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Section 8. Reducing the Incidence and Impact of Cancer Expert Comment: Professor William Denny (ONZM, PhD, DSc, FRSNZ), Director, Auckland Cancer Society Research Centre and Principal Investigator, Maurice Wilkins Centre for Molecular Biodiscovery “ Drug Development Globally, the R&D effort into new cancer therapies has never been higher. In 2007, oncology drugs became the biggest-selling category of drug within the WHO disease classification, and more than 500 new cancer drug trials are registered with the USFDA. Much research continues into improved “classical” cytotoxic drugs that disrupt DNA function. However, the major effort (both small molecules and antibodies) is now focused on “targeted” therapies aimed at up-regulated or mutant enzymes, primarily kinases in the signal transduction and gene surveillance networks, although additional targets do exist (e.g., DNA methylases and histone deacetylases). A third area of growing importance is tumour-selective prodrugs. This includes drugs that exploit physiological differences (e.g., hypoxia, pH and redox) between tumour and normal cells to become selectively activated in tumours. Another class exploits the ability of antibodies to accumulate on/in tumour cells by antigen binding (often followed by internalisation) to deliver/release attached toxins selectively. An area of growing research focus for all of these classes is noninvasive diagnostic methods to verify both the presence in tumours of the targeted enzyme (defining appropriate patients), and its blockade by the treatment (early evidence of efficacy). Research capacity/capability in NZ in these areas is remarkably good, with public-good/charity-supported basic research being complemented with commercial collaborations. Professor Denny co-authored 11 of the publications included in this section, in the area of drug development or oncogenesis. ” 112 Cancer Expert Comment: Dr Bridget Robinson, Medical Oncologist, Christchurch DHB and Associate Professor of Medicine, University of Otago, Christchurch “ Cancer Control Research into cancer control has addressed issues relevant to New Zealand. Disparities have been addressed to a much greater degree than before, with studies of the detection, presentation, characteristics (including genetics) and management of cancer in our variety of ethnic and socioeconomic settings. The specific attention paid to cancer in Māori and Pacific people is starting to yield results that have the potential to improve outcomes. Modelling projects will help plan future services. New studies focus on lifestyle factors including nutrition, obesity and physical activity. A number of internationally recognised research groups have contributed to the explosion of knowledge in the genetics and molecular biology of cancer. Some New Zealand researchers, such those working in the areas of stomach cancer and Wilm’s tumour, continue to lead the world in their fields of investigation. These fundamental studies will eventually lead to advances in management, whether by better diagnosis, prediction or a targeted therapy. Clinical trials remain very important in establishing best care, and now include translational molecular studies to stratify tumours and/or patients and predict outcome. Researchers have undertaken systematic Cochrane-type reviews to help guide cancer management by analysis of existing data and trials, whether or not they were published. The research has covered the full spectrum of cancer control, and has relevance for New Zealand and beyond. ” Dr Robinson co-authored four of the publications featured in this section, in the area of breast cancer or cancer disparities. Current Research Supported or Administered by the HRC District Health Board Research Fund (DHBRF) Improving Detection and Management Services in Primary Care for People with Cancer The Cancer Steering Committee for the DHBRF has developed a Request for Proposals (RFP) with the aim of improving the quality of primary care services for people with cancer. The research project should identify and describe ‘best practice’ solutions which can inform future development of service delivery Cancer 113 models for the detection of cancer (excluding formal screening) and those which are designed to provide effective and efficient subsequent management (including palliative care) for people in primary care. The research project should include recommendations for service delivery models, which can be practically and successfully implemented by any DHB in order to achieve the best outcomes. The Cancer Steering Committee is particularly interested in recommendations that identify barriers to best practice and recommendations leading to the implementation of service delivery models to improve health outcomes and reduce inequalities. Those service models demonstrating best practice should also have accompanying economic evaluations. The research will include an investigation of the interface between the primary, secondary and, tertiary health service providers, (including the interface with the NGO voluntary sector). This approach should demonstrate ways of improving population health including, primary and secondary clinical outcomes through examples of ‘best practice’ service delivery as well as providing opportunities for translational research. The RFP was released in July 2008. HRC Partnership Programme Initiatives Cancer Control RFPs The Ministry of Health and the HRC aim to support the New Zealand Cancer Control Strategy through the coordination of a Primary Prevention of Cancer and Other Chronic Diseases research programme that will provide the evidence base required to reduce the incidence of cancer. This research venture also presents an important opportunity to contribute to the Government’s priority area of reducing the burden of chronic disease as the risk factors and opportunities for primary prevention of cancer are the same as those for other chronic diseases such as cardiovascular disease and diabetes. For the first three years, research in this programme will be focused on two distinct research areas: tobacco control, and nutrition, physical activity and obesity. In June 2008, the second RFP in each of these areas was released. One RFP is focused on establishing ways to improve delivery of nutrition and physical activity interventions for Māori and Pacific peoples by the Healthy Eating Healthy Action (HEHA) workforce. The other RFP is focused on motivations to quit smoking and stay quit for Māori, Pacific and low-income New Zealanders. It is expected that research providers for these RFPs will be contracted in November 2008. Research providers have been confirmed for the initial RFPs that were released in February 2007, and details of the funded projects in each of the two research areas are listed below. Two research teams, led by Dr Cliona Ni Mhurchu and Mr Charles Waldegrave were contracted to complete work on complementary aspects of the nutrition, physical activity and obesity RFP. 114 Cancer Enhancing food security and physical activity for Māori, Pacific and low income whanau/families Principal investigator: Dr Cliona Ni Mhurchu Email address: [email protected] Host institution: Auckland UniServices Ltd Approved budget: $599,000 End date: 31/07/2009 HRC Ref: 08/002 Aims: (1) To clarify the interaction and contribution of environmental factors to food security and physical activity for Māori, Pacific and low-income whanau/families; (2) To identify how these factors might be modified to improve food security and physical activity. Methods: (1) A systematic literature review will be undertaken and will be supplemented by an analysis of relevant ongoing New Zealand research; (2) Focus groups will be conducted with urban and rural Māori, Pacific and low income New Zealanders (3) The ANGELO framework will be used to identify and prioritise key environmental factors; (4) Individual interviews will be conducted with 2,500 participants from the 2008 Adult National Nutrition Survey; (5) Key informant interviews will be conducted with representatives of Māori, Pacific and low income communities; (6) Findings from all sources will be triangulated to identify factors with most influence on food security and physical activity and how they could be targeted for intervention. Outcomes: This research will provide essential information on the association of key environmental factors with food security and physical activity amongst Māori, Pacific and low-income whanau/familites in New Zealand. Enhancing food security and physical activity for Māori, Pacific and low income whanau/families Principal investigator: Mr Charles Waldegrave Email address: [email protected] Host institution: The Family Centre Approved budget: $291,107 End date: 30/06/2009 HRC Ref: 08/572 This proposed research will complement a larger study of food security and physical activity for Māori, Pacific and low-income whanau/families. Together, the two studies will contribute to the Primary Prevention of Cancer and other Chronic Diseases Research Strategy. The research will involve a detailed qualitative study of the socioeconomic factors associated with food security and physical activity for Māori and Pacific people. The study will apply a theoretical framework using Bourdieu's concept of habitus and insights obtained from previous applications of Bourdieu's ideas to studying social aspects of food and the body. Cancer 115 The research will be informed by the three tikanga (Māori, Pacific and Pakeha/European) model of research and practice developed by the Family Centre Social Policy Research Unit and benefit from the Specialist Public and Māori Health research expertise of the Massey University Research Centre for Māori Health and Development, and the University of Otago Department of Human Nutrition. Developing strategies to reduce smoking uptake and SHS exposure of NZ children Principal investigator: Dr Richard Edwards Email address: [email protected] Host institution: University of Otago Approved budget: $599,000 End date: 31/01/2010 HRC Ref: 08/003 Phase one will involve a systematic review of local and international research, and targeted additional analyses of local datasets and original research which will be used in building explanatory models of the influences on smoking initiation and children's secondhand smoke (SHS) exposure in New Zealand. The models will focus on Māori communities and the role of parents/care-givers. We will carry out a preliminary investigation of how household smoking policies affect air quality and children's SHS exposure. In phase two, we will use the explanatory models to identify possible strategies to change parental/care-giver behaviours in Māori communities, while addressing likely barriers and constraints. We will then develop suggested community-based interventions. We will present these to members of potential target communities, implementation teams and other key stakeholders to assess their feasibility and appropriateness. The final intervention strategies will inform future public health practice to reduce smoking initiation and children's SHS exposure. Workplace Exposure to Carcinogens RFP In 2004, the HRC and the Department of Labour established the Occupational Health Research Strategy: a joint research initiative with both partners providing funding for strategic research projects. The Strategy aims to provide knowledge on current and emerging health issues in the workplace and help to build capability in the occupational health research area. In 2007, a RFP was released to purchase a research project that addresses workplace exposure to carcinogens. The following research provider has been confirmed: Workplace exposure to carcinogens in New Zealand Principal investigator: Dr Andrea t'Mannetje Email address: [email protected] Host institution: Massey University Approved budget: $399,531 End date: 31/10/2010 HRC Ref: 08/569 116 Cancer This project involves an assessment of exposure to workplace carcinogens in New Zealand, and the identification of strategies for the reduction of workplace exposures in key industries (including the agricultural and wood conversion sectors). It will involve: (i) a literature review of the occupational causes of cancer and the known solutions for reducing and/or preventing exposures; (ii) the development of a New Zealand specific Information System on Occupational Exposure to Carcinogens (NZ-CAREX); (iii) the development of a New Zealand specific Agricultural Chemicals Exposure Matrix (NZ-ACEM); (iv) a survey in key New Zealand industries, evaluating the work practices regarding occupational carcinogens currently in place, the knowledge and attitudes of employers, employees and health and safety personnel about workplace carcinogens and possible intervention strategies. This study will provide estimates of the number of workers exposed to carcinogens, and determine which interventions would result in marked reductions in occupational cancer. HRC International Investment Opportunities Fund (IIOF) IIOF Objective One RFP Inferring Genetic Pathways in Melanoma cells Principal investigator: Associate Professor Cristin Print Email address: [email protected] Host institution: The University of Auckland Approved budget: $567,000 End date: 31/12/2008 HRC Ref: 06/581 Melanoma is a devastating form of cancer which is especially common in New Zealand and which is incompletely understood. Gene network analysis produces circuit diagrams of the molecular signals that operate within cells. These diagrams will eb based on large amounts of experimental data collected from human melanoma calles after the disruption of over one hundred specific genes. The predictions made by this research teams’ gene networks will be rigourously tested in melanoma cells isolated from patients, and new mathematical methods for gene network construction will be developed. This work will be performed in close collaboration with the Japanese Drug Development company GNI ltd, further developing international collaborative links with the mushrooming Asian biotechnology industry. It will also develop an important emerging technology in New Zealand, which will provide a strong component of an overall strategy to improve melanoma treatment in this country. Phase II trial of selenomethionine with chemoradiation in head and neck cancer Principal investigator: Dr Michael Jameson Cancer Email address: Host institution: Approved budget: End date: HRC Ref: 117 [email protected] Waikato District Health Board $80,431 31/01/2010 08/028 We are collaborating with researchers in New York State who have shown in the laboratory that large doses of selenium (a trace mineral) can improve the side effects of chemotherapy and radiotherapy while helping them to work more effectively. We want to see if this works in people with head and neck cancers by giving 80 patients in NZ and the US either selenium or placebo capsules throughout their treatment. We will examine the impact of selenium on side effects as well as the response of their cancer. If the results are encouraging then we will develop much larger international trials to prove the effectiveness of selenium when used like this. Cancers of the head and neck require aggressive chemotherapy and radiotherapy, which causes severe side effects. If selenium can reduce these without reducing the effectiveness of treatment then this would be a major advance for these patients. Ongoing research funded through the HRC’s Round, awards and scholarships Annual Funding Physiological targeting in cancer therapy Principal investigator: Professor William Wilson Email address: [email protected] Host institution: The University of Auckland Approved budget: $3,270,316 End date: 30/06/2011 HRC Ref: 08/103 The dominant paradigm in anticancer drug discovery is to target specific genetic changes in cancer cells, but such agents are compromised by the enormous genetic variability within and between tumours. This programme takes a different approach by targeting higher-order (physiological) features of tumours such as hypoxia. It builds on our recent success in bringing a new hypoxia-activated prodrug, PR-104, to clinical trial, and will address gaps in knowledge to maximise its benefit in cancer treatment and to extend this approach. One project will determine whether the monotherapy activity of PR-104 is due to a bystander effect, a second will identify the activating enzymes, a third will combine it with clinical agents that enhance tumour hypoxia, and a fourth will target activation of prodrugs to tumours using an adenovirus that replicates in cells with retinoblastoma pathway defects. The programme represents a well-established multidisciplinary collaboration, but also incorporates emerging investigators. Therapeutics and diagnostic markers of cancer: From bench to clinic Principal investigator: Professor Michael Eccles Email address: [email protected] Host institution: University of Otago 118 Cancer Approved budget: End date: HRC Ref: $2,640,067 31/07/2009 07/284 The projects comprising this programme focus on issues directly relevant to the clinic. All projects are aimed at developing cancer diagnostics or therapeutics. They overlap in their biology and technology and all include the p53 tumour suppressor. Project A focuses on how the protein YB1 translocates to the nucleus, where it contributes to drug resistance and appears to be a determinant of cancer progression. Project B will identify the cancer phenotype that can be selectively killed by a specific adenoviral therapy. Project C investigates the effectiveness of silencing PAX genes as a means of killing cancer, as well as a novel gene therapy system. These will be tested for their ability to treat ovarian cancer and melanomas. Project D investigates the mechanism by which PAX gene expression promotes cell survival in normal and cancer cells. Genetics and Epigenetics of Cancer Principal investigator: Professor Anthony Reeve Email address: [email protected] Host institution: University of Otago Approved budget: $3,065,659 End date: 30/06/2009 HRC Ref: 03/265 This programme will integrate the core science of the investigators in the Cancer Genetics Laboratory. The first project (activated July 2002) headed by A. Reeve uses microarray technology to identify patterns of gene expression which will predict the aggressiveness/outcome of patients with colorectal cancer. The second project (activated July 2002) headed by P Guilford will expand our understanding of an inherited stomach cancer syndrome which is particularly prevalent in Māori. Triggers that may initiate the disease will be sought, and improved procedures for clinical management of the disease will be developed. The third project (funding sought this round) headed by I Morison seeks to identify very early genetic and epigenetics events during embryogenesis which predispose to childhood acute lymphoblastic leukemia. The fourth project (funding sought this round) headed by A. Reeve will investigate the hypothesis that epigenetic events programmed in utero determine ethnic variations in the incidence of Wilms tumour. Glycolipid adjuvants for anti-cancer immunotherapy Principal investigator: Dr Mattie Timmer Email address: [email protected] Host institution: Malaghan Institute of Medical Research Approved budget: $149,981 End date: 31/12/2010 HRC Ref: 08/427 Immunotherapy holds promise as a new treatment for cancer. It is based on the concept that a person's immune system can be stimulated to selectively recognize and eliminate malignant tumour cells. Cells that react to glycolipid molecules, called iNKT cells, have been shown to have significant regulatory influence over Cancer 119 the quality of immune responses, including anti-tumour immune responses. It is now clear that the structure of glycolipids recognised by iNKT cells can, in turn, influence the regulatory function of these cells. We propose that immunotherapy can be improved by selecting appropriate glycolipids to "fine tune" iNKT cell activity in vivo. We aim to synthesise a variety of novel glycolipids with the objective of promoting iNKT cell activities that favour immune responses to tumours. Stomach cancer in Māori Principal investigator: Dr Lis Ellison-Loschmann Email address: [email protected] Host institution: Massey University Approved budget: $951,382 End date: 30/06/2013 HRC Ref: 08/258 Stomach cancer has one of the largest ethnic inequalities of any cancer site in the New Zealand population with Māori rates being up to five times those of nonMāori in the late 1990s. Stomach cancer also shows a strong deprivation gradient for both incidence and mortality. Lifestyle factors, physiological factors, genetic factors and gene-environment interactions have all been identified as potential risk factors for the development of stomach cancer, but the relative contributions of these risk factors to stomach cancer in Māori are not well understood. We propose to conduct a case-control study of risk factors for stomach cancer in Māori, in order to identify the major risk factors and the priorities for interventions. Understanding the determinants of inequalities in breast cancer survival Principal investigator: Dr Lis Ellison-Loschmann Email address: [email protected] Host institution: Massey University Approved budget: $1,004,153 End date: 30/06/2011 HRC Ref: 08/251R We have demonstrated that Māori and Pacific people experience lower survival from breast cancer than non-Māori/non-Pacific people in New Zealand, as do people living in more deprived areas. There is no data on whether there are urban/rural differences in cancer survival. This study will investigate possible reasons for the inequalities in breast cancer survival, focussing on the role of access to primary care and pathways through care from diagnosis to treatment. We will recruit 2,100 women newly-diagnosed with breast cancer, identified through the Cancer Registry. Information on socio-demographic factors and facilitators/barriers to diagnostic and optimum cancer treatment services will be collected in a face-to-face interview. Over subsequent years, linkage with death records will be performed. We will conduct survival analyses to investigate which factors may explain the observed inequalities. This study will provide information to inform evidence-based practice recommendations to contribute to reducing inequalities in survival from breast cancer. 120 Cancer Wähine Hauora-Inequalities in uterine cancer: exploring the pre-diagnosis gap Principal investigator: Dr Beverley Lawton Email address: [email protected] Host institution: University of Otago Approved budget: $707,474 End date: 31/01/2011 HRC Ref: 08/216 Mäori women are more likely to get uterine (womb) cancer than non-Mäori, and are more likely to die from it. Uterine cancer can be treated if detected early enough or if caught in the pre-cancerous phase. Post-menopausal vaginal bleeding is the most common symptom of uterine cancer, and women with this symptom should be referred for specialist assessment urgently. Recent evidence suggests that Mäori women with gynaecological cancers gain access to specialist assessment later in the disease continuum than non-Mäori. This study aims to investigate the experience of Mäori women prior to reaching their first specialist assessment to find out what factors contribute to delays in access. The project will include the collection of quantitative and qualitative data that will help identify factors contributing to disparities in uterine cancer and inform strategies to reduce disability and death in the future. Phase 3 trial studying optimal radiotherapy timing after radical prostatectomy Principal investigator: Dr Maria Pearse Email address: [email protected] Host institution: Auckland District Health Board Approved budget: $1,169,103 End date: 30/09/2013 HRC Ref: 08/209R Radical prostatectomy is the most common curative approach offered to men with newly diagnosed prostate cancer. Unfortunately, up to half of these patients will have factors placing them at high risk of their cancer recurring. Having radiotherapy after an operation is known to improve cure rates, but what is not known is whether it should be given straight after the operation or only when there is a rising PSA after surgery indicating active cancer. Immediate RT may not benefit all men and can cause serious side effects such as bladder problems and impotence. International lack of consensus on the optimal timing of RT has resulted in varied clinical practice. This phase 3 trial will compare the two approaches. If RT at recurrence results in equivalent outcomes and improved quality of life, it would become the standard treatment. A total of 470 men from New Zealand and Australia will participate. Free Radical Studies and Disease Principal investigator: Associate Professor Robert Anderson Email address: [email protected] Host institution: The University of Auckland Approved budget: $1,405,446 End date: 30/06/2010 HRC Ref: 07/243 Cancer 121 Free radical reactions play important roles in the initiation and development of many disease states. Free radical reactions are extremely short-lived events, which require very fast techniques for their investigation in real time. The pulse radiolysis facility at the University of Auckland, developed with the help of HRC funding, is critical for several multi-disciplinary research projects being carried out in New Zealand. These include the development of new classes of anticancer drugs that act by a radical mechanism or are activated through one-electron processes. The technique is also being used to understand the mechanism of action of new TB drugs, prevention of damage by oxygen radicals and radiation, and to explore fundamental electron transport pathways in cells. The overall aim of this multi-faceted research application is to better understand the molecular mechanisms of such processes, and through this rationally contribute to improved treatments for a variety of different diseases. Colorectal cancer control in New Zealand Principal investigator: Professor Ann Richardson Email address: [email protected] Host institution: University of Otago Approved budget: $1,397,630 End date: 31/07/2010 HRC Ref: 07/124 Research objectives To provide essential information to reduce the impact of colorectal cancer (CRC) in NZ. Principal methodologies A computer model will be developed. This model, combined with epidemiological, clinical, economic and qualitative data, will estimate the future services and costs required for appropriate treatment and follow-up for people with CRC, surveillance for those at increased risk, and CRC screening in NZ. Potential health outcomes NZ health services cannot provide timely investigation and treatment for people with CRC, or provide surveillance for individuals at increased risk of CRC, let alone offer CRC screening. This research will provide information that is essential for health service planning. It will also produce a powerful research tool for NZ, because the approach can be adapted to other diseases to determine the requirements of new interventions. The approach is being applied to CRC in NZ initially, because information in this area is urgently needed. Dual activation of anticancer prodrugs by hypoxia and reductase-armed adenovirus Principal investigator: Professor William Denny Email address: [email protected] Host institution: The University of Auckland Approved budget: $1,150,070 End date: 30/06/2010 HRC Ref: 07/079C Cancer mortality rates are still high despite more than 50 years of drug discovery; innovative approaches are required to make significant impacts on patient survival. Virotherapy is a novel concept where viruses are engineered to infect 122 Cancer and spread in tumours, destroying cancer cells as they migrate. These viruses can also be 'armed' to express enzymes that make cancer cells sensitive to deactivated chemotherapy agents (prodrugs). We have developed an armed replicating adenovirus which can activate a prodrug (PR-104) that we have recently brought to clinical trial. We will test this combination in human tumour models to determine its antitumour potential and thus suitability for clinical evaluation. To assist the safe development of the virus/prodrug couple we will harness the prodrug activating enzyme to visualise the virus using non-invasive probes. This will allow clinicians to monitor the virus using whole-body scanning. We will also design 2nd generation prodrugs optimised for virotherapy. Pharmacokinetics and pharmacodynamics of the hypoxia-activated prodrug PR104 Principal investigator: Professor William Wilson Email address: [email protected] Host institution: The University of Auckland Approved budget: $1,157,615 End date: 30/06/2010 HRC Ref: 07/079A Tumours contain regions of hypoxia, which result from an inefficient blood supply. Hypoxic cells in tumours are a major problem because of their resistance to radiotherapy and chemotherapy, but at the same time represent a unique target that can potentially be exploited to activate prodrugs selectively in tumours. We have discovered such a compound (PR-104), with funding from a current HRC contract. PR-104 is currently in clinical trial in NZ and elsewhere as an anticancer agent. A surprising aspect of the drug in preclinical models is its efficacy against aerobic as well as hypoxic cells in tumours. The proposed study will test the hypothesis that this activity results from formation of active metabolites in hypoxic regions which then diffuse to (and kill) adjoining aerobic tumour cells (i.e. a "bystander effect"). The outcome of this research will impact directly on strategies for identifying patients most likely to benefit from PR-104. Fat and prostate cancer in the European Prospective Investigation into Cancer and Nutrition Principal investigator: Miss Francesca Crowe Email address: [email protected] Host institution: Oxford University (Girdlers Award) Approved budget: $180,000 End date: 31/01/2009 HRC Ref: 07/064 In many countries worldwide, the most common cancer in men is prostate cancer and therefore, identifying modifiable risk factors is an important element for reducing the population risk. There is evidence to suggest that dietary fat intake may have an important role in the aetiology of prostate cancer through the endogenous metabolism of hormones such as androgens and insulin-like growth factors. Therefore, the objective is to determine the association between dietary fat intake and the risk of prostate cancer in the entire cohort of men in the European Prospective Investigation into Cancer and Nutrition study. Furthermore, to determine in cross-sectional analyses, whether there are associations between fatty Cancer 123 acids, dietary fat and hormonal biomarkers of prostate cancer risk such as insulinlike growth factor and androgens in the controls from the nested-case control analysis of men in the Oxford cohort. Increasing the potency of dendritic cell based vaccines for treatment of cancer Principal investigator: Dr Ian Hermans Email address: [email protected] Host institution: Malaghan Institute of Medical Research Approved budget: $562,623 End date: 30/06/2009 HRC Ref: 06/316 Cancer patients are currently being treated with a trial vaccine that involves injecting specialised immune-stimulating cells called dendritic cells (DC) that have been "loaded" with tumour tissue in vitro. The injected DC have the unique ability to programme cells of the immune system to recognize and kill cancerous tissue. We propose to improve this vaccination strategy by first exposing the DC to a series of compounds that simulate microbial structures, thereby provoking the potent DC activity typically observed during infection. In addition, the DC will be loaded with a specific lipid to encourage interactions with lipid-reactive immune cells within the host that are also known to enhance DC activity. Antitumour activity will be assessed in a murine model of melanoma. These modifications should be applicable to current DC vaccination protocols in the clinic, potentially providing stronger anti-tumour responses in cancer patients. Cancer trends: Ethnic and socio-economic trends in cancer incidence and survival Principal investigator: Professor Tony Blakely Email address: [email protected] Host institution: University of Otago Approved budget: $924,356 End date: 31/01/2010 HRC Ref: 06/256 CANCERTRENDS will determine ethnic and socio-economic trends in cancer incidence and survival in NZ, and examine in depth research questions on colorectal, breast and testicular cancers and the contribution of active and passive smoking. CANCERTRENDS involves the linkage of census and cancer registration data from 1981-2004 to form cohort studies of the NZ population, with the additional linkage of mortality data to allow survival analyses. CANCERTRENDS will accurately determine trends from 1981-2004 in cancer incidence and survival by ethnicity and socio-economic position (income and education) for the first time in NZ. Such information is important, yet currently not available, for planning and prioritising within the Cancer Control Strategy. The inclusion of smoking in the 1981 and 1996 censuses will allow a determination of both the associations of a range of cancers with smoking, and the contribution of smoking to differential trends in cancer incidence by ethnicity and socioeconomic position. 124 Cancer PI3K inhibitors as targeted anticancer drugs Principal investigator: Dr Gordon Rewcastle Email address: [email protected] Host institution: The University of Auckland Approved budget: $1,324,194 End date: 30/09/2009 HRC Ref: 06/062A Human cancers each have key individual characteristics, in many cases involving a change to a single enzyme, which are vital for their survival. Targeted anticancer therapy involves identifying such target enzymes, generally present in only a proportion of cancers, and designing specific drugs to inhibit them. A good example for such an approach involves enzymes called phosphoinositide-3kinases, which play many important roles in the behaviour of the normal tissues of our body. Recent results show that one member of this family, called p110alpha, is mutated in certain cancers and sustains their survival and resistance to therapy. Our challenge is to develop new highly specific inhibitors of this enzyme that do not affect other family members and thus have minimal side effects. We have assembled a team of medicinal chemists, cell biologists and molecular biologists in an integrated approach to develop one or more new candidate drugs for clinical trial. Identification of new targets for anti-vascular therapies for cancer Principal investigator: Associate Professor Lai-Ming Ching Email address: [email protected] Host institution: The University of Auckland Approved budget: $1,054,162 End date: 30/09/2008 HRC Ref: 05/237R Cancer is the leading cause of death in New Zealand, and amongst the elderly, it is responsible for more deaths than heart disease, accidents and stroke combined. Developing effective therapies for cancer must therefore remain a foremost priority. Our work aims to develop treatments that activate cells within a tumour to release proteins that damage its blood vessels, thereby starving the tumour. This approach is radically different from, and offers a number of advantages over conventional chemotherapies. A prototype of our anti-vascular approach, DMXAA, is currently in clinical trials. In this project, we will capitalise on our extensive experience with DMXAA to identify, using state of the art proteomic technologies, the molecular targets and activation pathways that can be exploited to cause vascular-damaging responses in tumours. This research will uncover new targets for the design of innovative therapies urgently needed for the successful treatment of human cancers. Functional analysis Principal investigator: Email address: Host institution: Approved budget: End date: HRC Ref: of ERp29, a protein-folding assistant up-regulated in cancer Dr Elizabeth Ledgerwood [email protected] University of Otago $912,452 31/12/2008 05/176 Cancer 125 ERp29 is a new type of human protein that was discovered at the University of Otago. ERp29 is associated with many human diseases. Improved understanding of its biological function will assist in the development of new diagnostic and therapeutic opportunities. Our initial investigations suggest ERp29 may be important for the correct production of proteins needed for cell growth. In keeping with this, we have found that many types of cancer cells contain increased amounts of ERp29. This suggests ERp29 may be necessary for tumour development. In this study we will make mutant lung cancer cells that lack ERp29 and test how this change affects the ability of the cells to make proteins, and to grow as tumours. As well as defining the role of ERp29 in cancer, determining how ERp29 helps make proteins will benefit diseases that are caused by problems with protein folding, such as cystic fibrosis. Prospective, randomised, clinical study comparing laparoscopic & open surgery for colon cancer Principal investigator: Professor Philip Bagshaw Email address: [email protected] Host institution: University of Otago Approved budget: $347,100 End date: 30/06/2009 HRC Ref: 04/102 The proposal is to complete a multi-centre, prospective, randomised, clinical study (ALCCaS) comparing traditional open and new laparoscopic (keyhole) surgery for bowel cancer. New Zealand has among the world's highest incidences of bowel cancer. As our population ages, more bowel cancers are being diagnosed. Laparoscopic surgery may offer equal treatment of cancer and be less traumatic for patients. This study compares the open operation with the laparoscopic operation in a number of ways, including cancer clearance, pain, rate of recovery and cost. Already 445 of the required 600 patients have been recruited, randomized to have either open or laparoscopic surgery and are being followed for 5 years. Recruitment to this study began in 1998 and is scheduled for completion at the end of 2004. Published cancer outcomes from this research will be significant in determining the most effective, evidence based operation overall for the treatment of bowel cancer. A Brief Summary of Published Abstracts - New Zealand Research (1 June 2007 and 31 May 2008) The information below is produced from a review of abstracts only. Those wishing to draw conclusions from the research included should access the full papers, for which references are provided. References to additional, relevant publications are provided where these have not been included in the review. A total of 328 New Zealand research publications from the last 12 months were identified, of which 184 were deemed to be directly relevant to this objective. This is one research area in which there is a great deal of research underway, across all disciplines. Those publications classified as ‘reviews’ included articles from a 126 Cancer biomedical, clinical and public health perspective, as well as literature reviews on specific drugs (usually published by ADIS). The literature also covered a wide range of topics, although half the publications focused on drug development, breast, colorectal or reproductive cancers. There is a strong body of research on drug development, with a number of promising new agents being identified and new approaches taken to targeting existing cytotoxic drugs exclusively at cancer cells. A breakdown of journal articles published over the previous 12 months by research discipline and topic. A. Research Discipline B. Topic of Research 100% Chemotherapy Other 8 (4%) 14 (8%) 21% 80% Skin 9 (5%) Diet & Nutrition 2 (1%) Disparities 2 (1%) Reproductive 17 (9%) Drug development 29 (16%) Occupational 2 (1%) 22% 60% Lung 6 (3%) Lymphomas 2 (1%) Liver 2 (1%) 40% Haematological 8 (4%) Gastrointestinal 5 (3%) Colorectal 18 (10%) 20% 28% Cardiovascular 1 (1%) 0% Biomedical Oncogenesis 8 (4%) Head & neck 9 (5%) 22% Risk factors 3 (2%) Urinary tract 12 (7%) Brain & neurological 4 (2%) Breast 23 (13%) Disc 1 ipline Clinical Public Health Review Brain and Neurological Cancers Irwin et al.1 have looked at the effect of delays in radiotherapy treatment induced by resource constraints on the survival prospects of patients with high grade glioma. In a retrospective analysis of 172 patients with a histological diagnosis of WHO Grade 3 or 4 Astrocytoma who had undergone surgery at Wellington Hospital between 1993 and 2003, and who subsequently underwent radiotherapy, they found that time to radiotherapy from day of surgery was independently related to survival. Time to radiotherapy after surgery varied from 7 days to over 16 weeks. Every additional week of delay until the start of radiotherapy increased the risk of death (hazard ratio) by 8.9% (95%CI 2.0%-16.1%). A 6-week delay in starting radiotherapy (from 2 weeks post-op to 8 weeks) reduced median survival by 11 weeks for a typical patient. Multiple Cox regression analysis showed that age, performance status, tumour grade, extent of surgical resection and radiotherapy dose were also independently related to survival. The authors Cancer 127 conclude that delay in radiotherapy results in a clinically significant reduction in survival. A team from the Department of Psychiatry, Middlemore Hospital (Auckland)2 has highlighted the link between cancer and limbic encephalitis (LE). The case report of a 55-year-old Niuean, male school teacher with an acute onset of confusion and personality change is presented. The clinical data was obtained from various sources including the emergency room, medical ward, psychiatric ward as well as from discussions with other physicians involved in the management of this case. Family members and friends were also contacted to obtain corroborative historical information. LE was diagnosed in this case based on clinical presentation with psychiatric symptoms, ruling out delirium due to infections, metabolic and other toxins, as well as magnetic resonance imaging findings confirming temporal lobe changes. LE is a known paraneoplastic syndrome that may precede the diagnosis of an underlying malignancy. Recent advances in laboratory technology now allow for antibodies to be identified in specific malignancies. This behooves the clinicians to maintain a high level of diagnostic suspicion so that timely interventions with oncology can follow. The authors go on to say that liaison between psychiatry and other disciplines is important in managing this condition. Lum et al.3 present the case of a 5-year old boy with an ill-defined cortical tumour diagnosed as pilocytic astrocytoma on biopsy, and treated with radiotherapy. Nine years later, resection of the essentially unaltered tumour was performed for treatment of intractable seizures. Histologically, the tumour had some areas with the typical appearance of ependymoma as well as other areas which contained piloid cells. There was also evidence of focal infiltrative growth. These findings bore resemblance to a recently described entity ‘monomorphous angiocentric glioma/angiocentric neuroepithelial tumour, which combines features of ependymoma with pilocytic and diffuse astrocytomas. Both cortical ependymomas and angiocentric monomorphous glioma/angiocentric neuroepithelial tumour appear to be low-grade tumours, although their rarity makes accurate prognosis problematic. As this case has features of both entities, it suggests that they may be closely related. A review by Danesh-Meyer (Department of Ophthalmology, University of Auckland) stresses the devastating consequences of radiation-induced optic neuropathy (RION), a complication of radiotherapy to the anterior visual pathway, resulting in profound, irreversible visual loss4. Because of the poor prognosis associated with RION, the risk of its potential development should be factored into the decision to irradiate the brain. RION occurs commonly between 10-20 months, with an average of 18 months after treatment; but the onset may range from three months to 9 years. Cumulative doses of radiation that exceed 50 Gy or single doses to the anterior visual pathway of greater than 10 Gy are usually required for RION to develop. Treatment with systemic corticosteroids, anticoagulation and hyperbaric oxygen has been generally unsuccessful and disappointing. If visual dysfunction is detected early, hyperbaric oxygen might be beneficial, if treatment is initiated within 72 hours of visual loss. Additional Publications Lallu S, Naran S, Palmer D, Bethwaite P. Cyst fluid cytology of cerebellar hemangioblastoma: A case report. Diagn Cytopathol 2008;36(5):341-3. Contact: The 128 Cancer Cytology Unit, Department of Laboratory Services, Capital and Coast District Health Board, Wellington, New Zealand. Breast Cancer Aetiology A review by scientists at the Liggins Institute, University of Auckland5 highlights recent evidence linking growth hormone (GH) and breast cancer. The article also provides discussion of GH antagonism as a potential therapeutic approach for treatment. Accumulating literature implicates GH-mediated signal transduction in the development and progression of a wide range of malignancies, including breast cancer. Researchers from the Angiogenesis Research Group (Christchurch School of Medicine) have been studying thymidine phophorylase (TP) (an enzyme which is involved in promoting the formation of blood vessels) in breast cancer tissues6. TP is up-regulated in abnormal cell growth and this is associated with advanced tumour stage, microvessel density and prognosis in several tumour types. The team has published data confirming a role for TP in vascular remodelling involving several classes of genes, including the cell adhesion molecule, P-selectin. The authors say that confirmation of the role of TP-mediated cell adhesion molecule (CAM) induction is required; but this pathway may provide an attractive therapeutic target, since it is likely to affect several important tumour processes, including angiogenesis and metastasis. Histology The Cancer Genetics Research Group (University of Otago) has published a paper on determining subtypes of invasive ductal carcinoma (IDC) of the breast7. Most IDC are regarded as a single diagnostic entity, IDC of no special type (IDC-NST), which is subdivided further only by grading. However, recent research suggests that there is high clinical relevance in differentiating IDC subtypes. The Group used immunohistochemistry techniques to identify two main sub-types of IDC in their pilot cohort, and found that cytokeratin KRT8/18 expression differentiates distinct subtypes of grade 3 IDC of the breast. Additional Publications Walker LC, Harris GC, Wells JE, Robinson BA, Morris CM. Association of chromosome band 8q22 copy number gain with high grade invasive breast carcinomas by assessment of core needle biopsies. Genes Chromosomes Cancer 2008;47(5):405-17. Contact: Cancer Genetics Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand. Screening As the pain of mammography is recognised as a significant deterrent for women considering this examination, and may affect participation in breast screening, researchers from the Dunedin School of Medicine have reviewed interventions to Cancer 129 address this8. Seven RCTs, involving 1671 women were identified for inclusion. The review found that giving women information about the procedure prior to the mammogram may reduce pain and discomfort. Increasing women's control over breast compression could reduce pain experienced during the procedure, though mammogram image quality was only maintained if the technologist controlled the first compression. If the technologist reduced compression force of the mammogram, discomfort experienced was unchanged. The use of breast cushions reduced pain of mammography; however, image quality was impaired in 2% of women in the intervention group. Acetoaminophen as a premedication did not affect discomfort of mammography. Differences in interventions, and inconsistency in measures, validation of pain scales, and in assessment of mammogram quality, mean that results of these studies cannot be combined. All results are based on single studies. The authors surmise that, currently, there are very few proven interventions to reduce pain and discomfort of screening mammography, especially procedures that can be readily introduced to screening programmes. With mammography continuing as the preferred method for breast screening, more research on such interventions is needed. Chung et al. address the issue of difficulties in interpreting mammogram images9. Because X-ray images are 2D projections of a 3D object, it is not trivial to localise features identified in mammogram pairs within the breast volume. Furthermore, mammograms represent highly deformed configurations of the breast under compression, thus the tumour localisation process relies on the clinician's experience. Biomechanical models of the breast undergoing mammographic compressions have been developed to overcome this limitation. This team from the Bioengineering Institute (University of Auckland) present the development of a modelling framework that may be useful for tracking breast tumours between clinical images. Additional Publications Jeffreys M, Warren R, Highnam R, Davey Smith G. Breast cancer risk factors and a novel measure of volumetric breast density: cross-sectional study. Br J Cancer 2008;98(1):210-6. Contact: Centre for Public Health Research, Massey University Wellington Campus, Private Box 756, Wellington, New Zealand. [email protected]. Highnam R, Jeffreys M, McCormack V, Warren R, Davey Smith G, Brady M. Comparing measurements of breast density. Phys Med Biol 2007;52(19):5881-95. Contact: Highnam Associates Limited, Wellington, New Zealand. [email protected]. McCormack VA, Highnam R, Perry N, dos Santos Silva I. Comparison of a new and existing method of mammographic density measurement: intramethod reliability and associations with known risk factors. Cancer Epidemiol Biomarkers Prev 2007;16(6):1148-54. Contact: Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Wellington, New Zealand. [email protected]. 130 Cancer Treatment A review of the current literature by Poole and Paridaens10 looks at whether a 5year course of tamoxifen is still the optimal, standard adjuvant therapy for patients with hormone-dependent breast cancer. Recently, data from large randomised clinical trials have indicated that the third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen as adjuvant therapy in postmenopausal women with operable breast cancer when given either initially, or sequentially following initial tamoxifen therapy, within the first five years post-operatively. One large randomised trial demonstrated that administration of letrozole to high-risk (node-positive) postmenopausal patients who have completed 5 years' adjuvant tamoxifen further prevents late recurrences and contralateral breast cancer, contrary to the lack of obvious benefit of extending tamoxifen treatment to 10 years found in another large randomised study. Aromatase inhibitors and tamoxifen should not be administered concomitantly as this does not provide additional benefit, and a large, randomised study demonstrated reduced disease-free survival with the combination of anastrozole plus tamoxifen compared with anastrozole alone. Poole and Paridaens say that further studies are required to establish whether the third-generation aromatase inhibitors prolong overall survival compared with tamoxifen, to evaluate their long-term efficacy and tolerability profiles, and to determine the optimal treatment duration with these agents. Findlay et al. have published a review on oral chemotherapy for breast cancer11. Traditionally, anticancer therapy has been dominated by intravenous drug therapy. However, oral agents provide an attractive approach to chemotherapy and use of oral treatments is increasing. After reviewing a large amount of data the team concludes that the wealth of data available and the increasing use of oral agents in breast cancer suggest that many of the concerns and perceptions about oral therapy, including efficacy and bioavailability, have been overcome, and that oral therapy will play a major role in breast cancer management in the future in both the metastatic and adjuvant settings. Cheema et al. have done a systematic review of 10 clinical trials on progressive resistance training (PRT) in breast cancer12. PRT was prescribed with aerobic training in 8/10 trials reviewed, and in isolation in 2/10 trials reviewed. Upper body PRT was prescribed in 7/10 trials, including 4/5 RCTs. No exacerbation of objectively measured or subjectively reported lymphoedema symptoms was reported in any of these trials. Adverse events were rare, generally musculoskeletal in nature, and were managed effectively by conservative means. Overall, the studies reviewed suggest that women surgically treated for breast cancer can derive health-related and clinical benefits by performing PRT after breast cancer surgery. They conclude that further research may be required to stimulate greater advocacy for PRT among oncologists, and in community care settings. Farquhar et al. from the University of Auckland have undertaken a systematic review and meta-analysis of high-dose chemotherapy for poor prognosis breast cancer13. Thirteen trials with 5064 women were included. There was a significant benefit in event-free survival for the high-dose group at three years (RR 1.19 (95% CI 1.06, 1.19)) and four years (RR 1.24 (95% CI 1.03, 1.50)) and at five years this Cancer 131 benefit approached statistical significance (RR 1.06 (95% CI 1.00, 1.13)). Overall survival rates were not significantly different at any stage of follow up. There were significantly more treatment-related deaths on the high-dose arm (RR 8.58 (95% CI 4.13, 17.80)). Morbidity was higher in the high-dose group but there was no significant difference in the incidence of second cancers. The high-dose group reported significantly worse quality of life immediately after treatment, but there were few differences by one year. The research team says that there is insufficient evidence supporting routine use of high-dose chemotherapy with autograft for treating early, poor-prognosis breast cancer. Herceptin PHARMAC has published a review of the evidence underpinning funding decisions Herceptin in the New Zealand Medical Journal14. A 9-week regimen of trastuzumab (Herceptin) given concurrently with a taxane will be funded for HER2-positive early breast cancer patients in New Zealand. Five randomised, controlled trials have been reported but uncertainty persists about optimal regimen duration, dose and sequencing, how to minimise cardiotoxicity, and long-term clinical outcomes. However, the evidence for the 9-week concurrent regimen was sufficient to justify funding. This regimen has shown results comparable to longer duration treatments; allows more patients to be treated; is relatively cost-effective; and DHBs have indicated they can provide sufficient ancillary support services. Longer duration regimens remain unfunded because of uncertainty surrounding long-term clinical benefits and risks; the high cost; effects on DHB services; and their consequential unfavourable relative cost effectiveness. New data has cast further doubt on the extent and durability of the treatment effect for the sequential 12-month regimen. The sequential treatment arm of trial N9831 showed benefits that were small and statistically nonsignificant, and the HERA trial 23-month follow-up suggested a waning in efficacy with time. The authors stress that PHARMAC are supporting on-going research in the area and remain open to new evidence on efficacy or improved cost-effectiveness. Additional Publications Isaacs RJ, Frampton CM, Kuper-Hommel MJ. PHARMAC's funding of 9 weeks Herceptin: many assumptions in a high-risk decision. N Z Med J 2007;120(1259):U2676. Orman JS, Perry CM. Trastuzumab : in HER2 and hormone receptor co-positive metastatic breast cancer. Drugs 2007;67(18):2781-9. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. Scott LJ. Bevacizumab: in first-line treatment of metastatic breast cancer. Drugs 2007;67(12):1793-9. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA. [email protected]. Sekar R, Stone PR. Trastuzumab use for metastatic breast cancer in pregnancy. Obstet Gynecol 2007;110(2 Pt 2):507-10. Contact: Department of Obstetrics and Gynecology, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand. [email protected]. 132 Cancer Stuart EC, Larsen L, Rosengren RJ. Potential mechanisms for the synergistic cytotoxicity elicited by 4-hydroxytamoxifen and epigallocatechin gallate in 2007;30(6):1407-12. Contact: Department of MDAMB-231 cells. Int J Oncol Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. Stuart EC, Rosengren RJ. The combination of raloxifene and epigallocatechin gallate suppresses growth and induces apoptosis in MDA-MB-231 cells. Life Sci 2008;82(17-18):943-8. Contact: Department of Pharmacology & Toxicology, University of Otago, Dunedin, New Zealand. Ethnicity University of Auckland researchers based in the Department of Surgery at Middlemore Hospital (Weston et al.) have published a study on how the biological characteristics of breast cancer differ between ethnic groups in Auckland15. The prospective cohort study involved 1,577 people diagnosed with breast cancer in the greater Auckland area between 2000 and 2005, who agreed to participate. The results showed that New Zealand Māori and Pacific Island participants had larger tumours (P < 0.0001) and higher grade tumours (P < 0.0001), with more involved lymph nodes (P < 0.0001). When allowing for size, there was still an indication that Māori people had higher grade tumours (P = 0.03). There was no difference in oestrogen receptor, progesterone receptor or lymphovascular invasion between ethnic groups. The authors suggest that there are differences in tumour biology related to ethnicity in the Auckland population and this has implications for breast cancer screening and management. A team from Auckland University have looked the reasons that may explain differences in breast cancer survival based on race or ethnicity in older American women16. They used data from 41,020 women aged > or =68 years with incident breast cancer between 1994-1999 including African American (2479), Hispanic (1172), Asian/Pacific Island (1086), and white women (35,878). They found that African American woman had poorer survival rates than white women, although adjustment for predictor variables reduced this difference when the data from individuals at all cancer stages (0/I, II/III, and IV) at diagnosis were combined (Hazard Ratio(HR): 1.08; 95%CI 0.97-1.20). Screening mammography, tumour characteristics at diagnosis, biologic markers, and treatment each produced a similar reduction in HRs for women with stage II/III cancers (HR: 1.30; 95% CI: 1.10-1.54). Asian and Pacific Island women better survival than white women in the all-stage (HR: 0.88; 95% CI: 0.75-1.04) and stage II/III analysis (HR: 0.88; 95% CI: 0.75-1.04), although these findings did not reach statistical significance. There was no significant difference in survival by race or ethnicity noted among women diagnosed with stage IV disease. In summation, the authors say that predictor variables contribute to, but do not fully explain, racial or ethnic differences in breast cancer survival for elderly American women. Future analyses should further investigate the role of biology, demographics, and disparities in quality of care. Cancer 133 Risk Factors Geographic location (urban versus rural) did not affect breast cancer outcomes in a study conducted by the Australasian Faculty of Public Health Medicine in Hamilton17. Data from women listed on the NZCR between 1998 and 2002 was used in a survival analysis that controlled for age, ethnicity, deprivation, and cancer stage. Domicile was used to classify the women according to urban or rural status. This was not found to affect diagnosis or the effectiveness of treatment. McKenzie and colleagues18 have undertaken a study of all 21,586 breast cancer cases on the New Zealand Cancer Registry (July 1994-June 2004) and shown that Māori, Pacific and women in low socioeconomic brackets have a poorer prognosis for breast tumours on presentation. Women were categorised according to ethnicity on the Registry. Deprivation was analysed as quintiles of the New Zealand Deprivation Index 2001. The study found that Māori and Pacific women were more likely to have non-local stage, less well differentiated cancer, larger tumours and positive human epidermal growth factor receptor-type 2 (HER-2) status than non-Māori or non-Pacific women. Māori were less likely and Pacific women more likely than non-Māori or non-Pacific women to have negative oestrogen (ER) and progesterone receptor (PR) status. Adjusting for deprivation did not materially alter the results. Women living in more deprived areas had a higher risk of non-local stage and larger tumours. These associations were only partially explained by ethnicity. There was no relationship between tumour grade, ER, PR or HER-2 status and deprivation. Weighing Benefits versus Harm A ‘citizens’ jury’ approach has been advocated as a viable way to determine how complex benefits and harms are weighed by affected populations, particularly where experts and advocacy groups disagree19. Researchers at the Department of Preventive and Social Medicine, University of Otago, recruited eleven women aged 40-49 years (randomly selected from the electoral roll) and asked them to consider whether the New Zealand government should offer free mammography screening to all women aged 40-49 years. Participants met over a day and a half to hear evidence from expert witnesses with differing views and to deliberate the verdict. All but one woman changed their minds during the jury process, and voted against government provision of mammography screening in this age group. The main reasons reported were the inaccuracy of the test and the potential for harm, and the lack of firm evidence of saving lives in this age group. Cardiovascular Cancers The case of a 73-year-old man with a pulmonary artery sarcoma successfully treated as a result of an international surgical collaboration has been reported20. The tumour was initially deemed to be unresectable due to a lack of local expertise managing cardiac malignancies. Since the patient was unable to travel to a specialist centre in the United States, he was initially offered only palliative therapy. However, two surgeons with experience of treating malignant cardiac tumours travelled to New Zealand specifically to perform a potentially curative resection of his tumour. The authors say that there should be an emphasis placed 134 Cancer on the development of internationally acceptable protocols for the treatment of rare conditions and improved local access to overseas surgical expertise. Chemotherapy An evidence-based review by Bhana (ADIS, New Zealand) focuses on chemotherapy-induced neutropenia and primary prophylaxis21. Neutropenia is a frequent complication of chemotherapy associated with life-threatening infections, hospitalisation, and chemotherapy dose reductions and delays. Primary prophylaxis with granulocyte colony-stimulating factors has been shown to reduce the incidence and duration of neutropenia, febrile neutropenia, infections, hospitalisation and antibiotic use. Recent randomised clinical trials of filgrastim, lenograstim and pegfilgrastim showed variable results across patient groups at different risks of febrile neutropenia. Bhanu surmises that pegfilgrastim is at least as effective as filgrastim in the prophylaxis of chemotherapy-induced neutropenia and has improved pharmacokinetics requiring reduced administration. Murdoch and Sager (ADIS, New Zealand) have looked at whether targeted therapy has held its promise in an evidence-based review22. Many of the significant advances in cancer management in recent years have centred on the development and introduction of molecularly targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors. Despite targeted therapy that has clearly benefited and even cured certain patients (eg, imatinib, trastuzumab), the ultimate goal of curing cancer, and the more immediate goal of replacing non-targeted chemotherapies with less toxic, targeted agents has yet to be achieved for most cancer patients. The paper goes on to present data based on a systematic review of RCTs that show significant benefits in selected cancers: Non-Hodgkin's lymphoma (rituximab plus chemotherapy has a major survival advantage over chemotherapy alone); Renal cell carcinoma (temsirolimus or sunitinib has a significant survival benefit relative to interferon-alpha, and sorafenib carries such a benefit in patients resistant to standard therapy); colorectal cancer (bevacizumab plus 5-fluorouracil/leucovorin possesses a significant survival advantage over 5-fluorouracil/leucovorin and irinotecan/5fluorouracil/leucovorin). Non-small-cell lung cancer (erlotinib significantly prolongs survival, particularly in nonsmokers, and gefitinib may have some utility in patients of Asian ethnicity); head and neck squamous-cell carcinoma (cetuximab plus radiotherapy - versus radiotherapy alone - significantly improves locoregional control and survival, without worsening radiotherapy-related toxicity). DNA topoisomerase IIalpha is an essential enzyme for chromosome segregation during mitosis. Williams et al. report that this enzyme has been shown to be down-regulated in doxorubicin-resistant cell lines23. The paper presents data on specificity proteins (Sp 1 and Sp 3), which have been implicated in the regulation of topoisomerase II alpha transcription, and provides a mechanistic explanation for this effect. Additional Publications Carter NJ, Keam SJ. Trabectedin : a review of its use in the management of soft tissue sarcoma and ovarian cancer. Drugs 2007;67(15):2257-76. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected]. Cancer 135 Dhillon S, Lyseng-Williamson KA. Zoledronic acid: a review of its use in the management of bone metastases of malignancy. Drugs 2008;68(4):507-34. Contact: Wolters Kluwer Health Adis, Auckland, New Zealand. [email protected]. Dhillon S, Wagstaff AJ. Lapatinib. Drugs 2007;67(14):2101-8; discussion 2109-10. Contact: Wolters Kluwer Health | Adis, 41 Centorian Drive, Mairangi Bay, North Shore 074, Auckland, New Zealand. [email protected]. Jamieson SM, Liu JJ, Connor B, Dragunow M, McKeage MJ. Nucleolar enlargement, nuclear eccentricity and altered cell body immunostaining characteristics of large-sized sensory neurons following treatment of rats with paclitaxel. Neurotoxicology 2007;28(6):1092-8. Contact: Department of Pharmacology and Clinical Pharmacology, The University of Auckland, New Zealand. Keam SJ. Dasatinib: in chronic myeloid leukemia and Philadelphia chromosomepositive acute lymphoblastic leukemia. BioDrugs 2008;22(1):59-69. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected]. McKeage K, Plosker GL. Zoledronic acid: a pharmacoeconomic review of its use in the management of bone metastases. Pharmacoeconomics 2008;26(3):251-68. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected]. McKeage MJ. Satraplatin in hormone-refractory prostate cancer and other tumour types: pharmacological properties and clinical evaluation. Drugs 2007;67(6):859-69. Contact: Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. [email protected]. Colorectal Cancers Screening In 2005, a Colorectal Screening Advisory Group was appointed to provide independent, strategic advice and recommendations on population screening for colorectal cancer (CRC) in New Zealand. The group were appointed by the National Screening Unit of the Ministry of Health. Parry et al. have now published their advice24. After undertaking an evidence-based review of relevant literature and assessment of CRC screening using the New Zealand Criteria to Assess Screening Programmes, they have recommended that an immunochemical faeces-for-occult-blood test (FOBTi) has a higher analytical sensitivity than other laboratory tests available and would be assumed to achieve greater mortality reduction. The authors state that currently, public hospitals cannot deliver timely diagnostic or surveillance colonoscopy. The Advisory Group recommends that a feasibility study of CRC screening using FOBTi be undertaken. This would help determine the performance of the FOBTi in the New Zealand population and whether the New Zealand health system could support an acceptable, effective and economically efficient CRC screening programme. Furthermore, the Group suggests that to optimise the diagnosis and treatment of colorectal cancer, there is an immediate need to expand colonoscopy services and to ensure that the treatment outcomes for CRC, both surgical and oncological, meet international standards throughout New Zealand. Kerr et al. have undertaken a Systematic review of the effectiveness of population screening for colorectal cancer25. The aim of the study was to estimate the 136 Cancer effectiveness of colorectal cancer screening with faecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), and combinations of FOBT and FS in preventing colorectal cancer (CRC) deaths. METHOD: A systematic review was conducted examining randomised controlled trials (RCTs) published between 1997 and 2004 inclusive. Four RCTs were identified that examined FOBT screening. The three trials that investigated guaiac-based FOBT found CRC mortality was reduced in the screening group. In the two population-based trials, the pooled relative risk was 0.86 (95%CI 0.79-0.93). A fourth RCT was identified, with shorter term follow-up, which considered FOBT screening combined with FS compared with FOBT alone. No significant reduction in CRC mortality was reported in this trial. There authors found that there is high-quality evidence showing that guaiac-based FOBT screening reduces mortality from CRC. No such evidence exists for screening with FS either alone, or in combination with FOBT, but this should be re-evaluated once data become available from four large ongoing trials. Yeoman et al.26 have published the findings of a National Screening Unit commissioned survey aimed to determine the current level of colonoscopy provision in New Zealand's public hospitals, the gap in demand and provision for diagnostic and surveillance procedures, and factors limiting colonoscopy capacity. The researchers posted a survey, based on the United States SECAP study, to all public endoscopy units within New Zealand in April 2005. The overall survey response rate was 86% (24/28). Only 3 of 7 large centres, and 11 of 17 small centres, were able to offer a diagnostic colonoscopy to patients with symptoms suggestive of colorectal cancer (CRC) within 3 months of referral - and at the time of the survey, 828 patients had been waiting for longer than 6 months. The majority (85%) of public hospitals offer surveillance colonoscopy for most indications, and at the time of the survey, 2550 patients had been waiting greater than 6 months. Availability of endoscopy nurses and endoscopists were the main factors limiting colonoscopy provision. The authors conclude that a significant gap exists between colonoscopy demand and provision in New Zealand's public hospitals. Population screening for CRC would require a significant increase in colonoscopy capacity to ensure waiting times for symptomatic patients do not increase. Diagnosis A team at Middlemore hospital27 have identified criteria for prioritizing access to colonoscopy for suspected colon cancer. In a pilot study of 105 patients, they showed that patients over the age of 67 years who present with rectal bleeding, or have a family history of colorectal cancer or neoplasia, are at higher risk and should receive a colonoscopy prior to specialist assessment. Metastases Lin et al. (Cancer Genetics Laboratory, Department of Biochemistry,University of Otago) have identified genes associated with colorectal liver metastasis28. Tumour cells have to undergo gene expression changes in order to metastasise and adapt to a new site. The researchers investigated these changes in liver metastases of colorectal cancer by using genome-wide microarray analysis to profile the expression of 48 primary tumours and 28 liver metastases. Analyses revealed that genes associated with tissue remodelling and immune response were upregulated Cancer 137 in metastases relative to primary tumours, whereas genes associated with proliferation and oxidative phosphorylation were downregulated. The upregulation of genes associated with tissue remodelling and immune response are likely to be involved in metastatic invasion and colonisation of the new site because these genes can promote tumour progression. However, downregulation of genes associated with proliferation suggests that proliferation in metastases was reduced relative to primary tumours. Surgery Abbas and Merrie29, from Auckland City Hospital, demonstrated that removal of peritoneal metastases in patients with malignant small bowel obstruction offers a reasonable survival benefit in patients with resectable disease - outweighing the attendant risks. Hayes and Hansen30 have demonstrated that laparoscopic-assisted colectomy (LAC) for cancer may be cost-effective over open colectomy (OC). LAC entails greater operating time and the use of more disposable equipment costing, on average, $1257 more than an OC. However, two separate studies have estimated the gain in recovery time as being 12 and 33 days, respectively. Depending on the estimates taken, LAC may prove to be a cost-effective option, with further improvements expected as operating times and post-operative stays reduce with time. Wakeman et al.31 report that survival rates are considerably poorer in patients in which iatrogenic damage to the spleen requires splenectomy during resection of colorectal tumours. Fifty-five patients were identified who had an iatrogenic splenectomy and matched with control cases. In the group without splenectomy, cancer-specific survival at five years was 70 vs. 47 percent in those with a splenectomy and at ten years survival rates were 55 vs. 38 percent in the two groups. Randomised controlled trials have shown a benefit for epidurals on postoperative pain relief and ileus, and possibly respiratory, complications. There is no proven benefit with regard to length of stay. These are the findings from a review by Gendall et al. (Department of Surgery, Christchurch Hospital)32. They report that the majority of data demonstrate a superior effect of epidural analgesia on pain control after colorectal surgery. Well designed randomised controlled trials have also shown that epidural analgesia reduces the duration of ileus after colorectal surgery. Limited data suggest the additional benefit may be minimal after laparoscopic surgery or when epidural analgesia is used as part of a multimodal regime. Data does not convincingly show either a clear harmful or beneficial effect of epidural analgesia on rates of anastomotic leakage. Epidural analgesia may have beneficial effects on postoperative lung function but, due to low numbers, the effects on cardiovascular and thromboembolic complications are indeterminate. Specialist Colorectal Units At a time when specialist colorectal units are becoming increasingly common in tertiary centres, Clinicians from the Department of Surgery at Nelson hospital have published a review of colorectal cancer surgery conducted by one surgeon in 138 Cancer a provincial setting, from January 2000 to December 200433. The study illustrates that high-volume colorectal surgery is possible even in a smaller New Zealand province. Surgical practice and outcomes withstood comparison to published results - a broad general surgical case mix and low-volume hospital environment were not significant barriers to quality of colorectal care. The authors conclude that provincial colorectal cancer management remains an important resource for patients living outside major New Zealand centres. A further study conducted in Southland on colorectal cancer surgery conducted between June 1997 and May 2000 has produced similar results and the investigators emphasize the importance of retaining colorectal cancer services in non-specialised units 34. Chemotherapy and Radiotherapy A questionnaire-based survey involving 22 medical oncologists to document variations in chemotherapy prescription patterns has been conducted by investigators at the Department of Oncology, Waikato Hospital 35. The survey indicates that chemotherapy prescriptions for patients with colon cancer in New Zealand, although not uniform, are mostly in line with international recommendations. Abbas and Hill present the case of a 75-year-old farmer who was treated for rectal cancer with preoperative 45 Gy of radiotherapy and abdominoperineal resection and presented with radiation-induced sarcoma four years later36. He was diagnosed after he developed symptoms of bladder outlet obstruction and acute urinary retention. He underwent a transurethral resection of the prostate and histological examination and immunohistochemistry revealed it to be a poorly differentiated sarcoma. The authors say that the relationship between radiation exposure for treatment of cancer and occurrence of a second primary cancer at the irradiated site is well known. However, this phenomenon is rare in prostate cancer and they believe this to be the first reported case of radiation-induced sarcoma following radiotherapy treatment for rectal cancer. Since radiotherapy plays a pivotal role in the contemporary treatment of rectal adenocarcinoma, it is relevant to be aware of the potential long-term carcinogenic complications of radiotherapy of the pelvis. Additional Publications Hoy SM, Wagstaff AJ. Panitumumab in the treatment of metastatic colorectal cancer: profile report. BioDrugs 2007;21(2):135-7. Contact: Wolters Kluwer Health/Adis, Auckland, New Zealand. McCormack PL, Keam SJ. Bevacizumab: a review of its use in metastatic colorectal cancer. Drugs 2008;68(4):487-506. Contact: Wolters Kluwer Health Adis, Auckland, New Zealand. [email protected]. Follow-up Jeffery et al. say that is common clinical practice to follow patients with colorectal cancer (CRC) for several years following their definitive surgery and/or adjuvant therapy37. Despite this widespread practice, there is considerable controversy about how often patients should be seen, what tests should be performed and whether these varying strategies have any significant impact on patient outcomes. To address this, they have undertaken a review of the available evidence concerning the benefits of intensive follow up of colorectal cancer patients with Cancer 139 respect to survival. Only randomised controlled trials comparing different followup strategies for patients with non-metastatic CRC treated with curative intent were included, a total of eight studies. There was evidence that an overall survival benefit at five years exists for patients undergoing more intensive follow up OR was 0.73 (95% CI 0.59 to 0.91); and RD -0.06 (95% CI -0.11 to -0.02). The absolute number of recurrences was similar. Analyses demonstrated a mortality benefit for performing more tests versus fewer tests: OR was 0.64 (95% CI 0.49 to 0.85); and liver imaging versus no liver imaging: OR was 0.64 (95% CI 0.49 to 0.85). There were significantly more curative surgical procedures attempted in the intensively followed arm: OR 2.41(95% CI 1.63 to 3.54). No useful data on quality of life, harms or cost-effectiveness were available for further analysis. The results of the review suggest that there is an overall survival benefit for intensifying the follow up of patients after curative surgery for colorectal cancer. Additional Publications Frizelle FA. Colorectal cancer in New Zealand. N Z Med J 2007;120(1258):U2628. Yeoman A, Young J, Arnold J, Jass J, Parry S. Hyperplastic polyposis in the New Zealand population: a condition associated with increased colorectal cancer risk and European ancestry. N Z Med J 2007;120(1266):U2827. Contact: Department of Gastroenterology and Hepatology, Middlemore Hospital, Otahuhu, Auckland, New Zealand. Culturally Sensitive Services The Northern Regional Genetic Service (Auckland District Health Board) have published a report on their efforts to provide a process that is culturally sensitive to Māori38. They report that in familial cancer and other late-onset disorders, there is now the possibility of 'prediction' where a high risk conferred by family history can be confirmed or negated by genetic testing. The authors contend that current methods for providing information on mutational analysis are based on a Eurocentric model of individual autonomy that is not culturally appropriate for Māori. Diet and Nutrition Ferguson and Philpott39 have published a review on cancer prevention by dietary bioactive components that target the immune response. They say that dietary bioactive food components that interact with the immune response have considerable potential to reduce the risk of cancer. Reduction of chronic inflammation or its downstream consequences may represent a key mechanism that can be reduced through targeting signal transduction or through antioxidant effects. Major classes of macronutrients provide numerous examples, including amino acids (such as glutamine or arginine); lipids (such as the omega-3 polyunsaturated fatty acids); DHA or EPA; or novel carbohydrates such as various sources of beta-glucans. Vitamins such as C and E are commonly used as antioxidants, while zinc and selenium are minerals with a wide spectrum of impacts on the immune system. Some of the most potent immunomodulators are phytochemicals such as the polyphenols, epigallocatechin gallate (EGCG) or curcumin, or isothiocyanates such as PEITC. There is accumulating evidence for 140 Cancer cancer prevention by probiotics and prebiotics, and these may also affect the immune response. They go on to say that genomic approaches are becoming increasingly important in characterising potential mechanisms of cancer prevention, optimising the rational selection of dietary bioactive food components, or identifying humans with differing nutrient requirements for cancer protection. See also the study on folate supplementation under ‘Haematological Cancers - Risk Factors’. Disparities Blakey et al.40 used 1981, 1986, 1991, 1996, and 2001 censuses linked to mortality data to determine whether major structural economic reforms impacted on disparities between income and mortality. The study covered the entire New Zealand population aged 1-74 years. They found that although all-cause mortality declined over the 25-year period, relative inequalities in mortality increased from 1981-4 to 1996-9. While cardiovascular disease was the major contributor to the observed disparities between income and mortality, it decreased in importance from 45% in 1981-4 to 33% in 2001-4 for males and from 50% to 29% for females. However, the corresponding contribution of cancer increased from 16% to 22% for males and from 12% to 25% for females. Although the authors could not confidently draw a causal link between these disparities and structural reform, they call for a review of health priorities based on the difference in the impact of mortality causes over time. Dachs et al41 have published a review describing patterns of cancer incidence, mortality, and survival in indigenous populations compared with populations of European origin in Polynesia. They highlight the dearth of data for Pacific populations and report risk factors that differ between ethnicities, including smoking, viral infections, and obesity. See also the study by Mckenzie and colleagues and Weston et al. under ‘Breast Cancer’, the study undertaken at the Hugh Adamson Cancer Epidemiology Unit under ‘Prostate Cancer’ and the work of Stevens et al. under ‘Lung Cancer’. Drug Development Herst et al. from the Malaghan Institute of Medical Research have published a paper elucidating the primary molecular target for a new drug for drug-resistant ovarian cancer, currently in clinical trials42. Phenoxodiol, a synthetic isoflavene, is also in early stage clinical trials for prostate and cervical cancer. Phenoxodiol inhibits proliferation of many cancer cell lines and induces apoptosis (programmed cell death). In addition, phenoxodiol sensitises drug-resistant tumour cells to anticancer drugs including paclitaxel, carboplatin and gemcitabine. The investigators studied the effects of phenoxodiol on plasma membrane electron transport (PMET) and cell proliferation in human leukaemic HL60 cells and mitochondrial gene knockout HL60rho(o) cells that exhibit elevated PMET. They found that PMET may be a primary target for phenoxodiol in tumour cells and in activated T cells. Cancer 141 Kanwar et al. (LactoPharma Consortium, University of Auckland) have investigated 'Iron-saturated' lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy43. Bovine lactoferrin (bLf), an iron-containing natural defence protein found in bodily secretions, has been reported to inhibit carcinogenesis and the growth of tumours. The study was designed to establish whether natural bLf and iron-saturated forms of bLf differ in their ability to augment cancer chemotherapy. Mice were fed bLf (with varying degrees of iron enrichment), subsequently challenged subcutaneously with tumour cells and treated with chemotherapy they found. They found that mice fed iron-saturated bLf bearing either EL-4, Lewis lung carcinoma or B16 melanoma tumours completely rejected their tumours within 3 weeks following a single injection of either paclitaxel, doxorubicin, epirubicin or fluorouracil, whereas mice fed the control diet were resistant to chemotherapy. The BLf had to be iron saturated and had to be fed to mice for more than 2 weeks prior to chemotherapy to be wholly effective in eradicating tumours from all mice, suggesting that it acts as a competence factor. It significantly reduced tumour vascularity and blood flow, and increased antitumour cytotoxicity, tumour apoptosis and the infiltration of tumours by leukocytes. Importantly, iron-saturated bLf restored both red and white peripheral blood cell numbers depleted by chemotherapy, potentially fortifying the mice against cancer. In summary, the authors conclude that bLf is a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy, but needs to be saturated with iron to be effective. A review by McKeage (University of Auckland) focuses on the potential of DMXAA in combination with docetaxel in advanced prostate cancer44. DMXAA (5,6-Dimethylxanthenone-4-acetic acid) is a vascular disrupting agent developed by researchers at the University of Auckland’s Cancer Society Research Centre. It has demonstrated efficacy in combination with taxane-based chemotherapy in patients with advanced cancer. Complementary modes of action, a lack of pharmacokinetic interaction and distinct adverse effect profiles provide a strong rationale for combining these anticancer agents. In a Phase II trial in men with hormone refractory prostate cancer, DMXAA (ASA404) in combination with docetaxel achieved a prostate-specific antigen response in more patients than docetaxel therapy alone, and was generally well tolerated. Further clinical evaluation of this combination in this patient population is warranted. A team at the University of Otago’s Department of Pharmacology and Toxicology have investigated the efficacy of two naturally derived polyphenolic compounds in suppressing breast cancer cell growth45. Polyphenols are a class of phytochemicals found in plants, with known antioxidant properties. Both epigallocatechin gallate (EGCG, a catechin found in green tea) and curcumin (the principal curcuminoid found in tumeric) have shown efficacy in various in vivo and in vitro models of cancer. The research team tested their efficacy in killing cancer cells in vitro and in vivo, when given in combination. They found that the combination was synergistically cytotoxic both in vitro and in vivo (in mice). Tumour volume in the treated mice decreased 49% in comparison to the control mice. Thotathil and Jameson have provided an overview of early early experience with novel immunomodulators for cancer treatment46. Immunotherapy involves the 142 Cancer treatment of cancer by modification of the host-tumour relationship. It is now known that this relationship is quite complex and only some of the interactions have been elucidated. Early attempts at immunotherapy, such as Coley's toxins, were undertaken without an understanding of the processes mediating the effects. With a better understanding of the immunology of this anticancer response, recent trials have focussed on certain aspects of the process to stimulate an antitumour response. In this review, the authors discuss a number of novel biological response modifiers that work as general stimulants of the immune system, through varied mechanisms including induction of stimulatory cytokines (such as IFN-alpha, TNF-alpha and IL-12) and activation of T cells and the antigenpresenting dendritic cells. These compounds include Toll-like receptor agonists, several of which are in clinical trials at present. In addition to immunomodulatory activity, some compounds such as 5,6-dimethylxanthenone4-acetic acid (DMXAA) and thalidomide and its analogues also target existing or developing tumour vasculature. Some of these compounds have single-agent activity in clinical trials, while others such as DMXAA have shown promise in combination with chemotherapy without increasing toxicity. Lactoferrin is another compound that has shown clinical activity with low toxicity. At present, accepted indications for immunotherapy are limited to a few cancers such as renal cell carcinoma and melanoma. Thotathil and Jameson look at some of the reasons for the limited impact of immunotherapy so far and suggest possible avenues for further research with a greater likelihood of success. A review by a team based at the National School of Pharmacy, University of Otago, provides the latest information on peptides and small molecules targeting the plasminogen-activation system (PAS), which are under consideration as antimetastasis drugs for breast cancer47. Breast cancer is the most common malignancy afflicting Western women today and is responsible for many deaths due to metastatic disease. Upregulation of the plasminogen-activation system (PAS) has been shown to correlate with poor prognosis in metastatic breast cancer and targeting this system represents an attractive strategy for the development of anti-metastasis prophylactic drugs. Two promising classes of PAS-targeting agents are inhibitors of the serine protease activity of urokinase plasminogen activator (uPA) and antagonists of the interaction of uPA with its cell surface receptor (uPAR). The review begins with a brief overview of the role of PAS in cancer metastasis before describing in detail a subset of the small molecules and peptides from the patent literature that target either uPA activity or uPA/uPAR interactions for use as anti-metastasis drugs. Additional Publications Basse B, Ubezio P. A generalised age- and phase-structured model of human tumour cell populations both unperturbed and exposed to a range of cancer therapies. Bull Math Biol 2007;69(5):1673-90. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. [email protected]. Bridewell DJ, Porter AC, Finlay GJ, Baguley BC. The role of topoisomerases and RNA transcription in the action of the antitumour benzonaphthyridine derivative SN 28049. Cancer Chemother Pharmacol 2008. Contact: Auckland Cancer Society Cancer 143 Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand, [email protected]. Chung F, Liu J, Ching LM, Baguley BC. Consequences of increased vascular permeability induced by treatment of mice with 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and thalidomide. Cancer Chemother Pharmacol 2008;61(3):497-502. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Frederick R, Denny WA. Phosphoinositide-3-kinases (PI3Ks): combined comparative modeling and 3D-QSAR to rationalize the inhibition of p110alpha. J Chem Inf Model 2008;48(3):629-38. Contact: Auckland Cancer Society Research Centre (ACSRC), School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand. [email protected]. Guise CP, Wang AT, Theil A, Bridewell DJ, Wilson WR, Patterson AV. Identification of human reductases that activate the dinitrobenzamide mustard prodrug PR-104A: a role for NADPH:cytochrome P450 oxidoreductase under hypoxia. Biochem Pharmacol 2007;74(6):810-20. Contact: Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Hay MP, Hicks KO, Pruijn FB, et al. Pharmacokinetic/pharmacodynamic modelguided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with antitumour activity: the role of extravascular transport. J Med Chem 2007;50(25):6392-404. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1003, New Zealand. [email protected]. Hay MP, Pchalek K, Pruijn FB, et al. Hypoxia-selective 3-alkyl 1,2,4-benzotriazine 1,4-dioxides: the influence of hydrogen bond donors on extravascular transport and antitumour activity. J Med Chem 2007;50(26):6654-64. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand. [email protected]. Helsby NA, Goldthorpe MA, Tang MH, et al. Influence of mustard group structure on pathways of in vitro metabolism of anticancer N-(2-hydroxyethyl)3,5-dinitrobenzamide 2-mustard prodrugs. Drug Metab Dispos 2008;36(2):353-60. Contact: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. [email protected]. Herst PM, Hesketh EL, Ritchie DS, Berridge MV. Glycolytic metabolism confers resistance to combined all-trans retinoic acid and arsenic trioxide-induced apoptosis in HL60rho0 cells. Leuk Res 2008;32(2):327-33. Contact: Malaghan Institute of Medical Research, P.O. Box 7060, Wellington, New Zealand. [email protected]. Hicks KO, Myint H, Patterson AV, et al. Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine. Int J Radiat Oncol Biol Phys 2007;69(2):560-71. Contact: Auckland Cancer Society Research Centre, University of Auckland School of Medical Sciences, Auckland, New Zealand. [email protected]. Huck SP, Tang SC, Andrew KA, Yang J, Harper JL, Ronchese F. Activation and route of administration both determine the ability of bone marrow-derived dendritic cells to accumulate in secondary lymphoid organs and prime CD8+ T 144 Cancer cells against tumours. Cancer Immunol Immunother 2008;57(1):63-71. Contact: Malaghan Institute of Medical Research, PO Box 7060, Wellington South, New Zealand. Kendall JD, Rewcastle GW, Frederick R, et al. Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110alpha inhibitors. Bioorg Med Chem 2007;15(24):7677-87. Contact: Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand. Liu JJ, Galettis P, Farr A, et al. In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake. J Inorg Biochem 2008;102(2):303-10. Contact: Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland 1142, New Zealand. Nelson SM, Ferguson LR, Denny WA. Non-covalent ligand/DNA interactions: minor groove binding agents. Mutat Res 2007;623(1-2):24-40. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 10000, New Zealand. [email protected]. Palmer BD, Henare K, Woon ST, et al. Synthesis and biological activity of azido analogues of 5,6-dimethylxanthenone-4-acetic acid for use in photoaffinity labeling. J Med Chem 2007;50(16):3757-64. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Patel K, Lewiston D, Gu Y, Hicks KO, Wilson WR. Analysis of the hypoxiaactivated dinitrobenzamide mustard phosphate pre-prodrug PR-104 and its alcohol metabolite PR-104A in plasma and tissues by liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2007;856(1-2):302-11. Contact: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland, New Zealand. Patterson AV, Ferry DM, Edmunds SJ, et al. Mechanism of action and preclinical antitumour activity of the novel hypoxia-activated DNA cross-linking agent PR104. Clin Cancer Res 2007;13(13):3922-32. Contact: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Auckland, New Zealand. Singleton DC, Li D, Bai SY, et al. The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX411 (NTR). Cancer Gene Ther 2007;14(12):953-67. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. Smaill JB, Baker EN, Booth RJ, et al. Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole1,3 (2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases. Eur J Med Chem 2007. Contact: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand. Smaill JB, Lee HH, Palmer BD, et al. Synthesis and structure-activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole1,3 (2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases. Bioorg Med Chem Lett 2008;18(3):929-33. Contact: Auckland Cancer Society Research Centre, Cancer 145 School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Spicer JA, Rewcastle GW, Kaufman MD, et al. 4-anilino-5-carboxamido-2pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. J Med Chem 2007;50(21):5090-102. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. [email protected]. Tang MH, Helsby NA, Goldthorpe MA, Thompson KM, Al-Ali S, Tingle MD. Hepatic nitroreduction, toxicity and toxicokinetics of the anti-tumour prodrug CB 1954 in mouse and rat. Toxicology 2007;240(1-2):70-85. Contact: Department of Pharmacology and Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand. [email protected]. Wilson WR, Hicks KO, Pullen SM, Ferry DM, Helsby NA, Patterson AV. Bystander effects of bioreductive drugs: potential for exploiting pathological tumour hypoxia with dinitrobenzamide mustards. Radiat Res 2007;167(6):625-36. Contact: Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand. [email protected]. Zhao L, Marshall ES, Kelland LR, Baguley BC. Evidence for the involvement of p38 MAP kinase in the action of the vascular disrupting agent 5,6dimethylxanthenone-4-acetic acid (DMXAA). Invest New Drugs 2007;25(3):271-6. Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Gastrointestinal Cancers Humar and Guilford of the Cancer Genetics Laboratory (University of Otago) have presented a theory on the development of hereditary diffuse gastric cancer and lost cell polarity, as a short path to cancer48. They say that the mechanisms that underlie the initiation of human cancer are poorly understood. In this paper they describe the development of hereditary diffuse gastric cancer and argue that it arises from the disruption of the regenerative processes that are inherent to all epithelial tissues. This model supports the cancer stem cell hypothesis, in which tumours contain a sub-population of cells with the key stem cell characteristics of capacity for self renewal, differentiation and limitless replication. They argue that epigenetic modifications induced by common environmental and physiological pressures are able to initiate this disruption. The carcinogenic effects of these modifications are potentially reversible through the use of epigenetic therapies such as DNA demethylating agents and histone deacetylation inhibitors. A retrospective analysis of 13 years of surveillance data of Barrett’s oesophagus in 212 patients has highlighted that 88% of all adenocarcinoma occurred in a subset of only 11% patients49. All patients who developed cancer were male and all but one patient had dysplasia or ulcerations on index endoscopy. The authors conclude that to stratify surveillance for Barrett's esophagus, programmes could focus on male patients with dysplasia or ulcerations on index endoscopy. However, the cost-effectiveness of this approach remains unproven. 146 Cancer Additional Publications Deeks ED, Scott LJ. Docetaxel: in gastric cancer. Drugs 2007;67(13):1893-901. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected]. Dhillon S, Scott LJ. Capecitabine: in advanced gastric or oesophagogastric cancer. Drugs 2007;67(4):601-10. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA. [email protected]. Siddiqui MA, Scott LJ. Imatinib: a review of its use in the management of gastrointestinal stromal tumours. Drugs 2007;67(5):805-20. Contact: Wolters Kluwer Health/ Adis, Auckland, New Zealand. [email protected]. Haematological Cancers Treatment Hoy et al. (ADIS, New Zealand) report on the introduction of an intravenous formulation of busulfan, developed to replace the oral preparation as a conditioning treatment prior to haematopoietic stem cell transplantation (HSCT) in paediatric patients50. Busulfan is a cytotoxic bifunctional alkylating agent. Intravenous busulfan was considered to be well tolerated, in the particular context of HSCT, and no failure of HSCT due to organ toxicity was reported. Nonhaematologic adverse events commonly associated with busulfan conditioning regimens were frequent, but generally of mild to moderate severity. The intravenous busulfan regimen was frequently associated with elevated liver enzymes, but hepatic veno-occlusive disease (HVOD) was infrequent, of mild to moderate severity, and resolved within 10 days of diagnosis. Unlike oral busulfan, intravenous busulfan does not appear to be associated with severe HVOD or death due to organ toxicity. ScottEconomics has undertaken an economic evaluation of third-line treatment with alemtuzumab for chronic lymphocytic leukaemia51. Alemtuzumab was compared with fludarabine, cyclophosphamide and rituximab (FCR). Average costs and outcomes and incremental cost per patient treated, per survival month and per QALY gained, were calculated. All costs were presented in 2006 New Zealand dollars. Base-case direct medical costs for alemtuzumab per treatment regimen per patient were $NZ15,303 lower than those for FCR. The average direct medical cost per survival month gained for alemtuzumab was $NZ3,144 and for FCR was $NZ4,101, and the average direct medical cost per QALY gained was $NZ46,016 and for FCR was $NZ60,012. Additional Publications Cross SA, Lyseng-Williamson KA. Imatinib: in relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukaemia. Drugs 2007;67(17):2645-54. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA. [email protected]. Ganta S, Paxton JW, Baguley BC, Garg S. Development and validation of bioanalytical method for the determination of asulacrine in plasma by liquid chromatography. J Pharm Biomed Anal 2008;46(2):386-90. Contact: School of Cancer 147 Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Moen MD, McKeage K, Plosker GL, Siddiqui MA. Imatinib: a review of its use in chronic myeloid leukaemia. Drugs 2007;67(2):299-320. Contact: Wolters Kluwer Health, Adis, Auckland, New Zealand. Plosker GL, Robinson DM. Nilotinib. Drugs 2008;68(4):449-59. Contact: Wolters Kluwer Health Adis, Auckland, New Zealand. [email protected]. Sanford M, Lyseng-Williamson KA. Nelarabine. Drugs 2008;68(4):439-47. Contact: Wolters Kluwer Health Adis, Auckland, New Zealand. [email protected]. Risk Factors Researchers from the University of Otago52 have found no protective effect of folate supplementation in pregnancy on the development of acute lymphoblastic leukaemia (ALL) in childhood. In a national case-control study, the mothers of 97 children with ALL and 303 control children were interviewed about their intake of supplements during pregnancy. No association with folate intake was found, even when data from New Zealand were combined in a meta-analysis with data from a similar study in Australia (which reported a small protective effect) and a study in Quebec. Head and Neck Cancers Ewing’s Sarcoma A case report of a 22-year-old male with Extra-skeletal Ewing's sarcoma (EES) of the submandibular gland has been published by a team at the Head and Neck and Skull Base Surgery/Oncology Programme (Hutt Hospital)53. The team believes that this has not been described previously. Extra-skeletal Ewing's sarcoma (EES) is an uncommon malignancy, especially in the head and neck region, that may arise in various extra-osseous tissues. The patient, who underwent combined treatment with surgical resection and chemo-irradiation, was disease free for 22 months but succumbed to multi-organ metastases 14 months later. The case highlights the combined diagnostic role of immunohistochemical, cytogenetic and radiological evaluation of EES. EES is an aggressive cancer that requires multidisciplinary management with wide surgical excision and adjunctive chemoirradiation for the best outcome. Risk Factors Cannabis use does not increase the risk of head and neck cancer, according to the findings of a case control study published by the Medical Research Institute of New Zealand (Wellington)54. Researchers analysed data from 75 cases and 319 controls. An increased risk of cancer was found with increasing tobacco use, alcohol consumption, and decreased income but not increasing cannabis use. The highest tertile of cannabis use (>8.3 joint years) was associated with a nonsignificant increased risk of cancer (relative risk = 1.6; 95% confidence interval: 0.5-5.2) after adjustment for confounding variables. However, the research team cautions that, given the limited power of the study to detect a statistically significant effect and the duration of use studied, a small or longer-term effect cannot be excluded. 148 Cancer Thyroid Cancers Lallu et al. highlight two cases in which bland cytologic features seen following fine needle aspiration cytology could have led to misdiagnosis of metastatic thyroid carcinoma of the Hurthle cell type, had immunohistochemical stains not been carried out55. They stress that immunohistochemistry aids the definitive diagnosis of metastatic Hurthle cell carcinoma of thyroid, especially when the presence of a previous thyroid lesion is not communicated to the laboratory. Additional Publications Blick SK, Scott LJ. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs 2007;67(17):2585-607. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA. [email protected]. Ch'ng S, Low I, Ng D, et al. Epidermal growth factor receptor: a novel biomarker for aggressive head and neck cutaneous squamous cell carcinoma. Hum Pathol 2008;39(3):344-9. Contact: Department of Medicine, Wellington School of Medicine & Health Sciences, Wellington, 6021 New Zealand. Gunawardena I, Kenwright D, Steventon N, Ferguson C. Primitive neuroectodermal tumour of the tongue. J Laryngol Otol 2008;122(4):416-8. Contact: Department of Otolaryngology, Head and Neck Surgery, Wellington Hospital, Wellington, New Zealand. [email protected]. Lin E, Hwang TZ, Hornibrook J, Ormond T. Voice of postradiotherapy nasopharyngeal carcinoma patients: evidence of vocal tract effect. J Voice 2008;22(3):351-64. Contact: University of Canterbury, Communication Disorders, Christchurch, New Zealand. Liver Cancer A team at the New Zealand Transplant Unit of Auckland City Hospital56 presented data suggesting that careful patient selection for liver resection for hepatocellular carcinoma can achieve good long-term patient survival and acceptable levels of risk. Multivariate analysis showed that only tumour recurrence and presence of cirrhosis were significant determinants of the risk of tumour-related death. Sorafenib was recently approved in the US and the EU for treatment of patients with hepatocellular carcinoma, and has been shown to significantly improved survival in patients with advanced disease, as detailed in a recent review57. Monotherapy with oral sorafenib 400 mg twice daily was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse event profile. Cancer 149 Lung Cancer Disparities Stevens et al. 58 propose that low anti-cancer treatment rates may contribute to poorer survival outcomes of patients with lung cancer in New Zealand. Survival rates compare unfavourably with those from Australia and the United States. To ascertain whether these poorer outcomes were related to secondary care management or to other factors, the team documented stage of disease, comorbidities, and initial secondary care management for patients diagnosed with lung cancer in 2004, in Auckland and Northland (New Zealand). These data were compared with international data. Cases were identified from regional databases and the New Zealand Cancer Registry. Five hundred sixty-five eligible cases were identified. Overall, 70% of cases were referred to an anticancer service, and 50% received initial anticancer treatment. Potentially curative treatment was received by 20% of cases. The authors say that this cohort was characterised by high comorbidity and advanced disease. Although similar to the United Kingdom, initial treatment rates were low in comparison with Australia and the United States, despite similar stage distributions. Overall, 50% of patients, including 30% with early-stage disease, did not receive initial anticancer treatment. As individuals with early-stage, non-small-cell lung cancers (NSCLC) generally have a better of survival than those with other forms of the disease, Stevens et al.59 suggest that survival outcomes in these patients will be disproportionately affected by appropriate or inappropriate treatment. Using the same data as in the previous study, the team looked at management of stage I/II NSCLC, whether management differed from international practice, and factors influencing curative management. Of the 142 cases with stage I or II NSCLC, 79 patients (56%) were treated with curative intent and 61 (44%) were managed palliatively. Of those treated curatively, 69 underwent surgical resection, 9 received definitive radiation therapy and a single patient received concurrent chemo-irradiation. Of those managed palliatively, 21 received anti-cancer treatment and 40 received supportive care. Increasing age and co-morbidity reduced the chances of receiving curative treatment (P < 0.001, P = 0.004, respectively). However, discussion at a multidisciplinary meeting was associated with increased likelihood of curative management (P < 0.001). The investigators observed that disparity between New Zealand and overseas practice increased with increasing age and co-morbidity in the patients. They found that only half of those managed curatively commenced treatment within internationally recommended time frames. The authors postulate that these factors may contribute to the poorer survival rate in New Zealand and suggest that, as the management differences increased with increasing age and co-morbidity, more nihilistic attitudes may prevail in New Zealand. In a further study using the same data60, Stevens et al. found that Māori were 2.5 times more likely to have locally advanced disease than localised disease compared with Europeans (p < 0.01), and four times less likely to receive curative rather than palliative anti-cancer treatment compared with Europeans (p < 0.01). Māori had longer transit times from diagnosis to treatment (p < 0.001). Maori were more likely to decline treatment and miss appointments than Europeans, although this only partially explained management differences. The authors say 150 Cancer that multiple factors are potentially responsible for the higher case-fatality ratio in Māori. Such factors include presentation with more advanced disease, lower rates of curative treatment for non-metastatic disease, and longer transit times from diagnosis to treatment. The investigators also say that socioeconomic deprivation, co-morbidity levels, and failure to accept treatment did not fully explain ethnic differences in management and call for further assessment of the underlying issues by prospective evaluation. Risk Factors Aldington et al.61 from the Medical Research Institute of New Zealand (Wellington) have shown that long-term cannabis use increases the risk of lung cancer in young adults, with an increased relative risk of 5.7 (95% confidence intervals: 1.5-21.6) in the highest tertile of cannabis use. They identified patients up to 55 years of age from the New Zealand Cancer Registry (NZCR) and hospital databases and adjusted for confounding variables, such as cigarette smoking. A total of 79 cases of lung cancer were studied and 324 controls, in a study involving eight District Health Boards. Young et al. (Department of Medicine, University of Auckland) call for forced expiratory volume in one second (FEV(1)) to be considered a marker that identifies smokers at greatest need of medical intervention62. The authors say that FEV(1) is more than a measure of airflow limitation, but a marker of premature death with broad utility in assessing baseline risk of chronic obstructive pulmonary disease, lung cancer, coronary artery disease and stroke, collectively accounting for 70-80% of premature death in smokers. They propose that spirometry has broad utility in identifying smokers who are at greatest risk of cardiorespiratory complications and greatest benefit from targeted preventive strategies, such as smoking cessation, prioritised screening and effective pharmacotherapy. Additional Publications Wilson K, Widdowson M, Swanney M, Meyer R, Singh H, Beckert L. Chronic dyspnea and wheezing in a 46-year-old nonsmoker. Chest 2008;133(4):1034-7. Contact: Respiratory Physiology Laboratory, Department of Respiratory Medicine, Christchurch Hospital, Christchurch, New Zealand. [email protected]. Lymphatic Cancer A review of the literature on the use of fludarabine in non-hodgkin’s lymphoma concludes that it is as effective as several other standard treatment regimens in treatment-naïve patients and is also effective in patients with recurrent or refractory disease63. The efficacy of fludarabine therapy is improved with the use of rituximab, as part of the initial therapeutic regimen or as maintenance therapy, and deserves consideration. Fludarabine has generally acceptable tolerability; however, it is associated with haematological adverse events, including myelosuppression. In closing, the authors say that fludarabine, provides a highly effective first- or second-line option in the treatment of non-Hodgkin's lymphoma. Macann et al. (Department of Radiation Oncology, Auckland Regional Cancer and Blood Service and the German Hodgkin’s Lymphoma Study Group) have Cancer 151 published a study undertaken to assess whether radiotherapy influenced the severe pulmonary toxicity observed with concurrent administration of gemcitabine and bleomycin in patients with advanced-stage Hodgkin’s lymphoma64. Severe pulmonary toxicity was observed in the pilot study of BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine) for advanced-stage Hodgkin's lymphoma. Twenty-seven patients were enrolled on the study before its premature closure as a result of the development of serious pulmonary toxicity in 8 patients. The pulmonary toxicity occurred either during or immediately after the BAGCOPP chemotherapy course. Pulmonary toxicity contributed to one early fatality but resolved in the other 7 patients after cessation of gemcitabine and bleomycin, allowing continuation of therapy. Fifteen patients received consolidative radiotherapy, including 4 who previously had pulmonary toxicity. There were no reported cases of radiation pneumonitis and no exacerbation of pulmonary symptoms in the 4 patients who had had previous pulmonary toxicity. Gemcitabine (when administered without bleomycin) remains of interest in Hodgkin's lymphoma and is being incorporated into a new German Hodgkin's Lymphoma Study Group protocol that also includes consolidative radiotherapy. This study supports the concept of the integration of radiotherapy in gemcitabinecontaining regimens in Hodgkin's lymphoma if there is an interval of at least 4 weeks between the two modalities and with a schedule whereby radiotherapy follows the chemotherapy. Occupational Health A nationwide study of bladder cancer in adults65 has confirmed that hairdressers (odds ratio (OR): 9.15; 95% confidence interval (95%CI): 1.60-62.22), and sewing machinists (OR: 3.07; 95%CI: 1.35-6.96) appear to be at the high risk. The team from the Centre of Public Health Research at Massey University (Wellington) looked at 273 cases of bladder cancer and 471 controls. They also identified occupations that may confer elevated risk levels and deserved further study. These were: tailors and dressmakers, rubber and plastics-products machine operators, building workers, and female market farmers and crop growers. Firth and colleagues66 at the Otago University have undertaken a study of cancer mortality risk in New Zealand women in the six most common occupation groups: clerical workers, health professionals, teachers, farmers, cleaners and textile workers. In the group aged over 20 years (7236), leukaemia was significantly increased in health professionals (proportional mortality ratio (PMR) was 1.52; 95% CI: 1.08-2.09, n=38). In nurses alone, the PMR for leukaemia was 1.42; 95% CI: 0.96-2.01, n=31). Investigators at the Centre for Public Health Research (Massey University) have looked at occupational risk factors for non-Hodgkin's lymphoma (NHL) in New Zealand67. In a nationwide case-control study a total of 291 incident cases of NHL (age 25-70 years) notified to the New Zealand Cancer Registry during 2003 and 2004, and 471 population controls, were interviewed face-to-face. The questionnaire collected demographic information and a full occupational history. The relative risk for NHL associated with ever being employed in particular occupations and industries was calculated by unconditional logistic regression 152 Cancer adjusting for age, sex, smoking, ethnicity and socioeconomic status. An elevated NHL risk was observed for field crop and vegetable growers (OR: 2.74; 95% CI: 1.04-7.25) and horticulture and fruit growing (OR: 2.28; 95% CI: 1.37-3.79), particularly for women (OR: 3.44; 95% CI: 0.62-18.9; OR: 3.15; 95% CI: 1.50-6.61). Sheep and dairy farming was not associated with an increased risk of NHL. Meat processors had an elevated risk (OR: 1.97; 95% CI: 0.97-3.97), as did heavy truck drivers (OR: 1.98; 95% CI: 0.92-4.24), workers employed in metal product manufacturing (OR: 1.92; 95% CI: 1.12-3.28) and cleaners (OR: 2.11; 95% CI: 1.21-3.65). After semi-Bayes adjustment for the number of occupations examined the elevated risks for horticulture and fruit growing, metal product manufacturing and cleaners remained statistically significant, representing the most robust findings of this study. The study confirms previous research findings that crop farmers and meat workers are high-risk occupations for NHL in New Zealand, and authors identify several other occupations and industries of high NHL risk that merit further study. Olfactory Cancer Capelle and Krawitz report on a case of Esthesioneuroblastoma, a rare malignancy arising from the olfactory epithelium68. A 75-year-old man presented with a Kadish stage C esthesioneuroblastoma and underwent craniofacial surgery and adjuvant radiotherapy. Two years later he was found to have diffuse subdural deposits with distant bone and nodal metastases, treated with further radiotherapy. The patient's condition subsequently deteriorated and he died. Given this unusual pattern of failure, the authors review the recent published studies regarding the natural history, treatment and outcome for this tumour. Oncogenesis A team from the Children's Cancer and Developmental Genetics Research Group (Christchurch School of Medicine and Health Sciences) have published a review on the role of a gene with activity in fetal development and oncogenesis69. The authors say that embryonic and fetal development is a highly complex process choreographed by several families of genes that regulate early development of the embryo. Disruption in the structure and/or function of developmental genes produces morphogenic errors of development. (Morphogenesis is the differentiation and growth of organs or tissues during development.) One such family is the Hedgehog (Hh) signalling pathway, which plays an important role in the embryonal development of both invertebrates and vertebrates, including normal development of the brain, eye, limbs, foregut and its derivatives. Disruption of the Sonic hedgehog expression during critical periods of development is associated with developmental disorders of the brain, namely, holoprosencephaly, and the VATER association. Inappropriate activation of the pathway in post-embryonic development has been demonstrated in several human malignancies, including those of the brain and skin, both in children and adults. Specific inhibition of Hh signalling in these tumours inhibits growth of a wide range of malignancies. This demonstrates a requirement for Hh signalling in these tumours. These observations suggest that a better understanding of the genetic control of morphogenesis can ultimately provide us with greater knowledge of how congenital structural abnormalities occur, as well as the Cancer 153 processes that lead to several childhood and other tumours. The authors surmise that there may be a closer relationship between embryogenesis and oncogenesis than previously realised. Cox and Hampton of the Free Radical Research Group (University of Otago) have published findings suggesting that the anti-apoptotic oncogene Bcl-2 may promote tumourigenesis by preventing the removal of oxidatively damaged cells, rather than protecting cells from oxidative stress - as has previously been proposed70. The team looked at Jurkat T lymphoma cells exposed to hydrogen peroxide at doses that induced apoptosis (programmed cell death) or necrosis. At apoptotic doses, over-expression of Bcl-2 did block cell death. However, these cells still showed the same signs of oxidative damage, suggesting that the antiapoptotic activity is not associated with general antioxidant properties. Assessment of micronuclei formation in cells over-expressing Bcl-2 showed evidence of increased genomic instability, consistent with the impairment of apoptosis in damaged cells. Recently published data suggests that the increased levels of autocrine human growth hormone observed in endometriosis and endometrial adenocarcinoma stimulates oncogenicity of endometrial carcinoma cells. Researchers from the Liggins Institute and National Research Centre for Growth and Development, and Department of Molecular Medicine and Pathology (University of Auckland) have conducted studies to demonstrate this effect71. These studies demonstrate a pivotal role for autocrine human growth factor in the development and progression of endometrial carcinoma and indicate the potential therapeutic relevance of human growth factor antagonism in the treatment of endometrial carcinoma. A review summarising the current evidence for involvement of trefoil factors (TFFs) in human cancer has been published by researchers at the Liggins Institute (University of Auckland)72. TFFs are oestrogen-regulated genes, which are also regulated by other substances, including growth hormone, insulin-like growth factor-1 and epidermal growth factor, as well as oncogenic stimuli. They are secreted proteins present in serum and can act as growth factors promoting cell survival, anchorage-independent growth and motility. Recent compelling evidence has emerged from experimental and clinical studies to indicate a pivotal role of TFFs in oncogenic transformation, growth and metastatic extension of common human solid tumours. Additional Publications Ferguson LR, Denny WA. Genotoxicity of non-covalent interactions: DNA intercalators. Mutat Res 2007;623(1-2):14-23. Contact: Auckland Cancer Society Research Centre, Faculty of Medical & Health Science, The University of Auckland, New Zealand. [email protected]. Liu DX, Lobie PE. Transcriptional activation of p53 by Pitx1. Cell Death Differ 2007;14(11):1893-907. Contact: Liggins Institute and National Research Centre for Growth and Development, University of Auckland, Auckland, New Zealand. Mohankumar KM, Xu XQ, Zhu T, et al. HOXA1-stimulated oncogenicity is mediated by selective upregulation of components of the p44/42 MAP kinase pathway in human mammary carcinoma cells. Oncogene 2007;26(27):3998-4008. 154 Cancer Contact: The Liggins Institute and National Research Centre for Growth and Development, University of Auckland, Auckland, New Zealand. Shafiei F, Rahnama F, Pawella L, Mitchell MD, Gluckman PD, Lobie PE. DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells. Oncogene 2008;27(18):2602-12. Contact: National Research Centre for Growth and Development and the Liggins Institute, University of Auckland, Auckland, New Zealand. Orthopaedic Oncology Clinicians from the Orthopaedic Oncology Unit, Middlemore Hospital (Auckland) have published a review of their experience with 2-stage revision of uncemented Kotz Modular Femoral and Tibial Replacement System prostheses, over the last 15 years73. They describe the outcomes for the eleven patients that underwent second-stage revision and conclude that this procedure with retention of a wellingrown stem can be associated with successful eradication of infection. Palliative Care Researchers at the Department of General Practice of Dunedin Medical School have undertaken a qualitative study of seven women dying from cancer in a Dunedin hospice74. The key theme that came through from the questionnaires was uncertainty, throughout the diagnosis and treatment process and in living with disease (such as knowing whether they could manage an outing or be pain free). All felt that their bodies had let them down and that they were unable to fulfil the goal of “living until they die”. None were afraid of dying but all were affected by increased social isolation as they withdrew from employment and other activities. The authors conclude that having a ‘good death’ is affected not just by management and treatment by health professionals but by the perceptions of the individual held by others and themselves. The Hospice and Palliative Care Service, Nurse Maude Association (Christchurch) has undertaken an audit of the management of nausea, vomiting and bowel obstruction in metastatic ovarian cancer75. They included a focus on pharmacological and non-pharmacological interventions (e.g. dietary advice and relaxation strategies). The audit involved a retrospective chart review of 17 patients and identified the current clinical management of these symptoms in comparison with best practice guidelines. The results indicated many areas of symptom management were in line with current evidence-based practise. However, the use of non-pharmaceutical interventions was limited. There were several implications for clinical practice, specifically supporting the use of electronic integrated patient management systems and a greater use of nonpharmaceutical (complementary) interventions. William and Mcleod of the North Shore Hospice (Auckland) have published a review on the management of breakthrough pain (BTP) in patients with cancer76. They say that there is no consensus definition for BTP in patients with cancer, meaning that it is often inadequately diagnosed and assessed, therefore making it Cancer 155 more challenging to manage. Cancer pain is generally moderate to severe in intensity and persistent in nature. As most breakthrough analgesia fails to be effective in the time required for BTP, no useful analgesia is provided but drug adverse effects escalate. The frequency of BTP and its inadequate management means that it has significant adverse effects on patients, their families and those involved in their care. The article outlines a systematic, clinical and evidencebased approach to managing BTP in patients with cancer that emphasises a holistic approach and an understanding of multi-dimensional 'total pain'. Guidelines for managing BTP are presented and areas of developing research are identified. Post-Treatment Immunisation in Children An Australasian study77 of involving 45 paediatric oncologists (37 responded) has found that the majority of respondents (94%) would recommend commencing booster vaccinations 6 months post treatment, in keeping with current guidelines. Intensity of chemotherapy was seen to be an important factor, with 97% of respondents recommending re-immunisation after intensive chemotherapy and only 48% after a lower intensity regimen. Sixty-nine percent would recommend yearly influenza vaccinations for their patients. The authors highlighted the variability in the findings and called for a review of the evidence-base and guidelines on this important variable for cancer survival. Pancreatic Cancer A review has been published that provides practical advice for the clinician when confronted with questions about the risk of pancreatic cancer in relatives, and the role of genetic testing and screening in high-risk individuals78. The author says that there is now a sufficient body of evidence to inform relatives of their relative risk of developing the disease. Additional Publications Connor S. Branch-type intraductal papillary mucinous neoplasms. World J Surg 2008;32(2):279-80. Contact: Department of Surgery, Christchurch Hospital, Private Bag, 4710, Christchurch, New Zealand, [email protected]. Primary Care The education and training of primary care professionals in relation to cancer and primary care has been undertaken by a team from the Community and Home Detox Service (Auckland Community Alchohol and Drug Service)79. A semis structured telephone questionnaire was administered to 210 organisations in a national audit. The team found evidence of good adult education practice, and 95% of organisations ran accredited programmes. Although pharmaceutical industry support was not favoured, the majority (78%) described this as their main source of funding. They conclude that there is optimism and strong commitment among primary care cancer education and training providers. 156 Cancer Additional Publications McAvoy BR. General practitioners and cancer control. Med J Aust 2007;187(2):1157. Contact: Community and Home Detox Service, Auckland Community Alcohol and Drug Service, Auckland, New Zealand. [email protected]. Reproductive Cancers Cervical Cancer Prevention Jones et al. (Gynaecological Oncology Service, National Women's Hospital) call the introduction of the human papilloma virus (HPV) vaccine the single most important advance in the prevention of cervical cancer since the introduction of cervical cytology half a century ago80. Vaccination should ideally occur prior to a female's first sexual experience. The authors go on to suggest that the HPV vaccine should be publicly funded in New Zealand. Screening Lovell et al.81 explored why a country such as New Zealand, which has elevated awareness of cervical screening due to media coverage of adverse events, should still experience poor rates of uptake for the free screening programme. Qualitative interviews were conducted with 17 women who were overdue for a smear test in 2001-2002. Nine service providers were also interviewed. The authors conclude that, concurrent with socioeconomic limitations, concerns about exposing the body were key in the decision to delay screening. Māori and Pacific women in particular expressed embarrassment about exposing their bodies and concerns over violating cultural beliefs about sacredness. An in-depth study of 6 women (predominantly Māori) at least 6 months overdue for a cervical smear examined their reasons for not persisting with the screening programme. It found that the smear process could “violate women’s positive aloneness with their bodies” and suggested that primary care services should find a way of addressing this82. Disease Progression and Invasive Potential Researchers at the Department of Preventive and Social Medicine, University of Otago (Dunedin)83 have published a study on the invasive potential of cervical cancer at ‘stage 0’ of the disease. The unethical treatment of women diagnosed with stage 0 cervical cancer at the National Women’s Hospital between 1955 and 1976, for whom treatment was with-held as part of a clinical study, resulted in a judicial review. The research team accessed the records from the review and were able to make a study of outcomes for 1229 (86%) of the 1229 women who were diagnosed with stage 0 cervical carcinoma at the hospital during that time period. They found that 143 women were managed only by punch or wedge biopsy and that their cumulative incidence of invasive cancer of the cervix or vaginal vault was 31.3% (95% CI: 22.7-42.3) at 30 years, and 50.3% (95% CI: 37.3-64.9) in the subset of 92 such women who had persistent disease within 24 months. However, cancer risk at 30 years was only 0.7% (95% CI: 0.3-1.9) in 593 women whose initial Cancer 157 treatment was deemed adequate or probably adequate, and whose treatment for recurrent disease was conventional. The study shows the importance of prompt, conventional treatment for stage 0 carcinoma of the cervix and the low risk of progression if this is carried out appropriately. Surgery A review by researchers at the National Women’s Hospital (Auckland) discusses the literature on the association between cervical treatment and preterm birth, and the clinical implications of these findings84. Excision of a portion of the cervix for treatment of cervical intraepithelial neoplasia may have an adverse effect on pregnancy outcome. The methodology and findings of the published literature on the association between cervical treatment and preterm birth, and the clinical implications of these findings are discussed. Additional Publications Gray B, Lewis H, Casey D. New Zealand's cervical screening legislation-and response. N Z Med J 2008;121(1268):U2910. Contact: Keam SJ, Harper DM. Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted, adsorbed) [Cervarix]. Drugs 2008;68(3):359-72. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. demail.adis.co.nz. Schiffman M, Rodriguez AC. Heterogeneity in CIN3 diagnosis. Lancet Oncol 2008;9(5):404-6. Endometrial Cancer An evidence-based review of local therapy in endometrial cancer has been published by Deeks (ADIS, New Zealand)85. Surgery is the standard primary treatment for early stage endometrial cancer, with local adjuvant therapies such as pelvic radiotherapy and vaginal brachytherapy most often used in patients with high risk of recurrence. There are currently very few well designed studies evaluating local therapies in endometrial cancer. To date, the available evidence suggests that adjuvant external beam radiotherapy reduces locoregional recurrence in stage I disease but not the risk of death. Considering the high survival rate and low recurrence risk of patients with early stage disease, postoperative adjuvant radiotherapy should perhaps be limited to patients with high risk of recurrence, particularly since such radiotherapy is associated with increased long-term complications and toxicity. Adjunctive chemotherapy has so far failed to demonstrate any improvement over radiotherapy in terms of overall survival in patients with intermediate and high-risk endometrial cancer. Deeks says that further well controlled studies are required in order to confidently establish the optimal use of local treatments and other therapies in endometrial cancer. Ovarian Cancer Researchers from the Hospice and Palliative Care Service, Nurse Maude Association (Christchurch) have undertaken an audit of the management of nausea, vomiting and bowel obstruction in metastatic ovarian cancer75. Women living with metastatic ovarian cancer experience many distressing symptoms, such as vomiting and bowel obstruction, which challenge the expertise of nurses 158 Cancer working in Palliative Care to promote quality of life. The audit involved a retrospective chart review of 17 patients and identified the current clinical management of these symptoms in comparison with best practice guidelines. The results indicated many areas of symptom management were in line with current evidence-based practice. However, the use of non-pharmaceutical interventions was limited. There were several implications for clinical practice, specifically supporting the use of electronic, integrated patient-management systems and a greater use of non-pharmaceutical (complementary) interventions. The audit process provided useful data for the authors to analyse current practice and promote more effective management of these distressing symptoms. Prostate Cancer Aetiology Nicholson and Whittington (Department of Anatomy and Structural Biology, University of Otago) have published a review on the possible role oxytocin in prostate disease86. Oxytocin is a peptide hormone produced by the posterior lobe of the pituitary. The authors say that the discovery that the peptide is produced locally within the male and female reproductive tracts has raised the possibility that oxytocin may have paracrine and autocrine actions outside of the nervous system. Oxytocin and its receptor have been identified in the human prostate. Oxytocin has been shown to modulate contractility of prostate tissue and also to regulate local concentrations of the biologically active androgens. Oxytocin has also been shown to regulate cell growth. Prostate disease is common and results from abnormal growth of the gland. Oxytocin concentrations are altered in both benign and malignant prostate diseases and in vitro studies suggest that the peptide may be involved in the pathophysiology of these diseases. Screening A team from the Department of Pathology and Molecular Medicine, (Wellington School of Medicine and Health Sciences, Otago University) and the Department of Radiation Oncology (Wellington Hospital) has published a review of the new evidence base for diagnosis and treatment of prostate cancer87. Although prostate cancer (PC) has a significant mortality, there is debate regarding the utility of PC screening and major studies investigating the value of population-based screening have yet to be concluded. There is increasing evidence from preliminary reports relating to outcome prediction for PC, that early detection leads to improved outcomes and a decrease in the burden of metastatic disease on our healthcare system. PC is rarely symptomatic until it has metastasised to bone and because of this prostate specific antigen (PSA)-based screening remains the only widely available and reliable method of diagnosis for organ-confined disease. There is now compelling evidence to show the following. 1. Cancers diagnosed by screening are more likely to be early stage, when most can be cured by a number of different treatment options. 2. The maximum benefits of screening are for men aged 50-70 years. Older men have a greater chance of a clinically insignificant cancer being diagnosed for which treatment is not necessary. 3. The familial risks of PC are well recognised. In particular, men with one or more first-degree relatives already diagnosed with the disease should be actively encouraged to undergo screening. 4. Modern histopathological assessment of fine core needle biopsies of the prostate allows for the likely behaviour of cancer present to be accurately predicted. Changes that mimic those of malignancy can be confidently Cancer 159 identified, so these cases are no longer incorrectly diagnosed. In conclusion, the team says that these improvements mean that now most men aged 50-70 years diagnosed with PC will have clinically significant cancers that require treatment. Diagnosis Mitchell et al. report the case of a 55-year-old man whose diagnosis of prostate cancer was made following investigation of multiple cranial nerve palsies88. Cranial nerve palsies have previously been reported in metastatic prostate carcinoma, usually occurring late in the course of the disease. Disparities Researchers from the Hugh Adam Cancer Epidemiology Unit (University of Otago) have examined ethnic differences in prostate cancer survival in New Zealand through a national study89. Analyses were based on the 7,733 men with histologically confirmed prostate cancer diagnosed from the start of 1996 to the end of 1999 in New Zealand. Five-year adjusted prostate-specific mortality rates and hazard ratios were calculated for Māori, Pacific, and European men. In univariate analyses, Māori and Pacific men had higher mortality, particularly in the first year after a diagnosis of prostate cancer, than did European men. The strongest prognostic factors for prostate cancer were Gleason score and age. When survival analyses by ethnic group were adjusted for age and Gleason score the disparities in survival for Māori men and Pacific men with low-grade prostate cancers remained, with European men having the best survival. Several possible explanations have been proposed to explain the survival disparities by ethnicity in New Zealand. Differentials in Gleason grade of disease by ethnic group explain a lot of these disparities. The authors say that further data on stage of disease at diagnosis, co-morbidity, treatment, access to health services, and behavioural and environmental factors are needed to resolve these issues. Additional Publications Gilling PJ. Prostate Cancer Following BPH Treatments: What the Patient Should Know. Eur Urol 2008;53(6):1109-10. Contact: PO Box 56, Tauranga, New Zealand. Keam SJ, Scott LJ. Dutasteride: a review of its use in the management of prostate disorders. Drugs 2008;68(4):463-85. Contact: Wolters Kluwer Health Adis, Auckland, New Zealand. [email protected]. Wellington K, Keam SJ. Spotlight on bicalutamide 150mg in the treatment of locally advanced prostate cancer. Drugs Aging 2007;24(2):169-71. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. Risk Factors Travier et al. have explored a possible link between HbA(1c) levels and cancer risk 90. HbA(1c) measurements were made on blood samples of participants in a hepatitis B (HB) screening program (1999-2001). Cancer incidence was determined by linkage to cancer registrations and hospitalization records to the end of 2004. Participants previously diagnosed with diabetes or cancer were excluded. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox regression. Among the 46,575 participants (70% Māori, 12% Pacific, 5% Asian and 12% Other), 634 cancer cases were observed. For all cancers combined, 160 Cancer a significant increased risk was found in persons with moderately elevated HbA(1c) levels (6%-6.9%) (HR: 1.40; 95% CI: 1.11-1.76), with a smaller increased risk in persons with highly elevated levels of ≥ 7% (HR: 1.09; 95% CI: 0.80-1.48) as compared with persons having low HbA(1c) levels (<6%). The HRs for respiratory cancers were 2.27 (95% CI: 1.34-3.86) for the moderate HbA(1c) category and 1.58 (95% CI: 0.77-3.26) for the upper HbA(1c) category. For endometrial cancers, the HRs were 4.05 (95% CI: 1.10-14.88) and 5.07 (95% CI: 1.20-21.31), respectively. For other cancer sites, no significantly increased risks were found. The authors suggest that these findings are consistent with other evidence that abnormal glucose metabolism may be associated with an increased risk of some cancers. Researchers at the Department of Psychological Medicine (University of Otago) have studied peoples perceptions of modifiable cancer risk factors in New Zealand91. An anonymous telephone questionnaire was administered 438 respondents (68% participation) 20 years and older, randomly selected from telephone directory listings. Nearly 90% considered that there were things which people could do to reduce cancer risk. Unprompted, almost two-thirds mentioned nutrition, and more than half suggested “not smoking”. Other suggestions included being physically active, and protection from excessive sun exposure. Two-thirds believed they could reduce their own risk, and by interview end this increased significantly to 72%. Half named items which people could consume to reduce risk: more vegetables, fruit or water; less alcohol, fatty foods, and meat. Greatest awareness was of risks from sunburn, secondhand tobacco smoke, sunlamps, eating animal fat, and being overweight, and of the protective effects of eating grains, fruit, and vegetables. Many considered stress, cellular phones, and genetically modified foods as risks, and vitamin and mineral supplements as protective. Few indicated awareness of risks from hepatitis B or alcohol. The investigators believe that greater public awareness about avoiding tobacco smoking and excessive sun exposure suggests gains from past efforts. They go on to say that to achieve similar awareness for other cancer prevention strategies, and to correct misconceptions, comparable resources and efforts are likely to be required. Laugesen has published a review entitled “Snuffing out cigarette sales and the smoking deaths epidemic”92, in which it is pointed out that low-nitrosamine tobacco snuff is 20 times less dangerous than cigarette smoking. It is further contended that oral snuff has helped to reduce smoking to unusually low levels in Swedish men, is much less dangerous than smoking, and does not cause lung or mouth cancer. Moreover, smokeless tobacco (which includes snuff) could reduce smoking-caused health inequity for Māori. Snuff can improve population health, and more so if more smokers switch to it. Continued bans on snuff are now regarded by some experts as unsound public policy. See also the work of Aldington et al on cannabis use, under ‘Lung Cancer’. Skin Cancer A team from the Department of Dermatology at Waikato Hospital have investigated the relatively high rates of melanoma skin cancers found in people Cancer 161 from the Tauranga area93. Data were obtained from retrospective review of histology reports from the public and private health systems in greater Tauranga (Tauranga and Western Bay of Plenty Districts). Primary cutaneous melanomas (including both invasive and in situ melanomas) reported during 2003 were included. Age-standardized melanoma rates were calculated for the entire population as well as for the non-Maori population of the region, identified from the 2001 New Zealand Census. The age-standardized incidence of invasive melanoma in the non-Maori population of the greater Tauranga region was 79/100,000. The age-standardized rate for the entire population was 70/100,000. The rate of in situ disease was 78/100,000 for non-Maori and 72/100,000 for the entire population. The authors conclude that the Tauranga region of New Zealand has an exceptionally high incidence of invasive and in situ melanomas. This is likely related to environmental, geographical and societal factors, including relatively high levels of UV exacerbated in recent times by ozone depletion, relatively cool summer temperatures which encourage outdoor exposure, and relatively fair skin colouring. Wright et al. looked at the ultraviolet radiation (UVR) exposures of 345 primary schoolchildren at 23 schools around New Zealand, using electronic UVR monitors for 1-week periods over 12 weeks in 2004 and 200594. Children completed activity diaries during the period UVR measurements were made and provided information on their indoor and outdoor status and clothing and sun protection worn. Mean total UVR exposure was approximately 5% of the ambient UVR on a horizontal surface, on average. Mean time spent outdoors was 2.3 h per day. Differences in children's UVR exposure could be explained, in part, by activity where outdoor passive pursuits were associated with higher UVR exposure rates than outdoor active and outdoor travel pursuits. Compared with older children, the activities of younger children, although labelled the same, resulted in different UVR exposures, either as a result of reporting differences or a real difference in UVR exposure patterns. UVR exposure rates were generally higher on weekdays compared with the weekend, confirming the important role of school sun protection and skin cancer prevention programmes. High UVR exposure activities included physical education, athletics and lunch break. Reynolds et al. have developed ‘heat maps’ that can be used as a new tool to predict risk of melanoma spreading to the lymph nodes95. They report that lymphoscintigraphy accurately maps lymphatic drainage from sites of cutaneous melanoma to the draining sentinel lymph nodes. The Sydney Melanoma Unit has accumulated lymphoscintigraphy data from over 5000 patients with cutaneous melanoma over more than 15 years, collectively revealing patterns of skin lymphatic drainage. The investigators mapped these data onto a threedimensional computer model to provide improved visualisation and analysis of lymphatic drainage from sites of cutaneous melanoma. They created threedimensional, colour-coded heat maps that showed the drainage patterns from melanoma sites below the neck to individual lymph-node fields and to many lymph-node fields. These maps highlight the inter-patient variability in skin lymphatic drainage, and show the skin regions in which highly variable drainage can occur. To enable interactive and dynamic analysis of these data, they also developed software to predict lymphatic drainage patterns from melanoma skin sites to sentinel lymph-node fields. The heat maps confirmed that the commonly used Sappey's lines are not effective in predicting lymphatic drainage. The heat 162 Cancer maps and the interactive software could be a new resource for clinicians to use in preoperative discussions with patients with melanoma and other skin cancers that can metastasise to the lymph nodes, and could be used in the identification of sentinel lymph-node fields during follow-up of such patients. Additional Publications Henness S, Vereecken P. Management of Merkel tumours: an evidence-based review. Curr Opin Oncol 2008;20(3):280-6. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. Hill SE, Mortimer NJ, Hitchcock B, Salmon PJ. Parotid fistula complicating surgical excision of a basal cell carcinoma: successful treatment with botulinum toxin type A. Dermatol Surg 2007;33(11):1365-7. Contact: Department of Dermatology, Waikato Hospital, Hamilton, New Zealand. Reynolds HM, Dunbar PR, Uren RF, Thompson JF, Smith NP. Mapping melanoma lymphoscintigraphy data onto a 3D anatomically based model. Ann Biomed Eng 2007;35(8):1444-57. Contact: The Bioengineering Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand. [email protected]. Stoitzner P, Green LK, Jung JY, et al. Inefficient presentation of tumour-derived antigen by tumour-infiltrating dendritic cells. Cancer Immunol Immunother 2008. Contact: Malaghan Institute of Medical Research, Wellington, New Zealand, [email protected]. Stoitzner P, Green LK, Jung JY, et al. Tumour immunotherapy by epicutaneous immunization requires langerhans cells. J Immunol 2008;180(3):1991-8. Contact: Malaghan Institute of Medical Research, Wellington, New Zealand. [email protected]. Wagstaff AJ, Perry CM. Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs 2007;67(15):2187-210. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected]. Urinary Tract Cancers Prevention AgResearch (Hamilton) has reported the findings of a study designed to establish whether dietary administration of broccoli sprouts extract to rats inhibits the formation of bladder cancer induced by nitrosamine96. The incidence, multiplicity, size, and progression of bladder cancer were all inhibited by the extract, while the extract itself caused no histologic changes in the bladder. Isothiocyanates are a well-known class of cancer chemopreventive agents, and broccoli sprouts are a rich source of several isothiocyanates. The team found that the concentrations of isothiocyanate equivalents in the urine of treated rats were 2 to 3 orders of magnitude higher than those in plasma, indicating that the bladder epithelium, the major site of bladder cancer development, is most exposed to oral doses of isothiocyanate. Indeed, tissue levels of isothiocyanate equivalents in the bladder were significantly higher than in the liver. They conclude that broccoli sprout extract is a highly promising substance for bladder cancer prevention and Cancer 163 the isothiocyanates in the extract are selectively delivered to the bladder epithelium through urinary excretion. Additional Publications See also the study by Dryson et al. under Occupational Health. Dryson E, t Mannetje A, Walls C, et al. Case-control study of high risk occupations for bladder cancer in New Zealand. Int J Cancer 2008;122(6):1340-6. Contact: Centre for Public Health Research, Massey University, Wellington, New Zealand. Pathology A series of studies looking at prognostic and diagnostic factors in renal cell carcinoma have been published by Delahunt and colleagues of the Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences. The first concerns the classification of sarcomatoid renal cell carcinoma (SRC) versus clear cell renal carcinoma97. Sarcomatoid renal cell carcinoma is recognized as an extreme form of dedifferentiation in renal cell carcinoma and is associated with a poor prognosis. The team investigated collagen expression using immunohistochemistry in these 2 tumour types. They found a number of differences in collagen expression between the tumour types, including the fact that that only SRC showed cytoplasmic expression of collagen types I and II. The study provides validating evidence that these 2 morphotypes should not be considered together for classification purposes. The second article is a review of prognostic factors for renal tumours, according to histological subtype98. A wide variety of parameters have been investigated for their prognostic significance in mixed series of renal cell carcinoma (RCC). The classification of RCC into separate types with differing morphology, genotype and probable clinical outcome has led to a re-evaluation of many prognostic parameters with studies confined to a single RCC morphotype. Tumour stage remains the most important predictor of RCC outcome and recent investigations have focused upon tumour diameter and the prognostic significance of stromal, vascular and lymphatic invasion within the renal sinus. In large tumour series, morphotype has been correlated with patient survival, with clear cell RCC being associated with a less favourable outcome than chromophobe RCC and to a lesser extent papillary RCC, for organ confined tumours. The prognostic significance of nuclear grading remains controversial. Fuhrman grading has been shown to have prognostic utility for clear cell RCC in some series. The evidence for utility of other markers is also discussed. The third study was undertaken to assess the prognostic effectiveness of Fuhrman nuclear grading and the individual components of this grading system, in a series of chromophobe RCCs99. The authors conclude that neither Fuhrman grading, nor any of the components of the Fuhrman grading system, is useful as prognostic indicators for this tumour type. Additional Publications Holyoake A, O'Sullivan P, Pollock R, et al. Development of a multiplex RNA urine test for the detection and stratification of transitional cell carcinoma of the bladder. Clin Cancer Res 2008;14(3):742-9. Contact: Pacific Edge Biotechnology Ltd., Centre for Innovation, University of Otago, Dunedin, New Zealand. 164 Cancer Wilms’ Tumour Nephrogenic rests are clusters of developmentally immature cells and dysplastic (abnormal) cellular arrangements. In a review of the molecular pathology and epidemiology of nephrogenic rests and Wilms’ tumours, Fukuzawa et al. provide an explanation for the interethnic variations in the incidence100. Perilobar (PLNR) and intralobar nephrogenic rests (ILNR) are distinct precursor lesions of Wilms’ tumours that have different structural, clinical, genetic, and epidemiologic features. Wilms’ tumours in East-Asian children have unique epidemiologic features in that the incidence is about half that of white children, an early age at diagnosis, a male predominance, and an association with ILNR. Loss of IGF2 imprinting is associated with PLNR more commonly seen in Wilms’ tumours from white children than tumours from children of Asian descent. Therefore, this epigenetic difference and the higher frequency of PLNR provide an explanation for the interethnic variations in the incidence of Wilms’ tumour. The histopathologic, clinical, and genetic differences between ILNR and PLNR are described in this review, followed by a description of an epigenetic mechanism that underlies PLNR formation and the unique epidemiologic feature of Wilms’ tumours. Additional Publications (Wilms’ tumour) Fukuzawa R, Anaka M, Heathcott R, et al. Wilms tumour histology is determined by distinct types of precursor lesions and not epigenetic changes. J Pathol 2008. Contact: Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, PO Box 56, Dunedin, New Zealand. Fukuzawa R, Heathcott RW, More HE, Reeve AE. Sequential WT1 and CTNNB1 mutations and alterations of beta-catenin localisation in intralobar nephrogenic rests and associated Wilms’ tumours: two case studies. J Clin Pathol 2007;60(9):1013-6. Contact: Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand. [email protected]. Additional Publications Frampton JE, Keating GM. Bevacizumab: in first-line treatment of advanced and/or metastatic renal cell carcinoma. BioDrugs 2008;22(2):113-20. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected]. McKeage K, Wagstaff AJ. Sorafenib: in advanced renal cancer. Drugs 2007;67(3):475-83; discussion 484-5. Contact: Wolters Kluwer Health, Adis, Auckland, New Zealand. [email protected]. Simpson D, Curran MP. Temsirolimus : in advanced renal cell carcinoma. Drugs 2008;68(5):631-8. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA. Bibliography (Reviewed Abstracts) 1. Irwin C, Hunn M, Purdie G, Hamilton D. Delay in radiotherapy shortens survival in patients with high grade glioma. J Neurooncol 2007;85(3):339-43. Contact: Department of Neurosurgery, Wellington Hospital, Private Bag 7902, Wellington South, New Zealand. Cancer 165 2. Lucas-Ramadan T, Baxi S, Velamoor R. Acute limbic encephalitis: diagnostic and management implications. Aust N Z J Psychiatry 2008;42(2):166-9. Contact: Department of Psychiatry, Middlemore Hospital, Auckland, New Zealand. 3. Lum DJ, Halliday W, Watson M, Smith A, Law A. Cortical ependymoma or monomorphous angiocentric glioma? Neuropathology 2008;28(1):81-6. Contact: Department of Histopathology, Auckland City Hospital, Auckland, New Zealand. [email protected]. 4. Danesh-Meyer HV. Radiation-induced optic neuropathy. J Clin Neurosci 2008;15(2):95-100. Contact: Academic Neuro-ophthalmology and Glaucoma, Department of Ophthalmology, University of Auckland, Auckland, 1142, New Zealand. [email protected]. 5. Perry JK, Mohankumar KM, Emerald BS, Mertani HC, Lobie PE. The contribution of growth hormone to mammary neoplasia. J Mammary Gland Biol Neoplasia 2008;13(1):131-45. Contact: The Liggins Institute, University of Auckland, 2-6 Park Avenue, Private Bag 92019, Auckland, New Zealand. 6. Gunningham SP, Currie MJ, Morrin HR, et al. The angiogenic factor thymidine phosphorylase up-regulates the cell adhesion molecule P-selectin in human vascular endothelial cells and is associated with P-selectin expression in breast cancers. J Pathol 2007;212(3):335-44. Contact: Angiogenesis Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, PO Box 4345, Christchurch, New Zealand. 7. Walker LC, Harris GC, Holloway AJ, et al. Cytokeratin KRT8/18 expression differentiates distinct subtypes of grade 3 invasive ductal carcinoma of the breast. Cancer Genet Cytogenet 2007;178(2):94-103. Contact: Cancer Genetics Research Group, Department of Pathology, University of Otago at Christchurch, Christchurch, New Zealand. 8. Miller D, Livingstone V, Herbison P. Interventions for relieving the pain and discomfort of screening mammography. Cochrane Database Syst Rev 2008 (1):CD002942. Contact: Dunedin School of Medicine, University of Otago, Women's and Children's Health, PO Box 913, Dunedin, New Zealand. [email protected]. 9. Chung JH, Rajagopal V, Laursen TA, Nielsen PM, Nash MP. Frictional contact mechanics methods for soft materials: application to tracking breast cancers. J Biomech 2008;41(1):69-77. Contact: Bioengineering Institute, University of Auckland, Auckland, New Zealand. [email protected]. 10. Poole R, Paridaens R. The use of third-generation aromatase inhibitors and tamoxifen in the adjuvant treatment of postmenopausal patients with hormone-dependent breast cancer: evidence based review. Curr Opin Oncol 2007;19(6):564-72. Contact: Wolters Kluwer Health, Adis, Auckland, New Zealand. 11. Findlay M, von Minckwitz G, Wardley A. Effective oral chemotherapy for breast cancer: pillars of strength. Ann Oncol 2008;19(2):212-22. Contact: Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand. [email protected]. 166 Cancer 12. Cheema B, Gaul CA, Lane K, Fiatarone Singh MA. Progressive resistance training in breast cancer: a systematic review of clinical trials. Breast Cancer Res Treat 2008;109(1):9-26. Contact: Institute of Food, Nutrition and Human Health, Te Kura Hangarua o Kai-oranga-a-tangata, Massey University, Wellington Campus, Private Bag 756, Wellington, New Zealand, [email protected]. 13. Farquhar CM, Marjoribanks J, Lethaby A, Basser R. High dose chemotherapy for poor prognosis breast cancer: systematic review and meta-analysis. Cancer Treat Rev 2007;33(4):325-37. Contact: University of Auckland, Private Bag 92189, Auckland, New Zealand. [email protected]. 14. Metcalfe S, Evans J, Priest G. PHARMAC funding of 9-week concurrent trastuzumab (Herceptin) for HER2-positive early breast cancer. N Z Med J 2007;120(1256):U2593. Contact: PHARMAC, Wellington. [email protected]. 15. Weston MK, Moss DP, Stewart J, Hill AG. Differences in breast cancer biological characteristics between ethnic groups in New Zealand. Breast Cancer Res Treat 2007. Contact: Surgery, University of Auckland, Middlemore Hospital, PO Box 93311, Otahuhu, Auckland, 2105, New Zealand, [email protected]. 16. Curtis E, Quale C, Haggstrom D, Smith-Bindman R. Racial and ethnic differences in breast cancer survival: how much is explained by screening, tumor severity, biology, treatment, comorbidities, and demographics? Cancer 2008;112(1):171-80. Contact: Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. [email protected]. 17. Bennett H, Marshall R, Campbell I, Lawrenson R. Women with breast cancer in Aotearoa New Zealand: the effect of urban versus rural residence on stage at diagnosis and survival. N Z Med J 2007;120(1266):U2831. Contact: Australasian Faculty of Public Health Medicine, Hamilton. [email protected]. 18. McKenzie F, Jeffreys M, t Mannetje A, Pearce N. Prognostic factors in women with breast cancer: inequalities by ethnicity and socioeconomic position in New Zealand. Cancer Causes Control 2008;19(4):403-11. Contact: Centre for Public Health Research, Massey University, Wellington Campus, Private Box 756, Wellington, New Zealand, [email protected]. 19. Paul C, Nicholls R, Priest P, McGee R. Making policy decisions about population screening for breast cancer: the role of citizens' deliberation. Health Policy 2008;85(3):314-20. Contact: Department of Preventive and Social Medicine, University of Otago, PO Box 913, Dunedin 9054, New Zealand. [email protected]. 20. Kathiravel Y, Westwood D, Macemon J, Singh H. An international surgical collaboration for the management of pulmonary artery sarcoma: a New Zealand experience. N Z Med J 2007;120(1257):U2609. Contact: Department of Cardiothoracic Surgery, Christchurch Public Hospital, Christchurch. Cancer 167 21. Bhana N. Granulocyte colony-stimulating factors in the management of chemotherapy-induced neutropenia: evidence based review. Curr Opin Oncol 2007;19(4):328-35. Contact: Wolters Kluwer Health Adis, Auckland, New Zealand. 22. Murdoch D, Sager J. Will targeted therapy hold its promise? An evidencebased review. Curr Opin Oncol 2008;20(1):104-11. Contact: Wolters Kluwer Health Adis, Auckland, New Zealand. 23. Williams AO, Isaacs RJ, Stowell KM. Down-regulation of human topoisomerase IIalpha expression correlates with relative amounts of specificity factors Sp1 and Sp3 bound at proximal and distal promoter regions. BMC Mol Biol 2007;8:36. Contact: Institute of Molecular Biosciences, Massey University, Palmerston North, New Zealand. [email protected] <[email protected]>. 24. Parry S, Richardson A, Green T, et al. Prospects for population colorectal cancer screening in New Zealand. N Z Med J 2007;120(1258):U2633. Contact: Middlemore Hospital, Otahuhu, Auckland. [email protected]. 25. Kerr J, Day P, Broadstock M, Weir R, Bidwell S. Systematic review of the effectiveness of population screening for colorectal cancer. N Z Med J 2007;120(1258):U2629. Contact: New Zealand Health Technology Assessment, Department of Public Health and General Practice, University of Otago, Christchurch. 26. Yeoman A, Parry S. A survey of colonoscopy capacity in New Zealand's public hospitals. N Z Med J 2007;120(1258):U2632. Contact: Department of Gastroenterology, Morriston Hospital, Morriston, Swansea, Wales, United Kingdom. 27. Bhargava A, Aldameh A, Stewart J, Hill AG. Prioritization of patients with rectal bleeding for urgent outpatient colonoscopy--a pilot study. N Z Med J 2007;120(1258):U2637. Contact: Department of Surgery, University of Auckland, Middlemore Hospital, Otahuhu, Auckland. 28. Lin HM, Chatterjee A, Lin YH, et al. Genome wide expression profiling identifies genes associated with colorectal liver metastasis. Oncol Rep 2007;17(6):1541-9. Contact: Cancer Genetics Laboratory, Department of Biochemistry, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand. 29. Abbas SM, Merrie AE. Resection of peritoneal metastases causing malignant small bowel obstruction. World J Surg Oncol 2007;5:122. Contact: Colorectal Unit, Auckland City Hospital, Private Bag 92024, Auckland, New Zealand. [email protected]. 30. Hayes JL, Hansen P. Is laparoscopic colectomy for cancer cost-effective relative to open colectomy? ANZ J Surg 2007;77(9):782-6. Contact: Department of Surgery, Dunedin Hospital and Dunedin School of Medicine, Dunedin, New Zealand. [email protected]. 168 Cancer 31. Wakeman CJ, Dobbs BR, Frizelle FA, et al. The impact of splenectomy on outcome after resection for colorectal cancer: a multicenter, nested, paired cohort study. Dis Colon Rectum 2008;51(2):213-7. Contact: Department of Surgery, Christchurch Hospital, Christchurch, New Zealand. 32. Gendall KA, Kennedy RR, Watson AJ, Frizelle FA. The effect of epidural analgesia on postoperative outcome after colorectal surgery. Colorectal Dis 2007;9(7):584-98; discussion 598-600. Contact: Department of Surgery, Christchurch Hospital, Christchurch, New Zealand. 33. O'Grady G, Secker A. Colorectal cancer management in the provincial New Zealand setting of Nelson. ANZ J Surg 2007;77(11):1004-8. Contact: Department of General Surgery, Nelson Hospital, Nelson, New Zealand. [email protected]. 34. Samson PB, Ngaei G. Colorectal resection in peripheral New Zealand: workload, outcomes and its future. ANZ J Surg 2007;77(11):999-1003. Contact: Department of General Surgery, Southland Hospital, Invercargill, New Zealand. [email protected]. 35. Thotathil ZS, Long JE, Kennedy I, Jameson MB, Adams J, Kuper M. Chemotherapy prescription patterns in colon cancer: a patterns-of-care survey in New Zealand. N Z Med J 2007;120(1258):U2636. Contact: Department of Oncology, Waikato Hospital, Hamilton. [email protected]. 36. Abbas SM, Hill AG. Prostatic sarcoma after treatment of rectal cancer. World J Surg Oncol 2007;5:82. Contact: Department of Surgery, Middlemore Hospital, University of Auckland, New Zealand. [email protected]. 37. Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2007(1):CD002200. Contact: Christchurch Hospital, Oncology Service, Private Bag 4710, Christchurch, New Zealand. [email protected]. 38. Port RV, Arnold J, Kerr D, Gravish N, Winship I. Cultural enhancement of a clinical service to meet the needs of indigenous people; genetic service development in response to issues for New Zealand Maori. Clin Genet 2008;73(2):132-8. Contact: Northern Regional Genetic Service, Auckland District Health Board, Auckland, New Zealand. 39. Ferguson LR, Philpott M. Cancer prevention by dietary bioactive components that target the immune response. Curr Cancer Drug Targets 2007;7(5):459-64. Contact: Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. [email protected]. 40. Blakely T, Tobias M, Atkinson J. Inequalities in mortality during and after restructuring of the New Zealand economy: repeated cohort studies. Bmj 2008;336(7640):371-5. Contact: Health Inequalities Research Programme, University of Otago, Wellington, PO Box 7343, Wellington, New [email protected]. Cancer 169 41. Dachs GU, Currie MJ, McKenzie F, et al. Cancer disparities in indigenous Polynesian populations: Maori, Native Hawaiians, and Pacific people. Lancet Oncol 2008;9(5):473-84. Contact: Angiogenesis Research Group, Department of Pathology, University of Otago, Christchurch, New Zealand. 42. Herst PM, Petersen T, Jerram P, Baty J, Berridge MV. The antiproliferative effects of phenoxodiol are associated with inhibition of plasma membrane electron transport in tumour cell lines and primary immune cells. Biochem Pharmacol 2007;74(11):1587-95. Contact: Malaghan Institute of Medical Research, P.O. Box 7060, Wellington 6005, New Zealand. 43. Kanwar JR, Palmano KP, Sun X, et al. 'Iron-saturated' lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy. Immunol Cell Biol 2008;86(3):277-88. Contact: LactoPharma Consortium, University of Auckland, Auckland, New Zealand. 44. McKeage MJ. The potential of DMXAA (ASA404) in combination with docetaxel in advanced prostate cancer. Expert Opin Investig Drugs 2008;17(1):23-9. Contact: The University of Auckland, School of Medical Sciences, Department of Pharmacology and Clinical Pharmacology, Private Bag 92019, Auckland, New Zealand. [email protected]. 45. Somers-Edgar TJ, Scandlyn MJ, Stuart EC, Le Nedelec MJ, Valentine SP, Rosengren RJ. The combination of epigallocatechin gallate and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo. Int J Cancer 2008;122(9):1966-71. Contact: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. 46. Thotathil Z, Jameson MB. Early experience with novel immunomodulators for cancer treatment. Expert Opin Investig Drugs 2007;16(9):1391-403. Contact: Waikato Hospital, Department of Oncology, Hamilton, New Zealand. 47. Tyndall JD, Kelso MJ, Clingan P, Ranson M. Peptides and small molecules targeting the plasminogen activation system: towards prophylactic antimetastasis drugs for breast cancer. Recent Patents Anticancer Drug Discov 2008;3(1):1-13. Contact: National School of Pharmacy, University of Otago, Dunedin, New Zealand. [email protected]. 48. Humar B, Guilford P. Hereditary diffuse gastric cancer and lost cell polarity: a short path to cancer. Future Oncol 2008;4(2):229-39. Contact: University of Otago, Cancer Genetics Laboratory, Department of Biochemistry, Dunedin, New Zealand. [email protected]. 49. Switzer-Taylor V, Schlup M, Lubcke R, Livingstone V, Schultz M. Barrett's esophagus: A retrospective analysis of 13 years surveillance. J Gastroenterol Hepatol 2008. Contact: Department of Medical and Surgical Sciences, Medicine Section, University of Otago Medical School, Dunedin, New Zealand. 170 Cancer 50. Hoy SM, Lyseng-Williamson KA. Intravenous busulfan: in the conditioning treatment of pediatric patients prior to hematopoietic stem cell transplantation. Paediatr Drugs 2007;9(4):271-8. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected]. 51. Scott WG, Scott HM. Economic evaluation of third-line treatment with alemtuzumab for chronic lymphocytic leukaemia. Clin Drug Investig 2007;27(11):755-64. Contact: ScottEconomics, Wellington, New Zealand. [email protected]. 52. Dockerty JD, Herbison P, Skegg DC, Elwood M. Vitamin and mineral supplements in pregnancy and the risk of childhood acute lymphoblastic leukaemia: a case-control study. BMC Public Health 2007;7(147):136. Contact: Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand. [email protected]. 53. Agir H, Brasch HD, Tan ST. Extra-skeletal Ewing's sarcoma of the submandibular gland. J Plast Reconstr Aesthet Surg 2007;60(12):1345-8. Contact: Head and Neck and Skull Base Surgery/Oncology Programme, Wellington Regional Plastic, Maxillofacial and Burns Unit, Hutt Hospital, Private Bag 31907, High Street, Lower Hutt, New Zealand. 54. Aldington S, Harwood M, Cox B, et al. Cannabis use and cancer of the head and neck: case-control study. Otolaryngol Head Neck Surg 2008;138(3):374-80. Contact: Medical Research Institute of New Zealand, Wellington, New Zealand. 55. Lallu S, Naran S, Bethwaite P. Fine needle aspiration cytology of unsuspected metastatic hurthle cell carcinoma of the thyroid and its pitfalls: a report of two cases. Diagn Cytopathol 2007;35(7):439-43. Contact: Department of Cytology, Anatomic Pathology, Capital and Coast Wellington Hospital, Wellington, New Zealand. 56. Bartlett AS, McCall JL, Koea JB, et al. Liver resection for hepatocellular carcinoma in a hepatitis B endemic area. World J Surg 2007;31(9):1775-81. Contact: Department of Hepatobiliary and Transplant Surgery, New Zealand Liver Transplant Unit, Level 15, Support Building, Auckland City Hospital, Park Road, Grafton, Auckland, New Zealand. 57. Simpson D, Keating GM. Sorafenib: in hepatocellular carcinoma. Drugs 2008;68(2):251-8. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. 58. Stevens W, Stevens G, Kolbe J, Cox B. Lung cancer in New Zealand: patterns of secondary care and implications for survival. J Thorac Oncol 2007;2(6):48193. Contact: Discipline of Oncology, University of Auckland, Auckland, New Zealand. [email protected]. 59. Stevens W, Stevens G, Kolbe J, Cox B. Management of stages I and II nonsmall-cell lung cancer in a New Zealand study: divergence from international practice and recommendations. Intern Med J 2008. Contact: Department of Oncology, Auckland Hospital, Auckland, New Zealand. Cancer 171 60. Stevens W, Stevens G, Kolbe J, Cox B. Ethnic differences in the management of lung cancer in New Zealand. J Thorac Oncol 2008;3(3):237-44. Contact: Discipline of Oncology, University of Auckland, Auckland, New Zealand. [email protected]. 61. Aldington S, Harwood M, Cox B, et al. Cannabis use and risk of lung cancer: a case-control study. Eur Respir J 2008;31(2):280-6. Contact: Medical Research Institute of New Zealand, Wellington, New Zealand. 62. Young RP, Hopkins R, Eaton TE. Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes. Eur Respir J 2007;30(4):616-22. Contact: Department of Medicine, Auckland Hospital, Private Bag 92019, Auckland, New Zealand. [email protected]. 63. Anderson VR, Perry CM. Fludarabine: a review of its use in non-Hodgkin's lymphoma. Drugs 2007;67(11):1633-55. Contact: Wolters Kluwer Health, Adis, Auckland, New Zealand. 64. Macann A, Bredenfeld H, Muller RP, Diehl V, Engert A, Eich HT. Radiotherapy does not influence the severe pulmonary toxicity observed with the administration of gemcitabine and bleomycin in patients with advancedstage Hodgkin's lymphoma treated with the BAGCOPP regimen: a report by the German Hodgkin's Lymphoma Study Group. Int J Radiat Oncol Biol Phys 2008;70(1):161-5. Contact: Department of Radiation Oncology, Auckland Regional Cancer and Blood Service, Auckland, New Zealand. 65. Dryson E, t Mannetje A, Walls C, et al. Case-control study of high risk occupations for bladder cancer in New Zealand. Int J Cancer 2008;122(6):13406. Contact: Centre for Public Health Research, Massey University, Wellington, New Zealand. 66. Firth H, Gray A, Carpenter LM, Cox B. Cancer mortality by occupation among New Zealand women: 1988-1997. N Z Med J 2007;120(1266):U2833. Contact: Department of Preventive and Social Medicine, Dunedin School of Medicine, Otago Medical School, Dunedin. [email protected]. 67. t Mannetje A, Dryson E, Walls C, et al. High risk occupations for nonHodgkin's lymphoma in New Zealand: case-control study. Occup Environ Med 2008;65(5):354-63. Contact: Centre for Public Health Research, Massey University Wellington Campus, Private Box 756, Wellington, New Zealand. [email protected]. 68. Capelle L, Krawitz H. Esthesioneuroblastoma: a case report of diffuse subdural recurrence and review of recently published studies. J Med Imaging Radiat Oncol 2008;52(1):85-90. Contact: Department of Radiation Oncology, Auckland City Hospital, Auckland, New Zealand. [email protected]. 69. Arsic D, Beasley SW, Sullivan MJ. Switched-on Sonic hedgehog: a gene whose activity extends beyond fetal development--to oncogenesis. J Paediatr Child Health 2007;43(6):421-3. Contact: Children's Cancer and Developmental Genetics 172 Cancer Research Group, Department of Paediatrics, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand. 70. Cox AG, Hampton MB. Bcl-2 over-expression promotes genomic instability by inhibiting apoptosis of cells exposed to hydrogen peroxide. Carcinogenesis 2007;28(10):2166-71. Contact: Free Radical Research Group, Department of Pathology, Christchurch School of Medicine & Health Sciences, University of Otago, PO Box 4345, Christchurch, New Zealand. 71. Pandey V, Perry JK, Mohankumar KM, et al. Autocrine Human Growth Hormone Stimulates Oncogenicity of Endometrial Carcinoma Cells. Endocrinology 2008. Contact: Liggins Institute and National Research Centre for Growth and Development, and Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P.R. China; Department of Pathology, Anhui Medical University, Hefei, Anhui 230032, P.R. China. 72. Perry JK, Kannan N, Grandison PM, Mitchell MD, Lobie PE. Are trefoil factors oncogenic? Trends Endocrinol Metab 2008;19(2):74-81. Contact: Liggins Institute, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. 73. Flint MN, Griffin AM, Bell RS, Wunder JS, Ferguson PC. Two-stage revision of infected uncemented lower extremity tumor endoprostheses. J Arthroplasty 2007;22(6):859-65. Contact: Orthopaedic Oncology Unit, Middlemore Hospital, Auckland, New Zealand. 74. McKechnie R, MacLeod R, Keeling S. Facing uncertainty: the lived experience of palliative care. Palliat Support Care 2007;5(4):367-76. Contact: Department of General Practice, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. [email protected]. 75. Walker J, Lane P. Challenges and choices: an audit of the management of nausea, vomiting and bowel obstruction in metastatic ovarian cancer. Contemp Nurse 2007;27(1):39-46. Contact: Hospice and Palliative Care Service, Nurse Maude Association, Christchurch, New Zealand. 76. William L, Macleod R. Management of breakthrough pain in patients with cancer. Drugs 2008;68(7):913-24. Contact: North Shore Hospice, Takapuna, Auckland, New Zealand. 77. Crawford NW, Heath JA, Buttery JP. Immunisation practices of paediatric oncologists: an Australasian survey. J Paediatr Child Health 2007;43(9):593-6. Contact: NHMRC Centre for Clinical Research Excellence in Child and Adolescent Immunisation; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia. [email protected]. Cancer 173 78. Windsor JA. An update on familial pancreatic cancer and the management of asymptomatic relatives. HPB (Oxford) 2007;9(1):4-7. Contact: Faculty of Medical and Health Sciences, University of Auckland Auckland New Zealand. 79. McAvoy BR, Fletcher JM, Elwood M. Cancer education and training in primary health care--a national audit of training providers. Aust Fam Physician 2007;36(11):973-6. Contact: Community and Home Detox Service, Auckland Community Alcohol and Drug Service, Auckland, New Zealand. [email protected]. 80. Jones RW, Coughlan EP, Reid JS, Sykes P, Watson PD, Cook C. Human papilloma virus vaccines and their role in cancer prevention. N Z Med J 2007;120(1266):U2829. Contact: Gynaecological Oncology Service, National Women's Hospital, Private Bag 92 189, Auckland. [email protected]. 81. Lovell S, Kearns RA, Friesen W. Sociocultural barriers to cervical screening in South Auckland, New Zealand. Soc Sci Med 2007;65(1):138-50. Contact: Department of Geography, Queens University, Kingston, Ont., Canada. [email protected]. 82. Buetow S, Janes R, Steed R, Ihimaera L, Elley CR. Why don't some women return for cervical smears? A hermeneutic phenomenological investigation. Health Care Women Int 2007;28(9):843-52. Contact: Department of General Practice and Primary Health Care, University of Auckland, Auckland, New Zealand. [email protected]. 83. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol 2008;9(5):425-34. Contact: Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand. [email protected]. 84. Sadler L, Saftlas A. Cervical surgery and preterm birth. J Perinat Med 2007;35(1):5-9. Contact: National Women's Health, Auckland District Health Board, Department of Epidemiology and Biostatistics, School of Population Health, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand. [email protected]. 85. Deeks E. Local therapy in endometrial cancer: evidence based review. Curr Opin Oncol 2007;19(5):512-5. Contact: Wolters Kluwer Health, Adis, Auckland, New Zealand. 86. Nicholson HD, Whittington K. Oxytocin and the human prostate in health and disease. Int Rev Cytol 2007;263:253-86. Contact: Department of Anatomy and Structural Biology, University of Otago, New Zealand. 87. Lamb DS, Slaney D, Smart R, et al. Prostate cancer: the new evidence base for diagnosis and treatment. Pathology 2007;39(6):537-44. Contact: Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, and Department of Radiation Oncology, Wellington Hospital, New Zealand. 174 Cancer 88. Mitchell DM, Wynne CJ, Cowan I. Multiple cranial nerve palsies as the presenting features of prostate carcinoma. J Med Imaging Radiat Oncol 2008;52(2):194-6. Contact: Department of Radiation Oncology, Christchurch Hospital, Christchurch, New Zealand. [email protected]. 89. Sneyd MJ. Ethnic differences in prostate cancer survival in New Zealand: a national study. Cancer Causes Control 2008. Contact: Hugh Adam Cancer Epidemiology Unit, Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand, [email protected]. 90. Travier N, Jeffreys M, Brewer N, et al. Association between glycosylated hemoglobin and cancer risk: a New Zealand linkage study. Ann Oncol 2007;18(8):1414-9. Contact: Centre for Public Health Research, Massey University, Wellington, New Zealand. [email protected]. 91. Trevena J, Reeder A. Perceptions of New Zealand adults about reducing their risk of getting cancer. N Z Med J 2007;120(1258):U2630. Contact: Department of Psychological Medicine, Dunedin School of Medicine, University of Otago, Dunedin. [email protected]. 92. Laugesen M. Snuffing out cigarette sales and the smoking deaths epidemic. N Z Med J 2007;120(1256):U2587. Contact: SmokeLess New Zealand Trust, Lyttelton, Christchurch. [email protected]. 93. Salmon PJ, Chan WC, Griffin J, McKenzie R, Rademaker M. Extremely high levels of melanoma in Tauranga, New Zealand: possible causes and comparisons with Australia and the northern hemisphere. Australas J Dermatol 2007;48(4):208-16. Contact: Department of Dermatology, Waikato Hospital, Tuaranga, New Zealand. [email protected]. 94. Wright CY, Reeder AI, Bodeker GE, Gray A, Cox B. Solar UVR exposure, concurrent activities and sun-protective practices among primary schoolchildren. Photochem Photobiol 2007;83(3):749-58. Contact: Social & Behavioural Research in Cancer Group, Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand. 95. Reynolds HM, Dunbar PR, Uren RF, Blackett SA, Thompson JF, Smith NP. Three-dimensional visualisation of lymphatic drainage patterns in patients with cutaneous melanoma. Lancet Oncol 2007;8(9):806-12. Contact: Bioengineering Institute, University of Auckland, Auckland, New Zealand. [email protected]. 96. Munday R, Mhawech-Fauceglia P, Munday CM, et al. Inhibition of urinary bladder carcinogenesis by broccoli sprouts. Cancer Res 2008;68(5):1593-600. Contact: AgResearch Limited, Ruakura Agricultural Research Center, Hamilton, New Zealand. 97. Delahunt B, Bethwaite PB, McCredie MR, Nacey JN. The evolution of collagen expression in sarcomatoid renal cell carcinoma. Hum Pathol 2007;38(9):1372-7. Contact: Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, PO Box 7343, Wellington South, New Zealand. [email protected]. 98. Delahunt B, Bethwaite PB, Nacey JN. Outcome prediction for renal cell carcinoma: evaluation of prognostic factors for tumours divided according to histological subtype. Pathology 2007;39(5):459-65. Contact: Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, Wellington South, New Zealand. [email protected]. 99. Delahunt B, Sika-Paotonu D, Bethwaite PB, et al. Fuhrman grading is not appropriate for chromophobe renal cell carcinoma. Am J Surg Pathol 2007;31(6):957-60. Contact: Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, New Zealand. [email protected]. 100. Fukuzawa R, Reeve AE. Molecular pathology and epidemiology of nephrogenic rests and Wilms tumors. J Pediatr Hematol Oncol 2007;29(9):589-94. Contact: Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, PO Box 56, Dunedin, New Zealand.