of hyperglycaemia2Glucose concentration (mmol/L [mg/dL]) Whole blood Venous Capillary Diabetes mellitusFasting 6.1 ( 110) 6.1 ( 110) or 2 h post-glucose load 10.0 ( 180) 11.1 ( 200) or bothImpaired glucose tolerance (IGT)Fasting (if measured)< 6.1 (< 110) < 6.1 (< 110) and 2 h post-glucose load 6.7 ( 120) 7.8 ( 140) and < 10.0 (< 180) and < 11.1 (< 200) Impaired fasting glycaemia (IFG)Fasting 5.6 ( 100) and 5.6 ( 100) and < 6.1 (< 110) < 6.1 (< 110) 2 h post-glucose load (if measured)< 6.7 (< 120) < 7.8 (< 140) Glucose concentration (mmol/L [mg/dL]) Plasma* Venous Capillary Diabetes mellitusFasting< 7.0 ( 126) 7.0 ( 126) or 2 h post-glucose load 11.1 ( 200) 12.2 ( 220) or bothImpaired glucose tolerance (IGT)Fasting (if measured)<7.0 (<126) < 7.0 (< 126) and 2 h post-glucose load 7.8 ( 140) 8.9 ( 160) and < 11.1 (< 200) and < 12.2 (< 220) Impaired fasting glycaemia (IFG)Fasting 6.1 ( 110) and 6.1 ( 110) and < 7.0 (< 126) < 7.0 (< 126) 2 h post-glucose load (if measured)< 7.8 (< 140) < 8.9 (< 160) For epidemiological or population screening purposes, the fasting or 2 h value after 75 g oral glucose may be used alone. For clinical purposes, the diagnosis of diabetes should always be confirmed by repeating the test on another day, unless there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms. Glucose concentrations should not be determined on serum unless red cells are immediately removed, otherwise glycolysis will result in an unpredictable underestimation of the true concentrations. It should be stressed that glucose preservatives do not totally prevent glycolysis. If whole blood is used, the sample should be kept at 0-4oC or centrifuged immediately, or assayed immediately. Table reproduced with permission from Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. Copyright John Wiley & Sons Limited. Back to text2: Aetiological classification of disorders of glycaemia* Type 1 (-cell destruction, usually leading to absolute insulin deficiency) Autoimmune Idiopathic Type 2 (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance) Other specific types Genetic defects of -cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug or chemical induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes Gestational diabetes * As additional subtypes are discovered, it is anticipated they will be reclassified within their own specific category. Includes the former categories of gestational impaired glucose tolerance and gestational diabetes. Table reproduced with permission from Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. Copyright John Wiley & Sons Limited. Back to textBack to text

Peter G Colman · David W Thomas · Paul Z Zimmet · Timothy A Welborn · Peter Garcia-Webb

Participatory, non-punitive involvement of healthcare practitioners is needed MJA 1999; 170: 8-9 Increasing use of pathology services is a worldwide phenomenon in countries with substantially different healthcare systems.1 In Australia, for almost a decade and a half the annual growth rates of Medicare-funded services have shown that the rates for pathology services have generally exceeded, and often been more than double, those of other medical services.2-4 In the financial year 1997-98, pathology, diagnostic imaging and general practitioner services grew by 4.28%, 3.86% and 0.59%, respectively, compared with the previous 12-month period. In the same period, the Medicare outlays (ie, "benefits") paid by the Health Insurance Commission for total medical services were $6.334 billion, of which 14.59% were for pathology services and 14.81% for diagnostic imaging services. Together with general practitioner services (37.39%), these account for two-thirds of Medicare outlays. By the turn of the century, the Medicare outlays for pathology and diagnostic imaging services will each exceed $1.0 billion per year. Pathology services in the public health sector, or for workers compensation and traffic accident insurance, are largely funded at State level by arrangements distinct from Medicare. The extent of pathology services and outlays in these sectors is largely unknown, but service growth rates at hospital level are not uncommonly of the order of 1%-3% per year. At the National Pathology Forum (Canberra, 1995) the annual public health sector pathology expenditure was estimated to be $450 million to $600 million. What is the explanation for the growth of pathology services? There is no consensus, but many real, speculative, anecdotal and even light-hearted reasons are given:2,5 among these are diagnosis, monitoring, screening and prognosis; availability and accuracy of prior result; pressure from patients, relatives and peers; reassurance; medicolegal issues; profit; fraud; research; insecurity; and habit. Given this list, some services would clearly be unnecessary and wasteful in the clinical setting,2 but these reasons do not obviously explain the increasing use of pathology services in Australia2-4 and similar trends in other countries.1 Other suggestions for consideration include improved technology allowing larger throughput with shorter turnaround of services, cost-shifting from publicly funded to Medicare-funded services, and altered clinical practice, such as the increasing need in general practice to exclude organic disease when faced with non-specific symptoms. The nature of Medicare data does not allow for conclusive evaluation of these possibilities. Do we really know whether the growth in use of pathology services is appropriate or inappropriate? In a recent review of 44 published studies of laboratory test use,1 11 studies used implicit criteria that were not provided, were very broad, or had not been adequately assessed for their reliability as criteria. In the other studies, explicit criteria were based on the appropriateness of test choice, frequency, timing, and the probability of a positive result. Estimates of inappropriate laboratory test use ranged from 4.5% to 95%! The review authors concluded that the criteria used in these studies did not meet methodological standards suggested for audits of therapeutic interventions, and suggested that researchers should develop alternative evidentiary standards for measuring inappropriateness of pathology service use. They also concluded that, while the evidence supporting the explicit criteria was weak by methodological standards, it was strong according to principles of physiology, pharmacology, and probability. Perhaps the real issue is how to modify the use of pathology services rather than to seek a definitive explanation for the growth in services. The Commonwealth government has sought to reduce Medicare outlays for these services by restructuring the relevant sections of the Commonwealth Medical Benefits Schedule, by informing those requesting these services of their patterns of use, by licensing and reducing the number of pathology collection centres, and by limiting the number of pathology services allowed per episode (ie, per patient each day) that attract benefits. A three-year agreement to cap outlays within predetermined limits was reached between the Commonwealth government and pathology services in 1996. At State level, many hospitals are applying the principles of competitive neutrality (which aims to ensure that government businesses do not enjoy competitive advantage simply because of their public ownership) and even market testing6 to their own pathology departments in an attempt to reduce expenditure, if not use. Such measures are effectively cost-cutting activities, and are seen to be imposed by the funders, often without effective incentives for the users or providers to change.7 Passive information and educational material accompanying these activities is usually prepared by the funders, and may be seen by the users as of little relevance or of poor quality. Moreover, such measures may not prevent the development of further distortions in use of services (through, for example, inappropriate use of other clinical procedures or marketing of other pathology services). Are there ways, other than externally imposed cuts in outlays, to modify use of pathology services? In this issue of the Journal, Isouard reports on the impact of a total quality management approach on the appropriateness of pathology service use in acute myocardial infarction.8 His study used a team which included doctors, nurses and pathologists to determine unnecessary variation in ordering of tests. The outcome was an increase from 77.5% to 88.2% in the proportion of clinically indicated tests that were ordered, and an 81.7% reduction in the use of non-clinically indicated tests. This is associated with the potential to reduce expenditure. It would be all too easy to criticise Isouard's article as being overly enthusiastic about total quality management, as research based around modification of human behaviour, and for the difficulty in rigidly controlling such experiments. Further criticisms might include the need to verify such major improvements independently, and the observed reduction in compliance with the guidelines once the interventions ceased. However, the importance of Isouard's report is that it provides an alternative, non-punitive way to modify pathology service use. It focuses on the processes of ordering and using services, it uses the knowledge and expertise of all the healthcare practitioners involved in the processes, it has the potential to eliminate inefficient and redundant process steps, and it is more likely to provide incentives to healthcare practitioners to reduce variation and hence costs. It also allows for re-engineering the processes to maintain or enhance quality. Favourable outcomes have been reported for similar studies with total hip replacement,7 elective surgery,9 and addressing adverse drug events.10 In these difficult times of rapid change, healthcare practitioners face increasing pressures to reduce costs while providing high quality patient care. Reductions in funding and the use of the traditional scientific method, accoutred with reductionism and concepts developed in "wet" laboratory experiments, may prove inadequate as tools to deal with situations such as the growth in use of pathology services. Healthcare practitioners now need to include in their armamentarium quality improvement techniques,7,9 critical pathways analysis,7 process re-engineering,7,9 and other methods such as qualitative research.11 Robert A J Conyers Medical Director, Gribbles Pathology (Vic) Pty Ltd South Yarra, VIC Van Walraven C, Naylor CD. Do we know what inappropriate laboratory utilization is? A systematic review of laboratory clinical audits. JAMA 1998; 280: 550-558. Deeble J, Lewis-Hughes P. Directions for pathology. National Health Strategy Background Paper No 6. July 1991. Health Insurance Commission web site. <http://www.hic.gov.au>. Accessed 23 November 1998. Australian Medical Association Ltd. Medicare volume and expenditure report. Canberra: AMA Federal Council, August 1998. Lundberg GD. Perseveration of laboratory test ordering: a syndrome affecting clinicians. JAMA 1983; 249: 639. Knowles R. "Significant opportunities" for private sector in Victoria's public health services. Healthcover 1997; 7(5): 11-20. Evans J, Hwang Y, Nagarajan NJ. Cost reduction and process re-engineering in hospitals. J Cost Management 1997; May-June: 20-27. Isouard G. A quality management intervention to improve clinical laboratory use in acute myocardial infarction. Med J Aust 1999; 170: 11-14 Caplan GA, Brown A, Crowe PJ, et al. Re-engineering the elective surgical service of a tertiary hospital: a historical controlled trial. Med J Aust 1998; 169: 247-251. Jones BC. Every defect a treasure: learning from adverse events in hospitals. Med J Aust 1997; 166: 484-487. Peat JK, Toelle BG, Nagy SA. Qualitative research: a path to better healthcare. Med J Aust 1998; 169: 327-329.

MJA 1999; 170: 11-14 For editorial comment, see Conyers Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Author's details Abstract Objective: To assess the effect of a total quality management (TQM) approach on the appropriateness of clinical laboratory testing of patients with acute myocardial infarction. Design: Retrospective, control-group, quasi-experimental study. Setting: Two metropolitan teaching hospitals: one involved in the intervention (TQM experimental group); the other had no intervention (control group). Intervention: A multidisciplinary team involved in the development of improvement strategies, including laboratory testing guidelines, education programs, data collection, monitoring and feedback. Outcome measures: Total number of requested clinically indicated and non-clinically indicated tests. Results: The proportion of clinically indicated tests that were requested increased from 77.5% to 88.2% (P < 0.01) and the number of non-clinically indicated tests was reduced by 81.7% with the introduction of the TQM strategies (P < 0.01). Conclusions: The introduction of a TQM approach has improved the appropriateness of test ordering in acute myocardial infarction. The reduction in non-clinically indicated tests could produce substantial savings in hospital pathology costs, and the increase in clinically indicated tests provides better patient care. Introduction The determination of plasma creatine kinase (CK) and creatine kinase-MB fraction (CK-MB) is pivotal in the diagnosis of acute myocardial infarction (AMI).1 However, the inappropriate use of these and other laboratory tests has increased markedly during the past 10-15 years, contributing to escalating healthcare costs2 and undesirable clinical consequences because of false positive results in AMI, often leading to unnecessary further investigations.3A number of reports have indicated an excessive use of laboratory tests in patients admitted to hospital with AMI or other clinical disorders. One Australian study found that at one hospital up to 20% of all laboratory tests were unnecessary.4 Another found that there were three times as many clinical chemistry tests ordered as were appropriate for patients admitted with chest pain.5 Similarly, a recent study found inappropriate testing of calcium, phosphate and magnesium in the emergency department of a United States teaching hospital.6 The conventional approach to address inappropriate laboratory testing has been to target doctors through education,7 feedback8 and providing information on laboratory testing costs.9 Such measures have had limited success, and in most cases have had limited input from clinicians.10 I have examined the effect of a total quality management (TQM) approach (that was developed and introduced by clinicians and other healthcare professionals) on the appropriateness of clinical laboratory test use in the management of patients with AMI. Total quality management refers to the overall approach of managing the total aspects of an organisation's quality. In my study, this involves changing the way quality in test use is viewed, focusing on the customer and including everyone involved in its provision and use in the process of continuous improvement. The specific TQM model I used was the FOCUS-PDCA approach to quality improvement (Box 1).11 Methods Setting and patient groups The study was conducted from March 1993 to August 1995 at two teaching hospitals in Sydney. Patients at Bankstown-Lidcombe Hospital were designated the "experimental" group, and those at Nepean Hospital were the "control" group. Only the experimental group was subjected to the TQM intervention. At the time of the study, Bankstown-Lidcombe Hospital was a 454-bed hospital with 21 724 annual admissions from the Emergency Department and 2355 admissions to the Coronary Care Unit (CCU). Nepean Hospital was a 415-bed hospital with 20 485 annual admissions from the emergency department and 1891 admissions to the CCU. Within the study groups, two subgroups of AMI patients were identified: "suspected AMI" and "confirmed AMI". The suspected AMI group included all patients who were admitted to the CCU via the emergency department with chest pain and electrocardiographic (ECG) signs suggesting AMI: these were greater than 0.1 mV of ST-segment elevation in two or more limb leads or greater than 0.2 mV in two or more contiguous precordial leads, and the Minnesota code was used to classify Q-wave changes.12 Not all the cases of suspected AMI did in fact progress to AMI. Patients were included in the confirmed AMI group if they had a primary discharge diagnosis in accordance with the World Health Organization criteria.13 The diagnosis was confirmed if the patient had at least two of the following three findings: the presence of a typical history of characteristic chest pain, new ECG changes of pathological Q waves, and an elevation of serum CK to 390 U/L or above during the first 72 hours of admission. Improvement process A quasi-experimental design involving a pre-intervention and post-intervention phase with a concurrent control was used to test the effect of the TQM approach. The study was conducted in two 15-month stages. The first stage involved the collection of pre-intervention data. In the second stage the TQM intervention took place. Using the FOCUS-PDCA TQM model, a multidisciplinary team was empowered to make the necessary improvements, which were introduced during the intervention period as they were developed. The team included representatives from all clinical areas involved in the process of laboratory testing. These included the Emergency Department (Director of Emergency, Assistant Director of Nursing, Clinical Nurse Specialist and Senior Medical Officer), CCU (Director of Cardiology, Nurse Unit Manager, Clinical Nurse Specialist), Pathology Department (Director of Pathology, Senior Technologist), and Administration (Deputy Director of Medical Services). The hospital's Quality Assurance Officer was appointed the Quality Advisor for the TQM team. TQM team meetings were held weekly over the first two months of the 15-month intervention period, and then monthly. The TQM team established an overall review and improvement of the total systems and processes involved in test ordering. The team's mission statement was To ensure that the pathology services used are appropriate, effective and efficient for supporting clinical care in AMI. Practice guidelines were introduced for laboratory testing in the management of AMI. Clinicians in the team were actively encouraged to participate in the improvement process. Draft copies of the guidelines were circulated widely to other clinicians for comment. Suggestions for change were considered and incorporated into the guidelines as determined by the team. The guidelines provided details of all recommended laboratory tests during the 72-hour period following the admission of a patient with suspected AMI into hospital. Strategies were developed for education and training programs, feedback mechanisms and ongoing monitoring of performance through data collection and analysis. To implement the changes, the TQM team assigned responsibility to motivated individuals to accomplish specified tasks. Progress reports were provided at subsequent meetings. Medical staff requesting laboratory tests for suspected AMI patients were issued with pre-stamped pathology request forms that listed the recommended tests from the guidelines. Clinically indicated tests Requested laboratory tests were designated as "clinically indicated" if the ordered tests matched those listed in the AMI practice guidelines devised by the team, or if the tests were found to be justified when the patient's records were checked by one of the study's hospital medical officers. Conversely, "non-clinically indicated" tests were all requested tests found to be outside the recommendations of the AMI practice guidelines that could not be justified for inclusion when checked by one of the study's hospital medical officers. Data collection and statistical analysis Once the suspected AMI patients were transferred to the CCU of the experimental group hospital, an audit was undertaken of the laboratory tests requested and the time and date of each blood collection. The data were collected by me in collaboration with the Senior Technologist of the Pathology Department. The findings on the appropriateness of test use were reported to the Emergency Department and CCU staff, and at the team meetings. For each of the confirmed AMI groups, the number of clinically and non-clinically indicated tests were retrospectively determined. Group equivalency between the pre-TQM and post-TQM groups was determined using the t test. Only the results for the confirmed AMI groups are presented here. All data were coded, entered and analysed using SPSS for Windows.14 Ethical approval The study was approved by the Ethics Committees of both the South Western Sydney Area Health Service and the Nepean Health Service. Results The experimental and control groups did not differ in age, sex ratio or length of stay in hospital (Box 2). The proportion of clinically indicated tests that were requested for the experimental group increased from 77.5% before the TQM intervention to 88.2% in the intervention period (Box 3). For the control group, the proportion of clinically indicated tests that were requested did not change significantly (Box 4A). For the experimental group, the number of non-clinically indicated tests per admission was reduced by 81.7% in the intervention period (Box 4B), whereas for the control group this number did not change significantly. Overall, the total number of tests requested at the experimental hospital was approximately halved in the intervention period, whereas there was no change at the control hospital (Box 5). Discussion The introduction of TQM strategies achieved statistically highly significant improvements to the appropriateness of laboratory test ordering in AMI. The findings were sustained over the 15-month intervention period and were not replicated within the concurrently monitored control group hospital. The findings have a number of potentially important economic and patient care implications. Firstly, the 81.7% reduction of unnecessary tests may provide a substantial reduction in the overall cost of hospital inpatient pathology services if the TQM strategies were to be successfully introduced to more clinical situations. Such potential savings remain the challenge for future investigations. Secondly, there was an overall benefit to patient care through the increased use of clinically indicated laboratory tests. In addition, although not reported here, there was a statistically significant improvement to the clinically recommended timing of the blood collections for cardiac enzyme testing. I have not been able to find any study published in medical and health sciences journals during the past 15 years that has used TQM specifically to improve the appropriateness of clinical laboratory use in AMI. However, the FOCUS-PDCA model has had widespread and successful application within the healthcare system.15-16 As the model is process driven, it is likely to be adaptable to other test-ordering processes. My study supports the recent findings by Nardella et al of significant cost reductions and increased appropriateness of testing through the use of continuous quality improvement strategies.17 Although Nardella et al did not specifically use the FOCUS-PDCA model, they adopted a similar improvement approach. Methodologically, however, my study provided several strengths, with the inclusion of a pre-test and a concurrent control group to enable substantial control over threats to internal and external validity. The introduction of the TQM intervention was accompanied by additional staff time spent undertaking activities such as training, meetings, data collection and analysis. There was also medical, nursing and clerical staff time saved as a result of the accompanying improvements to the clerical systems used in test ordering. Although such costs and benefits were not quantified, I suspect that any savings made in staffing time were expended in establishing and maintaining the intervention. Following the 15-month intervention and the disbandment of the formal TQM team, the AMI laboratory testing guidelines remain in operation. However, recent discussions with key personnel from the original team reveal that the pre-stamped pathology request forms are no longer in use and that compliance with the testing guidelines has generally declined. These observations are consistent with those of other studies where improvements have failed to be sustained once improvement strategies had been completed.18-19 In view of the important economic and patient care implications, further investigations should be undertaken on the effects of the TQM approach in a variety of other clinical laboratory testing situations. Acknowledgements This research formed part of a major doctoral study undertaken by the author under the supervision of Professor Graeme Rawson, former Dean of the Faculty of Health, University of Western Sydney, Macarthur, NSW. Thanks also to Ms Margaret Gehrig, Quality Advisor to the study. I also acknowledge the contribution of the staff of the Bankstown-Lidcombe Hospital, particularly the Emergency Departments, Coronary Care Units, Pathology and Clinical Information Departments. Similarly, thanks also to the Clinical Information Department of the Nepean Hospital. References Hamm CW. New serum markers for acute myocardial infarction. N Engl J Med 1994; 331: 607-608. Deeble J, Lewis-Hughes P. Directions for pathology. Background Paper No. 6. Melbourne: National Health Strategy, 1991; 7. Gama R, Swain DG, Nightingale PG, et al. The effective use of cardiac enzymes and electrocardiograms in the diagnosis of acute myocardial infarction in the elderly. Postgrad Med J 1990; 66: 375-377. Grantham P, Weinstein S. Reducing pathology test misuse. Aust Health Rev 1993; 16: 16-23. Ratnaike D, Hunt D, Eilermann R, et al. The investigation of chest pain: audit and intervention. Med J Aust 1993; 159: 666-671. Rose WD, Martin JE, Abraham FM, et al. Calcium, magnesium and phosphorus: emergency department testing yield. Acad Emerg Med 1997; 4: 559-563. Hindmarsh JT, Lyon AW. Strategies to promote rational clinical chemistry test utilization. Clin Biochem 1996; 29: 291-299. Mugford M, Banfield P, O'Hanlon M. Effects of feedback of information on clinical practice: a review. BMJ 1991; 303: 398-402. Winkens RA, Ament AJ, Pop P, et al. Routine individual feedback on requests for diagnostic tests: an economic evaluation. Med Decis Making 1996; 16: 309-314. Goldman L. Changing physicians' behavior -- the pot and the kettle. N Engl J Med 1990; 322: 1524-1525. Hospital Corporation of America. Hospitalwide quality improvement process, strategy for improvement: FOCUS-PDCA. Nashville: Hospital Corporation of America, 1989. Rose GA, Blackburn H. In: Cardiovascular survey methods. WHO Monograph Series No. 56. Geneva: World Health Organization, 1968; 137-153. World Health Organization criteria for the diagnosis of acute myocardial infarction. Geneva: World Health Organization Cardiovascular Disease Unit, 1981. SPSS Inc. SPSS for Windows [computer program]. Version 6.0. Chicago Ill: SPSS Inc, 1992. Rhew E. Quality improvement project reviews: a tool to accelerate the transformation. Jt Comm J Qual Improv 1994; 20: 79-89. Schneider PD. FOCUS-PDCA ensures continuous quality improvement in the outpatient setting. Oncol Nurs Forum 1997; 24: 966-969. Nardella A, Farrell M, Pechet L, et al. Continuous improvement, quality control, and cost containment in clinical laboratory testing. Arch Pathol Lab Med 1994; 118: 965-968. Reeves CA, Bednar DA. What prevents TQM implementation in health care organisation? Qual Prog 1993; 26: 41-44. Chan YCL, Ho SJK. Continuous quality improvement -- a survey of American and Canadian healthcare executives. Hosp Health Serv Adm 1997; 42: 525-544. (Received 24 Oct 1997, accepted 3 Aug 1998) Author's details Division of Public Health, University of Western Sydney, Macarthur, NSW. Godfrey Isouard, BSc, PhD, Lecturer. Reprints will not be available from the author. Correspondence: Dr G Isouard, Division of Public Health, University of Western Sydney, Macarthur, PO Box 555, Campbelltown, NSW 2560. E-mail: g.isouardATuws.edu.au 1: The FOCUS-PDCA model Find a process to improve Organise a total quality management team select team members team building Clarify laboratory test-requesting process flow charts of test-requesting process identify problems customer requirements Uncover causes of poor quality test use causes of variation collect data Select process improvement determine proposed improvements prioritise Plan process improvement develop improvement strategies education and training development Do the improvement pilot test implement strategies collect and analyse data Check results check lessons learnt determine how effort could be improved Act to hold the gain standardise procedures establish monitoring and feedback processes plan continuous improvement 2: Comparison of characteristics of patients with confirmed acute myocardial infarction, before and during the total quality management intervention Experimental group Control group Pre-TQM intervention periodn=252n=203 Mean age in years (95% CI)60.3 (48.6-74.4)59.2 (47.5-71.8) Men:women (%)71.8:28.277.1:22.9 Median LOS in days (95% CI)8.8 (7.2-12.6)8.0 (6.8-11.4) TQM intervention periodn=253n=211 Mean age in years (95% CI)61.0 (49.1-77.3)59.6 (47.8-72.6) Men:women (%)74.7:25.370.8:29.2 Median LOS in days (95% CI)8.0 (6.3-11.4)7.3 (5.4-10.5) TQM=total quality management. CI=confidence interval. LOS=length of stay in hospital. 3: Changes in the use of clinically indicated tests for the experimental confirmed acute myocardial infarction group Pre-TQM intervention period TQM intervention periodPercentage point increase Number of testsNumber of testsin indicated tests Requested*Indicated†Ratio A‡Requested*Indicated†Ratio B§requested (B-A)P Sodium, potassium, chloride2193339464.6%2631318082.7%18.1<0.01 Urea00--00------ Creatinine17532953.2%28129495.6%42.4<0.01 Glucose31052958.6%37552271.8%13.2<0.01 Calcium, magnesium, phosphate758192.6%242885.7%-6.9<0.01 Cardiac enzyme profile§§1860201692.3%1962202496.9%4.70.18 Liver function tests#14715495.5%778491.7%-3.8<0.01 Cholesterol/triglyceride47950495.0%43850686.6%-8.5<0.01 Free thryoxine, thyrotropin304271.4%202676.9%5.5<0.01 Miscellaneous clinical chemical tests116116100.0%8686100.0%0-- All clinical chemical tests5385716575.2%5894675087.3%12.2<0.01 Automated blood count**1136130487.1%1028114889.6%2.40.20 Prothrombin index252252100.0%253253100.0%0-- Miscellaneous haematology tests2424100.0%4545100.0%0-- All haematology tests1412158089.4%1326144691.7%2.30.15 Urine microexamination1111100.0%1414100.0%0-- Miscellaneous microbiology tests1616100.0%2828100.0%0-- All microbiology tests2727100.0%4242100.0%0-- All tests6800877277.5%7262823888.2%10.6<0.01 TQM=total quality management. *Clinically indicated tests that were requested. †Total number of tests that were clinically indicated but not necessarily requested. ‡Pre-TQM tests requested/pre-TQM tests indicated. §TQM tests requested/TQM tests indicated. §§Creatine kinase and creatine kinase-MB. #Total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase, alkaline phosphatase, protein, albumin. **Haemoglobin, white cell count, red cell count, platelets. 4: Comparison of the changes in the use of clinically indicated tests (A) and non-clinically indicated tests (B) for the experimental and control confirmed AMI groups APre-TQM intervention period TQM intervention periodPercentage point increase Number of testsNumber of testsin indicated tests Requested*Indicated†Ratio A‡Requested*Indicated†Ratio B§requested (B-A)P Experimental group6800877277.5%7262823888.2%10.6<0.01 Control group7340893382.2%7399920080.4%-1.80.19 BPre-TQM intervention period TQM intervention periodReduction in Total number of tests requestedNumber of tests per admissionTotal number of tests requestedNumber of tests per admissionnon-clinically indicated tests per admissionP Experimental group966738.417767.081.7%<0.01 Control group489024.1484823.04.6%0.48 AMI=acute myocardial infarction. TQM=total quality management. *Clinically indicated tests that were requested. †Total number of tests that were clinically indicated but not necessarily requested. ‡Pre-TQM tests requested/pre-TQM tests indicated. §TQM tests requested/TQM tests indicated. 5: Total number of tests requested in the experimental and control confirmed acute myocardial infarction groups Pre-TQM intervention period TQM intervention period TotalIndicated*Not indicated†TotalIndicated*Not indicated† Experimental group1646768009667903872621776 Control group12230734048901224773994848 TQM=total quality management. *Number of clinically indicated tests requested. †Number of non-clinically indicated tests requested.

Godfrey Isouard

True Stories Acute appendicitis in childhood: did mother know best? A pathological analysis of 1409 cases A kernel of truth? Roger W Byard, Nicholas D Manton and Richard H Burnell MJA 1998; 169: 647-648 Introduction - Subjects and methods - Results - Discussion - References - Authors' details - - More articles on Pathology Introduction As children, all three of us were subjected to repeated injunctions by our respective mothers that under no circumstances should we swallow fruit pips or seeds. Underpinning the maternal reasoning was an unshakeable belief in the inevitable impaction of such ingested material in the appendix, resulting in inflammation, distress and eventual "surgical mutilation" (referred to by surgeons as "operative cure"). We analysed a series of acute appendicitis in children in an attempt to validate the maternal hypothesis and to dispel the memories of years of childhood terror. Subjects and methods The computerised database at the Department of Histopathology, Women's and Children's Hospital, Adelaide, South Australia, was searched for records of all cases of surgical removal of a vermiform appendix over the period 1972-1997. The cases had been coded using the SNOMED1 system and were searched for under the codes T-66000 (appendix), M-41000 (acute inflammation) and M-30400 (foreign body, NOS [not otherwise specified]). Results Among 2224 consecutive cases of surgically removed appendices there were 1409 cases in which there was sufficient evidence of acute inflammation to justify a diagnosis of acute appendicitis. In only one of these cases (1/1409; 0.07%) was a fruit seed discovered. This seed enteric entrapment disease state (SEEDS) involved a three-year-old girl who had presented in 1997 with a short history of right-sided lower-abdominal pain necessitating surgical intervention. Pathological examination of the excised appendix revealed a 10 mm round fruit seed in the distal portion of the appendix (Figure) associated with a transmural acute inflammatory infiltrate. Expert analysis of the seed revealed it to be consistent with a cherry pip (unidentified elderly white man representing Fresh Fruit and Vegetables Inc., Adelaide, SA, personal communication). While no subsequent immunohistochemical, electron microscopic or molecular biological evaluations of the foreign body were undertaken, we are in no doubt that, if they had been, the results would also have been consistent with the identification of a cherry pip. Discussion Although acute appendicitis is common, its aetiology remains "vague and indefinite".2 It was rarely recognised until the latter part of the 19th century, when an eminent text noted that it had become quite common in "highly civilized countries such as Great Britain", with lower occurrence rates in Denmark and Sweden.2 (Whether it occurred in the Antipodes at that time is not known, as for some reason rates for the colonies were not given.) A perforated appendix found in an Egyptian mummy, however, indicates that the disease has been around since ancient times.3Originally known as perityphlitis (Greek; peri, around + typhlos, blind + -itis, inflammation), the disease was described by John Hunter in a case at autopsy in 1769;4 the first use of "appendicitis" is credited to Fitz, who used the term at the inaugural meeting of the Association of American Physicians in 1886.4 The appendix is an unusual organ, and is apparently found only in humans, certain apes and the wombat.3 The similarity between humans and wombats certainly comes as no surprise to our group, as, using quite elaborate, expensive and time-consuming immunohistochemical techniques, we have previously been unable to distinguish between wombats and humans.5 However, we did note at the time that wombats tended to be hairier and smaller (R W B, unpublished observation). One of the earliest aetiological theories for acute appendicitis (to which our mothers still subscribe) is that a small foreign body, such as a seed, might lodge in the appendix, thus initiating an acute inflammatory reaction.6,7 This theory has not been universally accepted, with suggestions being made, as early as 1925, that most cases thought to be cherry stones, date seeds and grape seeds found within the appendix are not really seeds at all, but concentrically laminated faecoliths.8 Our study has clearly demonstrated, however, that impaction of fruit seeds within the appendix is a very real, although seemingly rare, possibility, with potentially dire consequences. The case of a boy who "died of his first berry" was reported as early as 1887 by Jacobi.9 Although it may be argued that the rate of SEEDS in our series was rather low, at 0.07%, the impact on the affected individual was obviously quite profound. In searching the literature we have uncovered reports of a host of other swallowed foreign bodies retrieved from appendices. One of the earliest documented cases of foreign body entrapment within the appendix involved perforation by a pin in a 12-year-old boy. The case was reported in 1736 by Claudius Amyand, sergeant-surgeon to George II, under the heading of "Some observations on wounds in the guts".10 As well as further reports of pins becoming lodged in the appendix (so-called "Halloween" appendicitis),11 there were also reports involving needles,9 balls of animal hair,12 snipe shot (birdshot)13 and bullets.14 Thus, it is clearly mandatory that pathologists insist that their registrars carefully scrutinise all faecoliths, diligently searching for such elusive treasures. Although our initial conclusion was that our mothers were entirely correct in espousing the belief that fruit seeds may be potentially lethal, a reviewer for the Journal disagreed and stated that our study demonstrated instead that our mothers were "incorrect in espousing the belief that fruit seeds or pips may cause appendicitis". As publication was at stake, we agreed to reverse our opinions while still using the same data. We would defend this apparent defection from the truth on pragmatic grounds, and also look to Cervantes for support in that "one swallow does not make a summer".14 The reader should be the final arbiter. References Cote RA, editor. Systematised nomenclature of medicine. 2nd ed. Skokie, Ill.: College of American Pathologists, 1979. Boyd W. Surgical pathology. 2nd ed. London: WB Saunders, 1925: 366. Williams RS. Appendicitis: historical milestones and current challenges. Med J Aust 1992; 157: 784-787. Bouchier IAD, Allan RN, Hodgson HJF, Keighley MRB. Textbook of gastroenterology. London: Bailliere Tindall, 1984: 733. Byard RW, Carli M, Moore A. An immunohistochemical study of the southern hairy-nosed wombat (Lasiorhinus latifrons). In: Wombats. Chipping Norton, Surrey: Beatty and Sons. In press. Taylor JM, Wells WH. Manual of the diseases of children. Philadelphia: P Blakiston's Son and Co, 1898: 234. Encyclopedia Americana. Montreal: Americana Corporation. 1955: 78. MacCallum WG. A text-book of pathology. 3rd ed. Philadelphia: WB Saunders, 1925: 237-238. Jacobi A. The intestinal diseases of infancy and childhood. Detroit: GS Davis, 1887: 234-235. Amyand C. Of an inguinal rupture, with a pin in the appendix caeci encrusted with stone: some observations on wounds in the guts. Philos Trans R Soc Lond 1736; 39: 329-336. Conforti FP, Smego DR, Kazarian KK. Halloween appendicitis: pin perforation of the appendix. Conn Med 1987; 51: 507. Miller GG, Fraser GC, Jevon G. "Pilonidal appendicitis" or "the hair of the dog": an unusual case of foreign body. J Pediatr Surg 1996; 31: 703. Osler W. The principles and practice of medicine. New York: D Appleton and Co, 1892: 406. Meyer J, Abuabara S, Barrett J, Lowe R. A bullet in the appendix. J Trauma 1982; 22: 424-425. Cervantes M. Don Quixote. Harmondsworth, Middlesex: Penguin, 1974: 100. (Received 6 Feb, accepted 27 Apr 1998) Picture at top: Opened appendix, demonstrating a typical case of seed enteric entrapment disease state (SEEDS) in a three-year-old girl. A cherry stone is firmly embedded in the distal portion of the acutely inflamed appendix. Authors' details Department of Histopathology, Women's and Children's Hospital, Adelaide, SA. Roger W Byard, MD, FRCPath, Associate Professor, Senior Consultant, Histopathologist Nicholas D Manton, MB BS, Histopathology Registrar Department of Paediatrics, University of Adelaide, SA. R H Burnell, MB BS, FRCP, Paediatrician Reprints will not be available from the authors. Correspondence: Associate Professor R W Byard, Department of Histopathology, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006. Email: rbyardATmad.adelaide.edu.au Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Roger W Byard · Nicholas D Manton · Richard H Burnell

Letter John Thomas sign: common distraction or useful pointer? MJA 1998; 169: 670 To the Editor: Anthropomorphic studies of the penis have largely centred on comparisons of length and girth and have not always grasped the substance of a more important companion feature, namely direction. The "John Thomas" (JT) sign refers to the position of the penis in relation to unilateral disease on routine x-ray, with a positive sign being implied when inclined to the side of the disorder (eg, a fractured hip). Although readily recognised, it has attracted little scholarly attention, being confined to darkroom banter or to impressing humourless medical students. While some degree of prudishness may have been responsible for curbing potential applications of the JT sign in the past, we believe that the position of the penis now needs to be set straight. We identified 65 consecutive male patients with a fractured right hip and 65 with a fractured left hip. The penile position was graded as positive (illustrated in the Figure), negative or equivocal (part of the glans below the symphysis). The penile bent was similarly defined in a further 65 patients in whom fracture was suspected but not identified. The JT sign was positive (ie, the penis inclined toward the fracture) in 70% of patients with hip fracture (91/130), negative in 11% (14/130) and equivocal in 19% (25/130). Consequently, the sensitivity (70%; 95% CI, 62%-78%) and specificity (67%; 95% CI, 60%-75%) for the JT sign are low. The genital disposition did not correlate with length of stay (r = 0.14). Demonstration of the JT sign before x-ray may be as useful as demonstrating leg shortening and external rotation -- synonymous but in no way diagnostic. And, if all patients with suspected hip fractures are routinely x-rayed, the prognostic significance of the pointer is minimised. Nonetheless, while the clinical utility of the JT sign may be limited, it appears to be real and reproducible. Thirty-one per cent of patients (20/65) presenting with a hip injury without fracture inclined to the injured side. If at least half of x-rays for hip fracture confirm the diagnosis, the predictive value of a positive JT sign is over 69%. Similar eponymous signs, such as Homan's, are widely flaunted. By comparison, the JT has been underexposed. Genital asymmetry is common and varies with handedness,1 although most incline leftward. That equal proportions of right (46/65) and left (45/65) hip fractures had positive signs in our study would reinforce the belief that somatic sensations can override higher cerebral control. Recent data suggest that genital inclination may be related to, among other things, different patterns of cognitive function and certain malignancies.2 The findings in our study, like those of the recent United States Starr Report,3 point to at least one more discriminating relationship. Merlin C Thomas Senior Registrar and corresponding author Brett D Lyons Associate Professor, Department of Nephrology Robert J Walker Senior Registrar, Department of Radiology Dunedin Department of Medicine, Dunedin Clinical School of Medicine University of Otago, Dunedin, New Zealand Bogaert AE. Genital asymmetry in men. Human Reprod 1997; 12: 68-72. Chang RH, Hsu FK, Chan ST, et al. Scrotal asymmetry and handedness. J Anat 1960; 94: 543-548. Starr KW. Referral to the United States House of Representatives pursuant to Title 28, United States Code, ¤595(c). Submitted by the Office of the Independent Counsel, September 9, 1998. [Monica Lewinsky v. President Clinton]. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Merlin C Thomas · Brett D Lyons · Robert J Walker

Snapshot! Carpenter's backache This gentleman presented to the emergency department for the second time in two months complaining of backache. The obvious foreign body was considered by the treating resident to be an "in the pocket" artifact and was thus discarded as an irrelevant finding. When I pointed out that it was actually a 10cm nail, located in the soft tissue above the right sacroiliac joint, the case was reviewed, but neither the patient nor his records could proffer any logical explanation (the patient's theory was that it must have been in his milk). As the patient had no signs or symptoms of sepsis or a pelvic abscess, it had probably been in that position for some time. The moral of the story? Sometimes it really is the x-ray findings that nail the case! Barnabus Bako Radiology Registrar The New Children's Hospital, Westmead, NSW Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Barnabus Bako

Snapshot! "Unto us is born a son..." So sings the carol; however, the long-held alternative view that children are brought by the stork may have some credence. Umbilical artery doppler from a third-trimester obstetric ultrasound shows a definite avian form perched next to the entwined vessels of the cord. Despite an eagle-eyed search of the amniotic cavity no other birds (nor any bees) were found. The stork's beak is empty, consistent with a developing intrauterine gestation. Indeed, not long afterwards the mother delivered a baby boy. David J E Lord Radiology Registrar Royal Prince Alfred Hospital, Sydney, NSW Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Snapshot! Got to cut those nails This patient attended the emergency department after a construction site accident in which a nail gun accidentally discharged into his left index finger. Could it be that there was some misunderstanding about the meaning of the word "nail" in nail-gun? Malcolm Thomson Consultant Paediatricians, Taranaki Base Hospital New Plymouth, New Zealand Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Malcolm Thomson

Automation in cervical cytology: whose cost and whose benefit? Our first priority should be to screen more women, and not to offer more screening to those who can pay MJA 1997; 167: 460-461 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - - ©MJA1997 Recently, women and doctors have been exposed to high pressure marketing about automated cervical cytology. Questions as to whether the patient is "getting the right Pap smear", and messages that doctors don't know what is being missed have created a climate of uncertainty and anxiety among both patients and practitioners. Population screening for cervical cancer by Pap smear has undoubtedly had a major impact on both morbidity and mortality from cervical cancer,1 a malignant disease which, on a worldwide basis, is the commonest cause of cancer death in women. The success of cervical screening has raised expectations for a perfect system and has also directed focus to its failures. Failures can occur at any point of the screening pathway: at recruitment, sampling, laboratory processing, notification, and in the management of women in whom abnormalities are detected.2 While systematic efforts have been made to improve each step of the pathway, the major failure remains the inability to persuade all women to undergo regular Pap smears: figures from the NSW Pap Test Register suggest that only 67% of women at risk of cervical cancer are screened in accordance with the national policy of biennial Pap smears.3 The remainder are failing to take advantage of the well established health benefits of regular conventional Pap smear screening. The current marketing strategy runs the risk of reducing confidence in the existing system and of introducing apparent inequity into cervical screening Attempts to reduce laboratory error in the processing of Pap smears have encouraged the automation of cytology, with developments on three fronts. Firstly, the use of liquid-based smear preparation which prepares a monolayer of cells on a slide in the laboratory; secondly, the use of microscope tracking to ensure that the cytotechnologist examines all areas of a slide; and thirdly, computer-assisted image analysis to rescreen conventionally prepared smears. All procedures ultimately rely on conventional cytopathology review and "they still do not detect all abnormal cases".4 Some of these techniques have been heavily marketed, both directly to women and to general practitioners, and none currently carry a Medicare rebate. The role of automated cervical cytology in Australia is currently being evaluated by an Australian Health Technology Advisory Committee Working Party and its report is expected shortly. This Journal has previously reported the experience of one Australian laboratory with a computerised rescreening technique, PapNet,5 and, in this issue Roberts and colleagues report the findings of another large laboratory on the use of a liquid-based technology, ThinPrep, as an adjunct to the conventional Pap smear.6 Both papers suggest a slight improvement in detection of abnormalities. The medical community must remain cautious in assessing the true place of such technology. These techniques have been marketed as offering improvements in laboratory quality assurance and thereby reducing false negatives. Additional claims for the liquid-based techniques (which prepare better slides) are that sampling is improved and the number of unsatisfactory samples reduced. They also theoretically open the way for additional tests such as typing for certain strains of human papilloma virus (HPV). As with all of the automated strategies, the impact on clinical outcomes of HPV testing still remains conjectural. The performance of automated techniques in quality assurance should be assessed against other methods of quality assurance, such as random rescreening of a mandated proportion of smears, directed rescreening of "high-risk" groups and "rapid rescreening". Mathematical models show that manual methods of rescreening provide superior cost-benefit ratios when compared with automated approaches.7 This conclusion was also reached by the Canadian Coordinating Office for Health Technology Assessment in its assessment of automated cytology,8 and is supported in a letter in this issue of the Journal by Gurley et al.9 Pathologists should be encouraged to establish the best and most cost-effective method of quality assurance and not simply pass on the cost of the most expensive method of quality assurance to consumers. The scientific assessment of these procedures has been clouded by opinions about potential medicolegal consequences for failure to recommend the use of such tests.10 Such suggestions fail to recognise that proof of medical negligence must involve a deviation from the standard of care, which is ultimately decided by the courts, but depends on the ordinary care and skill of a particular category of practitioner. Australian medical negligence cases involving cervical cancer have focused on the failure of doctors to take steps to either diagnose or exclude a diagnosis of cervical cancer in the presence of a range of symptoms. While the relative costs and benefits of automated cytology remain a subject of considerable debate, and without government endorsement of these techniques, it seems highly unlikely that a court would expect a doctor to recommend such additional tests in an asymptomatic patient. The size of the problem needs to be kept in perspective. From Victorian Cytology Register figures correlating screening histories on women who die from cervical cancer, it has been estimated that at most, eight Victorian women dying from cervical cancer each year could identify laboratory error as a factor.11 Adding $20 for ThinPrep and $30 for PapNet to each of the 600 000 smears done in Victoria each year would add $30 million to the laboratory costs of cervical screening.11 Nationally this figure would amount to approximately $70 million, and the health care community must ask whether this is the best use of available resources. With some innovative consideration of alternatives, this money could be applied to other areas with likely better outcomes. For example, one alternative may be to pay GPs a Medicare rebate for taking a Pap smear on a previously unscreened older woman. Offering a $20 rebate for every 50-70-year-old unscreened woman in Australia would cost around five million dollars per annum, and could be expected to prevent a substantial number of cervical cancers in this group most "at risk". The case for a massive investment of public funds into these technologies appears small, and Australian taxpayers should not be expected to bear the full cost of their development when other health systems have failed to endorse them. While providing advice and information to patients is part of the standard of care, health practitioners are not agents for commercial enterprises. The right of individual women to spend their own money on items of their choice is to be respected, but their choice should be free and informed. The health gain from such a purchase needs to be clear to women and represented accurately: the available information on this technology suggests that the incremental benefit of automated cytology over conventional cytology is really quite small, and is unlikely to be substantially better than having a repeat Pap smear two years later.12 The current marketing strategy runs the risk of reducing confidence in the existing system and of introducing apparent inequity into cervical screening -- a particular problem when screening rates are lowest and cervical cancer incidence is highest in women of low socioeconomic status.13 Finally, in the current medicolegal environment, suggesting that there may be legal implications for doctors who do not recommend these automated tests to their patients is unwelcome and unusually coercive. Gerard V Wain Director, NSW Cervical Screening Program, Westmead Hospital, NSW Mitchell HS, Giles GG. Cancer diagnosis after a report of negative cervical cytology. Med J Aust 1996; 164: 270-273. Koss L. The Papanicolou test for cervical cancer detection: a triumph and a tragedy. JAMA 1989; 251: 737-743. Cervical Screening in NSW: situation analysis, February 1997. Sydney: NSW Cervical Screening Program, 1997. Statement on technical devices for innovation in cervical cytology screening [editorial]. Am J Clin Pathol 1996; 106: 441. Farnsworth A, Chambers FM, Goldschmidt CS. Evaluation of the PAPNET system in a general pathology service. Med J Aust 1996; 165: 429-431. Roberts JM, Gurley AM, Thurloe JK, et al. Evaluation of the ThinPrep Pap test as an adjunct to the conventional Pap smear. Med J Aust 1997; 167: 466-469. Hutchinson M. Assessing the costs and benefits of alternative rescreening strategies. Acta Cytologica 1996; 40: 4-7. Assessment of techniques for cervical cancer screening. Ottawa: Canadian Coordinating Office for Health Technology Assessment, 1997. Gurley AM, Roberts JM, Thurloe JK, et al. Increasing the accuracy of the Pap test [letter]. Med J Aust 1997; 167: 507. Saunders C. Pap smear wizardry: new technologies raise difficult questions. Aust Doctor 1997; 27 June: 28-32. Check W. Too early to solve Pap device puzzle. CAP Today June 1997;11: 6. Mitchell H, Medley G. Detection of laboratory false negative smears by the PapNet cytological screening system. Acta Cytologica 1997. In press. Smith D, Taylor R, Coates M. Socioeconomic differentials in cancer incidence and mortality in urban New South Wales, 1987-1991. Aust N Z J Public Health 1996; 20: 129-137. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.