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PubMed1999

1998 Runme Shaw Memorial Lecture: somatic evolution of cancer.

The interpretation of cancer as a somatic evolutionary process involving genetic mutation followed by selection, traces its origins to the early years this century. The dramatic developments in molecular genetics have substantiated these early ideas. Through the application of positional cloning and genomic analysis, many mutations in particular genes, both dominant oncogenes and tumour suppressor genes have now been found in a wide variety of tumours. Other genetic events such as non-disjunction leading to haploid expression of a gene and so reduced gene dosage, or epigenetic changes following, for example, changes in methylation patterns leading to reduced or increased gene expression, may also play critical roles in the progression of a cancer. The analysis of mutations at different stages of colorectal cancer provides a good model for following the initiation and progression of a cancer. Mutations in the APC gene, which explain familial adenomatous polyposis, occur in a high proportion of sporadic colorectal carcinomas and appear to be the earliest known changes. Patterns of mutation in the gene suggest dominant negative or gain of function effects, and also reveal important low penetrance subpolymorphic missense mutations that nevertheless may have a very significant impact on the genetic contribution to colorectal cancer susceptibility. Mutations are also found in related genes in the APC pathway, such as beta-catenin and E-cadherin. Mutations in mismatch repair genes (hMLH1 and hMSH2) have also been shown to occur, as well as reduced expression due to methylation changes, in 10% to 20% of sporadic colorectal carcinomas. In addition, mutations in the well known oncogenes p53 and ras are commonly found. The growth of a cancer is a balance between the rate of cell division and the rate of cell death or apoptosis. Thus, genetic changes which reduce the probability of apoptosis, such as p53 and probably hMLH1, are as important a feature of the evolution of a cancer as those which enhance the independence (APC) and rate of cell division (growth factors). Simple models for the evolution of a cancer that take into account these two processes, show that cancers evolve initially by a series of finite increases in cell population size, following which there may be long periods of cell turnover during which there is an opportunity for further mutation and selection. This explains the long lag periods between the initiation and subsequent progression of most cancers. Our rapidly developing understanding of cancers at the fundamental genetic level provides new opportunities for developing targeted treatments, as well as novel approaches to prevention and early detection.

Adenomatous Polyposis Coli↗
PubMed1999

1998 Distinguished Academician Lecture: hepatic resection--a Western perspective.

During the past two decades, resection of the liver has progressed from a rarely to a commonly performed operation with a low morbidity and mortality. The description of the functional anatomy of the liver was instrumental in the change from non-anatomic to anatomic resections. Major hepatectomies dominated the early experience but segment orientated resections now play a more prominent role. Resections may be performed for a variety of malignant or benign lesions or as an emergency for trauma or other catastrophic event. In the author's institution, 923 liver resections have been performed. The indications for the 825 elective resections were: metastases (46%), primary malignancy (30%) and non-malignant disease (24%). Two-thirds of the 98 emergency hepatectomies were for severe liver trauma. The 30-day mortality was 3.6% for the total series; 2.9% for elective resection, 1.6% for the non-jaundiced patients. In the last 300 elective resections, there has been one postoperative death and the median blood transfusion was zero. The development of innovative graft reduction techniques has made a major contribution to liver transplantation. The lack of suitable whole liver grafts for paediatric recipients was addressed by volume of reduction of adult donor livers so that the left lateral segment could be implanted safely in an infant's abdomen. This technique was the forerunner of split-liver transplantation, auxiliary partial orthotopic transplantation and living-related liver transplantation.

Adult↗
PubMed1999

9th Chapter of Surgeons' Lecture: the orthopaedic surgeon: historical perspective, ethical considerations and the future.

From a fishing village with colonial surgeons from the East India Company, Singapore is now a medical and business hub servicing the region and beyond in trade and medical education. Orthopaedic Surgery is a young specialty and is the fastest growing sub-specialty in Surgery. Orthopaedic education in Singapore has a structured syllabus and training is coordinated with the Royal Colleges and the American Academy of Orthopaedic Surgeons. Part of the training as Fellows is in the United Kingdom and USA on an HMDP Fellowship. Ethics and Continuing Medical Education need further emphasis. Sub-specialisation in Orthopaedic Surgery is now well-established in Trauma, Adult Reconstructive Surgery, Sports Medicine, Spinal Surgery, Hand Surgery and Rehabilitation Medicine. Ageing in the next millennium with osteoporosis and hip fracture problems of gait and balance need more orthopaedic surgeons to be committed to rehabilitation medicine and voluntary service in the community. There is a need for good role models and knowledge on Quality Assurance, Clinical Pathways and Administration. Appropriate use of high technology and care for the aged in the community with dignity is fundamental to good ethical practice. Selfish, pecuniary interests will destroy the very soul and fabric of medicine.

Curriculum↗
PubMed1999

8th Seah Cheng Siang Memorial Lecture: new antithrombotic agents.

For the long-term prevention of thromboembolic events in patients with atherosclerotic vascular disease, aspirin is the preferred antiplatelet drug. Only clopidogrel was shown to be more effective and at least as safe than medium-dose aspirin in direct comparative large-scale trials. Aspirin inhibits the cyclooxygenase dependent pathway of platelet aggregation while ticlopidine and clopidogrel selectively bind to adenosine diphosphate (ADP) receptors on the platelet surface. Compounds which inhibit the synthesis of thromboxane synthase, block the thromboxane receptor or have the dual activity were effective in experimental thrombosis models in animals but not predictive of results in humans. Activation of the platelet glycoprotein (GPIIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GPIIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic as well as non-peptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as two weeks whereas synthetic GPIIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion but have the advantage of being also orally active. In the secondary prevention of atherothrombosis, large scale trials were successfully conducted with aspirin, dipyridamole and clopidogrel. In the first large-scale trials with GPIIb/IIIa inhibitors with abciximab was investigated. In aggregate, this class of platelet inhibitors, combined with aspirin and heparin, was shown to reduce ischaemic events in patients with high- and low-risk coronary intervention, stents, unstable angina and non-Q-wave infarction with long-term preservation of the initial benefit. With synthetic GPIIb/IIIa inhibitors there is no suppression of clinical evident restenosis 6 months after the end of treatment. With the doses presently used, bleeding occurs more often with the synthetic GPIIb/IIIa inhibitors (used for 3 days) than with abciximab (used for 12 hours) but there are no direct comparisons between these drugs.

Arteriosclerosis↗
PubMed1999

Tuberculosis in the 21st century: DOTS and SPOTS. Plenary lecture given at the 29th World Conference of the International Union Against Tuberculosis and Lung Disease, Bangkok, Thailand, 23-26 November 1998. Directly observed therapy.

Surveys of the global burden of disease have established that formidable health problems loom as the new millennium approaches. In both industrialized and developing countries lung disease is particularly problematic. Tuberculosis provides a concrete example of the ability of existing interventions such as directly observed therapy (DOT) to save millions of lives in the immediate future and the potential for new knowledge and tools to eventually eliminate the disease. Molecular epidemiology shows the potential of new technology to supplement established approaches in answering questions central to public health. Our knowledge of the complete genomic sequence of Mycobacterium tuberculosis now has us poised on the brink of a new era. Emerging technologies such as microscopic arrays comprised of thousands of spots of DNA will provide knowledge that will fundamentally alter our approach to disease control. The synergy of a balanced portfolio incorporating a globalized public health commitment and creative basic research will provide us with the infrastructure and tools needed to eliminate tuberculosis before the close of the 21st century.

Communicable Disease Control↗
PubMed1999

The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture.

It has been appreciated for more than 50 years that very low levels of oxygenation, or hypoxia, both protect cells from killing by X-irradiation and are present in solid tumors but not in normal tissues. Until recently, however, there has been no definitive proof that hypoxia in human tumors contributes to radiotherapy treatment failure. We now know that hypoxia in solid tumors is not only a major problem for radiation therapy but also leads to resistance to most anticancer drugs and, importantly, appears to accelerate malignant progression and increase metastasis. To date, efforts to overcome the problem of hypoxia have had only limited success. However, the recent development of new drugs that are nontoxic until they are activated in the hypoxic cell opens a new era. The first of these new drugs to be tested clinically, tirapazamine, a drug that is highly toxic to hypoxic but not aerobic cells, has already demonstrated efficacy in selective potentiation of cisplatin in randomized Phase III trials with non-small cell lung cancer. The unique presence of hypoxic cells in human tumors provides an important target for selective cancer therapy.

Animals↗