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1.
Recent Results Cancer Res ; 214: 169-187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473853

RESUMO

Treatment of patients with advanced metastatic melanoma has for decades been a story of very limited success. This dramatically changed when therapy with anti-PD-1 checkpoint blocking antibodies was approved in the USA and Europe in 2014 and 2015, respectively. The therapy exploits the capacity of CD8+ T cells to specifically kill tumor cells. Within the tumor microenvironment, CD8+ T cell activity is blocked by suppressive signals received via PD-1, an inhibitory co-receptor and so-called checkpoint of T cell activation. PD-1 binds to its ligand PD-L1 on melanoma cells which dampens the T cell's activity. Antibodies blocking inhibitory PD-1/PD-L1 interaction release T cells from suppression. Treatment of late-stage disease melanoma patients with antibodies targeting the PD-1/PD-L1 axis, termed immune checkpoint blocking therapy (ICBT), yields clinical frequently long-lasting responses in 30-40% of cases. Despite this remarkable breakthrough, still the majority of patients resists ICBT or develops resistance after initial therapy response. Administration of anti-PD-1 antibodies in combination with antibodies targeting CTLA-4, another inhibitory immune checkpoint increased clinical responses rate up to 50% but at costs of higher treatment-related toxicities. Thus, strong efforts are now directed toward the understanding of therapy resistance, the identification of biomarkers predicting therapy response, and the development of alternative PD-1-based combination treatment to improve patient outcomes.


Assuntos
Linfócitos T CD8-Positivos/citologia , Imunoterapia , Melanoma/terapia , Receptor de Morte Celular Programada 1 , Anticorpos Monoclonais , Antígeno B7-H1 , Europa (Continente) , Humanos , Microambiente Tumoral
2.
Adv Exp Med Biol ; 1164: 225-233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576552

RESUMO

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase , Imunoterapia , Melanoma , Animais , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Melanoma/terapia , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia
3.
Rinsho Ketsueki ; 60(9): 1341-1350, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597862

RESUMO

It has been eight years since the first immune checkpoint-blocking antibody, ipilimumab, was approved for metastatic malignant melanoma treatment by FDA in 2011. During this period, several other immune checkpoint blockers have been newly developed and approved for certain cancers, including malignant melanoma. However, there have been several concerns with some of these. The overall response rate did not exceed 30% in many cancers; although combination therapy with ipilimumab and nivolumab increased efficacy, immune-related adverse events also increased. This observation facilitated the reverse translational research (rTR) approach, using clinical specimens from treated patients to gradually elucidate the mechanism of resistance and biomarkers to select patients who can potentially benefit from immunotherapy. This has also promoted the development of novel combination therapies. In this review, immunological findings that highlight the resistance mechanisms of cancers against immune checkpoint blockers and the novel attempts to achieve a break-through will be discussed.


Assuntos
Imunoterapia , Ipilimumab/uso terapêutico , Melanoma/terapia , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/terapia , Resistencia a Medicamentos Antineoplásicos , Humanos , Pesquisa Médica Translacional
4.
Cancer Immunol Immunother ; 68(9): 1547-1559, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31482307

RESUMO

Engineered cytokine products represent promising agents for the treatment of immunogenic tumors, such as malignant melanoma, in addition to immune checkpoint inhibitors. Here we describe the results of a controlled, randomized phase II clinical trial, aimed at assessing the therapeutic potential of L19IL2, a fully human fusion protein consisting of the L19 antibody specific to the alternatively spliced extra-domain B of fibronectin, fused to human interleukin-2 in advanced metastatic melanoma. In one arm, patients received dacarbazine (DTIC; 1000 mg/m2 of body surface on day 1 of 21-day cycles) as single agent, while in two other arms L19IL2 (22.5 million international units of IL2 equivalents) was added, based on two different schedules of administration. In total, 69 patients with stage IV melanoma were enrolled (24 in the dacarbazine arm, 23 and 22 in the other combination arms, respectively) and 67 received treatment. Analyses of efficacy results show a statistically significant benefit in terms of overall response rate and median progression-free survival for patients receiving L19IL2 in combination with DTIC, compared to DTIC as single agent. In light of these results, further clinical investigations with L19IL2 (alone or in combination with other agents) are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/uso terapêutico , Melanoma/terapia , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Adulto Jovem
5.
Magy Onkol ; 63(3): 239-245, 2019 09 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31538441

RESUMO

Skin cancers represent the most common type of malignancy. The incidence rate of melanoma and non-melanoma skin cancer depicts a continuous rise worldwide, which is attributed mainly (but not exclusively) to the growing incidence of non-melanoma skin cancer in the elderly population. Most skin cancer types are sensitive to immunotherapy. Melanoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma showed response rates of at least 40% for PD-1 inhibitor therapy as reported in recent articles. In this article we review the current and future immunotherapy agents and procedures for skin cancers.


Assuntos
Imunoterapia/mortalidade , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Carcinoma de Célula de Merkel/imunologia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/terapia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Intervalo Livre de Doença , Feminino , Humanos , Hungria , Masculino , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Terapia de Alvo Molecular/métodos , Prognóstico , Medição de Risco , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Resultado do Tratamento
6.
Anticancer Res ; 39(9): 4995-5001, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519606

RESUMO

BACKGROUND/AIM: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) combined with non-myeloablative chemotherapy (NMA) has been shown to prolong survival in patients with metastatic disease. MATERIALS AND METHODS: Tissue harvesting was performed form a variety of sites. TILs were isolated, expanded and infused with bolus high-dose IL-2. RESULTS: Between 2008 and 2018, 242 lesions were resected for TILs harvesting from a range of sites form 196 patients without mortality and with minimal morbidity. Of those harvested, 75 were unable to complete therapy because of clinical deterioration during the wait period. Of 121 evaluable treated patients, there was no effect of metastatic site biopsied on the mean fold TIL expansion. Those receiving prior ipilimumab had a higher TIL fold expansion but a lower TIL fold expansion than those exposed to anti-PD1 therapy. CONCLUSION: Harvesting may be safely performed with successful TIL expansion from most sites. Prior check point inhibitory immunotherapy may potentially influence TIL fold expansion.


Assuntos
Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/terapia , Adolescente , Adulto , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Feminino , Humanos , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto Jovem
7.
Cancer Immunol Immunother ; 68(9): 1417-1428, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31422446

RESUMO

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Eosinófilos/imunologia , Imunoterapia/métodos , Interleucina-2/uso terapêutico , Melanoma/terapia , Neoplasias Cutâneas/terapia , Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inflamação , Ativação Linfocitária , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/imunologia , Regulação para Cima
8.
Int J Nanomedicine ; 14: 4319-4331, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354263

RESUMO

Objective: The study aimed to synthesize superparamagnetic NaYF4:Yb,Er@PE3@Fe3O4 upconversion nanoprobes and to study their photothermal effects for the treatment of malignant melanoma. Methods: Morphological characteristics of the synthesized nanoprobes were examined by scanning electron microscopy. Their biocompatibility and biodistribution profiles were assessed through blood routine/biochemistry tests and the inductively coupled plasma/optical emission spectrometry-based analysis of tissue metal elements. Their photothermal conversion efficiency and their potential as contrast agents for upconversion luminescence (UCL)/magnetic resonance imaging (MRI) dual-modal imaging were tested. Efficacy in photothermal therapy, which was achieved by combining nanoprobes with near-infrared (NIR) irradiation, was evaluated in both A375 cell line and BALB/c mice models. The underlying mechanisms were interrogated by molecular approaches including the MTT assay, flow cytometry, semiquantitative PCR, western blot, and immunohistochemistry. Results: 1) Our synthesized NaYF4:Yb,Er@PE3@Fe3O4 nanoprobes exhibited a uniform cubic morphology with a diameter of ~50 nm. Subcutaneous administration led to no severe, long-lasting adverse effects in mice, possibly due to complete removal of these nanomaterials within one month. 2) Our nanoprobes possessed superior photothermal conversion efficiency and strong contrasting effects during UCL/MRI dual-modal imaging, corroborating their applications in imaging-guided photothermal therapy. 3) Combinatorial treatment of these nanoprobes with NIR irradiation induced profound apoptosis/necrosis in A375 cells. Similarly, the same treatment modality led to strong therapeutic effects in BALB/c mice implanted with A375 tumor xenografts. Mechanistic studies suggested an involvement of heat shock protein 70 in mediating the observed antitumor effects of our nanoprobes. Conclusion: Our study describes a convenient method to synthesize a new type of superparamagnetic upconversion nanoprobes, which possess high biocompatibility and can be used in imaging-guided photothermal therapy for the treatment of malignant melanoma. Importantly, our findings will promote clinical applications of NaYF4:Yb,Er@PE3@Fe3O4 as novel theranostic agents in treating melanoma and many other tumors.


Assuntos
Érbio/química , Fluoretos/química , Hipertermia Induzida , Nanopartículas de Magnetita/uso terapêutico , Melanoma/terapia , Fototerapia , Ítrio/química , Animais , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Raios Infravermelhos , Imagem por Ressonância Magnética/métodos , Nanopartículas de Magnetita/ultraestrutura , Melanoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Distribuição Tecidual , Carga Tumoral
9.
Hautarzt ; 70(10): 804-810, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31267179

RESUMO

BACKGROUND: Treatment of patients with malignant melanoma includes informing the patients about their rights regarding social/disability benefits. In particular, every patient has the right to rehabilitation treatment according to SGB V and IX (SGB: Sozialgesetzbuch; Social Security Code) and to an examination regarding the classification of the disability. OBJECTIVES: The present study examines the extent to which patients with invasive malignant melanoma are informed after initial diagnosis about their social rights to medical rehabilitation measures and the classification of disability. MATERIALS AND METHODS: In the course of a survey in 2014, n = 1800 German dermatological practices were contacted and provided a standardized questionnaire on several care-relevant questions, including the aforementioned ones. RESULTS: Evaluable questionnaires were submitted by n = 424 practices. In all, 52% of dermatologists stated that they regularly provided information on the right to rehabilitation, 15% sometimes, 41% rarely or never. Furthermore, 44% of dermatologists regularly, 17% sometimes and 38% rarely or never informed their patients about the classification of disability. Relevant differences were found in regional comparisons. CONCLUSIONS: Practicing dermatologists seem to transfer the information requirement to the clinics involved in the treatment. It would be beneficial if the information were also provided again by the dermatologists in private practice. In view of the known limited capacity to receive new information from patients with newly diagnosed melanoma, repeated counselling appears to be more patient-friendly.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Melanoma/terapia , Educação de Pacientes como Assunto/métodos , Direitos do Paciente , Reabilitação/legislação & jurisprudência , Neoplasias Cutâneas/terapia , Assistência ao Convalescente/normas , Avaliação da Deficiência , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Inquéritos e Questionários
10.
Biomater Sci ; 7(9): 3866-3875, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31309204

RESUMO

Photothermal therapy (PTT) is emerging as a promising treatment for skin cancer. Plasmon-resonant gold-coated liposome nanoparticles (Au Lipos NPs) specifically absorb Near Infra-Red (NIR) light resulting in localized hyperthermia (PTT). In the current study, curcumin (a hydrophobic anticancer agent) was entrapped in Au Lipos NPs as nanocrystals to act as an adjuvant for the PTT of melanoma. NIR light irradiation on Au Lipos Cur NPs triggered the release of curcumin nanocrystals which coalesce to form curcumin microcrystals (CMCs). An in situ"nano to micro" transition in the crystal state of curcumin was observed. This in situ transition leads to the formation of CMCs. These CMCs exhibited sustained release of curcumin for a prolonged duration (>10 days). The localized availability of curcumin aids in enhancing PTT by inhibiting the growth and mobility of cancer cells that escape PTT. In the in vitro modified scratch assay, the Au Lipos Cur NP + Laser group showed >1.5 fold enhanced therapeutic coverage when compared with the Au Lipos NP + Laser group. In vivo PTT studies performed in a B16 tumor model using Au Lipos Cur NPs showed a significant reduction of the tumor volume along with the localized release of curcumin in the tumor environment. It was observed that the localized release of curcumin enables an immediate adjuvant effect resulting in the enhancement of PTT.


Assuntos
Adjuvantes Farmacêuticos/química , Antineoplásicos/química , Curcumina/química , Ouro/química , Lipossomos/química , Nanopartículas Metálicas/química , Adjuvantes Farmacêuticos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular , Quimioterapia Adjuvante , Cristalização , Curcumina/administração & dosagem , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Hipertermia Induzida , Raios Infravermelhos , Melanoma/terapia , Nanopartículas Metálicas/administração & dosagem , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Fototerapia/métodos , Neoplasias Cutâneas/terapia , Microambiente Tumoral
11.
Vet Clin North Am Equine Pract ; 35(2): 311-325, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31279435

RESUMO

All gray horses inherited a single gene mutation, STX17G, that unbalances melanocyte behavior to cause graying and propensities to develop vitiligo and melanoma. The coat color genes ASIPa and MC1RE add risk such that relative likelihood of melanoma based on pregraying coat color is black > bay > chestnut. Melanomas begin at about 4 years. Locoregional control of melanoma masses depends on surgical removal and/or intralesional chemotherapy (possibly with adjunctive hyperthermia or electroporation). Systemic treatment is not evidence based but immunomodulators (cimetidine, levamisole) and vaccines can be tried.


Assuntos
Doenças dos Cavalos/terapia , Melanoma/veterinária , Animais , Cor de Cabelo/genética , Doenças dos Cavalos/genética , Cavalos , Melanoma/genética , Melanoma/terapia
12.
Expert Opin Investig Drugs ; 28(8): 695-708, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31359805

RESUMO

Introduction: Immunotherapy has revolutionized the treatment of cancer. Given this growing success, at the same time, there are significant limitations and unanswered questions concerning response rates, duration of therapy, why some patients respond and others do not, and if combining different immune-agents would overcome this lack of response, increase the chance of success and postpone acquired resistance. Areas covered: The comprehension of how to properly modulate the immune pathways, the molecular and the immunological bases of the disease, will be fundamental to guide the development of therapeutic interventions and combinations that will be more suitable for treatment of cancer patients. In this review, we discuss the strategies of immunotherapy combinations in order to develop more effective immunotherapy programs, with a particular focus on melanoma and renal cancer patients, as well as the combination of immunotherapy and chemotherapy. Expert Opinion: Given the complexity of immune activation, combinatorial approaches are needed, and due to the considerable variability in tumor biology across patients and tumor types, patient selection and biomarkers need to be further explored. In summary, combined therapies have shown promising success, but additional and continuous research to identify the safety, efficacy, optimal combination, dosage and timing are still required.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Imunoterapia/métodos , Neoplasias/terapia , Animais , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Melanoma/imunologia , Melanoma/terapia , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
13.
Medicine (Baltimore) ; 98(30): e16366, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348237

RESUMO

RATIONALE: Primary melanomas of the female genital tract are rare and usually occur in the vulva and vagina. Involvement of the cervix, uterus, and ovary are extremely rare. Surgery and adjuvant therapy remain the mainstay of treatment. The majority of patients experience poor long-term survival. This report aimed at highlighting an extremely rare case of primary melanoma of the female genitalia, synchronously involving the vulva and uterine cervix. PATIENT CONCERNS: A 58-year-old multiparous female presented with postmenopausal bleeding for 10 days. DIAGNOSES: Speculum examination and histologic analysis of the surgical specimens revealed synchronous involvement of the vulva and uterine cervix by malignant melanoma. According to the American Joint Committee on Cancer stage grouping for melanoma, this tumor was at stage V. INTERVENTIONS: The patient subsequently underwent radical surgery and postoperative chemotherapy. OUTCOMES: She has been on regular follow-up, and is now free of disease for 50 months after the operation. LESSONS: Primary melanomas of the female genital tract have biologically aggressive characteristics. Optimal management consists of individualized surgery and adjuvant therapy. However, early recognition and prompt intervention offer maximal benefit from treatment.


Assuntos
Neoplasias dos Genitais Femininos/patologia , Melanoma/patologia , Colo do Útero/patologia , Feminino , Neoplasias dos Genitais Femininos/terapia , Humanos , Melanoma/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Vulva/patologia
14.
Medicine (Baltimore) ; 98(28): e16328, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305421

RESUMO

Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ≥2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.


Assuntos
Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/patologia , Pessoa de Meia-Idade , Padrões de Prática Médica , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
15.
J Surg Oncol ; 120(3): 558-564, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264725

RESUMO

BACKGROUND AND OBJECTIVES: Patients with in-transit or limited cutaneous metastatic melanoma may benefit from intralesional injections with talimogene laherparepvec (TVEC), a modified oncolytic herpesvirus. However, its use in patients with adverse prognostic scores in a real-life clinical setting has not been studied. METHODS: We performed a two-center retrospective analysis of 40 patients with metastatic melanoma treated with TVEC from 2015-2017. Demographics, overall response, and survival after therapy were noted. RESULTS: Overall, there was a durable response rate of 40%; median progression-free survival (PFS) was 10.5 months and median overall survival (OS) was not reached. Bulky disease was associated with decreased OS (15.7 months vs not reached, P < .05) and mPFS (2.3 months vs not reached, P < .05), when compared with smaller tumors. Poor performance status (ECOG 2-3) was associated with worse OS (10.2 months vs not reached, P < .05) and PFS (2.1 months vs not reached, P < .05) compared to patients with ECOG 0-1. There was no difference in the outcomes with age greater than 75 or with prior therapies. Adverse events were relatively tolerable. CONCLUSIONS: These findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma in a real-life clinical setting, and suggest parameters to aid in appropriate therapy selection for optimal response.


Assuntos
Herpesviridae/fisiologia , Melanoma/terapia , Terapia Viral Oncolítica/métodos , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Melanoma/virologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Cutâneas/virologia , Taxa de Sobrevida
16.
Nat Commun ; 10(1): 2782, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239444

RESUMO

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma.


Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Anticorpos Monoclonais/administração & dosagem , Melanoma/enzimologia , Melanoma/terapia , Adenosina/genética , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Animais , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Desmetilação , Feminino , Humanos , Imunoterapia , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Pol Merkur Lekarski ; 46(275): 220-223, 2019 May 27.
Artigo em Polonês | MEDLINE | ID: mdl-31152535

RESUMO

Skin melanomas rank among the malignant neoplasms that have the greatest dynamics of growth and number of incidents. Early identification of primary lesions and metastases in regional lymph nodes, possible due to location, creates a chance for complete recovery. CASE REPORT: The study presents a positive result of treatment in case of a 67-year old woman patient, with diagnosed malignant melanoma in the lateral ankle area in the right lower extremity. Decisive for the positive result of treatment was the proper course of treatment (early diagnostics, properly established diagnosis, surgical treatment), as well as complexity of therapeutic management. CONCLUSIONS: The management of a patient suffering from generalized melanoma should be individualized, depending on the place of primary lesion, the presence, number, and location of metastases, as well as clinical manifestations.


Assuntos
Melanoma , Neoplasias Cutâneas , Idoso , Tornozelo , Feminino , Humanos , Linfonodos , Metástase Linfática , Melanoma/diagnóstico , Melanoma/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia
18.
Nat Rev Cancer ; 19(7): 377-391, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209265

RESUMO

Malignant melanoma is notorious for its inter- and intratumour heterogeneity, based on transcriptionally distinct melanoma cell phenotypes. It is thought that these distinct phenotypes are plastic in nature and that their transcriptional reprogramming enables heterogeneous tumours both to undergo different stages of melanoma progression and to adjust to drug exposure during treatment. Recent advances in genomic technologies and the rapidly expanding availability of large gene expression datasets have allowed for a refined definition of the gene signatures that characterize these phenotypes and have revealed that phenotype plasticity plays a major role in the resistance to both targeted therapy and immunotherapy. In this Review we discuss the definition of melanoma phenotypes through particular transcriptional states and reveal the prognostic relevance of the related gene expression signatures. We review how the establishment of phenotypes is controlled and which roles phenotype plasticity plays in melanoma development and therapy. Because phenotype plasticity in melanoma bears a great resemblance to epithelial-mesenchymal transition, the lessons learned from melanoma will also benefit our understanding of other cancer types.


Assuntos
Adaptação Fisiológica/fisiologia , Melanoma/genética , Melanoma/patologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Humanos , Imunoterapia , Melanoma/terapia , Fenótipo
19.
Cancer Imaging ; 19(1): 31, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146793

RESUMO

OBJECTIVE: To investigate the outcome and safety data of chemosaturation with percutaneous hepatic perfusion (CS-PHP) of melphalan in patients with liver-dominant metastatic uveal melanoma. MATERIAL AND METHODS: This is a HIPAA compliant, IRB approved, retrospective study. A total of 28 CS-PHPs were performed in 16 individual patients (six men and ten women, median age 63.1 years [range 49.1 to 78.7 years], one to six CS-PHP procedures per patient) for treatment of liver-dominant metastatic uveal melanoma between June, 2015 and December, 2018. All patients received cross-sectional imaging at baseline and during follow-up. CS-PHP was performed with the Hepatic CHEMOSAT® Delivery System (Delcath Systems, Inc., NY, USA) facilitating extracorporeal filtration of hepatic blood for melphalan removal. Ideal body weight-adjusted melphalan doses were administered into the hepatic arteries. Serious adverse events (SAE), progression-free survival based on response criteria in solid tumors, and overall survival were noted. Survival data were analyzed using Kaplan-Meier estimates. RESULTS: Partial response after first CS-PHP was observed in nine patients (60%), stable disease in five patients (33%) and progressive disease in one patient (7%). Median overall survival was 27.4 months (95% CI 4.1 to 35.4 month) after first CS-PHP. Median progression-free survival was 11.1 months after first CS-PHP (95% CI 4.9 to 23.6 months). SAEs were observed in the majority of patients with most SAEs limited to grades one and two. Thirteen SAEs of grades three and four were observed in seven individual patients. No grade five SAE was observed. CONCLUSION: CS-PHP is an efficacious and safe treatment for patients presenting with liver-dominant metastatic uveal melanoma.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional/métodos , Melanoma/terapia , Melfalan/administração & dosagem , Neoplasias Uveais/terapia , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/instrumentação , Feminino , Humanos , Circulação Hepática , Masculino , Melanoma/patologia , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Uveais/patologia
20.
Autoimmun Rev ; 18(8): 814-824, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176875

RESUMO

The heritable genetic variation that explains phenotypic differences in a population fluctuates for different autoimmune disorders. Particularly in multiple sclerosis (MS) etiology, modest genetic and major environmental effects emerge. Increasingly recognized as a major environmentally shaped contributor to disease and treatment outcomes are gut microbiota. As discussed here, the observed impact of gut microbiome on MS pathophysiology, involves both quantitative and functional changes in composition, metabolism, gut permeability, homeostasis and modulation of the immune system. Although the first supplementary therapeutic interventions have been approached in general autoimmune disorders they are relatively cruder and a translation of knowledge from other pathologies is valuable but still required. Consequently initial therapeutic interventions with microbiota for autoimmune disorders could be correspondingly improved.


Assuntos
Microbioma Gastrointestinal , Esclerose Múltipla/microbiologia , Animais , Bactérias/classificação , Homeostase , Humanos , Melanoma/terapia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Probióticos/uso terapêutico , RNA Ribossômico 16S
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