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Galectin-3 plays an important role in adhesion, proliferation, differentiation, angiogenesis and metastasis in multiple tumours. To investigate the role of galectin-3 in melanoma pathogenesis we examined the expression of galectin-3 in melanocytic lesions and analysed the correlation between galectin-3 expression and clinicopathologic factors including patient survival and BRAF mutation status.We evaluated the expression of galectin-3 in 53 cases of benign naevi, 31 cases of dysplastic naevi, 59 in-situ melanomas, 314 cases of primary melanoma and 69 metastatic melanomas using tissue microarray and immunohistochemistry.Marked differences in expression of galectin-3 were seen between different categories of melanocytic lesions (ANOVA p0.0001). An increase in expression of galectin-3 between benign naevi and thin primary melanomas and a progressive decrease in expression between thin primary melanomas and thicker melanomas or metastatic melanomas was seen. Strong galectin-3 expression was associated with improved overall survival (p=0.002 and p=0.0002 for cytoplasmic and nuclear expression, respectively) and melanoma-specific survival (p=0.017 and p=0.003 for cytoplasmic and nuclear expression, respectively). A multifactorial Cox regression analysis suggested that galectin-3 expression was an independent prognostic marker for overall survival in melanoma (risk ratio 0.73, 95% CI 0.547-0.970, p=0.031 for cytoplasmic expression and risk ratio 0.76, 95% CI 0.587-0.985, p=0.036 for nuclear expression). No association between galectin-3 expression and BRAF mutation status was observed.This study suggests that galectin-3 is a marker of progression in melanocytic lesions and a novel prognostic marker in primary melanoma.

In March 2003, an international mulltidisciplinary group of scientists and clinicians with a specific interest in ovarian cancer met for 4 days to discuss research into and treatment of this challenging disease. Under the headings of molecular genetics, molecular biology, the biology of ovarian cancer, old therapies, new targets and the early detection of the disease, this Position Paper summarises the presentations and discussion from the 9th Biennial Helene Harris Memorial Trust Forum on Ovarian Cancer. In particular, we highlight the potential of international collaborations in translating laboratory science into useful clinical interventions. (C) 2003 Elsevier Ltd. All rights reserved.

Mixed mesodermal tumours (MMTs) are relatively rare gynaecological tumours that have been poorly studied in clinical and molecular terms. They are chemosensitive (at least initially), although ultimately they have a poor prognosis. The biology of the tumour is fascinating in view of its composition of both epithelial and mesenchymal entities. We review herein the literature on the clinical and biological aspects of this malignancy.

Two multicentre phase II trials were designed to determine if tumour responses can be achieved in progressive small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) patients treated with ISIS 5132, an inhibitor of C-raf kinase mRNA expression (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA), and to further characterise the safety of the compound. Between August 1998 and November 1999, 26 patients (18 NSCLC, 8 SCLC) were entered. Out of these, 23 were eligible, 22 (18 NSCLC, 4 SCLC) were treated with ISIS 5132 (2 mg/kg/day, 21 days continuous intravenous (i.v.) infusion every 4 weeks) and were evaluable for toxicity and 18 (15 NSCLC, 3 SCLC) were evaluable for efficacy. For the whole group haematological toxicity did not exceed grade 2. One patient experienced a grade 4 increased prothrombin time. Non-haematological toxicity was mild to moderate, with the observation of asthenia and nausea and vomiting. Progressive disease (PD) was diagnosed in 10 patients (8 NSCLC and 2 SCLC). 8 more patients (7 NSCLC, 1 SCLC) were considered as treatment failures. In conclusion, this study using ISIS 5132 with this dose and schedule of administration excludes a 20% response rate with 95% confidence intervals for NSCLC and cannot draw any conclusions for SCLC patients as only a few were involved in the study.

The anthracenedione analogue, BBR 2778 is an active antitumour agent preclinically and has reduced potential for cardiotoxicity compared with other similar drugs in preclinical models. BBR 2778 was administered 3 weekly by a 1 h intravenous (i.v.) infusion to 24 patients and the dose escalated rapidly from 20 to 240 mg/m2. The dose-limiting toxicity (DLT) was neutropenia, common toxicity criteria (CTC) grade 4 in 3/5 patients at 240 mg/m2. Other toxicities > or = CTC grade 3 were: vomiting, lymphopenia, thrombocytopenia and lethargy. Blue discoloration of veins and urine was also noted. In 1 patient (120 mg/m2, four cycles) left ventricular ejection reaction (LVEF) fell (CTC grade 2) but with no clinical sequelae. BBR 2778 plasma pharmacokinetics were biphasic (mean t(1/2) at 180 mg/m2 = 14.1 h) and the urinary elimination of the unchanged drug was < 10%. In a patient with previously treated small cell lung carcinoma (SCLC), a 49% reduction in measurable disease was noted with resolution of pericardial and pleural effusions (120 mg/m2 x eight cycles). From the results of this phase I study a dose of 180 mg/m2 as a 1 h infusion every 3 weeks would be recommended for phase II trials.

Having your work published in a good journal is the life-blood of research. Publications are the key element in scientific communication and influence future funding and cancer development for the authors. Every year more and more manuscripts are submitted and competition for acceptance is fierce. The editors of EJC recently held a workshop to discuss ways to improve manuscript writing, and this paper summarises their recommendations. Choose a title carefully, keep the introduction short, avoid confusing methods with results, and use figures wherever possible. Discuss only the relevance of new findings to published literature. Above all read the specific "instructions to authors" -- it is surprising how often this is ignored -- at peril!

This paper presents results of the in vitro and in vivo effects of anti-oestrogens on the growth of human ovarian cancer cells. Tamoxifen and the "pure" anti-oestrogens, ICI 164,384 and ICI 182,780, inhibited the oestrogen-stimulated growth of the oestrogen receptor (ER)-positive PE04 and PE01 cell lines grown in culture, the latter two compounds being more potent than tamoxifen. In the absence of 17 beta-oestradiol (E2), tamoxifen, but not the pure anti-oestrogens, produced a small degree of growth stimulation in the PE01 and PE04 lines at concentrations between 10((7) and 10(-9) M. In contrast, growth of the ER-negative PE014 line was unaffected by E2 and all three anti-oestrogens. The effects of tamoxifen and ICI 182,780 on PE04 cells grown as xenografts in nude mice were also studied. Both anti-oestrogens produce significant growth inhibitory effects. These results indicate that ovarian carcinoma cells may be sensitive to anti-oestrogens in vitro and in vivo, and support the view that anti-oestrogens merit further clinical studies in patients with ER-positive tumours.

‘What are the mechanisms of intrinsic drug resistance in solid tumours, and how might they be circumvented?’ These are key questions for molecular oncologists, for clinicians and patients. For many years, it was assumed that the interaction of a DNA damaging drug with its target would yield a lethal lesion, and that determinants of intrinsic drug resistance should therefore be sought upstream of this interaction, in drug metabolism or drug transport mechanisms. It is now apparent that cellular responses in vitro to a given DNA lesion can include necrosis, mitotic catastrophe, apoptosis, prolonged cell cycle arrest or even unrestrained growth. The response depends on the cellular genotype and, specifically, on the integrity of response pathways downstream of the drug–target interaction. Despite this progress in the laboratory, the proof that downstream events determine therapeutic responses in the clinic remains elusive. A seminal series of papers from Scott Lowe’s laboratory represent a major step in this direction. Lowe and colleagues prove conclusively that downstream determinants of apoptosis profoundly influence the response to therapy in vivo. They also demonstrate, for the first time, that prolonged drug induced growth arrest can result in prolonged disease stability whilst providing a residual pool of viable malignant cells from which late relapsing clones may ultimately emerge. These papers have mapped out new challenges and new opportunities for the oncologist of the future. Utilising the Em-myc transgenic murine model of B-cell lymphoma (in which myc overexpression drives lymphomagenesis), Lowe and colleagues have developed a rapid technique for the introduction of defined compound genetic lesions, allowing study of resulting phenotypes in a well-controlled fashion in vivo [1]. Primary lymphoma or haematopoetic stem cells, isolated from mice of known genetic background (Em-myc crossed with P53-null, or ARF-null or ARF/INK4a-null), are retrovirally transduced ex vivo with a gene of interest and reintroduced into the tail veins of syngeneic recipients. The transduction process itself does not alter the subsequent behaviour of the resulting lymphoma, so that controls transduced with the green fluorescent protein (GFP) gene alone yield lymphomas histopathologically indistinguishable from the parent lymphoma. Introduction of a gene of interest along with GFP in a bicistronic retroviral vector allows study of the effect of that gene on tumour behaviour by the elegant non-invasive means of whole-animal fluorescence imaging. An early paper in the series demonstrates conclusively that overexpression of the anti-apoptotic protein bcl-2 produces a multi-drug resistance phenotype in primary lymphomas in vivo [2]. This effect is suppressed by prior serial passage of the lymphoma lines in vitro, because the cells acquire multi-drug resistance merely as a consequence of prolonged cell culture. Furthermore, the effect of bcl-2 is completely obscured in standard clonogenic assays of drug sensitivity, because bcl-2 suppresses drug-induced apoptosis, but not prolonged growth arrest, both equally efficient means of reducing clonogenicity. These observations shed some light on why assays of drug response in established cell lines or xenografts derived from solid tumours have failed in the past to consistently predict clinical response, and indeed have often provided contradictory results. In general, such models simply cannot recapitulate conditions pertaining in vivo.

46 eligible patients with either anaplastic astrocytoma (AA) or glioblastoma (GBM) and clinical and computed-tomography-confirmed relapse following primary surgery and radiotherapy received oral tauromustine 130 mg/m2 every 5 weeks. A prospective design allowed for concurrent assessment of both clinical and radiological responses and drug toxicity. 41% of patients improved clinically whilst 46% improved radiologically with 3 complete, 7 partial and 7 minimal responses (WHO criteria). Toxicity included grade III or IV gastrointestinal side-effects (15%), grade III or IV leukopenia (24%) and grade III and IV thrombocytopenia (44%). In 9 clinically responding patients, haematological toxicity led to discontinuation of treatment. All patients were followed-up until death and second-line chemotherapy was not used. Median post-treatment survival was 26 weeks for patients with GBM and 57 weeks for patients with AA. Overall 2-year survival rate was 69% for AA and 23% for GBM. Tauromustine given at the time of relapse has demonstrable antitumour activity in patients not previously treated with chemotherapy.

Accepted 21 September 2006 Available online 14 November 2006 Probably the last thing anyone wants to think about in early The problem of ‘Affordability of Health Care’ is one of the January is food – but the title did catch your attention didn’t it? The question of abandoning research is not as stupid as it first might seem – ‘we have a problem’ as the astronauts famously said – there is a genuine crisis developing, analogous to a production line where no-one can clear the finished product from the end of the conveyer belt. The successful results of research over the past 20 years now present us with unparalleled opportunities to improve screening, diagnosis and treatment of patients with cancer – but we cannot afford to implement the new technologies. Examples are plentiful and of course not restricted to oncology, but the introduction of new drugs always catches headlines. The decision by the UK authority The National Institute for Clinical Excellence (NICE) not to recommend Avastin for patients with colorectal cancer last year was a landmark in deciding against the introduction of a drug approved for efficacy and safety for that indication by the UK’s own licensing board. I am not criticising that particular decision but using this as an example of modern science outstripping financial resource. It would be absurd to slow down or abandon research but we have to find new ways to facilitate the uptake of successful research or it becomes just an intellectual activity for academia with no commercial profitability (which feeds future research) and of course fails the principle goal of improving health. er Ltd. All rights reserved 20. major social problems facing every community worldwide – the affluent, the poor – everyone. This is all about assessing priorities. The problems in Europe are of particular concern since there is great variability in attitude towards priority setting as well as obvious variability in wealth. The particular problem of variable access to new medicines was addressed in the report from the Karolinska Institute, which is updated in a special issue of EJC soon to be published, but it is essential to embrace the problem in the context of cancer care in its totality and not just to focus on the introduction of new medicines. Within the oncology community we have to accept that the overall results of cancer treatment remain poor with the majority of patients dying from their disease and many within months or very few years from diagnosis. This contrasts with progress in other branches of medicine, but the high incidence of cancer and the devastation that it brings to families preserves its place on the political agenda. In countries such as the UK where governments attempt to provide healthcare free of charge (from taxation) it is already clear that the status quo is unsustainable – hence the NICE decision on drugs such as Avastin. Under these circumstances what do you do about totally new interventions such as national programmes for bowel cancer screening, or the vaccination of girls against herpes viruses to prevent

There are several reasons why Janus the ancient roman god sive cancer conferences to ensure that quality reigns over might be adopted as a patron of oncology. Suitably the guardian of the Gate of Heaven, Janus was represented with two faces, one in front and one behind. January is the month dedicated to Janus who presided over the entrance to the New Year, and with his two faces could look back to the past year and forward to the year ahead – we welcome the latter. 2005 was truly an ‘‘annus horribilis’’. Of all professions, oncologists are particularly used to tragedy and the unfairness of life-threatening illnesses at an inappropriate age, but last year the whole world witnessed natural disasters on an unprecedented scale: the Asian Tsunami; appalling drought in Africa and Western Europe; and in the USA, the hurricane Katrina. The now famous conference centre in New Orleans hosted many oncology conferences, for example, the huge 2004 ASCO meeting and it is through such events that many cancer researchers came to know and love the uniqueness of the ‘‘old’’ New Orleans. The future of this city is uncertain – especially as a conference venue upon which so much of the city s economy depended. Our heartfelt sympathy has been extended to all those involved. The world is already short of venues capable of hosting the ever increasingly large conferences for which there seems to be an insatiable appetite. Year on year there are more and more conferences attended by more and more enthusiasts – will it ever cease? I have written in these pages before to express a personal hope that we will move to fewer more comprehen

Defining and describing (dose-related) side-effects of chemotherapy are among the aims of phase I and II oncology trials. Phase I studies are intended to assess the safety of a drug or regimen, phase II to confirm the feasibility and assess long-term safety. They are usually performed in a single or just a few institutions. Due to the novelty of the regimen and the fact that safety is considered a major concern, it is sometimes the case that patient selection in such trials is rather conservative. If phase I and II trials are performed appropriately, the safety aspect should become less of a concern in phase III trials since investigators will know what to expect, how to manage the observed side-effects, and how to avoid entering patients that should not be entered in view of organ dysfunction, poor clinical condition and other factors. Nevertheless, since phase III studies have a different aim, and are mostly multi-centre, it is possible that the population becomes less well selected, whilst remaining within the limits of the protocol criteria. Most of the time, phase I and II studies have indeed appropriately predicted side-effects and designed ways to manage them. Fortunately, exceptions are truly rare. However, that does not mean that such exceptions do not occur. Whether this means that ‘‘Early mortality detected in a clinical trial is one of the most important parameters for assessing the safety of chemotherapy regimes’’, as indicated by Katopodis and colleagues [1], in their paper in the current issue of European Journal of Cancer entitled ‘‘60-Day all-cause mortality rates in patients treated for gastrointestinal cancers, in randomised

BB94 is the first matrix metalloproteinase inhibitor (MPI) to enter clinical trial. In experimental systems MPIs affect tumour growth, haematogenous spread and tumour induced angiogenesis. Animal models using a human ovarian carcinoma xenograft have indicated that BB94 increases survival in mice with malignant ascites. (Cancer Research 93: 53:2087.) In a phase I study, 23 patients (P) with malignant ascites were treated with intraperitoneal BB94. The drug was well tolerated with no acute toxicity. Plasma levels of BB94 were maintained for greater than 28 days at levels above the therapeutic range in pre-clinical models. In 16 P there was no reaccumulation of ascitic fluid requiring redrainage within 28 days. 40 P were treated in phase II. Conventional criteria are hard to apply to ascites, but preliminary results suggest that 10 (25%) P responded (including 8/24 ovarian P). Clinical data on all 63 patients will be presented.