Klaus F. Kölmel

Survival probabilities and hazard functions of malignant melanoma in Germany 1972–1996, an analysis of 10 433 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.

Melanomprävention durch Sonnenschutzmaßnahmen im Kindesalter Zeitliche Veränderungen im Bewußtsein von Eltern

ZusammenfassungZahlreiche epidemiologische Studien zu Risikofaktoren des malignen Melanoms belegen die bedeutende Rolle, welche der exzessiven Exposition gegenüber ultravioletter (UV) Strahlung, insbesondere im Kindesalter, bei der Ätiologie des Melanoms zukommt. An Eltern von Kleinkindern gerichtete Aufklärungskampagnen über Sonnenschutzmaßnahmen im Kindesalter wurden in mehreren Ländern entwickelt. Die Propagierung entsprechenden Wissens in Deutschland war Gegenstand der von der Arbeitsgemeinschaft Dermatologische Prävention (ADP) durchgeführten Aufklärungsaktionen unter Einbeziehung verschiedener Institutionen des deutschen Gesundheitswesens und der Medien ab dem Jahre 1993. Um einen ersten Eindruck der Auswirkungen dieser gesundheitsaufklärerischen und erzieherischen Bemühungen auf das Wissen und Verhalten der Eltern zu erhalten, wurden in Göttingen an allen 56 Kindergärten 2 zeitversetzte Querschnittsstudien mit demselben standardisierten Erhebungsinstrument durchgeführt. Die erste Befragung im Frühjahr 1993 (somit vor der Kampagne) umfaßte 1341 auswertbare Fragebögen, während die zweite Welle im Herbst 1994 (somit nach der Kampagne) einen Rücklauf von 1150 auswertbaren Fragebögen erbrachte. Der Wissensstand der Eltern über die Risiken der Melanomentstehung hatte sich in der 2. Befragung signifikant verbessert. Das Verhalten der Eltern hinsichtlich der von ihnen ergriffenen Schutzmaßnahmen beim Aufenthalt ihrer Kinder im Freien (unterschieden nach Strand und Garten) veränderte sich ebenfalls eindeutig. Einen optimalen textilen Sonnenschutz praktizierten in der 1. Befragung 21% der Eltern am Strand (36% im Garten). Diese Zahlen stiegen auf 34% (Strand) bzw. 57% (Garten) in der 2. Befragung. Der Anteil der Kinder, die den zurückliegenden Sommer (1992 in der 1. Befragung, 1994 in der 2. Befragung) ohne Sonnenbrand und Hautrötung überstanden hatte, stieg von 39% auf 51%. Geschlechtsspezifische Unterschiede im Verhalten der Eltern waren auffällig, so wurden Jungen besser geschützt als Mädchen. Das verwendete Design zweier zeitversetzter Querschnittsstudien kann methodisch nicht einwandfrei klären, ob die beobachteten positiven Veränderungen eine direkte Konsequenz der Aufklärungskampagne zu Sonnenschutzmaßnahmen im Kindesalter sind. Zweifelsfrei ist allerdings zu konstatieren, daß eine Verbesserung des Wissensstandes der betroffenen Eltern und eine Veränderung ihres Verhaltens in Richtung eines besseren Schutzes ihrer Kinder vor UV-Exposition stattgefunden hat. Diese Ergebnisse bieten somit Evidenz, von einem Erfolg der gesundheitsaufklärerischen und -erzieherischen Maßnahmen auszugehen, und unterstreichen die Notwendigkeit, derartige Aktivitäten in der Zukunft fortzusetzen.SummaryNumerous 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 questionnaires. 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 population 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.

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.

Differentialdiagnostik bei Lidschwellungen

ZusammenfassungAn den Augenlidern manifestieren sich unterschiedlichste Erkrankungen. Ein häufiges Symptom dieser Region ist die Schwellung, der wiederum oft ein Ödem zugrundeliegt. Neben einer Beschreibung der pathophysiologischen und anatomischen Grundlagen soll im vorliegenden Text vor allem eine praktische Anleitung – unter anderem mit Flußdiagrammen – zum differentialdiagnostischen Vorgehen bei Patienten mit Lidschwellung gegeben werden. Hierbei erweist sich die subjektive Symptomatik (Schmerzen, Juckreiz) als sinnvolles Orientierungskriterium. Die Erkrankungen werden, nach Inzidenz gereiht, in tabellarischer Form charakterisiert. Besonderes Augenmerk gilt den allergischen Ursachen für Lidschwellungen sowie dem Zusammenhang zwischen Lidschwellung und atrophischen Lidveränderungen.SummaryThe 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.

The biography of the immune system and the control of cancer: from St Peregrine to contemporary vaccination strategies

BackgroundThe historical basis and contemporary evidence for the use of immune strategies for prevention of malignancies are reviewed. Emphasis is focussed on the Febrile Infections and Melanoma (FEBIM) study on melanoma and on malignancies that seem to be related to an overexpression of human endogenous retrovirus K (HERV-K).DiscussionIt is claimed that, as a result of recent observational studies, measures for prevention of some malignancies such as melanoma and certain forms of leukaemia are already at hand: vaccination with Bacille Calmette-Guérin (BCG) of new-borns and vaccination with the yellow fever 17D (YFV) vaccine of adults. While the evidence of their benefit for prevention of malignancies requires substantiation, the observations that vaccinations with BCG and/or vaccinia early in life improved the outcome of patients after surgical therapy of melanoma are of practical relevance as the survival advantage conferred by prior vaccination is greater than any contemporary adjuvant therapy.SummaryThe reviewed findings open a debate as to whether controlled vaccination studies should be conducted in patients and/or regions for whom/where they are needed most urgently. A study proposal is made and discussed. If protection is confirmed, the development of novel recombinant vaccines with wider ranges of protection based, most likely, on BCG, YFV or vaccinia, could be attempted.

Is the acral-lentiginous melanoma (ALM) more malignant than the superficial spreading melanoma (SSM) in a high-risk location? A matched-pair comparison of 113 each ALM and SSM in a multicenter study

Zusammenfassung. Die Prognose des akrolentiginösen Melanoms (ALM) wird auch heute noch kontrovers beurteilt. Diese große Fallstudie schließt deshalb alle bekannten prognoserelevanten Faktoren ein. Aus einem Kollektiv von 3616 Melanomen wurden den vorhandenen 113 ALM genau 113 Symptom-Zwillinge des superfiziell spreitenden Melanoms (SSM) aus einer 619 Fälle umfassenden high-risk-Lokalisationgruppe zugeordnet, die sich in Tumordicke, Geschlecht und Behandlungsmodalität glichen. Die Nachbeobachtung betrug mindestens 5 Jahre. Die 5-Jahres-Überlebenskurven nach Kaplan-Meier der beiden Gruppen unterschieden sich nicht. Die oftmals beschriebene schlechtere Prognose des ALM ist eine Folge der Lokalisation und nicht des Typs. Das ALM ist demnach als akral lokalisiertes Melanom zu betrachten.Abstract. Even today, the prognosis of acral-lentiginous melanoma (ALM) remains a controversial topic. We present a large case study including all known factors relevant for prognosis. 113 ALMs in 3616 melanoma patients were paired as precisely as possible with their twins, i.e. with 113 superficial spreading melanomas (SSM) from a group of 619 SSMs with high-risk location. The ALMs and SSMs were equivalent in tumor thickness, patient gender and mode of treatment. The follow-up period was for at least 5 years. The 5-year Kaplan-Meier survival curves in both groups are identical. The poor prognosis often ascribed to ALM results from the prognostic factor location. ALM should therefore be regarded as acral localized melanoma.

Vaccination and melanoma risk

Dear Sir, Given the intensive efforts to treat melanoma by various forms of immunotherapy utilizing mostly Bacille CalmetteGuérin (BCG) vaccine or, to a lesser extent, vaccinia vaccine during the past decades, it is surprising that no epidemiological study so far has examined the potential relationship between vaccination history and melanoma risk.1 Although there is quite a difference between immunotherapy of an established lesion and immunological prevention of melanoma, we found it tempting to analyze in an epidemiological study whether the application of BCG vaccination, commonly administered to the newborn to provide protection against tuberculosis, and vaccinia vaccination, also commonly administered twice to children to provide protection against smallpox until the late 1970s, influences melanoma risk. Experimental evidence2 and clinical trials3–6 on the therapeutical benefits of these vaccinations for melanoma patients have shown promising results in the 1970s that could not be confirmed in later studies on large numbers of patients.7,8 Substantial heterogeneity among melanoma patients with respect to their response to such therapeutic regimes was, however, identified by Tan and Ho9 in a reanalysis of 20 randomized controlled clinical trials. The development of new strategies for melanoma therapy resulted in a decline of interest in this form of therapy, and further research in this area nearly stopped during recent years. We conducted a case-control study on incident melanoma cases and population controls in Sofia, Bulgaria, to address specifically the relationship between melanoma risk and vaccination history. From 1994 until 1997 we recruited 115 incident cases with histopathologically verified diagnosis of malignant melanoma of the skin and 115 population controls sampled from the same geographical area as the cases and frequency-matched to them with respect to gender and age. The participation rates among eligible cases and controls were 92% and 78%, respectively. In a standardized personal interview conducted at the study subject’s home the same interviewer ascertained detailed information on socio-economic and life style variables as well as on a variety of established risk factors for melanoma such as, e.g., number of nevi, skin type, freckling, and sun exposure. In addition, study subjects were asked for their personal history of BCG vaccination against tuberculosis and vaccinia vaccination against smallpox during childhood. Answers were verified by the interviewer by inspection of the subjects’ vaccination cards. We employed multiple logistic regression analysis to analyze the effect of the 2 different vaccinations on melanoma risk. Confounding variables included in all models were gender, age, skin type (according to Fitzpatrick’s classification),10 freckling index (according to the charts described by Gallagher et al.),11 number of nevi, and number of sunburns. First, we analyzed the effect of the different vaccinations in 2 separate logistic models, each of which comprised a dichotomous exposure variable for the specific vaccination. Then, to address the combined effect of both vaccinations we fitted a joint logistic model in which both exposure variables together with their interaction and all the confounders were incorporated. In this joint approach, results for the effect of vaccination history can be given for the following 4 disjoint vaccination patterns: neither vaccinated with BCG nor with vaccinia (reference category), only vaccinated with BCG but not with vaccinia, only vaccinated with vaccinia but not with BCG, and vaccinated with both BCG and vaccinia. Alternatively, in the joint approach the vaccination history has also been modelled as a dichotomous variable (being vaccinated with BCG or vaccinia vs. neither vaccinated with BCG nor with vaccinia). Results of the logistic regression analyses are given by the estimates of the adjusted odds ratios (OR) for the corresponding exposure variables related to vaccination status and their accompanied 95% confidence intervals (CI) obtained by the profile likelihood method.12 All statistical analyses were carried out by means of validated programs within the SAS software (SAS Institute Inc., Cary, NC). The study sample consisted of 118 males (59 cases, 59 controls) and 112 females (56 cases, 56 controls). The median age (in years) among cases and controls was 61 and 59 years, respectively, accompanied by a wide range in the age of cases (24–90 years) as well as controls (24–84 years). In the case group, the melanomas were rather advanced: one-third had a tumour thickness (according to Breslow’s method)13 above 4 mm, only one-sixth were thin melanomas less than 0.75 mm in thickness. The tumour was primarily located on the trunk (39%), followed by legs and feet (33%), head and neck (19%), and finally, arms and hands (9%). Whereas BCG and vaccinia vaccination were reported by 100 and 111 controls, respectively, only 85 and 104 cases did

Sun Protection of Children: Changing Patterns of Preventive Knowledge and Behaviour

Sufficient epidemiologic evidence exists that exposure to ultraviolet light in childhood is an important risk factor for developing malignant melanoma, a form of skin cancer rapidly increasing in incidence around the world. Public health campaigns focusing on sun protection of children have therefore been developed in several countries. In this paper, an evaluation of the effects of the German campaign launched during the summer of 1993 is described. The design, conduct and results of two successive cross-sectional studies devoted to evaluate changes in the patterns of preventive knowledge and behaviour among parents of children in nursery schools of Gottingen are delineated. In addition, the methodologic considerations when dealing with such an applied problem of epidemiologic classification are discussed.

Childhood infectious diseases and risk of leukaemia in an adult population.

Dear Editor, In a recent article in this journal, evidence was presented that certain acute infectious diseases occurring during childhood confer long-lasting protection against chronic lymphatic leukaemia and, possibly, other forms of leukaemia in the adult population. This study did not, however, determine whether chronic infections such as tuberculosis or vaccinations early in life likewise protect against adult leukaemia. In this context, there is evidence that vaccination with Bacille Calmette–Gu erin (BCG) confers protection against childhood leukaemia provided that it is given early in life and in regions in which it protects against tuberculosis. A study in Finland established that infection by the tubercle bacillus detected by a positive tuberculin reaction or BCG vaccination in tuberculin non-responders resulted in a reduced risk of all types of leukaemia over a 30-year follow-up period compared to those who were neither tuberculin reactors nor vaccinated. Natural infection and BCG vaccination appeared to give equal levels of protection. In this respect, it has been noted that the observed 4.5% annual increase in mortality due to leukaemia in children and young adults in England and Wales between 1911 and 1959 occurred at a time when bovine tuberculosis control measures commenced and before BCG vaccination was widespread. A relationship between a history of certain infections and vaccinations is not restricted to leukaemia and in a previous letter to this journal, we summarized the studies undertaken by the Febrile Infections and Melanoma working group of the European Organization for Research and Treatment of Cancer which showed that vaccination with BCG and vaccinia early in life and the 17D yellow fever vaccine later in life conferred a significant degree of protection against melanoma in adult life. A study in Denmark showed that BCG, but not vaccinia, vaccination reduced the risk of lymphomas and there was a similar trend in the case of leukaemia although a statistical analysis was compromised by low numbers of the latter. The mechanism(s) of protection is open to speculation. In the case of melanoma, we postulated that, by their possession of homologous epitopes, BCG, vaccinia and yellow fever vaccines generated populations of cytotoxic cells targeting an epitope, human endogenous retrovirus (HERV)-K-MEL, present in the cell membranes of most melanomas and coded for by an overexpressed HERV of the K series. A similar protective mechanism could apply to leukaemia and lymphoma as overexpression of HERV-K occurs in the majority of cases of both diseases. The finding that, in contrast to melanoma, vaccinia does not protect against leukaemia and lymphoma suggests, however, that the protective target epitopes differ. An alternative possible mechanism, which does not exclude the former, is that BCG has a non-specific effect on the maturation of the immune system and the generation of immunoregulatory pathways. This could be of particular relevance in regions where hygiene-related factors reduce exposure to populations of micro-organisms that play a key role in immune maturation. Whatever the mechanism, there is sufficient evidence to claim that vaccination strategies could have an important role in the prevention of leukaemia, lymphoma, melanoma and, possibly, other cancers and a history of vaccination therefore needs to be considered in any study on the impact of infections on the risk of cancer.