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Background: In malignant melanoma, liver metastases significantly reduce survival, even despite highly effective new therapies. Given the increase in metabolic liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), this study investigated the impact of liver sinusoidal endothelial cell (LSEC)-specific alterations in MASLD/MASH on hepatic melanoma metastasis. Methods: Mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for ten weeks to induce MASH-associated liver fibrosis, or a CDAA diet or a high fat diet (HFD) for shorter periods of time to induce early steatosis-associated alterations. Liver metastasis formation was assessed using melanoma cell lines B16F10Luc2 and Wt31. LSEC-specific GATA4 knockout mice (Gata4LSEC−KO/BL) developing MASH-like liver fibrosis without steatosis via a pathogenic angiocrine switch were included to compare the impact of liver fibrosis versus hepatic steatosis on hepatic melanoma metastasis. Bulk RNA-Seq of isolated LSECs from CDAA-fed and control mice was performed. Levels of adhesion molecules (VCAM1, ICAM1, E-selectin) were monitored, and ICAM1 and VCAM1 antibody therapy was employed. Results: Feeding a CDAA diet, in contrast to a HFD, led to increased metastasis before the development of liver fibrosis. Gata4LSEC−KO/BL mice characterized by vascular changes ensuing perisinusoidal liver fibrosis without steatosis also exhibited increased metastasis. Early molecular alterations in the hepatic vascular niche, rather than fibrosis or steatosis, correlated with metastasis, as shown by LSEC dedifferentiation and upregulation of endothelial adhesion molecules. The metastatic process in CDAA-fed mice was also dependent on the respective melanoma cell lines used and on the route of their metastatic spread. ICAM1 inhibition, but not VCAM1 inhibition reduced melanoma cell retention. Conclusion: We discovered that the hepatic vascular niche acts as a delicate sensor to even short-term nutritional alterations during the development of MASLD/MASH. The dynamic adaptations to the metabolic challenges of developing MASLD/MASH caused an early shift from the normal hepatic vascular niche to a pre-metastatic vascular niche that promoted hepatic melanoma metastasis in the context of cell-autonomous and acquired melanoma cell features. Altogether, our findings provide a potential avenue for angiotargeted therapies to prevent hepatic melanoma metastasis. [ABSTRACT FROM AUTHOR]

Objectives: To examine the rate of skin color reporting in randomized controlled trials (RCTs) involving melanoma in the top ten highest dermatology journals by impact factor over the past four decades. Methods: A systematic review of RCTs involving melanoma within the top ten dermatology journals, as determined by impact factor, was conducted from inception to July 10th, 2023. Studies were included if they reviewed the diagnosis and/or treatment of melanoma, were RCTs, directly involved patients and were written in English. Studies were characterized as positive for reporting skin of color (SOC) if the demographic data in the results or methods sections included any of the following: race, ethnicity, skin of color, Fitzpatrick scale, sunburn tendency, phototype, skin type, or skin tone. Results: Out of 76 studies initially identified, only 49 articles met inclusion criteria. Of these 49 articles, only 24 articles recorded data of skin color from their demographics (49%). Subgroup analysis showed no statistically significant difference in the rate of reporting between studies grouped by decade (p = 0.779) or by study location (p = 0.763). Conclusion: Darker skin tones can disguise melanotic skin lesions. Less than 50% of RCTs related to melanoma in the top ten international dermatology journals included skin color within their results section to characterize study participants. This has a negative impact on our understanding of this potentially devastating disease. [ABSTRACT FROM AUTHOR]

Background: Cutaneous Malignant Melanoma (CMM) is a significant global health challenge. Understanding regional differences in CMM prevalence and trends is crucial for developing targeted strategies. To address this, we analyzed epidemiological patterns and investigated risk factors for CMM-related mortality. Methods: This study analyzed CMM using data from the 2021 Global Burden of Diseases survey, covering 204 countries and territories. We evaluated the number and age-standardized rates of prevalence (ASPR), mortality (ASMR), disability-adjusted life years (ASDR), and annual percentage changes (EAPCs). Trends were stratified by region, country, age, sex, and Sociodemographic Index (SDI). A Bayesian Age-Period-Cohort model projected future prevalence, mortality, and DALYs, while decomposition analysis identified key drivers of CMM burden. Frontier analysis further associated CMM outcomes with socio-demographic development. Results: In 2021, the global prevalence of CMM reached 833,215 cases, a 161.3% increase since 1990. During this period, the ASPR rose from 19.13 to 25.37 per 100,000, while the ASMR declined from 0.84 to 0.73 per 100,000. DALYs increased by 60.5%, from 1,045,777 to 1,678,836. The high SDI region had the highest ASPR, ASMR, and ASDR. Decomposition analysis identified population growth, demographic aging, and epidemiological changes as equal drivers of CMM DALYs globally. Countries like New Zealand and Australia demonstrated the most significant effective differences, indicating potential for improvement in CMM management. By 2045, the global ASPR is projected to rise to 36.61, with ASMR and ASDR expected to decrease to 0.79 and 10.21 per 100,000. Conclusion: CMM poses an increasing global health concern, with ASPR steadily rising. While this analysis shows a decline in global ASMR and ASDR overall, these rates are actually increasing in low SDI regions, and projections indicate that this trend will likely continue until 2045. [ABSTRACT FROM AUTHOR]

Acral melanoma is a distinct subtype of cutaneous malignant melanoma that uniquely occurs on ultraviolet (UV)-shielded, glabrous skin of the palms, soles, and nail beds. While acral melanoma only accounts for 2–3% of all melanomas, it represents the most common subtype among darker-skinned, non-Caucasian individuals. Unlike other cutaneous melanomas, acral melanoma does not arise from UV radiation exposure and is accordingly associated with a relatively low tumor mutational burden. Recent advances in genomic, transcriptomic, and epigenomic sequencing have revealed genetic alterations unique to acral melanoma, including novel driver genes, high copy number variations, and complex chromosomal rearrangements. This review synthesizes the current knowledge on the clinical features, epidemiology, and treatment approaches for acral melanoma, with a focus on the genetic pathogenesis that gives rise to its unique tumor landscape. These findings highlight a need to deepen our genetic and molecular understanding to better target this challenging subtype of melanoma. [ABSTRACT FROM AUTHOR]

The prognosis of a patient with a primary cutaneous melanoma is known to be related to the Breslow thickness of their tumor. This study sought to determine long-term (30-year) survival rates for the 4 American Joint Committee on Cancer 8th edition T categories by analyzing Australian registry data for 210 042 melanoma patients diagnosed from 1982 to 2014. The 30-year incidence rates of death due to melanoma and nonmelanoma (with 95% confidence intervals [CIs]) were 7.1% (95% CI = 6.9% to 7.3%) and 32.8% (95% CI = 32.3% to 33.3%), respectively. For T2 melanomas, the corresponding rates were 21.6% (95% CI = 21.0% to 22.3%) and 35.6% (95% CI = 34.7% to 36.6%), for T3 melanomas 34.2% (95% CI = 33.4% to 35.1%) and 39.6% (95% CI = 38.5% to 40.8%), and for T4 melanomas 44.3% (95% CI = 43.2% to 45.3%) and 39.6% (95% CI = 38.3% to 41.0%). A plateau in melanoma-related deaths occurred in T4 patients after 20 years, but there were ongoing melanoma-related deaths for the other T categories beyond 30 years. A progressive rise in the risk of death from other causes occurred across all T categories. [ABSTRACT FROM AUTHOR]

Cutaneous malignant melanoma (MM) is the most aggressive form of skin cancer, associated with high mortality and rising incidence rates in Europe despite prevention efforts. Nodular MM, the most aggressive subtype, often mimics other skin tumors, complicating diagnosis. We present the case of a 66-year-old woman with a large, ulcerated tumor beneath the left scapula, along with multiple nodular lesions on the left arm and chest. Initially suspected to be an aggressive squamous cell carcinoma, the diagnosis was confirmed as invasive cutaneous MM with a BRAF(V600) mutation via biopsy. Staging with PET/CT revealed extensive glucose metabolism in the tumors and surrounding tissues, as well as metastatic lymphadenopathy. The disease was classified as stage IV (T4bN3cM1a0). Neoadjuvant systemic therapy with BRAF and MEK inhibitors (Dabrafenib and Trametinib) was initiated to reduce tumor size. Remarkable regression was observed within a week, with further reduction in tumor size after one month. A follow-up PET/CT after 3 months showed significant decreases in tracer uptake and lesion size, with a ΔSUVmax of 51.9%, a ΔMTV of 74.5%, and a ΔTLG of 83.5%, indicating an excellent response to targeted therapy. [ABSTRACT FROM AUTHOR]

Importance: Patients with a primary cutaneous melanoma (PCM) are at increased risk of developing a second primary melanoma (SPM). Earlier stage at diagnosis is associated with better 5-year mortality, yet low compliance with recommended follow-up after treatment for PCM and high rates of patients lost to follow-up are reported in the literature. Strategies to enhance population-based surveillance for SPM have not been well described. Objective: To determine whether the implementation of a systematic automated population-based program (SAPP) to ensure dermatologist total body skin exams (TBSEs) in the PCM population compared to the pre-automated period and pre-database periods improves compliance with follow-up, detects more SPMs, or affects mortality? Design: Quality Improvement Study. Setting: Large integrated health care system with internalized Dermatology services. Participants: Members with a PCM prior to, or during the study periods of interest, were included in this quality improvement study. There were 6317 eligible individuals with PCMs in 3 study periods: pre-Database (1/1/2005-11/1/2009), pre-Automation (11/1/09-7/31/15), and post-Automation (8/1/15-12/31/2021), respectively. Intervention(s) or Exposure(s): Manual registry for melanoma patients (pre-Automation) and systematic automated population-based program for PCM patients (post-Automation). Main Outcome(s) and Measure(s): Mean number of TBSE per person-year. Time Between TBSE. Incidence of SPM detection. Stage of SPM at diagnosis. Melanoma Death and All-Cause Mortality. Results: In patients with PCM, a SAPP to ensure dermatologist TBSE, reduces median time (months) between TBSEs from 12.3 pre-Database to 8.2 post-Automation (stage 0-2a PCM) and from 10.3 to 6.8 (stage 2b-4 PCM; P <.0001), improves number of TBSEs per person-year with each successive study period (pre-Database mean [SD] 0.56 [1.07]; pre-Automation 0.80 [1.25]; post-Automation 1.78 [4.17]; P <.0001), and improves SPM detection rates per 1000 person-years (pre-Database 20.2 [95% CI 12.2-30.9]; pre-Automation 27.5 [18.2-39.9]; post-Automation 27.5 [26.6-51.8], P <.0001 for trend) at earlier cancer stages. There is an associated annual reduction in all-cause (1.4 per 1000 person-years, P =.0004) and melanoma-cause mortality (0.2 per 1000 person-years, P =.0197). Conclusion: Implementing a systematic, automated population-based Melanoma program to ensure dermatologist TBSEs improves compliance with follow-up in patients with PCM. More patients received at least annual dermatologist TBSEs and more SPMs were detected at earlier stages. Improvements were sustained and there were significantly lower all-cause and melanoma-cause mortality. The system facilitates prioritization of higher risk patients for intervention and is a unique strategy enhancing patient safety, efficiency, and timeliness of care. [ABSTRACT FROM AUTHOR]

The pathogenesis of melanoma is influenced by a complex combination of environmental factors and individual genetic susceptibility. Familial melanoma refers to cases where there are two first‐degree relatives with a melanoma diagnosis. Less strict definitions include second‐degree relatives or even three or more of any degree from the same family, although this is not clearly defined in the literature. The term hereditary melanoma is reserved for sporadic or familial melanomas linked to high‐risk genes with high penetrance. The first genes related to melanoma were CDKN2A and CDK4, but recently, other genes, mostly tumor suppressor genes, have been described. Internal malignancies, particularly pancreatic cancer, have also been associated with melanoma. Recent studies suggest that there could be a link between melanoma and other neoplasms and tumor predisposition syndromes. This review presents an updated overview of familial melanoma criteria and genes involved in melanoma pathogenesis, emphasizing their clinicopathological aspects and other associated malignancies. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) is a slowly progressive, locally aggressive and rarely metastasizing cancer, and although its mortality is low, its morbidity and cost of disease are high. While BCC is more common, cutaneous malignant melanoma (CMM) is significant due to its higher mortality rate. These patients can be treated, but recurrence, metastasis and mortality may occur in such patients. Various environmental, phenotypic and genotypic factors, especially ultraviolet (UV) radiations, play a role in the etiology of BCC and CMM. Histopathological examination continues to be the “gold standard” in their diagnosis. Spexin (SPX) and DARS2 are newly discovered proteins linked to many diseases, including cancer. These proteins may have an effect on the development and expression of skin cancers such as BCC and CMM. In this study, we evaluated the potential of SPX and DARS2 expressions as immunohistochemical biomarkers in the differential diagnosis of BCC and CMM. This study was conducted retrospectively using samples taken from the pathology laboratory. A total of 180 patient samples were used. The control group consisted of healthy skin tissues of the patients, and the other groups consisted of BCC and CMM tissues of the same patients. Tissue samples of all three groups were evaluated immunohistochemically with SPX and DARS2. The immunoreactivity of SPX was found to be higher in BCC and CMM tissue samples than in healthy skin tissues in the control group. DARS2 immunoreactivity was found to be higher in CMM tissues compared to the other two groups, and statistically significant in BCC tissues when compared with healthy control group tissues. SPX can be used as an immunohistochemical biomarker in the diagnosis of BCC and CMM. Since DARS2 expression is statistically more significant in CMM tissues than in BCC tissues, it can be used in differential diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of Vogt-Koyanagi-Harada (VKH)-like uveitis under treatment with Dabrafenib and Trametinib for metastatic malignant melanoma, representing the longest follow-up (49 months) with retinal multimodal imaging. Methods: Retrospective case report. Results: A 49-year-old female with metastatic relapsing cutaneous malignant melanoma presented with blurry vision in both eyes for 1 week. She had been treated with Dabrafenib and Trametinib for 2 months. Fundus examination detected serous retinal detachments (SRDs) and hyperemic optic disks. Spectral-domain optical coherence tomography (SD-OCT) revealed SRDs, retinal pigment epithelium undulations, choroidal thickening, and loss of normal choroidal vascular architecture. The patient was diagnosed with VKH-like uveitis secondary to targeted agents since systemic investigations were unremarkable. Dabrafenib and Trametinib were discontinued, and pulse steroid treatment was started. Following the improvement of retinal and choroidal signs, the same targeted agents were restarted 6 weeks later. No recurrence of uveitis occurred during 49 months of follow-up; however, the convalescent phase findings of VKH were observed in the fundus examination. The systemic status of the patient, who is still using Dabrafenib and Trametinib, is stable. Conclusion: Although the mechanism is still unknown, the development of VKH-like uveitis secondary to targeted therapy may indicate successful tumor control in patients with metastatic melanoma. Providing effective immunosuppression with corticosteroids and making necessary dose modifications with a multidisciplinary approach may extend the survival of patients. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective cohort study. Objective: Calvarial osteoradionecrosis (ORN) is a rare but devastating complication of radiotherapy. The aim of this study was to describe the cumulative incidence of Calvarial ORN in patients in patients treated for cutaneous malignancy of the scalp. Methods: Data was compiled from patient records of a large tertiary hospital Plastic Surgery department and radiotherapy records of an affiliated cancer Center. We included all patients that were treated for cutaneous malignancies of the scalp that received radiotherapy. Patient demographics, cancer stage, treatment modalities, intraoperative details, and patient outcome data were recorded. Patients with incomplete radiotherapy data were excluded. Results: We analyzed 105 radiotherapy treatments to the scalp administered to 84 patients and recorded 7 cases of calvarial ORN resulting in a gross incidence of 6.67% per radiotherapy treatment. The parietal bone was the most frequently targeted site of radiotherapy and accordingly the most common site of ORN (85.7%). Median time from radiotherapy dose to the development of ORN was 846 days. Higher number of radiotherapy fractionation (P =.038), cumulative radiotherapy dose (P =.035), prolonged radiotherapy duration (P =.022) and skin grafting (P =.003) were associated with the development of ORN. Conclusions: Our findings suggest radiotherapy variables, such as prolonged radiotherapy duration, increased cumulative dose and higher radiotherapy fractions were strongly associated with the development of ORN. In addition, skin grafting following surgical resection was associated with the development of ORN. Further studies with larger sample sizes are required to further explore this relationship. [ABSTRACT FROM AUTHOR]

The article discusses Dr. Martin C. Mihm, Jr.'s role in the Pigmented Lesion Clinic at Massachusetts General Hospital 50 years ago, focusing on melanoma diagnosis and treatment practices in 1973. The clinic, led by Drs. Thomas B. Fitzpatrick and Martin C. Mihm, saw an average of seven patients per session on Friday mornings. Diagnostic equipment included a flashlight for side lighting and a Wood's light for assessing pigmentation. Treatment involved wide local excision with 5 cm margins and follow-up every 3 months for the first 2 years. The article highlights the historical context of melanoma diagnosis and treatment, emphasizing the evolution of practices over time. [Extracted from the article]

Simple Summary: Cutaneous melanoma is a malignancy of melanocytes with increasing global incidence. While most early-stage cases have favorable outcomes, melanomas can unexpectedly progress, highlighting the need for better risk prediction methods. This review examined the 31-gene expression profile (31-GEP) test, which analyzes the activity of 31 genes in melanoma tumors to predict the risk of metastasis. Data from multiple studies was systematically reviewed and analyzed to assess the 31-GEP test's efficacy in predicting melanoma patient outcomes. Our findings suggest that the 31-GEP test may improve risk prediction when used alongside standard clinical and pathological assessments. By using 31-GEP, physicians may be better able to make more informed decisions about treatment and follow-up care, potentially improving outcomes for melanoma patients. Background: Cutaneous melanoma is an increasingly common and potentially lethal form of skin cancer. Current staging systems based on clinical and pathological features have limitations in accurately predicting outcomes, particularly for early-stage disease. The 31-gene expression profile (31-GEP) test has emerged as a promising tool for improving risk stratification in melanoma patients. Methods: We conducted a systematic review and meta-analysis of studies evaluating the prognostic performance of the 31-GEP test in cutaneous melanoma. A comprehensive literature search was performed in multiple databases. Studies reporting survival outcomes stratified by 31-GEP class were included. Random-effects models were used to determine survival estimates across studies. Results: Thirteen studies comprising 14,760 patients were included in the meta-analysis. The 31-GEP test consistently stratified patients into risk groups with significantly different outcomes. The 5-year melanoma-specific survival rates were 99.8% (95% CI: 98–100%) for Class 1A, 97.6% (95% CI: 92.4–99.3%) for Class 1B/2A, and 83.4% (95% CI: 66.5–92.7%) for Class 2B. Similar trends were observed for recurrence-free and distant metastasis-free survival. Conclusions: This meta-analysis supports the prognostic utility of the 31-GEP test in cutaneous melanoma prognostication. The test consistently stratified patients into clinically meaningful risk groups across multiple survival metrics. These findings support the potential clinical utility of the 31-GEP test in enhancing current staging systems and informing personalized management strategies for melanoma patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous irAEs are some of the most reported adverse reactions to ICIs. This prospective monocentric study seeks to offer a comprehensive overview of the skin toxicity associated with these therapies in a single-center institution, with the aim of describing their incidence and our approach for management. Additionally, we aim to highlight the importance of dermatological assessment for affected patients, as it can have a major impact on both their quality of life and the decision to continue treatment. Background/Objectives: The landscape of advanced melanoma treatments has shifted dramatically in recent years. Target therapy and immunotherapy have changed the management of patients with both metastatic (stage IV according to AJCC 8th ed.) and nodal (stage IIB/C and III) disease. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, high-grade or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining a patient's quality of life is of paramount importance. Methods: We undertook a prospective, monocentric, and descriptive study in Bologna, Italy, including patients referred to the Oncologic Dermatology Unit of IRCCS AOU of Bologna who developed biopsy-proven cutaneous adverse events (AE) under treatment with immunotherapy for cutaneous melanoma with nodal (stage IIB/C, III) and metastatic (stage IV) disease from January 2016 to April 2024. Results: In 202 identified patients, 75 (37.5%) developed skin AEs. Ipilimumab was causal for 48.1% of skin AEs, followed by nivolumab (37%) and pembrolizumab (31.4%). Recorded types of skin AEs included erythematous rash, vitiligo, alopecia, lichenoid, maculopapular, acneiform, urticarial, psoriasiform, granulomatous, eczematous, and severe cutaneous AEs, such as Erythema multiforme/Stevens-Johnson syndrome and bullous autoimmune dermatoses. Most AEs were low-grade [CTCAE 1–2] (97%) and typically occurred after 10 weeks of treatment. Conclusions: This study comprehensively describes skin AEs occurring during systemic treatment with ICIs for cutaneous melanoma at a single center. [ABSTRACT FROM AUTHOR]

Objective: To explore the role of the reversion inducing cysteine rich protein with Kazal motifs (RECK) gene in inhibiting of cutaneous malignant melanoma (CMM) proliferation by vemurafenib. Methods: The expression of RECK gene in CMM tissue and adjacent tissue was verified through bioinformatics analysis, and divided the sample into low expression and high expression groups based on the expression of RECK gene in CMM tissue. The differences between the RECK gene low expression group and the high expression group were analysed by Kaplan Meier survival curve. Human malignant melanoma A375 cells were used to construct a nude mouse transplanted tumor model. When the tumor volume reached about 100 mm³, the tumor-bearing mice were divided into vemurafenib group (75 mg/kg/day gavage) and the control group (equal amount of solvent gavage), with 6 mice in each group. After treatment, CMM tissue was collected, and real-time fluorescence quantitative PCR was used to detect and compare the mRNA expression levels of RECK gene between the verbenib group and the control group. Western blot and immunohistochemical staining were used to detect and compare the differences in RECK protein expression levels between the remofenib group and the control group. Results: Bioinformatics analysis showed that the expression level of RECK gene in CMM tissues was significantly lower than that in adjacent tissues, with statis- tical significance (P<0.001). Kaplan Meier survival curve analysis showed that the level of RECK gene expression was correlated with the prognosis of CMM patients, the survival time of the RECK gene low expression group was shorter than that of the high expression group (P=0.007). After 16 consecutive days of administration, the relative tumor proliferation rate and tumor inhibition rate of the vemurafenib group were 37.60% and 63.45%, respectively, and successfully constructed a CMM nude mouse tumor inhibition model for transplantation. The relative amounts of RECK mRNA in the vemurafenib group and the control group were 1.02± 0.13 and 0.99± 0.15, respectively, with no statistically significant difference (P>0.05); The expression of RECK protein in the vemurafenib group and the control group was 0.19± 0.01 and 0.18± 0.01, respectively, with no statistically significant difference (P>0.05); Immunohistochemical staining showed that the RECK gene was negatively expressed in both the vemurafenib group and the control group. Conclusion: The RECK gene is correlated with the development and prognosis of CMM, but there is no significant change in RECK during the inhibition of CMM proliferation by veimofenib. [ABSTRACT FROM AUTHOR]

Purpose: Heat shock protein A4 (HSPA4) is associated with a variety of human diseases. However, its function in cutaneous malignant melanoma (CMM) remains uncertain. Patients and Methods: The gene and protein expression level of HSPA4 in CMM was investigated with public databases. Cell Counting Kit-8 (CCK8) assay was performed to assess the effect of HSPA4 on the proliferation of melanoma cells. Then, the diagnostic and prognostic value of HSPA4 in CMM were analyzed. Gene variations and methylation levels, and the correlation between HSPA4 expression and immune cell infiltration were evaluated, followed by the construction of HSPA4 related protein-protein interaction networks and functional enrichment analysis. Results: The mRNA and protein expression level of HSPA4 was significantly higher in CMM. Knocking down HSPA4 in A-375 cell line could inhibit tumor cell growth. The receiver operating characteristic (ROC) curve analysis confirmed the diagnostic value of HSPA4. Survival analysis showed that high expression of HSPA4 was associated with poor prognosis. HSPA4 gene alterations were observed in 3% of CMM patients. Five CpG sites are associated with the prognosis of CMM. HSPA4 is negatively correlated with most immune cells in CMM. The protein interaction network shows that HSPA4 is closely related to proteins such as DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1) and DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6), and the expression of DNAJB1 is positively correlated with HSPA4. Functional enrichment analysis indicated that HSPA4 may be associated with immune suppression and immune escape within the tumor microenvironment of CMM. Conclusion: HSPA4 may participate in the regulation of tumor development and microenvironment, which may be a potential diagnostic and prognostic marker of CMM. [ABSTRACT FROM AUTHOR]

The article discusses the association of MC1R variants with melanoma risk and their interaction with sun exposure. The study analyzed data from nine melanoma case-control studies to evaluate how sun exposure modifies the effect of MC1R variants on melanoma risk. The findings suggest that there is a significant additive interaction between MC1R R variants and high sunburn frequency, indicating potential at-risk subgroups for melanoma prevention and early diagnosis interventions. The study was supported by various research grants and ethical approval was obtained for all original studies. [Extracted from the article]

The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16INK4a. Melanocytes within skin biopsies from FMS patients express significantly less p16INK4a but express higher levels of the DNA‐damage protein 훾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence‐related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo. [ABSTRACT FROM AUTHOR]

Objective. The primary aims of the study were to (1) explore the association of skin cancer and four ultraviolet radiation (UVR) indicators (sunbed use, healthcare data on diagnosed melanocytic nevi (MN) and actinic keratosis (AK), and latitude of birthplace), and (2) find factors other than UVR that could explain the increasing trend in incidence of skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and cutaneous malignant melanoma (CMM). Methods. This population‐based cohort study used self‐reported questionnaire data from the Stockholm Public Health Cohort, encompassing 103 questions, merged with data from Swedish national registers. The study population included almost 35,000 Swedish‐born people aged 30–66 years in 2014. Binomial logistic regression was employed for analysis. A forward stepwise regression was applied to select significant risk factors among all the factors included. We tentatively tested >30 variables separately for any relationship with each of the three skin cancers. A 5% level of significance was applied. Melanoma in situ and SCC in situ were excluded. Results. The four UVR‐related factors (sunbed use, being diagnosed with AK or MN, birthplace latitude) had a significant association with at least one of the three skin cancers that remained after adjustment including behavioural, social, hereditary, and medical factors. Sunbed use >10 times before age 30 years was related to all three skin cancers; SCC adjusted odds ratio (aOR) 1.66, 95% confidence interval (CI) 1.12–2.47, CMM (aOR 1.57, 95% CI 1.11–2.22), and the clearest dose‐response association with BCC (aOR 1.74, 95% CI 1.46–2.06). None of the examined lifestyle factors, except physical activity, had any significant associations with UVR indicators or skin cancer. Conclusion. We did not find any preventable explanatory cause other than UVR exposure for the increasing incidence of skin cancers. This result remained when adjusting for an array of possible confounders including behavioural, social, hereditary, and medical factors. [ABSTRACT FROM AUTHOR]

Background: Globally, acral melanoma (AM) is underrepresented in most clinical trials, being predominant in Caucasian populations. Latin America is a niche that needs to be explored. Therefore, this study aimed to determine the clinical features, response patterns, outcomes and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) status in Peruvian patients with advanced AM. Methods: We retrospectively reviewed the medical records of 19 patients with advanced AM who received immunotherapy (IO) in first- or subsequent-line therapy. The samples were analysed, and their mutational state was performed by deoxyribonucleic acid sequencing, focusing primarily on the most frequently mutated gene, BRAF. Descriptive statistics were used to assess the baseline characteristics. Overall survival was estimated using the Kaplan-Meier method. Results: The median age was 64 years and 63.2% were men. Plantar was the site most frequently affected (84.2%). The most frequent stage was stage III (68.4%), with 26.4% receiving adjuvant therapy. The majority of cases exhibited a Breslow thickness of >4 mm (52%), a Clark level of IV/V (89.4%), and all patients presented ulceration and a high range of mitosis. During follow-up, all patients experienced recurrent advanced disease, with 52.6% developing visceral metastasis. Patients who received IO as first or subsequent line had an overall response rate (ORR) of 33.3%, and those who received it as first-line therapy had an ORR of 40%. Twenty-one percent of the patients harbored BRAF V6000E mutation and, showing an ORR of 50% compared to wild-type individuals (44.4%) after the first line of treatment. Conclusion: Our preliminary study reported that AM has poor clinico-pathological features and response rates to IO in Peruvian patients. However, those who received IO as a first-line treatment or harbored the BRAF mutation appeared to have a slightly better response than wild-type patients. [ABSTRACT FROM AUTHOR]

Background: Cutaneous malignant melanoma (CMM) ranks among the five most common cancers in young people in high‐income countries and it features peculiar clinicopathological traits. Very few studies have addressed the quality of care and the costs for adolescents and young adults (AYA) population. Objective: To provide a comprehensive epidemiological and clinicopathological profile of CMM in AYA. The study also addresses the cost‐of‐illness and the diagnostic‐therapeutic performance indicators by patient age category. Methods: This population‐based cohort study included 2435 incident CMM (age range 15–65 years; age 15–39 = 394; age 40–65 = 2041), as recorded in 2015, 2017 and 2019 by the Regional Veneto Cancer Registry (Italy). Cramer's‐V tested the strength of association between pairs of variables. The Kaplan–Meier method was used to test the association between age and survival rate. The clinical performance indicators were computed using the Clopper–Pearson exact method. Results: In AYA patients (16.2%), CMM incidence rates increased significantly from 1990 to 2019. Low‐stage CMM (p = 0.007), radial growth pattern (p = 0.026) and lower Clark levels (p = 0.007) prevailed; males had less advanced malignancies (p = 0.003), with the trunk as the most common primary site (67.5%); the lower limbs (32.6%) were the most common primary site for females (p < 0.001). Overall survival was better in AYA than adults. No significant difference was detected in the clinical management of the two age groups, with the only exception of the margin in wide local excision. The care costs were lower in AYA (€195.99 vs. €258.94, p = 0.004). Conclusions: In AYA patients, the CMM clinicopathological presentation shows a distinctive profile. The present results provide critical information for optimizing primary and secondary prevention strategies and for tailoring diagnostic therapeutic procedures to the peculiar profile of AYA CMM patients. [ABSTRACT FROM AUTHOR]

Cutaneous malignant melanoma accounts for 5% of cancer diagnoses and is the fifth most common cancer diagnosed in the United States. Risk factors for cutaneous malignant melanoma include ultraviolet radiation from sun exposure, Fitzpatrick skin type I or II, a history of dysplastic nevi, indoor tanning, older age, and a personal or family history of melanoma. The U.S. Preventive Services Task Force recommends counseling with patient education on minimizing early ultraviolet radiation exposure, including the use of protective clothing and sunscreen, especially for patients 6 months to 24 years of age. Tools to aid in the diagnosis of cutaneous malignant melanoma and the decision to biopsy include the ABCDE mnemonic, ugly duckling sign, and dermoscopy. Any suspicious pigmented lesion should be biopsied. Biopsy with a deep scoop shave, saucerization, punch biopsy, or full-thickness excision is preferred to ensure the entire lesion is removed to obtain an accurate measurement of Breslow depth. Breslow depth is important in staging, treatment consideration, and prognosis. Wide local excision by a dermatologist or surgeon with appropriate margins is the primary treatment of choice. Thin lesions with a Breslow depth of less than 0.8 mm usually do not need further treatment after wide local excision and have an excellent prognosis. Lesions with a Breslow depth greater than 0.8 mm may need further diagnostic tests or procedures, including sentinel lymph node biopsy, complete lymph node dissection, gene mutation analysis, and possible treatment with systemic immunotherapy. Use of systemic immunotherapies has improved the prognosis for advanced melanoma (stages III and IV), with 5-year survival rates of 74.8% and 35%, respectively, compared with 62.6% and 16% from 1975 to 2011 before immunotherapy was available. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous melanoma (CM) is an aggressive skin cancer that develops from melanocytic cells. The most important prognostic factor is still the vertical tumour thickness according to Breslow. Liver function is associated with better overall patient outcomes and is currently under increasing investigation in cancer patients. Current findings show that liver function is an important factor in different tumour entities and represents a potential biomarker. Therefore, we aimed to evaluate liver metabolism by using liver scores in CM. High tumour thickness (≥1.66 mm) and aspartate transaminase-to-platelet ratio index (APRI ≥ 0.2241) at the initial diagnosis were associated with a worse prognosis in stage I and II melanoma. Background: Neoadjuvant and adjuvant therapies are currently getting increasingly important in cutaneous melanoma (CM) management. However, there is still a lack of prognostic tools to identify which patients have a poor prognosis. There is increasing evidence that the liver score may be a potential prognostic parameter in different tumour types. The aim was to investigate whether established liver scores can establish the prognosis of CM. Methods: According to established methods, the APRI, the MELD score, the MELD-Na score and the De Ritis ratio were calculated from the laboratory values at the time of the initial diagnosis. Survival was compared with the Kaplan–Meier curve and tested with log-rank tests. Risk factors associated with cutaneous melanoma-specific survival (CMSS) and progression-free survival (PFS) were assessed by using the Cox proportional hazards regression model. To determine the diagnostic accuracy, we performed a time-dependent ROC analysis. Results: A total of 423 patients were included, including 141 patients in AJCC stage (2017) I (33.3%), 82 in stage II (19.4%), 128 in stage III (30.3%) and 72 in stage IV (17%). Median time until melanoma-specific death was 99 months (IQR: 37–126). In addition, 37.6% of patients relapsed with a median time to relapse of 88 months (IQR: 17.5–126). In all stages, tumour thickness and ulceration were independent markers for predicting CMSS and PFS (p < 0.05). The multivariable analysis with all stages showed no significant association with CM outcome for liver scores (p > 0.05). The subgroup analysis revealed that the APRI (≥0.2241) was associated with CMSS and PFS in melanoma stages I and II, independently of tumour thickness, age and ulceration (HR 2.57, 95% CI 1.14–5.75; HR 2.94, 95% CI 1.42–6.09, respectively). Conclusions: The 20-year prognosis of AJCC stage I and II CM was dependent on tumour thickness and the APRI. High tumour thickness and an APRI ≥ 0.2241 at the initial diagnosis were associated with a worse prognosis. Future studies should investigate the independent prognostic value of the APRI in low-stage CM. Furthermore, the APRI score could be a potential biomarker for nomograms. [ABSTRACT FROM AUTHOR]

Introduction: Cutaneous malignant melanomas rarely occur in the eye, usually in the eyelids or the conjunctiva. Conjunctival malignant melanomas are even rarer. Most melanomas are dark in color as they are pigmented. However, amelanotic conjunctival malignant melanomas, a scarce variant of the cancer, can be challenging to diagnose accurately. Case presentation: We present two cases of white Caucasian Swedish-born women who were diagnosed with unilateral amelanotic malignant melanoma in the conjunctiva of the eye. In the first case, the patient was an 81-year-old woman who was suffering from redness and foreign body sensation in the left eye. The initial diagnosis was blepharitis. Three biopsies were taken, which showed malignant melanoma in the eyelid and the conjunctiva. Unfortunately, the eye and the rest of the orbit could not be saved, and the patient had to undergo an orbital exenteration. In the second case, the patient was a 50-year-old woman, and the tumor was localized in the temporal conjunctiva of the left eye. The initial diagnosis was pinguecula, but at the time of surgery, the physician suspected conjunctival intraepithelial neoplasia. The tumor was not completely removed, so adjuvant brachytherapy and local chemotherapy were used. The eye was preserved. No neck and/or lung metastasis was detected in either case at the time of diagnosis. Conclusions: Conjunctival amelanotic malignant melanomas should be suspected when tumors are present in the eye and/or the eyelids. By suspecting amelanotic malignant melanoma, the delay in treatment can be shortened. Treating them as soon as possible is essential to minimize the risk of metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancer rates in Canada are rising quickly, with about one-third of Canadians likely to be affected in their lifetime. Despite this alarming trend, government actions to reduce skin cancer are limited. Our study, conducted in Manitoba, found that many residents have risky sun exposure habits and lack awareness about skin cancer. Over 65% reported a history of sunburns, more than half had used tanning beds, and a large majority recently tanned for pleasure. Misconceptions are common, with over 50% believing that tans are healthy or a sign of beauty. Moreover, sun protection practices are inadequate, with less than 60% using protective clothing and under 50% using sunscreen. These findings highlight the need for targeted public health campaigns to improve awareness and promote better sun protection behaviors to prevent future skin cancers in Manitoba. The rapidly increasing skin cancer rates in Canada are alarming, with current data estimating that 1/3 of Canadians will be affected in their lifetime. Thus, deeper understanding of high-risk sun exposure behaviors is needed to help counter this trend. Only limited action has been taken by federal/provincial governments to reduce skin cancer incidence. A cross-sectional survey study was conducted in Manitoba, with frequency counts, means, and percentages used to encapsulate responses. Age- and gender-adjusted odds ratios were calculated using logistic regression analyses. Our study identified worrying inadequacies in sun protective behaviors and attitudes, with the threat of such high-risk behaviors amplified by a lack of skin cancer awareness. Alarming elements were noted in participants' sun exposure history (>65% reported a history of sunburns, >50% previously used a tanning bed, and >75% recently tanned for pleasure), beliefs and attitudes (>50% believe that they look better/healthier with a tan, and >40% believe that having a base tan is protective against further sun damage), and sun protection efforts (sun protective clothing was used <60% of the time, sunscreen was used by <50%, and there was a lack of knowledge about sunscreen characteristics in ~30% of respondents), in addition to significant differences being established between demographic subgroups (based on gender, age, skin phototype, income, and education attained). This study provides worrisome insight onto the grim landscape of sun protective behaviors and attitudes in Manitoba, which will inevitably translate into higher skin cancer rates and should serve as a call to action to promote targeted public health messaging in this jurisdiction and beyond. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma is the deadliest of all skin cancers. Therapy paradigms in cutaneous melanoma have changed significantly over the past 20 years, following both changes in the initial staging work-up of melanoma as well as in the available therapies. Regional recurrences after initial surgery are normally treated with nodal basin resection. However, some regional recurrences may present as bulky masses that can pose significant challenges in the treatment and control of the disease. It is well established that radiation therapy (RT) plays a role in locoregional control of malignancies in general. This review will attempt to discuss evidence for radiation therapy's role in reducing regional recurrence in the adjuvant setting in melanoma, identify adjuvant systemic therapy options, discuss systemic therapy–radiation therapy combinations, and identify paradigms and emerging evidence for the use of radiation therapy after neoadjuvant systemic therapy strategies are employed. In the landscape of Stage III locoregionally advanced cutaneous melanoma treatment, the post-immunotherapy era has sparked a number of questions on the management of the nodal basin. However, much of the available literature is not focused on radiation therapy as an adjuvant therapy. This literature review aims to illuminate the evidence surrounding radiation therapy's potential to mitigate regional recurrences in the adjuvant setting for melanoma. Additionally, it seeks to identify adjunct systemic therapy options and explore the synergy between systemic therapy and radiation. Despite strides in surgical techniques and systemic therapies, controlling regional Stage III melanoma remains a formidable clinical hurdle. While historical data strongly suggest the efficacy of adjuvant radiation therapy in reducing regional recurrence risk, its evaluation predates the advent of MAPK pathway inhibitors and robust immunotherapy options. Notably, clinical trials have yet to definitively demonstrate a survival advantage with adjuvant radiation therapy. Additional research should focus on refining the definition of high risk for regional recurrence through gene expression profiling or tumor immune profiling scores and elucidate the optimal role of adjuvant radiation therapy in patients treated with neoadjuvant systemic therapy. [ABSTRACT FROM AUTHOR]

The aberrant activation of the hepatocyte growth factor receptor (c-Met) in malignant melanoma is associated with poor prognosis, fostering tumor progression, angiogenesis, and invasiveness. While therapeutic targeting of this pathway has shown promise in several tumors, our previous findings revealed increased tumorigenicity following tyrosine kinase inhibitor SU11274 treatment. Therefore, we hypothesized that administering c-Met inhibitors may elicit distinct effects in human melanoma cells. In this study, we investigated the influence of three c-Met inhibitors, SU11274, crizotinib, and PHA665752, on molecular characteristics, tumorigenicity, and metastatic behavior in three human melanoma cell lines, M4Beu, EGFP-A375 and its metastatic variant, EGFP-A375/Rel3 (Rel3). Crizotinib and PHA665752 induced upregulation of MET proto-oncogene, receptor tyrosine kinase (MET), alongside cancer stem cell marker Prominin 1 (CD133), pluripotency marker Nanog homeobox (Nanog), and genes encoding angiogenic factors and receptors in Rel3 cells, correlating with supportive effect on tumorigenicity in vivo. The increased tumorigenicity of the Rel3 cells following the SU11274 treatment correlated with the elevated phosphorylation of Akt, p70 S6 and RSK kinases. Our results demonstrate pleiotropic changes induced by small-molecule inhibitors of receptor tyrosine kinases in melanoma cell lines. [ABSTRACT FROM AUTHOR]

To investigate whether PSGL-1 is correlated with the prognosis of cutaneous malignant melanoma. Genetic data of PSGL-1 and cutaneous malignant melanoma were extracted from genomewide association studies (GWAS) and analyzed using inverse variance weighting, MR-Egger regression, weighted median, weighted mode, and simple mode methods, and sensitivity analyses were performed on the data. Survival information of cutaneous malignant melanoma was extracted from the TCGA database, and grouped according to high and low PSGL-1 expression, survival curves were plotted by the Kaplan-Meier method, and the Log-rank test was used to compare the difference between the two survival periods. Exploring the effects of PSGL-1 on the biological functions of A375 cells through in vitro experiments. The inverse variance weighted method analysis of PSGL-1 on cutaneous malignant melanoma resulted in OR=0.666, 95% CI (0.494-0.899), P=0.008. The median survival was 44.70 months in the PSGL-1 high expression group and 29.13 months in the PSGL-1 low expression group, P=0.000 2. PSGL-1 inhibits the migration of A375 cells in vitro. Increased PSGL-1 expression is a protective factor against cutaneous malignant melanoma and is a potential prognostic marker for cutaneous melanoma. [ABSTRACT FROM AUTHOR]

BackgroundCutaneous Malignant Melanoma (CMM) is a significant global health challenge. Understanding regional differences in CMM prevalence and trends is crucial for developing targeted strategies. To address this, we analyzed epidemiological patterns and investigated risk factors for CMM-related mortality.MethodsThis study analyzed CMM using data from the 2021 Global Burden of Diseases survey, covering 204 countries and territories. We evaluated the number and age-standardized rates of prevalence (ASPR), mortality (ASMR), disability-adjusted life years (ASDR), and annual percentage changes (EAPCs). Trends were stratified by region, country, age, sex, and Sociodemographic Index (SDI). A Bayesian Age-Period-Cohort model projected future prevalence, mortality, and DALYs, while decomposition analysis identified key drivers of CMM burden. Frontier analysis further associated CMM outcomes with socio-demographic development.ResultsIn 2021, the global prevalence of CMM reached 833,215 cases, a 161.3% increase since 1990. During this period, the ASPR rose from 19.13 to 25.37 per 100,000, while the ASMR declined from 0.84 to 0.73 per 100,000. DALYs increased by 60.5%, from 1,045,777 to 1,678,836. The high SDI region had the highest ASPR, ASMR, and ASDR. Decomposition analysis identified population growth, demographic aging, and epidemiological changes as equal drivers of CMM DALYs globally. Countries like New Zealand and Australia demonstrated the most significant effective differences, indicating potential for improvement in CMM management. By 2045, the global ASPR is projected to rise to 36.61, with ASMR and ASDR expected to decrease to 0.79 and 10.21 per 100,000.ConclusionCMM poses an increasing global health concern, with ASPR steadily rising. While this analysis shows a decline in global ASMR and ASDR overall, these rates are actually increasing in low SDI regions, and projections indicate that this trend will likely continue until 2045.

The article discusses the diagnostic accuracy of using photoacoustic imaging (PAI) for cutaneous malignant melanoma. The study combines PAI with established methods like dermoscopy and reflectance confocal microscopy (RCM) to improve diagnostic precision. Results show that PAI can visualize endogenous chromophores and aid in diagnosing skin lesions, with a 20% increase in sensitivity when combined with RCM. The study emphasizes the potential of advanced imaging techniques in reducing unnecessary skin biopsies and healthcare costs, highlighting the importance of operator expertise and cost-effectiveness in implementing these technologies. [Extracted from the article]

The editorial in Frontiers in Endocrinology discusses the direct and indirect endocrine and metabolic consequences of malignancies. Malignancies of endocrine organs and other organs can lead to various endocrine or metabolic syndromes, affecting patient prognosis. The impact of immunotherapy on endocrine homeostasis is also highlighted, with specific cases and research findings discussed. The article emphasizes the importance of early diagnosis and management of endocrine disorders in malignant tumors, as well as the need for effective biomarkers to predict and monitor endocrine adverse reactions in patients undergoing immunotherapy. [Extracted from the article]

Aim: Our purpose was to determine the constraints of sentinel lymph node biopsy (SLNB) in malignant melanoma (MM) and to optimize the necessity for additional research to enhance its precision. Materials and Methods: This retrospective study investigated the factors that influence the results of SLNB performed on patients with MM. Eighty-five patients with primary cutaneous MM were analyzed by their histopathological data, surgical records, and clinical follow-up information. An evaluation was conducted on variables including Breslow thickness, Clark level, mitotic rate, lymphatic and vascular invasion, negative predictive value (NPV), and SLNB results. Results: The statistical analysis showed that increased Breslow thickness, lymphatic or vascular invasion, and the presence of ulceration were found to have a significant impact on SLNB positivity. However, there was no correlation found between Clark level and SLNB outcomes. For the NPV of the test, it decreases with increasing Clark level and mitotic rate, as well as lymphatic or vascular invasion. In our study, the NPV was calculated as 81%. We also calculated the false-negative rate, which was found to be 19%. Conclusions: Further, investigation is warranted to optimize SLNB methodologies. To achieve this, we recommend additional investigations to refine SLNB techniques, explore unidentified risk factors, and incorporate advanced imaging methods for better detection of hidden lymph node metastases. In summary, understanding the factors influencing SLNB outcomes in MM is crucial for developing effective treatments and follow-up protocols. Key variables to consider in assessing nodal involvement include Breslow thickness and lymphatic or vascular invasion, among others.

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. [ABSTRACT FROM AUTHOR]

Background: Lentigo maligna (LM) exhibits a particular epidemiological profile compared to other histopathologic subtypes of melanoma, with a propensity for the head and neck area and a higher mean age at diagnosis. Few small‐scale studies have exclusively evaluated the risk factors for the development of LM. Objective: This study aims to compare LM to other histological subtypes of melanoma for the prevalence of known melanoma risk factors, including pigmentary characteristics, history of occupational sun exposure, nevus count, and familial melanoma history. Patients and methods: We conducted a case–control study of 152 patients with LM and 784 patients with other melanoma subtypes (OM). The Mann–Whitney t‐test and Pearson chi‐squared test were used to detect differences between the two groups in continuous and categorical variables, respectively. Univariate and multivariate logistic regression models were then constructed to identify risk factors for developing LM compared to other melanoma subtypes. Results: In multivariate logistic regression analysis, LM was positively associated with a lentigines count >50 and occupational sun exposure compared to OM (OR 2.10, 95% CI 1.35–3.29 and OR 2.18, 95% CI 1.33–3.57, respectively). In contrast, patients with an increased nevus count and fair or medium skin color were less likely to develop LM than OM (OR 0.93, P < 0.001, 95% CI 0.91–0.94, and OR 0.28, P < 0.001, 95% CI 0.17–0.46, respectively). In univariate analysis, LM exhibited a weaker association with all pigmentary traits than OM. No significant associations were found for atypical nevi count and family history. Conclusion: We found significant differences in the prevalence of known melanoma risk factors between LM and other melanoma subtypes, which supports the hypothesis of a distinct pathogenetic pathway of LM. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have emerged as a promising therapeutic option for melanoma, which demonstrating improved clinical outcomes in melanoma patients regardless of specific genetic mutations. However, the identification of reliable biomarkers for predicting immunotherapy response and prognosis remains a challenge. In this study, we performed genetic profiling of the melanoma patients with different subtypes and evaluated the efficacy of ICI treatment. A total of 221 melanoma patients were included in our cohort, consisting primarily of acral lentiginous melanoma (ALM), cutaneous malignant melanoma (CMM), and mucosal malignant melanoma (MMM). Genetic analysis revealed BRAF mutations was predominant in CMM and NRAS mutations was prevalent in ALM. Copy number variants (CNVs) and structural variants (SV) were also detected, with CCND1 and CDK4 being the most affected genes in CNV and BRAF, ALK and RAF1 being the druggable targets in SV. Furthermore, NRAS mutations were associated with a poor prognosis in ALM, while TERT mutations were linked to unfavorable outcomes in CMM after receiving PD-1 therapy. Additionally, ALK expression exhibited improved outcomes in both ALM and CMM subtypes. Our study provides a comprehensive genomic and pathological profiling of Chinese melanoma patients, shedding light on the molecular landscape of the disease. Furthermore, numbers of gene mutations and ALK expression were identified as prognostic indicators. These findings contribute to the understanding of melanoma genetics in the Chinese population and have implications for personalized treatment approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: A positive sentinel lymph node biopsy of cutaneous melanoma patients has a substantial impact on subsequent treatment decisions. The standard of care approach to identify the sentinel lymph node is technetium (Tc)-based lymphoscintigraphy. This technique comes with a radiation exposure and high costs. Indocyanine green (ICG)-based near-infrared fluorescence imaging could be an alternative if demonstrated to have a comparable diagnostic accuracy. Therefore, a systematic literature review and meta-analysis were conducted considering studies comparing the accuracy of ICG and Tc for intraoperative guidance. Within the seven included studies, no significant differences between the two modalities were found regarding the identification of metastatic patients or the false negative rate. ICG may be a non-inferior alternative to Tc for intraoperative identification of the sentinel lymph node in cutaneous melanoma patients. The standard of care approach to identify sentinel lymph nodes (SLNs) in clinically non-metastatic cutaneous melanoma patients is technetium (Tc)-based lymphoscintigraphy. This technique is associated with radiation exposure, a long intervention time, high costs, and limited availability. Indocyanine green (ICG)-based near-infrared fluorescence imaging offers a potential alternative if proven to be of comparable diagnostic accuracy. While several clinical cohorts have compared these modalities, no systematic review exists that provides a quantitative analysis of their results. Hence, a systematic literature review was conducted in December 2023 considering clinical studies comparing the diagnostic accuracy of ICG and Tc for sentinel lymph node biopsy in cutaneous melanoma patients. Three hundred nineteen studies were identified and further screened in accordance with the PRISMA 2020 guidelines, resulting in seven studies being included in the final meta-analysis. Tc identified a significantly higher number of SLNs and metastatic SLNs in prospective studies only. However, in the overall meta-analysis of all included comparative studies, no significant differences were found regarding the identification of metastatic patients or the false negative rate (FNR). ICG may be a non-inferior alternative to Tc for intraoperative guidance in sentinel lymph node biopsy in cutaneous melanoma patients. Future randomized controlled trials are needed, especially regarding the preoperative, transcutaneous identification of the affected lymph node basin. [ABSTRACT FROM AUTHOR]

Skin malignant melanoma (MM) is one of the most frequent and aggressive neoplasia worldwide. Its associated high mortality rates are mostly due to its metastases, while diagnosis and treatment of MM in its early stages is of favorable prognostic. Even skin superficial MMs at incipient local stages can already present with lymph node invasion and distant metastases. Therefore, knowledge of the controllable risk factors and pathogenic mechanisms of MM development, spreading, and metastatic pattern, as well as early diagnosis, are essential to decrease the high mortality rates associated with cutaneous malignant melanoma. Genetic factors are incriminated, although lifetime-acquired genetic mutations appear to be even more frequently involved in the development of MM. Skin melanocytes divide only twice per year and have time to accumulate genetic mutations as a consequence of environmental aggressive factors, such as UV exposure. In the search for more promising therapies, matrix metalloproteinases have become of significant interest, such as MMP-1, MMP-2, MMP-9, and MMP-13, which have been linked to more aggressive forms of cancer and earlier metastases. Therefore, the development of specific synthetic inhibitors of MMP secretion or activity could represent a more promising and effective approach to the personalized treatment of MM patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Advancements in immune, targeted, and regional therapies have emerged in the past fifteen years in the management of high-risk, advanced, and metastatic melanomas. Rare melanoma variants include acral, mucosal, uveal, and desmoplastic melanoma. Though underrepresented in larger landmark trials for modern therapeutic options, results from these trials have been extrapolated and applied in the management of these rarer subtypes of melanoma. This article aims to review the current treatment recommendations for acral, mucosal, uveal, and desmoplastic melanomas. Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma survival rates have been vastly improved by the use of immune checkpoint inhibitors. However, some patients do not respond to the treatment or experience progression of disease. Because of this variability of response, markers predicting efficacy of these treatments is of interest. This study aimed to clarify the role of primary tumor characteristics in melanoma treatment and survival. The authors demonstrated that cutaneous melanoma and its subtypes were significantly associated with response, progression-free survival, and overall survival compared with acral or unknown primary melanoma. Other primary features did not demonstrate an association on multivariable analyses. Thus, primary features, other than cutaneous primary, should likely not influence metastatic treatment selection. Identifying patients likely to benefit from immune checkpoint inhibitor (ICI) treatment remains a crucial goal for melanoma. The objective of this study is to assess the association between primary tumor features and immunotherapy response and survival in advanced melanoma patients. In this single-center retrospective cohort study, disease characteristics, response to immunotherapy, PFS, and OS were assessed among melanoma patients (excluding mucosal and uveal primaries) treated with ICI. Among 447 patients, 300 (67.1%) received anti-PD-1 monotherapy and 147 (32.9%) received ipilimumab/nivolumab. A total of 338 (75.6%) had cutaneous melanoma, 29 (6.5%) had acral melanoma, and 80 (17.9%) had melanoma of unknown primary. Ulceration and stage at initial presentation were associated with inferior outcomes on univariate analysis. However, on multivariate analysis, this result was not observed, but cutaneous melanoma and each of its subtypes (superficial spreading, nodular, other, unknown) were positively associated with response, longer PFS, and longer OS. Metastatic stage (M1c, M1d) at presentation (OR = 1.8, p < 0.05) and BRAFV600E mutation status (OR = 1.6, p < 0.001) were associated with shorter PFS. This study is limited by its retrospective and single-center design. Cutaneous melanoma and its subtypes were significantly associated with response, PFS, and OS compared with acral or unknown primary melanoma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background The psychological burden of cutaneous malignant melanoma (CM) is all-encompassing, affecting treatment adherence, recurrence and mortality. However, the prevalence and risk factors of anxiety and depression in CM remain unclear. Objectives To establish a benchmark pooled prevalence of anxiety and depression in CM, to provide magnitudes of association for clinical, therapeutic and demographic correlates, and to elucidate temporal trends in anxiety and depression from the time of diagnosis. Methods This review followed the MOOSE guidelines. MEDLINE, Embase, PsychINFO, Web of Science and the Cochrane Library were queried from database inception to 24 August 2023. Study selection, data extraction and quality assessment were performed by two independent authors, utilizing both the Joanna Briggs Institute (JBI) and National Institutes of Health risk-of-bias tools for the latter. The GRADE approach was used to rate the certainty of evidence. Prevalence rates, 95% confidence intervals (CIs) and prediction intervals (PIs) were derived using a random-effects model and estimating between- and within-study variance. Results Nine longitudinal and 29 cross-sectional studies were included (7995 patients). Based on the JBI and NIH tools, respectively, quality assessment found 20 and 17 to be at low risk of bias, 12 and 15 to be at moderate risk and 6 and 5 to be at high risk of bias. The prevalence of anxiety [30.6% (95% CI 24.6–37.0; PI 18–47%)] and depression [18.4% (95% CI 13.4–23.9; PI 10–33%)] peaked during treatment, declining to pretreatment levels after 1 year [anxiety: 48% vs. 20% (P = 0.005); depression: 28% vs. 13% (P = 0.03)]. Female sex [odds ratio (OR) 1.8, 95% CI 1.4–2.3; P < 0.001], age < 60 years (OR 1.5, 95% CI 1.2–2.0; P = 0.002) and low educational level (OR 1.5, 95% CI 1.2–2.0; P < 0.001) were likely to result in a large increase in the odds of anxiety. Depression was 12.3% higher in those with stage IV vs. those with stage I CM (P = 0.05). Relative to immune checkpoint inhibition, the rates of depression were 22% (P = 0.002) and 34% (P < 0.001) higher among patients with advanced-stage CM receiving interferon-α and chemotherapy, respectively. A significant reduction in self-reported depression scores was demonstrated over time (P = 0.003). Conclusions Notably, anxiety and depression in CM affect women, those younger than 60 years of age and the less educated, with up to 80% higher odds of anxiety in these groups. Anxiety and depression surge during chemotherapy and interferon treatment, especially in advanced CM. Our findings facilitate risk stratification and underscore the need for multidisciplinary vigilance. [ABSTRACT FROM AUTHOR]

Aim: Our purpose was to determine the constraints of sentinel lymph node biopsy (SLNB) in malignant melanoma (MM) and to optimize the necessity for additional research to enhance its precision. Materials and Methods: This retrospective study investigated the factors that influence the results of SLNB performed on patients with MM. Eighty-five patients with primary cutaneous MM were analyzed by their histopathological data, surgical records, and clinical follow-up information. An evaluation was conducted on variables including Breslow thickness, Clark level, mitotic rate, lymphatic and vascular invasion, negative predictive value (NPV), and SLNB results. Results: The statistical analysis showed that increased Breslow thickness, lymphatic or vascular invasion, and the presence of ulceration were found to have a significant impact on SLNB positivity. However, there was no correlation found between Clark level and SLNB outcomes. For the NPV of the test, it decreases with increasing Clark level and mitotic rate, as well as lymphatic or vascular invasion. In our study, the NPV was calculated as 81%. We also calculated the false-negative rate, which was found to be 19%. Conclusions: Further, investigation is warranted to optimize SLNB methodologies. To achieve this, we recommend additional investigations to refine SLNB techniques, explore unidentified risk factors, and incorporate advanced imaging methods for better detection of hidden lymph node metastases. In summary, understanding the factors influencing SLNB outcomes in MM is crucial for developing effective treatments and follow-up protocols. Key variables to consider in assessing nodal involvement include Breslow thickness and lymphatic or vascular invasion, among others. [ABSTRACT FROM AUTHOR]

Malignant melanoma of the parotid gland is an unusual tumor in the head and neck region, and most parotid melanoma is reported as a metastatic lesion of cutaneous malignant melanoma. We report a case of primary malignant melanoma arising in the parotid gland duct with diagnostic challenge. The patient was a 68-year-old man who complained of repeated right facial swelling that presented 3 months prior. Swelling was detected along the Stensen's duct of the cheek, and brown-colored saliva-like fluid was aspirated. On MR and CT images, a fluid-filled duct with small nodule and heterogeneously enhancing mass in the parotid parenchyma was detected. The nodular mass on the ductal wall grew rapidly, and the hyperintense T1 signal became significant on follow-up images. The final diagnosis via histopathologic examination using biopsy and parotidectomy specimen revealed the lesion as malignant melanoma of the duct and pleomorphic adenoma of the parenchyma. Even if the incidence of primary malignant melanoma is very low among tumors occurring in the parotid gland, efforts supporting an early diagnosis using imaging characteristics are important. [ABSTRACT FROM AUTHOR]

Simple Summary: We conducted a study at the Melanoma Unit of the Hospital Clinic of Barcelona to investigate brain metastases in patients with cutaneous melanoma. We collected data from patients diagnosed between January 1998 and September 2023. Patients with melanoma in situ or those with prior lung or breast cancer were excluded. Our aim was to identify factors associated with the development and survival outcomes of brain metastases. We analyzed patient demographics, tumor characteristics, and survival data. The diagnosis of brain metastases was confirmed using imaging techniques, and biopsies were performed when feasible. Our study followed strict guidelines for reporting observational studies. We found that younger age and larger primary tumor thickness increased the risk of developing brain metastases. Additionally, the presence of ulceration and microscopic satellitosis in the primary tumor were associated with a higher risk. Melanomas located on the trunk had a higher risk compared to those on the extremities. Patients with brain metastases had a median survival of around six months. Neurological symptoms and leptomeningeal involvement were associated with poorer survival outcomes. Higher number of brain lesions and elevated levels of lactate dehydrogenase (LDH) also predicted worse survival. Our findings highlight the importance of early detection and monitoring of melanoma patients, especially those at higher risk of brain metastases. Understanding these factors can aid in personalized treatment approaches and improving patient outcomes. Background: Melanoma is the cancer with the highest risk of dissemination to the central nervous system (CNS), one of the leading causes of mortality from this cancer. Objective: To identify patients at higher risk of developing CNS metastases and to evaluate associated prognostic factors. Methods: A cohort study (1998–2023) assessed patients who developed CNS melanoma metastases. Multivariate logistic regression was used to identify predictive factors at melanoma diagnosis for CNS metastasis. Cox regression analysis evaluated the CNS-independent metastasis-related variables impacting survival. Results: Out of 4718 patients, 380 (8.05%) developed CNS metastases. Multivariate logistic regression showed that a higher Breslow index, mitotic rate ≥ 1 mm2, ulceration, and microscopic satellitosis were significant risk factors for CNS metastasis development. Higher patient age and the location of the primary tumor in the upper or lower extremities were protective factors. In survival analysis, post-CNS metastasis, symptomatic disease, prior non-CNS metastases, CNS debut with multiple metastases, elevated LDH levels, and leptomeningeal involvement correlated with poorer survival. Conclusion: Predictive factors in the primary tumor independently associated with brain metastases include microscopic satellitosis, ulceration, higher Breslow index, and trunk location. Prognostic factors for lower survival in CNS disease include symptomatic disease, multiple CNS metastases, and previous metastases from different sites. [ABSTRACT FROM AUTHOR]