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•The Danish Metastatic Melanoma Database is a nationwide registry for medical therapy.•Disease registries are crucial to evaluate safety and efficacy of new treatments.•Real-world treatment efficacy and safety in comparison to clinical trial evidence.•Registry on real-world data for scientific investigation and socioeconomic decisions. Clinical trials enroll patients with specific diseases based on certain pre-defined eligibility criteria. Disease registries are crucial to evaluate the efficacy and safety of new expensive oncology medicines in broad non-trial patient populations. We provide detailed information on the structure, including variables, and the scientific results from a nation-wide Danish database covering advanced melanoma, illustrating the importance of continuous real-world data registration. Disease status and treatment-related information on all patients with American Joint Committee on Cancer (AJCC) 8th edition stage III or IV melanoma candidates to medical treatment in Denmark are prospectively registered in the Danish Metastatic Melanoma Database (DAMMED). By January 1st, 2021, DAMMED includes 4156 patients and 7420 treatment regimens. Response rates and survival data from published randomized clinical trial data are compared with real-world efficacy data from DAMMED and presented. Overall, nine independent manuscripts highlighting similarities and discrepancies between real-world and clinical trial results are already reported to date. Nation-wide disease registries take into consideration the complexity of daily clinical practice. We show a concrete example of how disease registries can complement clinical trials' information, improving clinical practice, and support health-related technology assessment.

Background Previous studies have investigated the protective effect of vitamin D serum levels, at diagnosis and during the follow-up period after treatment, on melanoma outcome. In the present study we assess whether vitamin D supplementation, in the follow-up period after diagnosis and surgical resection of the primary tumor, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with vitamin D levels in serum and Vitamin D Receptor immunoreactivity in the primary tumor. Methods/design This study is a multicenter randomized double blind placebo- controlled phase III trial. Patients between the age of 18 and 80 years diagnosed and treated surgically for a melanoma stage IB-III are eligible for randomization in a 1:1 ratio to active treatment or placebo. The study drug is taken each month and consists of either 100,000 International Unit cholecalciferol or arachidis oleum raffinatum used as a placebo. The primary endpoint is relapse free survival. The secondary endpoints are 25 hydroxyvitamin D3 serum levels at diagnosis and at 6 month intervals, melanoma subtype, melanoma site and stage of melanoma at diagnosis according to the 2009 American Joint Committee on Cancer melanoma staging and classification. At randomization a bloodsample is taken for DNA analysis. The study is approved by the local Ethics Committees. Discussion If we can confirm our hypothesis that vitamin D supplementation after removal of the tumor has a protective effect on relapse of cutaneous malignant melanoma we may reduce the burden of CMM at several levels. Patients, diagnosed with melanoma may have a better clinical outcome and improved quality of life. There will be a decrease in health care costs related to treatment of metastatic disease and there will be a decrease in loss of professional years, which will markedly reduce the economic burden of the disease. Trial registration Clinical Trial.gov, NCT01748448 , 05/12/2012

The association between hypertension and melanoma is unclear, and previous analyses of data from the ASPirin in Reducing Events in the Elderly (ASPREE) study demonstrated a reduced number of invasive melanoma events amongst aspirin-exposed hypertensive individuals. Data from the ASPREE study which included (1) the intervention period with a median follow-up of 4.7 years, and (2) the observational period with an additional 2 years follow-up, were combined for this analysis. Logistic regression analyses examined the association between baseline hypertension and treatment status and past melanoma history. Survival analyses examined the association between hypertension and melanoma risk, and the effect of aspirin across hypertension groups. Cox proportional hazards models were used to compare incidence across groups. 19,114 participants (median age of 74 years) were randomised to daily 100 mg aspirin or placebo. At baseline, hypertension and past melanoma history were recorded in 14,195 and 685 individuals, respectively. After adjustment for confounders, hypertension was significantly associated with past melanoma history (OR=1.34, 95%CI: 1.11–1.62). In a prospective analysis, baseline hypertension was not associated with melanoma risk. However, aspirin was associated with a reduced risk of incident melanoma amongst individuals with uncontrolled hypertension (blood pressure ≥140/90 mmHg; HR=0.63, 95%CI 0.44–0.89), but not in those with controlled hypertension (HR=1.04, 95%CI 0.74–1.46). Our results support a reduced melanoma incidence amongst individuals with uncontrolled hypertension exposed to aspirin. Additional studies are required to confirm these findings. •Aspirin may reduce incident melanoma risk in uncontrolled hypertensives.•High-risk groups who may benefit from aspirin chemoprevention need exploration.•The association between hypertension and melanoma warrant further investigation.

Background People increase their risk of melanoma unless they are protected from the harmful effects of sun exposure during childhood and adolescence. We aimed to assess the feasibility of a three-component sun protection intervention- presentation, action planning, and SMS messages - and trial parameters. Methods This feasibility wait-list trial was conducted in the United Kingdom in 2018. Students aged 13–15 years were eligible. Feasibility outcomes were collected for recruitment rates; data availability rates for objective measurements of melanin and erythema using a Mexameter and self-reported sunburn occurrences, severity and body location, tanning, sun protection behaviours and Skin Self-Examination (SSE) collected before (baseline) and after the school summer holidays (follow-up); intervention reach, adherence, perceived impact and acceptability. Quantitative data were analysed using descriptive statistics; qualitative data were analysed thematically. Results Five out of eight schools expressing an interest in participating with four allocated to act as intervention and one control. Four parents/carers opted their child out of the study. Four hundred and eighty-seven out of 724 students on the school register consented to the study at baseline (67%). Three hundred and eighty-five were in intervention group schools. Objective skin measurements were available for 255 (66%) of the intervention group at baseline and 237 (61%) of the group at follow up. Melanin increased; erythema decreased. Complete self-report data were available for 247 (64%) students in the intervention group. The number of students on the school register who attended the presentation and given the booklet was 379 (98%) and gave their mobile phone number was 155 (40%). No intervention component was perceived as more impactful on sun protection behaviours. Adolescents did not see the relevance of sun protection in the UK or for their age group. Conclusions This is the first study to use a Mexameter to measure skin colour in adolescents. Erythema (visible redness) lasts no more than three days and its measurement before and after a six week summer holiday may not yield relevant or meaningful data. A major challenge is that adolescents do not see the relevance of sun protection and SSE. Trial registration International Standard Randomised Controlled Trial Number ISRCTN11141528 . Date registered 0/2/03/2018; last edited 31/05/2018. Retrospectively registered.

Background Skin cancer survivors experience an increased risk for subsequent malignancies but the associated risk factors are poorly understood. This study examined the risk of a new primary cancer following an initial skin cancer and assessed risk factors associated with second primary cancers. Methods All invasive cutaneous malignant melanomas (CMM, N = 28 069) and squamous cell carcinomas (SCC, N = 24 620) diagnosed in Norway during 1955–2008 were included. Rates of new primary cancers in skin cancer survivors were compared to rates of primary malignancies in the general population using standardized incidence ratios (SIR). Discrete-time logistic regression models were applied to individual-level data to estimate cancer risk among those with and without a prior skin cancer, accounting for residential region, education, income, parenthood, marital status and parental cancer status, using a 20% random sample of the entire Norwegian population as reference. Further analyses of the skin cancer cohort were undertaken to determine risk factors related to subsequent cancers. Results During follow-up, 9608 new primary cancers occurred after an initial skin cancer. SIR analyses showed 50% and 90% increased risks for any cancer after CMM and SCC, respectively (p < 0.01). The logistic regression model suggested even stronger increase after SCC (130%). The highest risk was seen for subsequent skin cancers, but several non-skin cancers were also diagnosed in excess: oral, lung, colon, breast, prostate, thyroid, leukemia, lymphoma and central nervous system. Factors that were associated with increased risk of subsequent cancers include male sex, older age, lower residential latitude, being married and low education and income. Parental cancer did not increase the risk of a subsequent cancer after SCC, but was a significant predictor among younger CMM survivors. Conclusions Our results provide information on shared environmental and genetic risk factors for first and later cancers and may help to identify individuals at high risk for subsequent cancers, which will be important as skin cancer incidence continues to rise.

Purpose Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. Methods Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment ( n  = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. Results Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start ( r  = 0.31, p  < 0.01) and end of treatment ( r  = 0.42, p  < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. Conclusions Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80–100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A*0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.

Cutaneous melanoma is a malignancy arising from melanocytes of the skin. Incidence rates are rising, particularly in White populations. Cutaneous melanoma is typically driven by exposure to ultraviolet radiation from natural sunlight and indoor tanning, although there are several subtypes that are not related to ultraviolet radiation exposure. Primary melanomas are often darkly pigmented, but can be amelanotic, with diagnosis based on a combination of clinical and histopathological findings. Primary melanoma is treated with wide excision, with margins determined by tumour thickness. Further treatment depends on the disease stage (following histopathological examination and, where appropriate, sentinel lymph node biopsy) and can include surgery, checkpoint immunotherapy, targeted therapy, or radiotherapy. Systemic drug therapies are recommended as an adjunct to surgery in patients with resectable locoregional metastases and are the mainstay of treatment in advanced melanoma. Management of advanced melanoma is complex, particularly in those with cerebral metastasis. Multidisciplinary care is essential. Systemic drug therapies, particularly immune checkpoint inhibitors, have substantially increased melanoma survival following a series of landmark approvals from 2011 onward.

Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF)V600 (Val600) mutations using selected BRAF inhibitors combined with mitogen-activated protein kinase inhibitors have significantly improved response and overall survival. Furthermore, advanced cutaneous melanoma has developed into a prototype for testing checkpoint-modulating agents, which has increased hope for long-term tumour containment and a potential cure. These expectations have been sustained by clinical success with targeted agents and antibodies that block programmed cell-death protein 1 in locoregional disease, which induces prolongation of relapse-free, distant-metastasis-free, and overall survival times.

Background The incidence of melanoma is rising. Early detection is associated with a more favourable outcome. The factors that influence the timing of a patient’s presentation for medical assessment are not fully understood. The aims of the study were to measure the nature and duration of melanoma symptoms in a group of patients diagnosed with melanoma within the preceding 18 months and to identify the symptoms and barriers associated with a delay in presentation. Methods A questionnaire was distributed to a random sample of 200 of the 963 melanoma patients who had participated in the Cancer Patient Experience Survey 2010 and were known to be alive 1 year later. Data were collected on symptoms, duration of symptoms prior to presentation and the reasons for not attending a doctor sooner. Results A total of 159 patients responded to the questionnaire; 74 (47%) were men; mean age was 62 (range 24–90) years. Of the 149 patients who reported a symptom, 40 (27%) had a delayed presentation (i.e. >3 months). A mole growing bigger was the most common symptom and reporting this symptom was significantly associated with a delayed presentation (odds ratio (OR) 2.04, 95% confidence interval (95% CI) 1.14–5.08). Patients aged ≥65 years were less likely to report a barrier to presentation and were less likely to delay than those under 40, although this was of borderline statistical significance (OR 0.28, 95% CI 0.08–1.00). Conclusions This study highlights that an enlarging mole is a significant symptom influencing the timing of presentation. Increasing public awareness of the signs of melanoma and of the importance of early presentation is desirable. Health professionals should take advantage of the opportunity to educate patients on such symptoms and signs where feasible. Further exploration of the barriers to presentation in younger people should be considered.