RESUMEN

Surgical resection, the mainstay for melanoma treatment, faces challenges due to high tumor recurrence rates and complex postoperative wound healing. Chronic inflammation from residual disease and the risk of secondary infections impede healing. We introduce an innovative, injectable hydrogel system that integrates a multifaceted therapeutic approach. The hydrogel, crosslinked by calcium ions with sodium alginate, encapsulates a blood clot rich in dendritic cells (DCs) chemoattractants and melanoma cell-derived nanovesicles (NVs), functioning as a potent immunostimulant. This in situ recruitment strategy overcomes the limitations of subcutaneous tumor vaccine injections and more effectively achieves antitumor immunity. Additionally, the hydrogel incorporates Chlorella extracts, enhancing its antimicrobial properties to prevent wound infections and promote healing. One of the key findings of our research is the dual functionality of Chlorella extracts; they not only expedite the healing process of infected wounds but also increase the hydrogel's ability to stimulate an antitumor immune response. Given the patient-specific nature of the blood clot and NVs, our hydrogel system offers customizable solutions for individual postoperative requirements. This personalized approach is highlighted by our study, which demonstrates the synergistic impact of the composite hydrogel on preventing melanoma recurrence and hastening wound healing, potentially transforming postsurgical melanoma management.

Asunto(s)

Células Dendríticas , Hidrogeles , Melanoma , Cicatrización de Heridas , Hidrogeles/química , Animales , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Melanoma/terapia , Melanoma/patología , Cicatrización de Heridas/efectos de los fármacos , Humanos , Recurrencia Local de Neoplasia/prevención & control , Ratones Endogámicos C57BL , Antiinfecciosos/uso terapéutico , Antiinfecciosos/farmacología , Ratones , Línea Celular Tumoral , Femenino

RESUMEN

Recently, the increasing incidence of malignant melanoma has become a major public health concern owing to its poor prognosis and impact on quality of life. Consuming foods with potent antitumor compounds can help prevent melanoma and maintain skin health. Fucoxanthin (FX), a naturally occurring carotenoid found in brown algae, possesses antitumor properties. However, its bioavailability, safety risks, and in vivo effects and mechanisms against melanoma remain unclear. This research focused on evaluating the safety and prospective antimelanoma impact of simulated gastrointestinal digestion products (FX-ID) on HaCaT and A375 cells.The results indicate that FX-ID exerts negative effects on mitochondria in A375 cells, increases Bax expression, releases Cytochrome C, and activates cleaved caspase-3, ultimately promoting apoptosis. Additionally, FX-ID influences the mitogen-activated protein kinase (MAPK) pathway by enhancing cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB) levels, consequently facilitating apoptosis and inflammation without significantly impacting HaCaT cells. These findings provide insight into inhibitory mechanism of FX-ID against melanoma, guiding the development of functional foods for prevention.

Asunto(s)

Apoptosis , Queratinocitos , Melanoma , Xantófilas , Humanos , Melanoma/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Apoptosis/efectos de los fármacos , Xantófilas/farmacología , Xantófilas/química , Línea Celular Tumoral , FN-kappa B/metabolismo , FN-kappa B/genética , Digestión , Modelos Biológicos , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Antineoplásicos/farmacología , Antineoplásicos/química , Phaeophyceae/química , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 3/genética

RESUMEN

Uveal melanoma (UM) is a common health challenge worldwide as a prevalent intraocular malignancy because of its high mortality rate. However, clinical workers do not have an accurate prognostic tool now. Immune function is closely related to tumor development. Interestingly, researchers have identified that long noncoding RNAs (lncRNAs) are tightly associated with biological processes at the cellular level, particularly their involvements in immune response and its regulation of the growth of tumor cells. Hence, lncRNAs may be involved in the progression of uveal melanoma. UM patients' RNA expression matrices were extracted from TCGA database. The targeted immune genes were filtered by weighted correlation network analysis and the immune-related lncRNAs with a high prognostic relevance were obtained by Cox regression analysis and least absolute shrinkage and selection operator regression analysis. Each sample was scored according to those lncRNA expression and divided into high-risk and low-risk group. We confirmed the sensitivity and independence of our risk model compared to the tumor mutation burden score. Finally, we demonstrated the clinical relevance of our model by examining its sensitivity to different drugs. The risk score based on our risk model was significantly independent of other clinical parameters in either univariate (hazard ratio = 109.852 [15.738-766.749], P value < .001) or multivariate (hazard ratio = 114.075 [15.207-855.735], P value < .001) analyses. The ROC curves of this model imply high predictive accuracy for 1-year, 3-year, and 5-year survival (1-year area under the curve [AUC] = 0.849, 3-years AUC = 0.848, and 5-years AUC = 0.761). Our study revealed that immune-related lncRNAs are significant in the clinical diagnosis, treatment and prognosis of UM patients. We successfully constructed a lncRNA-based prognostic risk model which may serve as a future reference for the diagnosis and prognosis of UM. Based on this model we also validated the sensitivity of some cancer drugs, which has implications for the future immunotherapy and drug development.

Asunto(s)

Melanoma , ARN Largo no Codificante , Neoplasias de la Úvea , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/inmunología , Humanos , Melanoma/genética , Melanoma/mortalidad , Melanoma/inmunología , ARN Largo no Codificante/genética , Pronóstico , Masculino , Femenino , Medición de Riesgo/métodos , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Modelos de Riesgos Proporcionales

RESUMEN

Melanoma is a malignant tumor with the highest growth rate in the incidence and is the leading cause of death due to skin cancers. In Poland, approximately 1500 cases of melanoma are detected annually in advanced or metastatic stages. Intensive preventive measures can contribute to its early-stage diagnosis, consequently reducing the number of fatalities. The aim of the study was to assess the occurrence of melanoma risk factors among the residents of Silesia region and their knowledge about the diagnosis and prevention of this cancer. An original questionnaire was used in the study, and its completion was anonymous. The study was conducted among the residents of the Silesian Voivodeship. A total of 400 (100%) individuals were examined. Among them were 243 women and 157 men. The participants' ages ranged from 16 to 84 years (mean age = 34.38 ±â€…18.39). The participants were burdened with melanoma development risk factors such as fair skin complexion (235; 58.75%), having more than 50 pigmented lesions (158; 39.50%) and sunburns (105; 26.25%). Over 40% (166; 41.50%) of the participants had never examined their pigmented lesions. A staggering 78% (311; 77.75%) of the respondents had never undergone dermatoscopic examination, and over 50% (215; 53.75%) did not know what this examination entailed. Just under 16% (63; 15.75%) of the participants stated that their family doctor had examined their pigmented lesions, and almost % (154; 97.47%) of those with numerous pigmented lesions had never been referred to a dermatologist for dermatoscopy. The surveyed residents of the Silesian Voivodeship were burdened with numerous risk factors for melanoma development, with the most common being fair skin complexion, having more than 50 pigmented lesions, and sunburns. The knowledge of the participants regarding the diagnosis and prevention of melanoma development was insufficient, thus highlighting the necessity for conducting systematic educational initiatives in the mentioned field. These initiatives should ultimately lead to the preservation of health and life, as well as the maintenance of its high quality.

Asunto(s)

Melanoma , Neoplasias Cutáneas , Humanos , Masculino , Adulto , Femenino , Persona de Mediana Edad , Melanoma/prevención & control , Melanoma/diagnóstico , Melanoma/epidemiología , Polonia/epidemiología , Neoplasias Cutáneas/prevención & control , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/epidemiología , Anciano , Adulto Joven , Adolescente , Anciano de 80 o más Años , Factores de Riesgo , Conocimientos, Actitudes y Práctica en Salud , Encuestas y Cuestionarios , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos

Asunto(s)

Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Encefalitis , Melanoma , Humanos , Femenino , Melanoma/tratamiento farmacológico , Melanoma/secundario , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Encefalitis/inducido químicamente , Encefalitis/diagnóstico , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias Cutáneas , Enfermedad de Hashimoto/complicaciones , Persona de Mediana Edad

RESUMEN

BACKGROUND: Most primary cutaneous melanomas have pathogenesis driven by ultraviolet exposure and genetic mutations, whereas acral lentiginous melanoma (ALM) and metastatic melanoma are much less, if at all, linked with the former. Thus, we evaluated both ultraviolet related and non-ultraviolet related melanomas. Mutations in the MUC16 and TTN genes commonly occur concurrently in these melanoma patients, but their combined prognostic significance stratified by gender and cancer subtype remains unclear. METHODS: The cBioPortal database was queried for melanoma studies and returned 16 independent studies. Data from 2447 melanoma patients were utilized including those with ALM, cutaneous melanoma (CM), and melanoma of unknown primary (MUP). Patients were grouped based on the presence or absence of MUC16 and TTN mutations. Univariate Cox regression and Student's t-tests were used to analyze hazard ratios and total mutation count comparisons, respectively. RESULTS: TTN mutations, either alone or concurrently with MUC16 mutations, significantly correlated with worse prognosis overall, in both genders, and in CM patients. ALM patients with both mutations had better prognoses than CM patients, while ALM patients with neither mutation had worse prognosis than CM patients. For MUP patients, only MUC16 mutations correlated with worse prognosis. ALM patients with neither MUC16 nor TTN mutations had significantly more total mutations than MUP patients, followed by CM patients. CONCLUSION: TTN mutations are a potential marker of poor prognosis in melanoma, which is amplified in the presence of concurrent MUC16 mutations. ALM patients with neither gene mutations had worse prognosis, suggesting a protective effect of having both MUC16 and TTN mutations. Only MUC16 mutations conferred a worse prognosis for MUP patients. Comprehensive genetic profiling in melanoma patients may facilitate personalized treatment strategies to optimize patient outcomes.

Asunto(s)

Conectina , Melanoma , Mutación , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/mortalidad , Melanoma/patología , Femenino , Masculino , Pronóstico , Estudios Retrospectivos , Persona de Mediana Edad , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Conectina/genética , Antígeno Ca-125 , Factores Sexuales , Proteínas de la Membrana/genética , Anciano , Biomarcadores de Tumor/genética , Adulto

RESUMEN

Melanoma of the skin is the 17th most common cancer worldwide. Early detection of suspicious skin lesions (melanoma) can increase 5-year survival rates by 20%. The 7-point checklist (7PCL) has been extensively used to suggest urgent referrals for patients with a possible melanoma. However, the 7PCL method only considers seven meta-features to calculate a risk score and is only relevant for patients with suspected melanoma. There are limited studies on the extensive use of patient metadata for the detection of all skin cancer subtypes. This study investigates artificial intelligence (AI) models that utilise patient metadata consisting of 23 attributes for suspicious skin lesion detection. We have identified a new set of most important risk factors, namely "C4C risk factors", which is not just for melanoma, but for all types of skin cancer. The performance of the C4C risk factors for suspicious skin lesion detection is compared to that of the 7PCL and the Williams risk factors that predict the lifetime risk of melanoma. Our proposed AI framework ensembles five machine learning models and identifies seven new skin cancer risk factors: lesion pink, lesion size, lesion colour, lesion inflamed, lesion shape, lesion age, and natural hair colour, which achieved a sensitivity of 80.46 ± 2.50 % and a specificity of 62.09 ± 1.90 % in detecting suspicious skin lesions when evaluated using the metadata of 53,601 skin lesions collected from different skin cancer diagnostic clinics across the UK, significantly outperforming the 7PCL-based method (sensitivity 68.09 ± 2.10 % , specificity 61.07 ± 0.90 % ) and the Williams risk factors (sensitivity 66.32 ± 1.90 % , specificity 61.71 ± 0.6 % ). Furthermore, through weighting the seven new risk factors we came up with a new risk score, namely "C4C risk score", which alone achieved a sensitivity of 76.09 ± 1.20 % and a specificity of 61.71 ± 0.50 % , significantly outperforming the 7PCL-based risk score (sensitivity 73.91 ± 1.10 % , specificity 49.49 ± 0.50 % ) and the Williams risk score (sensitivity 60.68 ± 1.30 % , specificity 60.87 ± 0.80 % ). Finally, fusing the C4C risk factors with the 7PCL and Williams risk factors achieved the best performance, with a sensitivity of 85.24 ± 2.20 % and a specificity of 61.12 ± 0.90 % . We believe that fusing these newly found risk factors and new risk score with image data will further boost the AI model performance for suspicious skin lesion detection. Hence, the new set of skin cancer risk factors has the potential to be used to modify current skin cancer referral guidelines for all skin cancer subtypes, including melanoma.

Asunto(s)

Inteligencia Artificial , Melanoma , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/diagnóstico , Melanoma/diagnóstico , Factores de Riesgo , Masculino , Persona de Mediana Edad , Femenino , Metadatos , Detección Precoz del Cáncer/métodos , Adulto , Anciano , Aprendizaje Automático , Medición de Riesgo/métodos

RESUMEN

BACKGROUND: Precancerous and malignant tumours arise within the oral cavity from a predisposed "field" of epithelial cells upon exposure to carcinogenic stimulus. This phenomenon is known as "Field Cancerization". The molecular genomic and transcriptomic alterations that lead to field cancerization and tumour progression is unknown in Indian Oral squamous cell carcinoma (OSCC) patients. METHODS: We have performed whole exome sequencing, copy-number variation array and whole transcriptome sequencing from five tumours and dysplastic lesions (sampled from distinct anatomical subsites - one each from buccal anterior and posterior alveolus, dorsum of tongue-mucosal melanoma, lip and left buccal mucosa) and blood from a rare OSCC patient with field cancerization. RESULTS: A missense CASP8 gene mutation (p.S375F) was observed to be the initiating event in oral tumour field development. APOBEC mutation signatures, arm-level copy number alterations, depletion of CD8 + T cells and activated NK cells and enrichment of pro-inflammatory mast cells were features of early-originating tumours. Pharmacological inhibition of CASP8 protein in a CASP8-wild type OSCC cell line showed enhanced levels of cellular migration and viability. CONCLUSION: CASP8 alterations are the earliest driving events in oral field carcinogenesis, whereas additional somatic mutational, copy number and transcriptomic alterations ultimately lead to OSCC tumour formation and progression.

Asunto(s)

Caspasa 8 , Variaciones en el Número de Copia de ADN , Melanoma , Neoplasias de la Boca , Transcriptoma , Humanos , Caspasa 8/genética , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Melanoma/genética , Melanoma/patología , Transcriptoma/genética , Variaciones en el Número de Copia de ADN/genética , Secuenciación del Exoma , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Masculino , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Mutación Missense/genética , Femenino , Persona de Mediana Edad , Linfocitos T CD8-positivos

RESUMEN

Melanoma either intrinsically possesses resistance or rapidly acquires resistance to anti-tumor therapy, which often leads to local recurrence or distant metastasis after resection. In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. Next, to address the complexity in the combination of multiple bioactive molecules with distinct therapeutic properties, we developed a polysaccharides-based organohydrogel (OHG) configured with a heterogenous network. Therein, hydroxypropyl chitosan (HPC)-stabilized emulsions for hydrophobic drug entrapment were crosslinked with oxidized dextran (Odex) to form a hydrophilic gel matrix to facilitate antibody accommodation, which demonstrated a tunable sustained release profile by optimizing emulsion/gel volume ratios. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.

Asunto(s)

Quitosano , Dextranos , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética , Melanoma , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Quitosano/química , Quitosano/análogos & derivados , Dextranos/química , Animales , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/inmunología , Ratones , Humanos , Epigénesis Genética/efectos de los fármacos , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Hidrogeles/química , Línea Celular Tumoral , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química

RESUMEN

BACKGROUND: Cutaneous melanoma (CM) is associated with a higher mortality rate than most other skin cancers. The purpose of this expert consensus panel was to review the published literature on new technological advancements for the diagnosis and prognosis for CM and provide updated guidance on their usage. METHODS: A comprehensive literature search of PubMed, Scopus, and Google Scholar was completed for English-language original research articles on the topics of non-invasive diagnostic and prognostic testing for CM, including gene expression profiling (GEP) and electrical impedance spectroscopy (EIS). A panel of 10 dermatologists with significant expertise in the treatment of CM gathered to review the articles and create consensus statements. A modified Delphi process was used to approve each statement and a strength of recommendation was assigned using widely recognized Strength of Recommendation Taxonomy criteria. RESULTS: The literature search produced 200 articles that met the criteria. A screening of the studies resulted in 19 articles. These were distributed to all panelists for review prior to a roundtable discussion. The panel unanimously voted to adopt 7 consensus statements and recommendations, 5 of which were given a strength of "A", 1 of which was given a strength of "B," and 1 of which was given a strength of "C". CONCLUSION: The 2-GEP test and EIS can aid in the precise diagnosis of clinically indeterminate lesions and the 23-GEP test can be used when histopathology is equivocal. The 31-GEP test can enhance prognostic assessment beyond AJCC8 staging and improve clinical decision-making. J Drugs Dermatol. 2024;23(9):774-781. doi:10.36849/JDD.8365R1.

Asunto(s)

Consenso , Espectroscopía Dieléctrica , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Pronóstico , Espectroscopía Dieléctrica/métodos , Perfilación de la Expresión Génica , Técnica Delphi

RESUMEN

Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2Y641F interacts with the immune regulator Stat3 and together they affect anti-tumor immunity. However, given the numerous downstream targets and pathways affected by Ezh2, many mechanisms that determine its oncogenic activity remain largely unexplored. Using genetically engineered mouse models, we further investigated the role of pathways downstream of Ezh2 in melanoma carcinogenesis and identified significant enrichment in several autophagy signatures, along with increased expression of autophagy regulators, such as Atg7. In this study, we investigated the effect of Atg7 on melanoma growth and tumor immunity within the context of a wild-type or Ezh2Y641F epigenetic state. We found that the Atg7 locus is controlled by multiple Ezh2 and Stat3 binding sites, Atg7 expression is dependent on Stat3 expression, and that deletion of Atg7 slows down melanoma cell growth in vivo, but not in vitro. Atg7 deletion also results in increased CD8 + T cells in Ezh2Y641F melanomas and reduced myelosuppressive cell infiltration in the tumor microenvironment, particularly in Ezh2WT melanomas, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.

Asunto(s)

Proteína 7 Relacionada con la Autofagia , Proteína Potenciadora del Homólogo Zeste 2 , Factor de Transcripción STAT3 , Animales , Factor de Transcripción STAT3/metabolismo , Ratones , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Microambiente Tumoral/inmunología , Ratones Endogámicos C57BL , Regulación Neoplásica de la Expresión Génica , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/genética , Melanoma/patología , Epigénesis Genética , Línea Celular Tumoral , Humanos , Autofagia/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo

RESUMEN

BACKGROUND: PD-L1 expression on cancer cells is an important mechanism of tumor immune escape, and immunotherapy targeting the PD-L1/PD1 interaction is a common treatment option for patients with melanoma. However, many patients do not respond to treatment and novel predictors of response are emerging. One suggested modifier of PD-L1 is the p53 pathway, although the relationship of p53 pathway function and activation is poorly understood. METHODS: The study was performed on human melanoma cell lines with various p53 status. We investigated PD-L1 and proteins involved in IFNγ signaling by immunoblotting and mRNA expression, as well as membrane expression of PD-L1 by flow cytometry. We evaluated differences in the ability of NK cells to recognize and kill target tumor cells on the basis of p53 status. We also investigated the influence of proteasomal degradation and protein half-life, IFNγ signaling and p53 activation on biological outcomes, and performed bioinformatic analysis using available data for melanoma cell lines and melanoma patients. RESULTS: We demonstrate that p53 status changes the level of membrane and total PD-L1 protein through IRF1 regulation and show that p53 loss influences the recently discovered SOX10/IRF1 regulatory axis. Bioinformatic analysis identified a dependency of SOX10 on p53 status in melanoma, and a co-regulation of immune signaling by both transcription factors. However, IRF1/PD-L1 regulation by p53 activation revealed complicated regulatory mechanisms that alter IRF1 mRNA but not protein levels. IFNγ activation revealed no dramatic differences based on TP53 status, although dual p53 activation and IFNγ treatment confirmed a complex regulatory loop between p53 and the IRF1/PD-L1 axis. CONCLUSIONS: We show that p53 loss influences the level of PD-L1 through IRF1 and SOX10 in an isogenic melanoma cell model, and that p53 loss affects NK-cell cytotoxicity toward tumor cells. Moreover, activation of p53 by MDM2 inhibition has a complex effect on IRF1/PD-L1 activation. These findings indicate that evaluation of p53 status in patients with melanoma will be important for predicting the response to PD-L1 monotherapy and/or dual treatments where p53 pathways participate in the overall response.

Asunto(s)

Antígeno B7-H1 , Factor 1 Regulador del Interferón , Melanoma , Factores de Transcripción SOXE , Transducción de Señal , Proteína p53 Supresora de Tumor , Humanos , Factor 1 Regulador del Interferón/metabolismo , Factor 1 Regulador del Interferón/genética , Melanoma/genética , Melanoma/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Factores de Transcripción SOXE/metabolismo , Factores de Transcripción SOXE/genética , Interferón gamma/metabolismo , Interferón gamma/genética , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/inmunología , Regulación Neoplásica de la Expresión Génica

RESUMEN

BACKGROUND: Following major achievements seen with drug therapies for the treatment of advanced melanoma in the last decade, they now also have an ever-increasing role for the treatment of earlier stage disease. This review outlines the current drugs used to treat melanoma, and how general practitioners (GPs) can assist in the management of patients with melanoma and the associated toxicities with treatment. OBJECTIVE: This review summarises the evolving status of melanoma care, emphasising when to refer patients to medical oncologists as part of the multidisciplinary team. It provides guidance into recognising and managing immune-related adverse events (irAEs) associated with immunotherapy, and provides insights into the future changes in clinical practice. DISCUSSION: Drug therapies are increasingly used for the treatment of many patients with melanoma. Early referral is crucial, and clinical trials remain the best choice for most patients. Recognition and prompt management of irAEs is vital, and collaboration between GPs and oncologists is essential for best care.

Asunto(s)

Médicos Generales , Melanoma , Humanos , Melanoma/tratamiento farmacológico , Médicos Generales/tendencias , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Rol del Médico

Asunto(s)

Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/diagnóstico , Melanoma/diagnóstico , Melanoma/fisiopatología

RESUMEN

Neoantigen-based immunotherapy is an attractive potential treatment for previously intractable tumors. To effectively broaden the application of this approach, stringent biomarkers are crucial to identify responsive patients. ARID1A, a frequently mutated subunit of SWI/SNF chromatin remodeling complex, has been reported to determine tumor immunogenicity in some cohorts; however, mutations and deletions of ARID1A are not always linked to clinical responses to immunotherapy. In this study, we investigated immunotherapeutic responses based on ARID1A status in targeted therapy-resistant cancers. Mouse and human BRAFV600E melanomas with or without ARID1A expression were transformed into resistant to vemurafenib, an FDA-approved specific BRAFV600E inhibitor. Anti-PD-1 antibody treatment enhanced antitumor immune responses in vemurafenib-resistant ARID1A-deficient tumors but not in ARID1A-intact tumors or vemurafenib-sensitive ARID1A-deficient tumors. Neoantigens derived from accumulated somatic mutations during vemurafenib resistance were highly expressed in ARID1A-deficient tumors and promoted tumor immunogenicity. Furthermore, the newly generated neoantigens could be utilized as immunotherapeutic targets by vaccines. Finally, targeted therapy resistance-specific neoantigen in experimental human melanoma cells lacking ARID1A were validated to elicit T-cell receptor responses. Collectively, the classification of ARID1A-mutated tumors based on vemurafenib resistance as an additional indicator of immunotherapy response will enable a more accurate prediction to guide cancer treatment. Furthermore, the neoantigens that emerge with therapy resistance can be promising therapeutic targets for refractory tumors. Significance: Chemotherapy resistance promotes the acquisition of immunogenic neoantigens in ARID1A-deficient tumors that confer sensitivity to immune checkpoint blockade and can be utilized for developing antitumor vaccines, providing strategies to improve immunotherapy efficacy.

Asunto(s)

Antígenos de Neoplasias , Proteínas de Unión al ADN , Resistencia a Antineoplásicos , Melanoma , Factores de Transcripción , Vemurafenib , Animales , Humanos , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Ratones , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Resistencia a Antineoplásicos/inmunología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/terapia , Inmunoterapia/métodos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/inmunología , Línea Celular Tumoral , Femenino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mutación , Terapia Molecular Dirigida/métodos , Ratones Endogámicos C57BL

RESUMEN

The internal mammary artery perforator (IMAP) flap has been widely used for chest wall and neck reconstruction. The color of its skin paddle closely resembles that of facial skin, making it attractive for facial reconstruction. However, there has been insufficient investigations reporting the use of free IMAP flap. Furthermore, even in such studies, somewhat invasive procedures, including rib cartilage resection, were employed to ensure sufficient pedicle length, potentially increasing donor morbidity. Our report presents two cases of successful facial defect reconstruction using a free IMAP flap harvested with minimal donor site damage, showing its feasibility. In the first case, a 48-year-old male underwent wide excision for a malignant melanoma on his right cheek, resulting in a 4 × 4.5 cm full-thickness defect. A free IMAP flap with a 2.5 cm pedicle, was harvested without rib cartilage resection, preserving IMA main trunk, and transferred with anastomosed to the angular vessels within the defect. The second patient presented with a 4.5 × 3.5 cm basal cell carcinoma on the left cheek, necessitating wide excision and leaving a 6 × 5 cm defect. A free IMAP flap was harvested with the same approach and successfully reconstructed the defect with connected to the superficial temporal vessels using vascular bridge. Both patients were discharged complication-free, with no recurrence during 24 and 15 months of follow-up, respectively. They were highly satisfied with the final skin color and texture outcomes. Harvesting a free IMAP flap while minimizing donor morbidity may offer an attractive option for facial reconstruction.

Asunto(s)

Colgajo Perforante , Procedimientos de Cirugía Plástica , Neoplasias Cutáneas , Humanos , Masculino , Persona de Mediana Edad , Colgajo Perforante/irrigación sanguínea , Procedimientos de Cirugía Plástica/métodos , Neoplasias Cutáneas/cirugía , Arterias Mamarias/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Carcinoma Basocelular/cirugía , Neoplasias Faciales/cirugía , Melanoma/cirugía , Colgajos Tisulares Libres/trasplante , Recolección de Tejidos y Órganos/métodos , Mejilla/cirugía

RESUMEN

OBJECTIVES: To estimate the incidence of melanoma in Australia among people with ancestries associated with low, moderate, or high risk of melanoma, by sex and 5-year age group; to establish whether age-specific incidence rates by ancestry risk group have changed over time. STUDY DESIGN: Modelling study; United States (SEER database) melanoma incidence rates for representative ancestral populations and Australian census data (2006, 2011, 2016, 2021) used to estimate Australian melanoma incidence rates by ancestry-based risk. SETTING, PARTICIPANTS: Australia, 2006-2021. MAIN OUTCOME MEASURES: Age-specific invasive melanoma incidence rates, and average annual percentage change (AAPC) in age-specific melanoma rates, by ancestry-based risk group, sex, and 5-year age group. RESULTS: The proportion of people in Australia who reported high risk (European) ancestry declined from 85.3% in 2006 to 71.1% in 2021. The estimated age-standardised melanoma incidence rate was higher for people with high risk ancestry (2021: males, 82.2 [95% confidence interval {CI}, 80.5-83.8] cases per 100 000 population; females, 58.5 [95% CI, 57.0-59.9] cases per 100 000 population) than for all Australians (males, 67.8 [95% CI, 66.5-69.2] cases per 100 000 population; females, 45.4 [95% CI, 44.3-46.5] cases per 100 000 population). AAPCs were consistently positive for Australians aged 50 years or older, both overall and for people with high risk ancestry, but were statistically significant only for some age groups beyond 65 years. AAPCs were negative for people aged 34 years or younger, but were generally not statistically significant. CONCLUSIONS: Melanoma incidence has declined in some younger age groups in Australia, including among people with high risk ancestry. Social and behavioural changes over the same period that lead to lower levels of ultraviolet radiation exposure probably contributed to these changes.

Asunto(s)

Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/epidemiología , Australia/epidemiología , Incidencia , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Neoplasias Cutáneas/epidemiología , Adulto Joven , Distribución por Edad , Adolescente , Anciano de 80 o más Años , Factores de Riesgo , Población Blanca/estadística & datos numéricos , Niño , Distribución por Sexo , Factores de Edad

Asunto(s)

Melanoma , Neoplasias Cutáneas , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Factores de Edad , Pueblos de Australasia , Australia/epidemiología , Incidencia , Melanoma/epidemiología , Neoplasias Cutáneas/epidemiología

RESUMEN

The microbiome can influence cancer development and progression. However, less is known about the role of the skin microbiota in melanoma. Here, we took advantage of a zebrafish melanoma model to probe the effects of Staphylococcus aureus on melanoma invasion. We found that S. aureus produces factors that enhance melanoma invasion and dissemination in zebrafish larvae. We used a published in vitro 3D cluster formation assay that correlates increased clustering with tumor invasion. S. aureus supernatant increased clustering of melanoma cells and was abrogated by a Rho-Kinase inhibitor, implicating a role for Rho-GTPases. The melanoma clustering response was specific to S. aureus but not to other staphylococcal species, including S. epidermidis. Our findings suggest that S. aureus promotes melanoma clustering and invasion via lipids generated by the lipase Sal2 (officially known as GehB). Taken together, these findings suggest that specific bacterial products mediate melanoma invasive migration in zebrafish.

Asunto(s)

Melanoma , Invasividad Neoplásica , Staphylococcus aureus , Pez Cebra , Animales , Pez Cebra/microbiología , Melanoma/patología , Melanoma/microbiología , Línea Celular Tumoral , Lípidos/química , Movimiento Celular/efectos de los fármacos , Larva/microbiología , Humanos , Proteínas de Pez Cebra/metabolismo , Agregación Celular/efectos de los fármacos

RESUMEN

Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.

Asunto(s)

Autoanticuerpos , Autoantígenos , Melanoma , Penfigoide Ampolloso , Humanos , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/etiología , Melanoma/inmunología , Melanoma/etiología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/etiología , Colágeno Tipo XVII , Colágenos no Fibrilares/inmunología , Melanocitos/inmunología , Melanocitos/patología , Animales , Relevancia Clínica