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1.
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
2.
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
3.
Hautarzt ; 70(10): 815-830, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31511903

RESUMO

Cutaneous lymphomas comprise different subgroups with distinct biological behavior. Mycosis fungoides, the most common cutaneous lymphoma, presents with patches, plaques, tumors and erythroderma. Therapeutic options depend on stage and comprise local skin-directed treatment in early stages, while later stages and Sézary syndrome require systemic therapies including bexarotene, interferon or brentuximab vedotin. While the rare CD4-positive lymphoproliferation and acral CD8-positive lymphoma present with an invariably indolent course, cutaneous peripheral T­cell lymphomas exhibit an aggressive clinical behavior. Among the subgroup of cutaneous B­cell lymphomas, primary cutaneous marginal zone lymphoma and follicle center cell lymphoma belong to indolent entities with almost unrestricted overall survival, whereas cutaneous large B­cell lymphoma presents with a significant risk of systemic dissemination and is associated with high lethality.


Assuntos
Linfoma de Células B/terapia , Linfoma não Hodgkin/terapia , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/terapia , Micose Fungoide/diagnóstico , Micose Fungoide/terapia , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Linfoma , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Linfoma Cutâneo de Células T/mortalidade , Micose Fungoide/mortalidade , Síndrome de Sézary/mortalidade , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida
4.
N Engl J Med ; 381(16): 1535-1546, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31562797

RESUMO

BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Seguimentos , Humanos , Ipilimumab/efeitos adversos , Melanoma/genética , Melanoma/mortalidade , Pessoa de Meia-Idade , Mutação , Nivolumabe/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida
5.
Lancet ; 394(10197): 471-477, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31280965

RESUMO

BACKGROUND: The optimal surgical excision margins are uncertain for patients with thick (>2 mm) localised cutaneous melanomas. In our previous report of this multicentre, randomised controlled trial, with a median follow-up of 6·7 years, we showed that a narrow excision margin (2 cm vs 4 cm) did not affect melanoma-specific nor overall survival. Here, we present extended follow-up of this cohort. METHODS: In this open-label, multicentre randomised controlled trial, we recruited patients from 53 hospitals in Sweden, Denmark, Estonia, and Norway. We enrolled clinically staged patients aged 75 years or younger diagnosed with localised cutaneous melanoma thicker than 2 mm, and with primary site on the trunk or upper or lower extremities. Patients were randomly allocated (1:1) to treatment either with a 2-cm or a 4-cm excision margin. A physician enrolled the patients after histological confirmation of a cutaneous melanoma thicker than 2 mm. Some patients were enrolled by a physician acting as responsible for clinical care and as a trial investigator (follow-up, data collection, and manuscript writing). In other cases physicians not involved in running the trial enrolled patients. Randomisation was done by telephone call to a randomisation office, by sealed envelope, or by computer generated lists using permuted blocks. Patients were stratified according to geographical region. No part of the trial was masked. The primary outcome in this extended follow-up study was overall survival and the co-primary outcome was melanoma-specific survival. All analyses were done on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT03638492. FINDINGS: Between Jan 22, 1992, and May 19, 2004, 936 clinically staged patients were recruited and randomly assigned to a 4-cm excision margin (n=465) or a 2-cm excision margin (n=471). At a median overall follow-up of 19·6 years (235 months, IQR 200-260), 621 deaths were reported-304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group (unadjusted HR 0·98, 95% CI 0·83-1·14; p=0·75). 397 deaths were attributed to cutaneous melanoma-192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78-1·16, p=0·61). INTERPRETATION: A 2-cm excision margin was safe for patients with thick (>2 mm) localised cutaneous melanoma at a follow-up of median 19·6 years. These findings support the use of 2-cm excision margins in current clinical practice. FUNDING: The Swedish Cancer Society, Stockholm Cancer Society, the Swedish Society for Medical Research, Radiumhemmet Research funds, Stockholm County Council, Wallström funds.


Assuntos
Extremidade Inferior/patologia , Melanoma/mortalidade , Melanoma/cirurgia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/cirurgia , Tronco/patologia , Extremidade Superior/patologia , Idoso , Dinamarca , Estônia , Feminino , Humanos , Análise de Intenção de Tratamento , Extremidade Inferior/cirurgia , Masculino , Margens de Excisão , Melanoma/patologia , Pessoa de Meia-Idade , Mortalidade , Noruega , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Suécia , Tronco/cirurgia , Resultado do Tratamento , Extremidade Superior/cirurgia
6.
Anticancer Res ; 39(6): 3147-3157, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177161

RESUMO

BACKGROUND/AIM: Regional lymph node recurrence (RLNR) is the most common pattern of recurrence within 2 years from the diagnosis of patients with non-metastatic malignant cutaneous melanoma. However, isolated RLNR without distant metastasis has been rarely studied. PATIENTS AND METHODS: Forty patients with isolated RLNR as a first recurrence were analyzed retrospectively. The clinical outcomes and prognostic impact of clinicopathologic parameters were analyzed. Immunostaining for FOXP3, VEGF, pAKT, and pS6 was also performed. RESULTS: The median disease-free interval from first diagnosis to isolated RLNR and post-recurrence recurrence-free survival (pRFS) were 12 months and 7.2 months, respectively. Distant failure was the most common pattern of failure after isolated RLNR (67.5%). The number of initially harvested lymph nodes (LN) >7 and LN ratio >22.2% at the time of recurrence were prognosticators for pRFS in multivariate analysis. None of the tested biomarkers were significantly related to prognosis. The 5-year post-recurrence overall survival rate was 84.9%. CONCLUSION: Most patients with isolated RLNR will experience a second failure within months, especially distantly. The number of initially harvested LNs and LN ratio at the time of recurrence could predict pRFS.


Assuntos
Melanoma/secundário , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Bases de Dados Factuais , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Melanoma/química , Melanoma/mortalidade , Melanoma/cirurgia , Pessoa de Meia-Idade , Fosforilação , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-akt/análise , Estudos Retrospectivos , Proteína S6 Ribossômica/análise , Fatores de Risco , Neoplasias Cutâneas/química , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/cirurgia , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/análise , Adulto Jovem
7.
Cancer Immunol Immunother ; 68(7): 1187-1194, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31187176

RESUMO

BACKGROUND: PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment. METHODS: We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy. RESULTS: 29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged. CONCLUSIONS: The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Denosumab/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Denosumab/farmacologia , Feminino , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Ligante RANK/antagonistas & inibidores , Ligante RANK/imunologia , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia
8.
Nat Commun ; 10(1): 2678, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213601

RESUMO

Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte/metabolismo , Melanoma Experimental/imunologia , Proteínas de Membrana/metabolismo , Monócitos/imunologia , Neoplasias Cutâneas/imunologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem Celular Tumoral/transplante , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Feminino , Ativação Linfocitária/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
9.
N Engl J Med ; 381(7): 626-636, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31166680

RESUMO

BACKGROUND: Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Seguimentos , Humanos , Imidazóis/efeitos adversos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Oximas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem
10.
J Dermatol ; 46(6): 498-506, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30945333

RESUMO

Melanoma is one of the most serious form of skin cancer. Nowadays, ipilimumab is used for advanced melanoma refractory to first-line anti-programmed death 1 (PD-1) antibodies. Thirty patients (male : female ratio, 18:12; median age, 60.5 years) sequentially treated with ipilimumab after anti-PD-1 antibody (nivolumab or pembrolizumab), while 58 (male : female ratio, 27:31; median age, 66.5 years) with anti-PD-1 antibody only. The kind of therapy and schedules were as follows: nivolumab, 2 mg/kg at 3-week intervals or at 3 mg/kg every 2 week; pembrolizumab, 2 mg/kg every 3 weeks; ipilimumab, 3 mg/kg at 3-week intervals for four doses. The sequential therapy was selected for the patients with disease progression and/or recovered from severe (immune-related [ir]) adverse events (AE) after PD-1 blockade monotherapy. We evaluated multiple parameters and analyzed their relevance to overall survival (OS). The best objective response rate was 6.7% in sequential ipilimumab treatment. Median OS was 163 days (range, 16-489). Baseline absolute lymphocyte count (ALC) and performance status (PS) before sequential ipilimumab were associated with OS in univariate analyses. Baseline PS and irAE within 6 weeks after ipilimumab administration showed significant differences on multivariate analysis. Prior to first-line PD-1 blockade, these parameters were not associated with OS. The other factors (i.e. age, sex, number of doses, absolute neutrophil counts, neutrophil : lymphocyte ratio, lactate dehydrogenase and C-reactive protein) were not associated with OS. [Correction added on 17 April 2019, after first online publication: 'not related to OS' has been amended to 'not associated with OS'.] Ipilimumab as sequential therapy did not appear to improve OS and was associated with more severe irAE than PD-1 blockade monotherapy. We need to carefully consider treating patients with poor PS and low ALC.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Progressão da Doença , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Ipilimumab/efeitos adversos , Masculino , Melanoma/diagnóstico , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Índice de Gravidade de Doença , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida
11.
Ann Hematol ; 98(7): 1647-1655, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31001658

RESUMO

Extranodal NK/T cell lymphoma (NKTCL), nasal type (ENKL) that shows no apparent nasal involvement, is termed extranasal NKTCL or non-nasal NKTCL. In this study, we aimed to explore therapeutic approaches and outcomes in patients with extranasal NKTCL in current clinical practice. A data set of patients with newly diagnosed NKTCL who were diagnosed at 31 institutes in Japan between 2000 and 2013 was used for analysis. The patients' fitness for steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy was assessed using the major inclusion criteria of the SMILE phase 2 study. Of 358 patients, 47 (13%) had extranasal NKTCL. The most frequent extranodal sites of involvement in extranasal NKTCL were skin/subcutaneous tissue (n = 18). Six (13%) of the patients with extranasal NKTCL had localized disease and were diagnosed before 2010. With a median follow-up of 5.8 years, the 2-year overall survival (OS) in patients with nasal and extranasal NKTCL was 70% (95% confidence interval [CI], 65-75%) and 34% (95% CI, 21-47%), respectively. OS in patients with nasal NKTCL had a trend toward better according to treatment era (P = 0.063). In contrast, no obvious improvement of OS was observed in extranasal NKTCL (P = 0.43). The major inclusion criteria of the SMILE-P2 were met in 21% (10/47) of patients with extranasal NKTCL and 60% (188/311) of those with nasal NKTCL (P < 0.001). Despite the advent of new treatments for ENKL, OS remains unfavorable in extranasal NKTCL. A more effective therapy is needed for extranasal NKTCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Extranodal de Células T-NK , Neoplasias Cutâneas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asparaginase/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Japão/epidemiologia , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/mortalidade , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Esteroides/administração & dosagem
12.
J Korean Med Sci ; 34(16): e126, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31020815

RESUMO

BACKGROUND: Malignant melanoma is a cutaneous malignancy with a high mortality rate and high potential for metastases. Detailed information on the clinicopathologic characteristics and prognostic factors of cutaneous melanoma is currently limited in Korea. This study aimed to identify the epidemiological and clinicopathologic characteristics of primary cutaneous melanoma in Korean patients, and to assess which prognostic variables could influence both the development of metastases in primary cutaneous melanoma and overall survival (OS). METHODS: A total of 261 patients diagnosed with primary cutaneous melanoma in seven medical centers between 1997 and 2017 were retrospectively investigated with regard to clinical presentation, localization of the tumor, histopathologic subtype, and survival time. RESULTS: The nodular histologic subtype, ulceration, and Breslow thickness were significantly associated with the development of metastasis; and overweight and obesity (body mass index > 23) were significantly associated with increased Breslow thickness. The location of the metastases appeared to influence OS: brain metastases were associated with the highest risk of death, followed by gastrointestinal, lung, and extra-regional lymph node metastases. CONCLUSION: In this study, tumor thickness, nodular histologic subtype, and ulceration predicted metastatic spread of primary cutaneous melanoma. In addition, OS was associated with the location of metastases. Obesity was related to the prognosis of primary cutaneous melanoma. Clinicians should bear these findings in mind when forming a diagnosis because of the risk of a poor prognosis.


Assuntos
Melanoma/patologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundário , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Obesidade/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Neoplasias Cutâneas/mortalidade , Adulto Jovem
13.
Melanoma Res ; 29(3): 281-288, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026246

RESUMO

Patients diagnosed with metastatic melanoma have varied clinical courses, even in patients with similar disease characteristics. We examine the impact of initial stage of melanoma diagnosis, BRAF status of primary melanoma, and receiving adjuvant therapy on postmetastatic overall survival (pmOS). We studied melanoma patients presenting to Perlmutter Cancer Center at New York University and prospectively enrolled in New York University melanoma biospecimen database and followed up on protocol-driven schedule. Patients were stratified by stage at initial melanoma diagnosis as per AJCC 7th ed. guidelines. pmOS was determined using the Kaplan-Meier method and Cox's proportional hazards models were used to assess hazard ratios (HRs). Three hundred and four out of 3204 patients developed metastatic disease over the time of follow-up (median follow-up 2.2 years, range: 0.08-35.2 years). Patients diagnosed with stage I (n=96) melanoma had longer pmOS (29.5 months) than those diagnosed with stage II (n=99, pmOS 14.9 months) or stage III (n=109, pmOS 15.1 months) melanoma (P=0.036). Initial stage of diagnosis remained significant in multivariate analysis when controlling for lactate dehydrogenase and site of metastases [primary diagnosis stage II (HR 1.44, P=0.046), stage III (HR 1.5, P=0.019)]. Adjuvant treatment was associated with better survival but BRAF mutation status did not show an association. Our data challenge the general assumption that primary melanomas converge upon diagnosis of metastatic disease and behave uniformly. Primary stage of melanoma at the time of diagnosis may be prognostic of outcome, similar to lactate dehydrogenase and metastatic disease sites.


Assuntos
Melanoma/mortalidade , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias/estatística & dados numéricos , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Melanoma/secundário , Melanoma/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estudos Prospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida
14.
Melanoma Res ; 29(3): 342-344, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026248

RESUMO

Validating newly discovered biomarkers in large, publicly available data sets is often difficult and requires specialized computer programming skills. Melanoma Explorer is a web application that enables easy interrogation of melanoma omics data sets that are freely available in online data repositories with a point-and-click interface. Two use cases are demonstrated. First, the relationship of lysozyme mRNA expression is shown to be prognostic in two independent gene expression microarray data sets. Second, a figure from a journal article showing the relationship of tumour thickness and miR-382 abundance is reproduced. Melanoma Explorer is demonstrated to be a useful tool for reproducing results of published studies and providing additional evidence for biomarkers in independent data sets.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Internet , Melanoma/genética , Recidiva Local de Neoplasia/genética , Neoplasias Cutâneas/genética , Software , Metilação de DNA , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/mortalidade , Melanoma/patologia , Melanoma/terapia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Linguagens de Programação , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário , Neoplasias Cutâneas/terapia , Taxa de Sobrevida
15.
Br J Surg ; 106(6): 729-734, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30816996

RESUMO

BACKGROUND: For patients with intermediate-thickness melanoma, surveillance of regional lymph node basins by clinical examination alone has been reported to result in a larger number of lymph nodes involved by melanoma than if patients had initial sentinel node biopsy and completion dissection. This may result in worse regional control. A prospective study of both regular clinical examination and ultrasound surveillance was conducted to assess the effectiveness of these modalities. METHODS: Between 2010 and 2014, patients with melanoma of thickness 1·2-3·5 mm who had under-gone wide local excision but not sentinel node biopsy were recruited to a prospective observational study of regular clinical and ultrasound nodal surveillance. The primary endpoint was nodal burden within a dissected regional lymph node basin. Secondary endpoints included locoregional or distant relapse, progression-free and overall survival. RESULTS: Ninety patients were included in the study. After a median follow-up of 52 months, ten patients had developed nodal relapse as first recurrence, four had locoregional disease outside of an anatomical nodal basin as the first site of relapse and six had relapse with distant disease. None of the patients who developed relapse within a nodal basin presented with unresectable nodal disease. The median number of involved lymph nodes in patients undergoing lymphadenectomy for nodal relapse was 1 (range 1-2; mean 1·2). CONCLUSION: This study suggests that ultrasound surveillance of regional lymph node basins is safe for patients with melanoma who undergo a policy of nodal surveillance.


Assuntos
Linfonodos/diagnóstico por imagem , Melanoma/patologia , Cuidados Pós-Operatórios/métodos , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Masculino , Melanoma/diagnóstico por imagem , Melanoma/mortalidade , Melanoma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Estudos Prospectivos , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/cirurgia , Análise de Sobrevida , Resultado do Tratamento
16.
Br J Surg ; 106(6): 672-681, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30912591

RESUMO

BACKGROUND: The role of completion lymph node dissection (CLND) in patients with sentinel lymph node (SLN)-positive melanoma continues to be debated. This systematic review and meta-analysis evaluated survival and recurrence rate in these patients who underwent CLND, compared with observation. METHODS: A comprehensive MEDLINE and Embase database search was performed for cohort studies and RCTs published between January 2000 and June 2017 that assessed the outcomes of CLND compared with observation in patients with SLN-positive melanoma. The primary outcome was survival and the secondary outcome was recurrence rate. Studies were assessed for quality using the Cochrane risk-of-bias tool for RCTs and Newcastle-Ottawa Scale for cohort studies. Pooled relative risk or hazard ratio with 95 per cent confidence intervals were calculated for each outcome. The extent of heterogeneity between studies was assessed with the I2 test. The protocol was registered in PROSPERO (CRD42017070152). RESULTS: Fifteen studies (13 cohort studies with 7868 patients and 2 RCTs with 2228 patients) were identified for qualitative synthesis. Thirteen studies remained for quantitative meta-analysis. Survival was similar in patients who underwent CLND and those who were observed (risk ratio (RR) for death 0·85, 95 per cent c.i. 0·71 to 1·02). The recurrence rate was also similar (RR 0·91, 0·79 to 1·05). CONCLUSION: Patients with SLN-positive melanoma do not have a significant benefit in survival or recurrence rate if they undergo CLND rather than observation.


Assuntos
Excisão de Linfonodo/métodos , Melanoma/cirurgia , Linfonodo Sentinela/patologia , Neoplasias Cutâneas/cirurgia , Humanos , Metástase Linfática , Melanoma/mortalidade , Melanoma/patologia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Conduta Expectante
17.
Zhonghua Bing Li Xue Za Zhi ; 48(3): 215-219, 2019 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-30831648

RESUMO

Objective: To investigate the clinicopathologic features and prognosis of ALK-positive Spitz tumors. Methods: Thirteen patients with ALK-positive Spitz tumors diagnosed at Shanghai Cancer Center, Fudan University from October 2016 to December 2017 were collected. All cases were routinely evaluated histopathological features in HE staining and detected ALK protein expression by immunohistochemistry. The ALK fusions of 7 cases were confirmed by fluorescence in situ hybridization (FISH).Follow-up data was collected. Results: The age of patients including 2 males and 11 females ranged from 4 to 47 years (mean 25 years). 12 patients were diagnosed with atypical Spitz tumors and 1 patient was diagnosed with Spitz nevus. Clinically, most lesions presented as papules or nodules, while a few lesions presented as plaques. Histologically, most tumors were exophytic (9/13). More than half of the tumors were amelanotic and the junctional component was mainly composed of melanocytic nests. Kamino bodies were not found. The bases of the tumors were mainly wedge-shaped (5/13) and flat (7/13). Eight tumors displayed mixed cell types, while 5 tumors were composed of only spindle cells. All the tumors showed a plexiform and/or intersecting fascicular growth pattern, and perineural extension was observed in 3 tumors. ALK immunohistochemistry showed diffuse and intense cytoplasmic staining in 13 cases, and 7 of them were detected by FISH to confirm the presence of ALK fusions. All patients were followed up for 7 to 21 months (median=12), with no recurrence or lymph node dissemination. Conclusions: Spitz tumors with ALK fusions have their special histopathologic features.ALK fusions mainly occur in Spitz nevi and atypical Spitz tumors. The follow-up data of the existing literatures and our research indicates that the prognosis of ALK-positive Spitz tumors may be good.


Assuntos
Quinase do Linfoma Anaplásico/análise , Proteínas de Neoplasias/análise , Nevo de Células Epitelioides e Fusiformes/química , Nevo de Células Epitelioides e Fusiformes/patologia , Neoplasias Cutâneas/química , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , China , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Nevo de Células Epitelioides e Fusiformes/mortalidade , Prognóstico , Neoplasias Cutâneas/mortalidade , Adulto Jovem
18.
J Surg Oncol ; 119(8): 1060-1069, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30883783

RESUMO

BACKGROUND: The prognostic benefit of sentinel lymph node biopsy (SLNB) and factors predictive of survival specifically in patients with acral lentiginous melanoma (ALM) are unknown. METHODS: The SEER database was queried for ALM cases that underwent SLNB from 1998 to 2013. Clinicopathological factors were correlated with SLN status, overall survival (OS), and melanoma-specific survival (MSS). RESULTS: Median age for the 753 ALM study patients was 65 years, and 48.2% were male. Median thickness was 2 mm with 38.1% of cases having ulceration. SLN metastases were detected in 194 of 753 cases (25.7%). Multivariable analysis showed that thickness, Clark level IV-V, and ulceration significantly predicted for SLN metastasis (P < 0.05). For patients with positive SLN, 5-year OS and MSS were significantly worse at 48.1% and 58.9%, respectively, compared with 78.7% and 88.5%, respectively, for patients with negative SLN (P < 0.0001). On multivariable analyses, older age, male gender, increasing thickness, ulceration, and a positive SLN significantly predicted for worse OS and MSS (all P < 0.05). CONCLUSION: This study confirms the important role of SLNB in ALM. SLN metastases are seen in 25.7% of ALM cases, providing significant prognostic information. In addition, thickness, ulceration status, and SLNB status significantly predict survival in patients with ALM.


Assuntos
Melanoma/mortalidade , Melanoma/patologia , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Linfonodo Sentinela/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Idoso , Feminino , Humanos , Lentigo/mortalidade , Lentigo/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Programa de SEER , Estados Unidos/epidemiologia
19.
Aust Vet J ; 97(4): 89-92, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30919442

RESUMO

BACKGROUND: Devil facial tumour disease (DFTD) is a contagious cancer causing marked population declines in wild Tasmanian devils. In response to this threat, a captive insurance population has been established. This study investigated causes of death in captive Tasmanian devils. METHODS: Clinical and laboratory records of captive Tasmanian devils held in seven Tasmanian captive facilities were analysed for cause of death or severe morbidity requiring euthanasia. RESULTS: Neoplasia was found to be the most common cause of mortality/severe morbidity, accounting for 27/63 of deaths. Cutaneous lymphoma was the most frequently observed tumour (10/27), at a higher incidence than previously reported. The most common cause of severe morbidity, following neoplasia, was leucoencephalomyelopathy, which caused severe, progressive hindlimb paresis and ataxia. CONCLUSION: Neoplasia, specifically cutaneous lymphoma, and degenerative neurological conditions are the most frequent causes of death in captive Tasmanian devils in Tasmania. Further work to determine the aetiologies of these conditions, as well as effective treatments, would be valuable.


Assuntos
Eutanásia/estatística & dados numéricos , Marsupiais , Morbidade , Neoplasias/veterinária , Animais , Feminino , Leucoencefalopatias/epidemiologia , Leucoencefalopatias/mortalidade , Leucoencefalopatias/veterinária , Linfoma/epidemiologia , Linfoma/mortalidade , Linfoma/veterinária , Masculino , Neoplasias/mortalidade , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/mortalidade , Doenças Neurodegenerativas/veterinária , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/veterinária , Tasmânia/epidemiologia
20.
Dermatol Surg ; 45(6): 772-781, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30789511

RESUMO

BACKGROUND: The single most important prognostic indicator for mortality in patients with cutaneous squamous cell carcinoma (SCC) is the development of nodal metastasis (NM). OBJECTIVE: To characterize the risk factors for and clinical course of cutaneous SCC with NM. METHODS: Ten-year retrospective cohort study (2006-2017) at an academic tertiary care center reviewing 53 cutaneous SCC tumors with NM. RESULTS: Most patients were men (84.6%, 44/52), and almost all primary tumors were on the head and neck (96.2%, 51/53). Most primary tumors were characterized by known "high-risk features" including perineural invasion (56.6%, 30/53), diameter ≥2 cm (54.7%, 29/53), invasion beyond subcutaneous fat (43.4%, 23/53), and poor differentiation (32.1%, 17/53). In addition, many tumors were recurrent (52.8%, 28/53), and many patients were immunosuppressed (30.8%, 16/52). Disease-free survival after treatment of nodal disease was 7.5% (4/53) at 5 years. CONCLUSION: To the best of the authors' knowledge, this study is the largest retrospective cohort of cutaneous SCC with NM to date. The results verify the significance of "high-risk features" used by current staging systems while highlighting additional features that may have prognostic value. This study may be used to refine current staging systems, improve early detection, and optimize management for these aggressive tumors.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Linfonodos/patologia , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Neoplasias Cutâneas/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
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