Incidence and survival of cutaneous melanoma in Belgium and the Netherlands from 2004 to 2016: striking differences and similarities of two neighbouring countries.

BACKGROUND: Cutaneous melanoma (CM) is a multifactorial disease, with both environmental and genetic factors involved. The incidence of CM has risen rapidly during the last decades, making it a growing public health problem. OBJECTIVES: The purpose of this retrospective study was to compare incidence and survival data of CM between two neighbouring countries, Belgium (BE) and the Netherlands (NL). METHODS: Data were collected by the Belgian Cancer Registry (BCR) and the Netherlands Cancer Registry (NCR) from 1 January 2004 until 31 December 2016. Mucosal melanoma, in situ CM and melanoma in children from 0 to 14 years were excluded. Age-standardized incidence rates were calculated using the World Standard Population (WSR) per 100 000 persons. Five-year relative survival ratios were calculated using the Ederer II methodology. RESULTS: Total number of CM was higher in NL (63 789) compared with BE (27 679). The WSR was 1.5 times higher in NL compared with BE (27.7 vs. 18.6/100 000/year). The WSR of stage IV tumours was higher in BE than in NL (0.3 vs. 0.2/100 000/year). Five-year relative survival of stage IV tumours was higher in BE compared with NL (27.2% vs. 13.7%). CONCLUSIONS: Incidence of CM was higher in NL, indicating a higher risk of CM diagnosis. Stage IV tumours were relatively more frequent in BE for both sexes, while relative survival of stage IV tumours was higher in BE. As geographical location and latitude of both neighbouring countries are almost identical, other factors like differences in behaviour, follow-up and/or treatment may explain these differences.

Poor agreement between the automated risk assessment of a smartphone application for skin cancer detection and the rating by dermatologists.

BACKGROUND: Several smartphone applications (app) with an automated risk assessment claim to be able to detect skin cancer at an early stage. Various studies that have evaluated these apps showed mainly poor performance. However, all studies were done in patients and lesions were mainly selected by a specialist. OBJECTIVES: To investigate the performance of the automated risk assessment of an app by comparing its assessment to that of a dermatologist in lesions selected by the participants. METHODS: Participants of a National Skin Cancer Day were enrolled in a multicentre study. Skin lesions indicated by the participants were analysed by the automated risk assessment of the app prior to blinded rating by the dermatologist. The ratings of the automated risk assessment were compared to the assessment and diagnosis of the dermatologist. Due to the setting of the Skin Cancer Day, lesions were not verified by histopathology. RESULTS: We included 125 participants (199 lesions). The app was not able to analyse 90 cases (45%) of which nine BCC, four atypical naevi and one lentigo maligna. Thirty lesions (67%) with a high and 21 with a medium risk (70%) rating by the app were diagnosed as benign naevi or seborrhoeic keratoses. The interobserver agreement between the ratings of the automated risk assessment and the dermatologist was poor (weighted kappa = 0.02; 95% CI -0.08-0.12; P = 0.74). CONCLUSIONS: The rating of the automated risk assessment was poor. Further investigations about the diagnostic accuracy in real-life situations are needed to provide consumers with reliable information about this healthcare application.

Sex matters: men with melanoma have a worse prognosis than women.

BACKGROUND: In Europe, one of the highest melanoma incidences is found in the Netherlands. Like in several other European countries, females are more prone to develop melanoma as compared to males, although survival is worse for men. OBJECTIVE: To identify clinicopathological gender-related differences that may lead to gender-specific preventive measures. METHODS: Data from the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) were retrieved from patients with primary, cutaneous melanoma in the Netherlands between 2000 and 2014. Patients initially presenting as stage I, II and III without clinically detectable nodal disease were included. Follow-up data were retrieved from the Netherlands Cancer Registry. Gender-related differences were assessed, and to compare relative survival between males and females, multivariable relative excess risks (RER) were calculated. RESULTS: A total of 54.645 patients were included (43.7% men). In 2000, 41.7% of the cohort was male, as compared to 47.3% in 2014 (P < 0.001). Likewise, in 2000, 51.5% of the deceased cohort was male compared to 60.1% in 2014 (P < 0.001). Men had significantly thicker melanomas at the time of diagnosis [median Breslow thickness 1.00 mm (interquartile range (IQR): 0.60-2.00) vs. 0.82 mm (IQR: 0.50-1.50) for females] and were significantly older at the time of diagnosis, more often had ulcerated melanomas and melanomas localized on the trunk or head and neck. Over time, survival for females improved while that of men decreased (P < 0.001). RER for dying was 1.37 (95% CI: 1.31-1.45) for men in multivariable analysis. CONCLUSION: There are evident clinicopathological differences between male and female melanoma patients. After multivariable correction for all these differences, relative survival remains worse for men. Clinicians as well as persons at risk for melanoma should be aware of these differences, as awareness and prevention might lead to a lower incidence and mortality of melanoma. This indicates the need of prevention campaigns integrating and targeting specific risk profiles.

The impact of dermoscopy on the management of pigmented lesions in everyday clinical practice of general dermatologists: a prospective study.

BACKGROUND: Dermoscopy greatly improves the clinical diagnosis of pigmented lesions. Few studies have investigated, however, how dermoscopy is guiding management decisions in everyday clinical practice. In addition, most studies have been performed in the setting of dermoscopy experts working in pigmented lesion clinics. OBJECTIVES: To assess the impact of dermoscopy on clinical diagnosis and management decisions for pigmented lesions in everyday practice of general dermatologists. METHODS: We performed a prospective study in general dermatology clinics in community hospitals run by dermatologists with intermediate dermoscopy experience and expertise. Each clinician independently included suspicious lesions from consecutive patients. Pre- and postdermoscopy diagnoses and management decisions were recorded. Pathology was used as reference diagnosis. RESULTS: In total, 209 suspicious lesions were included in the study by 17 dermatologists. Fourteen lesions were histologically proven in situ or invasive malignant melanomas. Based on clinical diagnoses, dermoscopy improved sensitivity from 0.79 to 0.86 (P = 1.0). All 14 melanomas were intended to be excised based on naked eye examination alone, independent of dermoscopic evaluation. Specificity increased from 0.96 to 0.98 (P = 0.22). Dermoscopy resulted in a 9% reduction of the number of excisions. CONCLUSIONS: Dermoscopy reduced the number of excisions, but did not improve the detection of melanomas. Our results suggest that in everyday clinical practice of general dermatologists the main contribution of dermoscopy is a reduction of unnecessary excisions.

Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo.

Dendritic cells (DC) were cultured from mouse bone marrow (BM) progenitors in low concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) (GM(lo) DC) by two different protocols. The phenotype and functional properties of these GM(lo) DC were compared to those of standard BM-DC cultures generated in high concentrations of GM-CSF (GM(hi) DC) or in low GM-CSF plus IL-4 (GM(lo)/IL-4 DC). An effect of IL-4 on maturation was observed only at low but not high doses of GM-CSF. Compared to mature DC, GM(lo) DC were phenotypically immature, weak stimulators of allogeneic and peptide-specific T cell responses, but substantially more potent in presentation of native protein. Immature GM(lo) DC were resistant to maturation by lipopolysaccharide, TNF-alpha or anti-CD40 monoclonal antibodies, as the expression of co-stimulatory molecules was not increased, and stimulatory activity in oxidative mitogenesis was not enhanced. These maturation-resistant immature GM(lo) DC induced T cell unresponsiveness in vitro and in vivo. GM(lo) DC also prolonged haplotype-specific cardiac allograft survival (from 8 days to >100 days median survival time) when they were administered 7 days (but not 3, 14 or 28 days) before transplantation. Our findings may have important implications for future studies in T cell tolerance induction in vivo.

Formation and kinetics of MHC class I-ovalbumin peptide complexes on immature and mature murine dendritic cells.

Dendritic cells (DC) are professional antigen-presenting cells that are able to induce primary T cell responses. Therefore, several strategies employ peptide-pulsed DC in tumor immunotherapy. For efficient antigen presentation and induction of an immune response by DC the number and stability of MHC I-peptide complexes is crucial. We studied this issue by using the antibody 25-D1.16 that specifically detects OVA peptide SIINFEKL in conjunction with H-2 Kb molecules, and determined its kinetics on mature and immature bone marrow-derived murine DC. Optimal peptide loading was reached after 8-16 h at 50 microM peptide pulse, and was comparable in serum-free versus serum-containing medium. Stimulation of DC with LPS or Poly I:C, and to a lesser extent TNF-alpha, upregulated the total number of surface MHC I molecules and thus improved peptide loading. Pulse-chase experiments revealed a constant half-life of peptide/Kb complexes independent of preceding DC stimulation or their maturation stage. The duration of peptide/Kb complex expression on mature DC, however, could be extended from 24 h to 72 h when the cultures were pretreated with LPS or Poly I:C, but not TNF-alpha. These data might have important implications for the clinical application of peptide-pulsed DC in tumor immunotherapy.

Culture of bone marrow cells in GM-CSF plus high doses of lipopolysaccharide generates exclusively immature dendritic cells which induce alloantigen-specific CD4 T cell anergy in vitro.

Dendritic cells (DC) can be generated from mouse bone marrow (BM) in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Bacterial stimuli such as endotoxin / lipopolysaccharide (LPS) can induce their final maturation. When BM-DC cultures were treated at day 6 or later with LPS, this final maturation was induced in vitro within 24 h. Such mature DC exhibited high levels of surface MHC II molecules and potent T cell sensitizing, but reduced endocytosis capacity. In contrast, immature DC express only few MHC II molecules and are weak T cell stimulators but highly endocytic. When BM-DC cultures in GM-CSF were treated with 1 microg / ml LPS at day 0 of the culture or throughout the culture, only immature DC developed as defined by phenotype (MHC II low) and function (high endocytosis, weak primary mixed lymphocyte reaction). Those early LPS-treated immature DC induced alloantigen-specific anergy of CD4(+) T cells in vitro. These findings might contribute to the understanding of reduced T cell immunity in the course of septic shock and find application in DC-mediated tolerogenic immunotherapy strategies.

Modulation of irritation-induced increase of E-selectin mRNA in vivo by topically applied corticosteroids.

There is a continuous need for methods to evaluate the biologic effects of topically applied drugs in the skin. Irritation of the epidermis with sodium dodecyl sulfate leads to an upregulation of E-selectin on endothelial cells and E-selectin mRNA can be detected in vivo within a short time. This study was aimed to investigate whether this biologic response can be used as a read-out for the anti-inflammatory effect of topically administered corticosteroids. We investigated skin of healthy volunteers treated according to the two following experimental protocols: (i) topical application of different corticosteroids (versus basic ointments as controls) for 12 h and irritation with sodium dodecyl sulfate 1% for 4 h; (ii) irritation with sodium dodecyl sulfate 1% for 12 h and application of the corticosteroids for 5 h. The biopsy specimens were subjected to RNA extraction and reverse transcription and competitive reverse transcriptase-polymerase chain reaction was performed using defined concentrations of a pre-constructed mimic DNA. As result, we found strong positive signals for wild-type E-selectin mRNA in all biopsies pretreated with basic ointments, whereas in biopsies from areas pretreated with corticosteroids the bands for wild-type E-selectin DNA could be detected at 10-1000 lower levels of mimic DNA concentrations. The reverse experiment, application of corticosteroids after the irritation, again yielded significantly reduced signals for E-selectin mRNA. In both experimental settings, the different strength of the topical corticosteroids used was reflected by significant differences in the amount of E-selectin mRNA found in the biopsies. This study demonstrates the pharmacologic effect of topical corticosteroids on the irritation-induced E-selectin mRNA expression on dermal endothelial cells in vivo using very small tissue samples and this approach may be of value for further pharmaceutical studies.

An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow.

As dendritic cells (DC) are rare populations in all organs, their generation from hematopoietic precursors in large quantities has proven critical to study their biology. From murine bone marrow about 5 x 10(6) cells at 70% purity are obtained per mouse after 8 days of culture with GM-CSF. We have improved this standard method and routinely achieve a 50-fold higher yield, i.e., 1-3 x 10(8) immature and mature DC per mouse at 90-95% purity. The major modifications were: (i) the avoidance of any active depletion of bone marrow cell subpopulations to circumvent loss of precursors, (ii) a lower plating density of bone marrow cells, (iii) a prolonged culture period of 10-12 days, (iv) the reduction of the GM-CSF dose from day 8 or 10 onwards to reduce granulocyte contaminations. The final non-adherent population at day 10-12 constitutes a mixture of immature and mature DC. Further maturation of DC could be induced by high doses of LPS or TNF-alpha for the last 24 h, where 50-70% of the non-adherent fraction represented mature DC with high levels of NLDC-145, CD86 and CD40. This method allows by simple means the generation of high numbers of murine DC with very low B cell or granulocyte contaminations. It will be valuable to study DC biology notably at the molecular level.