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.

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.

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.

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.

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.

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.

Epidemiology of cutaneous malignant melanoma in Reunion Island.

INTRODUCTION: The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. The aim of this study was to evaluate the epidemiology of CMM in Reunion Island, a French overseas department whose population is characterized by high ethnic diversity and high exposure to ultraviolet radiation. METHODS: This cross-sectional study examined all cases of in situ CMM and invasive CMM diagnosed between 1 January and 31 December 2015 in the Reunionese population. RESULTS: One hundred and three new cases of CMM were recorded in Reunion Island in 2015: 33 cases of in situ CMM and 70 cases of invasive CMM. The sex ratio of men to women was 1.3 and 80% of patients had a fair skin phototype (Fitzpatrick skin phototype≤III). Age-standardized incidence rates of invasive CMM for all skin phototypes combined were 6.7/100,000 person-years (PY) in women and 5.3/100,000 PY in men. Crude incidence rates of invasive CMM for fair skin phototypes were estimated to be over 21/100,000 PY in women and over 25/100,000 PY in men. CONCLUSIONS: In Reunion Island, the incidence of CMM in the population with fair skin phototype is very high. Primary and secondary prevention measures should be reinforced and tailored to the local context.

Mid-term trends and recent birth-cohort-dependent changes in incidence rates of cutaneous malignant melanoma in Italy.

In Oceania, North America and north-western Europe, after decades of increase, cutaneous malignant melanoma (CMM) rates began to stabilise or decline before 2000. Anecdotal evidence suggests that the reversal of the incidence trend is extending to southern Europe. To obtain a formal confirmation, this nationwide study from Italy investigated the incidence trends by birth cohort. Twenty-one local cancer registries covering a population of 15 814 455 provided incidence data for primary CMM registered between 1994 and 2013. Trends in age-standardised rates were analysed using joinpoint regression models and age-period-cohort models. Age-standardised incidence showed a consistent increase throughout the period (estimated annual percent change, 3.6 [95% confidence interval, 3.2-4.0] among men and 2.5 [2.0-3.1] among women). This pattern was confirmed by a sensitivity analysis with removal of low-risk populations of southern Italy. The rates, however, showed a stabilisation or a decrease in men and women aged below 35. Using the cohort of 1949-the median cohort with respect to the number of cases for both genders-as a reference, the incidence rate ratio increased for successive cohorts born until 1973 (women) and 1975 (men), and subsequently tended to decline. For the most recent cohorts in both genders, the risk of disease returned to the level of the cohort of 1949. The changes observed in the latest generations can be interpreted as the earliest manifestations of a birth-cohort-dependent incidence decrease. Our study adds to previous data indicating that the reversal of the long-term upward incidence trend of CMM is extending to southern Europe.

Active surveillance of patients who have sentinel node positive melanoma: An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy Trial II (MSLT-2).

BACKGROUND: For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown. METHODS: In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment. CONCLUSIONS: Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients. LAY SUMMARY: For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.

ZFPM2-AS1 facilitates cell proliferation and migration in cutaneous malignant melanoma through modulating miR-650/NOTCH1 signaling.

Aberrant expression of long non-coding RNA (lncRNA) zinc finger protein, FOG family member 2 antisense RNA 1 (ZFPM2-AS1) has been identified in many tumors, but its role in cutaneous malignant melanoma remains largely obscure. Our present study was intended to unveil the role and potential mechanism of ZFPM2-AS1 in cutaneous malignant melanoma. RT-qPCR was utilized to analyze ZFPM2-AS1 expression in cutaneous malignant melanoma cells. Cell counting kit-8 (CCK-8), colony formation, flow cytometry, and transwell analyses were utilized to assess ZFPM2-AS1 function on cell proliferation, apoptosis, and migration. Luciferase reporter, RNA immunoprecipitation, and RNA-pull down assays were applied to probe the regulatory mechanism of ZFPM2-AS1 in cutaneous malignant melanoma cells. Up-regulation of ZFPM2-AS1 was discovered in cutaneous malignant melanoma cells. ZFPM2-AS1 deletion restrained cell proliferation, migration, and elevated cell apoptosis in cutaneous malignant melanoma. ZFPM2-AS1 regulated notch receptor 1 (NOTCH1) to activate the NOTCH pathway. ZFPM2-AS1 acted as a competing endogenous RNA (ceRNA) to affect NOTCH1 expression via sponging miR-650. Collectively, ZFPM2-AS1 exerted an oncogenic role in cutaneous malignant melanoma progression via targeting miR-650/NOTCH1 signaling. Our study might offer a novel sight for cutaneous malignant melanoma treatment.

Clinical and prognostic significance of Krüppel-like transcription factor 6 expression in 67 patients with cutaneous malignant melanoma in China.

Krüppel-like transcription factor 6 (KLF6) is a ubiquitous tumor suppressor gene involved in regulating cell growth, proliferation, differentiation and angiogenesis. The objective of the study was to investigate the clinical and prognostic significance of KLF6 expression in cutaneous malignant melanoma (CMM) patients. A total of CMM 67 patients were enrolled in this study. The specimens were evaluated by immunohistochemistry to detect KLF6. The positive KLF6 expression in CMM tissues was significantly lower than in normal skin tissues (p < 0.01).The presence of KLF6 in CMM was correlated with ulceration (p < 0.01), lymph node metastasis (p < 0.01) and clinical stage (p < 0.01). The overall 5-year survival rate of the 67 patients was 13.4%. The 5-year survival rate of patients with negative KLF6 expression was correlated with KLF6 expression (p < 0.01), ulceration (p < 0.01), lymph node metastasis (p < 0.01), clinical stage (p < 0.01) and operation type (p < 0.01). Ulceration and clinical staging were independent relevant factors. In conclusion, the presence of KLF6 in CMM was correlated with ulceration, lymph node metastasis, clinical stage and poor prognosis.

Predictive value of global dermoscopic pattern in patients diagnosed with cutaneous melanoma.

INTRODUCTION: Dermoscopy is one of the most commonly used methods in early diagnosis of melanoma. It is conducted to differentiate between benign and malignant patterns in melanocytic lesions. AIM: To determine if there is a predominance of one dermoscopic pattern in patients with melanoma and if there is a significant difference in dominant global dermoscopic pattern in patients with cutaneous melanomas correlated with patients' sex and the location of the primary tumor. MATERIAL AND METHODS: The study included 162 patients with prior diagnosis of cutaneous melanoma. Dermoscopic and videodermoscopic pictures and patient data were analyzed with regard to the pattern: reticular, globular, homogeneous and mixed pattern (two-component pattern; reticular-globular pattern) with central or peripheral globules and multicomponent (mixed - at least 3 types of structures in one nevus). RESULTS: The reticular pattern was significantly more prevalent in male patients (38.57%, 27 patients) in comparison to female patients (18.45%, 17 patients). We also found a statistically significant lower prevalence of reticular pattern in patients diagnosed with melanomas located on upper limbs. The homogeneous pattern was statistically significantly more prevalent in patients in whom primary tumors were located on the head and upper limbs. CONCLUSIONS: Our study suggests that predominant complex patterns are more commonly observed in patients diagnosed with cutaneous melanoma, although there is a significant number of patients with predominant reticular and homogeneous patterns, which are not often associated with an increased risk of development of melanoma.

TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma.

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only. METHODS: The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group. DISCUSSION: This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM. RESULTS: The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412.

Guizhi Fuling pills inhibit the proliferation, migration and invasion of human cutaneous malignant melanoma cells by regulating the molecular axis of LncRNA TPT1-AS1 / miR-671-5p.

The current research was aimed to explore the effects of Guizhi Fuling Pills on the proliferation, migration and invasion of human cutaneous malignant melanoma cells and its regulation on the molecular axis of LncRNA TPT1-AS1 / miR-671-5p. Human cutaneous malignant melanoma cells A375 were cultured in vitro and randomly divided into Con group, Guizhi Fuling pills-L group, Guizhi Fuling pills-M group, Guizhi Fuling pills-H group, Guizhi Fuling pills-H + pcDNA group, Guizhi Poria pills-H + pcDNA-TPT1-AS1 group. MTT was used to detect cell proliferation. The Transwell cell test was used to detect cell migration and invasion. qRT-PCR was used to detect the expression of TPT1-AS1 and miR-671-5p. The dual-luciferase report experiment verified the targeting relationship of TPT1-AS1, miR-671-5p. Western blot was used to detect the expression of Ki-67, PCNA, MMP-2 and MMP-9. Compared with Con group, Guizhi Fuling Pills could inhibit cell proliferation, migration and invasion (p<0.05), and also inhibit the expression of Ki-67, PCNA, MMP-2, MMP-9, TPT1-AS1 (p<0.05), promote the expression of miR-671-5p (p<0.05)., and the differences between the indexes of Guizhi Fuling Pill-L group, Guizhi Fuling Pill-M group and Guizhi Fuling Pill-H group were statistically significant (p<0.05). The dual-luciferase report experiment confirmed that TPT1-AS1 could target and bind to miR-671-5p and could regulate the expression and activity of miR-671-5p. Overexpression of TPT1-AS1 could reduce the inhibitory effect of Guizhi Fuling Pills on proliferation, migration and invasion of A375 cells. Guizhi Fuling Pill may reduce the proliferation, migration and invasion of human cutaneous malignant melanoma cells by down-regulating the expression of TPT1-AS1 and up-regulating the expression of miR-671-5p.

Dermoscopic features in different dermatopathological stages of cutaneous melanomas.

INTRODUCTION: Due to the rising incidence of cutaneous melanoma there is a great need for the development of new diagnostic techniques as well as the improvement of those that are already well known, such as dermoscopy. Since early detection and a proper technique for excising the tumor are crucial for patients' survival, early staging of the tumor is very important. AIM: To investigate whether there is a significant difference between the presence of selected dermoscopic features compared to the location on the skin and pathology results: Breslow's depth, mitotic index and ulceration. MATERIAL AND METHODS: We examined videodermoscopic images of cutaneous melanomas in 81 patients and compared their features with the histological results such as Breslow's depth, mitotic index and ulceration. In the study, we divided and compared the tumors in groups: in situ and invasive, ≤ 1.0 mm and > 1.0 mm thick on the Breslow scale. RESULTS: In the study we observed statistically significantly higher prevalence of pseudopods (30.5%) and multicomponent pattern (69.5%) in invasive melanomas in comparison to in situ melanomas (9.1% and 36.4% respectively). White regression structures were more commonly described in invasive melanomas thicker than 1.0 mm on Breslow's scale. Atypical blood vessels and nodules were more specific to invasive melanomas with ulcerations and mitotic index ≥ 1. The atypical pigment network was more specific for thin invasive melanomas. CONCLUSIONS: Presence of pseudopods, a multicomponent pattern, white regression structures, atypical blood vessels and nodules on dermoscopy suggest invasive (high stage) melanoma.

GSTO1 regards as a meritorious regulator in cutaneous malignant melanoma cells.

BACKGROUND: Glutathione S-transferase omega 1 (GSTO1), as a member of the glutathione S-transferase (GST) family genes, has been discovered to be up-regulated in several cancer cell lines which exhibited strong aggressiveness. However, the function of GSTO1 on cutaneous malignant melanoma (CMM) has not been illuminated. METHODS: Outcome of expression level and prognosis of GSTO1 were obtained from Oncomine and TCGA database. The specific effects of GSTO1 on the characteristics and regulatory mechanism of CMM cells were demonstrated by cell counting kit-8, colony formation, flow cytometry, and transwell assays in vitro. Western blot was employed to analyze the expression of proliferating cell nuclear antigen (PCNA), p53 and epithelial-to-mesenchymal (EMT) related proteins. RESULTS: We observed that GSTO1 was up-regulated in CMM samples when compared with the corresponding controls. Moreover, patients in CMM with high expression of GSTO1 were more likely to have a poor prognosis. Through in vitro experiments, silenced GSTO1 resulted in inhibition of CMM cells growth and aggressiveness, increased cell apoptosis, and blocked cell cycle. Finally, the expression of PCNA, p53 and EMT-related proteins were changed due to reduction of GSTO1. CONCLUSIONS: To sum up, our outcomes exhibited that weakening GSTO1 reduced the proliferation and mobility of CMM cells, increased the apoptosis ability of CMM cells, and arrested cell cycle at G1 phase, which can be achieved by affecting the expression of PCNA, p53 and the EMT process. This discovery provided a new perspective for elucidating the mechanism of CMM, and offered theoretical support for searching clinical therapeutic targets in the future.

Cutaneous malignant melanoma incidence and mortality trends in Canada: A comprehensive population-based study.

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) is on the rise in many parts of the world. However, there is limited knowledge on the epidemiology of CMM in Canada. OBJECTIVE: To conduct a comprehensive population-based study of CMM in Canada. METHODS: We examined patient clinical and pathologic characteristics as well as the incidence and mortality trends of CMM in Canada using 3 independent population-based registries. RESULTS: In total, 72,565 Canadian patients were given CMM diagnoses during 1992-2010; 47.5% were women. Average age at the time of diagnosis was 56.5 years for women and 60.4 years for men. We report a steady increase in CMM incidence and mortality rates in both sexes. The overall incidence rate of CMM in Canada was 12.29 cases/100,000 person-years. We also report important differences in the incidence and mortality rates between Canadian provinces and territories; the highest incidence of this cancer was documented in Nova Scotia and Prince Edward Island. LIMITATIONS: Data on race, clinical disease stage, and Breslow depth of CMM was not available. CONCLUSION: This study, for the first time, defines the disease burden of CMM in Canada and highlights important longitudinal, geographic, and spatial differences in the distribution of CMM in this country.

Incidence, Mortality, and Spatiotemporal Distribution of Cutaneous Malignant Melanoma Cases Across Canada.

BACKGROUND: We recently reported a steady increase in the incidence and mortality of cutaneous malignant melanoma (CMM) in Canada during 1992-2010. OBJECTIVES: The objective of this article is to examine the distribution of Canadian CMM patients at the level of provinces, cities, and forward sortation area (FSA) postal codes. METHODS: Using 3 Canadian population-based registries, we conducted an in-depth examination of the incidence and mortality trends for 72 565 Canadian CMM patients over the period 1992-2010. RESULTS: We found that among 20- to 39-year-olds, the incidence of CMM in women (7.17 per 100 000 individuals) was significantly higher than in men (4.60 per 100 000 individuals per year). Women age 80 years and older had an incidence of CMM (58.46 cases per 100 000 women per year) more than 4 times greater than the national average (12.29 cases per 100 000 population per year) and a corresponding high mortality rate (20.18 deaths per 100 000 women per year), when compared with the Canadian melanoma mortality of 2.4 deaths per 100 000 per year. In other age groups men had higher incidence and corresponding melanoma mortality rates. We also studied CMM incidence by province, city, and FSA postal codes and identified several high-incidence communities that were located near the coast/waterfronts. In addition, plotting latitude measures for cities and FSAs vs CMM incidence rate confirmed the inverse relationship between geographical latitude and incidence of melanoma in Canada (slope = -0.22 ± 0.05). CONCLUSIONS: This research may help develop sex-, age- and geographic region-specific recommendations to decrease the future burden of CMM in Canada.

High serum vitamin D level correlates with better prognostic indicators in primary melanoma: A pilot study.

BACKGROUND/OBJECTIVES: Sunlight is a major risk factor for cutaneous melanoma. However, its interaction with melanoma is complex. In particular, vitamin D is a UVB-derived hormone that has been shown to have anti-cancer effects. In this retrospective pilot study we sought to determine an association between the clinicopathological features of melanoma and the patients' corresponding serum vitamin D level. METHODS: In total, 109 primary melanomas diagnosed between 2001 and 2013 were retrospectively identified from our institutional database with a corresponding 25-hydroxyvitamin D3 level estimated within 6 months of diagnosis. Tumour, clinical (age, sex, tumour location) and pathological (thickness, mitosis, ulceration, Clark level, subtype, metastatic status) parameters were correlated with vitamin D. For statistical analysis, an unpaired Student's t-test and anova was used for categorical variables, and Spearman's correlation for continuous variables. RESULTS: Vitamin D level was inversely associated with Breslow thickness as a dichotomous, categorical and continuous variable. The association remained significant when controlled for patient's age and sex (P = 0.026). Vitamin D was higher in non-ulcerated tumours compared with ulcerated tumours (P = 0.006) and in tumours with mitotic rate <1/mm2 compared with ≥1/mm2 (P = 0.036). A significant association was found between vitamin D level and tumour histological subtype (P = 0.019). On subgroup analysis, significant associations were found between superficial spreading melanoma (SSM) and nodular melanoma (P = 0.026), and SSM and acral lentiginous melanoma (P = 0.007). CONCLUSION: A high vitamin D status may benefit prognosis in patients diagnosed with primary melanoma. A prospective cohort analysis with a large sample and controlled for other vitamin D confounders would validate these findings.

Reduced disease-specific survival following a diagnosis of multiple primary cutaneous malignant melanomas-a nationwide, population-based study.

Outcome data comparing patients with multiple primary invasive cutaneous malignant melanomas (MPMs) to single primary invasive cutaneous malignant melanomas (SPMs) show conflicting results. We have analyzed differences in disease-specific survival between these patients in a nationwide population-based setting. From the Swedish Melanoma Register, 27,235 patients were identified with a first invasive cutaneous malignant melanoma (CMM) between 1990 and 2007, followed-up through 2013. Of these, 700 patients developed MPMs. Cox proportional hazard regression was used for adjusted cause-specific hazard ratios (HRs). An interval of ≤5 years between CMM diagnoses was significantly correlated to a decreased CMM-specific survival in Stage I-II MPM- vs. SPM-patients (HR 1.32; 95% CI 1.04-1.67; p = 0.02). MPM-patients with longer time interval between diagnoses experienced similar risk of CMM-death as SPM-patients. The risk of CMM-death increased by almost 50% above the expected outcome according to stage of the index CMM by the diagnosis of a second CMM (HR 1.48; 95% CI 1.19-1.85; p < 0.001). MPM vs. SPM-patients had a worse outcome (HR 1.38; 95% CI 1.05-1.83; p = 0.001). This emphasizes the importance of prevention efforts in SPM-patients to decrease the risk of subsequent CMMs and has implications for more vigilant follow-up in MPM-patients.