G protein-coupled estrogen receptor 1 and collagen XVII endodomain expression in human cutaneous melanomas: can they serve as prognostic factors?

Melanoma incidence is increasing globally. Although novel therapies have improved the survival of primary melanoma patients over the past decade, the overall survival rate for metastatic melanoma remains low. In addition to traditional prognostic factors such as Breslow thickness, ulceration, and mitotic rate, novel genetic and molecular markers have been investigated. In our study, we analyzed the expression of G-protein coupled estrogen receptor 1 (GPER1) and the endodomain of collagen XVII (COL17) in relation to clinicopathological factors in primary cutaneous melanomas with known lymph node status in both sexes, using immunohistochemistry. We found, that GPER1 expression correlated with favorable clinicopathological factors, including lower Breslow thickness, lower mitotic rate and absence of ulceration. In contrast, COL17 expression was associated with poor prognostic features, such as higher tumor thickness, higher mitotic rate, presence of ulceration and presence of regression. Melanomas positive for both GPER1 and COL17 had significantly lower mean Breslow thickness and mitotic rate compared to cases positive for COL17 only. Our data indicate that GPER1 and COL17 proteins may be of potential prognostic value in primary cutaneous melanomas.

GP100 expression is variable in intensity in melanoma.

Drugs or cellular products that bind to gp100 are being investigated for treatment of cutaneous melanoma. The relative specificity of gp100 expression in melanocytes makes it an attractive target to harness for therapeutic intent. For example, Tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, has generated significant enthusiasm in recent years due to its success in improving outcomes for uveal melanoma and is being studied in cutaneous melanoma. However, the extent and intensity of gp100 expression in advanced cutaneous melanoma has not been well studied. Here, we interrogated a large cohort of primary and metastatic melanomas for gp100 expression by immunohistochemistry. Expression in metastatic samples was globally higher and almost uniformly positive, however the degree of intensity was variable. Using a quantitative immunofluorescence method, we confirmed the variability in expression. As gp100-binding drugs are assessed in clinical trials, the association between activity of the drugs and the level of gp100 expression should be studied in order to potentially improve patient selection.

Exploring the Germline Genetics of In Situ and Invasive Cutaneous Melanoma: A Genome-Wide Association Study Meta-Analysis.

Importance: It is unknown whether germline genetic factors influence in situ melanoma risk differently than invasive melanoma risk. Objective: To determine whether differences in risk of in situ melanoma and invasive melanoma are heritable. Design, Setting, and Participants: Three genome-wide association study meta-analyses were conducted of in situ melanoma vs controls, invasive melanoma vs controls, and in situ vs invasive melanoma (case-case) using 4 population-based genetic cohorts: the UK Biobank, the FinnGen cohort, the QSkin Sun and Health Study, and the Queensland Study of Melanoma: Environmental and Genetic Associations (Q-MEGA). Melanoma status was determined using International Statistical Classification of Diseases and Related Health Problems codes from cancer registry data. Data were collected from 1987 to 2022, and data were analyzed from September 2022 to June 2023. Exposure: In situ and invasive cutaneous melanoma. Main Outcomes and Measures: To test whether in situ and invasive melanoma have independent heritable components, genetic effect estimates were calculated for single-nucleotide variants (SNV; formerly single-nucleotide polymorphisms) throughout the genome for each melanoma. Then, SNV-based heritability was estimated, the genetic correlation between melanoma subtypes was assessed, and polygenic risk scores (PRS) were generated for in situ vs invasive status in Q-MEGA participants. Results: A total of 6 genome-wide significant loci associated with in situ melanoma and 18 loci with invasive melanoma were identified. A strong genetic correlation (genetic r = 0.96; 95% CI, 0.76-1.15) was observed between the 2 classifications. Notably, loci near IRF4, KLF4, and HULC had significantly larger effects for in situ melanoma compared with invasive melanoma, while MC1R had a significantly larger effect on invasive melanoma compared with in situ melanoma. Heritability estimates were consistent for both, with in situ melanoma heritability of 6.7% (95% CI, 4.1-9.3) and invasive melanoma heritability of 4.9% (95% CI, 2.8-7.2). Finally, a PRS, derived from comparing invasive melanoma with in situ melanoma genetic risk, was on average significantly higher in participants with invasive melanoma (odds ratio per 1-SD increase in PRS, 1.43; 95% CI, 1.16-1.77). Conclusions and Relevance: There is much shared genetic architecture between in situ melanoma and invasive melanoma. Despite indistinguishable heritability estimates between the melanoma classifications, PRS suggest germline genetics may influence whether a person gets in situ melanoma or invasive melanoma. PRS could potentially help stratify populations based on invasive melanoma risk, informing future screening programs without exacerbating the current burden of melanoma overdiagnosis.

Neutrophil extracellular trap related risk score exhibits crucial prognostic value in skin cutaneous melanoma, associating with distinct immune characteristics.

BACKGROUND: Neutrophil extracellular traps (NETs) are related to the prognosis of cancer patients. Nevertheless, the potential prognostic values of NETs in skin cutaneous melanoma (SKCM) remains largely unknown. MATERIALS AND METHODS: The NET-related gene signature was constructed by LASSO Cox regression analysis using the TCGA-SKCM cohort. The overall survival (OS) and immune status in SKCM patients between the high- and low-NET score (high-score, low-score) groups were explored. The scRNA-seq dataset GSE115978 was used to understand the role of NET score in SKCM at single cell resolution. RESULTS: A five NET genes-based signature (TLR2, CLEC6A, PDE4B, SLC22A4 and CYP4F3) was constructed as the NET-related prognostic model for SKCM. The OS of SKCM patients with low-score was better than that in patients with high-score. Additionally, NET score was negatively associated with infiltration of some immune cells (e.g. type I Macrophages, CD8-T cells, CD4-T cells). Moreover, patients with high-score had low stromal, immune and ESTIMATE scores. Furthermore, drug sensitivity analysis results showed that Lapatinib, Trametinib and Erlotinib may have better therapeutic advantages in patients with high-score. CONCLUSION: We established a NET-related five gene signature in SKCM and found that the NET-related signature may exhibit a good predictive ability for SKCM prognosis. The NET score may not only predict the survival outcome and drug sensitivity in SKCM, but also reflect the immune conditions of SKCM patients.

Identification of potential therapeutic targets for skin cutaneous melanoma on the basic of transcriptomics.

BACKGROUND: Advanced skin cutaneous melanoma (SKCM) is responsible for the majority of skin cancer-related deaths. Apart from the rare BRAF V600F mutation, which can be targeted with specific drugs, there are currently no other novel effective therapeutic targets. METHODS: We used SMR analysis with cis-expressed quantitative trait locus (cis-eQTL) as the exposure variable and SKCM as the outcome variable to identify potential therapeutic targets for SKCM. Colocalization assays and HEIDI tests are used to test whether SKCM risk and gene expression are driven by common SNPs. Replication analysis further validated the findings, and we also constructed protein-protein interaction networks to explore the relationship between the identified genes and known SKCM targets. Drug prediction and molecular docking further validated the medicinal value of drug targets. Transcriptome differential analysis further validated that there were differences between normal tissues and SKCM for the selected targets. RESULTS: We identified 13 genes significantly associated with the risk of SKCM, including five protective genes and eight harmful genes. The HEIDI test and co-localization analysis further indicates a causal association between genes (SOX4, MAFF) and SKCM, categorized as Class 1 evidence targets. The remaining 11 genes, except for HELZ2 show a moderately causal association with SKCM, categorized as Class 2 evidence targets. Target druggability predictions from DGIdb suggest that SOX4, MAFF, ACSF3, CDK10, SPG7, and TCF25 are likely to be future drug targets. CONCLUSION: The study provides genetic evidence for targeting available drug genes for the treatment of SKCM.

Prognostic and immune infiltration implications of SIGLEC9 in SKCM.

The occurrence and progression of skin cutaneous melanoma (SKCM) is strongly associated with immune cells infiltrating the tumor microenvironment (TME). This study examined the expression, prognosis, and immune relevance of SIGLEC9 in SKCM using multiple online databases. Analysis of the GEPIA2 and Ualcan databases revealed that SIGLEC9 is highly expressed in SKCM, and patients with high SIGLEC9 expression had improved overall survival (OS). Furthermore, the mutation rate of SIGLEC9 in SKCM patients was found to be 5.41%, the highest observed. The expression of SIGLEC9 was positively correlated with macrophages, neutrophils and B cells, CD8 + T cells, CD4 + T cells, and dendritic cells, according to TIMER. Based on TCGA-SKCM data, we verified that high SIGLEC9 expression is closely associated with a good prognosis for SKCM patients, including overall survival, progression-free interval, and disease-specific survival. This positive prognosis could be due to the infiltration of immune cells into the TME. Additionally, our analysis of single-cell transcriptome data revealed that SIGLEC9 not only played a role in the normal skin immune microenvironment, but is also highly expressed in immune cell subpopulations of SKCM patients, regulating the immune response to tumors. Our findings suggest that the close association between SIGLEC9 and SKCM prognosis is primarily mediated by its effect on the tumor immune microenvironment.

Cutaneous Melanoma: An Overview of Physiological and Therapeutic Aspects and Biotechnological Use of Serine Protease Inhibitors.

BACKGROUND: Metastatic melanoma stands out as the most lethal form of skin cancer because of its high propensity to spread and its remarkable resistance to treatment methods. METHODS: In this review article, we address the incidence of melanoma worldwide and its staging phases. We thoroughly investigate the different melanomas and their associated risk factors. In addition, we underscore the principal therapeutic goals and pharmacological methods that are currently used in the treatment of melanoma. RESULTS: The implementation of targeted therapies has contributed to improving the approach to patients. However, because of the emergence of resistance early in treatment, overall survival and progression-free periods continue to be limited. CONCLUSIONS: We provide new insights into plant serine protease inhibitor therapeutics, supporting high-throughput drug screening soon, and seeking a complementary approach to explain crucial mechanisms associated with melanoma.

Innate Immune Cells in Melanoma: Implications for Immunotherapy.

The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients' clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy.

Evolving patterns in systemic treatment utilization and survival among older patients with advanced cutaneous melanoma.

INTRODUCTION: In the last decade, melanoma treatment has improved significantly. However, data on population-level treatment utilization and survival trends among older patients is limited. This study aimed to analyze trends in systemic anticancer therapy (Rx), including the uptake of immune checkpoint inhibitors (ICIs), in conjunction with trends in cause-specific survival among older patients (66+) diagnosed with advanced melanoma (2008-2019). METHODS: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare Condensed Resource to assess any Rx utilization among patients first diagnosed with advanced melanoma in 2008-2010, 2011-2014, and 2015-2019, stratified by stage, and type of first-line Rx among patients receiving Rx. The SEER dataset was used to evaluate trends in cause-specific survival by year of diagnosis. RESULTS: Rx utilization (any type) almost doubled, from 28.6% (2008-2010) to 55.4% (2015-2019) for stage 3 melanoma, and from 35.5% to 68.0% for stage 4 melanoma. In 2008-2010, the standard first-line treatment was cytokines/cytotoxic chemotherapy/other. By 2015-2019, only 5.1% (stage 3) and <3.6% (stage 4) of patients receiving Rx received these agents, as ICIs emerged as the dominant treatment. Both 1-year and 5-year cause-specific survival significantly improved since 2010 for stage 4 and since 2013 for stage 3. CONCLUSIONS: This study shows a significant rise in Rx utilization and a rapid transition from cytokines/cytotoxic chemotherapy to ICIs, reflecting a rapid uptake of highly effective treatment in a previously challenging disease with limited options before 2011. The documented survival improvement aligns with the adoption of these novel treatments, underscoring their significant impact on real-world patient outcomes.

The Expression and Prognostic Value of Multiple Glucose Transporters in Cutaneous Melanoma.

BACKGROUND/AIM: Over-expression of glucose transporters (GLUTs), membrane proteins that facilitate glucose transport, has been implicated in cutaneous melanomas. Our prior studies have demonstrated increased expression of GLUT1 and GLUT3 in melanomas and their association with poorer prognosis. This study aimed to investigate the expression of GLUT isoforms 4 and 8 in melanocytic lesions, examine the co-expression status of multiple GLUTs, and evaluate their prognostic significance. MATERIALS AND METHODS: We analyzed 171 melanocytic lesions (97 primary melanomas, 19 metastatic melanomas, and 55 nevi) using a tissue microarray and immunohistochemistry using antibodies against GLUT4 and GLUT8. Membranous expression of GLUTs was scored using a semi-quantitative method. A combined GLUT total score was generated by summing scores from GLUT1, GLUT3, GLUT4, and GLUT8 (including data from previous studies). RESULTS: A significant up-regulation of GLUT4 and GLUT8 expression was found in melanomas compared to nevi (p<0.0001 for both). Concurrent over-expression of multiple GLUTs was more prevalent in melanomas compared to nevi (p<0.0001), and it was also more frequent in metastatic melanomas compared to primary melanomas (p=0.047). Importantly, high total GLUT expression scores were significantly correlated with negative prognostic factors, such as ulceration and mitoses (p=0.03 and p=0.008 respectively). Additionally, Kaplan-Meier survival curves revealed that patients with elevated GLUT total score in their melanomas had a lower disease-specific survival (p=0.006). Furthermore, analysis of multiple GLUTs improved diagnostic sensitivity. CONCLUSION: Similar to GLUT1 and GLUT3, melanoma exhibits up-regulation of GLUT 4 and GLUT8 compared to nevi. Evaluation of multiple GLUT isoforms improves diagnostic and prognostic values.

ACOT7 positively regulated by CREB1 promotes the progression of cutaneous melanoma.

Cutaneous melanoma (cM) is a prevalent invasive cancer resulting from the malignant transformation of melanocytes. At present, the primary treatment for melanoma is surgical resection, which is not appropriate for patients with metastasis. Therefore, it is necessary to identify effective therapeutic targets for the early diagnosis and treatment of metastatic melanoma. Acyl-CoA thioesterase 7 (ACOT7) has been reported to be involved in the progression of multiple cancer, while its role in melanoma has not been extensively researched. Through gain-of-function and loss-of-function experiments, ACOT7 was identified as a tumor promoter that facilitates the progression of melanoma cells. Cell proliferation was promoted by overexpressing ACOT7 in M14 cells, and was suppressed by silencing ACOT7 in MeWo cells. Knockdown of ACOT7 induced cell cycle arrest by increasing the expressions of cyclin dependent kinase inhibitor 1B (P27) and cyclin dependent kinase inhibitor 1 A (P21), while simultaneously reducing proliferating cell nuclear antigen (PCNA) expression. Upregulation of ACOT7 promoted the cell cycle of melanoma cells. Additionally, apoptosis was induced by the absence of ACOT7 through activating caspase-3 and poly (ADP-ribose) polymerase (PARP). The metastatic and invasive capacity of melanoma cells was significantly enhanced by the overexpression of ACOT7 and inhibited by the downregulation of ACOT7. Moreover, the cAMP responsive element binding protein 1 (CREB1) positively regulates ACOT7 expression by binding to its promoter region. A decrease of cell proliferation, migration and invasion, as well as an increase of cell apoptosis induced by silencing CREB1 were obviously reversed by ACOT7. In summary, ACOT7 transcriptionally activated by CREB1 elevates the progression of cM.

Adjuvant anti-PD1 immunotherapy of resected skin melanoma: an example of non-personalized medicine with no overall survival benefit.

Randomized clinical trials demonstrated a recurrence-free survival benefit with adjuvant anti-programmed death-1 (anti-PD1) inhibitors of resected stage IIB-IV melanoma. However, no improvement in overall survival has been observed thus far. Furthermore, there are no predictive markers for immunotherapy response in melanoma, therefore adjuvant treatment is offered to all comers based exclusively on the pathological and clinical stages. Additionally, one year of treatment duration and the risk of chronic immune-related adverse effects may negatively impact patients´ quality of life. In this review, we will try to answer whether the currently available data on adjuvant anti-PD1 therapy of stage IIB-IV resected melanoma is sufficient to make this strategy available to all patients. We will also discuss the economic impact of this therapy on healthcare system budgets. Recent studies suggest that the high cost of cancer drugs may affect access to these agents globally by raising questions of sustainability for patients and society.

Efficacy of TIL therapy in advanced cutaneous melanoma in the current immuno-oncology era: updated systematic review and meta-analysis.

BACKGROUND: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL-ACT) has consistently shown efficacy in advanced melanoma. New results in the field provide now the opportunity to assess overall survival (OS) after TIL-ACT and to examine the effect of prior anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] therapy on its efficacy. METHODS: A comprehensive search was conducted in PubMed up to 29 February 2024. Ιn this meta-analysis we focused on studies including high-dose interleukin 2, doubling the patient numbers from our previous meta-analysis conducted up to December 2018 and using OS as the primary endpoint. Objective response rate (ORR), complete response rate (CRR), and duration of response were secondary endpoints. Findings are synthesized using tables, Kaplan-Meier plots, and forest plots. Pooled estimates for ORR and CRR were derived from fixed or random effects models. RESULTS: A total of 13 high-dose interleukin 2 studies were included in this updated meta-analysis, with OS information available for 617 patients. No difference was found in median OS between studies with prior anti-PD-(L)1 treatment {n = 238; 17.5 months [95% confidence interval (CI) 13.8-20.5 months]} and without [n = 379; 16.3 months (95% CI 14.2-20.6 months)] (log-rank P = 0.53). ORR was estimated to be 34% (95% CI 16%-52%) and 44% (95% CI 37%-51%), for the studies with and without prior anti-PD-(L)1, respectively. The pooled estimate for CRR was 10% for both groups. No statistically significant difference was observed between the two groups, either for ORR (P = 0.15) or CRR (P = 0.45). CONCLUSIONS: Prior anti-PD-(L)1 treatment has no effect on the clinical response or survival benefit from TIL-ACT in advanced cutaneous melanoma. The benefit of TIL therapy in the second-line setting is also present after anti-PD-(L)1 treatment. Our data reinforce the evidence that TIL-ACT should be considered as a treatment of choice in second line for metastatic melanoma patients failing anti-PD-(L)1 therapy.

Comprehensive analysis of aberrantly methylated differentially expressed genes and validation of CDC6 in melanoma.

BACKGROUND: Skin Cutaneous Melanoma (SKCM) is a highly aggressive malignant tumor with a significant increase in mortality upon metastasis. The molecular mechanisms driving melanoma progression remain largely unclear. Recent studies have highlighted the importance of epigenetic alterations, especially DNA methylation, in melanoma development. This study aims to identify and analyze methylation-regulated differentially expressed genes (MeDEGs) in genome-wide profiles between primary and metastatic melanoma. METHODS: Gene expression profiling datasets GSE8401 and gene methylation profiling datasets GSE86355 were collected from the GEO database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were systematically identified. Integration of DEGs and DMGs yielded a set of MeDEGs, which subsequently underwent functional enrichment analysis. The protein-protein interaction (PPI) network was constructed using STRING and visualized using Cytoscape software. Survival analysis was used to select prognostic hub genes. In addition, 37 SKCM and 37 normal skin tissues from the First Affiliated Hospital of Soochow University (FAHSU) were collected for immunohistochemical (IHC) staining and evaluation. Furthermore, DNA methylation patterns of CDC6 were analyzed. To validate these findings, SKCM cell cultures were utilized to elucidate the expression and behavioral characteristics of CDC6. Additionally, gene set enrichment analysis (GSEA) and immune infiltration analysis were conducted for CDC6. RESULTS: In our study, we discovered 120 hypomethylated-upregulated genes and 212 hypermethylated-downregulated genes. The hypomethylated-upregulated genes were notably associated with biological processes such as spindle assembly checkpoint signaling, mitotic spindle assembly, and negative regulation of mitotic metaphase/anaphase transition. Our pathway analysis revealed significant enrichment in pathways related to dilated cardiomyopathy, amino sugar metabolism, progesterone-mediated oocyte maturation, and chemical carcinogenesis. Conversely, hypermethylated-downregulated genes were found to be enriched in processes like epidermis development, keratinocyte differentiation, and skin development. Additionally, pathway analysis highlighted associations with estrogen signaling, Staphylococcus aureus infection, axon guidance, and arachidonic acid metabolism. Following the establishment of PPI networks and survival analysis, we identified 11 prognostic hub genes: CCNA2, CDC6, CDCA3, CKS2, DTL, HJURP, KRT5, KRT14, KRT15, KRT16, and NEK2. Notably, among the 11 hub genes, our findings indicate that CDC6 plays a pivotal role in enhancing the proliferation, migration, and invasion capabilities of melanoma cells in vitro. CONCLUSIONS: Our comprehensive genomic analyses reveal that genes with aberrant methylation exhibit differential expression during the transition from primary to metastatic melanoma. The identified genes, especially CDC6, which plays a crucial role in enhancing melanoma cell proliferation, migration, and invasion, provide valuable insights into potential methylation-based biomarkers. These findings could contribute significantly to advancing precision medicine in SKCM.

Cancer incidence in a cohort of Danish firefighters: An extended long-term follow-up 1968-2021.

OBJECTIVES: To update and extend the examination of cancer incidence in a cohort of Danish firefighters, now adding 7 years of follow-up and 2766 additional firefighters. The primary focus was directed toward cancer sites that recently contributed to the hazard evaluation conducted by the International Agency for Research on Cancer (IARC). METHODS: The updated cohort consisted of 11,827 male Danish firefighters who were followed up for cancer from 1968 to 2021. Cohort cancer morbidity was compared with a working population reference group, and standardized incidence ratios (SIR) were used for estimation of relative risks, along with 95% confidence intervals (95% CI). RESULTS: Among full-time firefighters, SIR of skin melanoma was 1.30 (95% CI: 1.02-1.66), and SIR = 1.37 (95% CI: 1.02-1.85) for over 5 years of employment. Slightly positive associations were also observed for cancer of the urinary bladder (SIR = 1.16; 95% CI: 0.93-1.45), prostate (SIR = 1.11; 95% CI: 0.97-1.28), and testis (SIR = 1.11; 95% CI: 0.75-1.63). CONCLUSIONS: This updated study provides evidence indicating an elevated risk of skin melanoma in firefighters. Consistent with IARC's evaluation, we also identified positive associations for urinary bladder, prostate, and testis cancer. In contrast, our findings did not suggest an increased risk of colon cancer, non-Hodgkin lymphoma, and mesothelioma. The latter may be due to small numbers in our still relatively young cohort. Continuous follow-up for cancer in firefighters is warranted, including assessment of influence from surveillance bias.

The causal relationship between immune cells mediating FIT3L, CCL4, OSM, and skin-derived deteriorated tumors.

OBJECTIVE: Observational studies have identified a dual effect of circulating inflammatory proteins and immune cells on cancer progression. However, the specific mechanisms of action have not been clarified in the exacerbation of cutaneous-origin tumors. Therefore, this study aims to investigate whether the causal relationship between circulating inflammatory factors and basal cell carcinoma (BCC), cutaneous malignant melanoma (SKCM), and cutaneous squamous cell carcinoma (cSCC) is regulated by immune cells. METHODS: This study employed the Two-Sample Mendelian Randomization (TSMR) approach to investigate the causal relationships between 91 circulating inflammatory factors and three prevalent types of skin cancer from a genetic perspective. Bayesian Weighted Mendelian Randomization (BWMR) was also used to validate correlation and reverse MR to assess inverse relationships. Subsequent sensitivity analyses were conducted to limit the impact of heterogeneity and pleiotropy. Finally, the two-step Mendelian Randomization (two-step MR) method was utilized to ascertain the mediating effects of specific immune cell traits in the causal pathways linking circulating inflammatory factors with BCC, SKCM, and cSCC. RESULTS: The Inverse Variance Weighted (IVW) method and the Bayesian Weighted Algorithm collectively identified nine inflammatory factors causally associated with BCC, SKCM, and cSCC. The results from Cochran's Q test, mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger intercept were not statistically significant (p < 0.05). Additionally, the proportions mediated by CD4+ CD8dim T cell %leukocyte, CD4-CD8-Natural Killer T %T cell, and CD20 on IgD-CD38-B cell for FIt3L, CCL4, and OSM were 9.26%, 8.96%, and 10.16%, respectively. CONCLUSION: Immune cell levels potentially play a role in the modulation process between circulating inflammatory proteins and cutaneous-origin exacerbated tumors. This finding offers a new perspective for the in-depth exploration of cutaneous malignancies.

Staging in thick cutaneous malignant melanoma: A sequenced approach.

BACKGROUND: Patients with thick cutaneous pT4 malignant melanoma are at high risk for metastatic disease, and optimal staging is poorly defined. This study examines the frequency and modality of pre-operative staging to provoke thought on optimal staging. METHODS: A retrospective study was performed of patients with clinical T4N0 melanoma diagnosed between 2015-2017. The modality (sentinel lymph node biopsy and/or imaging), timing, and findings of staging investigations were assessed. RESULTS: One hundred thirty-six patients with pT4a or pT4b cutaneous melanoma and clinically negative regional lymph nodes were included. Forty patients underwent no staging. Thirty-six patients underwent pre-operative imaging, and of these, regional or distant disease was identified in seven patients (19%). Another 36 patients underwent upfront sentinel lymph node biopsy concurrently with wide local excision. A positive sentinel lymph node biopsy was found in eight (22%) of these patients, of which two had regional or distant metastatic disease on postoperative imaging. Of 16 who underwent a sentinel lymph node biopsy after negative pre-operative imaging, three had a positive sentinel lymph node biopsy. CONCLUSION: Staging is non-standardized and underutilized in patients with thick melanoma. With evolving systemic treatment options, a well-defined approach to staging, with consideration for pre-operative imaging in pT4 patients, is essential for high-risk patients.