Peroxiredoxin-2 represses NRAS-mutated melanoma cells invasion by modulating EMT markers.

The second most common mutation in melanoma occurs in NRAS oncogene, being a more aggressive disease that has no effective approved treatment. Besides, cellular plasticity limits better outcomes of the advanced and therapy-resistant patients. Peroxiredoxins (PRDXs) control cellular processes through direct hydrogen peroxide oxidation or by redox-relaying processes. Here, we demonstrated that PRDX2 could act as a modulator of multiple EMT markers in NRAS-mutated melanomas. PRDX2 knockdown lead to phenotypic changes towards invasion in human reconstructed skin and the treatment with a PRDX mimetic (gliotoxin), decreased migration in PRDX2-deficient cells. We also confirmed the favorable clinical outcome of patients expressing PRDX2 in a large primary melanoma cohort. This study contributes to our knowledge about genes involved in phenotype switching and opens a new perspective for PRDX2 as a biomarker and target in NRAS-mutated melanomas.

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.

Breast Metastasis From Cutaneous Melanoma: Beyond the Infiltrating Ductal Carcinoma.

Breast metastases of extramammary origin are an extremely rare entity. Solid organ metastases to the breast include malignant melanoma, epithelial carcinoma (adenocarcinoma and squamous cell carcinoma of the lung and gastrointestinal tract), and sarcoma. A breast neoplasm can be caused by a primary tumor, in-transit metastasis, breast metastasis, and skin metastasis. A 42-year-old female patient presented with a hyperpigmented lesion on the first finger of her left hand. An incisional biopsy was carried out, reporting pigmented epithelioid melanoma. Amputation of the finger was performed, as well as an axillary sentinel lymph node excision. Later during the treatment and follow-up by medical oncology, a breast tumor was located, followed by a protocol and the approach of possible differential diagnoses. Finally, it was characterized as metastatic cutaneous melanoma. The therapeutic approach regarding the possible origin of the metastatic neoplastic character of breast tumors culminated in this case in the palliative treatment with immunotherapy of cutaneous malignant melanoma. The diagnosis of breast metastases from cutaneous malignant melanoma is a real challenge, so an extensive history and high clinical suspicion are crucial in order to provide adequate treatment, despite the gloomy prognosis.

North-south differences in incidence and surveillance of cutaneous malignant melanoma in Italy.

BACKGROUND: In Italy, the incidence of cutaneous malignant melanoma is two-fold higher in the north than in the south. This gradient might be associated with differences in incidence trends and disease surveillance. We compared the time trends in incidence rates, mortality rates, dermatologic office visit rates and skin biopsy rates between the Emilia-Romagna Region (northern Italy) and the Sicily Region (southern Italy). METHODS: The cancer registries of Parma, Modena, Ferrara and Romagna (current population, 2,606,465) and Catania-Messina-Enna, Siracusa and Ragusa (2,775,019) provided incidence and mortality records for the years 2008-2017. The records of outpatient services delivered in public health facilities were obtained from the two Regional Administrations. Trends in rates were assessed with the estimated average annual percent change. North-south differences were expressed as age-standardised rate ratios. RESULTS: In the context of a generalised increasing incidence trend, which was more moderate in the female population of the Sicily Region, the standardised rate ratios were: 5.31 (males) and 5.20 (females) for in situ cutaneous malignant melanoma; 2.10 and 2.07 for invasive cutaneous malignant melanoma, with an excess incidence concentrated in lesions ⩽1.00 mm thick (3.58 and 3.05); 3.00 and 2.44 for dermatologic office visits; and 5.25 and 5.02 for skin biopsies. Mortality was stable in both Regions. CONCLUSIONS: In the Emilia-Romagna Region, as compared with the Sicily Region, a higher incidence of cutaneous malignant melanoma -especially of in situ and early invasive cutaneous malignant melanoma- coexisted with a higher level of clinical surveillance. The question of the direction of the cause-effect relationship between increased incidence and increased diagnostic scrutiny remains open.

Prospective associations of leucocyte subtypes and obesity with the risk of developing cutaneous malignant melanoma in the UK Biobank cohort.

BACKGROUND: Obesity is associated with chronic low-grade inflammation, which is linked to cancer development. Abdominal obesity (a body mass index, ABSI), however, has unusually been associated inversely with cutaneous malignant melanoma (CMM), while general obesity (body mass index, BMI) is associated positively. Leucocytes participate in inflammation and are higher in obesity, but prospective associations of leucocytes with cutaneous malignant melanoma are unclear. METHODS: We examined the prospective associations of neutrophil, lymphocyte, and monocyte counts (each individually), as well as the prospective associations of ABSI and BMI, with cutaneous malignant melanoma in UK Biobank. We used multivariable Cox proportional hazards models and explored heterogeneity according to sex, menopausal status, age (≥ 50 years at recruitment), smoking status, ABSI (dichotomised at the median: ≥73.5 women; ≥79.8 men), BMI (normal weight, overweight, obese), and time to diagnosis. RESULTS: During a mean follow-up of 10.2 years, 2174 CMM cases were ascertained in 398,450 participants. There was little evidence for associations with neutrophil or lymphocyte counts. Monocyte count, however, was associated inversely in participants overall (HR = 0.928; 95%CI: 0.888-0.971; per one standard deviation increase; SD = 0.144*109/L women; SD = 0.169*109/L men), specifically in older participants (HR = 0.906; 95%CI: 0.862-0.951), and more clearly in participants with low ABSI (HR = 0.880; 95%CI: 0.824-0.939), or with BMI ≥ 25 kg/m2 (HR = 0.895; 95%CI: 0.837-0.958 for overweight; HR = 0.923; 95%CI: 0.848-1.005 for obese). ABSI was associated inversely in pre-menopausal women (HR = 0.810; 95%CI: 0.702-0.935; SD = 4.95) and men (HR = 0.925; 95%CI: 0.867-0.986; SD = 4.11). BMI was associated positively in men (HR = 1.148; 95%CI: 1.078-1.222; SD = 4.04 kg/m2). There was little evidence for heterogeneity according to smoking status. The associations with monocyte count and BMI were retained to at least 8 years prior to diagnosis, but the association with ABSI was observed up to 4 years prior to diagnosis and not for longer follow-up time. CONCLUSIONS: Monocyte count is associated prospectively inversely with the risk of developing CMM in older individuals, while BMI is associated positively in men, suggesting a mechanistic involvement of factors related to monocytes and subcutaneous adipose tissue in melanoma development. An inverse association with ABSI closer to diagnosis may reflect reverse causality or glucocorticoid resistance.

Novel insights into rosacea's role in cancer risk: A Mendelian randomization approach.

BACKGROUND: Chronic inflammation has been shown to promote cancer progression. Rosacea is indeed a long-term inflammatory skin condition and had been reported to link with increased risk for several types of malignancies, but evidence for causality is lacking. OBJECTIVES: To systematically estimate the causal relationship between rosacea and several types of cancer, including cutaneous malignant melanoma (CMM), cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), actinic keratosis (AK), thyroid cancer, breast cancer, glioma and hepatic cancer, as well as explore the potential underlying pathogenesis. METHODS: We conducted a bidirectional two-sample Mendelian randomization study to probe the potential causal relationships between rosacea and several types of cancer. Instrumental variables were established using genome-wide significant single nucleotide polymorphisms associated with rosacea and cancers. The assessment of causality was carried out through multiple methods, and the robustness of the results was evaluated via sensitivity analyses. RESULTS: There was no significant indication of causal effects of rosacea on CMM (pivw = 0.71), cSCC (pivw = 0.45), BCC (pivw = 0.90), AK (pivw = 0.73), thyroid cancer (pivw = 0.59), glioma (pivw = 0.15), and hepatic cancer (pivw = 0.07), but the genetic risk of rosacea was associated with an increased susceptibility to human epidermal growth factor receptor (HER)-negative malignant neoplasm of breast (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18; pivw = 0.01). TANK (TRAF family member associated nuclear factor kappa B (NFKB) activator) was identified as a common protective gene for both rosacea (OR, 0.90; 95% CI, 0.82-0.99; pivw = 0.048) and HER-negative malignant neoplasm of the breast (OR, 0.86; 95% CI, 0.75-0.98; pivw = 0.032), which was primarily enriched in the negative regulation of NF-κB signal transduction and may contribute to the genetic links between rosacea and this subtype of breast cancer. CONCLUSIONS: Our findings provide suggestive evidence for causal links between rosacea and HER-negative malignant neoplasm of the breast risk.

Recent advancements in the diagnosis and treatment of acral melanoma. / è‚¢ç«¯é»‘è‰²ç´ ç˜¤çš„è¯Šæ–­å’Œæ²»ç–—è¿›å±•.

Acral melanoma (AM) is the most common histologic subtype of melanoma in dark-skinned patients and is associated with a worse prognosis and a high mortality rate, largely due to the inconspicuous nature of early-stage lesions, which can lead to late diagnosis. Because of the overlapping clinical and histopathological features of AM with other forms of cutaneous melanomas, early detection of AM requires a multidisciplinary approach that integrates various diagnostic modalities, including clinical examination, dermoscopy, histopathology, molecular testing, radiological imaging, and blood tests. While surgery is the preferred method of treatment for AM, other therapeutic options may be employed based on the stage and underlying etiology of the disease. Immune checkpoint inhibitors, molecular targeted therapy, radiotherapy, chemotherapy, and oncolytic virotherapy represent promising advanced treatment options for AM. In this review, we provide an overview of the latest advancements in diagnostic and therapeutic methods for AM, highlighting the importance of early detection and the prompt, individualized management of this challenging disease.

Treated Primary Cutaneous Malignant Melanoma With Later Metastasis Found in Clinical Presentation of Left Axilla Lymphadenopathy: A Case Report.

This case report details the rare instance of metastatic spread of cutaneous malignant melanoma to the breast in a 50-year-old female. The patient presented with a palpable axillary mass confirmed to be metastasis despite excision and closure of the primary malignancy. The mass seen in clinical and radiological presentations presented with features of complicated differentiation from a primary breast tumor. Biopsy and staining with immunohistochemical markers S100 and Sox10 played a critical role in confirming the melanocytic origin of this metastatic lesion. Breast metastases are associated with poor prognosis, and this case emphasizes the importance of in-depth evaluations for patients with a history of malignant melanoma and the need for ongoing clinical awareness in this field.

The reduced mortality of malignant melanoma at the population level is mainly attributable to treatment advances for the past decade.

BACKGROUND: Cutaneous malignant melanoma (CMM) causes most skin cancer deaths in the United States (US). The mortality has been decreasing in the US population. We hypothesize that this population-level reduction is mainly attributable to the treatment advances, rather than the successful primary and secondary prevention. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) databases, we collected the incidence, incidence-based mortality (IBM), and 5-year survival (5-YS) rates of CMM from 1994 to 2019. Trends by stage and sex were examined by joinpoint regression analyses and age-period-cohort analyses. RESULTS: The overall incidence of CMM rose by 1.6% yearly from 1994 to 2006 (95% confidence interval [CI]: 0.9% to 2.2%) and then increased with a numerical trend. And we projected the incidence will continue to increase until 2029. In contrast, the IBM for all CMM has decreased yearly by 2.8% (95% CI: -3.9% to -1.8%) since 2010 after continuously increasing by 3.8% annually (95% CI: 3.2% to 4.4%) from 1996 to 2010. For early-stage (localized and regional) CMM, we found the incidence since 2005 plateaued without further increase, while the incidence for CMM at distant stage continuously increased by 1.4% per year (95% CI: 0.9% to 2.0%). Improvements in 5-YS were observed over the study period for all CMM and were most obvious in distant stage. And significant period effects were noted around the year 2010. CONCLUSION: This study demonstrated improved survival and reduced mortality of CMM at the US population level since 2010, which were consistent with the introduction of novel therapies. Encouraging effects of primary prevention among adolescents in the most recent cohorts were found. However, the plateaued overall incidence and early diagnosis rates indicated that advances in primary and secondary prevention are very much needed to further control the burden of CMM.

The clinicopathological impact of tumor-associated macrophages in patients with cutaneous malignant melanoma.

BACKGROUND: Tumor-associated macrophages (TAMs) are an immune component of the cutaneous malignant melanoma (CMM) microenvironment and affect tumor growth. TAMs can polarize into different phenotypes, that is, proinflammatory M1 and anti-inflammatory M2 macrophages. However, the role of the macrophage phenotype in CMM remains unclear. METHODS: We examined 88 patients with CMM. Tissue microarrays were constructed, and the density of M1 and M2 macrophages was analyzed by immunohistochemistry. Immune cells coexpressing CD68 and phosphorylated signal transducer and activator of transcription 1 (pSTAT1) were considered M1 macrophages, whereas those coexpressing CD68 and c-macrophage activating factor (c-Maf) were defined as M2 macrophages. These TAMs were counted, and the relationships between the density of M1 and M2 macrophages and clinicopathological factors including prognosis were investigated. RESULTS: The CD68/c-Maf score ranged from 0 to 34 (median: 5.5). The patients were divided based on the median score into the CD68/c-Maf high (≥5.5) and low (<5.5) expression groups. Univariate and multivariate analyses revealed that CD68/c-Maf expression was an independent predictive factor for progression-free survival and an independent prognostic factor for overall survival. CD68/pSTAT1 expression was found in only two patients. CONCLUSION: We suggest that CD68/pSTAT1 coexpression is rarely observed in patients with CMM, and high CD68/c-Maf expression is a predictor of worse prognosis in these patients.

Knockdown of FOXRED2 restrains proliferation, invasion and migration of human melanoma cells.

Objectives: This experiment investigated the role of the FAD-dependent oxidoreductase domain-containing 2 (FOXRED2) in the development of cutaneous malignant melanoma. Methods: We explored the expression and prognostic effects of FOXRED2 in cutaneous malignant melanoma by performing bioinformatics analyses and immunohistochemical staining experiments and verified the biological influence of FOXRED2 on human melanoma cells using in vitro experiments. Results: FOXRED2 expression was significantly higher in cutaneous malignant melanoma compared to normal skin and nevus tissues and closely associated with prognosis. The expression levels of FOXRED2 mRNA and protein were significantly upregulated in human melanoma cell lines, and knocking down FOXRED2 expression inhibits proliferation, invasion, and migration, promotes apoptosis, and alters tumor cell biology in A2058 and A375 cells. Conclusion: FOXRED2 may play a crucial role in the development and progression of cutaneous malignant melanoma.

Thyroid dysfunction and risk of cutaneous malignant melanoma: a bidirectional two-sample Mendelian randomization study.

Background: Epidemiologic and observational data have found a risk association between thyroid dysfunction and cutaneous malignant melanoma (CMM), however, the cause and direction of these effects are yet unknown. By using a bidirectional two-sample Mendelian randomization (MR) methodology, we hoped to further investigate the causal link between thyroid dysfunction and CMM in this work. Methods: A genome-wide association study (GWAS) of 9,851,867 single nucleotide polymorphisms (SNPs) in a European population was used to develop genetic tools for thyroid dysfunction. Hypothyroidism was linked to 22,687 cases and 440,246 controls. For hyperthyroidism, there were 3545 cases and 459,388 controls. A total of 3751 cases and 372016 controls were included in the genetic data for CMM from UK Biobank (http://www.nealelab.is/uk-biobank) (the Dataset: ieu - b - 4969). Among them, inverse variance weighting (IVW) is the main MR Analysis method for causality assessment. MR-Egger method, MR Pleiotropic residual and outlier test (MR-PRESSO), and simple and weighted median (VM) were used to supplement the IVW method. Sensitivity analyses, mainly Cochran's Q test, leave-one-out analysis, and MR Egger intercept test were performed to assess the robustness of the outcomes. Results: The two-sample MR Analysis results revealed a negative correlation between genetically predicted hypothyroidism and the probability of CMM (OR=0.987, 95%CI =0.075-0.999, p=0.041). The supplemental MR Analysis did not reveal any statistically significant differences, although the direction of the effect sizes for the other approaches was consistent with the IVW effect sizes. The results of the causal analysis were relatively robust, according to a sensitivity analysis. The risk of CMM was unaffected by hyperthyroidism (p>0.05). No correlation between CMM and thyroid dysfunction was seen in the reverse MR analysis. Conclusion: Although the magnitude of the causal association is weak and further investigation of the mechanism of this putative causal relationship is required, our findings imply that hypothyroidism may be a protective factor for CMM.

The Krüppel-like factor 6 represses proliferation and invasion of cutaneous malignant melanoma.

Cutaneous carcinoma is one of the most common neoplasm tumors in the West. Its incidence rate is one of the fastest growing tumors in China. The Krüppel-like factor 6 (KLF6) is a latent tumor suppressor. Decreased KLF6 is related to the occurrence and progression of many cancers in human. Our previous studies have demonstrated that KLF6 was down-regulation in cutaneous malignant melanoma (CMM), and was significant correlated with ulcer, lymph node metastasis and clinical stage, suggesting that KLF6 loss is expected to become a biological indicator of poor prognosis in CMM patients. In this research, we would further study the features of KLF6 in the malignant progression of CMM. The expression of KLF6 was up-regulated by lentivirus infection containing KLF6, and short hairpin RNA (shRNA) was used for knockdown of KLF6 in CMM cells. Western blot, RT-qpcr, CCK8 assay, transwell migration assays, wound healing assay and flow cytometry were used to test the role of KLF6 in the CMM. We found that reduced expression of KLF6 significantly enhanced proliferation, migration and invasion. Moreover, KLF6 induced CMM cell apoptosis and G1 cycle arrest. The decreased KLF6 expression is expected to be a biological indicator of poor prognosis in CMM patients.

Phosphatase and Tensin Homolog (PTEN) Expression as a Surrogate Biomarker Correlated With the Depth of Invasion in Cutaneous Malignant Melanoma.

Objective The aim of this study is to evaluate the expression of the phosphatase and tensin homolog (PTEN), which is a tumor suppressor gene that is implicated in the pathogenesis of cutaneous malignant melanoma, in normal skin and melanoma tissue samples. The study also aimed to correlate PTEN expression levels with various clinicopathological parameters of melanoma lesions, thus highlighting the utility of PTEN expression as a prognostic biomarker for melanoma. Study design Immunohistochemistry (IHC) staining was performed on tissue microarray samples representing normal skin and melanoma biopsies of different clinicopathological parameters. Tissue photomicrographs were evaluated with Aperio ImageScope, which has a positive-pixel-counting algorithm built in. Subsequently, a histochemical score (H-score) was derived from the percentage of positive cells (%-staining) and their staining intensity. The H-scores were averaged in groups of tissue samples representing the different melanomas' tumor (T), node (N), and distant metastasis (M), also known as TNM parameters, as set forth by the American Joint Committee on Cancer (AJCC) classification. The mean H-scores were statistically compared using a two-tailed unpaired t-test. Results The PTEN protein expression was measured by IHC and found to be correlated with tumor thickness (T), which is a reliable indicator for survival rates. Specifically, PTEN was significantly downregulated in tumors with a thickness over 2 mm (T3+T4) compared to tumors with a thickness at or below 2 mm (T1+T2). Conclusions The PTEN protein expression, as measured by immunohistochemistry, helped differentiate between tumors with a thickness over 2 mm and tumors with a thickness at or below 2 mm, suggesting PTEN as a potential surrogate marker for the melanoma's invasion depth along with possible prognostic implications. Longitudinal studies evaluating risk stratification based on the expression of PTEN are needed to establish the utility of this promising biomarker in the clinic as an adjunct for pathological examination.

Predicting cutaneous malignant melanoma patients' survival using deep learning: a retrospective cohort study.

BACKGROUND: Cutaneous malignant melanoma (CMM) has the worst prognosis among skin cancers, especially metastatic CMM. Predicting its prognosis accurately could direct clinical decisions. METHODS: The Surveillance, Epidemiology, and End Results database was screened to collect CMM patients' data. According to diagnosed time, patients were subdivided into three cohorts, train cohort (diagnosed between 2010 and 2013), validation cohort (diagnosed in 2014), and test cohort (diagnosed in 2015). Train cohort was used to train deep learning survival model for cutaneous malignant melanoma (DeepCMM). DeepCMM was then evaluated in train cohort and validation cohort internally, and validated in test cohort externally. RESULTS: DeepCMM showed 0.8270 (95% CI, confidence interval, CI 0.8260-0.8280) as area under the receiver operating characteristic curve (AUC) in train cohort, 0.8274 (95% CI 0.8286-0.8298) AUC in validation cohort, and 0.8303 (95% CI 0.8289-0.8316) AUC in test cohort. Then DeepCMM was packaged into a Windows 64-bit software for doctors to use. CONCLUSION: Deep learning survival model for cutaneous malignant melanoma (DeepCMM) can offer a reliable prediction on cutaneous malignant melanoma patients' overall survival.

Angiopoietin-2 expression and its relationship with lymphangiogenesis and clinicopathological characteristics in cutaneous malignant melanoma.

Objective: The aim of this study was to investigate angiopoietin-2 (Ang-2/ANGPT2) expression and its relationship with lymphangiogenesis and clinicopathological characteristics in cutaneous malignant melanoma (CMM). Methods: Gene expression differences between metastatic melanoma and melanoma in situ in 472 patients from the TCGA database were analyzed. The target gene Ang-2 was screened. A clinical study was conducted to analyze the correlation between Ang-2 expression in CMM and tumor-associated lymphangiogenesis. A total of 42 patients with primary CMM who underwent extended tumor resection procedures at the Affiliated Hospital of Jiangsu University were included in this study. Clinical data (gender, age, lymph node metastasis, Breslow thickness, and clinical stage) were collected. The expression levels of both Ang-2 and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) proteins were detected by immunohistochemistry (IHC). Lymphatic vascular density (LVD) was counted by using LYVE-1 to label lymphatic endothelial cells (LECs) in peritumoral and intratumoral areas per high-magnification field of view. Statistical analysis was performed using the Pearson correlation test and Student's t-test. Results: Using the TCGA database, it was found that the gene expression level of Ang-2 in 368 cases of metastatic melanoma was significantly higher than that in 104 cases of melanoma in situ. Correlation analysis showed a significant relationship between Ang-2 and LYVE-1, and vascular endothelial growth factor receptor 3(VEGFR3) expression, respectively, in CMM. Moreover, the optimal cutoff value of survival analysis showed that high Ang-2 expression in CMM had a worse prognosis, based on data from the TCGA database. Our research showed that Ang-2 was more highly expressed in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients than in the group of patients with no lymph node metastasis and in the group of stage 0-3B patients. Our research also showed that LVD in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients was significantly higher than that in the group of no lymph node metastasis and in the group of stage 0-3B patients, respectively. Breslow thickness also correlated with Ang-2 expression and LVD. Ang-2 expression was not related to sex or age. Ang-2 expression was obviously correlated with LVD. Conclusion: An evaluation of Ang-2 expression and LVD can be used to predict the risk of tumor lymphatic metastasis and determine the prognosis of CMM. These results may also provide a new clinical treatment strategy for CMM.

PRAME expression in cutaneous melanoma does not correlate with disease-specific survival.

BACKGROUND: Immunohistochemistry-based protein biomarkers can provide useful prognostic information in cutaneous melanoma. The independent prognostic value of Ki-67 has been studied with variable results. PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is a useful new ancillary tool for distinguishing cutaneous nevi from melanoma; however, its prognostic value has not been well studied. We evaluated PRAME as a prognostic marker in cutaneous melanoma, compared to Ki-67. METHODS: We analyzed the immunohistochemical expression of PRAME and Ki-67 in 165 melanocytic lesions, including 92 primary melanomas, 19 metastatic melanomas, and 54 melanocytic nevi using tissue microarrays. PRAME immunostaining was scored based on the percentage of positive nuclei: 0 <1%, 1+ 1%-25%, 2+ 26%-50%, 3+ 51%-75%, and 4+ >75%. The percentage of Ki-67-positive tumor nuclei was used to calculate the proliferation index. RESULTS: PRAME and Ki-67 both showed significantly increased expression in melanomas compared to nevi (p < 0.0001 and p < 0.001, respectively). There was no significant difference in PRAME expression in primary versus metastatic melanomas. By contrast, the Ki-67 proliferation index was higher in metastatic melanoma than in primary melanoma (p = 0.013). Increased Ki-67 index correlated with ulceration (p < 0.001), increased Breslow depth (p = 0.001), and higher mitotic rate (p < 0.0001), whereas increased PRAME expression correlated with higher mitotic rate (p = 0.047) and Ki-67 index (p = 0.007). Increased Ki-67 index correlated with worse disease-specific survival in patients with primary melanoma (p < 0.001), but PRAME expression did not show prognostic significance in disease-specific survival (p = 0.63). In a multivariable analysis of patients with primary melanoma, tumor Breslow depth, ulceration, mitotic rate, and Ki-67 index were each independent predictors of disease-specific survival (p = 0.006, 0.02, 0.001, and 0.04, respectively); however, PRAME expression was not predictive of disease-specific survival (p = 0.64). CONCLUSION: Ki-67 is an independent prognostic marker; although increased PRAME expression correlates with the Ki-67 proliferation index and mitotic rate, PRAME is not an independent prognostic marker for cutaneous melanoma. PRAME and Ki-67 are useful ancillary tools for distinguishing benign from malignant melanocytic lesions.

Deep-learning-based survival prediction of patients with cutaneous malignant melanoma.

Background: This study obtained data on patients with cutaneous malignant melanoma (CMM) from the Surveillance, Epidemiology, and End Results (SEER) database, and used a deep learning and neural network (DeepSurv) model to predict the survival rate of patients with CMM and evaluate its effectiveness. Methods: We collected information on patients with CMM between 2004 and 2015 from the SEER database. We then randomly divided the patients into training and testing cohorts at a 7:3 ratio. The likelihood that patients with CMM will survive was forecasted using the DeepSurv model, and its results were compared with those of the Cox proportional-hazards (CoxPH) model. The calibration curves, time-dependent area under the receiver operating characteristic curve (AUC), and concordance index (C-index) were used to assess the prediction abilities of the model. Results: This study comprised 37,758 patients with CMM: 26,430 in the training cohort and 11,329 in the testing cohort. The CoxPH model demonstrated that the survival of patients with CMM was significantly influenced by age, sex, marital status, summary stage, surgery, radiotherapy, chemotherapy, postoperative lymph node dissection, tumor size, and tumor extension. The C-index of the CoxPH model was 0.875. We also constructed the DeepSurv model using the data from the training cohort, and its C-index was 0.910. We examined how well the aforementioned two models predicted outcomes. The 1-, 3-, and 5-year AUCs were 0.928, 0.837, and 0.855, respectively, for the CoxPH model, and 0.971, 0.947, and 0.942 for the DeepSurv model. The DeepSurv model presented a greater predictive effect on patients with CMM, and its reliability was better than that of the CoxPH model according to both the AUC value and the calibration curve. Conclusion: The DeepSurv model, which we developed based on the data of patients with CMM in the SEER database, was found to be more effective than the CoxPH model in predicting the survival time of patients with CMM.

Peritoneal Carcinomatosis From Malignant Melanoma After Wide Local Excision of a T1a Lesion: A Case Report.

Cutaneous melanoma is an aggressive skin cancer with a high propensity for distant metastasis. Peritoneal metastasis from cutaneous malignant melanoma is extremely rare and associated with a low five-year overall survival rate. This report reviews a case of a 78-year-old man with peritoneal carcinomatosis after a wide local excision of a T1a invasive malignant melanoma of the scalp 10 months prior. Although rare, patients with a recent history of melanoma who present with obscure or odd symptoms should be worked up for metastatic disease by their surgeon or medical oncologist. Carcinomatosis can develop, and early treatment with immunotherapy has been shown to improve five-year overall survival and progression-free survival in patients with advanced melanoma.

Genetic Characteristics of Primary Cutaneous Malignant Melanoma in Koreans Compared With Western Populations.

BACKGROUND/AIM: Cutaneous melanoma, a melanocyte malignancy, can be divided into many clinical subtypes that differ in presentation, demographics, and genetic profile. In this study, we used next-generation sequencing (NGS) analysis to review genetic alterations in 47 primary cutaneous melanomas in the Korean population and compared them to alterations from melanomas in Western populations. PATIENTS AND METHODS: We retrospectively reviewed clinicopathologic and genetic features of 47 patients diagnosed with cutaneous melanomas between 2019-2021 at Severance Hospital, Yonsei University College of Medicine. NGS analysis was performed at diagnosis to evaluate single nucleotide variations (SNVs), copy number variations (CNVs), and genetic fusions. Genetic features in Western cohorts of melanoma were then compared with previous studies performed in the USA: Cohort 1 (n=556), Cohort 2 (n=79), and Cohort 3 (n=38). RESULTS: The most common histological classification of melanoma was the acral lentiginous type (23/47, 48.9%). BRAF V600 mutation was most frequent (11/47, 23.4%), but was significantly lower compared to Cohort 1 (240/556, 43.2%) and Cohort 2 (34/79, 43.0%) (p=0.0300). CNV analysis identified amplifications in chromosomes 12q14.1-12q15 (11/47, 23.4%) including CDK4 and MDM2 genes and 11q13.3 (9/47, 19.2%) including CND1, FGF19, FGF3, and FGF4 genes more frequently in the present study population than Cohort 1 (p<0.0001). CONCLUSION: These results clearly demonstrated differences in genetic alterations between melanomas in Asian and Western populations. Therefore, BRAF V600 mutation should be considered a significant signaling pathway explaining melanoma pathogenesis occurrence in both Asian and Western populations, whereas loss of chromosome 9p21.3 is unique to melanomas in Western populations.