RESUMO
Previous reports proposed the concept and criteria of epidermotropic metastatic malignant melanoma (EMMM): (a) dermal involvement equal to or broader than the epidermal involvement, (b) atypical melanocytes within the dermis, (c) thinning of the epidermis, (d) widening of the papillary dermis with an epithelial collarette, and (e) vascular invasion of atypical melanocytes. However, it remains unclear whether EMMM also involves the mucosal epithelium. In this case, the patient was diagnosed with EMMM based on the histopathological findings of the patient's multiple skin lesions and clinical course. The patient also developed metastasis to the hypopharynx. Although histopathological findings of the lesion suggested the possibility of melanoma in situ, as the lesion included atypical melanocytes in the mucosal epithelium, the clinical course supported the diagnosis of hypopharyngeal metastasis from EMMM. This case suggests that EMMM may have epitheliotropic features not only in the skin but also in the mucosa.
Assuntos
Neoplasias Hipofaríngeas , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Melanoma/secundário , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundário , Neoplasias Hipofaríngeas/patologia , MasculinoRESUMO
Numerous clinical trials have demonstrated a significant improvement in recurrence-free survival among melanoma patients receiving high-dose interferon-α, immune checkpoint inhibitors (pembrolizumab, nivolumab), and BRAF/MEK inhibitors (dabrafenib-trametinib). This study aimed to investigate whether these findings hold true in real-world conditions for patients with stage III and IV melanoma. In particular, the study explores the efficacy and side effects of adjuvant therapies, focusing on anti-PD-1 antibodies and BRAF/MEK inhibitors. While clinical trials have shown comparable efficacy, differences in side-effect profiles, especially the persistence of immune-related adverse events with anti-PD-1 antibodies, highlight the need for careful consideration in adjuvant settings. In the absence of established biomarkers for guiding adjuvant therapy decisions, it becomes imperative to transparently communicate the advantages and disadvantages of drug administration to patients. The study also delved into the impact of melanoma subtype and BRAF mutation status on the effectiveness of adjuvant therapy, emphasizing the need for further investigation.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Imidazóis/efeitos adversos , Quinases de Proteína Quinase Ativadas por MitógenoAssuntos
Melanoma , Neoplasias Cutâneas , Uveíte , Humanos , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaAssuntos
Melanoma , Neoplasias Primárias Desconhecidas , Neoplasias Cutâneas , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/genética , Melanoma/diagnóstico , Melanoma/genética , Mutação , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Análise Mutacional de DNARESUMO
Cancer immunotherapy is now the first-line treatment for many unresectable cancers. However, it remains far from a complete cure for all patients. Therefore, it is necessary to develop innovative methods for cancer immunotherapy, and immune cell therapy could be an option. Currently, several institutions are attempting to generate immune cells from induced pluripotent stem cells (iPSCs) for use in cancer immunotherapy. A method for generating dendritic cells (DCs) and macrophages (MPs) from iPSC has been established. iPSC-derived DCs (iPS-DCs) can activate T cells via antigen presentation, and iPSC-derived macrophages (iPS-MPs) attack cancer. Since iPSCs are used as the source, genetic modification is easy, and various immune functions, such as the production of anti-tumour cytokines, can be added. Furthermore, when iPS-DCs and iPS-MPs are immortalized, cost reduction through mass production is theoretically possible. In this review, the achievements of cancer research using iPS-DCs and iPS-MPs are summarized, and the prospects for the future are discussed.
Assuntos
Células-Tronco Pluripotentes Induzidas , Neoplasias , Humanos , Imunoterapia/métodos , Macrófagos , Citocinas , Células Dendríticas , Neoplasias/terapiaRESUMO
Combination therapy with BRAF and MEK inhibitors (BRAF/MEKi) has shown significantly prolonged progression-free survival (PFS) and overall survival (OS) for BRAF mutated melanoma. Over 90% of the activating mutations are BRAFV600E or BRAFV600K changes. There are no reports of BRAFV600R in Japanese patients with melanoma. The third most common BRAF mutation is BRAFV600R. In this case, we detected the BRAFV600R mutation with FoundationOne CDx in a Japanese patient with melanoma.. The patient was treated with BRAF/MEKi and maintained stable disease status for 1 year.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Japão , Melanoma/tratamento farmacológico , Melanoma/genética , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genéticaRESUMO
Turning non-inflamed (cold) tumors into inflamed (hot) tumors is important for maximizing the effect of immune checkpoint inhibitors (ICIs) against malignancies. We showed that lactate, a product of the Warburg effect, inhibited the efficacy of ICIs and suppressed IL-12 p40 expression in dendritic cells (DCs) through reducing NF-κB p65, p50, and c-Rel DNA-binding activity to the IL-12 p40 promoter. Additionally, lactate promoted the expression of early growth response protein 1 (EGR1), whose expression was increased in human invasive melanoma compared with non-invasive melanoma. We also found that EGR1 interacts with serum response factor (SRF) and represses the expression of CD80 in DCs. These findings suggest that lactate and its induced EGR1 are key factors that turn hot tumors into cold tumors and may represent targets in cancer treatment with ICIs.
RESUMO
BACKGROUND: The development of BRAF/MEK inhibitors in patients with metastatic melanoma harboring BRAF mutations has garnered attention for liquid biopsy to detect BRAF mutations in cell-free DNA (cfDNA) using droplet digital PCR (ddPCR) or next-generation sequencing methods. OBJECTIVE: To investigate gene mutations in tumor DNA and cfDNA collected from 43 melanoma patients and evaluate their potential as biomarkers. METHODS: ddPCR and CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) techniques were performed to detect gene mutations in plasma cfDNA obtained from patients with metastatic melanoma. RESULTS: Gene variants, including BRAF, NRAS, TP53, GNAS, and MET, were detectable in the plasma cfDNA, and the results were partially consistent with the results of those identified in the tissues. Among the variants examined, copy numbers of MET mutations were consistent with the disease status in two melanoma patients. CONCLUSION: Liquid biopsy using CAPP-Seq and ddPCR has the potential to detect tumor presence and mutations, especially when tissue biopsies are unavailable. MET mutations in cfDNA may be a potential biomarker in patients with metastatic melanoma.
Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Variações do Número de Cópias de DNA , Análise Mutacional de DNA/métodos , Estudos de Viabilidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida/métodos , Masculino , Melanoma/sangue , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Adulto JovemAssuntos
Imunoterapia/métodos , Melanoma/terapia , Células Mieloides/transplante , Neoplasias Cutâneas/terapia , Animais , Diferenciação Celular/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Interferon beta/genética , Interferon beta/imunologia , Interferon beta/metabolismo , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-15/metabolismo , Melanoma/imunologia , Melanoma/patologia , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores de Interleucina-15/genética , Receptores de Interleucina-15/imunologia , Receptores de Interleucina-15/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Evasão Tumoral/imunologiaRESUMO
We have established an immune cell therapy with immortalized induced pluripotent stem-cell-derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological "cold tumor" to "hot tumor".
Assuntos
Ligante 4-1BB/metabolismo , Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Células Mieloides/metabolismo , Células Mieloides/transplante , Neoplasias Cutâneas/terapia , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores CXCR6/metabolismo , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Melanoma is one of the deadliest skin cancers. The treatment of advanced melanoma has been dramatically improved by immune checkpoint inhibitors and targeted therapies. However, many patients still do not respond to these therapies. OBJECTIVE: To investigate whether NAP1L4 can be a new therapeutic target for melanoma. METHODS: Immunohistochemical analysis of human nevus and melanoma tissues was performed. Real-time RT-PCR and immunoblotting were performed using human samples and melanoma cell lines. Next, we examined the effect of NAP1L4 knockdown in melanoma cell lines using cell migration and invasion assays. To investigate the molecular mechanism related to these results, immunoblotting of p21 and Slug was examined. MMP-2 and MMP-9 activity assays were also performed. Further, pathway analysis between NAP1L4 and MMP-2 was performed. Finally, the effects of NAP1L4 knockdown on cell proliferation, apoptosis, and cell cycle were analyzed. RESULTS: NAP1L4 was overexpressed in melanoma tissues compared to the nevus tissue. NAP1L4 knockdown reduced melanoma cell migration and invasion. NAP1L4 knockdown upregulated p21 and downregulated Slug expression in melanoma cells. NAP1L4 knockdown decreased the active levels of MMP-2 in the supernatant from melanoma cells. NAP1L4 knockdown inhibited apoptosis in camptothecin-induced DNA damage, induced cell cycle arrest at the G1/S phase, and inhibited cell proliferation. CONCLUSIONS: NAP1L4 may play a role in cell migration and invasion in melanoma cells through the regulation of Slug. We propose that NAP1L4 can be a new therapeutic target for proliferation and invasion of melanoma cells.
Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Melanoma/genética , Proteínas Nucleares/metabolismo , Neoplasias Cutâneas/genética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Melanoma/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle , Estadiamento de Neoplasias , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Fatores de Transcrição da Família Snail/genéticaRESUMO
BACKGROUND: A previous study revealed that matrin-3 is an essential component in maintaining fibroblast growth factor 2 (FGF2)-mediated undifferentiation of neural stem cells (NSCs) using a proteomics approach. Malignant melanoma (MM) arises from melanocytes that originate from neural crest stem cells during development. Additionally, it has been reported that the expression of FGF2 is positively correlated with the progression of MM. OBJECTIVE: We expected that matrin-3, as a downstream component of FGF2, might be associated with the aggressiveness or differentiation of MM. METHODS: Matrin-3 expression was measured in human melanoma patient tissues and human MM cell lines. We analyzed the effect of matrin-3 siRNA on the proliferation of human MM cell lines and focused on cell cycle progression and apoptosis. We carried out in vivo xenograft tumor experiments by implanting A375 cells transfected with matrin-3 shRNA. RESULTS: Matrin-3 was highly expressed in MM, and matrin-3 knockdown inhibited the proliferation of melanoma cellsin vivo and in vitro. Furthermore, we found that matrin-3 knockdown led to an accumulation of cells in the G1 phase and an increase in apoptotic cell number. CONCLUSION: Our results suggest that matrin-3 could be a new therapeutic target for the treatment of MM.
Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Nevo/genética , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/genética , Biópsia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Criança , Pré-Escolar , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Pessoa de Meia-Idade , Nevo/patologia , Proteínas Associadas à Matriz Nuclear/antagonistas & inibidores , Proteínas Associadas à Matriz Nuclear/genética , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
Methyl-CpG binding domain protein 3 (MBD3) belongs to the methyl-CpG binding protein family. MBD3 facilitates the initiation of neural stem cell reprogramming. Melanoma originates in melanocytes derived from neural crest stem cells; therefore, we investigated the role of MBD3 in melanoma. MBD3 was overexpressed in melanoma compared with pigmented nevi. MBD3 knockdown had no effect on the proliferation of melanoma cells (A375 and A2058 cells). Contrarily, it significantly reduced the migration and invasion of A375 cells, but had no significant effect on A2058 cells. Furthermore, MBD3 knockdown reduced N-cadherin protein levels and matrix metalloproteinase-2 (MMP-2) activity in A375 cells, but had no significant effect on A2058 cells. Based on these results, the MBD3 expression level may be a useful biomarker for the diagnosis of melanoma. Thus, MBD3 has potential as a novel therapeutic target for some melanoma patients.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Melanoma/diagnóstico , Nevo Pigmentado/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Epigênese Genética/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Nevo Pigmentado/tratamento farmacológico , Nevo Pigmentado/patologia , Pele/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaRESUMO
Immune checkpoint inhibitors improved the survival rate of patients with unresectable melanoma. However, some patients do not respond, and variable immune-related adverse events have been reported. Therefore, more effective and antigen-specific immune therapies are urgently needed. We previously reported the efficacy of an immune cell therapy with immortalized myeloid cells derived from induced pluripotent stem cells (iPS-ML). In this study, we generated OX40L-overexpressing iPS-ML (iPS-ML-Zsgreen-OX40L) and investigated their characteristics and in vivo efficacy against mouse melanoma. We found that iPS-ML-Zsgreen-OX40L suppressed the progression of B16-BL6 melanoma, and prolonged survival of mice with ovalbumin (OVA)-expressing B16 melanoma (MO4). The number of antigen-specific CD8+ T cells was higher in spleen cells treated with OVA peptide-pulsed iPS-ML-Zsgreen-OX40L than in those without OX40L. The OVA peptide-pulsed iPS-ML-Zsgreen-OX40L significantly increased the number of tumor-infiltrating T lymphocytes (TILs) in MO4 tumor. Flow cytometry showed decreased regulatory T cells but increased effector and effector memory T cells among the TILs. Although we plan to use allogeneic iPS-ML in the clinical applications, iPS-ML showed the tumorgenicity in the syngeneic mice model. Incorporating the suicide gene is necessary to ensure the safety in the future study. Collectively, these results indicate that iPS-ML-Zsgreen-OX40L therapy might be a new method for antigen-specific cancer immunotherapy.
Assuntos
Antígenos de Neoplasias/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Células Mieloides/patologia , Ligante OX40/metabolismo , Neoplasias Cutâneas/imunologia , Linfócitos T/imunologia , Animais , Proliferação de Células , Apresentação Cruzada/imunologia , Citocinas/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Estadiamento de Neoplasias , Ovalbumina/imunologia , Peptídeos/imunologia , Peritônio/patologia , Neoplasias Cutâneas/patologia , Baço/patologia , Regulação para CimaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Coagulação Intravascular Disseminada/diagnóstico , Inibidores de Checkpoint Imunológico/efeitos adversos , Ipilimumab/efeitos adversos , Nivolumabe/efeitos adversos , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/imunologia , Coagulação Intravascular Disseminada/induzido quimicamente , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/imunologia , Quimioterapia Combinada/métodos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Melanoma/imunologia , Melanoma/secundário , Melanoma/terapia , Pessoa de Meia-Idade , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaAssuntos
Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/sangue , MicroRNA Circulante/sangue , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , MicroRNA Circulante/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Melanoma/sangue , Melanoma/genética , Melanoma/imunologia , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Resultado do TratamentoRESUMO
This is the first case of an angiosarcoma patient with brain abscess, and it might be responsible for skin defect and cranial bone necrosis by surgical excision and radiation. Our patient was treated with 10 courses of triweekly paclitaxel therapy, radical radiotherapy (70 Gy), and surgical excision (2 cm margin apart from a lesion) for angiosarcoma. At two years after the operation he was diagnosed as brain abscess. Brain abscess was managed with antibiotic drugs and drainage, his clinical symptoms improved by these treatments. He achieves replace free survival without the exacerbation of angiosarcoma and brain abscess for three years.