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1.
An Acad Bras Cienc ; 92(3): e20180985, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33175013

RESUMO

The major impact in the clinical field is the harm posed by cancer. One most common type of cancer occurs in the skin. Though the conventionally existing modalities are successful in some cases, there is a need for new sensible methods to detect tumors at their initial stage. In accordance to these reasons and in addition to the incapability of the drugs to cross cellular barriers in skin the conventional administration methods are often compromised. To eradicate these problems the research work aims to develop the electrical analogue of skin involving layers like dermis, subcutaneous tissues, bones and muscular layers. The mathematical model has been developed to determine the electrical network of skin. The response of different skin layers are analyzed through simulation studies. It is observed that the cells present in each layer absorbs some amount of drug and let out the remaining to the neighboring layers. Further to minimize the diffusion rate of the drug a conventional controller has been incorporated and the results are analyzed by the contrast of the absorption and diffusion capacities for different layers of skin.


Assuntos
Preparações Farmacêuticas , Neoplasias Cutâneas , Administração Cutânea , Difusão , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias Cutâneas/tratamento farmacológico
2.
Acta Gastroenterol Belg ; 83(3): 482-484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33094598

RESUMO

We report a case of a 67-years-old woman presenting a severe acute lymphocytic gastritis induced by pembrolizumab, an immune check point inhibitor (ICI). This gastritis was her third auto-immune adverse event after 5 years of treatment with pembrolizumab, it was metabolically active at the PET Scan and confirmed by analysis of the gastric biopsies. Pembrolizumab treatment cessation and high doses of corticosteroids completely normalized the stomach clinically, endoscopically and histologically. This patient was in complete remission of her metastatic melanoma. Therefore, pembrolizumab therapy was not restarted and the patient is still in remission 6 months later. This strategy is supported by recent publications describing a relapse rate inferior to 10% in patients in complete remission after 2 years of immunotherapy. Particularities of this case are: rareness of this adverse event, late onset after introduction of pembrolizumab, evocative PET scan image, specific endoscopic aspect and histology. In addition, the favorable oncologic evolution of the patient after treatment cessation confirms the prolonged remission after immunotherapy.


Assuntos
Anticorpos Monoclonais Humanizados , Gastrite , Melanoma , Neoplasias Cutâneas , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Gastrite/induzido quimicamente , Gastrite/diagnóstico , Humanos , Melanoma/tratamento farmacológico , Recidiva Local de Neoplasia , Neoplasias Cutâneas/tratamento farmacológico
3.
Medicine (Baltimore) ; 99(44): e22913, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126349

RESUMO

INTRODUCTION: Malignant cutaneous epithelial tumors comprise various skin malignancies originating from the cutaneous epithelium, including cutaneous squamous cell carcinoma, basal cell carcinoma, and malignant cutaneous adnexal tumors. Treatment options are limited, as the rarity of these tumors, especially among Asians, renders well-controlled clinical trials extremely challenging to conduct. Thus, we designed a clinical trial to evaluate the efficacy and safety of the anti-programmed cell death-1 (PD-1) monoclonal antibody nivolumab in patients with metastatic cutaneous squamous cell carcinomas and other rare metastatic cutaneous epithelial tumors. METHODS AND ANALYSIS: This is an open-label, single-arm, multicenter, phase 2 clinical trial involving patients with metastatic malignant cutaneous epithelial tumors. Nivolumab (480 mg) will be administered intravenously every 4 weeks for a maximum of 26 doses. The primary outcome of the study will be the response rate based on response evaluation criteria in solid tumors, version 1.1. Assuming a null hypothesis of a response rate ≤5% and an alternative hypothesis of a 25% response rate, a minimum of 26 patients are required to achieve a 5% two-sided type I error and 80% power based on the exact binomial distribution. Finally, a target cohort size of 30 patients was determined as some patient dropout will be expected. DISCUSSION: This is the first phase 2 clinical trial evaluating the efficacy and safety of the PD-1 inhibitor nivolumab in Asian patients with metastatic malignant cutaneous epithelial tumors. The findings of the study will contribute to the development of novel treatment approaches for patients with rare cutaneous malignancies, which remains an unmet clinical need. TRIAL REGISTRATION: Registry number: jRCT 2031190048.


Assuntos
Carcinoma Basocelular/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Anexos e de Apêndices Cutâneos/tratamento farmacológico , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Humanos , Japão , Masculino , Estadiamento de Neoplasias , Neoplasias de Anexos e de Apêndices Cutâneos/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Cutâneas/patologia
4.
J Cosmet Sci ; 71(4): 191-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33022203

RESUMO

This review summarizes the evidence on the protection against skin cancer afforded by sunscreen. Solid evidence can come only from randomized controlled trials, despite a multitude of case-control and cohort studies that have addressed the issue, because observational evidence is intractably confounded since those at highest risk of skin cancer are naturally the highest users of sunscreen. Findings of the single human trial conducted in subtropical Australia during 1992-1996 with follow-up to 2014 showed that the application of a broad-spectrum, sun protection factor 16 sunscreen to exposed skin of the head and neck and upper limbs at least 3-4 days per week in adulthood can reduce the risk of developing cutaneous squamous cell carcinoma and melanoma but does not appear to reduce the risk of basal cell carcinoma (BCC) overall, although it may reduce the occurrence of multiple BCCs over time.


Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Melanoma , Neoplasias Cutâneas , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/prevenção & controle , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/prevenção & controle , Humanos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Protetores Solares
5.
Int J Nanomedicine ; 15: 8075-8095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116519

RESUMO

Purpose: Sonodynamic therapy (SDT) is a new therapeutic modality for the noninvasive cancer treatment based on the association of ultrasound and sonosensitizer drugs. Topical SDT requires the development of delivery systems to properly transport the sonosensitizer, such as zinc phthalocyanine (ZnPc), to the skin. In addition, the delivery system itself can participate in sonodynamic events and influence the therapeutic response. This study aimed to develop ZnPc-loaded micelle to evaluate its potential as a topical delivery system and as a cavitational agent for low-frequency ultrasound (LFU) application with the dual purpose of promoting ZnPc skin penetration and generating reactive oxygen species (ROS) for SDT. Methods: ZnPc-loaded micelles were developed by the thin-film hydration method and optimized using the Quality by Design approach. Micelles' influence on LFU-induced cavitation activity was measured by potassium iodide dosimeter and aluminum foil pits experiments. In vitro skin penetration of ZnPc was assessed after pretreatment of the skin with LFU and simultaneous LFU treatment using ZnPc-loaded micelles as coupling media followed by 6 h of passive permeation of ZnPc-loaded micelles. The singlet oxygen generation by LFU irradiation of the micelles was evaluated using two different hydrophilic probes. The lipid peroxidation of the skin was estimated using the malondialdehyde assay after skin treatment with simultaneous LFU using ZnPc-loaded micelles. The viability of the B16F10 melanoma cell line was evaluated using resazurin after treatment with different concentrations of ZnPc-loaded micelles irradiated or not with LFU. Results: The micelles increased the solubility of ZnPc and augmented the LFU-induced cavitation activity in two times compared to water. After 6 h ZnPc-loaded micelles skin permeation, simultaneous LFU treatment increased the amount of ZnPc in the dermis by more than 40 times, when compared to non-LFU-mediated treatment, and by almost 5 times, when compared to LFU pretreatment protocol. The LFU irradiation of micelles induced the generation of singlet oxygen, and the lipoperoxidation of the skin treated with the simultaneous LFU was enhanced in three times in comparison to the non-LFU-treated skin. A significant reduction in cell viability following treatment with ZnPc-loaded micelles and LFU was observed compared to blank micelles and non-LFU-treated control groups. Conclusion: LFU-irradiated mice can be a potential approach to skin cancer treatment by combining the functions of increasing drug penetration and ROS generation required for SDT.


Assuntos
Indóis/farmacologia , Micelas , Compostos Organometálicos/farmacologia , Ultrassom , Alumínio/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma Experimental/patologia , Fosfatidiletanolaminas/química , Fármacos Fotossensibilizantes/farmacologia , Polietilenoglicóis/química , Iodeto de Potássio/química , Oxigênio Singlete/química , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Suínos
6.
Int J Nanomedicine ; 15: 7627-7650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116492

RESUMO

The skin is the largest organ in the human body, providing a barrier to the external environment. It is composed of three layers: epidermis, dermis and hypodermis. The most external epidermis is exposed to stress factors that may lead to skin conditions such as photo-aging and skin cancer. Some treatments for skin disease utilize the incorporation of drugs or bioactive compounds into nanocarriers known as liposomes. Liposomes are membranes whose sizes range from nano to micrometers and are composed mostly of phospholipids and cholesterol, forming similar structures to cell membranes. Thus, skin treatments with liposomes have lower toxicity in comparison to traditional treatment routes such as parenteral and oral. Furthermore, addition of edge activators to the liposomes decreases the rigidity of the bilayer structure making it deformable, thereby improving skin permeability. Liposomes are composed of an aqueous core and a lipidic bilayer, which confers their amphiphilic property. Thus, they can carry hydrophobic and hydrophilic compounds, even simultaneously. Current applications of these nanocarriers are mainly in the cosmetic and pharmaceutic industries. Nevertheless, new research has revealed promising results regarding the effectiveness of liposomes for transporting bioactive compounds through the skin. Liposomes have been well studied; however, additional research is needed on the efficacy of liposomes loaded with bioactive peptides for skin delivery. The objective of this review is to provide an up-to-date description of existing techniques for the development of liposomes and their use as transporters of bioactive compounds in skin conditions such as melanoma and skin inflammation. Furthermore, to gain an understanding of the behavior of liposomes during the process of skin delivery of bioactive compounds into skin cells.


Assuntos
Inflamação/patologia , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Pele/patologia , Transporte Biológico , Humanos , Lipossomos/ultraestrutura , Absorção Cutânea
8.
Z Rheumatol ; 79(8): 818-825, 2020 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32926216

RESUMO

Since its introduction in 2011 the checkpoint inhibitor ipilimumab, has revolutionized the whole of oncology. After this first major step more checkpoint inhibitors, such as the PD­1 antibodies nivolumab and pembrolizumab have been developed. The results are groundbreaking, especially in advanced malignant melanoma, which only a few years ago led to certain death in most cases after only a few months. Currently, the application of checkpoint inhibitors has been extended to many more tumor entities, with very promising results.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Melanoma , Neoplasias Cutâneas , Humanos , Imunoterapia/métodos , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico
10.
PLoS One ; 15(9): e0239088, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32977329

RESUMO

Previously, we demonstrated the in vitro anti-tumor effects of desethylamiodarone (DEA) in bladder and cervix cancer cell lines. In the present study, we intended to establish its potentiality in B16-F10 metastatic melanoma cells in vitro and in vivo. We assessed cell proliferation, apoptosis and cell cycle by using sulforhodamine B assay, Muse™ Annexin V & Dead Cell and Muse® Cell Cycle assays, respectively. We determined colony formation after crystal violet staining. For studying mechanistic aspects, immunoblotting analysis was performed. We used a C57BL/6 experimental lung metastasis model for demonstrating in vivo anti-metastatic potential of DEA. DEA inhibited in vitro proliferation and colony formation, and in vivo lung metastasizing properties of B16-F10 cells. It arrested the cells in G0/G1 phase of their cycle likely via p21 in a p53-dependent fashion, and induced caspase mediated apoptosis likely via inversely regulating Bcl-2 and Bax levels, and reducing Akt and ERK1/2 activation. In this study, we provided in vitro and in vivo experimental evidences for DEA's potentiality in the therapy of metastatic melanomas. Since DEA is the major metabolite of amiodarone, a worldwide used antiarrhythmic drug, safety concerns could be resolved more easily for it than for a novel pharmacological agent.


Assuntos
Amiodarona/análogos & derivados , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Amiodarona/uso terapêutico , Animais , Antiarrítmicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Cutâneas/patologia
11.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(9): 1011-1016, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-32933636

RESUMO

To study the clinical effect of oral sirolimus in the treatment of children with blue rubber bleb nevus syndrome (BRBNS) in the gastrointestinal tract, a retrospective analysis was performed on the clinical data and follow-up results of two children with BRBNS treated by sirolimus. The two children with BRBNS had gastrointestinal bleeding and anemia and were treated with sirolimus at a dose of 1 mg/day as part of treatment. The plasma concentration of the drug was maintained between 2.5-12.0 ng/mL. The children showed disappearance of gastrointestinal bleeding and improvements in anemia and coagulation function, and blood transfusion could be stopped during treatment, with no obvious adverse drug reactions. PubMed, Wanfang Data, and CNKI were searched for related articles on sirolimus in the treatment of BRBNS. A total of 26 cases of children with BRBNS, aged 0-18 years, were obtained. With the addition of the 2 cases in this study, sirolimus treatment achieved a satisfactory clinical effect in all 28 cases. Sirolimus may be effective and safe in the treatment of children with BRBNS, and further prospective studies are needed to evaluate the long-term efficacy of this drug.


Assuntos
Neoplasias Gastrointestinais , Nevo Azul , Sirolimo/uso terapêutico , Neoplasias Cutâneas , Adolescente , Criança , Pré-Escolar , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Nevo Azul/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico
12.
N Engl J Med ; 383(12): 1139-1148, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32877599

RESUMO

BACKGROUND: In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed. METHODS: We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached. RESULTS: The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period. CONCLUSIONS: In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/uso terapêutico , Melanoma/tratamento farmacológico , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/genética , Análise de Sobrevida
13.
J Cancer Res Ther ; 16(4): 922-925, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930142

RESUMO

Lung carcinoma is the most common carcinoma seen in males with the skin being a rare metastatic site. Adenosquamous carcinoma as a rare histologic subtype, showing cutaneous metastasis is an unusual event with no reports in the literature till date. Skin metastasis is an alarming sign, carries poor prognosis, and is associated with shortened survival. Herein, we report a case of 60-year-old male who presented with isolated cutaneous metastasis as a chronic nonhealing ulcer over the sternal region for 3 years (unusual) in the first place, without any other associated symptoms and clinical evidence of the primary. Wide local excision of the lesion was performed after proper workup which revealed metastatic adenosquamous carcinoma. The patient was advised systemic chemotherapy. A high index of suspicion along with clinico-radio-pathological correlation in these cases is of utmost importance and forms the basis of accurate diagnosis.


Assuntos
Carcinoma Adenoescamoso/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/secundário , Úlcera Cutânea/diagnóstico , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/patologia , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Úlcera Cutânea/patologia , Tomografia Computadorizada por Raios X/métodos
14.
Nat Commun ; 11(1): 3946, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770055

RESUMO

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , RNA-Seq , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mutat Res ; 785: 108321, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32800272

RESUMO

BRAF is a member of the RAF family of serine/threonine-specific protein kinases. Oncogenic BRAF, in particular, BRAF V600E, can disturb the normal protein folding machinery in the endoplasmic reticulum (ER) leading to accumulation of unfolded/misfolded proteins in the ER lumen, a condition known as endoplasmic reticulum (ER) stress. To alleviate such conditions, ER-stressed cells have developed a highly robust and adaptable signaling network known as unfolded protein response (UPR). UPR is ordinarily a cytoprotective response and usually operates through the induction of autophagy, an intracellular lysosomal degradation pathway that directs damaged proteins, protein aggregates, and damaged organelles for bulk degradation and recycling. Both ER stress and autophagy are involved in the progression and chemoresistance of melanoma. Melanoma, which arises as a result of malignant transformation of melanocytes, exhibits exceptionally high therapeutic resistance. Many mechanisms of therapeutic resistance have been identified in individual melanoma patients and in preclinical BRAF-driven melanoma models. Recently, it has been recognized that oncogenic BRAF interacts with GRP78 and removes its inhibitory influence on the three fundamental ER stress sensors of UPR, PERK, IRE1α, and ATF6. Dissociation of GRP78 from these ER stress sensors prompts UPR that subsequently activates cytoprotective autophagy. Thus, pharmacological inhibition of BRAF-induced ER stress-mediated autophagy can potentially resensitize BRAF mutant melanoma tumors to apoptosis. However, the underlying molecular mechanism of how oncogenic BRAF elevates the basal level of ER stress-mediated autophagy in melanoma tumors is not well characterized. A better understanding of the crosstalk between oncogenic BRAF, ER stress and autophagy may provide a rationale for improving existing cancer therapies and identify novel targets for therapeutic intervention of melanoma.


Assuntos
Autofagia , Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Resposta a Proteínas não Dobradas , Apoptose , Humanos , Melanoma/tratamento farmacológico , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico
17.
Yonsei Med J ; 61(7): 562-571, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32608199

RESUMO

Melanoma, originating from epidermal melanocytes, is a heterogeneous disease that has the highest mortality rate among all types of skin cancers. Numerous studies have revealed the cause of this cancer as related to various somatic driver mutations, including alterations in KIT-a proto-oncogene encoding for a transmembrane receptor tyrosine kinase. Although accounting for only 3% of all melanomas, mutations in c-KIT are mostly derived from acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, inhibition of c-KIT has been exploited for clinical trials in advanced melanoma. Here, apart from the molecular background of c-KIT and its cellular functions, we will review the wide distribution of alterations in KIT with a catalogue of more than 40 mutations reported in various articles and case studies. Additionally, we will summarize the association of KIT mutations with clinicopathologic features (age, sex, melanoma subtypes, anatomic location, etc.), and the differences of mutation rate among subgroups. Finally, several therapeutic trials of c-KIT inhibitors, including imatinib, dasatinib, nilotinib, and sunitinib, will be analyzed for their success rates and limitations in advanced melanoma treatment. These not only emphasize c-KIT as an attractive target for personalized melanoma therapy but also propose the requirement for additional investigational studies to develop novel therapeutic trials co-targeting c-KIT and other cytokines such as members of signaling pathways and immune systems.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Feminino , Humanos , Masculino , Melanoma/genética , Membrana Mucosa/metabolismo , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/genética , Neoplasias Cutâneas/genética
18.
An Bras Dermatol ; 95(5): 615-618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32711929

RESUMO

Biological therapies, including anti-TNF agents, are important in the treatment of various chronic inflammatory diseases, including psoriasis, rheumatoid arthritis or inflammatory bowel disease. The increased use of these drugs translates into an increasing awareness of its adverse effects, which include malignancy. In this paper, we describe the case of a 28-year-old woman who developed a spitzoid melanocytic tumor after starting infliximab therapy for ulcerative colitis. The evidence for causality between anti-TNF and melanocytic proliferations is still sparse; nonetheless, treatment-associated immunosuppression seems to play a key role in this phenomenon. Therefore, a regular follow-up with a rigorous skin examination is essential in these patients. Noninvasive techniques such as dermoscopy or reflectance confocal microscopy are particularly useful diagnostic tools in these circumstances.


Assuntos
Nevo de Células Epitelioides e Fusiformes , Neoplasias Cutâneas , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Infliximab/efeitos adversos , Nevo de Células Epitelioides e Fusiformes/induzido quimicamente , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Fator de Necrose Tumoral alfa
19.
Crit Rev Oncol Hematol ; 153: 103044, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32673997

RESUMO

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is increasingly used in patients with advanced melanoma. Immune checkpoint inhibitors and BRAF/MEK-targeted therapy have transformed the therapeutic landscape of metastatic melanoma. Consequently, a need for markers predicting (early) response to treatment and for monitoring treatment (toxicity) has arisen. This systematic review appraises the current literature evidence for rational use of 18F-FDG PET/CT scans in staging, clinical decision-making, treatment monitoring and follow-up in advanced melanoma. 18F-FDG PET/CT has high overall accuracy for detection of distant metastases and is, combined with cerebral MRI, the preferred imaging strategy for staging metastatic melanoma. In contrast, strong evidence supporting the standard use of 18F-FDG PET/CT for predicting and monitoring therapy response and toxicity is currently lacking. Essential for determining the position of 18F-FDG PET/CT during treatment course in advanced melanoma are well-designed studies with standardized scanning protocols, incorporation of clinical parameters and comparison with contrast-enhanced CT alone.


Assuntos
Melanoma , Neoplasias Cutâneas/tratamento farmacológico , Fluordesoxiglucose F18 , Humanos , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos
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