Assessing skin pigmentation in epidemiological studies: the reliability of measurements under different conditions.

BACKGROUND/PURPOSE: Different devices are used for the non-invasive measurement of (constitutive) skin pigmentation in (epidemiological) studies. Reproducibility of measurements with the Chromameter (CM, model CR 300, Minolta, Osaka) and the Reflectometer (RM, Courage & Khazaka, Cologne) has not yet been examined in detail and was addressed in a set of four experiments and studies respectively. METHODS: Regarding the CM, the Y value of the Yxy CIE 1931 colour system was utilized, representing lightness in this colour space, while the RM measured reflectance at 660 nm with a small bandwidth of 20 nm. Both devices measure reflectance on a scale from 0 to 100%, however, in different wavelength ranges. Between 3 and 20 repetitions were performed on standard grey scales and different sets of human volunteers, including RM measurements in a large epidemiological field study. RESULTS: While the coefficient of variation (V) increases and the intraclass correlation coefficient decreases from controlled laboratory to field conditions, reproducibility remained in a range considered acceptable, if adequate study conditions were maintained. In a direct comparison on human skin, V of the RM was significantly smaller than that of the CM. CONCLUSION: Both devices can be used confidently in field studies; however, based on considerations of skin optics and in view of slightly lesser variability, the RM may be preferable.

A comparison of patterns of sun protection during beach holidays and everyday outdoor activities in a population sample of young German children.

BACKGROUND: Reducing exposure to ultraviolet (UV) radiation is the main effective measure for preventing skin cancer. Educational campaigns targeting sun protection have been focused either on behaviour on the beach during the summer holiday alone, or during everyday outdoor activities of the children. Little is known about the comparison between these different settings. OBJECTIVES: To analyse whether parents apply similar protective measures to reduce UV exposure for their young children in different outdoor environments. METHODS: Families (n = 2619) with children aged 3-6 years (response: 64·7%) were enrolled in a population-based survey in the German city of Erlangen and its surrounding rural county. Using a self-administered standardized questionnaire parents gave information about demographic and photosensitivity data of their children, their knowledge about risk factors for skin cancer and their typical instructions given to their children when these played outside on a summer day in different outdoor environments. RESULTS: Significant discrepancies regarding the four UV protective measures (clothes, shade, sunhat, sunscreen) for children between an everyday outdoor setting and a holiday setting on the beach were observed. A high level of parental risk factor knowledge was significantly associated with a better protection for children in all four measures only on the beach. Photosensitivity and demographic characteristics had some impact on protective behaviour, too. Measures of sun protection were reduced with children's increasing age. CONCLUSIONS: Skin cancer prevention campaigns should target the encouragement of sun protection for children also in outdoor activities of daily living, not only during a summer holiday on the beach.

Effectiveness of skin protection measures in prevention of occupational hand eczema: results of a prospective randomized controlled trial over a follow-up period of 1 year.

BACKGROUND: We recently found a very low adherence to a generally recommended skin protection regimen in a sample of 1355 metalworkers. OBJECTIVES: The present study assessed the effectiveness of skin protection as presently recommended, especially the differential contribution of skin care and skin protection, to the prevention of occupational hand eczema. Methods Of 1355 metalworkers screened, 1020 male volunteers, all fit for work, were recruited for a prospective intervention study with four arms (skin care, skin protection, both combined, and control group, i.e. no recommendation). The study was performed from winter 2006/2007 to spring 2008, following each subject for up for 12 months. Both hands were examined using a quantitative skin score, and a standardized personal interview was performed three times. The change of the objective skin score from baseline to 12 months was used as primary outcome measure. RESULTS: After 12 months 800 subjects were included (78.4% of those recruited). The compliance to follow the randomized measure depended on the recommended measure and ranged from 73.7% to 88.7%. While in the control group a significant deterioration was found, the largest and significant improvement was noted in the group following the generally recommended skin protection programme (skin care + skin protection) followed by skin protection alone as second best. CONCLUSIONS: The generally recommended skin protection regimen seems to provide effective prevention of occupational skin disease. Therefore, the compliance to follow the skin protection regimen, especially the use of skin protection, should be enhanced.

The importance of context information in the diagnostic rating of digital images of patch test reactions.

BACKGROUND: Patch test (PT) guidelines recommend classifying PT reactions based on morphological criteria only, i.e. irrespective of context information such as substance, concentration and vehicle. OBJECTIVES: To analyse reclassification of PT reactions after revelation of context information subsequent to an initial blinded reading. METHODS: One hundred and twenty-two participants (experienced dermatologists and researchers) rated 20 digital images of different PT reactions twice, first blinded, then unblinded regarding substance, concentration and vehicle. Agreement between both ratings was quantified with Cohen's kappa, and systematic differences statistically examined with tests for marginal homogeneity. RESULTS: Mostly, ratings remained stable, e.g. in > 90% of cases of images showing typical strong or extreme positive PT reactions. Reclassification was comparatively often observed in images depicting irritant reactions. Conversely, 16 of 122 participants re-rated doubtful reactions to thiuram mix and dichromate, respectively, as 'allergic' (weak or strong positive) after knowing the substance. CONCLUSIONS: The considerable proportion of participants who choose an 'allergic' rating, despite a morphological presentation definitely not justifying this, points to a conceptual problem of the PT reading scale: the mixing up of morphological classification and interpretation. We therefore suggest amending the scale. Moreover, standardization of PT reading can be improved by continual PT training sessions.

[Contact allergy to topical ophthalmological drugs - epidemiological risk assessment]. / Kontaktallergien gegen ophthalmologische Lokaltherapeutika - eine epidemiologische Risikobewertung.

BACKGROUND: Contact allergies (CA) against active agents of topical ophthalmological therapeutics, causing inflammation of the conjunctiva and/or the lid, are usually not life-threatening, but occur not infrequently. As yet, the assessment of the CA-eliciting risk has been based on clinical data alone, while a valid epidemiological risk assessment is lacking. MATERIALS AND METHODS: The Information Network of Departments of Dermatology supplied information on diagnostic results obtained in 4,102 patients patch-tested for suspected CA to ophthalmic drugs between 1995 and 2004. Clinical prevalences were extrapolated to incidences at the German population level. These estimates served as numerator for a relative incidence (RI), which included the nationwide frequency of prescriptions collected by the WIdO, Bonn, in terms of a standardised defined daily dose (DDD) as denominator. RESULTS: The estimated annual incidence of CA ranges from 155 (atropine sulphate) to 2077 (gentamicin sulphate) and can thus be regarded as moderate. If incidence estimates are related to prescription frequencies, the highest risk was found for kanamycin and neomycin sulphate (RI > 8 / 100,000 DDD). In contrast, the RI of pilocarpine-HCl (0.3) was virtually negligible. CONCLUSIONS: The substance-specific risk of CA has been evaluated for the first time and found to differ between therapeutics (with a similar spectrum of application). CA risk should be considered in differential therapeutic decision-making.

Outdoor work and skin cancer incidence: a registry-based study in Bavaria.

OBJECTIVE: To analyse the association between occupational ultraviolet (UV) light exposure and skin cancer (basal cell carcinoma, BCC; squamous cell carcinoma, SCC; cutaneous malignant melanoma, CMM) based on data from the Bavarian population-based cancer registry. METHODS: The population-based cancer registry of Bavaria (Germany) provided data on incident cases of BCC, SCC, and CMM, respectively, during the period 2001 until 2005. Eleven Bavarian districts with complete skin cancer registration were included in this analysis based on 2,156,336 person years. Cases were assigned to "indoor", "mixed indoor/outdoor", and "outdoor" exposure categories according to their job title. We computed age-specific and age-adjusted incidence rates of BCC (n = 1,641), SCC (n = 499), and CMM (n = 454) by work type, and the relative risk (RR) of skin cancer occurrence for "outdoor" and "mixed indoor/outdoor" workers, respectively, compared to "indoor" workers. RESULTS: The risk of BCC was substantially elevated in male (RR, 2.9; 95% CI, 2.2-3.9) and female (RR, 2.7; 95% CI, 1.8-4.1) outdoor workers compared to male and female indoor workers, respectively. We also found an elevated risk of similar magnitude for SCC in male (RR, 2.5; 95% CI, 1.4-4.7) and female (RR, 3.6; 95% CI, 1.6-8.1) outdoor workers compared to male and female indoor workers, respectively. CMM risk was not significantly associated with outdoor work. CONCLUSION: Our study confirms previous reports on the increased risk of BCC and SCC in outdoor workers compared to indoor workers.

Point and interval estimation of partial attributable risks from case-control data using the R-package 'pARccs'.

The attributable risk (AR) is an epidemiologic measure quantifying the relationship between an exposure factor and a disease at the population level. In addition to its original use as a one-dimensional parameter the AR is increasingly applied in multifactorial epidemiologic situations when the combined impact of multiple exposure factors has to be partitioned into factor-specific components. We discuss the point and interval estimation of the resulting multidimensional parameter termed partial attributable risk (PAR) and introduce the R-package 'pARccs', a comprehensive software enabling the application of the methods. 'pARccs' allows for point and interval estimation of PAR from case-control data utilizing the non-parametric bootstrap with stratified resampling in combination with the percentile or BC(a) method to compute confidence intervals. We illustrate the concept of partial attributable risks and the application of the software by an example from a recent case-control study on risk factors for melanoma. We also discuss practical aspects of the software application for epidemiologic purposes and its limitations.

Allergic contact dermatitis to topical drugs--epidemiological risk assessment.

PURPOSE: Estimation of the population-based relative incidence (RI) of contact sensitization to a set of topical drug allergens (cases/100,000 defined daily doses (DDDs) per year) (1995-2004) and comparison of the RI for drugs with a similar therapeutic scope. METHODS: Clinical data regarding the frequency of contact sensitization to important topical drug allergens in Germany were obtained from the Information Network of Departments of Dermatology (IVDK). This was extrapolated to the general population level using the 'clinical epidemiology and drug utilization research' (CE-DUR) approach. As denominator of exposure, national prescription data (DDDs of topical drug specialties) provided by the WIdO Research Institute (Bonn) were aggregated per substance. RESULTS: The probable RIs of contact sensitization to topical 'skin' corticosteroids ranged from 0.3 (dexamethasone phosphate disodium salt) to 23.3 (amcinonide) cases/100,000 DDDs per year. Concerning topical aminoglycoside antibiotics, the RI of framycetin sulphate was about threefold higher than that of gentamicin sulphate. Regarding topical ophthalmic use, the RI of kanamycin sulphate was higher compared to gentamicin sulphate. Active principles marketed over-the-counter (OTC) had, in general, lower RIs, with the exception of bufexamac, benzocaine, clioquinol and phenylephrine. CONCLUSIONS: The population-based risk assessment--quantitatively considering exposure in the RI estimation--revealed a ranking of contact sensitization risk to topical drugs which partly differed from the respective frequencies in the clinical patch test population. Some drugs available OTC carry non-negligible risk, too. The current findings should contribute to differential therapeutic considerations regarding topical drug use.

Double-smoothing in kernel hazard rate estimation.

OBJECTIVES: In oncological studies, the hazard rate can be used to differentiate subgroups of the study population according to their patterns of survival risk over time. Nonparametric curve estimation has been suggested as an exploratory means of revealing such patterns. The decision about the type of smoothing parameter is critical for performance in practice. In this paper, we study data-adaptive smoothing. METHODS: A decade ago, the nearest-neighbor bandwidth was introduced for censored data in survival analysis. It is specified by one parameter, namely the number of nearest neighbors. Bandwidth selection in this setting has rarely been investigated, although the heuristical advantages over the frequently-studied fixed bandwidth are quite obvious. The asymptotical relationship between the fixed and the nearest-neighbor bandwidth can be used to generate novel approaches. RESULTS: We develop a new selection algorithm termed double-smoothing for the nearest-neighbor bandwidth in hazard rate estimation. Our approach uses a finite sample approximation of the asymptotical relationship between the fixed and nearest-neighbor bandwidth. By so doing, we identify the nearest-neighbor bandwidth as an additional smoothing step and achieve further data-adaption after fixed bandwidth smoothing. We illustrate the application of the new algorithm in a clinical study and compare the outcome to the traditional fixed bandwidth result, thus demonstrating the practical performance of the technique. CONCLUSION: The double-smoothing approach enlarges the methodological repertoire for selecting smoothing parameters in nonparametric hazard rate estimation. The slight increase in computational effort is rewarded with a substantial amount of estimation stability, thus demonstrating the benefit of the technique for biostatistical applications.

The impact of meteorological conditions on patch test results with 12 standard series allergens (fragrances, biocides, topical ingredients).

BACKGROUND: Fluctuating irritability of the skin induced by low ambient temperature and humidity may compromise the reproducibility of patch testing. OBJECTIVES: To assess the impact of temperature and absolute humidity at the time of patch testing on the occurrence of irritant or doubtful (IR/?), weak positive (+) and (strong) positive (++/+++) reactions, respectively, among 12 allergens included in the German Standard Series. METHODS: Analysis of clinical data collected in the surveillance network IVDK (http://www.ivdk.org) between January 1993 and December 2001 (n = 73 691 patients) combined with meteorological data obtained by the national services in Germany and Austria. Multinomial logistic regression analysis was used to estimate the risk associated with temperature, absolute humidity and vapour pressure, respectively, adjusted for sex, age, atopic dermatitis and duration of patch test application. RESULTS: For low temperature and humidity, a relevant increase of IR/? reaction frequency was observed in the cases of paraben mix and (chloro-) methylisothiazolinone. Both IR/? and + reactions were significantly increased with respect to the allergens fragrance mix, oil of turpentine, methyldibromo glutaronitrile + phenoxyethanol and particularly formaldehyde, while ++/+++ reactions were hardly affected by weather conditions. CONCLUSIONS: The observed increase of IR/? reactions may be due to epidermal barrier function impairment. The impact of dry/cold weather on + reactions in terms of possibly false-positive reactions is restricted to few allergens. In the case of + reactions of unknown relevance, a re-test under warm conditions or verification tests such as the repeated open application test or the provocative use test may be recommendable.

Flexible modeling of malignant melanoma survival.

OBJECTIVES: This paper compares the diagnostic capabilities of flexible ensemble methods modeling the survival time of melanoma patients in comparison to the well established proportional hazards model. Both a random forest type algorithm for censored data as well as a model combination of the proportional hazards model with recursive partitioning are investigated. METHODS: Benchmark experiments utilizing the integrated Brier score as a measure for goodness of prediction are the basis of the performance assessment for all competing algorithms. For the purpose of comparing regression relationships represented by the models under test, we describe fitted conditional survival functions by a univariate measure derived from the area under the curve. Based on this measure, we adapt a visualization technique useful for the inspection and comparison of model fits. RESULTS: For the data of malignant melanoma patients the predictive performance of the competing models is on par, allowing for a fair comparison of the fitted relationships. Newly introduced MODplots visualize differences in the fitting structure of the underlying models. CONCLUSION: The paper provides a framework for comparing the predictive and diagnostic performance of a parametric, a non-parametric and a combined approach.

Retrospective interactive rigid fusion of (18)F-FDG-PET and CT. Additional diagnostic information in melanoma patients.

AIM: This study investigates whether interactive rigid fusion of routine PET and CT data improves localization, detection and characterization of lesions compared to separate reading. For this purpose, routine PET and CT scans of patients with metastases from malignant melanoma were used. PATIENTS, METHODS: In 34 patients with histologically confirmed malignant melanoma, FDG-PET and spiral CT were performed using clinical standard protocols. For all of these patients, gold standard was available. Clinical and radiological follow-up identified 82 lesions as definitely pathological. Two board-certified nuclear medicine physicians and two board-certified radiologists analyzed PET and CT images independently from each other. For each patient up to 32 anatomical regions (24 lymph node regions, 8 extranodular regions) were systematically classified. Discordant areas were interactively analyzed in manually and rigidly registered images using a commercially available fusion tool. No side-by-side reading was performed. RESULTS: Image fusion disclosed that the evaluation of the PET images alone led to a mislocalization in 26 of 91 focally FDG enhancing lesions. The overall sensitivities of PET, CT, and image fusion were 85, 88, and 94%, respectively; the overall specificities of PET, CT and image fusion were 98, 95 and 100%, respectively. Image fusion exhibited statistically significant higher specificity values as compared with CT. Ten definitely malignant sites were false-negative in CT, but could be detected by PET. On the other hand, twelve metastases were false-negative in PET, but could be detected by CT. These included two lesions, which had a clear correlate on the PET image when the fused images were evaluated. On the whole, registration of the PET and CT images yielded additional diagnostic information in 44% of the definitely malignant lesions. CONCLUSION: Retrospective image fusion of independently obtained PET and CT data is particularly valuable in exactly localizing foci of abnormal FDG uptake and improves the detection of metastases of malignant melanoma.

[Anatomical accuracy of lesion localization. Retrospective interactive rigid image registration between 18F-FDG-PET and X-ray CT]. / Genauigkeit der Lokalisierung maligner Herde mittels retrospektiver, interaktiver starrer Bildfusion von FDG-PET und CT.

UNLABELLED: The aim of this study was to evaluate the anatomical accuracy and reproducibility of retrospective interactive rigid image registration (RIR) between routinely archived X-ray computer tomography (CT) and positron emission tomography performed with 18F-deoxyglucose (FDG-PET) in oncological patients. METHODS: Two observers registered PET and CT data obtained in 37 patients using a commercially available image fusion tool. RIR was performed separately for the thorax and the abdomen using physiological FDG uptake in several organs as a reference. One observer performed the procedure twice (O1a and O1b), another person once (O2). For 94 malignant lesions, clearly visible in CT and PET, the signed and absolute distances between their representation on PET and CT were measured in X-, Y-, and Z-direction with reference to a coordinate system centered in the CT representation of each lesion (X-, Y-, Z-distances). RESULTS: The mean differences of the signed and absolute distances between O1a, O1b, and O2 did not exceed 3 mm in any dimension. The absolute X-, Y-, and Z-distances ranged between 0.57 +/- 0.58 cm for O1a (X-direction) and 1.12 +/- 1.28 cm for O2 (Z-direction). When averaging the absolute distances measured by O1a, O1b, and O2, the percentage of lesions misregistered by less than 1.5 cm was 91% for the X-, 88% for the Y-, and 77% for the Z-direction. The larger error of fusion determined for the remaining lesions was caused by non-rigid body transformations due to differences in breathing, arm position, or bowel movements between the two examinations. Mixed effects analysis of the signed and absolute X-, Y-, and Z-distances disclosed a significantly greater misalignment in the thorax than in the abdomen as well as axially than transaxially. CONCLUSION: The anatomical inaccuracy of RIR can be expected to be <1.5 cm for the majority of neoplastic foci. Errors of alignment are bigger in the thorax and in Z-direction, due to non-rigid body transformations caused, e.g., by breathing.

Contact allergy to neomycin sulfate: results of a multifactorial analysis.

PURPOSE: To perform a comprehensive, multifactorial analysis of potential risk factors (demographic and clinical) for contact allergy to neomycin sulfate, a common adverse reaction resulting from the topical use of this drug; especially in some subgroups of the population. METHODS: Retrospective analysis of allergy test data of the Information Network of Departments of Dermatology (IVDK, www.ivdk.org) between 1998 and 2003, including all patients patch tested with a standard screening series because of suspected allergic contact dermatitis (ACD). As one outcome, a positive (allergic) test reaction to neomycin sulfate was considered. An alternative outcome included only those patients with a positive test to neomycin sulfate and a final diagnosis of ACD. The association between outcome and potential risk factors was analyzed with Poisson regression analysis, deriving prevalence ratios (PR) as risk estimates. RESULTS: Of the 47,559 patients tested, 2.5% had positive reactions to neomycin sulfate, while in 1.1% ACD was additionally diagnosed. The results of the multifactorial analysis indicated that the risk of both outcomes decreased slightly during the period covered; was higher among patients with leg dermatitis; varied significantly with age and increased progressively with the number of additional positive reactions to other standard series allergens. Cross-reactivity to other, selectively tested, aminoglycoside antibiotics was substantial (kappa = 0.67; 95%CI: 0.63-0.71) for framycetin sulfate, to low (kappa = 0.33; 95%CI: 0.27-0.37) for gentamicin sulfate. CONCLUSIONS: The prevalence of contact sensitization to neomycin sulfate was noteworthy among patients patch tested in the IVDK centers. Supplementing clinical epidemiology, neomycin contact allergy has been estimated to be relatively common even on the level of the unselected population (prevalence approx. 1%). Hence, the topical use of neomycin sulfate by patients should be carefully monitored, considering its potential to induce ACD, with emphasis on subgroups at risk.

The effects of joint misclassification of exposure and disease on the attributable risk.

While there is extensive methodological literature analysing the effects of misclassification on the relative risk under various misclassification scenarios, for the attributable risk only the effects of non-differential misclassification either of exposure or disease, and the effects of non-differential independent misclassification of exposure and disease have been discussed for the 2 x 2-situation. The paper investigates the effects of non-differential correlated misclassification of exposure and disease on the attributable risk taking possible correlations of both types of misclassification into account. Furthermore, a comparison with the corresponding effects on the relative risk is drawn. We propose a matrix-based approach to describe the underlying structure of non-differential misclassification. The bias arising from non-differential misclassification in the attributable risk and relative risk is evaluated in four examples assuming under- or overreporting of exposure and disease. In each of the four examples we found scenarios where pronounced differences in degree and, more importantly, in direction of bias occurred. Our results clearly demonstrate the danger lying in the stereotype transfer of findings regarding misclassification effects on the relative risk to other epidemiologic risk measures and underline the necessity of specific analyses of the effects of misclassification on the attributable risk.

Attenuation correction of SPECT images based on separately performed CT: Effect on the measurement of regional uptake values.

AIM: A new software approach uses separately acquired CT images for attenuation correction after retrospective fusion with the SPECT data. This study evaluates the effect of this CT-based attenuation correction on indium-111-pentetreotide-SPECT images. METHODS: Indium-111-pentetreotide-SPECT imaging using a dual-head gamma camera e.cam (Siemens Medical Solutions, Erlangen, Germany) as well as separate spiral computed tomography (CT) was performed in 13 patients. After fusion of SPECT and CT data, the bilinear attenuation coefficients were calculated for each pixel in the CT image volume using their Hounsfield unit values and attenuation-corrected images were reconstructed iteratively (OSEM 2D). Regions of interest (ROIs) were drawn on 24 suspicious foci and background, and target to background ratios were calculated for corrected (TBAC) and uncorrected (TBNAC) images. The shortest distance from the centre of the lesion to the surface of the body (DS) was measured on the corresponding CT slice. Furthermore, ROIs were drawn over the rim and the centre of the liver. Ratios of hepatic count rates for corrected (LRAC) and uncorrected (LRNAC) images were also compared. RESULTS: In lesions located more centrally, TBAC was up to 52% higher, whereas in peripherally located lesions, TBAC was up to 63% lower than TBNAC. The TBAC/TBNAC quotient was linearly correlated with DS. In the liver, attenuation correction resulted in a 35% increase of LRAC compared with LRNAC. CONCLUSIONS: Attenuation correction of SPECT images performed by separately acquired CT data is quick and simple. It improves the contrast between target and background for lesions located more centrally in the body and improves homogeneity of the visualisation of tracer uptake in the liver.

A multifactorial analysis of concurrent patch-test reactions to nickel, cobalt, and chromate.

BACKGROUND: Previous research indicates that positive patch tests to nickel (II) sulphate, cobalt (II) chloride and potassium dichromate commonly occur together. METHODS: To further examine the relationship between nickel, cobalt, chromate, and the factors that may potentially be related to concurrent sensitizations to two or all three metal allergens, data from the Information Network of Dermatology Departments have been investigated. RESULTS: Women had a higher conditional odds of concurrent nickel-cobalt (OR = 6.80; 95% CI: 5.65-8.19) and nickel-chromate (OR = 2.13; 95% CI: 1.67-2.72) reactions than men. Construction workers had a significantly higher odds of cobalt-chromate reactions (OR = 13.89; 95% CI: 10.36-18.64), while the odds of isolated cobalt allergy was only 0.92 (95% CI: 0.48-1.74). Patients with underlying atopic eczema/dermatitis syndrome had a 40-90% higher chance of any positive outcome, which involved chromate. Polysensitization, defined as the number of positive reactions to standard series substances other than nickel, cobalt, and chromate, was also significantly associated with the concurrent reactions; moreover, steady and significant effect gradients were noted. CONCLUSIONS: This research confirms the occupational nature of cobalt-chromate concurrent reactions, in particular, in construction workers. Polysensitization, which is considered to represent susceptibility to delayed-hypersensitivity in general, is also associated with the concurrent reactions to the metals. Hence, not only coupled exposure, but also individual susceptibility may be responsible for concurrent reactions to metals in man.

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.