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1.
Nat Commun ; 11(1): 4909, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999291

RESUMO

Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.


Assuntos
Micropartículas Derivadas de Células/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Melanoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno CD47/metabolismo , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/secundário , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Camundongos , Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/imunologia , Nucleotídeos Cíclicos/administração & dosagem , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
2.
Medicine (Baltimore) ; 99(43): e22974, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120861

RESUMO

The current study aimed to elucidate the molecular mechanisms and identify the potential key genes and pathways for metastatic uveal melanoma (UM) using bioinformatics analysis.Gene expression microarray data from GSE39717 included 39 primary UM tissue samples and 2 metastatic UM tissue samples. Differentially expressed genes (DEGs) were generated using Gene Expression Omnibus 2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the online Database for Annotation, Visualization and Integrated Discovery (DAVID) tool. The web-based STRING tool was adopted to construct a protein--protein interaction (PPI) network. The MCODE tool in Cytoscape was used to generate significant modules of the PPI network.A total of 213 DEGs were identified. GO and KEGG analyses revealed that the upregulated genes were mainly enriched in extracellular matrix organization and blood coagulation cascades, while the downregulated DEGs were mainly related to protein binding, negative regulation of ERK cascade, nucleus and chromatin modification, and lung and renal cell carcinoma. The most significant module was extracted from the PPI network. GO and KEGG enrichment analyses of the module revealed that the genes were mainly enriched in the extracellular region and space organization, blood coagulation process, and PI3K-Akt signaling pathway. Hub genes, including FN1, APOB, F2, SERPINC1, SERPINA1, APOA1, FGG, PROC, ITIH2, VCAN, TFPI, CXCL8, CDH2, and HP, were identified from DEGs. Survival analysis and hierarchical clustering results revealed that most of the hub genes were associated with prognosis and clinical progression.Results of this bioinformatics analysis may provide predictive biomarkers and potential candidate therapeutic targets for individuals with metastatic UM.


Assuntos
Biologia Computacional/métodos , Melanoma/genética , Melanoma/secundário , Neoplasias Uveais/patologia , Biomarcadores Tumorais/metabolismo , Análise por Conglomerados , Progressão da Doença , Regulação para Baixo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Humanos , Programas de Rastreamento/métodos , Análise em Microsséries/métodos , Prognóstico , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética , Regulação para Cima , Neoplasias Uveais/genética , Neoplasias Uveais/secundário
3.
Clin Nucl Med ; 45(10): 817-818, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32796240

RESUMO

A 47-year-old woman with a history of surgically treated abdominal paraganglioma and left thigh melanoma underwent an F-FDOPA PET/CT for suspected locoregional recurrence of paraganglioma. F-FDOPA PET/CT disconfirmed this recurrence but revealed 2 FDOPA-avid left inguinal lymph nodes, confirmed on a subsequent F-FDG PET/CT. Excision and pathology characterized these lymph nodes as melanoma metastases. F-FDOPA PET/CT is a widely used and valuable tool in the assessment of paraganglioma, both for staging and recurrence detection. Uptake of FDOPA has only rarely been documented in metastatic melanoma that could be a pitfall for detecting neuroendocrine tumors.


Assuntos
Di-Hidroxifenilalanina/análogos & derivados , Achados Incidentais , Melanoma/diagnóstico por imagem , Melanoma/secundário , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paraganglioma/patologia , Recidiva
4.
Nat Commun ; 11(1): 4306, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855398

RESUMO

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.


Assuntos
Evolução Clonal , Heterogeneidade Genética , Melanoma/genética , Neoplasias Cutâneas/genética , Idoso , Biópsia , Análise Mutacional de DNA , Humanos , Masculino , Melanoma/secundário , Estudos Prospectivos , Pele/patologia , Neoplasias Cutâneas/patologia , Sequenciamento Completo do Genoma
6.
Eur J Cancer ; 135: 147-149, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32585589
7.
Medicine (Baltimore) ; 99(21): e19936, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481257

RESUMO

Rapid growth of cutaneous melanoma is associated with aggressive histopathologic features and poor prognosis. However, the impact of growth rate (GR) in acral melanoma (AM) remains largely unknown.We performed this study to identify the impact of GR on lymph node metastasis and survival in AM.We analyzed cases of invasive AM diagnosed at our institution between 1998 and 2017. We investigated the impact of GR on the prognosis of AM.A total of 126 cases of invasive AM were included. Log (GR) was significant associated with lymph node metastasis in the univariate logistic regression analysis (P = .005). The log-rank test revealed statistically significant differences in disease-free survival (DFS) and disease-specific survival (DSS) among the GR quartiles. In the Cox regression analysis, log (GR) was an independent predictor for DFS (P = .041), but not for DSS in multivariate analysis. In the subgroup analysis, log (GR) was an independent predictor for early-stage (≤2A) AM (DFS, P = .002; DSS, P = .004).The limitations of this study include the retrospective design of the study and possible recall bias.Our results suggest that GR is an important prognostic factor for DFS and DSS in AM patients and an independent predictor for early-stage AM.


Assuntos
Doenças do Pé/mortalidade , Doenças do Pé/patologia , Mãos , Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Prognóstico , República da Coreia , Estudos Retrospectivos , Taxa de Sobrevida
8.
J Cancer Res Clin Oncol ; 146(11): 3003-3012, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32564137

RESUMO

BACKGROUND: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a novel interventional procedure, which delivers high doses of melphalan directly to the liver in patients with liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. We have previously shown promising efficacy for patients with ocular melanoma (OM) and cholangiocarcinoma (CCA) within our single-center and multi-center experiences. The aim of this study was to analyze the safety and efficacy of CS-PHP after 141 treatments at Hannover Medical School, Germany. METHODS: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median Overall survival (mOS), median progression-free survival (mPFS), and median hepatic PFS (mhPFS) were analyzed using the Kaplan-Meier estimation. RESULTS: Overall, 60 patients were treated with CS-PHP in the salvage setting from October 2014 until January 2019 at Hannover Medical School with a total of 141 procedures. Half of the patients were patients with hepatic metastases of ocular melanoma (OM) (n = 30), 14 patients had CCA (23.3%), 6 patients had hepatocellular carcinoma (10%), and 10 patients were treated for other secondary liver malignancies (16.7%). In total, ORR and disease stabilization rate were 33.3% and 70.3% (n = 25), respectively. ORR was highest for patients with OM (42.3%), followed by patients with CCA (30.8%). Independent response-associated factors were normal levels of lactate dehydrogenase (odds ratio (OR) 13.7; p = 0.015) and diagnosis with OM (OR 9.3; p = 0.028). Overall, mOS was 9 months, mPFS was 4 months, and mhPFS was 5 months. Patients with OM had the longest mOS, mPFS, and mhPFS with 12, 6, and 6 months, respectively. Adverse events included most frequently significant, but transient, hematologic toxicities (80% of grade 3/4 thrombopenia), less frequently hepatic injury up to liver failure (3.3%) and cardiovascular events including two cases of ischemic insults (5%). CONCLUSION: Salvage treatment with CS-PHP is safe and effective particularly in patients OM and CCA. Careful attention should be paid to possible, serious hepatic, and cardiovascular complications.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Quimioterapia do Câncer por Perfusão Regional , Colangiocarcinoma/tratamento farmacológico , Melanoma/tratamento farmacológico , Melfalan/administração & dosagem , Neoplasias Uveais/tratamento farmacológico , Idoso , Neoplasias dos Ductos Biliares/patologia , Quimioterapia do Câncer por Perfusão Regional/instrumentação , Quimioterapia do Câncer por Perfusão Regional/métodos , Colangiocarcinoma/patologia , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Terapia de Salvação/instrumentação , Terapia de Salvação/métodos , Neoplasias Uveais/secundário
9.
World Neurosurg ; 140: 320-324, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32428722

RESUMO

BACKGROUND: Metastatic malignant melanoma of the spine is rare, while the spinal metastatic melanoma with unknown primary lesions presenting as radiculopathy is even rarer. Summarizing and analyzing this disease can provide insight into disease development and allow optimization of clinical management. CASE DESCRIPTION: A 55-year-old male patient was admitted to our institution presenting with lower back pain that had persisted for 3 years. It was aggravated, with radiating pain in bilateral lower extremities lasting 2 weeks. Neurologic examination revealed bilateral L5 motor deficit with paresis. Radiologic findings showed an irregularly destructive lesion of the L5 vertebral body, and the lesion extended dorsally, obstructing the spinal canal. The patient underwent complete resection of the L5 vertebral tumor with titanium mesh implantation and posterior fusion and instrumentation from L3-S2. The pathologic diagnosis after surgery was malignant melanoma. No obvious primary lesion was detected anywhere on the skin surface, mucosa, and retina. A postoperative positron emission tomography-computed tomography scan of the whole body displayed no abnormal uptake in other parts of the body. However, the patient didn't receive any chemotherapy or radiotherapy. Five months after operation, the tumor recurred and metastasis was detected in other sites. CONCLUSIONS: Although spinal metastatic melanoma with unknown primary lesions presenting as radiculopathy is rare, effective management and treatment of these patients remains an important challenge for surgeons. Surgical resection can alleviate patients' chief complaints and improve their quality of life. However, it may not prolong the survival period and improve the prognosis. Postoperative radiotherapy and/or chemotherapy may be needed.


Assuntos
Melanoma/complicações , Radiculopatia/etiologia , Neoplasias da Coluna Vertebral/complicações , Humanos , Masculino , Melanoma/diagnóstico por imagem , Melanoma/secundário , Melanoma/cirurgia , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Radiculopatia/diagnóstico por imagem , Radiculopatia/cirurgia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/cirurgia , Resultado do Tratamento
10.
J Surg Oncol ; 122(3): 555-561, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32441371

RESUMO

BACKGROUND AND OBJECTIVES: Metastasectomy for melanoma provides durable disease control in carefully selected patients. Similarly, BRAF-targeted and immune checkpoint inhibition has improved median overall survival (OS) in metastatic patients. We hypothesized that there is an increasing role for metastasectomy in melanoma patients responding to these therapies. METHODS: Retrospective analysis of a prospectively maintained database identified 128 patients with stage IV melanoma who received targeted molecular and/or checkpoint inhibitors at an academic institution from 2006 to 2017. Records were reviewed to characterize clinicopathologic characteristics, response to treatment, and intent of surgery for those who underwent metastasectomy. OS was analyzed by the Kaplan-Meier method. RESULTS: Median OS from stage IV diagnosis was 31.3 months. A total of 81 patients received checkpoint inhibitors, 11 received targeted inhibitors, and 36 received both. A total of 73 patients underwent metastasectomy. Indications for surgery included the intent to render disease-free (54%), palliation (34%), and diagnostic confirmation (11%). Responders to systemic therapy who underwent metastasectomy had improved OS compared to responders who did not (84.3 vs. 42.9 months, P = .018). CONCLUSIONS: Metastasectomy for melanoma is associated with improved OS in patients that respond to targeted molecular or immunotherapy. Resection should be strongly considered in this cohort as multimodality treatment results in excellent OS.


Assuntos
Melanoma/secundário , Melanoma/terapia , Feminino , Humanos , Imunoterapia/métodos , Masculino , Melanoma/mortalidade , Melanoma/cirurgia , Metastasectomia , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Estudos Retrospectivos
11.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188380, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32461135

RESUMO

Cellular communication through gap junctions and hemichannels formed by connexins and through channels made by pannexins allows for metabolic cooperation and control of cellular activity and signalling. These channel proteins have been described to be tumour suppressors that regulate features such as cell death, proliferation and differentiation. However, they display cancer type-dependent and stage-dependent functions and may facilitate tumour progression through junctional and non-junctional pathways. The accumulated knowledge and emerging strategies to target connexins and pannexins are providing novel clinical opportunities for the treatment of cancer. Here, we provide an updated overview of the role of connexins and pannexins in malignant melanoma. We discuss how targeting of these channel proteins may be used to potentiate antitumour effects in therapeutic settings, including through improved immune-mediated tumour elimination.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Conexinas/metabolismo , Melanoma/secundário , Neoplasias Cutâneas/patologia , Pele/patologia , Animais , Antineoplásicos Imunológicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Carcinogênese/patologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Conexinas/agonistas , Conexinas/antagonistas & inibidores , Modelos Animais de Doenças , Progressão da Doença , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/patologia , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/mortalidade , Microbiota/imunologia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Estadiamento de Neoplasias , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Pele/citologia , Pele/microbiologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
Cardiovasc Pathol ; 47: 107211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32268262

RESUMO

Immune checkpoint inhibitor (ICI)-induced myocarditis carries a poor prognosis and is not fully understood. Similar to lymphocytic myocarditis and acute cellular rejection in heart transplant, ICI-induced myocarditis requires immune suppressive strategies. We aimed to describe ICI-induced myocarditis by presenting findings of comprehensive cardiovascular evaluations and outcomes of patients following a therapeutic approach similar to autoimmune disorders or allograft transplant rejection, and to discuss the molecular basis of the benefits of immune modulation and statins in ICI-myocarditis. Three patients with ICI-induced myocarditis (2 with positive biopsies and 1 based on cardiac magnetic resonance imaging with negative biopsy) underwent a complete cardiovascular workup, including cardiac catheterization with endomyocardial biopsy. Treatment was with intravenous immunoglobulins (IVIG) and statins in all cases, with additional colchicine (2 cases) or hydroxychloroquine (1 case). Immunohistochemical analysis demonstrated varied subsets of T cells involved in the inflammatory response. Therapy with IVIG and statins led to symptom resolution and cardiac function normalization at 1-month follow-up in all patients. Cancer therapy was resumed in all patients. One patient expired 10 months after the myocarditis episode due to advanced malignancy; two patients were alive, free of heart failure symptoms and cancer progression, at 1-year follow-up, and 1 patient was rechallenged with ICI. We suggest that treatment with IVIG and statins may allow for a prompt resumption of anti-cancer therapy (including ICI) and improve outcomes.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Miocardite/tratamento farmacológico , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Cardiotoxicidade , Colchicina/uso terapêutico , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Melanoma/imunologia , Melanoma/secundário , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Miocardite/induzido quimicamente , Miocardite/imunologia , Miocardite/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do Tratamento
14.
Cancer Immunol Immunother ; 69(8): 1423-1436, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32246174

RESUMO

On-treatment steroids for countering immune checkpoint inhibitor-induced inflammatory responses (irAEs) are a hallmark of cancer immunotherapy. However, the suppressive nature of steroids has raised questions regarding their ability to compromise the function of the 'proliferative burst' of effector T cells induced by immune checkpoint antibodies. We investigated the effector functions and the co-inhibitory receptor profile of stimulated peripheral blood mononuclear cells (PBMCs) pre-treated with prednisone and dexamethasone alone or in the presence of anti-PD-1/CTLA-4 antibodies. Also, clinical analysis of a patient who exhibited irAEs following combination (anti-PD-1/CTLA-4) in the presence of glucocorticoids was done. We found that prednisone in contrast to dexamethasone did not compromise T cell cytokine production (IL-2, IFN-γ and TNF-α) and proliferation in the absence or presence of anti-PD-1/CTLA-4 antibodies, when a physiological concentration was used. Neither single prednisone treatment nor co-treatment with checkpoint inhibitors impacted the expression of co-inhibitory receptors PD-1, CTLA-4, TIM-3 and LAG-3. In contrast, dexamethasone treatment promoted downregulation of LAG-3 expression by T cells. In addition, co-treatment of PD-1 + Jurkat cells with prednisone and/or dexamethasone with anti-PD-1 before stimulation significantly reduced SHP-2 phosphorylation, indicative of increased T cell function. Our findings hereby demonstrate a differential steroid effect on T cell function, which should be taken into consideration for patients undergoing immunotherapy. Also, the clinical analysis of a patient who exhibited irAEs following combination (anti-PD-1/CTLA-4) therapy indicated complete metabolic response in the presence of glucocorticoids. Therefore, concomitant use of prednisone does not appear to interfere with the function of immune checkpoint blockade.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Leucócitos Mononucleares/imunologia , Melanoma/imunologia , Prednisona/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Anticorpos Monoclonais/farmacologia , Dexametasona/administração & dosagem , Humanos , Imunoterapia , Células Jurkat , Leucócitos Mononucleares/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/secundário , Prognóstico , Linfócitos T/efeitos dos fármacos
15.
World Neurosurg ; 139: 226-231, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32330622

RESUMO

BACKGROUND: The use of targeted therapies and immune checkpoint inhibitors has drastically changed the management of patients with melanoma and brain metastases. Specifically, combination therapy with ipilimumab, a cytotoxic T-lymphocyte antigen 4 inhibitor, and nivolumab, a programmed cell death protein 1 inhibitor, has become a preferred systemic therapy option for patients with melanoma and asymptomatic brain metastases. However, the efficacy and toxicity profile of these agents in combination with brain-directed radiation therapy is not well described. CASE DESCRIPTION: In this case series, we highlight a series of patients with melanoma demonstrating severe radiation necrosis immediately refractory to surgical resection following brain-directed stereotactic radiation therapy with concurrent ipilimumab and nivolumab. Three patients described in this series each received stereotactic radiation therapy to a dose of 30 Gy in 5 fractions to a melanoma brain metastasis. These areas developed radiographic evidence of necrosis, which was managed surgically and progressed immediately and rapidly after resection. Re-resection, bevacizumab, steroids, and/or discontinuation of nivolumab was used to mitigate further necrosis with varying efficacy. CONCLUSIONS: Patients with metastatic melanoma receiving brain-directed radiation therapy with concurrent ipilimumab and nivolumab are at risk for developing severe, surgically refractory radiation necrosis and should be closely followed clinically and with imaging. The exact mechanism for such severe necrosis is unknown, and future studies are needed to better understand this pathophysiology and identify optimal treatment strategies.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Encefálicas/terapia , Terapia Combinada/efeitos adversos , Melanoma/secundário , Lesões por Radiação/etiologia , Radiocirurgia/efeitos adversos , Adulto , Neoplasias Encefálicas/secundário , Terapia Combinada/métodos , Feminino , Humanos , Ipilimumab/efeitos adversos , Masculino , Melanoma/terapia , Pessoa de Meia-Idade , Necrose , Nivolumabe/efeitos adversos
16.
World Neurosurg ; 139: 378-381, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32348887

RESUMO

BACKGROUND: Pituitary melanoma metastases (PMMs) are extremely rare and only a few cases are reported in the literature. PMMs can grow rapidly and present local invasiveness, leading to acute onset of neurological symptoms such as headache, visual and oculomotion disorders or endocrinological signs such as diabetes insipidus and hypopituitarism, and can be life-threatening. For this reason, PMMs must be recognized and treated promptly. CASE DESCRIPTION: The authors present 2 cases of PMMs managed at their institution, performing a review of the dedicated literature and analyzing current therapeutic strategies.


Assuntos
Melanoma/secundário , Neoplasias Hipofisárias/secundário , Neoplasias Cutâneas/secundário , Adulto , Humanos , Masculino , Melanoma/cirurgia , Procedimentos Neurocirúrgicos/métodos , Neoplasias Hipofisárias/cirurgia , Neoplasias Cutâneas/cirurgia
17.
Am J Ophthalmol ; 216: 156-164, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32278769

RESUMO

PURPOSE: To evaluate the consistency of hepatic ultrasonography (US) with staging computed tomography (CT) and magnetic resonance imaging (MRI), to analyze why US was inconsistent with CT/MRI, and to compare CT/MRI. DESIGN: Reliability analysis. METHODS: Two hundred fifteen patients whose primary uveal melanoma was managed in the Helsinki University Hospital and who were diagnosed with hepatic metastases by US within 60 days of staging CT/MRI from January 1999 to December 2016 were included. Patients attended a real-life follow-up schedule including hepatic US, liver function tests (LFT), and a confirmatory CT/MRI. We evaluated the consistency of US with staging CT/MRI regarding the presence and number of metastases. RESULTS: The enrolled patients underwent 215 US, 167 CT, and 69 MRI examinations, and 67% of them had biopsy-confirmed metastases. Screening was regular for 98% of the patients, and 66% were asymptomatic. US was fully consistent with CT/MRI in detecting metastases in 113 (53%) patients, in 63 (29%) CT/MRI showed more metastases, and in 16 (7%) CT/MRI showed fewer metastases than US. CT/MRI was inconsistent with US in 23 (11%) patients. The sensitivity of US in detecting metastases was 96% (95% confidence interval, 92-98). US failed to suggest metastases in 10 patients. LFT were abnormal in 6 of them, and a newly detected hepatic lesion was present by US in 4. CONCLUSIONS: Hepatic US is a sensitive screening modality in detecting metastases in patients with primary uveal melanoma, if combined with LFT and, in case of any newly detected lesion, a confirmatory MRI.


Assuntos
Neoplasias Hepáticas/diagnóstico por imagem , Imagem por Ressonância Magnética , Melanoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Ultrassonografia , Neoplasias Uveais/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Adulto Jovem
18.
J Plast Reconstr Aesthet Surg ; 73(7): 1263-1267, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32245735

RESUMO

BACKGROUND: In-transit metastases (ITMs) in melanoma are associated with poor prognosis, however a significant proportion of these patients survive for extended periods without further disease progression. We routinely use locoregional treatment e.g. Diphencyprone (DPCP) and/or isolated limb infusion (ILI) as long-term palliation. This study aimed to identify correct sequencing of these therapies based on disease burden and progression. METHOD: Retrospective evaluation of all melanoma patients with ITMs treated with DPCP/ILI/both from 2010 to 2017 at our Cancer Centre was performed. Patients were initially assessed in a multidisciplinary setting and empirically prescribed DPCP for low-disease burden, ILI for high-disease burden. Patient demographics, tumour characteristics, response to therapy, ITM progression and patient outcomes were analysed. RESULTS: 78 patients (M:F = 30:48), aged 47-95years (median 74years) treated with DPCP/ILI/both (n = 44/21/13) were identified. Progression-free survival (PFS) was significantly increased in patients responsive to DPCP or ILI as initial treatment. Patients who failed on DPCP and subsequently treated with ILI had a significantly increased PFS compared to DPCP alone (p = 0.026, HR = 0.048). This was not the case with patients who were treated with DPCP following failed ILI. All patients who failed to respond to the initial therapy progressed within 6 months. CONCLUSION: Our study shows that careful stratification ITM patients according to disease burden is fundamental to optimal outcomes. High-disease burden patients benefit from initial ILI; low-disease burden patients should commence on DPCP. ILI can be considered in DPCP patients who fail early. Systemic therapy should be considered when locoregional therapies fail after 12 months or after rapid relapse following ILI.


Assuntos
Quimioterapia do Câncer por Perfusão Regional , Ciclopropanos/administração & dosagem , Melanoma/tratamento farmacológico , Melanoma/secundário , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Idoso , Idoso de 80 Anos ou mais , Efeitos Psicossociais da Doença , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
Eur J Cancer ; 131: 18-26, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32248071

RESUMO

BACKGROUND: Anti-[programmed cell death protein 1 (PD-1)] antibodies nivolumab and pembrolizumab were approved for adjuvant treatment of melanoma as they demonstrated improved relapse-free survival. Currently, combined anti-PD-1 plus anti-[cytotoxic T-lymphocyte-associated protein 4 (CTLA4)] blockade is being investigated in adjuvant and neoadjuvant trials. Sarcoidosis-like reactions have been described for immune checkpoint inhibitors and are most likely drug-induced. The reported rate of sarcoidosis/sarcoidosis-like reactions within clinical melanoma trials is <2%. We observed that a remarkably higher number of melanoma patients (10/45 patients, 22%) treated with immune checkpoint inhibitor (ICI) within an adjuvant clinical trial-developed drug induced sarcoidosis-like reaction (DISR) mimicking metastasis. CASE PRESENTATION: Of 45 stage III melanoma patients who were treated at our institute with adjuvant ICI (either nivolumab alone or in combination with ipilimumab) within a two-armed, blinded clinical trial, ten developed a DISR. Three of the ten patients were men, median age was 52 years (range, 32-70 years). DISRs were asymptomatic and generally detected radiographically at first radiographic imaging after the start of therapy (median time, 2.8 months) and described as a differential diagnosis to tumour progression. In one patient, DISR was only apparent 13.1 months after start of therapy and 4 weeks after the end of ICI treatment. DISR presented as mediastinal/hilar lymphadenopathy in 8/10 patients (as only site or in addition to lung, skin and/or bone involvement), one patient had only lung and cutaneous, one patient only cutaneous DISR. Biopsies from lymph nodes, skin and bone were taken in 8/10 patients, and histology confirmed sarcoidosis-like reactions (SLRs). As patients were asymptomatic, no treatment for DISR was required, and study treatment was stopped for DISR in only one patient due to bone involvement. DISRs have resolved or are in remission in all patients. At a median follow-up time of 15.3 months (range, 12-17.6 months), two patients experienced melanoma relapse. CONCLUSIONS: In most cases, sarcoidosis could only be differentiated from melanoma progression on biopsy. Treating physicians as well as radiologists have to be aware of the potentially higher rate of DISR in patients receiving adjuvant ICI. A thorough interdisciplinary workup is required to discriminate from true melanoma progression and to decide on continuation of adjuvant ICI treatment.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Pulmonares/diagnóstico , Melanoma/diagnóstico , Sarcoidose/diagnóstico , Neoplasias Cutâneas/terapia , Adulto , Idoso , Biópsia , Quimioterapia Adjuvante/efeitos adversos , Diagnóstico Diferencial , Progressão da Doença , Feminino , Seguimentos , Humanos , Ipilimumab/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Imagem por Ressonância Magnética , Masculino , Melanoma/imunologia , Melanoma/secundário , Melanoma/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/imunologia , Nivolumabe/efeitos adversos , Sarcoidose/induzido quimicamente , Sarcoidose/epidemiologia , Sarcoidose/imunologia , Pele/diagnóstico por imagem , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Tomografia Computadorizada por Raios X
20.
Cancer Res ; 80(12): 2586-2598, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32303578

RESUMO

The angiopoietin (Angpt)-TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1-TIE2 signaling to destabilize the microvasculature during pathologic disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing ISH-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of patients with melanoma. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell-expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced reactive oxygen species (ROS) production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell-expressed ANGPT2 as an autocrine-positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of patients with melanoma. SIGNIFICANCE: This study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.


Assuntos
Angiopoietina-2/metabolismo , Melanoma/secundário , Nevo/patologia , Neoplasias Cutâneas/patologia , Angiopoietina-2/genética , Animais , Comunicação Autócrina , Biópsia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases , Melanoma/mortalidade , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Pele/patologia , Neoplasias Cutâneas/mortalidade , Análise Serial de Tecidos , Microambiente Tumoral
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