RESUMO
BACKGROUND: Taxanes are the current first-line treatment for advanced cutaneous angiosarcoma (CAS) for patients who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. However, no effective second-line therapy for such patients has been established. METHODS: We designed a single-arm prospective observational study of eribulin mesylate (ERB) administered at a dose of 1·4 mg m-2 on days 1 and 8 in a 21-day cycle. Patients with advanced CAS who were previously treated with a taxane and were scheduled to begin ERB treatment were enrolled. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate (RR), progression-free survival (PFS) and toxicity assessment. RESULTS: We enrolled a total of 25 patients. The median OS and PFS were 8·6 months and 3·0 months, respectively. The best overall RR was 20% (five of 25). In total, 16 grade 3/4 severe adverse events (SAEs) occurred; however, all patients recovered. Patients who achieved partial response or stable disease as best response had longer OS than those with progressive disease (median OS not reached and 3·3 months, respectively; P < 0·001). Patients who did not experience SAEs showed longer OS than those who did (median OS 18·8 months and 7·5 months, respectively; P < 0·05). Patients with distant metastasis had shorter median OS than those with locoregional disease, but without statistically significant difference. CONCLUSIONS: ERB showed a promising RR and is a potential candidate for second-line treatment for patients with CAS, after treatment with taxanes. However, owing to the occurrence of SAEs in over half of the participants, caution should be exercised regarding ERB use in elderly patients. What is already known about this topic? Taxanes are the current first-line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. No effective therapy for taxane-resistant CAS has been established thus far. Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes. What does this study add? In our single-arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression-free survival were 8·6 and 3·0 months, respectively. Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively. Although 16 grade 3/4 severe adverse events occurred, all patients recovered. Eribulin showed a promising response rate and is a potential candidate for second-line treatment in CAS after taxane treatment. Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797-798.
Assuntos
Neoplasias da Mama , Hemangiossarcoma , Idoso , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes , Furanos , Hemangiossarcoma/tratamento farmacológico , Humanos , Cetonas , Taxoides , Resultado do TratamentoRESUMO
BACKGROUND: Interaction between cancer cells and fibroblasts mediated by extracellular matrix metalloproteinase inducer (emmprin, CD147) is important in the invasion and proliferation of cancer cells. However, the exact mechanism of emmprin mediated stimulation of matrix metalloprotease-2 (MMP-2) production from fibroblasts has not been elucidated. Our previous studies using an inhibitory peptide against emmprin suggested the presence of a molecule on the cell membrane which forms a complex with emmprin. Here we show that CD73 expressed on fibroblasts interacts with emmprin and is a required factor for MMP-2 production in co-cultures of sarcoma cells with fibroblasts. METHODS: CD73 along with CD99 was identified by mass spectrometry analysis as an emmprin interacting molecule from a co-culture of cancer cells (epithelioid sarcoma cell line FU-EPS-1) and fibroblasts (immortalized fibroblasts cell line ST353i). MMP-2 production was measured by immunoblot and ELISA. The formation of complexes of CD73 with emmprin was confirmed by immunoprecipitation, and their co-localization in tumor cells and fibroblasts was shown by fluorescent immunostaining and proximity ligation assays. RESULTS: Stimulated MMP-2 production in co-culture of cancer cells and fibroblasts was completely suppressed by siRNA knockdown of CD73, but not by CD99 knockdown. MMP-2 production was not suppressed by CD73-specific enzyme inhibitor (APCP). However, MMP-2 production was decreased by CD73 neutralizing antibodies, suggesting that CD73-mediated suppression of MMP-2 production is non-enzymatic. In human epithelioid sarcoma tissues, emmprin was immunohistochemically detected to be mainly expressed in tumor cells, and CD73 was expressed in fibroblasts and tumor cells: emmprin and CD73 were co-localized predominantly on tumor cells. CONCLUSION: This study provides a novel insight into the role of CD73 in emmprin-mediated regulation of MMP-2 production.
Assuntos
5'-Nucleotidase/metabolismo , Basigina/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Técnicas de Cocultura , Fibroblastos , Proteínas Ligadas por GPI/metabolismo , Humanos , Imuno-Histoquímica , Espectrometria de Massas , Modelos Biológicos , Proteômica/métodosAssuntos
Antineoplásicos Imunológicos/uso terapêutico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Povo Asiático , Análise Mutacional de DNA , Feminino , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Mutação , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologiaAssuntos
Hemangiossarcoma , Neoplasias Cutâneas , Adulto , Biomarcadores , Quimiocina CXCL10 , Furanos , Humanos , CetonasAssuntos
Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/sangue , Melanoma/tratamento farmacológico , Nivolumabe/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Estudos de Viabilidade , Humanos , Japão , Lactato Desidrogenases/sangue , Contagem de Linfócitos , Linfócitos , Melanoma/sangue , Melanoma/imunologia , Melanoma/patologia , Estadiamento de Neoplasias , Neutrófilos , Nivolumabe/uso terapêutico , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologiaAssuntos
Carcinoma de Célula de Merkel/diagnóstico por imagem , Carcinoma de Célula de Merkel/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Célula de Merkel/patologia , Proliferação de Células , Feminino , Fluordesoxiglucose F18 , Transportador de Glucose Tipo 1/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Masculino , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Carga TumoralRESUMO
Interferon (IFN)-alfa as an adjuvant therapy has been found to improve relapse-free survival in patients with malignant melanoma (MM). However, the efficacy of IFN-beta has not been studied in detail. This study evaluated the contribution of adjuvant IFN-beta therapy to improvements in the prognosis of patients with MM. We reviewed 63 patients with resected stage II/III primary MM at our institution. Of these, 36 had been treated with IFN-beta adjuvant therapy (subcutaneous injection, 3 × 106 IU/day, 10 days), while 27 patients had undergone observation alone. In comparisons of all patients (stage II/III), overall survival and relapse-free survival were significantly better in the IFN-beta group than in the observation group (P < 0.001 for both). The 75-month overall survival rate was 41.2% in the observation group and 68.7% in the IFN-beta group. Adjuvant therapy with IFN-beta may become a new treatment option for patients with stage II/III MM.
Assuntos
Antineoplásicos/uso terapêutico , Interferon beta/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Injeções Subcutâneas , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Melanoma/cirurgia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/cirurgia , Taxa de SobrevidaRESUMO
Phototherapy is a useful noninvasive therapy, but it can induce cutaneous malignant tumours, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). We report on a 79-year-old man who had long-standing mycosis fungoides for 40 years, which had been treated with psoralen ultraviolet A therapy for 37 years at a dose of approximately 5000 J/cm2 . Approximately 6 years before presentation, numerous types of cutaneous malignancies, including actinic keratosis, BCC and SCC, had begun to develop all over the patient's body. We hypothesized that he was experiencing a pathogenesis similar to patients with xeroderma pigmentosum (XP), and we therefore assessed his DNA repair capacity. Based on these investigations, the patient was eventually diagnosed as non-XP, even though we detected that his DNA repair capacity was slightly lower than that of normal controls, which may have led to the skin cancers. We speculate that multiple skin malignancies can be induced by long-term phototherapy in patients with slightly impaired DNA repair capacity.
Assuntos
Distúrbios no Reparo do DNA/diagnóstico , Micose Fungoide/radioterapia , Neoplasias Induzidas por Radiação , Neoplasias Cutâneas/patologia , Terapia Ultravioleta/efeitos adversos , Idoso , Carcinoma Basocelular/etiologia , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/etiologia , Distúrbios no Reparo do DNA/complicações , Humanos , Masculino , Melanoma/etiologia , Melanoma/patologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/radioterapiaRESUMO
We previously reported that PU.1 is downregulated in the majority of myeloma cell lines and primary myeloma cells of certain myeloma patients, and conditional expression of PU.1 in such myeloma cell lines induced cell cycle arrest and apoptosis. We found downregulation of IRF4 protein in the U266 myeloma cell line following induction of PU.1. Previous studies reported that knockdown of IRF4 in myeloma cell lines induces apoptosis, prompting us to further investigate the role of IRF4 downregulation in PU.1-induced cell cycle arrest and apoptosis in myeloma cells. PU.1 induced downregulation of IRF4 at the protein level, cell cycle arrest and apoptosis in six myeloma cell lines. Chromatin immunoprecipitation (ChIP) revealed that PU.1 directly binds to the IRF4 promoter, whereas a reporter assay showed that PU.1 may suppress IRF4 promoter activity. Stable expression of IRF4 in myeloma cells expressing PU.1 partially rescued the cells from apoptosis induced by PU.1. As it was reported that IRF4 directly binds to the IRF7 promoter and downregulates its expression in activated B cell-like subtype of diffuse large B cell lymphoma cells, we performed ChIP assays and found that IRF4 directly binds the IRF7 promoter in myeloma cells. It is known that IRF7 positively upregulates interferon-ß (IFNß) and induces apoptosis in many cell types. Binding of IRF4 to the IRF7 promoter decreased following PU.1 induction, accompanied by downregulation of IRF4 protein expression. Knockdown of IRF7 protected PU.1-expressing myeloma cells from apoptosis. Furthermore, IFNß, which is a downstream target of IRF7, was upregulated in myeloma cells along with IRF7 after PU.1 induction. Finally, we evaluated the mRNA expression levels of PU.1, IRF4 and IRF7 in primary myeloma cells from patients and found that PU.1 and IRF7 were strongly downregulated in contrast to the high expression levels of IRF4. These data strongly suggest that PU.1-induced apoptosis in myeloma cells is associated with IRF4 downregulation and subsequent IRF7 upregulation.
Assuntos
Fatores Reguladores de Interferon/fisiologia , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Apoptose , Humanos , Fator Regulador 7 de Interferon/genética , Fatores Reguladores de Interferon/genética , Interferon beta/biossíntese , Mieloma Múltiplo/patologia , Regiões Promotoras Genéticas , Transcrição Gênica , Células U937Assuntos
Carcinoma Basocelular/química , Carcinoma Basocelular/patologia , Inibidor de Quinase Dependente de Ciclina p27/análise , Quinases Ciclina-Dependentes/análise , Neoplasias Cutâneas/química , Neoplasias Cutâneas/patologia , Idoso , Proliferação de Células , Feminino , Humanos , Imuno-Histoquímica , Coloração e RotulagemRESUMO
BACKGROUND: Transplant coronary arterial vasculopathy (TCAV) is a major cause of death after heart transplantation (HTx). Palliative coronary revascularization has been attempted in patients with severe TCAV; however, the outcome has not been fully elucidated. METHODS: Ninety-six patients who were treated after HTx at our institute between 1999 and 2015 were screened for TCAV. TCAV was defined as >70% stenosis on coronary angiography (CAG) or a maximal intimal thickness of >0.5 mm in the right or left coronary arteries on intracoronary ultrasonography (IVUS). In the present study, the outcomes of patients with severe TCAV who underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were investigated. RESULTS: TCAV containing donor-transmitted atherosclerosis was cumulatively found in 69 patients (71.9% of the total; mean age, 34.6 ± 13.1 years; 52 men; mean follow-up duration, 83.0 ± 60.4 months). Five (7.2%) and 64 (92.8%) of the 69 patients were diagnosed as having TCAV by use of CAG and IVUS, respectively. All 5 patients diagnosed by with the use of CAG underwent coronary revascularization between 1 and 236 months after HTx. Three patients underwent PCI with drug-eluting stents, with a primary success rate of 100%. No angiographic restenosis occurred in 2 patients at 31 and 36 months after PCI, respectively. Meanwhile, 2 patients underwent CABG. No peri-operative complications occurred, and all grafts were patent as assessed by use of CAG at 34 and 5 months after CABG. CONCLUSIONS: Coronary revascularization was feasible and effective for severe TCAV with middle-term follow-up.