Purpose To identify key factors for the best practice of knowledge transfer from high-income settings to low- and middle-income settings. Results Interactive sessions led to the identification of European learnings that can and should be shared beyond Europe. Furthermore, methods were characterised which may lead to successful knowledge transfer with subsequent quality improvement. Conclusion To ensure successful implementation of knowledge and new methods, political support is extremely important. A strong focus should be an improvement of collaboration and network development. Rehabilitation, early and late pallative care, cost effectiveness and long-term follow-up are priorities. Limitations are budget constraints which limit the execution of NCCPs.

Comprehensive Cancer Centres (CCCs) serve as critical drivers for improving cancer survival. In Europe, we have developed an Excellence Designation System (EDS) consisting of criteria to assess “excellence” of CCCs in translational research (bench to bedside and back), with the expectation that many European CCCs will aspire to this status.

e17565 Background: Oncology is a specialty requiring a combination of multidisciplinary expertises, novel technology, integration of innovation into care and research efforts in order to improve the quality of life and survival of patients. Provision of high-quality care and improvement of disease outcome should be promoted in cancer centers. Methods: The Organization of European Cancer Institutes developed an Accreditation Programme combining: 1-a quantitative questionnaire assessing the human, technical and financial resources and activities in care, research and education dedicated to oncology; 2- a set of standards and criteria for high-quality cancer management integrated in an electronic tool with a scoring system of compliance; 3- a peer-review process for review of the self-assessment outcome and on-site visits; 4- a report and improvement plan allowing to designate comprehensive cancer centers complying with required criteria for high-quality comprehensive cancer patient management. All components of the Accreditation Programme were tested in 8 different voluntary cancer centers in Europe. The objectives were to assess the feasibility, reproducibility and acceptance of the Accreditation Programme; to improve the standards and criteria in terms of understanding and consensus; to validate the peer review methodology and establish a method for reporting and implementing an improvement plan; to provide with a preliminary system of designation of comprehensive cancer centers based on criteria of high-quality integrated research, care and education. Results: The 2 consecutive pilot tests allowed to validate 1- relevant items for the quantitative questionnaire; 2-criteria and standards for high-quality integrated multidisciplinary cancer patient's management. 3-The impact of the Accreditation Programme on improvement of patients management and professionals involvement. Conclusions: The OECI Accreditation Programme is ready for dissemination. Participation to the Programme allows development of improvement plans for innovative and integrated comprehensive cancer patients management in cancer centers. No significant financial relationships to disclose.

When the Millennium Development Goals (MDGs) [1] were being developed, priority was given to the problems of the poorest billion people in the world. In terms of health, this was translated into a set of targets of indicators in health that give visibility to maternal and child health, (under) nutrition, acquired immunodeficiency syndrome (AIDS), malaria, and tuberculosis, and a vague catch-all category, 'and other diseases'. While progress has been made in developing specific plans with budgets to address the named MDG targets, no further work has been carried out on defining what constitute priority other diseases, or which interventions should be emphasized to address them.

Recent studies have shown that the PIK3CA gene, which encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinases, is mutated in human cancers. To determine whether PIK3CA is altered in cutaneous melanoma, we screened a series of 101 melanoma metastases. We identified PIK3CA missense mutations in three metastases (3%). Interestingly, these mutations were observed only in tumours that were negative for NRAS mutations. Using immunohistochemistry, we also analysed our metastases for the expression of phosphorylated Akt. These analyses revealed a moderate to strong phosphorylated Akt expression in 78% (21 of 27) of metastases with NRAS mutations and in 73% (54 of 74) of metastases without NRAS mutations. Interestingly, the three metastases with mutations in PIK3CA all exhibited a strong expression of phosphorylated Akt. Taken together, our results show that PIK3CA is mutated in a minority of melanomas and suggest that mutations in this gene may represent an alternative mechanism of Akt activation in cutaneous melanoma.

Purpose: Both the retinoblastoma and p53 pathways are often genetically altered in human cancers and their complex regulation is in part mediated by the three gene products p16, p14ARF, and p15 of the INK4 locus on chromosome 9p21. Partial or complete biallelic deletions of the INK4 locus have been recognized in a variety of malignant tumors, including malignant melanoma. We have in the present study measured the frequency of INK4 deletions in a large number of melanoma metastases and determined their association with clinicopathologic variables and survival data. Experimental Design: Quantitative real-time PCR, as well as fluorescence-based fragment analysis, has been used to perform measurements of the relative allelic concentrations of the INK4 genes in 112 human melanoma tumor samples from 86 patients. Results: Thirty-eight of 86 melanoma patients (44%) had metastases with biallelic losses in INK4. Ten of 20 patients with multiple metastases showed similar deletion patterns in all analyzed tumors. There was no significant association between any of the clinicopathologic variables and loss of INK4. However, loss of INK4 had an adverse effect on median survival from time of diagnosis. Patients with tumors with diploid INK4 had a median survival of 142 months, whereas those with monoallelic or biallelic loss in INK4 had a median survival of only 47 months (P = 0.006). Conclusions: Our results point to homozygous deletions in the INK4 region as being one of the most common genetic alterations in malignant cutaneous melanoma. INK4 deletions are associated with an adverse prognosis.

The prognostic impact of different anatomical sites in patients with cutaneous malignant melanoma (CMM) has been widely debated and requires further elucidation. Therefore, we developed EssDoll©, a new computerized method to address the question of site in relation to prognosis. A population-based cohort of 1891 patients, diagnosed between 1976 and 1987 with invasive CMM without evidence of metastasis, was identified. The body surface was divided into 24 areas. Hazard ratios (HRs) for CMM death were calculated and areas were compared in both the whole model and in pairs. Cox's proportional hazard regression model was used and adjustments were made for established prognostic factors. Furthermore, the overall effect of site was calculated using the likelihood ratio test. Overall, the tumour site was of prognostic importance (P=0.0036). There was a significantly increased risk of CMM-specific death in patients with a primary tumour site in the middle and lower back (HR=1.8, P=0.04) and in the supramammary and mammary area (HR=1.8, P=0.05). When all areas were analysed in pairs, the dorsal shoulder, superior back and clavicular area also showed a worse prognosis. CMM diagnosed in other anatomical regions, including the calves, Achilles, upper arms, forehead, temples, cheeks and face, seemed to be related to a better prognosis. It can be concluded that the tumour site is of prognostic importance, and that the middle and lower back and supramammary and mammary areas are independent factors related to a poor prognosis.

A large European case–control study investigated the association between sunbed use and cutaneous melanoma in an adult population aged between 18 and 49 years. Between 1999 and 2001 sun and sunbed exposure was recorded in 597 newly diagnosed melanoma cases and 622 controls in Belgium, France, The Netherlands, Sweden and the UK. Fifty three precent of cases and 57% of controls ever used sunbeds. The overall adjusted odds ratio (OR) associated with ever sunbed use was 0.90 (95% CI: 0.71–1.14). There was a South-to-North gradient with high prevalence of sunbed exposure in Northern Europe and lower prevalence in the South (prevalence of use in France 20%, OR: 1.19 (0.68–2.07) compared to Sweden, prevalence 83%, relative risk 0.62 (0.26–1.46)). Dose and lag-time between first exposure to sunbeds and time of study were not associated with melanoma risk, neither were sunbathing and sunburns (adjusted OR for mean number of weeks spent in sunny climates >14 years: 1.12 (0.88–1.43); adjusted OR for any sunburn >14 years: 1.16 (0.9–1.45)). Host factors such as numbers of naevi and skin type were the strongest risk indicators for melanoma. Public health campaigns have improved knowledge regarding risk of UV-radiation for skin cancers and this may have led to recall and selection biases in both cases and controls in this study. Sunbed exposure has become increasingly prevalent over the last 20 years, especially in Northern Europe but the full impact of this exposure on skin cancers may not become apparent for many years.

of neural crest origin, as are the cells in all vertebrates including humans. The various genera of fish and early studies of inheritance on fish models have all added to our knowledge of pigment formation and the process of benign and malignant proliferation of pigment cells. The occurrence of pigment cell tumors in subsequent generations of Xiphophorus has led to a better understanding of familial melanoma, its mode of inheritance and presentation in successive generations. The presence of melanoma in gray mares has served as a model in a rare type of melanoma in humans with very similar morphology and behavior to the animal form. A review of the evolution of the understanding of the melanocyte biology in the various genera and the impact of this cell on an understanding of melanomagenesis in humans will be presented.

Recent developments in radiation therapy have made it possible to optimize the high dose region to cover almost any target volume and shape at the same time as the dose level to adjacent organs at risk is acceptable. Further implementations of IMRT (Intensity Modulated Radiation Therapy), and inverse treatment planning using already available technologies but also foreseeable improved design of therapy accelerators delivering electron- and photon beams, will bring these advances to the benefit of a broad population of cancer patients. Protons will therefore generally not be needed since in most situations the improvement will be insignificant or moderate due to the large lateral penumbra with deep proton therapy. A further step would be to use He-ions, which have only half the penumbra width of protons and still a fairly low-LET in the spread-out Bragg peak. There is however still a group of patients that cannot be helped by these advances as the tumor might be radioresistant for the presently utilized low ionization density beam qualities. The ultimate step in the therapy development process should therefore be to optimize the beam quality for each tumor-normal tissue situation. To facilitate beam quality optimization light ions are needed. It is argued that in many radioresistant tumors a dose-mean LET of 25-50 eV/nm in the target would be optimum as then tumor cells will be lost in the highest proportion through apoptotic cell kill and the superficial tissues will still be irradiated with a fairly low LET. Light ions using Li, Be, B, and C would then be the ideal choice. In this paper a light ion facility is outlined for the Karolinska University Hospital facilitating both dose distribution and beam quality optimization.

Hansson, J.; Grafström, E.; Omholt, K.; Egyházi, S.; Ringborg, U.; Platz, A. Author Information

Skin cancer is conventionally separated into two categories: melanoma and non-melanoma skin cancer (NMSC). Cutaneous melanoma, which comprises over 90% of all melanoma, is divided into three major histological types. The majority of melanomas in white-skinned populations are superficial spreading and nodular melanomas. Lentigo maligna melanoma (Hutchinson's melanotic freckle) occurs later in life than the other types and more specifically on exposed sites. Acral lentiginous melanoma has not been studied epidemiologically: it is rare in white-skinned populations although it comprises a substantial proportion of melanomas in Japan [1.Elwood J.M. Epidemiology and control of melanoma in white populations and in Japan.J Invest Dermatol. 1989; 92: 214S-221SAbstract Full Text PDF PubMed Scopus (26) Google Scholar]. Non-melanoma skin cancers are generally considered as squamous cell carcinomas (SCC) and basal cell carcinomas (BCC). There is much more known about the epidemiology of melanoma than non-melanoma skin cancers. It is estimated that in 2000there were 132000 cases of melanoma diagnosed world-wide and 37000 deaths caused by melanoma. In Europe, it is estimated that in 2000 there were 35000 cases of melanoma diagnosed and 9000 deaths caused by melanoma. The annual world-wide melanoma burden is split unevenly between high-resource countries (104000 cases and 25000 deaths) and low- and medium-resource countries (28500 cases and 12000 deaths) [2.Ferlay J. Bray F. Pisani P. Parkin D.M. GLOBOCAN. Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0.IARC CancerBase. 5. France: IARC Press, Lyon2000: 2001Google Scholar]. The death:incidence ratio is strikingly different in these categorizations. There are no similar data available for NMSC. The highest incidence rates of melanoma are reported from (essentially European migrant populations in) Australia and New Zealand (non-Maori population) where the annual incidence is more than double the highest rates recorded in Europe [3.Parkin D.M. Whelan S.L. Ferlay J. et al.Cancer Incidence in Five Continents.VIII. Lyons, France: IARC2003Google Scholar]. Incidence rates have been increasing rapidly for several decades in all Caucasian populations [4.P Boyle, JF Dore, P Autier et al. European Institute of Oncology Advisory Group Report on Prevention and Control of Melanoma. Eur J Cancer (in press).Google Scholar] although there is now an indication that in those areas where the incidence is highest, the mortality rate is beginning to stabilise or fall [5.Giles G.G. Armstrong B.K. Burton R.C. et al.Has mortality from melanoma stopped rising in Australia? Analysis of trends between 1931 and 1994.Br Med J. 1996; 312: 1121-1125Crossref PubMed Scopus (168) Google Scholar]. In Europe, during the 1990s, incidence rates were higher in northern and western Europe whereas mortality was higher in men in eastern and southern Europe. Mortality rates have been rising steadily and in Northern Europe a deceleration took place from the early 1980s. Mortality rates have also leveled off in western Europe whereas in eastern and southern Europe both incidence and mortality are still rising [6.De Vries E. Bray F.I. Coebergh J.W. Parkin D.M. Changing epidemiology of malignant cutaneous melanoma in Europe, 1953–1997: Rising trends in incidence and mortality but recent stabilizations in Western Europe and decreases in Scandinavia.Int J Cancer. 2003; 107: 119-126Crossref PubMed Scopus (318) Google Scholar]. The net effect is that melanoma mortality rates in the mid-1990s (1993–1997) are highest in Nordic countries and lowest in southern European populations, such as Greece, Spain and Portugal [7.Boyle P. Smans M. Cancer Mortality Atlas of European Union.1993–1997. Oxford University Press, Oxford, UK2003Google Scholar]. There is little information systematically collected and available regarding NMSC in populations although there have been some very recent publications giving insight into the epidemiology of this topic. Although skin cancer is not unknown in children and young adults, where melanoma predominates, it is essentially a disease of ageing populations [8.Pearce M.S. Parker L. Cotterill S.J. et al.Skin cancer in children and young adults: 28 years' experience from the Northern Young Persons's Malignant Disease Registry.UK. Melanoma Res. 2003; 13: 421-426Crossref PubMed Scopus (48) Google Scholar]. In Maastricht, the Netherlands, squamous cell cancer was the commonest form of cancer among the very elderly (aged over 95) [9.Boi S. Cristofolini M. Micciolo R. et al.Epidemiology of Skin Tumours: Data from the Cutaneous Cancer Registry in Trentino, Italy.J Cutan Med Surg. 2003; 167: 339-388Google Scholar]. The commonest type of NMSC is basal cell carcinoma. In Trentino, Italy, the Skin Cancer Registry calculated (for the period 1993–1998) that the incidence rate of BCC was 88 per 100000, of SCC it was 29 per 100000 and it was 14 per 100000 for melanoma [10.de Rijke J.M. Schouten L.J. Hillen H.F. et al.Cancer in the very elderly Dutch population.Cancer. 2000; 89: 1121-1133Crossref PubMed Scopus (57) Google Scholar]. This tendency was confirmed in Izmir, Turkey, where nearly half the lesions appeared on the face and, while SCC was equally common in men and women, BCC were nearly three times more frequent in men [11.Ceylan C. Ozturk G. Alper S. Non-melanomatous skin cancers between the years of 1990 and 1999 in Izmir, Turkey: demographic and clinicopathological characteristics.J Dermatol. 2003; 30: 123-131Crossref PubMed Scopus (28) Google Scholar]. In Vaud, Switzerland, BCC were the commonest form of skin cancer reported in both men and women and the incidence has been rising steadily since registration was introduced in the mid 1970s [12.Levi F. Te V.C. Randimbison L. et al.Trends in Skin Cancer Incidence in Vaud: an update, 1976–1998.Eur J Cancer Prev. 2001; 10: 371-373Crossref PubMed Scopus (53) Google Scholar]. In Sweden, 39805 SCC were registered between 1961 and 1995 [12.Levi F. Te V.C. Randimbison L. et al.Trends in Skin Cancer Incidence in Vaud: an update, 1976–1998.Eur J Cancer Prev. 2001; 10: 371-373Crossref PubMed Scopus (53) Google Scholar]. Incidence rates increased substantially in men (by 42%) and in women (by 146%) during this period and interpretation of mathematical models led the authors to conclude that these increases could probably be explained by increased cumulative sun exposure and increasing incidence among the elderly [13.Wassberg C. Thorn M. Johansson A.M. et al.Increasing incidence rates of squamous cell carcinoma of the skin in Sweden.Acta Derm Venereol. 2001; 81: 268-272Crossref PubMed Scopus (55) Google Scholar]. Between 1978 and 1995, the Slovakian Cancer Registry registered 38629 cases of NMSC (19 600 in men and 19029 in women). During this period, incidence rates of BCC increased by 70.4% in men and 65% in women while incidence rates of SCC increased by 13.5% in men and 18.8% in women. Head and neck were the most common sites (84.2% BCC and 74.7% SCC) followed by the trunk for BCC (17% in men and 11% in women) and upper limbs for SCC (12% in men and 12.5% in women) [14.Plesko I. Severi G. Obsitnikova A. Boyle P. Trends in the incidence of non-melanoma skin cancer in Slovakia, 1978–1995.Neoplasma. 2000; 47: 137-142PubMed Google Scholar]. Mortality from NMSC is almost always from SCC, a form of cancer whose risk is strongly linked to cumulative lifetime sun exposure [15.Rosso S. Zanetti R. Martinez C. et al.The multicentre south European study 'Helios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin.Br J Cancer. 1996; 73: 1447-1454Crossref PubMed Scopus (335) Google Scholar]. NMSC mortality in Europe presents an entirely different picture than melanoma. The rates are higher in men and women in southern European countries (Greece, Spain, Portugal and Italy) and low in the Nordic countries [7.Boyle P. Smans M. Cancer Mortality Atlas of European Union.1993–1997. Oxford University Press, Oxford, UK2003Google Scholar]. Although morbidity and mortality are low, skin cancers are far more common than other malignancies. Representative Medicare claims data were obtained from the Medicare current beneficiary survey (1992–1995) and weights were applied to give nationally representative estimates [16.Housman T.S. Feldman S.R. Williford P.M. et al.Skin cancer is among the most costly of all cancers to treat for the Medicare population.J J Am Acad Dermatol. 2003; 48: 425-429Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar]. Average Medicare expenditure on cancer management was $13 billion per year and the five most costly cancers to Medicare were lung and bronchus, prostate, colon and rectum, breast and NMSC. Such considerations give NMSC a far higher public health significance than can be obtained from consideration of death statistics. Skin cancer has several unique epidemiological features. Skin cancers range from the potentially very serious melanomas, through squamous carcinomas, to the low-morbidity and low-mortality BCC. While a patient with a primary melanoma has a 10-fold increased risk of a second primary, such second cancers are rare in absolute terms and in comparison to the many people who can have multiple BCC. Although cutaneous malignant melanoma is still a relatively rare neoplasm in many populations, incidence rates are increasing in Caucasian populations around the world. Melanoma continues to be a major public health issue given the large increases in incidence and the notable case fatality rate. NMSC are also increasing in incidence in Caucasian populations and these trends may be exacerbated by further increases in both acute and prolonged exposure to sunshine (see Rosso et al. [15.Rosso S. Zanetti R. Martinez C. et al.The multicentre south European study 'Helios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin.Br J Cancer. 1996; 73: 1447-1454Crossref PubMed Scopus (335) Google Scholar]) together with the increasing number of older people in the population. This latter observation is of crucial significance in Europe. Although the population of the (25 Member State) European Union will remain constant at around 500 million between 2000 and 2015, there will be a 22% increase in the numbers aged 65 and over and a 50% increase in those aged 80 and over [17.Quinn M.J. d'Onofrio A. Møller B. et al.Cancer Mortality Trends in the EU and Acceeding States up to 2015.Ann Oncol. 2003; 14: 1148-1152Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. Consequent to this ageing of the European population, there will be a notable increase in the number of skin cancers to be diagnosed and treated. Although not life-threatening, BCC is an important public health problem due to the frequency of the cancers and the costs of their treatment on national health resources. It is important that NMSC do not remain forgotten forms of cancer. Skin cancer is clearly identified as one form of cancer thatwill become more important in public health terms in the coming decades in the absence of effective intervention today. Enough is known about the causes of skin cancers to shift the focus of population research activity from aetiology to prevention. The European Code Against Cancer [18.Boyle P. Autier P. Bartelink H. et al.European Code Against Cancer and Scientific Justification: Third Version (2003).Ann Oncol. 2003; 14: 973-1005Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar] recommends that 'Care must be taken to avoid excessive sun exposure. It is specifically important to protect children and adolescents. For individuals who have a tendency to burn in the sun active protective measures must be taken throughout life'. Widespread implementation of this recommendation would lead to a reduction in NMSC incidence, as has been demonstrated in Australia [19.Staples M. Marks R. Giles G. Trends in the incidence of non-melanocytic skin cancer (NMSC) treated in Australia 1985–1995: are primary prevention programs starting to have an effect?.Int J Cancer. 1998; 78: 144-148Crossref PubMed Scopus (246) Google Scholar], and have a significant impact on making more resources available to treat clinical cancers, of this and other organs. It is a pleasure to acknowledge that his work was conducted within the framework of support from the Italian Association for Cancer Research (Associazone Italiana per la Ricerca sul Cancro).

BACKGROUND Germline alterations in cyclin-dependent kinase inhibitor 2A (CDKN2A) are important genetic factors in familial predisposition to melanoma. Activating mutations of the NRAS proto-oncogene are among the most common somatic genetic alterations in cutaneous malignant melanomas. We investigated the occurrence of NRAS mutations in melanomas and dysplastic nevi in individuals with germline CDKN2A mutations. METHODS Genomic DNA was extracted from 39 biopsy samples (including primary melanomas, metastatic melanomas, and dysplastic nevi) from 25 patients in six Swedish families with a hereditary predisposition to melanoma who carried germline CDKN2A mutations. DNA was also extracted from 10 biopsy samples from patients with sporadic melanomas. NRAS was analyzed using polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequence analysis. Differences in NRAS mutation frequency between hereditary and sporadic melanomas were analyzed by the chi-square test. All statistical tests were two-sided. RESULTS Activating mutations in NRAS codon 61, all of which were either CAA(Gln)-AAA(Lys) or CAA(Gln)-CGA(Arg) mutations, were found in 95% (20/21) of primary hereditary melanomas but in only 10% (1/10) of sporadic melanomas (P<.001). Multiple activating NRAS mutations were detected in tumor cells from different regions of individual primary melanomas in nine patients. Activating mutations that were detected in the primary melanomas of these patients were also retained in their metastases. NRAS mutations at sites other than codon 61 were also present in the primary melanomas, indicating genetic instability of this locus. NRAS codon 61 mutations were also detected in dysplastic nevi and in an in situ melanoma, suggesting a role for such mutations during early melanoma development. CONCLUSIONS The high frequency of NRAS codon 61 mutations detected in these hereditary melanomas may be the result of a hypermutability phenotype associated with a hereditary predisposition for melanoma development in patients with germline CDKN2A mutations.