Development and validation of risk calculators for people with "thin" melanomas on their skin to predict the likelihood that their cancer will return: a plain language summary of publication.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article describing the development of risk calculators for use in people who develop a type of melanoma on their skin called "thin" melanoma to predict the likelihood that their cancer will return. The article was originally published in the Journal of Clinical Oncology in 2021. HOW WERE THE CALCULATORS DEVELOPED?: Calculations were performed to predict the chance of people with thin melanomas surviving without their melanoma recurring. Three graphical prediction calculators (called nomograms) were developed, along with easy-to-use online calculators using the same underlying calculation methods. The model was developed using data for 25,930 Dutch people diagnosed with thin melanomas (called the "development set"). To test its ability to predict melanoma recurrence, it was then compared with data for 2,968 Australian people with melanoma (the "validation set"). The calculators developed in the Dutch patients were found to accurately predict the risk of melanoma recurring for people with melanoma in the Australian "validation" group. WHAT DO THE RESULTS MEAN?: The calculators provide estimates of the risk of the melanoma returning for people with thin melanomas. The easy-to-use online calculators are freely available on a smartphone, tablet or computer, and will assist in providing accurate estimates of recurrence risks for individuals with thin melanomas, allowing more intensive follow-up of those whose predicted risk of their melanoma returning is high.

High discordance rate in assessing sentinel node positivity in cutaneous melanoma: Expert review may reduce unjustified adjuvant treatment.

INTRODUCTION: Identification of sentinel node (SN) metastases can set the adjuvant systemic therapy indication for patients with stage III melanoma. Studies re-evaluating the diagnosis of initially positive SN biopsies are scarce. MATERIALS AND METHODS: Dutch patients with melanoma who underwent SN biopsy between 2003 and 2014 were selected from PALGA, the Dutch Pathology Registry. Histopathological slides of SN-positive patients were retrieved for review. A random sample was reassessed by an expert melanoma pathologist. Recurrence-free survival (RFS) of patients who were misclassified (false-positive) was compared with those with a true positive SN status. For comparison, a group of SN-negative patients was included. Multivariable logistic analysis was performed to assess clinicopathological characteristics associated with misclassification of SN status. RESULTS: Diagnosis was downgraded from melanoma metastasis to nodal nevus in 38 of the 322 reviewed patients (11.8%). Considering the inclusion criteria of phase III adjuvant trials, at least 4.3% of patients would have falsely qualified for adjuvant therapy. In multivariable analysis, patients with a low SN tumour burden and subcapsular SN tumour location had a significantly higher chance of being misclassified. The five-year RFS of the 38 downgraded patients was 86.7% (95% confidence interval [CI] = 72.6-96.6), similar to the 85.9% (95% CI = 84.9-86.8, p = 0.18) for 6413 SN-negative patients and better than the 53.2% (95% CI = 47.2-59.9, p = 0.009) of 284 patients who were truly SN positive upon review. CONCLUSION: More than 10% of originally positive SN biopsies of patients with melanoma concern misclassified nodal nevi. We advocate that when adjuvant treatment is considered in patients with stage III melanoma, SN biopsies should be reassessed by an expert melanoma pathologist.

Plasma cells in primary melanoma. Prognostic significance and possible role of IgA.

Melanoma is not only one of the most immunogenic cancers but also one of the most effective cancers at subverting host immunity. The role of T lymphocytes in tumor immunity has been extensively studied in melanoma, whereas less is known about the importance of B lymphocytes. The effects of plasma cells (PCs), in particular, are still obscure. The aim of this study was to characterize pathological features and clinical outcome of primary cutaneous melanomas associated with PCs. Moreover, we investigated the origins of the melanoma-associated PCs. Finally, we studied the outcome of patients with primary melanomas with PCs. We reviewed 710 melanomas to correlate the presence of PCs with histological prognostic markers. Immunohistochemistry for CD138 and heavy and light chains was performed in primary melanomas (PM) and in loco-regional lymph nodes (LN), both metastatic and not metastatic. In three PM and nine LN with frozen material, VDJ-rearrangement was analyzed by Gene Scan Analysis. Survival analysis was performed on a group of 85 primary melanomas >2 mm in thickness. Forty-one cases (3.7%) showed clusters/sheets of PCs. PC-rich melanomas occurred at an older age and were thicker, more often ulcerated and more mitotically active (P<0.05). PCs were polyclonal and often expressed IgA in addition to IgG. In LN, clusters/sheets of IgA+ PCs were found both in the sinuses and subcapsular areas. Analysis of VDJ-rearrangements showed the IgA to be oligoclonal. Melanomas with clusters/sheets of PCs had a significantly worse survival compared with melanomas without PCs while, interestingly, melanomas with sparse PCs were associated with a better clinical outcome (P=0.002). In conclusion, melanomas with sheets/clusters of PCs are associated with worse prognosis. IgG and IgA are the isotypes predominantly produced by these PCs. IgA oligoclonality suggests an antigen-driven response that facilitates melanoma progression by a hitherto unknown mechanism.

Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients.

Autologous dendritic cell (DC) therapy is an experimental cellular immunotherapy that is safe and immunogenic in patients with advanced melanoma. In an attempt to further improve the therapeutic responses, we treated 15 patients with melanoma, with autologous monocyte-derived immature DC electroporated with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively active TLR4 (caTLR4) together with mRNA encoding a tumor-associated antigen (TAA; respectively gp100 or tyrosinase). In addition, DC were pulsed with keyhole limpet hemocyanin (KLH) that served as a control antigen. Production of this DC vaccine with high cellular viability, high expression of co-stimulatory molecules and MHC class I and II and production of IL-12p70, was feasible in all patients. A vaccination cycle consisting of three vaccinations with up to 15×106 DC per vaccination at a biweekly interval, was repeated after 6 and 12 months in the absence of disease progression. mRNA-optimized DC were injected intranodally, because of low CCR7 expression on the DC, and induced de novo immune responses against control antigen. T cell responses against tyrosinase were detected in the skin-test infiltrating lymphocytes (SKIL) of two patients. One mixed tumor response and two durable tumor stabilizations were observed among 8 patients with evaluable disease at baseline. In conclusion, autologous mRNA-optimized DC can be safely administered intranodally to patients with metastatic melanoma but showed limited immunological responses against tyrosinase and gp100.

Experimental treatment of NRAS-mutated neurocutaneous melanocytosis with MEK162, a MEK-inhibitor.

Neurocutaneous melanosis (NCM) is a rare congenital disorder characterized by the association of large and/or multiple congenital melanocytic nevi (CMN) of the skin with melanocytic lesions of the leptomeninges, including melanocytosis. Leptomeningeal melanocytosis carries a poor prognosis once neurological symptoms develop. Despite surgery, which is often not radical, few other treatment options exist. Recently, it was demonstrated that early embryonic, post-zygotic somatic mutations in the NRAS gene are implicated in the pathogenesis of NCM.In this report, we present a 13-year-old boy with NCM and progressive symptomatic leptomeningeal melanocytosis. A somatic NRASQ61K mutation was present in both CMN as well as the melanocytosis. Despite repeated surgery, the patient showed clinical progression. Therefore, treatment with MEK162, a MEK inhibitor, was started on compassionate use base. The patient died only five days later, i.e. too early to expect a clinical effect of MEK162 therapy. We therefore studied the effect of MEK162 at the protein level in the leptomeningeal tumor by immunohistochemical and Western Blot analyses using Ki67 and pERK antibodies. We observed lower MIB-1 expression and lower pERK expression in the post-treatment samples compared to pre-treatment, suggesting a potential effect of MEK inhibiting therapy. Further studies are needed to determine whether MEK inhibitors can effectively target NRAS-mutated symptomatic NCM, a rare but potentially fatal disease.

Molecular cytogenetics of cutaneous melanocytic lesions - diagnostic, prognostic and therapeutic aspects.

This review intends to update current knowledge regarding molecular cytogenetics in melanocytic tumours with a focus on cutaneous melanocytic lesions. Advantages and limitations of diverse, already established methods, such as (fluorescence) in situ hybridization and mutation analysis, to detect these cytogenetic alterations in melanocytic tumours are described. In addition, the potential value of more novel techniques such as multiplex ligation-dependent probe amplification is pointed out. This review demonstrates that at present cytogenetics has mainly increased our understanding of the pathogenesis of melanocytic tumours, with an important role for activation of the mitogen-activated protein kinase (MAPK) signalling pathway in the initiation of melanocytic tumours. Mutations in BRAF (in common naevocellular naevi), NRAS (congenital naevi), HRAS (Spitz naevi) and GNAQ (blue naevi) can all cause MAPK activation. All these mutations seem early events in the development of melanocytic tumours, but by themselves are insufficient to cause progression towards melanoma. Additional molecular alterations are implicated in progression towards melanoma, with different genetic alterations in melanomas at different sites and with varying levels of sun exposure. This genetic heterogeneity in distinct types of naevi and melanomas can be used for the development of molecular tests for diagnostic purposes. However, at the moment only few molecular tests have become of diagnostic value and are performed in daily routine practice. This is caused by lack of large prospective studies on the diagnostic value of molecular tests including follow-up, and by the low prevalence of certain molecular alterations. For the future we foresee an increasing role for cytogenetics in the treatment of melanoma patients with the increasing availability of targeted therapy. Potential targets for metastatic melanoma include genes involved in the MAPK pathway, such as BRAF and RAS. More recently, KIT has emerged as a potential target in melanoma patients. These targeted treatments all need careful evaluation, but might be a promising adjunct for treatment of metastatic melanoma patients, in which other therapies have not brought important survival advantages yet.