Melanoma Death Research Articles

Melanoma-specific survival before and after inclusion in a familialmelanoma dermatologic surveillance program in CDKN2A mutation carriers and non-carriers.

Inherited mutations in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Further, previous studies have reported inferior melanoma-specific survival in CDKN2A mutation carriers. Here, the melanoma-specific survival was studied, depending on CDKN2A carrier status and if the melanomas had been diagnosed before or after families were included in a surveillance program. Melanoma-prone families participating in this study were identified through a nationwide preventive program starting in 1987. Information on melanoma tumours and deaths was obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan-Meier and Cox proportional hazards regression models were used to assess melanoma-specific survival in four defined cohorts, CDKN2A mutation (MUT) carriers with first invasive melanoma before or after inclusion [MUT-pre (n=53) and MUT-post (n=43)] and likewise in CDKN2A wild type (WT) cases [WT-pre (n=255) and WT-post (n=122)]. The MUT-pre and MUT-post cases were diagnosed with their first invasive melanoma at a significantly younger ages (38 and 42 years, respectively) than the WT-pre and WT-post cases (48 and 57 years, respectively). The melanomas in the MUT-pre had significantly higher T stage compared with MUT-post (p=0.006), whereas no such difference was seen comparing WT-pre with WT-post (p=0.849). MUT-pre had compared with WT-pre, significantly worse melanoma-specific survival, unadjusted (HR 2.33, 95% CI 1.33-4.08, p=0.003) adjusted (HR 2.70, 95% CI 1.46-5.00, p=0.001). However, the MUT-post cases had compared with the WT-post cases, no significant survival differences. This study is the first to address the impact on survival from introducing a dermatologic surveillance program to familial melanoma cases with or without CDKN2A mutations. The CDKN2A-mut carriers appeared to have a clear benefit with less advanced melanomas diagnosed and better melanoma-specific survival after inclusion. Among the CDKN2A-wt cases, the effect of the inclusion on the studied outcomes was less evident.

Comprehensive characterisation of immunogenic cell death in melanoma revealing the association with prognosis and tumor immune microenvironment.

Increasing evidence has highlighted the critical functions of immunogenic cell death (ICD) within many tumors. However, the therapeutic possibilities and mechanism of utilizing ICD in melanoma are still not well investigated. Melanoma samples involved in our study were acquired from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. First, pan-cancer analysis of ICD systematically revealed its expression characteristics, prognostic values, mutation information, methylation level, pathway regulation relationship in multiple human cancers. The non-negative matrix factorization clustering was utilized to separate the TCGA-melanoma samples into two subtypes (i.e. C1 and C2) with different prognosis and immune microenvironment based on the expression traits of ICD. Then, LASSO-Cox regression analysis was utilized to determine an ICD-dependent risk signature (ICDRS) based on the differentially expressed genes (DEGs) between the two subtypes. Principal component analysis and t-distributed stochastic neighbor embedding analysis of ICDRS showed that high- and low-risk subpopulations could be clearly distinguished. Survival analysis and ROC curves in the training, internal validation, and external validation cohorts highlighted the accurate prognosis evaluation of ICDRS. The obvious discrepancies of immune microenvironment between the different risk populations might be responsible for the different prognoses of patients with melanoma. These findings revealed the close association of ICD with prognosis and tumor immune microenvironment. More importantly, ICDRS-based immunotherapy response and targeted drug prediction might be beneficial to different risk subpopulations of patients with melanoma. The innotative ICDRS could function as a marker to determine the prognosis and tumor immune microenvironment in melanoma. This will aid in patient classification for individualized melanoma treatment.

Pathways of Targeted Therapy for Colorectal Cancer

One of the most common and deadly cancers in the world, colorectal cancer (CRC) caused around 881,000 melanoma deaths in 2018. The third most frequent cause overall cancer-related death worldwide is colorectal cancer (CRC). A difficult issue related to chemotherapy is the subsequent adverse effects brought on by the toxicity of conventional medications. Location-specific/targeted distribution of chemotherapeutic medicines precisely to the afflicted site of something like the colon in a foreseeable and reliable way is obviously of concern. For many years, cancer sufferers' initial choices have been surgery and chemotherapy. The prognosis for CRC, particularly for those with metastatic tumours, has never been satisfactory. A recent optional strategy called targeted therapy has been effective in extending patients with CRC's overall survival. Following achievements with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new drugs that inhibit several important pathways and immune checkpoints are being developed at an unheard-of rate. The growing number of high-quality clinical trials is being used as a basis for updating guidelines worldwide regarding the recommended targeted medications. An overview of current CRC-targeted drugs and their underlying processes is given in this review, along with a discussion of their drawbacks and potential directions.
 Keywords: Colorectal cancer, Chemotherapeutic medicines, Bevacizumab, Cetuximab,

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting

BackgroundThe role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood.ObjectiveTo perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS.MethodsWe conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10–8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts.ResultsTwo loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61–2.71, P = 2.08 × 10–8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77–3.21, P = 1.07 × 10–8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83–0.94, P = 6.93 × 10–5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78–0.90).ConclusionWe found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.

The molecular mechanisms of vulpinic acid induced programmed cell death in melanoma.

Malignant melanoma is an aggressive skin tumor with a rapidly increasing incidence and there is not yet a successful treatment strategy. Vulpinic acid (VA) is derived from secondary metabolites from lichen species. In the current study, we, for the first time, investigated the anti-cancer effects of VA and the underlying mechanism VA induced programmed cell death in melanoma. The anti-cancer effects of VA on melanoma cells were evaluated by the xCELLigence system, flow cytometry, caspase-3 activity and RT-PCR analysis. Our results showed that VA had a strong anti-proliferative effect on A-375 melanoma cells without damaging human epidermal melanocyte cells. Additionally, VA promoted apoptotic cell death through G2/M arrest and the activation of both intrinsic and extrinsic apoptosis pathways according to the analysis of 88 genes associated with apoptosis by qRT-PCR. Our findings suggest that VA could become an alternative topical and transdermal treatment strategy in the treatment of maligned melanoma cancer. However, further investigations are needed to assess the underlying molecular mechanism of VA mediated apoptotic cell death in the treatment of melanoma.

ROS-triggered nanoinducer based on dermatan sulfate enhances immunogenic cell death in melanoma.

Due to its complexity, diversity and heterogeneity, melanoma is a kind of malignant tumor. It has been proved that the enhancement of anti-tumor immune response such as immunogenic cell death (ICD) is an important therapeutic strategy. In previous studies, we confirmed that dermatan sulfate (DS) from skin tissue could specifically homing to melanoma B16F10 cells. In this study, we propose a nanoinducer (DOX/ADS NP) based on a functional DS for melanoma. This nanosystem is composed of DS as framework, aromatic thioketal derivative (ATK) as functional grafting unit and doxorubicin (DOX) designed as an ICD inducer. Through the intermolecular interaction between DOX and ATK, DOX/ADS NP with specific-homing, high-loading and ROS-triggering release was obtained via self-assemble. Compared with free DOX and non-functionalized nanomedicine, DOX/ADS NP could release DOX into B16F10 cells better, and strongly induce the translocation of calreticulin (CRT) to the cell membrane. CRT is a marker of ICD, also as a "eat me" signal to stimulate the maturation and antigen presentation of dendritic cells. Therefore, a series of subsequent immune responses were activated: maturation of dendritic cells, T cells proliferation, increased tumor-infiltrating CTLs and the ratio of CTLs to Tregs, and up-regulated cytotoxic cytokine expression. In conclusion, DOX/ADS NP promoted ICD-associated immune response through more specific targeting effect and sensitive responsive DOX release, achieving better inhibitory effect on melanoma than free DOX and other nanoformulation. This biomimetic ICD nanoinducer based on DS is expected to provide new strategies and references for the treatment of melanoma.

The impossibility of mortality evaluation of skin cancer screening in Germany based on health insurance data: a case–control study

BackgroundThe aim of this paper was to perform a mortality evaluation of skin cancer screening (SCS) in Germany using General Local Health Insurance Fund (AOK) data. MethodsAOK-insured men and women aged 35–99 years who died of cutaneous malignant melanoma in 2015–2016 were identified. Controls were AOK-insured people who survived to the end of each case's year of death. For each case, 10 controls were matched. The SCS history of each individual was reconstructed using the billing codes 01745 and 01746. ResultsIn total, 1037 melanoma deaths and 10,370 controls were included. Cumulative SCS prevalence increased among controls over calendar years, as expected (males and females, 2009: 13.5% and 12.5%; 2015: 52.1% and 55.1%). In contrast, among cases, cumulative SCS prevalence was already high in 2009 and did not show a monotonic increase over the years of diagnosis. Of the 1037 melanoma deaths, 224 (21.6%) had at least one SCS settled in the 12 months after diagnosis. DiscussionA mortality evaluation with health insurance data alone is not possible because SCS billing codes are not only used for real SCS but also for occasion-related diagnostic work-up of abnormal skin findings. A mortality evaluation with health insurance data requires an individual linking with data of the screening physician and the cancer registries.

Did new treatments contribute to a decrease in melanoma deaths?

Melanoma is one of the most common cancers diagnosed in New Zealand, and New Zealand has one of the highest rates of melanoma incidence and mortality in the world. Monitoring by Environmental Health Intelligence NZ (EHINZ) has found a recent sharp decline in melanoma mortality rates in New Zealand. Since 2014 and 2015 (with 376 and 378 melanoma deaths, respectively), melanoma deaths have declined to 362 deaths in 2016, 308 deaths in 2017, and 296 deaths in 2018. We believe that two new PD-1 inhibitor drug treatments introduced in New Zealand in 2016-nivolumab (Opdivo, BMS) and pembrolizumab (Keytruda, MSD)-may have contributed to this decrease in melanoma mortality. Other factors are unlikely to have had such a major effect, with the drop unlikely due to random variation, and no major changes in melanoma registrations or melanoma thickness at diagnosis over the past decade. While our monitoring of the time trend is descriptive only, and cannot attribute causality, it does suggest a recent decrease in melanoma mortality rates at the population level. These national-level statistics reflect both what might be expected in the New Zealand situation with the introduction of PD-1 inhibitor treatments, based on clinical trials, and what oncologists are seeing at an individual level. Further studies could investigate this observational finding, to confirm whether PD-1 inhibitor drug treatments are having an impact on melanoma mortality and survival rates in New Zealand.

Coupled fibromodulin and SOX2 signaling as a critical regulator of metastatic outgrowth in melanoma

We aimed to study mechanisms controlling metastatic outgrowth of melanoma into clinically relevant lesions, a critical process responsible for the majority of melanoma deaths. To this end, we developed novel in vivo models and identified molecular events that can be ascribed to their distinct phenotypes, indolent or highly metastatic. Induction of a proliferative state at distant sites was associated with high levels of the stem-like/progenitor marker, SOX2, and required the upregulation of FMOD, an extracellular matrix component, which modulates tumor–stroma interactions. Functional studies revealed a possible link between FMOD and SOX2; dual FMOD and SOX2 silencing nearly abolished brain metastasis and had a similar effect on distant metastasis to other sites. Our in vitro data suggests that FMOD and SOX2 cooperation plays an important role in tumor vasculogenic mimicry. Furthermore, we found that FMOD and SOX2 functional roles might converge at the activation of transcriptional co-factors YAP and TAZ, possibly via crosstalk with the tumor suppressor Hippo pathway. Finally, high expression of both genes in patient specimens predicted early development of brain metastasis. Thus, our study identifies FMOD and SOX2 cooperation as a novel regulatory mechanism that might be linked functionally to melanoma metastatic competence.

The Genetics of Early-Stage Melanoma in a Veteran Population.

To improve understanding of the genetic signature of early-stage melanomas in Veterans, hotspot mutation profiling using next-generation sequencing (NGS) was performed on melanoma tissue samples from patients at the Iowa City Veterans Affairs Medical Center (VAMC). Genetic analysis identified BRAF (36.3%), TP53 (25.9%), NRAS (19.3%), CDKN2A (11.1%), KIT (8.1%), and BAP1 (7.4%) mutations with the highest prevalence. Although common variants in BRAF were detected at lower rates than what is reported for the general population, 55.6% of cases showed activating mutations in the RAS/RAF pathways. Variants in TP53 and KIT were detected at higher rates than in the general population. Veterans with prior history of melanoma were at significantly higher odds of having TP53 mutation (OR = 2.67, p = 0.04). This suggests that TP53 may be a marker for recurrent melanoma and possibly alternative exposures in the military population. This study provides new information regarding the genetics of melanoma in a Veteran population and early-stage melanomas, highlighting risk factors unique to this population and contributing to the conversation about preventing melanoma deaths in US Military personnel.

Prevalence and Clinicopathologic Features of Canine Metastatic Melanoma Involving the Central Nervous System: A Retrospective Analysis and Comparative Review.

BackgroundCentral nervous system (CNS) involvement is the leading cause of death in malignant melanoma. Rodent models, while vital to mechanistic investigation, have had limited success identifying effective therapies for melanoma brain metastases. The companion dog with de novo melanoma is a promising complementary model for developmental therapeutic investigation, as these tumors occur in an immunologically outbred host that has shared environmental exposures with humans. However, relatively little is known regarding the prevalence and clinicopathological features of canine melanoma metastasis to the CNS. To further validate the dog as an appropriate model for human metastatic melanoma, the aims of this study were to determine the rate of CNS metastasis and associated clinicopathologic features in canine malignant melanoma.MethodsMedical records of dogs diagnosed with malignant melanoma from 1985-2019 at the University of California Davis Veterinary Medical Teaching Hospital were assessed retrospectively. Clinicopathologic features were compared between dogs with CNS metastasis (CNS+) and dogs without CNS metastasis (CNS-). Site of CNS involvement and associated neurological signs were analyzed via Wilcoxon-Mann-Whitney rank sum and Fisher’s exact tests. Survival data were analyzed via Kaplan-Meier estimates.ResultsCNS metastasis was identified in 38% of dogs in this study (20/53). The oral cavity was the most common site of primary melanoma in both groups [CNS+: n=12 (60%) vs. CNS-: n=22 (67%); p>0.99]. The total burden of metastatic disease was higher in the CNS+ group (CNS+: 4, 95% CI 3-5 vs. CNS-: 3, 95% CI 1-3; p<0.001). The cerebrum was the most common site of CNS metastasis (n=15, 75%) and seizures were the most observed neurological sign (n=9, 64%). There was no difference in overall survival between CNS+ and CNS- groups. However, the median survival time following onset of neurological signs was 9.5 days (95% CI 1-43), with 5 dogs euthanized within 24 hours of the onset of neurological signs.ConclusionsCanine and human MM patients share similar rates of CNS metastasis and clinical presentation. This study will guide clinical management of canines with malignant melanoma and inform future studies using dogs with spontaneously occurring melanoma as a preclinical model for human melanoma brain metastases.

Cost-effectiveness of a policy-based intervention to reduce melanoma and other skin cancers associated with indoor tanning.

BackgroundThe use of indoor tanning devices causes melanoma and other skin cancers with resulting morbidity, mortality and increased healthcare costs. Policymakers require robust economic evidence to inform decisions about a possible ban of such devices to mitigate these burdens.ObjectivesTo assess the health costs and consequences of introducing a policy‐based intervention across England to ban commercial indoor tanning with an accompanying public information campaign.MethodsA cost‐effectiveness analysis, adopting a healthcare system perspective, was conducted using a decision model to track a national cohort of 18‐year‐olds over a lifetime time horizon. A nationwide ban on commercial indoor tanning combined with a public information campaign (the policy‐based intervention) was compared with the status quo of availability of commercial indoor tanning. The expected costs (currency, GBP; price year, 2019) and quality‐adjusted life‐years (QALYs) were calculated. Net monetary benefit (NMB) (net benefit measured in cost compared with an accepted threshold) and net health benefit (NHB) (net gain in QALYs compared with an accepted threshold) of implementation were calculated. A probabilistic sensitivity analysis was used to calculate the probability that the intervention was cost‐effective.ResultsCompared with the current situation, a ban on commercial indoor tanning combined with a public information campaign would result in 1206 avoided cases of melanoma, 207 fewer melanoma deaths and 3987 averted cases of keratinocyte cancers over the lifetime of all 18‐year‐olds (n = 618 873) living in England in 2019. An additional 497 QALYs would be realized along with healthcare cost‐savings of £697 858. This intervention would result in an NMB of £10.6m and an NHB of 530 QALYS. Multiple sensitivity analyses confirmed the robustness of the findings. At a cost‐effectiveness threshold of £20 000, there is a 99% likelihood of this policy‐based intervention being cost‐effective.ConclusionsThe implementation of a ban on commercial indoor tanning across England with an accompanying public information campaign would be an effective use of healthcare resources.

Incidence of Second Primary Melanoma in Cutaneous Melanoma Survivors.

Cutaneous melanoma survivors are at increased risk of a second primary melanoma. Valid estimates facilitate counseling on recommended surveillance after a melanoma diagnosis. However, most estimates of 5- and 10-year incidences of second melanomas are from older cohorts and/or single institutions. This study aimed to determine the 5- and 10-year incidences of second primary cutaneous melanomas in survivors of cutaneous melanoma. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify cases of non-metastatic, first cutaneous melanoma diagnosed between 1998 and 2012 (follow-up through December 2017). Eligible survivors were 18 years old or older who underwent surgery as a treatment component. Kaplan-Meier survival analysis was used to estimate 5- and 10-year incidences of a second melanoma, excluding new diagnoses within 3 months after the initial diagnosis. Patients were censored at second melanoma diagnosis, death, or 10-years, whichever was first. Multivariable Cox regression analysis was used to identify factors associated with a second cutaneous melanoma diagnosis. The study cohort comprised 152,811 patients. The incidence of second primary melanoma was 3.9% at 5 years (95% confidence interval [CI], 3.8-4.0%) and 6.7% at 10 years (95% CI, 6.6-6.9%). Older age, male sex, and regional disease were associated with increased risk of a second primary melanoma diagnosis. Melanoma survivors are at risk of a second primary melanoma, making routine skin surveillance part of recommended follow-up evaluation. A higher incidence of second melanoma with older age and regional disease at presentation is possibly explained by increased health care use providing more diagnostic opportunities, whereas male sex may represent an inherent risk factor.

Revisiting the melanomagenic pathways and current therapeutic approaches.

Melanoma is one of the most aggressive forms of skin cancer with a steady increase in global incidence and mortality rate over the past five decades. Paradoxically, both reduced and excessive sun exposure has been linked to increased risk of melanoma incidence and death. Although the histological classification of melanoma is useful in diagnosis, its molecular subtypes are often determined by somatic mutations, which could be UV-dependent or -independent. Multiple genes involved in cancer development are often mutated dysregulating molecular pathways with concomitant phenotypic heterogeneity. Hence, treating melanoma has been a challenge, with patients experiencing poor clinical outcomes to current therapeutic options. This presents an unmet need to understand the interaction of molecular networks underpinning melanogenesis. This review describes the crosstalk of signaling cascades in melanoma development and the putative druggable targets, with the view of elucidating newer and better therapeutic strategies for the disease.

Suppressing Effect of Na+/Ca2+ Exchanger (NCX) Inhibitors on the Growth of Melanoma Cells.

The role of calcium ion (Ca2+) signaling in tumorigenicity has received increasing attention in melanoma research. Previous Ca2+ signaling studies focused on Ca2+ entry routes, but rarely explored the role of Ca2+ extrusion. Functioning of the Na+/Ca2+ exchanger (NCX) on the plasma membrane is the major way of Ca2+ extrusion, but very few associations between NCX and melanoma have been reported. Here, we explored whether pharmacological modulation of the NCX could suppress melanoma and promise new therapeutic strategies. Methods included cell viability assay, Ca2+ imaging, immunoblotting, and cell death analysis. The NCX inhibitors SN-6 and YM-244769 were used to selectively block reverse operation of the NCX. Bepridil, KB-R7943, and CB-DMB blocked either reverse or forward NCX operation. We found that blocking the reverse NCX with SN-6 or YM-244769 (5–100 μM) did not affect melanoma cells or increase cytosolic Ca2+. Bepridil, KB-R7943, and CB-DMB all significantly suppressed melanoma cells with IC50 values of 3–20 μM. Bepridil and KB-R7943 elevated intracellular Ca2+ level of melanoma. Bepridil-induced melanoma cell death came from cell cycle arrest and enhanced apoptosis, which were all attenuated by the Ca2+ chelator BAPTA-AM. As compared with melanoma, normal melanocytes had lower NCX1 expression and were less sensitive to the cytotoxicity of bepridil. In conclusion, blockade of the forward but not the reverse NCX leads to Ca2+-related cell death in melanoma and the NCX is a potential drug target for cancer therapy.

BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma.

Melanoma with a BRAF mutation is more common to develop into a fatal disease. BRAF mutation inhibitor-induced autophagy affects the drug efficacy in many cancer types. The role of autophagy during BRAF inhibition in uveal melanoma (UM) remains unclear. In this study, we examined the autophagic flux and compared the number of autophagic vacuoles during the BRAF inhibition in UM. The PKR-like endoplasmic reticulum (ER) kinase (PERK) arm was studied to test whether the ER stress was involved. The effects of downregulation of ER stress by targeting the PERK arm (pharmacologically and genetically) were also assessed. We found a dose-dependent increase of autophagic flux in OCM1A cells during the BRAF inhibition. This phenomenon was further verified by an enhanced number of GFP-LC3 puncta and was finally confirmed by raised autophagic index examined by transmission electron microscopy. Pathway analysis revealed that the vemurafenib (the BRAF inhibitor)-induced autophagy was independent of the MAPK signaling pathway. Instead, it was possibly regulated via the enhanced ER stress response. We further found that the inhibition of ER stress response rescued cell death. Therefore, our results suggest BRAF inhibition promotes ER stress response-induced autophagy in UM. Targeting ER stress response can partially revert autophagy and rescue cell death, which may impair the anti-tumor effect of BRAF inhibitor in UM.

Ulcerated melanoma: Systems biology evidence of inflammatory imbalance towards pro-tumourigenicity.

Microscopic ulceration is an independent predictor of melanoma death. Here, we used systems biology to query the role of host and tumour-specific processes in defining the phenotype. Albumin level as a measure of systemic inflammation was predictive of fewer tumour-infiltrating lymphocytes and poorer survival in the Leeds Melanoma Cohort. Ulcerated melanomas were thicker and more mitotically active (with corresponding transcriptomic upregulated cell cycle pathways). Sequencing identified tumoural p53 and APC mutations, and TUBB2B amplification as associated with the phenotype. Ulcerated tumours had perturbed expression of cytokine genes, consistent with protumourigenic inflammation and histological and transcriptomic evidence for reduced adaptive immune cell infiltration. Pathway/network analysis of multiomic data using neural networks highlighted a role for the β-catenin pathway in the ulceration, linking genomic changes in the tumour to immunosuppression and cell proliferation. In summary, the data suggest that ulceration is in part associated with genomic changes but that host factors also predict melanoma death with evidence of reduced immune responses to the tumour.

Trends and projections in cutaneous melanoma death in the Netherlands from 1950 to 2045.

Child sun protection has recently been linked to the future disappearance of fatal melanoma in adults in successive generations. In the Netherlands, however, mortality rates from melanoma have increased gradually from the 1950s, with some indication of stabilisation since 2010, which may be compatible with a birth cohort effect by sun-protective measures and screening. To study the trajectories ahead a trend analysis was applied. Numbers of people with cutaneous melanoma as underlying cause of death from 1950 to 2018 and population data were derived from Statistics Netherlands. A graphical approach was used to explore trends in mortality by age, calendar period, and cohorts born in the successive periods of 1889 to 1979. Age–period–cohort modelling outcomes and population forecasts provided projections of mortality until 2045. Based on 24,151 cases of melanoma death (13,256 men, 10,895 women), age-standardised mortality rates were similar from 1950 to 1989 for both genders, and increased thereafter more in men. The age-curve patterns changed gradually towards higher death rates at older age, implying the existence of a birth cohort effect. The age–period–cohort models showed an increase in melanoma mortality rates in successive generations. For women, the birth cohort effect plateaued for generations born since the mid-1980s. The projected total mortality number was predicted to rise in the next 3 decades.It is concluded that a small future decline of mortality in younger generations can be expected in the Netherlands, but mortality is still rising for the total population.

Spatiotemporal trends of the global burden of melanoma in 204 countries and territories from 1990 to 2019: Results from the 2019 global burden of disease study.

This study aimed to estimate the latest magnitudes and temporal trends of melanoma burden at the national, regional, and global levels. The data on melanoma incidence, deaths, and disability-adjusted life-years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease 2019 Study. Estimated annual percentage change (EAPC) was calculated to depict the temporal trends and Spearman rank correlation was used to analyze the influential factors of EAPC. From 1990 to 2019, the incident cases of melanoma increased by 170% to 289,950, death increased by 90% to 62,840, and DALYs increased by 67% to 1,707,800 globally. The age-standardized incidence rate (ASIR) of melanoma increased globally by an average of 1.13 [95% confidence interval (CI): 0.93–1.32], while the age-standardized rates of death and DALYs both declined with the EAPC of −0.27 (95% CI: −0.36 to −0.19) and −0.49 (95% CI: −0.57 to −0.41). In 2019, the highest burden of melanoma was observed in Australasia, followed by high-income North America and Europe regions, which all presented an incremental growth in ASIR. The positive association between the EAPC in ASIR and socio-demographic index (SDI) in 2019 (ρ = 0.600, P < 0.001) suggested that countries with higher SDI have experienced a more rapid increase in ASIR of melanoma. In conclusion, the burden of melanoma is increasing globally but differed greatly across the world. Notably, the high burden areas are facing a continuing increase in incidence, which implies more targeted strategies should be taken for reducing the increasing melanoma burden.

PURPL represses autophagic cell death to promote cutaneous melanoma by modulating ULK1 phosphorylation

Uncontrolled overactivation of autophagy may lead to autophagic cell death, suppression of which is a pro-survival strategy for tumors. However, mechanisms involving key regulators in modulating autophagic cell death remain poorly defined. Here, we report a novel long noncoding RNA, p53 upregulated regulator of p53 levels (PURPL), functions as an oncogene to promote cell proliferation, colony formation, migration, invasiveness, and inhibits cell death in melanoma cells. Mechanistic studies showed that PURPL promoted mTOR-mediated ULK1 phosphorylation at Ser757 by physical interacting with mTOR and ULK1 to constrain autophagic response to avoid cell death. Loss of PURPL led to AMPK-mediated phosphorylation of ULK1 at Ser555 and Ser317 to over-activate autophagy and induce autophagic cell death. Our results identify PURPL as a key regulator to modulate the activity of autophagy initiation factor ULK1 to repress autophagic cell death in melanoma and may represent a potential intervention target for melanoma therapy.