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Abstract
Skin cancer has become the most common neoplasm in the United States. With early diagnosis and appropriate management, most skin cancers have an overall 5-year survival rate of 95%. Cutaneous malignant melanoma (CMM), however, has a significantly higher morbidity and mortality, resulting in 65% of all skin cancer deaths. Although the long-term survival rate for patients with metastatic melanoma is only 5%, early detection of CMM carries an excellent prognosis, with surgical excision often being curative. Primary care physicians can play a critical role in reducing morbidity and mortality from CMM by recognizing patients at risk, encouraging the adoption of risk-reducing behaviors, and becoming adept at identifying suspicious lesions.
... L'application de ces techniques à la culture d'explants ex vivo s'est révélée pertinente pour reproduire des réactions similaires à celles observées in vivo lors de l'évaluation de la toxicité de composés pharmaceutiques (Abaci et al. 2015), et ouvre des perspectives en termes d'optimisation des recherches précliniques. Il existe 4 principaux types de mélanomes cutanés (Cummins et al. 2006, Données de l'Institut National du Cancer) : ...
... Le développement du mélanome est associé à différents facteurs de risque (Oliveria et al. 2006;Cummins et al. 2006;Armstrong et al. 2011;Lo and Fisher 2014 (Cummins et al. 2006). ...
... Le développement du mélanome est associé à différents facteurs de risque (Oliveria et al. 2006;Cummins et al. 2006;Armstrong et al. 2011;Lo and Fisher 2014 (Cummins et al. 2006). ...
Le mélanome métastatique est le cancer de la peau le plus agressif. Bien que son taux d’incidence soit inférieur à 1%, plus de 75% des décès associés à un cancer de la peau lui sont attribués. Au cours des dernières années, de nouvelles stratégies thérapeutiques ont permis d’améliorer la survie des patients. Cependant, des mécanismes de résistance à ces traitements se développent dans la majorité des cas, conduisant à une phase de rechute, et une survie à 5 ans inférieure à 20%. Des modèles d’étude expérimentaux sont nécessaires afin de comprendre les mécanismes impliqués dans l’apparition de ces résistances et développer de nouvelles stratégies thérapeutiques. Différents modèles in vitro sont actuellement utilisés pour le développement de drogues anti-tumorales, tels que celui du sphéroïde. Bien qu’il permette de reproduire l’organisation tridimensionnelle d’une tumeur, l’absence de microenvironnement tumoral empêche l’étude des interactions entre les cellules tumorales et celui-ci alors que ces facteurs jouent un rôle primordial dans la croissance tumorale et le développement de métastases. Dans ce contexte, mes travaux ont porté sur le développement et la caractérisation d’un modèle ex vivo de mélanome humain complet permettant l’étude de l’évolution d’une tumeur dans le tissu sain et l’évaluation de composés pharmacologiques. Les travaux réalisés ont tout d’abord conduit au développement d’un modèle de cancer cutané basé sur la combinaison d’un modèle de sphéroïde de lignée cellulaire de mélanome humain et du modèle de peau humaine ex vivo NativeSkin®, développé par la société Genoskin. Une procédure a été développée et validée pour permettre l’implantation reproductible d’un sphéroïde dans le derme des explants de peau. Parallèlement, j’ai développé une approche d’imagerie in situ par microscopie à feuille de lumière après transparisation des modèles. J’ai également développé une stratégie d’analyse d’images permettant la caractérisation quantitative de l'évolution du sphéroïde implanté en 3 dimensions et de suivre la dispersion des cellules du tumorales au sein de l’explant de peau. La caractérisation histologique du modèle implanté a révélé de façon très inattendue une perte progressive de l’intégrité du sphéroïde après implantation, associée à une diminution rapide de la prolifération des cellules le constituant et l’apoptose massive des cellules situées à sa périphérie. Ce phénomène a été observé de façon similaire lors de l’implantation de sphéroïdes produits à partir de différents types cellulaires. Afin de comprendre ces résultats, j’ai étudié l’implication potentielle de différents paramètres dans l’induction de la mortalité cellulaire observée tels que les conditions d’implantation, les facteurs synthétisés par le modèle et la contrainte mécanique exercée par le derme. Les résultats obtenus suggèrent que les facteurs sécrétés par les modèles après implantation du sphéroïde ont un effet antiprolifératif sur les sphéroïdes de mélanome et qu’ils induisent la mortalité des cellules situées à sa périphérie. Par ailleurs, l’application d’une contrainte mécanique extérieure sur les sphéroïdes de mélanome entraîne la perte de la cohésion de leur structure. Enfin, l’implantation de sphéroïdes dans le derme de biopsies de peau préalablement desséchées, induisant une perte de la viabilité cellulaire, a conduit à des résultats opposés à ceux observés avec de la peau normale : la structure des sphéroïdes reste cohésive et la prolifération des cellules est maintenue en périphérie du sphéroïde sans qu’aucune apoptose massive ne soit observée. L'ensemble de ces travaux semble suggérer que la mortalité du sphéroïde pourrait être, en partie, la conséquence d’une contrainte mécanique exercée par la peau sur le sphéroïde et/ou de facteurs produits par la peau durant sa culture. Ces données ouvrent des perspectives intéressantes dans le domaine de l’ingénierie tissulaire pour l’évaluation pharmacologique de composés thérapeutiques.
... Melanoma, the second most common invasive cancer in young adults, although accounting for only 4% of skin cancers, accounts for over 80% of skin cancer deaths due to its metastatic nature [1,2]. Melanoma, unlike other cancers, is largely unaffected by chemo-and radio-therapies [3]; however, encouragingly, surgical excision is highly effective in non-metastatic melanoma, with a ~90% 5-year survival rate [4,5]. However, if tumors metastasize, the survival rate is extremely poor [4,5]. ...
... Melanoma, unlike other cancers, is largely unaffected by chemo-and radio-therapies [3]; however, encouragingly, surgical excision is highly effective in non-metastatic melanoma, with a ~90% 5-year survival rate [4,5]. However, if tumors metastasize, the survival rate is extremely poor [4,5]. Identification of novel drug therapies are therefore essential. ...
Melanoma is the leading cause of skin cancer–related death. As prognosis of patients with melanoma remains problematic, identification of new therapeutic targets remains essential. Matricellular proteins are nonstructural extracellular matrix proteins. They are secreted into the tumor microenvironment to coordinate behavior among different cell types, yet their contribution to melanoma is underinvestigated. Examples of matricellular proteins include those comprising the CCN family. The CCN family member, CCN1, is highly proangiogenic. Herein, we show that, in human patients with melanoma, although found in several tumor cell types, CCN1 is highly expressed by a subset of cancer-associated fibroblasts (CAF) in patients with melanoma and this expression correlates positively with expression of proangiogenic genes and progressive disease/resistance to anti-PD1 checkpoint inhibitors. Consistent with these observations, in a syngeneic C57BL6 mouse model of melanoma, loss of CCN1 expression from Col1A2-Cre-, herein identified as “universal,” fibroblasts, impaired metastasis of subcutaneously injected B16F10 tumor cells to lung, concomitant with disrupted neovascularization and collagen organization. Disruption of the extracellular matrix in the loss of CCN1 was validated using a novel artificial intelligence–based image analysis platform that revealed significantly decreased phenotypic fibrosis and composite morphometric collagen scores. As drug resistance is linked to matrix deposition and neoangiogenesis, these data suggest that CCN1, due to its multifaceted role, may represent a novel therapeutic target for drug-resistant melanoma. Our data further emphasize the essential role that cancer-associated, (universal) Col1A2-Cre-fibroblasts and extracellular matrix remodeling play in coordinating behavior among different cell types within the tumor microenvironment.
Significance
In human patients, the expression of proangiogenic matricellular protein CCN1 in CAFs correlates positively with expression of stroma and angiogenic markers and progressive disease/resistance to checkpoint inhibitor therapy. In an animal model, loss of CCN1 from CAFs impaired metastasis of melanoma cells, neovascularization, and collagen deposition, emphasizing that CAFs coordinate cellular behavior in a tumor microenvironment and that CCN1 may be a novel target.
... Certain phenotypic features are largely recognized as predisposing factors for CM, regardless of family history. Such particularities include blonde or red hair, light complexion, and light eye color (especially when associated with Central or Northern European ancestry), with a consequently heightened sensitivity and an altered response to ultraviolet radiation (UVR) exposure [32][33][34]. These qualities are often associated with the inability to tan and the tendency to develop freckles or moles, and emphasize the importance of UVR in the development of a cutaneous neoplasm [35][36][37][38][39][40][41]. ...
... CM can emerge anywhere on the body but is most common in areas chronically exposed to the sun [64]. The most significant environmental risk factor for CM oncogenesis is UVR from sunlight exposure [65][66][67], which induces melanocyte transformation by triggering DNA damage to the skin [33,68,69]. Exposure to UV-B spectrum radiation has been proven to consistently increase the risk of developing CM [70]. ...
Both cutaneous melanoma (CM) and uveal melanoma (UM) represent important causes of morbidity and mortality. In this review, we evaluate the available knowledge on the differences and similarities between cutaneous melanoma and uveal melanoma, focusing on the epidemiological aspects and risk factors. Uveal melanoma is a rare condition but is the most prevalent primary intra-ocular malignant tumor in adults. Cutaneous melanoma, on the other hand, is significantly more common. While the frequency of cutaneous melanoma has increased in the last decades worldwide, the incidence of uveal melanoma has remained stable. Although both tumors arise from melanocytes, they are very distinct entities biologically, with complex and varied etiologies. Both conditions are encountered more frequently by individuals with a fair phenotype. ultraviolet-radiation is an important, well-documented risk factor for the development of CM, but has shown not to be of specific risk in UM. Although cutaneous and ocular melanomas seem to be inherited independently, there are reported cases of concomitant primary tumors in the same patient.
... Melanoma is an extremely malignant cancer that accounts for less than 20% of all skin cancers (1) but accounts for more than 80% of deaths caused by skin cancers (2). Melanoma often exhibits high invasion ability and metastasizes to the brain, liver, lung, and skin. ...
... Melanoma often exhibits high invasion ability and metastasizes to the brain, liver, lung, and skin. Current evidence suggests that conventional chemotherapy has little effect on melanoma (2). The immunotherapy drug called 1methyl-D-tryptophan (1MT) is well established to have poor water solubility, which restricts its clinical treatment for the treatment of melanoma (3,4). ...
In this study, we synthesized a molecule GA-1MT (GM) composed of indoleamine 2,3-dioxygenase (IDO) inhibitor (1-methyl-d-tryptophan, 1MT) called NLG8189 and gallic acid (GA) and verified its therapeutic effect on B16F10 melanoma cells and an orthotopic tumor-bearing mouse model. The synthesized molecule GM was analyzed by ¹H NMR and mass spectrometry (MS). In addition, we confirmed that GM could mediate the immune response in the B16F10 cell tumor model by flow cytometry and immunofluorescence. The synthesized GM molecule could increase the solubility of 1MT to enhance the drug efficacy and lower costs. Moreover, GM could inhibit melanoma growth by combining 1MT and GA. In vivo experiments showed that GM could effectively inhibit the expression of tyrosinase, regulate the proportion of CD4⁺ T cells, CD8⁺ T cells, and regulatory T cells (Treg cells) in tumors, and significantly suppress melanoma growth. The newly synthesized drug GM could more effectively inhibit melanoma than GA and 1MT alone or in combination.
... Generally melanoma was restricted cancer but in the last 50 years, its proportion has ascended more rapidly than nearly any other cancer. Standing to the American Cancer Society in 2019, roughly 96,480 people are foreseen to be determined to have melanoma in the US alone, while 7230 people are required to pass on due to melanoma [13]. While it actually addresses under 5% of all dermatological malignancies, Melanoma represents the greatest part of skin cancer deaths [36]. ...
... Specif icity = T N T N + F P (12) P recision = T P T P + F P (13) F 1 − score = 2 × Recall × P recision Recall + P recision (14) Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Skin cancer is considered one of the most dangerous and popular sorts of cancer. The deadliest form of this type of cancer is called melanoma, it happens while pigmented cells named melanocytes begin to subdivide tensely. If early detected melanoma could be easily and accurately healed. Hence, immediate diagnosis of this kind of skin cancer is crucial. Currently, dermoscopy has become one of the most efficient tools utilized in pigmented skin lesions diagnosis. Due to the expense of processing each patient by dermatologists, a computerized recognition system is highly required to evaluate every patient’s state. This paper aims to automatize the process of classifying dermoscopic images containing skin lesions into benign or malignant. Therefore an improved deep learning-based solution with a convolutional neural network is proposed. Regularization, dropout, and data augmentation are used to avoid the CNN model over-fitting. The proposed method has been tested on three different publicly available datasets and the obtained results demonstrate its effectiveness when compared to the state-of-the-art methods. Thus, the proposed framework can be adopted for assisting dermatologists with melanoma diagnosis.
... A skin lesion is a serious and deadliest form of cancer, which is the irregular development of cells that affects any part of the human body [3]. Melanoma is among the worst types of skin cancer, with a survival rate of about 5% [4]. The expansion of skin cancer has increased rapidly in the last few years. ...
A serious, all-encompassing, and deadly cancer that affects every part of the body is skin cancer. The most prevalent causes of skin lesions are UV radiation, which can damage human skin, and moles. If skin cancer is discovered early, it may be adequately treated. In order to diagnose skin lesions with less effort, dermatologists are increasingly turning to machine learning (ML) techniques and computer-aided diagnostic (CAD) systems. This paper proposes a computerized method for multiclass lesion classification using a fusion of optimal deep-learning model features. The dataset used in this work, ISIC2018, is imbalanced; therefore, augmentation is performed based on a few mathematical operations. After that, two pre-trained deep learning models (DarkNet-19 and MobileNet-V2) have been fine-tuned and trained on the selected dataset. After training, features are extracted from the average pool layer and optimized using a hybrid firefly optimization technique. The selected features are fused in two ways: (i) original serial approach and (ii) proposed threshold approach. Machine learning classifiers are used to classify the chosen features at the end. Using the ISIC2018 dataset, the experimental procedure produced an accuracy of 89.0%. Whereas, 87.34, 87.57, and 87.45 are sensitivity, precision, and F1 score respectively. At the end, comparison is also conducted with recent techniques, and it shows the proposed method shows improved accuracy along with other performance measures.
... Melanoma, an aggressive form of skin cancer originating from melanocytes [1], poses a significant challenge with its escalating incidence and bleak prognosis upon metastasis [2][3][4][5]. Despite available therapies like molecular-targeted and immunotherapies, treatment efficacy is hampered by drug resistance and suboptimal patient response [1,6,7]. ...
Malignant melanoma represents a form of skin cancer characterized by a bleak prognosis and heightened resistance to traditional therapies. Quercetin has demonstrated notable anti-carcinogenic, anti-inflammatory, anti-oxidant, and pharmacological effects across various cancer types. However, the intricate relationship between quercetin’s anti-cancer properties and ganglioside expression in melanoma remains incompletely understood. In this study, quercetin manifests specific anti-proliferative, anti-migratory, and cell-cycle arrest effects, inducing mitochondrial dysfunction and apoptosis in two melanoma cancer cell lines. This positions quercetin as a promising candidate for treating malignant melanoma. Moreover, our investigation indicates that quercetin significantly reduces the expression levels of ganglioside GD3 and its synthetic enzyme. Notably, this reduction is achieved through the inhibition of the FAK/paxillin/Akt signaling pathway, which plays a crucial role in cancer development. Taken together, our findings suggest that quercetin may be a potent anti-cancer drug candidate for the treatment of malignant melanoma.
... In dermatology, the mean Young's modulus of hands with scleroderma is 51% higher than that of healthy hand tissues [2]. Malignant melanoma (MM) of the skin accounts for 65% of all skin cancer deaths, but it is generally curable with early detection and surgical excision [3]. Precise estimation of the Young's modulus of tissue has the potential to evaluate pathological status [4][5][6] for early diagnosis. ...
Increased stiffness of tissues has been recognised as a diagnostic feature of pathologies. Tissue stiffness characterisation usually involves the detection of tissue response from mechanical stimulation. Air-puff optical coherence elastography (OCE) can generate impulse surface acoustic waves (SAWs) on tissue surface without contact and evaluate the mechanical properties of tissue. This study endeavours to explore the optimal excitation angle for air-puff OCE, a parameter that lacks standardisation at present, by investigating the relationship between the frequency bandwidth and peak-to-peak signal-to-noise ratio (SNR) of SAWs for different excitation angles (relative to the normal surface) of air-puff on the sample, from 5° to 85°, with an interval of 5° applied on the phantom. Due to the unevenness of human hands, 20°, 45° and 70° angles were employed for human skin (10 healthy adults). The results show that a smaller excitation angle could produce higher wave frequency bandwidth; a 5° angle generated an SAW with 1747 Hz frequency bandwidth, while an 85° angle produced an SAW with 1205 Hz. Significant differences were not shown in peak-to-peak SNR comparison between 5° and 65° on the phantom, but between 65° and 85° at the excitation position, a reduction of 48.6% was observed. Furthermore, the group velocity of the SAWs was used to evaluate the bulk Young’s modulus of the human tissue. The outcomes could provide essential guidance for air-puff-based elastography studies in clinical applications and future tissue research.
... Malignant melanoma is an aggressive form of skin cancer that accounts for approximately 75% of skin cancer-related deaths worldwide [1,2]. According to American Cancer Society, estimate for melanoma in the United States for 2023 was about 97,610 new cases of invasive and 89,070 cases of in-situ melanoma will be diagnosed in United States, while 7,990 (approx) people are expected to die of melanoma Melanoma will be leading cause of death world wide. ...
Objective: The goal of the current research is to identify the dominant phytochemical from the plantNyctanthesarbor-tristis Linn. and to investigate their binding affinities against the proteins BRaf Kinase mutant (3OG7) and Hsp90 Chaperone (2VCJ) that causesmelanoma. Methods: In this work, Schrodinger software was utilized to investigate the anti-cancer potential of phytochemicals Nyctanthesarbor-tristis against specific target proteins, namely BRaf Kinase mutant (3OG7) and Hsp90 Chaperone (2VCJ) Inhibitors. Results: Based on the outcome of the docking investigation, phytochemicals that exhibited highest binding affinity to the specified protein targets were subjected to induced fit docking and MM-GBSA computations using the Schrodinger Maestro version 2021.2 in prime module. According to the analysis, the compounds with the highest binding affinities for 2VCJ and 3OG7 are Arbortristoside D and Nicotiflorin respectively. The compound that interacted with both the proteins wasArbortristoside B. These phytochemicals appear to be more effective to the FDA-approved V600E-BRaf inhibitor Vemurafenib and Hsp90 Chaperone Inhibitor Diclonine. Conclusion: One of the most common, deadly, and dangerous malignant diseases with a high global prevalence rate is melanoma (skin cancer). The present study may prove more helpful in developing an ideal targeted drug delivery system of phytochemicals obtained from plant Nyctanthesarbor-tristisfor treatment of melanoma. This suggests that these substances could be evolved into highly effective anti-melanoma drugs.
... Cutaneous melanoma is a very aggressive skin cancer that can metastasize, that is, spread to other organs and be difficult to treat (Cummins et al., 2006). However, the compounds derived from the specialized metabolism of plants can be used as therapeutic agents, helping to combat tumor cells. ...
The essential oil from Piper corcovadense D.DC. (EOPc), an important plant belonging to the Piperaceae family, which is commonly found in the northern region of Brazil and poorly explored scientifically, was used in this study. Thus, the EOPc was characterized chemically by Gas Chromatography/Mass Spectrometry (GC/MS) and the antioxidant and antimicrobial activities and their potential effects on cutaneous melanoma (SK-MEL-28) and healthy peripheral blood mononuclear (PBMC) cells were determined. The major compounds identified in the EOPc were: trans-sesquisabinene hydrate, trans-caryophyllene, β-pinene, trans-β-farnesene, 14-hydroxycaryophyllene, limonene and p-cymene. The EOPc demonstrated antioxidant activity as evaluated by Folin-Ciocalteu reagent (FC) reducing capacity, DPPH, and ABTS methods. The values found were respectively 5.41 ± 0.17 mg GAE mL⁻¹ (GAE: Gallic acid equivalent), 2.88 ± 0.17 µmol TE mL⁻¹ (TE: Trolox equivalent) and 6.26 ± 0.02 µmol TE mL⁻¹. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for different bacterial strains. The EOPc at a concentration of 2.61 µg mL⁻¹ exhibited both bactericidal and bacteriostatic properties against Escherichia coli. The EOPc showed potential antitumor activity as it reduced the cell viability of human cutaneous melanoma cells SK-MEL-28. Besides, the EOPc did not exhibit cytotoxic activity against healthy PBMCs, indicating that it does not harm healthy cells at the tested concentrations. The EOPc increased the levels of ROS at concentrations of 250 µg mL⁻¹. The EOPc also did not stimulate the mobilization of endogenous antioxidant defenses, as assessed by total thiol (PSH) and non-protein thiols (NPSH). Thus, the study suggests that the EOPc has antioxidant and antimicrobial properties due to the presence of specific compounds. It also exhibits antitumor potential against cutaneous melanoma cells while showing no cytotoxicity to healthy PBMCs. It directly influenced ROS levels at the highest tested concentration in the cells, suggesting an antitumor effect related to the intrinsic apoptosis pathway. Nevertheless, while the study has initial findings, the results are promising and indicate an attractive biological potential of P. corcovadense, mainly in human cutaneous melanoma cells.
... El cáncer de vulva representa el 5% del total de cánceres ginecológicos y el 1% de la pato logía maligna femenina. El tipo histológico más frecuente corresponde al carcinoma de células escamosas (9095%), mientras que el melano ma maligno es el segundo (810%) [1]. El mela noma cutáneo es un proceso neoplásico que se produce a partir de la degeneración maligna de los melanocitos. ...
El cáncer de vulva representa solo el 1% de los canceres en las mujeres, siendo el melanoma maligno el menos frecuente dentro de este tipo de cáncer. Se presenta en mujeres de edad avanzada. Su manejo es principalmente quirúrgico y tiene una elevada mortalidad principalmente por enfermedad metastásica. Presentamos el caso de una mujer que llegó con una masa en los labios mayores y fue diagnosticada como melanoma maligno vulvar, tratada con cirugía y radioterapia de forma oportuna, pero que presenta metástasis pulmonar, quien recibe actualmente tratamiento para esto.
... Early detection and treatment are vital for patients' survival. 27 The ophthalmology legal claim has the second rate (16.2%) of legal malpractice claims after the dermatology legal claim in the current study. Laser advances in ophthalmology are one of the most important medical applications of lasers in medical science. ...
Background: the purpose of the present study is to investigate the common causes of injuries, claims, and decisions related to laser therapy medical malpractice during a nine-year survey.
Study design: This study is a retrospective descriptive study.
Methods: The legal documents in the coroner’s Office of Forensic Medicine were investigated in a national database from 2012 to 2020 in Tehran, Iran. The frequency and nature of the cases, including the year of litigation, the location and certificate of the provider, the injury sustained, the cause of legal action and judgment were collected.
Results: Three hundred and eighty-three cases related to injury from laser therapy were registered in the coroner’s Office of Forensic Medicine during the study period. The incidence of litigation related to laser surgery showed an increasing trend, with a peak occurrence in 2020.
Laser hair removal was the most common (51.2%) litigated procedure. General practice operators (48%) recorded the highest rate of laser-related medical complaints. lack of skill was the most common reason for failure. Among 383 cases with public decisions, 62.4% of them were fault liability in paid judgment.
Conclusions: Medical claims related to laser application are increasing. However, as it is clear, the growth of laser technology and the increasing demand for lasers in medical science require more surveillance to avoid probable injuries and improve patient safety, especially surveillance of the physicians who work outside the scope of their specialty.
... Cutaneous melanoma is the leading cause of death from skin cancer [1], even though it is the third most common skin cancer [2]. In predominantly fair-skinned, developed countries, such as the United States, cutaneous melanoma incidence has grown over 320% since 1975 [3]. ...
Objective
The aim of this study is to evaluate the expression of the phosphatase and tensin homolog (PTEN), which is a tumor suppressor gene that is implicated in the pathogenesis of cutaneous malignant melanoma, in normal skin and melanoma tissue samples. The study also aimed to correlate PTEN expression levels with various clinicopathological parameters of melanoma lesions, thus highlighting the utility of PTEN expression as a prognostic biomarker for melanoma.
Study design
Immunohistochemistry (IHC) staining was performed on tissue microarray samples representing normal skin and melanoma biopsies of different clinicopathological parameters. Tissue photomicrographs were evaluated with Aperio ImageScope, which has a positive-pixel-counting algorithm built in. Subsequently, a histochemical score (H-score) was derived from the percentage of positive cells (%-staining) and their staining intensity. The H-scores were averaged in groups of tissue samples representing the different melanomas' tumor (T), node (N), and distant metastasis (M), also known as TNM parameters, as set forth by the American Joint Committee on Cancer (AJCC) classification. The mean H-scores were statistically compared using a two-tailed unpaired t-test.
Results
The PTEN protein expression was measured by IHC and found to be correlated with tumor thickness (T), which is a reliable indicator for survival rates. Specifically, PTEN was significantly downregulated in tumors with a thickness over 2 mm (T3+T4) compared to tumors with a thickness at or below 2 mm (T1+T2).
Conclusions
The PTEN protein expression, as measured by immunohistochemistry, helped differentiate between tumors with a thickness over 2 mm and tumors with a thickness at or below 2 mm, suggesting PTEN as a potential surrogate marker for the melanoma's invasion depth along with possible prognostic implications. Longitudinal studies evaluating risk stratification based on the expression of PTEN are needed to establish the utility of this promising biomarker in the clinic as an adjunct for pathological examination.
... The A375 cell line is a cell line isolated from human melanoma, a tumour developed at the level of melanocytes and characterized by a very high invasive capacity and risk of metastasis. The most common forms of melanoma are those of ectodermal origin and those of cutaneous nature [14]. The therapeutic approach to human melanoma is difficult due to the lack of cellular sensitivity to radiotherapy, so the tumour develops rapidly and requires the administration of immunosuppressants or alkylating agents [44]. ...
... Melanoma is a malignant tumor derived from melanocytes that occurs on the surface of the skin. 1) It is the most serious and deadly type of skin cancer, accounting for 6.8 to 20% of skin cancers. 2) Epidemiological studies have shown that the number of melanoma patients in the world has increased year by year in recent years, and the mortality rate of patients is relatively high, which poses a serious threat to people's life and health. 3) Although many scholars have conducted extensive research on melanoma and improved treatment options, 4,5) it remains a great challenge for clinicians to completely cure melanoma. ...
Ponicidin (PON), a diterpenoid extracted from the Chinese herb Rubescens, has been reported to be a therapeutic cytotoxic drug for the treatment of various types of human cancers. According to the statistics, the incidence of malignant melanoma is increasing year by year and the degree of malignancy is extremely high, so early treatment is very important. In the present study, we demonstrated the antitumor effect of PON on melanoma in vitro and in vivo. Cell Counting Kit-8 (CCK-8) assay was used to detect cell proliferation rate, crystal violet staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) kit was used to detect cell apoptosis, and Western blotting was used to detect the expression of apoptotic indicators and related signaling pathway proteins. Finally, the tumor-bearing mouse model was constructed. Treating melanoma B16F0 and B16F10 cells with different concentrations (10 and 20 µmol/L) of PON magnificantly decreased cell viability. In addition, PON significantly activates the expression of pro-apoptotic proteins, including cleaved-poly(ADP-ribose)polymerase (PARP) (cl.PARP), Bak and Bim proteins, and also inhibits the expression of anti-apoptotic protein Mcl-1 and nuclear transcription factor nuclear factor-kappaB (NF-κB) in melanoma cells. Lastly, PON effectively inhibits the growth of mouse xenografts in vivo. These results suggest that PON induces apoptosis of melanoma cells may be achieved by inhibiting NF-κB signal pathway, but the specific mechanism remains to be further elucidated. Taken together, PON may serve as an effective potential drug for the treatment of melanoma.
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... The skin cancer type that is most deadly, cutaneous melanoma, is challenging to cure and has gained attention recently due to an increase in incidence around the world. Resistance, serious side effects, and a poor quality of life have all been connected to the use of antitumoral therapies for this neoplasm [114]. Cancer immunotherapies are now often utilized as adjuvant and neoadjuvant therapy in melanoma patients and have improved previously low survival rates, such as checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab [115,116]. ...
Although immunotherapy is already a staple of cancer care, many patients may not benefit from these cutting-edge treatments. A crucial field of research now focuses on figuring out how to improve treatment efficacy and assess the resistance mechanisms underlying this uneven response. For a good response, immune-based treatments, in particular immune checkpoint inhibitors, rely on a strong infiltration of T cells into the tumour microenvironment. The severe metabolic environment that immune cells must endure can drastically reduce effector activity. These immune dysregulation-related tumour-mediated perturbations include oxidative stress, which can encourage lipid peroxidation, ER stress, and T regulatory cells dysfunction. In this review, we have made an effort to characterize the status of immunological checkpoints, the degree of oxidative stress, and the part that latter plays in determining the therapeutic impact of immunological check point inhibitors in different neoplastic diseases. In the second section of the review, we will make an effort to assess new therapeutic possibilities that, by affecting redox signalling, may modify the effectiveness of immunological treatment.
... Early detection and treatment of CMM can increase the 5-year overall survival rate to 95%. However, after metastasis, only 5% of patients with CMM survive over the long term (7,8). Of course, the prognosis of different patients is affected by many factors, and the survival rate is also different, even very different. ...
Background
This study obtained data on patients with cutaneous malignant melanoma (CMM) from the Surveillance, Epidemiology, and End Results (SEER) database, and used a deep learning and neural network (DeepSurv) model to predict the survival rate of patients with CMM and evaluate its effectiveness.
Methods
We collected information on patients with CMM between 2004 and 2015 from the SEER database. We then randomly divided the patients into training and testing cohorts at a 7:3 ratio. The likelihood that patients with CMM will survive was forecasted using the DeepSurv model, and its results were compared with those of the Cox proportional-hazards (CoxPH) model. The calibration curves, time-dependent area under the receiver operating characteristic curve (AUC), and concordance index (C-index) were used to assess the prediction abilities of the model.
Results
This study comprised 37,758 patients with CMM: 26,430 in the training cohort and 11,329 in the testing cohort. The CoxPH model demonstrated that the survival of patients with CMM was significantly influenced by age, sex, marital status, summary stage, surgery, radiotherapy, chemotherapy, postoperative lymph node dissection, tumor size, and tumor extension. The C-index of the CoxPH model was 0.875. We also constructed the DeepSurv model using the data from the training cohort, and its C-index was 0.910. We examined how well the aforementioned two models predicted outcomes. The 1-, 3-, and 5-year AUCs were 0.928, 0.837, and 0.855, respectively, for the CoxPH model, and 0.971, 0.947, and 0.942 for the DeepSurv model. The DeepSurv model presented a greater predictive effect on patients with CMM, and its reliability was better than that of the CoxPH model according to both the AUC value and the calibration curve.
Conclusion
The DeepSurv model, which we developed based on the data of patients with CMM in the SEER database, was found to be more effective than the CoxPH model in predicting the survival time of patients with CMM.
... More recently, therapy became more effective owing to the use of rapidly accelerated fibrosarcoma B (BRAF) and mitogen-activated protein kinase (MEK) inhibitors, which are active against BRAF-mutated melanomas. A further step has been immunotherapy with monoclonal antibodies inhibiting immune-checkpoint receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) [48,61,62]. These can unblock the anti-tumor immune response, which is particularly relevant in this highly immunogenic tumor. ...
The most important limitations of chemotherapeutic agents are severe side effects and the development of multi-drug resistance. Recently, the clinical successes achieved with immunotherapy have revolutionized the treatment of several advanced-stage malignancies, but most patients do not respond and many of them develop immune-related adverse events. Loading synergistic combinations of different anti-tumor drugs in nanocarriers may enhance their efficacy and reduce life-threatening toxicities. Thereafter, nanomedicines may synergize with pharmacological, immunological, and physical combined treatments, and should be increasingly integrated in multimodal combination therapy regimens. The goal of this manuscript is to provide better understanding and key considerations for developing new combined nanomedicines and nanotheranostics. We will clarify the potential of combined nanomedicine strategies that are designed to target different steps of the cancer growth as well as its microenvironment and immunity interactions. Moreover, we will describe relevant experiments in animal models and discuss issues raised by translation in the human setting.
... Incidence of malignant melanoma is increasing day by day and causing the deaths which are %65 of all scin cancer deaths in the United States. [30] FDG-PET is applied clinically for detection of regional or distant metastases and management of patients with cutaneous melanoma. [31] Falk et al studied on 60 patients with malignant cutaneous melanoma who were performed FDG-PET/CT. ...
... Cutaneous melanoma (CM) is an aggressive and difficult-to-treat skin cancer subtype that originates from malignant mutations in melanocytes. It can spread to other organs in a process called metastasis [1]. The incidence of melanoma continues to increase worldwide and deserves attention. ...
Cutaneous melanoma is the most aggressive type of skin cancer; it is difficult to treat, and has been highlighted in recent years due to increasing numbers of cases worldwide. The use of antitumoral therapeutics for this neoplasm has been associated with severe side effects, low quality of life, and resistance. We aimed in this study to explore the effect of the phenolic compound rosmarinic acid (RA) on human metastatic melanoma cells. SK-MEL-28 melanoma cells were treated for 24 h with different concentrations of RA. In parallel, peripheral blood mononuclear cells (PBMCs) also were treated with RA under the same experimental conditions to verify the cytotoxic effect on non-tumoral cells. Then, we assessed cell viability and migration, levels of intracellular and extracellular reactive oxygen species (ROS), as well as nitric oxide (NOx), non-protein thiols (NPSH), and total thiol (PSH). Gene expression of the caspase 8, caspase 3 and NLRP3 inflammasome was evaluated by RT-qPCR. The enzymatic activity of the caspase 3 protein was assessed by a sensitive fluorescent assay. Fluorescence microscopy was employed to corroborate the effects of RA on melanoma cell viability, mitochondria transmembrane potential and apoptotic bodies formation. We found that RA potently reduces melanoma cell viability and migration after 24 h of treatment. On the other hand, it has no cytotoxic effect on non-tumoral cells. The fluorescence micrographics indicated that RA reduces transmembrane potential of mitochondria and induces apoptotic bodies formation. Moreover, RA significantly decreases intracellular and extracellular ROS levels, and increases the antioxidant defenders NPSH and PSH. A remarkable feature found in our study was that RA strongly upregulates the gene expression of the caspase 8 and caspase 3, and downregulates NLRP3 inflammasome expression. Similar to gene expression, RA greatly increases the enzymatic activity of caspase 3 protein. Taken together, we have shown for the first time that RA reduces cell viability and migration of human metastatic melanoma cells, in addition to modulates apoptosis-related gene expression. We suggest that RA may have the potential to be used in a therapeutic perspective, particularly for CM cell treatment.
... Although novel treatments such as targeted and immune therapies have improved patient survival in melanoma, chemoresistance prevents improving patients' survival. The prognosis is still unsatisfactory, with most patients relapsing soon after their initial response [3]. As a result, new therapeutic targets must be identified to improve existing therapies and the prognosis of refractory melanomas. ...
Melanoma is the most lethal type of skin cancer that originates from the malignant transformation of melanocytes. Although novel treatments have improved patient survival in melanoma, the overall prognosis remains poor. To improve current therapies and patients outcome, it is necessary to identify the influential elements in the development and progression of melanoma.
Due to UV exposure and melanin synthesis, the melanocytic lineage seems to have a higher rate of ROS (reactive oxygen species) formation. Melanoma has been linked to an increased oxidative state, and all facets of melanoma pathophysiology rely on redox biology. Several redox-modulating pathways have arisen to resist oxidative stress. One of which, the Nrf2 (nuclear factor erythroid 2-related factor 2), has been recognized as a master regulator of cellular response to oxidative or electrophilic challenges. The activation of Nrf2 signaling causes a wide range of antioxidant and detoxification enzyme genes to be expressed. As a result, this transcription factor has lately received a lot of interest as a possible cancer treatment target.
On the other hand, Nrf2 has been found to have a variety of activities in addition to its antioxidant abilities, constant Nrf2 activation in malignant cells may accelerate metastasis and chemoresistance. Hence, based on the cell type and context, Nrf2 has different roles in either preventing or promoting cancer. In this study, we aimed to systematically review all the studies discussing the function of Nrf2 in melanoma and the factors determining its alteration.
... На ранних стадиях меланома зачастую поддается успешному хирургическому лечению, однако это не исключает возможности прогрессирования заболевания даже спустя годы после первичной терапии. Для пациентов с метастатическим процессом результаты лечения на протяжении длительного времени оставались крайне неудовлетворительными: по данным литературы, до 2010 г. 5-летняя выживаемость не превышала 6-10 % [2]. Приблизительно в 3,2 % случаев обнаружить первичный очаг меланомы не представляется возможным, что является дополнительной проблемой диагностики и лечения этой патологии [3]. ...
Cutaneous melanoma is characterized by an aggressive course associated with a tendency to metastasis. For a long time, the prognosis of patients with metastatic melanoma remained extremely poor. However, the introduction of immunooncological drugs into clinical practice has changed the approaches to the treatment of patients with metastatic melanoma, and fundamentally improved the prognosis and quality of life of such patients, which undoubtedly became a breakthrough in the treatment of this pathology. This article presents a clinical case of the treatment with immunological drugs of a patient with metastatic melanoma of the skin with lymph nodes of rare localization with a complete tumor response.
... The two of the most critical factors in reducing melanoma mortality are early detection and prompt treatment (16). Surgical resection is considered the primary treatment for early-stage melanoma, but it still has the possibility of metastasis and affects long-term survival outcomes (17). The US Food and Drug Administration (FDA)-approved treatments for metastatic melanoma, including immune checkpoint blocking antibodies (such as anti-CTLA-4 and anti-PD-1), have an effect on reducing population mortality (18). ...
Melanoma is one of the most lethal tumors with highly aggressive and metastatic properties. Although immunotherapy and targeted therapy have certain therapeutic effects in melanoma, a significant proportion of patients still have drug resistance after treatment. Recent studies have shown that long noncoding RNAs (lncRNAs) are widely recognized as regulatory factors in cancer. They can regulate numerous cellular processes, including cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) progression and the immune microenvironment. The role of lncRNAs in malignant tumors has received much attention, whereas the relationship between lncRNAs and melanoma requires further investigation. Our review summarizes tumor suppressive and oncogenic lncRNAs closely related to the occurrence and development of melanoma. We summarize the role of lncRNAs in the immune microenvironment, immunotherapy and targeted therapy to provide new targets and therapeutic methods for clinical treatment.
... Cutaneous melanoma is the most aggressive skin cancer. Surgery is still the best treatment today, but it has a very poor prognosis when it becomes metastatic [4,[31][32][33][34]. In this work, we studied cell migration, which is an important mechanism involved during cancer progression. ...
Cutaneous melanoma is a cancer with a very poor prognosis mainly because of metastatic dissemination and therefore a deregulation of cell migration. Current therapies can benefit from complementary medicines as supportive care in oncology. In our study, we show that a dynamized ultra-low dilution of Ruta Graveolens leads to an in vitro inhibition of migration on fibronectin of B16F10 melanoma cells, as well as a decrease in metastatic dissemination in vivo. These effects appear to be due to a disruption of plasma membrane organization, with a change in cell and membrane stiffness, associated with a disorganization of the actin cytoskeleton and a modification of the lipid composition of the plasma membrane. Together, these results demonstrate, in in vitro and in vivo models of cutaneous melanoma, an anti-cancer and anti-metastatic activity of ultra-low dynamized dilution of Ruta graveolens and reinforce its interest as complementary medicine in oncology.
... Melanoma presents a notable case in our study findings, because it is to a large part caused by sun exposure [41,42]. Only few studies have investigated the seasonal influence in melanoma survival, which have produced conflicting results [30,43,44]. ...
In Switzerland, there is a large seasonal variation in sunlight, and vitamin D deficiency is relatively common during winter. The season of diagnosis may be linked to cancer survival via vitamin D status. Using data from the Cancer Registry of Zurich, Zug, Schaffhausen, and Schwyz with more than 171,000 cancer cases registered since 1980, we examined the association of the season of diagnosis with survival for cancers including prostate (ICD10 code C61; International Categorization of Diseases, version 10), breast (C50), colorectal (C18-21), lung (C34), melanoma (C43), and all sites combined. Cox proportional hazards regression models were used to assess the differences in the all-cause mortality by the season of the diagnosis. Winter was used as the reference season. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for all the cancers combined (excluding nonmelanoma skin cancer) and for prostate (in men), breast (in women), colorectal, lung cancer, and melanomas, separately. A diagnosis in summer and/or autumn was associated with improved survival in all the sites combined for both sexes (men: HR 0.97 [95% CI 0.96–0.99]; women: HR 0.97 [95% CI 0.94–0.99]) and in colorectal (HR 0.91 [95% CI 0.84–0.99]), melanoma (HR 0.81 [95% CI 0.65–1.00]), and breast cancer (HR 0.91 [95% CI 0.94–0.99]) in women. Our study results suggest that a cancer diagnosis in summer and/or autumn is associated with a better prognosis. The improved seasonal survival coincides with the seasonal variation of sun-induced vitamin D, and vitamin D may play a protective and beneficial role in cancer survival.
... Malignant melanoma (MM) is an intractable cutaneous cancer originating from melanocytes with an extremely high mortality rate (65% of all skin cancer deaths) (1). Although eyelid melanoma accounts for only ∼1% of all cutaneous melanomas, it can camouflage melanocytic nevus (the most common benign eyelid tumor) both in the naked eye and under a microscope. ...
PurposeThe lack of finely annotated pathologic data has limited the application of deep learning systems (DLS) to the automated interpretation of pathologic slides. Therefore, this study develops a robust self-supervised learning (SSL) pathology diagnostic system to automatically detect malignant melanoma (MM) in the eyelid with limited annotation.DesignDevelopment of a self-supervised diagnosis pipeline based on a public dataset, then refined and tested on a private, real-world clinical dataset.SubjectsA. Patchcamelyon (PCam)-a publicly accessible dataset for the classification task of patch-level histopathologic images. B. The Second Affiliated Hospital, Zhejiang University School of Medicine (ZJU-2) dataset – 524,307 patches (small sections cut from pathologic slide images) from 192 H&E-stained whole-slide-images (WSIs); only 72 WSIs were labeled by pathologists.Methods
Patchcamelyon was used to select a convolutional neural network (CNN) as the backbone for our SSL-based model. This model was further developed in the ZJU-2 dataset for patch-level classification with both labeled and unlabeled images to test its diagnosis ability. Then the algorithm retrieved information based on patch-level prediction to generate WSI-level classification results using random forest. A heatmap was computed for visualizing the decision-making process.Main outcome measure(s)The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were used to evaluate the performance of the algorithm in identifying MM.ResultsResNet50 was selected as the backbone of the SSL-based model using the PCam dataset. This algorithm then achieved an AUC of 0.981 with an accuracy, sensitivity, and specificity of 90.9, 85.2, and 96.3% for the patch-level classification of the ZJU-2 dataset. For WSI-level diagnosis, the AUC, accuracy, sensitivity, and specificity were 0.974, 93.8%, 75.0%, and 100%, separately. For every WSI, a heatmap was generated based on the malignancy probability.Conclusion
Our diagnostic system, which is based on SSL and trained with a dataset of limited annotation, can automatically identify MM in pathologic slides and highlight MM areas in WSIs by a probabilistic heatmap. In addition, this labor-saving and cost-efficient model has the potential to be refined to help diagnose other ophthalmic and non-ophthalmic malignancies.
... There are various medical specialties to which a patient with a skin lesion can be presented to, including dermatology and plastic surgery, but most patients end up presenting to primary care clinics [24]. Primary care physicians play an important role in distinguishing skin lesions that warrant referral to specialized clinics, or even lesions that might need clinic based interventions [25,26]. Many efforts have been evaluated for improving the diagnostic accuracy of primary care physicians for diagnosing malignant melanoma such as short training courses [13,27,28]. ...
Background
Color vision deficiency describes the inability to distinguish certain shades of color. The aim of this study was to assess the impact of having color vision deficiency on the accuracy of distinguishing benign and malignant skin lesions by naked-eye examination.
Methods
This was a cross-sectional study conducted during the period August 2020 to February 2021. We randomly selected a total of 20 nevi and 20 melanoma images from an open access image database. The 40 images were divided into four sets of images, each set contained 5 benign and 5 malignant skin lesion images simulated as if they were seen by a protanope physician, deuteranope physician, tritanope physician, and a set of images presented without simulation. In an online survey, students who were in their final year of medical school or had newly graduated were asked to diagnose each image as benign or malignant.
Results
A total of 140 participants were included with a mean (SD) age of 24.88 (1.51). We found a significantly higher mean accuracy for non-simulated images compared to deuteranope simulated images (p< 0.001, mean difference = 11.07, 95% CI 8.40 to 13.74). We did not find a significant difference in accuracy classification for protanope simulated images (p = 0.066), nor for tritanope simulated images (p = 0.315). Classification accuracy for malignant lesions was higher than classification accuracy for benign lesions, with the highest difference belonging to deuteranope simulated images, with a difference in mean accuracy of classifying malignant lesions by 32.2 (95% CI 27.0 to 37.6).
Conclusion
Deuteranope participants (i.e., green color deficiency) had a significantly lower accuracy of distinguishing pigmented skin lesions as benign or malignant, an impact not found for other color vision deficiencies, which was mainly for misdiagnosing benign lesions as malignant.
... Melanoma accounts for a much smaller proportion, yet it is the cause of 65% of skin cancer-related deaths. [7][8][9] Mortality from malignant melanoma continues to increase among men and women over the age of 65 but appears to be stabilizing in the younger population. [10][11][12][13] Treatment of skin cancer poses a significant economic burden in the United States with an annual average cost of $8.1 billion. ...
Skin cancer education targeted to patients' needs is a goal of practicing dermatologists. Data regarding dermatology patients' baseline knowledge regarding skin cancer could aid clinicians in tailoring education efforts.
Objective:
To help quantify existing patients' existing visual recognition of skin cancer and common benign lesions, with the goal of helping to provide more targeted and meaningful education to patients.
Methods:
Two hundred forty-four adult patients from the dermatology clinics at University of Oklahoma and Loyola University Chicago were surveyed using digital images and questions regarding personal and family history of skin cancer, sun protection practices and sun protection knowledge.
Results:
Of the 244 subjects, 43% percent had a positive personal history of skin cancer, 40% had a positive family history. Scores differed minimally by personal history of skin cancer (p = .37) but differed more markedly by family history of skin cancer (p = .02).
Limitations:
Lack of generalizability to the general public, age range of subjects.
Conclusions:
There are knowledge gaps within the dermatology patient population regarding common benign and malignant skin lesions.
... It is derived from the abnormal transformation of melanocytes that produce uncontrolled melanin in the basal layer of the epidermis because of ultraviolet (UV) radiation exposure [2]. Melanoma can also occur in specific skin areas not exposed to UV light but constantly subjected to enormous mechanical stress, such as in the palmoplantar and fingernail beds [3]. Although surgical excision remains the most common treatment applied to reduce the progression and eliminate the tumor, patients commonly suffer from deep lesions and cosmetic disfigurement [4]. ...
Advances in biomimetic three-dimensional (3D) melanoma models have brought new prospects of drug screening and disease modeling, since their physiological relevancy for recapitulating in vivo tumor architectures is more accurate than traditional two-dimensional (2D) cell culture. Gelatin methacryloyl (GelMA) is widely used as a tissue-engineered scaffold hydrogel for 3D cell culture. In the present study, an in vitro 3D malignant melanoma model based on GelMA was fabricated to evaluate the efficiency of hypericin (Hy)-loaded microemulsion (ME) in photodynamic therapy against melanoma. The ME was produced by the spontaneous emulsification method to enhance the bioavailability of Hy at tumor sites. Hy-loaded MEs were applied to a 3D malignant melanoma model made using 6% GelMA and the co-culture of B16F10 and Balb/c 3T3 cells, followed by crosslinking using violet light (403 nm). The observation revealed excellent cell viability and the presence of F-actin cytoskeleton network. Hy-loaded MEs exhibited higher phototoxicity and cell accumulation (about threefold) than free Hy, and the cells cultured in the 3D system displayed lower susceptibility (about 2.5-fold) than those in 2D culture. These findings indicate that the developed MEs are potential delivery carriers for Hy; furthermore, GelMA hydrogel-based modeling in polydimethylsiloxane (PDMS) molds is a user-friendly and cost-effective in vitro platform to investigate drug penetration and provide a basis for evaluating nanocarrier efficiency for skin cancer and other skin-related diseases.
... MiMels induced 8, 10, 12, 15 weeks and B16 cells have significant differences in their relative melanin content before and after a-MSH stimulation for 24H and 48H (p < 0.05) (Fig. 2b). MC1R, the a-MSH receptor, is expressed in both melanocytes and melanoma cells, but the number of expressions in melanoma cells far exceeds that of normal melanocytes [34]. a-MSH binds to the receptor MC1R to generate a cascade reaction to activate tyrosinase [35]. ...
Background
A large number of autologous melanocytes are required for surgical treatment of depigmentation diseases such as vitiligo. The purpose of this experiment is to explore the application of melanocytes induced by mesenchymal stem cells to clinical treatment. Therefore, we have induced mouse bone marrow mesenchymal stem cells (BMMSCs) into melanocytes (miMels) in the previous experiment. This experiment continues the previous experiment to further study the biological functions of miMels and their application in tissue engineering.
Methods
We examined whether miMels can produce active tyrosinase, melanin, and response to α-MSH. The ability of miMels to produce melanin to keratinocytes was tested by co-culture. By applying miMels to tissue-engineered skin, the survival and function of miMels on the surface of nude mice were verified.
Results
MiMels can produce active tyrosinase and melanin, and can pass melanin to the co-cultured keratinocytes. Under the stimulation of α-MSH, the active tyrosinase and melanin content of miMels increased. We tried to apply it to the establishment of tissue-engineered skin and obtained tissue-engineered skin containing miMels. Then we tried to transplant tissue-engineered skin on the back skin of nude mice and succeeded. The transplanted miMels survived in local tissues, synthesized active tyrosinase and melanin, and expressed the marker protein of melanocytes.
Conclusion
In short, miMels can be used as a cell source for tissue engineering skin. MiMels not only have a typical melanocyte morphology but also have the same biological functions as normal melanocytes. What's more important is its successful application in mouse tissue-engineered experiments.
... From the several existing types of melanomas, cutaneous melanoma is recognized as the most prevalent (Rebecca et al., 2020). The severity of melanoma resides in it accounting for over 75% of the total skin cancer deaths despite comprising less than 5% of all skin cancers (Cummins et al., 2006;Shenenberger, 2012). The NCSC origin of melanocytes has been thought to be responsible for the ability of melanoma to both migrate and thrive in major organs, such as the brain and the lungs (Rebecca et al., 2020). ...
Melanoma is an aggressive type of skin cancer that accounts for over 75% of skin cancer deaths despite comprising less than 5% of all skin cancers. Despite promising improvements in surgical approaches for melanoma resection, the survival of undetectable microtumor residues has remained a concern. As a result, hyperthermia- and drug-based therapies have grown as attractive techniques to target and treat cancer. In this work, we aim to develop a stimuli-responsive hydrogel based on chitosan methacrylate (ChiMA), porcine small intestine submucosa methacrylate (SISMA), and doxorubicin-functionalized reduced graphene oxide (rGO-DOX) that eliminates microtumor residues from surgically resected melanoma through the coupled effect of NIR light-induced photothermal therapy and heat-induced doxorubicin release. Furthermore, we developed an in silico model to optimize heat and mass transport and evaluate the proposed chemo/photothermal therapy in vitro over melanoma cell cultures.
... Cutaneous Melanoma (CM) is a malignant skin cancer originating from epidermal melanocytes [1,2]. Even though it is less common than other skin cancers, CM is more lethal due to its high metastatic potential [2][3][4]. ...
Background
The microbiome alterations are associated with cancer growth and may influence the immune system and response to therapy. Particularly, the gut microbiome has been recently shown to modulate response to melanoma immunotherapy. However, the role of the skin microbiome has not been well explored in the skin tumour microenvironment and the link between the gut microbiome and skin microbiome has not been investigated in melanoma progression. Therefore, the aim of the present study was to examine associations between dysbiosis in the skin and gut microbiome and the melanoma growth using MeLiM porcine model of melanoma progression and spontaneous regression.
Results
Parallel analysis of cutaneous microbiota and faecal microbiota of the same individuals was performed in 8 to 12 weeks old MeLiM piglets. The bacterial composition of samples was analysed by high throughput sequencing of the V4-V5 region of the 16S rRNA gene. A significant difference in microbiome diversity and richness between melanoma tissue and healthy skin and between the faecal microbiome of MeLiM piglets and control piglets were observed. Both Principal Coordinate Analysis and Non-metric multidimensional scaling revealed dissimilarities between different bacterial communities. Linear discriminant analysis effect size at the genus level determined different potential biomarkers in multiple bacterial communities. Lactobacillus, Clostridium sensu stricto 1 and Corynebacterium 1 were the most discriminately higher genera in the healthy skin microbiome, while Fusobacterium, Trueperella, Staphylococcus, Streptococcus and Bacteroides were discriminately abundant in melanoma tissue microbiome. Bacteroides, Fusobacterium and Escherichia-Shigella were associated with the faecal microbiota of MeLiM piglets. Potential functional pathways analysis based on the KEGG database indicated significant differences in the predicted profile metabolisms between the healthy skin microbiome and melanoma tissue microbiome. The faecal microbiome of MeLiM piglets was enriched by genes related to membrane transports pathways allowing for the increase of intestinal permeability and alteration of the intestinal mucosal barrier.
Conclusion
The associations between melanoma progression and dysbiosis in the skin microbiome as well as dysbiosis in the gut microbiome were identified. Results provide promising information for further studies on the local skin and gut microbiome involvement in melanoma progression and may support the development of new therapeutic approaches.
... Melanoma is one of the most aggressive types of cancers with extremely low survival rates [19][20][21][22][23]. Previous studies have shown a beneficial effect of S. fruticosa against human breast and colorectal cancers [10,12,15,24,25]. ...
Malignant melanoma is one of the most aggressive types of skin cancer with an increasing incidence worldwide. Thus, the development of innovative therapeutic approaches is of great importance. Salvia fruticosa (SF) is known for its anticancer properties and in this context, we aimed to investigate its potential anti-melanoma activity in an in vitro model of human malignant melanoma. Cytotoxicity was assessed through a colorimetric-based sulforhodamine-B (SRB) assay in primary malignant melanoma (A375), non-malignant melanoma epidermoid carcinoma (A431) and non-tumorigenic melanocyte neighbouring keratinocyte (HaCaT) cells. Among eight (8) different fractions of S. fruticosa extracts (SF1-SF8) tested, SF3 was found to possess significant cytotoxic activity against A375 cells, while A431 and HaCaT cells remained relatively resistant or exerted no cytotoxicity, respectively. In addition, the total phenolic (Folin–Ciocalteu assay) and total flavonoid content of SF extracts was estimated, whereas the antioxidant capacity was measured via the inhibition of tert-butyl hydroperoxide-induced lipid peroxidation and protein oxidation levels. Finally, apoptotic cell death was assessed by utilizing a commercially available kit for the activation of caspases - 3, - 8 and - 9. In conclusion, the anti-melanoma properties of SF3 involve the induction of both extrinsic and intrinsic apoptotic pathway(s), as evidenced by the increased activity levels of caspases - 8, and - 9, respectively.
... At present, the long-term survival rate for patients with metastatic melanoma remains unfavourable. 3 Therefore, it is of great clinical significance to clarify the molecular mechanisms and genetic alterations underlying melanoma growth and metastasis. ...
Melanoma is one of the most aggressive and life‐threatening skin cancers, and in this research, we aimed to explore the functional role of circular RNA VANGL1 (circVANGL1) in melanoma progression. The expression levels of circVANGL1 were observed to be significantly increased in clinical melanoma tissues and cell lines. Moreover, circVANGL1 knockdown suppressed, while circVANGL1 overexpression promoted the proliferation, migration and invasion abilities of melanoma cells. Further investigations confirmed the direct binding relation between circVANGL1 and miR‐150‐5p in melanoma, and restoration of miR‐150‐5p blocked the effects of circVANGL1 overexpression in melanoma cells. We further found that circVANGL1 was up‐regulated by TGF‐β treatment, and the enhanced EMT of TGF‐β‐treated melanoma cells was blocked by circVANGL1 knockdown. In conclusion, these results indicated that circVANGL1 might serve as a promising therapeutic target for melanoma.
Objective
To evaluate the diagnostic value of [ ⁶⁸ Ga] Ga-Pentixafor in malignant melanoma patients.
Methods
In this prospective study, patients with histology-proven melanoma were included and underwent [ ¹⁸ F]fluoro-D-glucose ([ ¹⁸ F]FDG) and [ ⁶⁸ Ga] Ga-Pentixafor PET/computed tomography (CT) within a week. Suspicious lesions were interpreted as benign vs. malignant, and the corresponding semi-quantitative PET/CT parameters were recorded and compared.
Results
Twelve consecutive melanoma patients (mean age: 60 ± 6) were included. Two patients were referred for initial staging, two for detecting recurrence and eight for evaluating the extent of metastases. Overall, [ ¹⁸ F]FDG PET/CT showed 236 tumoral lesions, including two primary tumors, two recurrent lesions, 29 locoregional metastases and 203 distant metastases. In [ ⁶⁸ Ga]Ga-Pentixafor PET/CT, 101 tumoral lesions were detected, including two primary tumors, one recurrence, 16 locoregional metastases and 82 distant metastases. Notably, a documented brain metastasis was only visualized on [ ⁶⁸ Ga]Ga-Pentixafor PET/CT images. Compared with [ ¹⁸ F]FDG, [ ⁶⁸ Ga]Ga-Pentixafor PET/CT provided a 42% detection rate. Regarding semi-quantitative measures, the intensity of uptake and tumor-to-background ratios were significantly lower on [ ⁶⁸ Ga]Ga-Pentixafor PET/CT [average maximum standard uptake value (SUV max ) of 2.72 ± 1.33 vs. 11.41 ± 14.79; P value <0.001 and 1.17 ± 0.53 vs. 5.32 ± 7.34; P value <0.001, respectively].
Conclusion
When comparing [ ⁶⁸ Ga]Ga-Pentixafor PET/CT with [ ¹⁸ F]FDG PET/CT, not only did [ ⁶⁸ Ga]Ga-Pentixafor PET/CT detect fewer lesions, but the intensity of uptake and the TBRs were also lower on [ ⁶⁸ Ga]Ga-Pentixafor PET/CT. Thus, our results may indicate a limited potential of this novel tracer in cutaneous melanoma patients compared to [ ¹⁸ F]FDG PET/CT. Given the lower TBRs, applying this radiotracer in radioligand therapies is also questionable.
Background
We explore sphingolipid-related genes (SRGs) in skin melanoma (SKCM) to develop a prognostic indicator for patient outcomes. Dysregulated lipid metabolism is linked to aggressive behavior in various cancers, including SKCM. However, the exact role and mechanism of sphingolipid metabolism in melanoma remain partially understood.
Methods
We integrated scRNA-seq data from melanoma patients sourced from the GEO database. Through the utilization of the Seurat R package, we successfully identified distinct gene clusters associated with patient survival in the scRNA-seq data. Key prognostic genes were identified through single-factor Cox analysis and used to develop a prognostic model using LASSO and stepwise regression algorithms. Additionally, we evaluated the predictive potential of these genes within the immune microenvironment and their relevance to immunotherapy. Finally, we validated the functional significance of the high-risk gene IRX3 through in vitro experiments.
Results
Analysis of scRNA-seq data identified distinct expression patterns of 4 specific genes (SRGs) in diverse cell subpopulations. Re-clustering cells based on increased SRG expression revealed 7 subgroups with significant prognostic implications. Using marker genes, lasso, and Cox regression, we selected 11 genes to construct a risk signature. This signature demonstrated a strong correlation with immune cell infiltration and stromal scores, highlighting its relevance in the tumor microenvironment. Functional studies involving IRX3 knockdown in A375 and WM-115 cells showed significant reductions in cell viability, proliferation, and invasiveness.
Conclusion
SRG-based risk signature holds promise for precise melanoma prognosis. An in-depth exploration of SRG characteristics offers insights into immunotherapy response. Therapeutic targeting of the IRX3 gene may benefit melanoma patients.
Background and Purpose
Safe and effective drug delivery is crucial for the treatment of cancer, which is quite impossible to achieve through traditional methods. Among all types of cancer, skin melanoma is known for its aggressive metastasizing ability and an unprecedented higher degree of lethalness, limiting the overall therapeutic efficacy. Here, we focus on the different types of nanomaterials (NMs) and their drug delivery applications against melanoma.
Experimental Approach
All relevant publications, including research papers, reviews, chapters and patents, were assessed using search engines such as Scopus and PubMed, up to the end of August of 2023. The keywords used in the search were: nanomaterials, melanoma, drug delivery routes for melanoma, and nanomaterial-based drug delivery systems (DDS). Most of the publications out of 234 cited in this review are from the last five years.
Key Results
The recent advancement and mechanism of action of various NMs against melanoma, including inorganic metallic and carbon-based NMs, organic polymeric and lipid-based NMs, and cell-derived vesicles are discussed. We also focus on the application of different NMs in the delivery of therapeutic agents for melanoma therapy. In addition, the skin and melanoma, genetic mutation and pathways for melanoma, conventional treatment options, and delivery routes for therapeutic agents are also discussed briefly.
Conclusion
There are few NM-based DDS developed in the lab set up recently. The findings of this review will pave the path for the development of NM-based DDS on an industrial scale and help in the better management of skin melanoma.
Melanoma is a potentially lethal form of skin cancer resulting from the unlimited proliferation of melanocytes. Melanocytic lineage appears to have a greater rate of reactive oxygen species (ROS) production, possibly as a result of exposure to ultraviolet (UV) light and the production of melanin. It has been established that nuclear factor erythroid 2‐related factor 2 (Nrf2) serves as a master regulator of the cellular response to oxidative stresses. Recent research has shown that the Nrf2 and its critical negative regulator Kelch‐like ECH‐associated protein 1 (Keap1) are misregulated in melanoma, and the Keap1‐Nrf2 pathway has emerged as a promising new target for treating and preventing melanoma. In melanoma, Nrf2 may either limit tumor growth or promote its development. This review covers a wide range of topics, including the dual functions played by the Keap1‐Nrf2 signaling pathway in melanoma and the most recent targeting techniques of the Nrf2.
Introduction:
Treatment of advanced melanoma has been transformed by novel systemic therapies. The purpose of this study is to describe the current utilization patterns of immunotherapies with respect to survival outcomes in advanced melanoma.
Methods:
We performed a retrospective cohort study of patients with Stage 3 and 4 melanoma at our institution (2009-2019). Primary outcomes included overall survival (OS) and progression free survival (PFS). Kaplan-Meier survival analysis and Cox proportional hazards regression analysis evaluated associations between covariates and survival outcomes.
Results:
Of 244 patients, 5-y OS was 62.4%. Lymphovascular invasion (hazard ratio [HR] = 2.462, P = 0.030) was associated with shorter PFS whereas female gender (HR = 0.324, P = 0.010) was associated with longer PFS. Residual tumor (HR = 146, P = 0.006) and Stage 4 disease (HR = 3.349, P = 0.011) were associated with shorter OS. Use of immunotherapy increased from 2% to 23% over the study period, and use of neoadjuvant immunotherapy also increased up to 2016. Timing of immunotherapy administration was not significantly associated with survival. Of the 193 patients who received 2 or more treatment types, the most common treatment sequence was surgery followed by immunotherapy (n = 117, 60.6%).
Conclusions:
Immunotherapy is increasingly used for treatment of advanced melanoma. In this heterogeneous cohort, there was no significant association between timing of immunotherapy and survival outcomes.
Melanoma is one of the worst types of skin cancer. It appears on the skin’s surface and is caused by melanocytes. The same cells are also responsible for benign lesions known as moles, which resemble melanoma in its early stages. Melanoma is frequently curable if properly treated. Much research is now focused on the automated detection of melanomas. In this paper, we present an automated melanoma identification system based on convolutional neural networks and global average pooling. When compared to other approaches on a large publically available dataset, the experimental evaluation on the same dataset reveals that our suggested technique has a high classification accuracy
(98.26%), sensitivity (98.91%), and specificity (97.66%). Thus,
the suggested framework may be used to help dermatologists
diagnose melanoma.
Neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the most vulnerable neurons in Parkinson's disease (PD). Recent work suggests that the accumulation of oxidized dopamine and neuromelanin mediate the convergence of mitochondrial and lysosomal dysfunction in patient-derived neurons. In addition, the expression of human tyrosinase in mouse SNpc led to the formation of neuromelanin resulting in the degeneration of nigral dopaminergic neurons, further highlighting the importance of neuromelanin in PD. The potential role of neuromelanin in PD pathogenesis has been supported by epidemiological observations, whereby individuals with lighter pigmentation or cutaneous malignant melanoma exhibit higher incidence of PD. Because neuromelanin and melanin share many functional characteristics and overlapping biosynthetic pathways, it has been postulated that genes involved in skin pigmentation and melanin formation may play a role in the susceptibility of vulnerable midbrain dopaminergic neurons to neurodegeneration. Here, we highlight potential mechanisms that may explain the link between skin pigmentation and PD, focusing on the role of skin pigmentation genes in the pathogenesis of PD. We also discuss the importance of genetic ancestry in assessing the contribution of pigmentation-related genes to risk of PD. © 2022 International Parkinson and Movement Disorder Society.
Malignant melanoma is the most lethal type of skin cancer with high rates of mortality. Although current treatment options provide a short-clinical benefit, acquired-drug resistance highlights the low 5-year survival rate among patients with advanced stage of the disease. In parallel, the involvement of an aberrant epigenetic landscape, (e.g., alterations in DNA methylation patterns, histone modifications marks and expression of non-coding RNAs), in addition to the genetic background, has been also associated with the onset and progression of melanoma. In this review article, we report on current therapeutic options in melanoma treatment with a focus on distinct epigenetic alterations and how their reversal, by specific drug compounds, can restore a normal phenotype. In particular, we concentrate on how single and/or combinatorial therapeutic approaches have utilized epigenetic drug compounds in being effective against malignant melanoma. Finally, the role of deregulated epigenetic mechanisms in promoting drug resistance to targeted therapies and immune checkpoint inhibitors is presented leading to the development of newly synthesized and/or improved drug compounds capable of targeting the epigenome of malignant melanoma.
Polyphenols are secondary metabolites of plants, and one of the most important phytochemicals found in herb plants, vegetables, and fruits. In recent years, these compounds have attracted increased attention due to the potential health benefits of dietary plant polyphenols as antioxidants. Epidemiological studies have noted the lower risk of chronic diseases, such as cardiovascular diseases, cancer, hypertension, diabetes, and neurodegenerative diseases, with the consumption of diets rich in fruits and vegetables owing to the antioxidant and antiinflammatory properties of phenolic compounds. However, the bioavailability of each phenolic compound differs and there is no relation between the quantity of polyphenols in food and their bioavailability in human organisms. This chapter aimed to show the current evidence relating to polyphenols and health and the potential uses of polyphenols.
Cancer is a major global health issue and one of the main causes of mortality worldwide. In recent years, cancer mortality and morbidity rates have risen dramatically due to variety of factors. Despite therapeutic alternatives, chemotherapy medications have major adverse effects and many kinds of drug resistance that severely diminish their effectiveness. Galangin, 3,5,7-trihydroxyflavone, is considered as the bioactive constituent of galangal and honey. In general, galangin exhibits several pharmacological effects, such as anti-inflammatory, antioxidant, anticancer, and antiviral activities. The anticancer effects of galangin are mostly due to its abilities to inhibit cell cycle progression, inhibiting mitogen-activated protein kinase (MAPK), protein kinase B (Akt), or mammalian target of rapamycin (mTOR) activity leading to apoptotic cell death by stimulating caspase-9/8/3 and inhibiting tumor invasion and metastasis by decreasing the upregulation of matrix metalloproteinase-2/-9 (MMP-2/-9). These molecular pathways of galangin are involved in suppressing different malignancies, such as lung cancer, hepatic cancer, breast cancer, ovarian cancer, gastric cancer, colorectal cancer, retinoblastoma, and osteosarcoma. The present work is emphasized on the anticancer mechanisms of galangin.
Graphical abstract
Skin cancer is one of the most frequently diagnosed malignancies worldwide and its incidence constantly increases. The disease divides in two major subtypes: non-melanoma and melanoma skin cancer. The main drawbacks of the traditional skin cancer therapy are primary and acquired drug resistance and serious side effects due to the nonspecific treatments targeting. Despite advances in therapy strategies there is a need of new affordable natural anti-skin cancer agents, which to possess higher efficiency without causing detrimental side effects. Medicinal plants provide great possibility for the discovery of new anticancer therapeutics with preventive and treatment potential. Cotinus coggygria Scop. is a plant species widely applied in phytotherapy predominantly against disorders of the skin and mucosal tissues. The herb has a large range of valuable biological activities but its anticancer properties have not been thoroughly studied. The aim of the present research was to assess the antiproliferative properties of the crude leaf aqueous ethanolic extract from Bulgarian herb C. coggygria and its chloroformic and aqueous fractions on a panel of human skin cancer cell lines: basal cell carcinoma (TE 354.T), squamous cell carcinoma (A431) and malignant melanoma (A375) and to compare them to the cell growth inhibitory potential on normal dermal cell line (BJ). The antiproliferative capacity of the plant substances was investigated using MTT assay and microscopy cell morphology observation after 72 h cell treatment in a wide scale of concentrations. The obtained results showed that the crude extract and both fractions inhibit significant proliferation of A431 squamous cell carcinoma and A375 melanoma cells with the highest cytostatic effect registered for the aqueous fraction on A375 cells with a half maximal inhibitory concentration value of 44.33 ?g/ml. C. coggygria exhibited no cytostatic activity towards TE 354.T basal cell carcinoma cells. The established marked slight
To assess the association between the incidence of cutaneous melanoma; intermittent, occupational and total sun exposure; and history of sunburn at different ages, we conducted a systematic review using results of all published case-control studies which have assessed incident melanoma, sun exposure and sunburn. Twenty-nine studies contributed data on sun exposure and 21 on sunburn. Overall, there was a significant positive association (odds ratio [OR] = 1.71) for intermittent exposure, a significantly reduced risk for heavy occupational exposure (OR = 0.86) and a small, marginally significant excess risk for total exposure (OR = 1.18). There was a significantly increased risk with sunburn at all ages or in adult life (OR = 1.91) and similarly elevated relative risks for sunburn in adolescence (OR = 1.73) and in childhood (OR = 1.95). There was significant heterogeneity with all of these estimates except that of all ages or adult sunburn. These results show the specificity of the positive association between melanoma risk and intermittent sun exposure, in contrast to a reduced risk with high levels of occupational exposure. The association with sunburn also is likely to reflect intermittent exposure; the results do not suggest any strong relationship to age at sunburn. These associations are similar to those reported for basal cell skin cancer but different from those reported for squamous cell cancer. The mechanisms by which intermittent exposure increases risk, while other patterns of exposure do not, remain to be elucidated. Int. J. Cancer 73:198–203, 1997. © 1997 Wiley-Liss, Inc.
Despite the importance of early detection in preventing mortality from melanoma, little is known regarding how patients with the disease come to diagnosis.
In a population-based, matched case-control study from the South Swedish Health Care Region, which has the highest risk for melanoma in Sweden, the relation between the use of sunbeds or sunlamps and malignant melanoma was investigated . Between July 1, 1988, and June 30, 1990, a total of 400 melanoma patients and 640 healthy controls aged 15–75 years answered a comprehensive questionnaire containing different epidemiologic variables. Questions regarding the use of sunbeds or sunlamps were included. The odds ratio for developing malignant melanoma after ever having used sunbeds or sunlamps was 1.3. Considering all age groups, the odds ratio was significantly elevated after exposure more than 10 times a year to sunbeds or sun-lamps (odds ratio (OR) = 1.8). When the study was restricted to patients and controls younger than age 30 years because the use of tanning devices is much more common among young persons, the odds ratio was higher (OR = 7.7 for more than 10 times a year vs. none). These findings were independent of constitutional factors and factors regarding sun exposure. A dose-response relation was evident. Furthermore, among melanoma patients in this young age group, the ratio of females to males was significantly higher than in older patients. When different melanoma presentation sites were considered, only lesions of the trunk were significantly associated with sunbed or sunlamp use (OR = 4.2 for more than 10 times a year vs. none).
Background and Design:
A controlled trial was undertaken from December 1987 to December 1990 to test the hypothesis that a strong sunscreen can reduce the number of cancerous and precancerous skin lesions. Candidates were selected from a high-risk population attending either a university- or Veterans Affairs—based dermatology practice in Lubbock, Tex, for a prospective, double-blind, controlled trial of daily application of sunscreen vs placebo over a 2-year period. Participants were asked to volunteer if they had demonstrated premalignant changes (actinic keratoses) or nonmelanoma skin cancer (basal cell carcinoma or squamous cell carcinoma), had continuing sun exposure, and were not using sunscreen on a regular basis. Fifty-three volunteers were initially enrolled in the study, and 37 came for the final 24-month visit.Results:
The rate of appearance of new precancerous skin lesions was less for the treatment group than for control subjects. People with darker skin had fewer actinic keratoses, women had fewer lesions than men, and people with fewer lesions at enrollment had fewer lesions during the study. The numbers of new nonmelanoma skin cancers appearing during the study period were too small for statistical analysis.Conclusions:
The regular use of sunscreens can significantly reduce cutaneous neoplasia, as indicated by its suppression of precancerous lesions. A longer and/or larger study would be necessary to demonstrate an effect on malignant lesions.(Arch Dermatol. 1995;131:170-175)
Background and Design:
The frequency of melanoma and nonmelanoma skin cancer is increasing rapidly in the United States. However, the linkage of these cancers to sun exposure has been questioned because of differences in anatomic site distribution. To obtain insights into the development of these skin cancers, we examined reports of 132 patients with xeroderma pigmentosum (XP), an inherited cancer-prone, DNA repair—deficient disorder with marked clinical and laboratory UV hypersensitivity.
Results:
Malignant skin neoplasms were present in 70% of the patients with XP at a median age of 8 years, which is 50 years earlier than in the US white population. Fifty-seven percent of the patients had basal cell or squamous cell carcinoma, and 22% had melanoma. The frequency of melanomas, like the frequency of nonmelanoma skin cancers (basal cell and squamous cell carcinomas), anterior eye cancers, and tongue cancers, but unlike that of internal neoplasms, was increased 1000-fold or more in patients with XP who were younger than 20 years. As in the general population, the anatomic distribution of melanomas was different from that of nonmelanomas in the patients with XP.
Conclusions:
These data suggest that (1) DNA repair plays a major role in the prevention of cutaneous cancers in the general population and (2) sunlight exposure is responsible for the induction of melanoma as well as nonmelanoma skin cancer in patients with XP, although acting by different mechanisms for the two types of skin cancer.(Arch Dermatol. 1994;130:1018-1021)
Seventeen commercially available sunscreens were tested to determine their relative protection at 305 nm of monochromatic radiation. Tests, using 23 volunteers, were also made with four representative sunscreens: P-aminobenzoic acid (PABA) in alcoholic solution (Presun), cinoxate and menthyl anthranilate (Maxafil), the benzophenone mixture of oxybenzone and dioxybenzone (Solbar), and an ester of PABA (Pabafilm) were tested in the sunburn range at 295, 300, 305, and 313 nm. Alcoholic solutions of PABA were the most effective, with a mean protection factor (PF) of 17.6; esters of PABA were less effective, with a mean PF that ranged from 5.5 to 8.3, and were comparable to the benzophenones. A combination of cinoxate and menthyl anthranilate (Maxafil) gave a mean PF of 9.6. There was no significant difference in the PF with the different wavelengths 295 to 313 nm.
BACKGROUND
Despite the importance of early detection in preventing mortality from melanoma, little is known regarding how patients with the disease come to diagnosis.METHODS
The authors prospectively evaluated 471 newly diagnosed melanoma patients between 1995 and 1998. Patients completed a questionnaire that included 1) identification of the person who detected the lesion, 2) the anatomic location of the lesion, and 3) family history of melanoma. Logistic regression analysis was performed to examine the relation between detection patterns and lesion thickness, adjusting for age, gender, anatomic site of the primary lesion, and family history of melanoma.RESULTSThe majority of patients detected their own melanoma (n = 270; 57%). Females were more likely to self-detect than males (69% vs. 47%; P < 0.0001). Physicians detected the melanoma in 16% of patients (n = 74), followed by “spouse” in 11% of patients (n = 51). Within this group, detection by wives was 7.5 times more common than detection by husbands (P < 0.0001). Logistic regression analysis revealed that physicians were 3.6 times more likely to detect thin lesions (≤0.75 mm) compared with nonphysician detectors (95% confidence interval [95% CI], 2.1, 6.5; P = 0.0001). In addition, patients who reported a family history of melanoma had a 2.7-fold increased likelihood of presenting with a thin lesion (95% CI, 1.6, 4.7; P = 0.0003).CONCLUSIONS
Physician detection and a report of a family history of melanoma are associated with the presentation of patients with early melanoma, suggesting that awareness of the disease among physicians and the public is critical for preventing mortality from melanoma. Increasing melanoma awareness in males may be a particularly effective means of secondary prevention. Cancer 2000;89:342–7. © 2000 American Cancer Society.
Application of 5% para-aminobenzoic acid (PABA) to hairless mice one hour Prior to ultra-violet light (UVL) irradiation will almost totally protect these animals from developing tumors induced by chronic exposure to UVL in the 290 to 320 nm range in conjunction with a chemical carcinogen. Mice exposed to UVL and not protected by PABA developed primarily squamous cell carcinomas. Two months after cessation of chronic UVL exposure, the non-PABA-treated irradiated mouse skin appeared thickened, yellow, and wrinkled while showing elevated DNA synthesis, hyperplasia. hypergranulosis, and increased amounts of elastotic material. The PABA-treated skin was grossly normal.
Objective:The objective of this study was to evaluate, in an international multicenter phase III trial, the accuracy, use, and morbidity of intraoperative lymphatic mapping and sentinel node biopsy (LM/SNB) for staging the regional nodal basin of patients with early-stage melanoma. Summary Background Data: Since our introduction of LM/SNB in 1990, this technique has been widely adopted and has become part of the American Joint Committee on Cancer (AJCC) staging system. Eleven years ago, the authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT-I) to compare 2 treatment approaches: wide excision (WE) plus LM/SNB with immediate complete lymphadenectomy (CLND) for sentinel node (SN) metastases, and WE plus postoperative observation with CLND delayed until the subsequent development of clinically evident nodal metastases. Methods: After each center achieved 85% accuracy of SN identification during a 30-case learning phase, patients with primary cutaneous melanoma (>= 1 mm with Clark level >= III, or any thickness with Clark level >= IV) were randomly assigned in a 4:6 ratio to WE plus observation (WEO) with delayed CLND for nodal recurrence, or to WE plus LM/SNB with immediate CLND for SN metastasis. The accuracy of LM/SNB was determined by comparing the rates of SN identification and the incidence of SN metastases in the LM/SNB group versus the subsequent development of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was completed on March 31, 2002, after enrollment of 2001 patients. Results: Initial SN identification rate was 95.3% overall: 99.3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rate of false-negative LM/SNB during the trial phase, as measured by nodal recurrence in a tumor-negative dissected SN basin, decreased with increasing case volume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. There were no operative mortalities. The low (10.1%) complication rate after LM/SNB increased to 37.2% with the addition of CLND; CLND also increased the severity of complications. Conclusions: LM/SNB is a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma. Even after a 30-case learning phase and 25 additional LM/SNB cases, the accuracy of LM/SNB continues to increase with a center's experience. LM/SNB should become standard care for staging the regional lymph nodes of patients with primary cutaneous melanoma.
Different pigmentary characteristics as well as different parameters of sun exposure have previously been identified as risk factors for developing cutaneous melanoma. The aim of the present study was to identify significant risk factors, de- termine the related magnitude of their estimated relative risks, and define criteria for the detection of persons at risk. Five hundred thirteen melanoma patients and 498 controls matched for age and sex underwent a whole-body examination for the number and type of melanocytic lesions and were interviewed on ultraviolet exposure and other potential risk factors. The total number of common melanocytic nevi on all body sites represented the most important risk factor in multiple logistic regression analysis with a relative risk of 7.6 for subjects with more than 100 versus no more than 10 melanocytic nevi. Other significant independent risk factors were the number of atypical melanocytic nevi (relative risk, 6.1 for at least 5 melanocytic nevi versus none), the number of actinic lentigines (relative risk, 3.5 for many versus none), hair color, skin type, and reported melanocytic nevus growth. No single parameter of sun exposure was significantly related to melanoma risk in the multivariate analysis. Groups with an estimated relative risk between 1 and 121.0 were distinguished by considering common and atypical melanocytic nevi as well as actinic lentigines as the decisive criteria. In conclusion, even without any information on the case history, whole-body examination and diagnosis of pigmented lesions was found to be an effective strategy for identifying persons at risk of developing melanoma. Furthermore, clinical recognition of at least 5 atypical melanocytic nevi without histologic examination is a key for identifying subjects at high risk.Keywords: melanoma, risk factors, actinic lentigines, melanocytic nevi, atypical melanocytic nevi, UV irradiation
The study objective was to assess whether exposure to sunlamps and sunbeds represents a risk factor for cutaneous malignant melanoma (CMM). A 1-to-1 unmatched case-control study was conducted among subjects 20 years old or more with naturally non-pigmented skin in Germany, France and Belgium. A total of 420 consecutive patients with CMM diagnosed from I January 1991 onward were derived from hospital registers; 447 controls with no history of skin cancer were chosen at random in the same municipality as the cases. Exposure to sunlamps or sunbeds starting before 1960 is associated with a crude estimated risk of CMM of 2.71 (95% CI: 1.06-7.78) for at least 10 hr of accumulated exposure. This risk is of 2.12 (95% CI: 0.84-5.37) after adjustment for age, sex, hair colour and average number of holiday weeks each year in sunny resorts. Subjects who experienced skin-burn due to sunlamps or sunbeds, and who had accumulated at least 10 hr of exposure, displayed a crude estimated CMM risk of 4.47 (95% CI: 1.45-13.7), which rose to 8.97 (95% CI: 2.10-38.6) for those who exposed their skin for tanning purposes. The risk associated with skin-bum is only marginally modified after multiple adjustments for host characteristics and recreational exposure to sunlight. Apparently, sunlamps and sunbeds share the increased risk of CMM, which seems to concentrate in subjects exhibiting hazardous behaviour towards ultraviolet radiation sources. However, although it is reasonable to believe that high doses of pure ultraviolet A radiation can be dangerous, this is not firmly established by this study. Most exposures to ultraviolet A tanning devices began after 1980; therefore, epidemiologic studies have difficulty in revealing any increase in risk of CMM starting after 1980 because of the latent period between exposure and occurrence of melanoma. Public health authorities should have a cautious approach towards the rapidly developing fashion of tanning under sunlamps or sunbeds.
Although thin cutaneous melanomas generally have a favorable prognosis, in some cases they may undergo progression. The current study was undertaken to identify variables that may predict a more aggressive clinical outcome in these patients. In addition to classic clinicopathologic features, the authors tested the prognostic impact of three new morphometric quantitative parameters: 1) tumor thickness plus regression thickness (T+R), 2) percentage of skin thickness infiltrated by tumor cells (T/S ratio), and 3) percentage of skin thickness infiltrated by tumor cells and regression ([T+R]/S ratio).
Use of sunscreens is widely advocated as a preventive measure against sun-induced skin cancers. However, to date, no epidemiologic study has reported a decreased melanoma risk associated with sunscreen use. We have conducted a case-control study aimed at evaluating the influence of sunscreen use on the occurrence of cutaneous malignant melanoma. In 1991 and 1992, 418 melanoma cases and 438 healthy controls were interviewed in Germany, France and Belgium. The questionnaire used differentiated between regular sunscreens, psoralen sunscreen (prepared with 5-methoxypsoralen, a tanning activator and photocarcinogen), and self-tanning cosmetics (which produce a tan without ultraviolet radiation). After adjusting for age, sex, hair colour and holiday weeks spent each year in sunny resorts, the melanoma risk was of 1.50 (95% CI:1.09–2.06) for regular sunscreens, and of 2.28 (95% CI: 1.28–4.04) for psoralen sunscreens. No melanoma risk was associated with use of self-tanning cosmetics. Among subjects with a poor ability to tan, psoralen sunscreen users displayed a melanoma risk of 4.45 (95% CI: 1.25–15.8) when compared with regular sunscreen users. There was a significant negative interaction between regular sunscreen use and sunburns experienced in adulthood. Use of sunscreens, especially psoralen sunscreen, was associated with higher density of pigmented lesions of the skin. Although we cannot exclude the presence of an unknown confounding factor, our results support the hypothesis that sunscreens do not protect against melanoma, probably because of their ability to delay or avoid sunburn episodes, which may allow prolonged exposure to unfiltered ultraviolet radiation. Serious doubts are raised regarding the safety of sunscreens containing psoralens. © 1995 Wiley-Liss, Inc.
SUMMARYA case-control study of cutaneous malignant melanoma (CMM) was based on 523 incident cases and 505 age- and sex-matched controls selected from the general population. The purpose was to investigate the relative risk of developing CMM associated with different sun habits and indicators of pigmentation, such as skin type, eye colour and hair colour. Compared to people with black hair, blonde subjects had a relative risk of 744 (95% confidence interval, 45.8–120.8). Associations with skin type and eye colour were considerably weaker. Relative risks of about 1.5–2.5 were found for certain sun habits. The results suggest that in a population of Caucasian origin with a predominantly fair complexion, pigmentary status characterized by hair colour is a far more important aetiological factor than sun habits.
Clinical and pathologic characteristics of melanoma were compared among 1647 clinical Stage I patients treated at the University of Alabama in Birmingham (USA) and The University of Sydney (Australia) between 1955 and 1980 to determine what changes occurred over a quarter century. Over this period, the number of patients treated annually has increased substantially. There was a steady increase in the proportion of patients presenting with localized disease (clinical Stage I). Melanomas became thinner, less invasive, less ulcerative and thus more curable. They also exhibited more of a radial growth phase. The median thickness of melanomas decreased in Australia from 2.5 mm prior to 1960 to 1.1 mm during the period 1976 to 1980, while in Alabama it has decreased from 3.3 to 1.4 mm. There was a significant increase in melanomas located on the trunk in males and a corresponding decrease in male head and neck melanomas. No significant change in the site distribution was observed for any major anatomical area on female patients. There were minimal differences in the incidence of both clinical and pathologic parameters among melanoma patients in Alabama, USA and in New South Wales, Australia even when accounting for their year of diagnosis. Long-term survival rates in patients with localized disease were found to increase slightly during the 25 year time frame of this analysis. The changes that have occurred are likely due to earlier diagnosis and changes in the biological nature of the disease.
BACKGROUND
This study reviews the case-mix characteristics, management, and outcomes of melanoma cases occuring in the U. S. within the last decade.METHODS
Analyses of the National Cancer Data Base (NCDB) were performed on cases diagnosed between 1985 through 1994. A total of 84,836 cases comprised of cutaneous and noncutaneous melanomas were evaluated.RESULTSThe percentages of melanomas that were cutaneous, ocular, mucosal, and unknown primaries were 91.2%, 5.2%, 1.3%, and 2.2%, respectively. For cutaneous melanomas, the proportion of patients presenting with American Joint Committee on Cancer Stages 0, I, II, III, and IV were 14.9%, 47.7%, 23.1%, 8.9%, and 5.3%, respectively. Factors associated with decreased survival included more advanced stage at diagnosis, nodular or acral lentiginous histology, increased age, male gender, nonwhite race, and lower income. Multivariate analysis identified stage, histology, gender, age, and income as independent prognostic factors. For ocular melanomas, 85.0% were uveal, 4.8% were conjunctival, and 10.2% occurred at other sites. During the study period, there was a large increase in the proportion of ocular melanoma patients treated with radiation therapy alone. For mucosal melanomas, the distribution of head and neck, female genital tract, anal/rectal, and urinary tract sites was 55.4%, 18.0%, 23.8%, and 2.8%, respectively. Patients with lymph node involvement had a poor prognosis. For unknown primary melanomas, the distribution of metastases as localized to a region or multiple sites at presentation was 43.0% and 57.0%, respectively. Surgical treatment of patients with unknown primary site of the melanoma resulted in better survival compared with no treatment.CONCLUSIONS
Treatment of early stage cutaneous melanoma resulted in excellent patient outcomes. In addition to conventional prognostic factors, socioeconomic factors were found to be associated with survival. Cancer 1998;83:1664-1678. © 1998 American Cancer Society.
Melanoma prognosis is dependent upon early recognition and treatment. There is a need for good clinical guidelines that focus on the early signs of melanoma. The ABCD (asymmetry, border, colour and diameter) rule states that most melanomas are more than 6 mm in diameter. Critics crave a modification, arguing that small diameter melanomas are not infrequent.
The aim of the present study was to describe the frequency and prognosis of melanomas less than 7 mm in a clinical setting.
The Norwegian Melanoma Project was conducted as a multicentre, prospective study with inclusion criteria. Patients were recruited from five dermatological departments in Norway from 1990 to 1993.
The frequency of small melanomas was 11.4% (18/158). One-third was in situ melanoma, the rest invasive with a median thickness of 0.8 mm. Four small melanomas were T2 lesions, with a Breslow thickness of more than 1 mm. One nodular T2 melanoma recurred locally 2 years after diagnosis and the patient died of distant metastasis only months later.
The ABCD rule remains a practical guide for early recognition of melanoma. Clinicians must be aware of its limitations.
Previous studies have shown that people often apply less sunscreen than the recommended amount of 2 mg/cm2. Our purpose in this study was to determine objectively how photoprotection varies with application thickness. The protection provided by differing quantities of sunscreens containing varying amounts of titanium dioxide was measured in vitro using excised human epidermis as the substrate. It was found that application thickness had a significant effect on the sun protection factor (SPF), with most users probably achieving a mean SPF of between 20-50% of that expected from the product label. Underprotection due to inadequate application, coupled with overexposure to the sun, might partially explain why sunscreen use has been reported to be a risk factor in melanoma.
To assess the ability of sunscreens to protect connective tissue from actinic damage, hairless mice were irradiated with Westinghouse FS20 sunlamps thrice weekly for 30 weeks. Each exposure, consisting mainly of UV-B and the less energetic UV-A, was approximately 6 human minimal erythema doses under these lights. One group of animals received irradiation only. The other 2 groups were treated, prior to irradiation, with sunscreens of either low or high sun protection factors (SPF 2 and SPF 15, respectively). Skin biopsies were taken at 10-week intervals and were stained with various histochemical stains to reveal changes in the dermis. The unprotected, irradiated animals showed a great increase in the following: reticulin fibers, elastic fibers to the extent of elastosis, neutral and acid mucopolysaccharides and melanin production. The SPF 15 sunscreen completely prevented these changes. The SPF 2 sunscreen was less effective. These effects were substantiated by ultrastructural examination of the tissues by electron microscopy. A surprising histologic finding was the repair capability of the dermis in the post-irradiation period.
In a population-based, matched case-control study from the South Swedish Health Care Region, which has the highest risk for melanoma in Sweden, the relation between the use of sunbeds or sunlamps and malignant melanoma was investigated . Between July 1, 1988, and June 30, 1990, a total of 400 melanoma patients and 640 healthy controls aged 15–75 years answered a comprehensive questionnaire containing different epidemiologic variables. Questions regarding the use of sunbeds or sunlamps were included. The odds ratio for developing malignant melanoma after ever having used sunbeds or sunlamps was 1.3. Considering all age groups, the odds ratio was significantly elevated after exposure more than 10 times a year to sunbeds or sun-lamps (odds ratio (OR) = 1.8). When the study was restricted to patients and controls younger than age 30 years because the use of tanning devices is much more common among young persons, the odds ratio was higher (OR = 7.7 for more than 10 times a year vs. none). These findings were independent of constitutional factors and factors regarding sun exposure. A dose-response relation was evident. Furthermore, among melanoma patients in this young age group, the ratio of females to males was significantly higher than in older patients. When different melanoma presentation sites were considered, only lesions of the trunk were significantly associated with sunbed or sunlamp use (OR = 4.2 for more than 10 times a year vs. none).
Queensland, Australia, had the world's highest incidence rates of invasive cutaneous melanoma in the 1970s.
The purpose of this study was to monitor trends in melanoma incidence in Queensland.
We studied two time periods in which ascertainment was comparable.
In the 7.5 years up to 1987, the incidence of invasive melanoma in Queensland increased by more than one half in women (to 42.89 per 100,000) and more than doubled in men (to 55.81 per 100,000), with the most dramatic increase seen in men over age 50 years. This higher increase in men is a reversal of the previously higher rates in women. In Queensland, cumulative risks of total cutaneous melanoma (in persons aged 0-74 years), including preinvasive melanoma, have increased to one in 14 in men and to one in 17 in women. There were large increases in age-standardized incidence rates of thin lesions (less than 0.75 mm) in both sexes but not of in situ lesions, and there were also increases in thicker lesions, especially on the backs of males.
Although increased awareness and earlier diagnosis appear to have accompanied increased incidence, increased exposure to solar UV radiation during the past 50 years appears to be the most likely explanation for the rise in incidence rates.
A better understanding is needed of the causes of melanoma and of the complex relationships between constitutional factors, ambient UV radiation, and sun-exposure behavior.
We examined the chronic effect of long daily suberythemal, fluorescent solar-stimulated radiation (FSSR; ultraviolet B (UVB)+A(UVA)) and UVA alone on female Skh-1 hairless albino mouse skin. Mice were dorsally irradiated 8 h every weekday for 16 weeks with FSSR or UVA, or 32 weeks with UVA alone. Various topical, low concentration, UVB and/or UVA sunscreens were applied before irradiation. Damage was assessed by skin-fold thickness, histology and biochemically by changes in the proportion of type III collagen. All FSSR-exposed mice showed increased skin thickening, elastic fibre hyperplasia, collagen damage and an increased proportion of type III collagen. Application of the UVB sunscreen (2.00%) resulted in marked protection for all nonbiochemical endpoints. There was no obvious advantage of adding 0.75% UVA sunscreen to the UVB sunscreen, but adding 2.00% UVA sunscreen reduced biochemical changes and connective tissue damage. Sixteen weeks of UVA irradiation caused skin thickening and laxity but the histology and biochemistry were indistinguishable from the controls. The mice irradiated with UVA for 32 weeks showed slight elastic fibre hyperplasia and collagen damage histologically, and increased skin thickening and laxity; these changes were unmodified by the 0.75% UVA sunscreen. These mice showed a significant increase in the proportion of type III collagen against which the UVA sunscreen offered protection. Our data suggest that UVA may be important in photoaging and that the use of low sun protection factor UVB+ UVA sunscreens on a day-to-day basis may offer some protection from solar photoaging.
The American Cancer Society's Department of Epidemiology and Statistics reports its 25th annual compilation of cancer incidence, survival, and mortality data for the United States and around the world.
Data are presented from a large case-control study (583 cases, 608 controls) to estimate the association of melanoma with the use of sunbeds and sunlamps. Odds ratios of 1.88 and 1.45 were found for ever having used a sunbed or sunlamp in males and females, respectively, which was statistically significant in males and of borderline significance in females. These effects persisted when adjustments were made for age and a variety of potential confounders. The effect was slightly stronger for lentigo maligna and for lesions of the face, head, neck, and arms. The risk was greater and significant for both sexes for domestic use of sunbeds/sunlamps, and increased with duration and amount of use. A comparison of 43 cases interviewed before a diagnosis of melanoma had been made with the other 540 cases suggests that recall bias was not responsible for the association. The authors conclude that use of artificial tanning devices appears to be a risk factor for melanoma.
The effect of changes in the ozone layer on the incidence of skin cancer was explored using data for Norway. Attempts were made to arrive at a relationship between the ‘environmental effective UV-dose’ and the skin cancer incidence. Norway is well suited for this purpose because of the large variation in the annual UV-dose from north to south. Furthermore we have a well developed cancer registry and a homogeneous population with regard to skin type.
Four different regions of the country, each with a broadness of 1° in latitude (approximately 111 km), were selected (located around 69.5, 63.5, 60 and 58.5° N). The annual effective UV-doses for these regions were calculated, assuming normal ozone conditions throughout the year and the action spectrum proposed by CIE, which extends up to 400 nm. The incidence rate (in the period 1970–1980) of malignant melanoma and non-melanoma skin cancer (mainly basal cell carcinoma) increased with the annual environmental UV-doses. For both these types of cancer a quadratic dose-effect relationship seems to be valid to a first approximation.
The present data indicate that the incidence of skin cancer would increase by approximately 2% for each percent ozone reduction.
Two hundred forty-eight cases of melanoma accessioned from 1984 through 1985 were independently reviewed by a panel of dermatopathologists for the presence of nevomelanocytic proliferations in histologic contiguity with melanoma. One hundred ninety-seven cases remained in the sample for analysis after cases with insufficient histologic material and those diagnosed without primary melanoma were excluded. We found that 32.5% of melanomas (95% confidence interval, 25.9% to 39.7%) were associated with a benign or dysplastic nevus in histologic contiguity. Melanoma type and anatomic location were significant predictors of contiguous nevomelanocytic proliferations when considered alone. After adjustment, however, only melanoma type significantly predicted the presence of a contiguous histologic evidence of a precursor nevus than was nodular melanoma (odds ratio, 11.1; 95% confidence interval, 1.4 to 86.6) and were almost 22 times more likely to be associated with a nevus than was lentigo maligna melanoma (odds ratio, 21.45; 95% confidence interval, 2.8 to 162.4). This evidence supports the concept of the heterogeneity of melanoma histogenesis.
A population-based case-control study of 474 patients with cutaneous malignant melanoma and 926 population controls, conducted in East Denmark over a 3-year period, included an evaluation of the relationship of UV-light exposure to cutaneous melanoma risk. Patients with lentigo maligna melanoma were not included. Significantly increased risk was associated with severe sunburn before age 15 (RR = 2.7 for 5 + vs. never), sunbathing (RR = 1.6), boating (RR = 1.4) and vacations spent in the sun (RR = 1.4 for very sunny vs. never). A significant decrease in risk was associated with occupational exposure during the summer in males (RR = 0.7), and no association with cutaneous microtopography was seen. These findings were independent of the effects of constitutional risk factors (naevi, freckles and light hair colour). No association was found between the risk of cutaneous melanoma and exposure to artificial UV-light (fluorescent light, sun lamps, or sun beds). No significant difference was found between superficial spreading melanoma and nodular melanoma with regard to any of the sun exposure variables. Our data indicate that exposure to intermittent intense sunlight is an important risk factor for cutaneous malignant melanoma, while long-term continuous exposure does not appear to be risk factor.
Photoprotection against ultraviolet A (UVA) by three sunscreens was evaluated in humans, with erythema and pigmentation used as end points in normal skin and in skin sensitized with 8-methoxypsoralen and anthracene. The test sunscreens were Parsol 1789 (2%), Eusolex 8020 (2%), and oxybenzone (3%). UVA was obtained from two filtered xenon-arc sources. UVA protection factors were found to be significantly higher in sensitized skin compared with normal skin. Both Parsol and Eusolex provided better and comparable photoprotection (approximately 3.0) than oxybenzone (approximately 2.0) in sensitized skin, regardless of whether 8-methoxypsoralen or anthracene was used. In normal unsensitized skin, Parsol 1789 and Eusolex 8020 were also comparable and provided slightly better photoprotection (approximately 1.8) than oxybenzone (approximately 1.4) when pigmentation was used as an end point. The three sunscreens, however, were similar in providing photoprotection against UVA-induced erythema. Protection factors obtained in artificially sensitized skin are probably not relevant to normal skin. It is concluded that pigmentation, either immediate or delayed, is a reproducible and useful end point for the routine assessment of photoprotection of normal skin against UVA.
UVA, in high-dose single exposures, can, like UVB, be deleterious to skin. Dermal damage resulting from chronic exposure to UVA has not been studied. To investigate the long-term effects, we irradiated albino hairless mice for 30-34 weeks with UVA radiation, alone, from two sources with differing spectral qualities, and in combination with UVB as solar-simulating radiation. The results were compared to UVB alone.
Like UVB, the UVA waveband, especially that with a spectral distribution similar to solar UVA, caused elastic fiber damage, increased glycosaminoglycan levels, and produced hypertrophy of deep dermal tissues. There were, however, striking differences between UVB- and UVA-irradiated skin. A combination of UVA and UVB summated the effects of both wavebands. Substantial protection against these effects was afforded by a broad-spectrum sunscreen.
Telephone interviews were conducted with 111 patients with cutaneous melanoma and 107 controls to determine sun-exposure habits during various life periods. Painful or blistering sunburns during either childhood or adolescence were associated with subsequent increased risk of developing cutaneous melanoma. While solar exposure does not appear to be a factor in some patients, when patients were divided into subgroups by age, sex, or sun type, each subset showed some increased risk associated with a factor related to short-term excessive sun exposure. Ill effects due to such exposures appeared to increase the risk of melanoma.
This review deals with topical and systemic approaches for protection of human skin against the harmful effects of solar radiation. Two concerns about the deleterious effects of sun exposure involve: (1) acute effects (e.g., sunburn and drug-induced phototoxicity) and (2) potential long-term risks of repeated sun exposures leading to development of solar elastosis, keratoses, induction of both nonmelanoma and melanoma skin cancer, and alteration of immune responses and functions. Action spectra of normal and abnormal reactions of human skin to acute and chronic effects of solar radiation are presented with a view to helping the physician prescribe the appropriate sunscreens. Factors that influence acute effects of sunburn are reviewed. Various artificial methods effective in minimizing or preventing harmful effects of solar radiation, both in normal individuals and in patients with photosensitivity-related problems, are discussed. Emphasis is placed on the commercially available chemical sunscreens and their properties. Sun protection factor (SPF) values of several brand-name formulations determined with a solar simulator under indoor conditions (laboratory) and with solar radiation under natural, field conditions are presented. Factors responsible for variations of SPF values observed under indoor and outdoor conditions are reviewed. Systemic photoprotective agents and their limitations are outlined. The photobiology of melanin pigmentation (the tanning reaction) is briefly discussed, with emphasis on the dangers of using quick-tanning lotions for stimulation of the tanning reaction.
Sunscreens of low or high sun protection factors (SPF*) were tested for their ability to inhibit ultraviolet (UV) carcinogenesis in two varieties of hairless mice. Low protection (SPF = 2) reduced by 50% the number of albino animals developing tumors. High protection (SPF =15) prevented tumor formation. Tumorigenesis was totally prevented in the lightly pigmented variety with either sunscreen, demonstrating the added protection of melanin. In mice and man, UV-induced cancer is a cumulative process. Reducing the amount of UV light reaching the basal layer will retard that process.
Studies published have suggested a possibility that regular use of sunscreen to prevent skin cancer may put the population, particularly elderly people, at risk of vitamin D deficiency. We aimed to determine whether regular use of sunscreens in the normal adult population, as recommended by public health authorities for the prevention of skin cancer, may put individuals at risk of vitamin D deficiency. A randomized double-blind control trial of the daily use of a broad-spectrum sunscreen (sun protection factor [SPF] 17) vs placebo cream over a summer period in Australia was conducted in 113 people aged 40 years and over, with sampling stratified by age. All participants had at least one solar keratosis. Serum samples taken at the beginning and at the end of the study were analyzed for 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3.
Mean levels of 25-hydroxyvitamin D3 rose significantly by the same amount in both groups over the period of the study (placebo, +12.8 mmol/L; sunscreen, +11.8 mmol/L). Mean levels of 1,25-dihydroxyvitamin D3 increased significantly in the placebo group only (placebo, +10.8 pmol/L; sunscreen, +1.3 pmol/L), but for no subject in either group was the level of 1,25-dihydroxyvitamin D3 outside the reference range either at the start or at the end of the study. There were no significant differences by age, sex, and skin type in the change in 25-hydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 over the study period.
No person, including those aged 70 years and over, developed any vitamin D levels outside the normal reference range during the period of the study. The data suggest that over an Australian summer sufficient sunlight is received, probably through both the sunscreen itself and the lack of total skin cover at all times, to allow adequate vitamin D production in people who are recommended to use sunscreens regularly. More work is required to elucidate the relationship between 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3, particularly during the different seasons of the year.
The relation between use of sunscreens, different host factors and malignant melanoma was investigated in a population-based, matched case-control study of malignant melanoma in the South Swedish Health Care Region, which has the highest risk for melanoma in Sweden, between 1 July 1988 and 30 June 1990. In total, 400 melanoma patients and 640 healthy controls aged 15-75 years answered a comprehensive questionnaire regarding different epidemiologic variables, including questions on use of sunscreens and different constitutional factors. The use of sunscreens was not found to protect against developing malignant melanoma. Instead, an unexpected relation between the use of sunscreens and the risk of developing malignant melanoma was seen (odds ratio (OR) 1.8 for almost always vs never using sunscreens). A tentative dose-response relation was found. Virtually the same ORs were seen in both sexes. Furthermore, persons younger than 50 years had a higher OR than persons older than 50 years. When different melanoma presentation sites were considered, lesions of the trunk were associated with sunscreen use in females (adjusted OR = 3.7 for almost always vs never using sunscreens), while lesions of the extremity or head and neck were associated with sunscreen use in males (adjusted OR = 3.2 for almost always vs never using sunscreens). Raised naevi on the left arm and freckling were shown to be the major constitutional risk factors (OR = 3.9 for more than three naevi vs none and OR = 1.4, respectively). The results were essentially unaltered in a histopathologically re-examined material. Further investigations are needed in order to form a basis for melanoma prevention.
A total of 452 women with cutaneous malignant melanoma and 930 control subjects aged 25-59 years participated in a population-based case-control study carried out in the San Francisco Bay Area between 1981 and 1986. Interviews were conducted in the homes of the women. Questions were asked about various phenotypic characteristics, including eye, hair, and complexion color, presence of freckles, and number of nevi, as well as medical history, history of exposure to sunlight, ability to tan, occupation, use of cigarettes and alcohol, and demographic factors. Histologic type of melanoma was considered in the analysis: 355 (79%) women were diagnosed with superficial spreading melanoma, 61 (13%) had nodular melanoma, 13 (3%) had lentigo maligna melanoma, and 23 (5%) had other melanomas that could not be further classified. For all cutaneous melanoma subjects combined, univariate results related to host factors showed that risk increased with the presence of nevi greater than 5 mm in diameter; light eyes, hair, and complexion; freckles; a history of skin cancer other than melanoma; a history of skin cancer in relatives; and maternal and paternal Northern or Central European ancestry. After adjustment for each other and for sun exposure factors, the phenotypic and host factors associated with all types of cutaneous malignant melanoma and superficial spreading melanoma were the presence of large nevi, light hair color, light complexion, and maternal Northern or Central European ancestry. Host factors associated with nodular melanoma after adjustment for other factors were the presence of large nevi, light hair color, ever being overweight by 20 pounds (9 kg) or more, and the presence of freckles.
A population-based case-control study of cutaneous malignant melanoma (CMM) was conducted in 452 women with melanoma and 930 control subjects aged 25-59 years in five San Francisco Bay Area counties between 1981 and 1986. Women were interviewed in their homes with regard to history of sunlight exposure and sunburns during different periods in their lives, phenotypic and host characteristics, medical history, occupation, and demographic factors. Data were analyzed by the patients' histologic type of melanoma; 355 women were classified as having superficial spreading melanoma (SSM), 61 had nodular melanoma (NM), 13 had lentigo maligna melanoma, and 23 had other melanomas that could not be further classified upon histologic review by University of California dermatopathologists. Univariate results from analysis of factors related to sun exposure showed that the risk of all histologic types of CMM, SSM, and NM increased with increasing tendency of the subject to sunburn and with history of increased severity and/or frequency of sunburns up to age 12 years. Risk of all types of CMM and SSM also increased with increasing number of sunburns for all age groups and with lack of use of sunscreen. After adjustment for each other and for phenotypic factors, history of sunburn up to age 12 and lack of sunscreen use were the primary sun-related factors associated with an increased risk of all types of CMM and SSM, while tendency to sunburn when exposed to 1/2 hour of noontime sun and lack of use of sunscreen were related to NM. Although having frequent sunburns before age 12 and having severe sunburns before age 12 were both strongly associated with melanoma, having large numbers of sunburns during any time period from elementary school through age 30 years and having sunburns during the 10 years prior to diagnosis or interview were all associated with a doubling of risk for SSM after adjustment for other factors. These results suggest that the increased risk of melanoma related to sunburns is not confined to childhood sunburns. Maintenance of an all-year tan provided no protective effect against melanoma after adjustment for tendency to burn. No association was noted with use of fluorescent lights or exposure to sunlamps for all types of CMM, SSM, or NM.
Use of sunscreens is widely advocated as a preventive measure against sun-induced skin cancers. However, to date, no epidemiologic study has reported a decreased melanoma risk associated with sunscreen use. We have conducted a case-control study aimed at evaluating the influence of sunscreen use on the occurrence of cutaneous malignant melanoma. In 1991 and 1992, 418 melanoma cases and 438 healthy controls were interviewed in Germany, France and Belgium. The questionnaire used differentiated between regular sunscreens, psoralen sunscreen (prepared with 5-methoxypsoralen, a tanning activator and photocarcinogen), and self-tanning cosmetics (which produce a tan without ultraviolet radiation). After adjusting for age, sex, hair colour and holiday weeks spent each year in sunny resorts, the melanoma risk was of 1.50 (95% Cl:1.09-2.06) for regular sunscreens, and of 2.28 (95% Cl: 1.28-4.04) for psoralen sunscreens. No melanoma risk was associated with use of self-tanning cosmetics. Among subjects with a poor ability to tan, psoralen sunscreen users displayed a melanoma risk of 4.45 (95% Cl: 1.25-15.8) when compared with regular sunscreen users. There was a significant negative interaction between regular sunscreen use and sunburns experienced in adulthood. Use of sunscreens, especially psoralen sunscreen, was associated with higher density of pigmented lesions of the skin. Although we cannot exclude the presence of an unknown confounding factor, our results support the hypothesis that sunscreens do not protect against melanoma, probably because of their ability to delay or avoid sunburn episodes, which may allow prolonged exposure to unfiltered ultraviolet radiation. Serious doubts are raised regarding the safety of sunscreens containing psoralens.
A computer-aided search identified 16 case-control studies which specifically assessed sunburn as a risk factor for cutaneous malignant melanoma. Using unadjusted estimates, a history of sunburn was associated with significantly increased risk of melanoma in all but one study. Four studies were defined as core studies after assessment of study quality; however, only two of these had sufficiently similar definitions of sunburn to allow pooling of results. Using pooled data, the risk of melanoma in those ever sunburned was 2.0 (95 percent confidence interval [CI] = 1.6-2.6), while the highest category of sunburn exposure had a risk of 3.7 (CI = 2.5-5.4). The suggestion that sunburns in childhood carry greater risk of melanoma cannot be supported by pooled analysis. This review demonstrated considerable variation in design and method among the studies, and identified sources of bias which prevented a pooled analysis using all available data. The need for strong epidemiologic evidence relating sunburn to melanoma, particularly in childhood, is of prime importance, since avoidance of sunburn is one of the few potential means of primary prevention of melanoma.
The age relationship between sunburns and malignant melanoma was investigated in a population-based, matched, case-control study from the South Swedish Health Care Region (the highest risk area for melanoma in Sweden). Between 1988 and 1990, a total of 400 patients with a first diagnosis of malignant melanoma and 640 healthy controls aged 15-75 years answered a comprehensive questionnaire including questions regarding ultraviolet radiation exposure. In addition, a literature review was performed. The average number of episodes of sunburn per year was significantly associated with malignant melanoma (relative risk, RR = 1.9 for > or = three episodes per year versus never). Outdoor employment during the summer was associated with a decreased risk for the development of malignant melanoma (RR = 0.8). Data from case-control studies and migration studies concerning age relationship between sunburns and melanoma are inconsistent. From our own data, we did not find a higher risk of melanoma developed in individuals who had experienced severe sunburns in childhood. Instead, a significantly increased risk was associated with sunburns after age 19 years, RR = 2.2 for a history of more than five times versus never. Even if the hypothesis is biologically plausible, that episodes of sunburn early in life are associated with a higher risk of melanoma, so far epidemiological evidence is scarce. There is a need for better prospective epidemiological studies addressing this issue.
A controlled trial was undertaken from December 1987 to December 1990 to test the hypothesis that a strong sunscreen can reduce the number of cancerous and precancerous skin lesions. Candidates were selected from a high-risk population attending either a university- or Veterans Affairs-based dermatology practice in Lubbock, Tex, for a prospective, double-blind, controlled trial of daily application of sunscreen vs placebo over a 2-year period. Participants were asked to volunteer if they had demonstrated premalignant changes (actinic keratoses) or nonmelanoma skin cancer (basal cell carcinoma or squamous cell carcinoma), had continuing sun exposure, and were not using sunscreen on a regular basis. Fifty-three volunteers were initially enrolled in the study, and 37 came for the final 24-month visit.
The rate of appearance of new precancerous skin lesions was less for the treatment group than for control subjects. People with darker skin had fewer actinic keratoses, women had fewer lesions than men, and people with fewer lesions at enrollment had fewer lesions during the study. The numbers of new nonmelanoma skin cancers appearing during the study period were too small for statistical analysis.
The regular use of sunscreens can significantly reduce cutaneous neoplasia, as indicated by its suppression of precancerous lesions. A longer and/or larger study would be necessary to demonstrate an effect on malignant lesions.
It is well established that exposure to solar UVB (290-320 nm) gives rise to mutations in oncogenes and tumor suppressor genes that initiate the molecular cascade toward skin cancer. Although UVA (320-400 nm) has also been implicated in multistage photocarcinogenesis, its potential contribution to sunlight mutagenesis remains poorly characterized. We have determined the DNA sequence specificity of mutations induced by UVB (lambda > 290 nm), and by UVA (lambda > 350 nm), at the adenine phosphoribosyltransferase locus of Chinese hamster ovary cells. This has been compared to results previously obtained for stimulated sunlight (lambda > or = 310 nm) and 254-nm UVC in the same gene. We demonstrate that T-->G transversions, a generally rare class of mutation, are induced at high frequency (up to 50%) in UVA-exposed cells. Furthermore, this event comprises a substantial proportion of the simulated sunlight-induced mutant collection (25%) but is significantly less frequent (P < 0.05) in cells irradiated with either UVB (9%) or UVC (5%). We conclude that the mutagenic specificity of broad-spectrum solar light in rodent cells is not determined entirely by the UVB component and that UVA also plays an important role.
The frequency of melanoma and nonmelanoma skin cancer is increasing rapidly in the United States. However, the linkage of these cancers to sun exposure has been questioned because of differences in anatomic site distribution. To obtain insights into the development of these skin cancers, we examined reports of 132 patients with xeroderma pigmentosum (XP), an inherited cancer-prone, DNA repair-deficient disorder with marked clinical and laboratory UV hypersensitivity.
Malignant skin neoplasms were present in 70% of the patients with XP at a median age of 8 years, which is 50 years earlier than in the US white population. Fifty-seven percent of the patients had basal cell or squamous cell carcinoma, and 22% had melanoma. The frequency of melanomas, like the frequency of nonmelanoma skin cancers (basal cell and squamous cell carcinomas), anterior eye cancers, and tongue cancers, but unlike that of internal neoplasms, was increased 1000-fold or more in patients with XP who were younger than 20 years. As in the general population, the anatomic distribution of melanomas was different from that of nonmelanomas in the patients with XP.
These data suggest that (1) DNA repair plays a major role in the prevention of cutaneous cancers in the general population and (2) sunlight exposure is responsible for the induction of melanoma as well as nonmelanoma skin cancer in patients with XP, although acting by different mechanisms for the two types of skin cancer.
This study addressed the impact of exposure to ultraviolet radiation on the risk of cutaneous malignant melanoma (CMM), as well as the behavioral components at stake in its occurrence. We performed a one-to-one unmatched case-control study among subjects aged 20 years or more with naturally non-pigmented skin in Germany, France and Belgium. Four-hundred and twenty consecutive patients with CMM diagnosed from 1 January 1991 on were derived from hospital registries; 447 controls were chosen randomly in the same municipality as cases. Subjects unaware of the dangers of exaggerated exposure to sunlight display an estimated CMM risk of 3.72% (95% confidence interval 2.63-5.26). The number of holiday weeks spent annually in sunny resorts and sunbathing during the hot hours of the day are strong risk factors in the three countries, but not the number of years spent outdoors, as farmers or building workers. Multiple logistic adjustments on the host characteristics increases the CMM risk associated with recreational exposure to sunlight, as well as the adjustment on the unawareness of the dangers of exaggerated exposure to sunlight. Recreational exposure to sunlight and sunburn early in life seem capable of fostering the proliferation of pigmented lesions of the skin. Our data support the hypothesis that most CMM develop from pigmented lesions of the skin containing initiated melanocytes, and that the cell proliferation due to brutal, intermittent exposures to solar radiation amplifies the likelihood of a melanocyte entering into a malignant process.(ABSTRACT TRUNCATED AT 250 WORDS)
Epidemiologic evidence suggests that exposure to UV radiation plays a significant role in the development of melanoma skin cancers. As early surgical removal of the melanoma is the only effective therapy, current strategies for reducing mortality from melanoma focus on prevention of the disease. Chemical sunscreens protect mice from development of skin cancers that resemble sunlight-induced human squamous cell cancers, but there appears to be a complex relationship between UV radiation exposure and development of melanoma.
We asked whether common sunscreens would protect mice against UV radiation-induced enhancement of melanoma incidence.
C3H mice were exposed to 4.8 kJ/m2 UVB from FS40 sunlamps twice a week for 3 weeks. Sunscreens containing 7.5% 2-ethylhexyl-p-methoxycinnamate, 8% octyl-N-dimethyl-p-aminobenzoate, 6% benzophenone-3, or the oil-in-water vehicle alone were applied to the ears and tails of the mice 20 minutes before irradiation. At various times during and after exposure, we determined UV radiation-induced inflammation by measuring ear swelling. We also examined the ears histologically for UV radiation-induced alterations. One day after the final irradiation, 2.5 x 10(4) syngeneic K1735 melanoma cells were injected into the external ears. Mice were examined weekly for tumor growth for 5-8 weeks after tumor cell injection. Control mice were treated in the identical way except for exposure to UV radiation.
The incidence of melanomas was significantly higher in the UV-irradiated mice. All three sunscreens protected against UV radiation-induced ear swelling and clearly diminished histopathologic alterations, including sunburn cell formation, epidermal hyperplasia, and mononuclear cell infiltrate in the dermis. However, the sunscreens failed to protect against UV radiation-induced increase in melanoma incidence. The sunscreens or vehicle alone did not significantly alter tumor growth.
Protection against sunburn does not necessarily imply protection against other possible UV radiation effects, such as enhanced melanoma growth.
Sunscreen protection against UV radiation-induced inflammation may encourage prolonged exposure to UV radiation and thus may actually increase the risk of melanoma development. These findings suggest that further research on the ability of sunscreens to prevent melanoma is urgently needed.