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Background Anti-programmed cell death 1 antibodies (PD-1 Abs) are widely used for advanced melanoma, but information on the efficacy of anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Ab-treatment, particularly in patients with melanoma who are refractory to anti-PD-1 Abs. The aim of this study was to evaluate anti-PD-1 Ab-treatment in combination with TM5614 (a plasminogen activator inhibitor-1 inhibitor) in patients with unresectable melanoma. Methods The TM5614-MM study was a multicentre, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at seven Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0–4 weeks) and 180 mg once daily (5–8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614. Results Thirty-nine patients were enrolled, and 34 patients were included in the anti-PD-1 Ab-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% confidence interval 12.9–44.9%, P = 0.027) in 27 patients who were anti-PD-1 Ab-refractory based on investigator assessment in the protocol per set cohort. Seven patients discontinued treatment owing to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort. Conclusions TM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma. [ABSTRACT FROM AUTHOR]

This article explores the genetic characteristics of malignant melanoma in adults with congenital nevi, a topic that has been primarily studied in children. The researchers analyzed a group of 76 patients and identified seven adults with melanoma arising from a congenital nevus. The study found that adult CMN melanomas had different genetic features compared to pediatric CMN melanomas, including the presence of certain mutations and deletions. The findings suggest potential therapeutic targets but also indicate resistance to immune checkpoint inhibitor treatment. Further research is needed to gain a better understanding of the genomic characteristics of CMN melanomas in adults. [Extracted from the article]

Background Increasing melanoma incidence with less increasing mortality is observed in several countries. This discrepancy is not well understood. Objectives In this study, our aim was to discuss factors [ultraviolet radiation (UVR) exposure, melanoma treatment, diagnostic activity, overdiagnosis, pathologists' diagnostic threshold and clinicians' propensity to remove suspect skin lesions] that might influence melanoma incidence and mortality in Denmark. Methods This was a register study with the number of melanocyte-related lesions and melanoma mortality based on comprehensive national pathology and mortality databases for the period 1999–2019. We investigated melanocyte-related diagnoses and mortality in a population of 5.5 million with a national healthcare system. Age-adjusted melanoma mortality and age-adjusted incidence of benign naevi, atypical lesion, or melanoma in situ and of invasive melanoma were computed for data analysis. Results In total, 1 434 798 biopsies were taken from 704 682 individuals (65% female). The mean age at biopsy was 39.8 years in males and 37.6 in females. In males and females, the incidence of invasive melanoma increased by 87% during the period 1999–2011. During the subsequent period it increased by 9% in males but remained unchanged in females. The incidence of melanoma in situ increased by 476% in males and 357% in females during the study period, while the increases for atypical melanocytic lesions were 1928% and 1686%, respectively. Biopsy rates increased by 153% in males and 118% in females from 1999 through 2011 but fell by 20% in males and 22% in females during the subsequent period. Mortality varied slightly from year to year without any significant time trend for males or females. We identified no evidence of increased UVR exposure over the latest 30 years in Denmark. Immunotherapy of advanced melanoma was introduced in Denmark in 2010 and came into general use in 2014. Conclusions Comprehensive national data demonstrate increasing melanoma incidence correlated with increasing biopsy rates, but with no change in mortality. Previously suggested explanations for such a trend are a lowered threshold of melanoma diagnosis among pathologists, increased diagnostic activity in the presence of overdiagnosis and improved melanoma treatment. Because the study is observational and we have more explanatory factors than outcomes, the findings do not warrant conclusions about causal relationships. [ABSTRACT FROM AUTHOR]

Background Use of artificial intelligence (AI), or machine learning, to assess dermoscopic images of skin lesions to detect melanoma has, in several retrospective studies, shown high levels of diagnostic accuracy on par with – or even outperforming – experienced dermatologists. However, the enthusiasm around these algorithms has not yet been matched by prospective clinical trials performed in authentic clinical settings. In several European countries, including Sweden, the initial clinical assessment of suspected skin cancer is principally conducted in the primary healthcare setting by primary care physicians, with or without access to teledermoscopic support from dermatology clinics. Objectives To determine the diagnostic performance of an AI-based clinical decision support tool for cutaneous melanoma detection, operated by a smartphone application (app), when used prospectively by primary care physicians to assess skin lesions of concern due to some degree of melanoma suspicion. Methods This prospective multicentre clinical trial was conducted at 36 primary care centres in Sweden. Physicians used the smartphone app on skin lesions of concern by photographing them dermoscopically, which resulted in a dichotomous decision support text regarding evidence for melanoma. Regardless of the app outcome, all lesions underwent standard diagnostic procedures (surgical excision or referral to a dermatologist). After investigations were complete, lesion diagnoses were collected from the patients' medical records and compared with the app's outcome and other lesion data. Results In total, 253 lesions of concern in 228 patients were included, of which 21 proved to be melanomas, with 11 thin invasive melanomas and 10 melanomas in situ. The app's accuracy in identifying melanomas was reflected in an area under the receiver operating characteristic (AUROC) curve of 0.960 [95% confidence interval (CI) 0.928–0.980], corresponding to a maximum sensitivity and specificity of 95.2% and 84.5%, respectively. For invasive melanomas alone, the AUROC was 0.988 (95% CI 0.965–0.997), corresponding to a maximum sensitivity and specificity of 100% and 92.6%, respectively. Conclusions The clinical decision support tool evaluated in this investigation showed high diagnostic accuracy when used prospectively in primary care patients, which could add significant clinical value for primary care physicians assessing skin lesions for melanoma. [ABSTRACT FROM AUTHOR]

A study published in the British Journal of Dermatology found that 13% of patients developed a rash after receiving co-trimoxazole treatment while on immune checkpoint inhibitor (CPI) therapy. The severity of the rash was higher in this patient group, and they had a significantly shorter median overall survival compared to those who did not develop the rash. Prompt recognition and withdrawal of co-trimoxazole treatment is recommended in the context of CPI therapy. Further studies are needed to validate these findings and understand the mechanisms behind the increased incidence and severity of the rash. [Extracted from the article]

Background Malignant melanoma (MM) is a highly aggressive form of skin cancer whose incidence continues to rise worldwide. If diagnosed at an early stage, it has an excellent prognosis, but mortality increases significantly at advanced stages after distant spread. Unfortunately, early detection of aggressive melanoma remains a challenge. Objectives To identify novel blood-circulating biomarkers that may be useful in the diagnosis of MM to guide patient counselling and appropriate disease management. Methods In this study, 105 serum samples from 26 healthy patients and 79 with MM were analysed using an untargeted approach by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) to compare the metabolomic profiles of both conditions. Resulting data were subjected to both univariate and multivariate statistical analysis to select robust biomarkers. The classification model obtained from this analysis was further validated with an independent cohort of 12 patients with stage I MM. Results We successfully identified several lipidic metabolites differentially expressed in patients with stage I MM vs. healthy controls. Three of these metabolites were used to develop a classification model, which exhibited exceptional precision (0.92) and accuracy (0.94) when validated on an independent sample. Conclusions These results demonstrate that metabolomics using LC-HRMS is a powerful tool to identify and quantify metabolites in bodily fluids that could serve as potential early diagnostic markers for MM. [ABSTRACT FROM AUTHOR]

Modulation of immune responses through immune checkpoint blockade has revolutionized cutaneous melanoma treatment. However, it is still the case that not all patients respond successfully to these therapies, indicating the presence of as yet unknown resistance mechanisms. Hence, it is crucial to find novel targets to improve therapy efficacy. One of the described resistance mechanisms is regulated by immune inhibitory Siglec receptors, which are engaged by the carbohydrates sialic acids expressed on tumour cells, contributing to programmed cell death protein-1 (PD1)-like immune suppression mechanisms. In this review, we provide an overview on the regulation of sialic acid synthesis, its expression in melanoma, and the contribution of the sialic acid–Siglec axis to tumour development and immune suppressive mechanisms in the tumour microenvironment. Finally, we highlight potential sialic acid–Siglec axis-related therapeutics to improve the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Background Mutant BRAF targeted therapies remain a standard of care for the treatment of metastatic malignant melanoma (MM); however, high initial response rates are tempered by the persistence of residual MM cells that eventually lead to disease recurrence and mortality. As MM recurrence during targeted therapy can present with the simultaneous occurrence of multiple tumour nodules at the original body sites, we hypothesized the presence of an intrinsically resistant MM cell subpopulation. Objectives To identify an MM cell subpopulation that is intrinsically resistant to targeted therapy and possibly responsible for MM recurrence. Methods Using melanoma cell lines, we defined culture conditions for the reproducible three-dimensional growth of melanospheres to investigate putative cancer stem cell populations. We undertook RNA sequencing and bioinformatic analysis to characterize cell populations between adherent and nonadherent culture, and cells expressing or not expressing CD20. Furthermore, we defined an in vitro assay to evaluate the killing of melanoma cancer stem cells as a therapeutic test using combination therapies targeting driver mutation and CD20. Results We described the culture conditions that promote MM cells to form melanospheres with a reproducible colony-forming efficiency rate of 0.3–1.3%. RNA sequencing of melanosphere vs. conventional MM cell cultures (n = 6), irrespective of the BRAF mutation status, showed that melanosphere formation was associated with growth and differentiation transcriptional signatures resembling MM tumours. Importantly, melanosphere formation also led to the emergence of a CD20+ MM cell subpopulation, similar to that observed in primary human MM tumours. CD20+ MM cells were resistant to BRAF inhibitor therapy and, consistent with this finding, demonstrated a Forkhead box protein M1 transcriptomic profile (n = 6). Combining BRAF inhibitor and anti-CD20 antibody treatment led to the additional killing of previously resistant CD20+   BRAF mutant MM cells. Conclusions In patients with MM that harbour a CD20+ subpopulation, combined therapy with BRAF inhibitor and anti-CD20 antibody could potentially kill residual MM cells and prevent disease recurrence. [ABSTRACT FROM AUTHOR]

Background Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of -metastasis. Objectives To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. Methods Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. Results Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant, with a hazard ratio of 3.469 (95% confidence interval 1.403–8.580, P = 0.007) and an overall NPV of 96.5%. Conclusions These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence. [ABSTRACT FROM AUTHOR]

Background Cutaneous squamous cell carcinoma (cSCC) and melanoma have different associations with sun exposure. Objectives To compare trends in the incidence rates of cSCC and melanoma, to provide insight into changing patterns of exposure to ultraviolet radiation (UVR). Methods We compared trends in the incidence of cSCC and melanoma in seven susceptible populations residing at mid-to-high latitudes: Finland, Norway, Sweden, Denmark, Scotland, the Netherlands and Tasmania (Australia). We fitted Joinpoint models to describe trends in age-standardized incidence rates for melanoma and cSCC and calculated the average annual percentage rate of change for the period 1989–2020 (1989–2018 for Tasmania). We calculated the incident rate ratio (IRR) as the ratio of the age-standardized rates (European Standard Population) for cSCC to melanoma and conducted age–period–cohort modelling to compare age, period and cohort effects. Results The ratio of cSCC-to-melanoma incidence increased with proximity to the equator and over time. In the most recent time period, the incidence of cSCC was higher than the incidence of melanoma for men and women in all seven populations. While the ratio of cSCC-to-melanoma incidence was higher for men vs. women, in most countries the cSCC-to-melanoma IRR increased over time to a greater extent in women than in men. Melanoma incidence was higher among younger people and cSCC incidence was higher among older people; the age at which the incidence of cSCC overtook the incidence of melanoma was progressively younger with proximity to the equator. Conclusions Despite concerted international efforts to preserve the ozone layer over the past four decades resulting in significant reductions in surface ultraviolet B at mid-latitudes, the incidence of skin cancer, particularly cSCC, continues to rise in those regions. Our findings are consistent with a stronger association with age-associated cumulative sun exposure for cSCC vs. melanoma and suggest that women are currently receiving greater UV radiation exposure than in the past. [ABSTRACT FROM AUTHOR]

The article discusses the recent approval of a cell therapy called lifileucel for the treatment of melanoma. Lifileucel uses a patient's own tumor-infiltrating T lymphocytes (TILs) to target and treat melanoma. This approval marks a significant advancement in cancer treatment, as it is the first cell therapy to be approved for a solid tumor. Clinical trials have shown that lifileucel has a response rate between 30% and 50%, making it a valuable addition to the treatment options for melanoma patients who do not respond to other therapies. However, there are still challenges to overcome, such as the need for a surgical procedure to isolate TILs and the exclusion of patients with certain conditions. Ongoing research is focused on improving the effectiveness and specificity of T-cell therapies for melanoma. [Extracted from the article]

Background Nodular melanoma (NM) is a challenge to diagnose early due to its rapid growth and more atypical clinical presentation, making it the largest contributor to melanoma mortality. Objectives Our study aim was to perform a rare-variant allele (RVA) analysis of whole-exome sequencing of patients with NM and non-NM (minor allele frequency ≤ 1% non-Finnish European) for a set of 500 candidate genes potentially implicated in melanoma. Methods This study recruited 131 participants with NM and 194 with non-NM from South-east Queensland and patients with NM from Victoria to perform a comparative analysis of possible genetic differences or similarities between the two melanoma cohorts. Results Phenotypic analysis revealed that a majority of patients diagnosed with NM were older males with a higher frequency of fair skin and red hair than is seen in the general population. The distribution of common melanoma polygenic risk scores was similar in patients with NM and non-NM, with over 28% in the highest quantile of scores. There was also a similar frequency of carriage of familial/high-penetrant melanoma gene and loss-of-function variants. We identified 39 genes by filtering 500 candidate genes based on the greatest frequency in NM compared with non-NM cases. The genes with RVAs of greatest frequency in NM included PTCH1 , ARID2 and GHR. Rare variants in the SMO gene, which interacts with PTCH1 as ligand and receptor, were also identified, providing evidence that the Hedgehog pathway may contribute to NM risk. There was a cumulative effect in carrying multiple rare variants in the NM-associated genes. A 14.8-fold increased ratio for NM compared with non-NM was seen when two RVAs of the 39 genes were carried by a patient. Conclusions This study highlights the importance of considering frequency of RVA to identify those at risk of NM in addition to known high penetrance genes. [ABSTRACT FROM AUTHOR]

Background Compared with the general population, people with a previous melanoma are at increased risk of developing another primary melanoma. Understanding the risk factors associated with multiple primary melanomas can inform patient education and tailored surveillance. Objectives To examine the risk factors for subsequent primary melanoma in people with a previous melanoma, by conducting a systematic review and meta-analysis of the available data. Methods A systematic literature search was conducted in CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Embase and MEDLINE. Studies that reported a risk estimate or raw frequencies and conducted between 1982 and August 2022 were included. Adjusted risk estimates were prioritized over univariable risk estimates. PRISMA reporting guidelines were followed. Random effects meta-analysis was conducted to derive pooled estimates. Quality assessment was conducted by two researchers using the Newcastle-Ottawa scale. GRADE was used to rate the certainty and quality of the evidence. Results Data from 27 studies involving 413 181 participants were pooled and analysed. Risk factors assessed included age and sex, environmental, lifestyle, phenotypic, genetic and histopathological factors, and there was wide variation in how they were categorized and analysed. Independent risk factors identified from pooled analyses included male sex [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.40–1.53], increasing age per 10 years (HR 1.19, 95% CI 1.14–1.24), light skin colour (HR 1.44, 95% CI 1.23–1.70), family history [odds ratio (OR) 1.79, 95% CI 1.25–2.56], CDKN2A mutation (OR 5.29, 95% CI 2.70–10.37), a high or moderate naevus count [OR 2.63 (95% CI 1.61–4.30) and OR 1.64 (95% CI 1.07–2.51), respectively], one or more atypical naevi (OR 3.01, 95% CI 1.52–5.97), first lesions occurring on the head or neck, lentigo maligna subtype (HR 1.16, 95% CI 1.15–1.17), other subtype (HR 1.14, 95% CI 1.03–1.27) and inadequate sun protection (HR 1.85, 95% CI 0.98–3.50). Based on the GRADE criteria, there was high to very low confidence in the pooled effect estimates. Conclusions This meta-analysis identified several consistent, independent risk factors for the development of subsequent primary melanoma. These findings will help stratify the risk of subsequent melanoma, tailor skin-check schedules and inform patient education. [ABSTRACT FROM AUTHOR]

This article discusses a study published in the British Journal of Dermatology that examines the risk of melanoma in patients with a history of keratinocyte carcinoma (KC), with a specific focus on skin of color patients. The study analyzed Medicare claims data from 2009 to 2018 and found that skin of color patients with KC had a higher risk of melanoma compared to patients with seborrhoeic keratosis (SK). The research emphasizes the importance of including skin of color patients in skin cancer studies and calls for further research in this population. Another aspect of the study examined the association between actinic keratosis (AK) and melanoma in Medicare patients aged 65 and older. The study found that a history of AK was associated with an 85% increased risk of melanoma in skin of color patients. However, the absolute risks of melanoma in this group were still low, at less than 1% at 5 years. The study acknowledges limitations, such as the use of claims data and the exclusion of certain patient categories. Overall, the study highlights the increased risk of melanoma in skin of color patients with a history of AK. [Extracted from the article]

Background Melanomas < 0.8 mm in Breslow depth have less than a 5% risk for nodal positivity. Nonetheless, nodal positivity is prognostic for this group. Early identification of nodal positivity may improve the outcomes for these patients. Objectives To determine the degree to which ulceration and other high-risk features predict sentinel lymph node (SLN) positivity for very thin melanomas. Methods The National Cancer Database was reviewed from 2012 to 2018 for patients with melanoma with Breslow thickness < 0.8 mm. Data were analysed from 7 July 2022 through to 25 February 2023. Patients were excluded if data regarding their ulceration status or SLN biopsy (SLNB) performance were unknown. We analysed patient, tumour and health system factors for their effect on SLN positivity. Data were analysed using χ2 tests and logistic regressions. Overall survival (OS) was compared by Kaplan–Meier analyses. Results Positive nodal metastases were seen in 876 (5.0%) patients who underwent SLNB (17 692). Factors significantly associated with nodal positivity on multivariable analysis include lymphovascular invasion [odds ratio (OR) 4.5, P < 0.001], ulceration (OR 2.6, P < 0.001), mitoses (OR 2.1, P < 0.001) and nodular subtype (OR 2.1, P < 0.001). Five-year OS was 75% and 92% for patients with positive and negative SLN, respectively. Conclusions Nodal positivity has prognostic significance for very thin melanomas. In our cohort, the rate of nodal positivity was 5% overall in these patients who underwent SLNB. Specific tumour factors (e.g. lymphovascular invasion, ulceration, mitoses, nodular subtype) were associated with higher rates of SLN metastases and should be used to guide clinicians in choosing which patients will benefit from SLNB. [ABSTRACT FROM AUTHOR]

Primary cutaneous melanoma is frequently diagnosed when the tumour thickness (Breslow) is <= 1 mm and is termed thin invasive melanoma. Recent advances in the systemic treatment of advanced melanoma based on immune checkpoint inhibitor therapies have led to successful trials in patients diagnosed with clinically high-risk primary melanomas.[10] In a significant proportion of patients with high-risk primary melanoma their disease will not recur if left untreated; therefore, they are at risk of overtreatment and exposure to toxicities. Liquid biopsies provide a promising, noninvasive avenue for a more accurate diagnosis and prognosis of melanoma via detection of circulating biomarkers. [Extracted from the article]

Background Noninvasive molecular biomarkers are needed to improve the early, accurate and precise diagnosis of invasive cutaneous melanoma. Objectives To independently validate a previously identified circulating microRNA signature of melanoma (MEL38), and, secondly, to develop a complementary microRNA signature, optimized for prognostication. Patients and Methods MicroRNA expression profiling was performed on plasma samples from a multicentre observational case–control study, involving patients with primary or metastatic melanoma, melanoma in situ , nonmelanoma skin cancer, or benign naevi. MicroRNA profiles from patients with length of survival, treatment and sentinel lymph node biopsy (SLNB) data were used to develop the prognostic signature. The primary outcome of interest for MEL38 was its association with melanoma status, including area under the curve, binary diagnostic sensitivity and specificity, and incidence-adjusted positive and negative predictive values. The prognostic signature was assessed using rates of survival per risk group and relationship to conventional predictors of outcome. Results Circulating microRNA profiles of 372 patients with invasive melanoma and 210 control individuals were generated. The average age of all participants was 59 years; 49% were male. A MEL38 score > 5.5 indicated the presence of invasive melanoma. Overall, 551/582 (95%) of patients were correctly diagnosed, with 93% sensitivity and 98% specificity. MEL38 score ranged from 0 to 10 with an area under the curve of 0.98 (95% confidence interval 0.97–0.99, P < 0.001). A novel prognostic 12-microRNA signature (MEL12) developed from 232 patients identified low-, standard- or high-risk groups, with 94%, 78% and 58% rates of 10-year melanoma-specific survival, respectively (log-rank P < 0.001). MEL12 prognostic risk groups were significantly associated with clinical staging (χ2, P < 0.001) and SLNB status (P = 0.027). Patients who were classified as high risk by MEL12 were approximately three times more likely to have melanoma detected in their sentinel lymph nodes compared to low-risk patients.  Conclusions The circulating MEL38 signature may assist in diagnosing patients with invasive melanoma vs. other conditions associated with a lower – or negligible – risk of mortality. A complementary and prognostic MEL12 signature is predictive of SLNB status, clinical stage and probability of survival. Plasma microRNA profiling may help to optimize existing diagnostic pathways as well as enable personalized, risk-informed melanoma treatment decisions. [ABSTRACT FROM AUTHOR]

Cancer is caused by the accumulation of pathogenic alterations of the genome and epigenome that result in permanent changes that disrupt cellular homeostasis. The genes that become corrupted in this process vary among different tumour types, reflecting specific vulnerabilities and dependencies of the cell from which the cancer originated. This also applies to 'melanoma', a cancer that constitutes not one, but multiple diseases that can be separated based on their cell of origin, aetiology, clinical appearance and course, and response to treatment. In this article, we review the current classification of melanoma within distinct evolutionary pathways and the associated genetic alterations. In addition, we review the application of molecular diagnostics to the diagnosis of melanocytic tumours in the context of histopathological assessment.

BackgroundMelanoma aetiology has been proposed to have two pathways, which are determined by naevi and type of sun exposure and related to the anatomical site where melanoma develops.ObjectivesWe examined associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus phenotypes, ultraviolet radiation exposure and polygenic risk.MethodsWe analysed harmonized data from 2617 people with incident first invasive melanoma and 975 healthy controls recruited through two population-based case-control studies in Australia and the UK. Questionnaire data were collected by interview using a single protocol, and pathway-specific polygenic risk scores were derived from DNA samples. We estimated adjusted odds ratios using unconditional logistic regression that compared melanoma cases at each anatomical site with all controls.ResultsWhen cases were compared with control participants, there were stronger associations for many naevi vs. no naevi for melanomas on the trunk, and upper and lower limbs than on the head and neck (P-heterogeneity

The article "Prediction of melanoma metastasis using dermatoscopy deep features: an international multicentre cohort study" published in the British Journal of Dermatology discusses the use of deep learning technology, specifically convolutional neural networks, to predict the development of metastasis in melanoma patients. The study compared the predictive performance of deep features against established histopathological prognostic factors and found that the deep features model demonstrated similar performance to Breslow thickness and ulceration in predicting metastasis. The findings suggest that deep features derived from dermatoscopy could serve as potential prognostic biomarkers for melanoma, particularly in refining patient selection for adjuvant therapy. [Extracted from the article]

Acral melanoma, a subtype of cutaneous melanoma that affects the palms, soles, and nail units, is understudied and associated with poorer prognosis compared to other types of melanoma. The genetic landscape of acral melanoma differs from nonacral melanomas, and it has been hypothesized that differences in clinical outcomes may be due to differences in the melanocyte cell of origin across anatomical locations. Amelanotic melanoma, which lacks pigmentation, presents a diagnostic challenge and may have different treatment strategies due to transcriptional differences. In a recent study, researchers used spatial sequencing to compare amelanotic and pigmented acral melanomas and found differences in protein synthesis pathways, immune infiltrate composition, and gene expression associated with antigen processing and presentation. Further research is needed to determine if these differences can be targeted for therapy. [Extracted from the article]

A study published in the British Journal of Dermatology examined the impact of COVID-19 lockdowns on melanoma cases in the Netherlands. The study found that limited access to healthcare services during the pandemic did not have a significant effect on the diagnosis of melanoma. The researchers focused on changes in the stages of melanoma at diagnosis and the thickness of melanoma. The study provides detailed data on the incidence rates of melanoma during different periods of the pandemic. Another study, which this document reevaluates, found that there was a decrease in melanoma cases during the first lockdown period, but an increase in cases during the post-lockdown periods, suggesting a catch-up of undiagnosed cases. The study also found a slight increase in advanced-stage melanomas during the lockdown periods, but this may be due to statistical fluctuations. The authors stress the importance of using standardized incidence ratios to accurately compare cancer rates over time and between populations. The study was not funded by any specific grant and the author has no conflicts of interest. [Extracted from the article]

Of the 107 evaluable patients, 18 (16.8%) achieved a complete response (CR), 21 (19.6%) achieved a partial response (PR), 25 (23.4%) had stable disease (SD) and 43 (40.2%) experienced progressive disease (PD). Use of immune checkpoint inhibitors prolonged overall survival in a Japanese population of advanced malignant melanoma patients: retrospective single institutional study. [Extracted from the article]

Background Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored. Objectives To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K– individuals. Materials and methods Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ 2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/– cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank). Results The cohort comprised 1165 MITF E318K– and 322 E318K+ individuals. In E318K– cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67–2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54–1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20–1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals. Conclusions RHC alleles/genotypes modify melanoma risk differently in MITF E318K– and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K– individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals. [ABSTRACT FROM AUTHOR]

Graph: Figure 1 Predicted probabilities and 95% confidence intervals of melanoma thickness categories according to physical activity (PA) level, for first primary invasive melanomas (n = 1444), stratified by anatomical site, in the Norwegian Women and Cancer cohort, 1991-2018. Dear Editor, Knowledge about factors associated with melanoma thickness, the most important prognostic factor for localized primary melanoma survival,[1] may help reduce the risk of melanoma deaths. To our knowledge, only one study has reported on PA and melanoma survival[8] and only one on PA and melanoma thickness;[3] both found no association, in line with our results in Norwegian women. [Extracted from the article]

Background Proton-pump inhibitors (PPIs) are commonly used by patients with cancer, although they could reduce the absorption of oral anticancer targeted therapies. The US Food and Drug Administration states that the effect of PPIs on the efficacy of dabrafenib use by patients with metastatic melanoma is unknown. As a precautionary measure, the European Society for Medical Oncology recommends avoiding PPIs for patients receiving dabrafenib. Objectives To determine the effect of the concomitant use of PPIs and BRAF/MEK inhibitors in patients with metastatic melanoma. Methods Patients with advanced melanoma receiving BRAF/MEK inhibitors as first-line treatments between 2015 and 2017 in France were selected using the French National Health Insurance database. We compared time-to-treatment discontinuation (TTD) and overall survival (OS) according to concomitant PPI exposure. We balanced the baseline characteristics of patients exposed and nonexposed to PPIs using an overlap weighting method based on a propensity score. Results The metastatic melanoma cohort comprised 1028 patients receiving BRAF/MEK inhibitors, including 361 (35.1%) patients using PPIs. PPI users had more comorbidities and a more severe metastatic disease. After having equally distributed metastatic sites and comorbidities across patients exposed and nonexposed to PPIs, concomitant PPI use was not associated with shorter TTD [weighted hazard ratio (wHR) 1.03, 95% confidence interval (CI) 0.86–1.24] or OS (wHR 1.11, 95% CI 0.88–1.39). Consistent results were observed when restricting the population to patients receiving dabrafenib, or when narrowing exposure to PPIs with stronger inhibition of cytochromes. Conclusions In a population-based cohort of patients with advanced melanoma, the concomitant use of PPIs and BRAF/MEK inhibitors was not associated with worse outcome. [ABSTRACT FROM AUTHOR]

Https://doi.org/10.1093/bjd/ljad183 DearEditor, Although anti-PD-1 antibody (Ab) and dabrafenib plus trametinib combined therapy have been effective for postoperative cutaneous melanoma in the adjuvant setting,[1] there have been few patients with acral and mucosal melanoma enrolled in clinical trials.[2],[3] In this study, the efficacies and safety profiles of anti-PD-1 Abs or the combination of BRAF + MEK inhibitors were further analysed in 120 patients with stage III/IV melanoma in the adjuvant setting. Before adjuvant therapy, 26 patients with stage III cutaneous and acral melanoma were treated with complete lymph node dissection, whereas 65 patients were not. Of the treatment-related factors, patients treated with BRAF plus MEK inhibitors showed better RFS than those treated with anti-PD-1 inhibitors (HR 0.14, 95% CI 0.045-0.47; I P i = 0.0002). [Extracted from the article]

In 2021, the crude incidence rates showed a significant rise compared with 2019 for total diagnoses, and for stage I and stage II MM, with the greatest IRR seen in stage II diagnoses: from 4.67 (95% CI 4.49-4.85) to 5.94 PY [95% CI 5.74-6.15 (IRR 1.27, 95% CI 1.21-1.34; I P i < 0.001)]. Https://doi.org/10.1093/bjd/ljad117 Dear Editor, A delayed diagnosis of malignant melanoma (MM) increases mortality. [Extracted from the article]

A study published in the British Journal of Dermatology examines the mental burden of cutaneous melanoma (CM) and its treatment. The study finds that anxiety and depression are prevalent among patients with CM, with the highest rates occurring during treatment. Risk factors for anxiety and depression include younger age, female gender, and low educational attainment. The study highlights the importance of addressing the mental health needs of patients with CM and suggests the use of psychotherapy and pharmacological interventions to improve their quality of life. [Extracted from the article]

Introduction and aims Melanoma is the deadliest form of skin cancer and has an increasing worldwide incidence. It is well established that the melanoma tumour microenvironment (TME) has a large immune cell infiltrate, including a prominent monocytic compartment. Monocytic cells within the TME support melanoma growth, survival and metastasis. Contrastingly, such cells can be stimulated to promote tumour killing when engaged with monoclonal antibodies (mAbs) against cancer antigens, owing to their expression of multiple Fc receptors (FcRs). However, little is known about the monocytic subsets present within melanoma, the FcRs they express and how engaging their FcRs may influence function. Methods Flow cytometry on peripheral monocytes isolated from patients with melanoma and healthy volunteers enabled the characterization of cell surface markers. Next, publicly available single-cell RNA-Seq datasets were analysed to explore the transcriptome of melanoma-associated macrophages and these phenotypes were recapitulated in vitro. Finally, monocytes and macrophages were cocultured with melanoma cells, with or without the addition of mAbs against a melanoma antigen, in order to assess the effect of FcR crosslinking on monocyte and macrophage phenotype and function. Results Circulating monocytes in patients with melanoma feature an inhibitory phenotype, and express multiple FcRs, including Fcε and Fcγ receptors, which could be targeted with mAbs of multiple isotypes. Secondly, monocytic cells within the melanoma TME express protumour genes, including metalloproteinases and angiogenic factors. However, FcR expression suggests that tumour-promoting subsets can be targeted with mAbs. Finally, in ex vivo cocultures with melanoma cells, the FcRs of both human monocytes and macrophages are able to engage antimelanoma mAbs of multiple isotypes, inducing differential phenotype change. This is demonstrated by the upregulation of activation markers and costimulatory cell surface markers. Conclusions Together, these data suggest that tumour-promoting monocytic cells within the melanoma TME can be engaged and harnessed using different isotypes of mAbs targeting melanoma. [ABSTRACT FROM AUTHOR]

The 10th edition of Rook's Textbook of Dermatology, published in the British Journal of Dermatology, reflects the advancements in dermatology over the past 8 years. The new edition covers topics such as inflammatory dermatology, cutaneous oncology, genodermatoses, and melanoma in detail, with chapters authored by experts like Reinhard Dummer and Simone Goldinger. It also includes updated sections on vascular anomalies, viral infections like SARS-CoV-2 (COVID-19), and offers electronic access for readers seeking a more portable option. [Extracted from the article]

Https://doi.org/10.1093/bjd/ljad100 Dear Editor, Skin cancer rates are increasing worldwide due to ageing populations, sun-seeking behaviours and increasing rates of immunosuppression.[1] This places significant demands on the National Health Service (NHS). The highest EASRs (2017-2019) for all skin cancer types were seen in Peninsula (BCC EASR 425.62/100 000 PY; 95% CI 420.38-430.90) and Surrey and Sussex (BCC EASR 381.54/100 000 PY; 95% CI 377.56-385.55). Our objective was to report the regional incidence of the three most common types of skin cancer in England: basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and melanoma. [Extracted from the article]

Https://doi.org/10.1093/bjd/ljad076 Dear Editor, People diagnosed with a primary melanoma have a higher risk of developing subsequent primary melanomas compared with the general population; however, individual risk varies substantially.[1] A better understanding of the risk factors and absolute risk of developing a subsequent primary melanoma among individuals with a previous melanoma is important to guide follow-up recommendations for skin surveillance.[2] Using a population-based cohort with long follow-up, we aimed to identify risk factors and absolute risk for developing a second primary melanoma. Table 1 Cox proportional hazard model estimates of risk of developing a second primary melanoma after diagnosis of a first primary melanoma HT