Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients.

There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guerin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.

Monitoring of nevus density in children as a method to detect shifts in melanoma risk in the population.

BACKGROUND: Nevus density in children, a well-known risk factor for malignant melanoma, depends both on constitutional factors and on previous ultraviolet (UV) exposure. Secular trends of childhood UV exposure could thus be indirectly monitored by repeated standardized surveys assessing nevus density in children, such as the "childhood monitoring of nevus density (CMONDE-Study)". METHODS: Two complete surveys comprising all children at the time of school enrolment were performed in the city and county of Göttingen, Germany, during the years 1999 and 2000. A total of 4252 children with a median age of 6.25 years were examined as part of the mandatory school enrolment health assessment, and complete data were available for 3881 children. RESULTS: Median nevus density was 5.8/m(2) in the entire study group. The subgroup-specific median increased from "Fitzpatrick skin type" IV to II, but the density was not increased for the type I subgroup. Similarly, nevus density rose with increasing lightness of hair color, but was very low in red-haired individuals. While the number of freckles was also strongly associated with nevus density, the association between iris color and skin reflectance, respectively, was weak. The duration of the additional examination for CMONDE was on average 3-5 min per child. CONCLUSION: We regard CMONDE as a highly feasible surveillance instrument, which should be implemented as an important addition to regular regional or national health reporting.

Inter-relation between variables determining constitutional UV sensitivity in Caucasian children.

BACKGROUND/PURPOSE: Sensitivity to ultraviolet (UV) light is associated with phenotypic variables like iris or hair colour or freckling, which are all strongly inter-related. We assessed the pattern of association among these factors to construct a summary measure reflecting constitutional UV sensitivity in a simple one-dimensional score with sufficient discriminating power. METHODS: Information on iris and hair colour (3 and 4 categories, respectively), freckling (none vs. any) and the reaction to mid-day summer sunlight as an outcome (dichotomized into 'burn' and 'tan') was collected in a cross-sectional study among children at school enrollment in 1999 and 2000 in Göttingen, Germany (n=3765 with complete data). Chi-squared automatic interaction detector (CHAID) analysis and log-linear modelling was used to assess the pattern of mutual inter-relations. RESULTS: Hair colour turned out to be the factor most strongly associated with UV sensitivity. In case of blonde or brown hair (the most common phenotypes in our sample), the consideration of freckling further refined the classification system, whereas iris colour did not contribute additional information. The results of the CHAID and log-linear analyses suggest a simple five-point score capturing constitutional UV sensitivity. The discriminating power of this score was high in our sample, with the proportion of persons who burned ranging from 7.7 (lowest category) to 73% (highest category). CONCLUSION: The new scoring system summarized efficiently relevant information on individual constitutional UV sensitivity in our sample. Its further validation in independent studies comprising Caucasian children or adults is necessary to assess objectively its properties for future applications.

Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study.

A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a 'masking effect' by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.

Survival probabilities and hazard functions of malignant melanoma in Germany 1972-1996, an analysis of 10433 patients. Evolution of gender differences and malignancy.

The evaluation of the impact of prevention activities on the course of survival in conjunction with the individual hazard rate of dying is described using data from a follow-up study of 10433 melanoma patients during three observation periods (1972-1980, 1981-1988, 1989-1996). Kaplan-Meier survival curves combined with hazard functions were calculated. At all observation periods, survival of men was lower compared with women and their maximum dying risk was earlier (70 versus 100 months after removal of the primary tumour). In 1989-1996, differences in the survival rates were approximately halved compared with those for 1972-1980 or 1981-1988, respectively. This improvement was predominantly seen in young men. There was a lower survival rate of men compared with women with identical thickness categories. The maximum dying risk for those men with tumours >4 mm peaked at approximately 60 months, the other thickness categories showing a lower and later maximum; in women, the maximum dying risk for tumours >4 mm was also seen at approximately 60 months, but less pronounced. Over time, the influence of Breslow thickness on the survival rates remained constant in women; in men, with the exception of thick tumours, there was a trend towards a better survival. Melanoma awareness campaigns conducted in Germany since the late 1980s have resulted in a trend towards a remarkable increase of thin tumours in recent years, whereas the number of new cases with thick tumours has remained constant.

[Monitoring of naevus density--an approximate marker of previous UV exposure--in children at school enrollment as a method to detect shifts in melanoma risk in the population]. / Pigmentmaldichte bei Kindern im Einschulungsalter - wiederholte standardisierte Querschnittsuntersuchung zur Einschätzung des zu erwartenden Melanomrisikos in der Bevölkerung.

OBJECTIVE: Naevus density in children depends both on constitutional factors (see below) and on previous (solar) UV exposure, which is a well-known risk factor for malignant melanoma. Secular trends of childhood UV exposure - e. g., due to intervention programmes - can be monitored by repeated, standardised cross-sectional studies assessing naevus density in children. METHODS: The 'CMONDE-Study (childhood monitoring of naevus density)' appears as a suitable instrument, introduced into the process of school enrollment for children of the years 1999 and 2000 in Göttingen. RESULTS: Analyses are based on 3883 children. Median age was 6.25 years, the proportion of girls 47 %. Median naevus density was 5.8/m(2), with an increase of density from 'Fitzpatrick skin type' IV to II, but marked decrease in type I. Similarly, naevus density increased with increasing lightness of hair colour, but was very low in red-haired individuals. While the number of freckles was also strongly associated with naevus density, the association between iris colour and skin darkness, respectively, was weak. CONCLUSION: To meet the objective of continual monitoring, further comparative cross-sectional studies are needed.

Cowpox virus in a 12-year-old boy: rapid identification by an orthopoxvirus-specific polymerase chain reaction.

Although smallpox was eradicated 20 years ago, other members of the genus Orthopoxvirus (OPV), such as cowpox virus (CPXV) or monkeypox virus, are still a threat to humans. Because human CPXV infection is rare, it is seldom suspected on clinical grounds only. We report a boy who presented with two necrotic ulcers with surrounding erythema. Infection with OPV was suspected, as antibiotic treatment had not produced improvement and smears were negative for anthrax. An OPV was isolated and an OPV-specific polymerase chain reaction combined with a subsequent restriction enzyme fragment length polymorphism assay confirmed infection by CPXV. Although the patient's cat had had no skin lesions, OPV-specific antibodies were found at a titre of 1 : 8 in a plaque reduction assay, suggesting that the cat had transmitted the virus to the boy.

[Mortality of invasive malignant cutaneous melanoma. A review with special consideration of gender distribution]. / Zur Sterblichkeit am kutanen invasiven malignen Melanom. Ubersicht unter besonderer Berücksichtigung der Geschlechterverteilung.

BACKGROUND AND OBJECTIVE: The final goals of malignant melanoma prevention are lowering incidence and mortality. We assessed the parameter "survival" for both men and women as the beginning point for future gender-directed prevention campaigns. We compared the periods 1972-1980, 1981-1988, 1989-1996, and determined the influence of age and of Breslow' tumor thickness on survival. PATIENTS/METHODS: We had sufficient follow-up on 10.433 patients. We calculated survival curves according to Kaplan-Meier and defined differences by the logrank test. RESULTS: At all periods of time, survival of women was higher compared with men, but with no impressive changes over time. This was especially true for younger men. The most important prognostic factor was the Breslow tumor thickness. Within all periods of time, its median was higher in men. A trend downwards for both genders could be observed with higher influence on survival in men. CONCLUSIONS: Our findings justify melanoma prevention campaigns addressed to men. Evaluation of such campaigns has to take into account an already existing upwards trend for male survival, which exceeds that of female survival.

Timing of excessive ultraviolet radiation and melanoma: epidemiology does not support the existence of a critical period of high susceptibility to solar ultraviolet radiation- induced melanoma.

BACKGROUND: The existence of a 'critical period' early in life characterized by a high susceptibility to melanoma initiation due to excessive ultraviolet (UV) radiation has been suggested by various authors based on epidemiological findings from migration studies and some case-control studies. However, the evidence so far is controversial as several epidemiological investigations failed to corroborate these results. Objective To compare the increase in melanoma risk due to excessive UV radiation between different periods in life. METHODS: In a multicentre case-control study we recruited 603 melanoma cases and 627 population controls in seven European countries. We obtained data on the history of sunburns during 'childhood' ( 15 years), respectively, in standardized personal interviews. We employed logistic regression analyses to estimate the impact of the exposure factors under study, while simultaneously controlling for the effect of a variety of confounding variables. RESULTS: We found a very similar upward gradient of melanoma risk in exposure categories related to the frequency of sunburns during both periods in life. More than five sunburns doubled the melanoma risk, irrespective of their timing in life. CONCLUSIONS: Our data do not provide supporting evidence for the existence of a 'critical period'. The hazardous impact of sunburns seems to persist lifelong and thus activities concerned with melanoma prevention should be directed to the entire population rather than being focused only on younger age groups.

[Ultraviolet exposure in childhood and in adulthood: which life period modifies the risk of melanoma more substantially?]. / UV-Exposition in der Kindheit und im Erwachsenenalter: Welche Lebensperiode beeinflusst das Melanomrisiko entscheidender?

The paper is devoted to the analysis of the relationship between the frequency of sunburns in childhood and adulthood, respectively, and the occurrence of malignant melanoma of the skin. The analysis is based on case-control data of 603 melanoma cases and 627 population controls from 11 participating centers in seven European countries. The results confirm the increase in melanoma risk for an increasing number of sunburns during childhood and adulthood in the same magnitude of risk elevation. The maximum OR for the highest exposure category of more than five sunburns was during the childhood 2.0 (95%-CI: 1.2-3.5) and during the adulthood 2.1 (95%-CI: 1.4-3.3), respectively. The analysis of the joint effects of sunburns during child- and adulthood on melanoma development corroborated these findings. In this joint analysis an OR of 2.1 (95%-CI: 1.3-3.5) quantifies the melanoma risk of those with three or more sunburns during child- and adulthood, respectively, compared to those without any sunburns during these periods. The study does therefore provide no supporting evidence for the presence of "critical period" during childhood in which a higher melanoma risk due to sunburns has been suggested by other studies.

Is there a relationship between influenza vaccinations and risk of melanoma? A population-based case-control study.

The aim of the present case-control study was to ascertain whether, in adults, yearly repeated anti-influenza vaccinations (AIV) enhance protection against cutaneous melanoma (CM), as do repeated febrile infections. Ninety-nine new cases of histologically confirmed CM and 104 healthy controls (matched to cases for sex, age, and skin colour) selected from the general population were examined in order to ascertain their skin type, the number of nevi on both arms, and the intensity of freckles on the face and the arms; in these subjects, a structured questionnaire was used to obtain information on age, sex, education, social class, exposure and susceptibility to sunlight, history of febrile infectious diseases, and vaccinations. The odds ratio (OR) and the 95% confidence interval (CI) were estimated by commonly used methods and by fitting models of logistic regression. The risk of CM was reduced in subjects with a history of febrile (temperature above 38.5 degrees C) infections in the 5 years prior to CM surgery (cases) or interview (controls), but was increased in those with voluntary exposure to sunlight in tropical countries. By holding the above factors constant at logistic regression analysis, it was found that a history of repeated AIV (3-5 times in the last 5 years) halved the risk (OR: 0.43; CI: 0.19-1.00; p < 0.05). With the variable 'nevi on arms' included, the protective influence of repeated AIVs was observed in a similar magnitude. The inverse relationship found between melanoma and influenza vaccinations is unlikely to have depended on a bias, even if based on replies in a questionnaire, because neither the interviewers nor the interviewers were informed in advance of the working hypothesis.

Infections and melanoma risk: results of a multicentre EORTC case-control study. European Organization for Research and Treatment of Cancer.

Immune function plays a prominent role in the defence against cutaneous malignant melanoma and the increased risk of melanoma development during immunosuppression. Since the immune system is challenged beyond its routine activity by an infection, the effect of previous infectious diseases on the risk of melanoma may also be crucial. In a European Organization for Research and Treatment of Cancer (EORTC) case-control study performed in six European countries and Israel, we compared the history of severe infections in 603 melanoma patients with that in 627 population controls. We calculated adjusted odds ratios (ORs) to estimate the effect of infectious diseases on melanoma risk. The ORs for melanoma risk were below 1 for nearly all types of infections (except two) if body temperature was not taken into consideration, and for all infections with a body temperature above 38.5 degrees C. In the latter category significantly lowered ORs were found for pulmonary tuberculosis (0.16; 95% confidence interval [CI] 0.01-0.98), Staphylococcus aureus infections (0.54; 95% CI 0.31-0.94), sepsis (0.23; 95% CI 0.06-0.70), influenza and related infections (0.65; 95% CI 0.48-0.86) and pneumonia (0.45; 95% CI 0.27-0.73). Analysis of the cumulative influence revealed a consistent pattern of results pointing to a reduction in melanoma risk with increasing numbers of recorded infections and fever height. This apparent dose-response relationship suggests a causal association. Speculations on the underlying mechanism include a Shwartzman-like phenomenon when melanoma formation precedes the infection and/or an infection-related Th1-cell activation preventing the establishment of the tumour.

[Prevention of melanoma by sun protective measures in childhood. Temporal changes in awareness of parents]. / Melanomprävention durch Sonnenschutzmassnahmen im Kindesalter. Zeitliche Veränderungen im Bewusstsein von Eltern.

Numerous epidemiological studies on risk factors of malignant melanoma confirm the etiologic role of excessive UV-exposure especially in childhood. Preventive educational campaigns directed to parents of pre-school children have been inaugurated in several countries. In Germany the information was distributed by the "Working group for Preventive Measures in Dermatology" in cooperation with different public health institutions and the media starting in 1993. To evaluate the influence of these efforts on the knowledge and behaviour of the parents, two successive cross-sectional studies at all 56 nursery schools using the same standardised questionnaire were performed. The first interview took place in spring 1993 (before the campaign) with 1341 evaluable questionnaires', the second in fall 1994 (after the campaign) with 1150 evaluable questionnaire. The knowledge of the parents on melanoma risk factors was significantly improved in the second interview. Also the parental behavior regarding sun-protective measures when their children were outdoor at the beach or in the garden definitely changed. In 1993 the best textile sun protection was used by 21% of the parents at the beach and 36% in the garden. These numbers rose to 34% (beach) and 57% (garden) by the second interview. The percentage of children with no sunburn recorded during the preceding summer rose from 39% to 51%. According to the child's gender the parental behavior was different between the sexes; boys were always better protected than girls. The design of this study with two cross-sectional surveys in the same populations does not provide a methodologically sound basis for attributing the observed positive changes to the campaign. Without any doubt it can be stated that the parental knowledge and their attention to sun protection in their children showed substantial improvement in the second survey after the campaign. Thus, these results provide some evidence for the success of the preventive activities and confirm the necessity to continue with such activities.

Public awareness of malignant melanoma risk factors in Germany.

STUDY OBJECTIVE: To evaluate the effects of a German public education campaign which aimed to improve knowledge on risk factors for malignant melanoma. DESIGN: Comparison of data from two successive cross sectional surveys conducted before (spring 1993) and after (autumn 1994) the campaign. SETTING: All 56 nursery schools in Göttingen, the capital of southern Lower Saxony, Germany. PARTICIPANTS: Parents of children attending the nursery schools. Altogether 1341 questionnaires from parents were included in the first survey (response rate 64.9%) and 1150 questionnaires in the second survey (response rate 61.4%). MAIN RESULTS: The respondents in the second survey were much better at distinguishing true melanoma risk factors from false ones. The distribution of scores measuring the degree of accurate knowledge about melanoma risks indicated that this had improved significantly (p < 0.001). The most pronounced change with regard to knowledge of single risk factors could be observed for "sunburn during childhood," which was correctly identified by 63.1% in the first survey and by 85.6% in the second. Substantial improvement in accurate knowledge about the influence of constitutional skin factors--number of naevi, skin type etc--was also found. CONCLUSIONS: Notwithstanding the methodological problems in this analysis (non-randomised design, only before and after comparison, no control group, number of non-respondents), it is concluded that this campaign improved understanding of the risks of melanoma. Continuing public education activities should be implemented to sustain and improve further knowledge on prevention of malignant melanoma.

Induction of heat shock protein 70 genes in human lymphocytes during fever therapy.

The induction of heat shock protein 70 (HSP70) genes has been studied in peripheral blood mononuclear cells of individuals undergoing fever therapy because of metastatic malignant melanoma. Induction of HSP70 was assessed at the protein level by metabolic labelling or, for the HLA-linked HSP70-1 and HSP70-2 genes, at the RNA level by in situ hybridization. However, de novo expression of HSP70 could be observed during fever (usually above 39 degrees C) in only about half of the cases. No simple threshold model for inducibility of HSP70 in vivo could be applied. The HSP70-1 gene was induced more easily than HSP70-2. Thus, heat-inducible HSP70 genes, including HLA-linked HSP70 genes, become expressed in human lymphocytes during fever, but not regularly.

[Differential diagnosis of eyelid edema]. / Differentialdiagnostik bei Lidschwellungen.

The eyelids are the site of many different pathological conditions. Swelling--often oedematous--is a frequent symptom. This publication deals with the pathophysiological and anatomical basis of eyelid swelling and mainly provides a practical approach for differential diagnosis with the help of flow and short characterisations of possible causes. The subjective complaints of the patient charts (pain, pruritus) are shown to be important criteria for orientation. Special interest is focussed on allergic diseases and atrophic conditions as causes of eyelid swelling.

[Prognostic advantage for defined risk groups by lymphocyte dissection. Long-term study of 3,616 melanoma patients]. / Prognosevorteil für definierte Risikogruppen durch die Lymphknotendissektion. Langzeitstudie an 3616 Melanompatienten.

Nine medical centres with different practices in elective lymph node dissection (ELND) but comparable standards regarding diagnosis, excision of the primary tumour, classification, and follow-up, have collected their data on 3616 patients with primary melanoma of the skin (tumour category pT 2 to pT 4a, N 0, M 0 [UICC 1987] with the aim of producing an unbiased analysis of the prognostic benefit of ELND. The multivariate risk analysis (Cox's proportional hazard model) revealed tumour thickness (Breslow or alternative pT categories), sex, anatomic site of the primary tumour, and ELND therapy ("yes" or "no") as independent prognostic factors. Observed survival curves (Kaplan-Meier) show a significant difference of prognosis with regard to ELND therapy in the following risk groups: women with melanomas over 2.5 to 4 mm thick on head, neck, thorax, and in acral locations; men with melanomas over 1.5 to 4 mm thick on head, neck, thorax, and in acral locations; and finally men with melanomas over 2.5 to 4 mm thick on abdomen and extremities. Further investigations and the discovery of additional prognostic factors would help in more precisely formulation of guidelines for ELND.

[In vivo fluorescence spectroscopy of human skin: principles and application to penetration measurements]. / In vivo-Fluoreszenzspektroskopie an menschlicher Haut: Grundlagen und Anwendung auf Penetrationsmessungen.

The fluorescence properties of untreated human skin and the penetration of topically applied drugs were measured in vivo using a commercially available fluorescence spectrometer which was adapted to in vivo-measurements on skin by means of optical fibres and a remote viewing head. The intensity and characteristics of the intrinsic fluorescences of human skin and their dependences upon several parameters like pigmentation, water content of the skin or depth of the horny layer are shown. The principles of the penetration measurements based on the fluorescence of the skin or the fluorescence of the drug topically applied to the skin are described and measurements of the penetration of some drugs are reported.