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1.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810045

RESUMEN

Melanoma is a highly metastatic disease with an increasing rate of incidence worldwide. It is treatment refractory and has poor clinical prognosis; therefore, the development of new therapeutic agents for metastatic melanoma are urgently required. In this study, we created a lung-seeking A375LM5IF4g/Luc BRAFV600E mutant melanoma cell clone and investigated the bioefficacy of a plant sesquiterpene lactone deoxyelephantopin (DET) and its novel semi-synthetic derivative, DETD-35, in suppressing metastatic A375LM5IF4g/Luc melanoma growth in vitro and in a xenograft mouse model. DET and DETD-35 treatment inhibited A375LM5IF4g/Luc cell proliferation, and induced G2/M cell-cycle arrest and apoptosis. Furthermore, A375LM5IF4g/Luc exhibited clonogenic, metastatic and invasive abilities, and several A375LM5IF4g/Luc metastasis markers, N-cadherin, MMP2, vimentin and integrin α4 were significantly suppressed by treatment with either compound. Interestingly, DET- and DETD-35-induced Reactive Oxygen Species (ROS) generation and glutathione (GSH) depletion were found to be upstream events important for the in vitro activities, because exogenous GSH supplementation blunted DET and DETD-35 effects on A375LM5IF4g/Luc cells. DET and DETD-35 also induced mitochondrial DNA mutation, superoxide production, mitochondrial bioenergetics dysfunction, and mitochondrial protein deregulation. Most importantly, DET and DETD-35 inhibited lung metastasis of A375LM5IF4g/Luc in NOD/SCID mice through inhibiting pulmonary vascular permeability and melanoma cell (Mel-A+) proliferation, angiogenesis (VEGF+, CD31+) and EMT (N-cadherin) in the tumor microenvironment in the lungs. These findings indicate that DET and DETD-35 may be useful in the intervention of lung metastatic BRAFV600E mutant melanoma.


Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Asteraceae/química , Lactonas/aislamiento & purificación , Lactonas/farmacología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Animales , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Apoptosis/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Lactonas/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Melanoma/patología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Proteínas Proto-Oncogénicas B-raf/genética , Especies Reactivas de Oxígeno/metabolismo , Sesquiterpenos/química , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Nat Commun ; 12(1): 1999, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33790276

RESUMEN

Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. Herein, we investigate whether localized delivery of the TLR agonist, resiquimod (R848), via platelet membrane-coated nanoparticles (PNP-R848) elicits antitumor responses. The membrane coating provides a means of enhancing interactions with the tumor microenvironment, thereby maximizing the activity of R848. Intratumoral administration of PNP-R848 strongly enhances local immune activation and leads to complete tumor regression in a colorectal tumor model, while providing protection against repeated tumor re-challenges. Moreover, treatment of an aggressive breast cancer model with intratumoral PNP-R848 delays tumor growth and inhibits lung metastasis. Our findings highlight the promise of locally delivering immunostimulatory payloads using biomimetic nanocarriers, which possess advantages such as enhanced biocompatibility and natural targeting affinities.


Asunto(s)
Imidazoles/uso terapéutico , Inmunoterapia/métodos , Nanopartículas/uso terapéutico , Neoplasias/terapia , Microambiente Tumoral/efectos de los fármacos , Animales , Plaquetas/química , Plaquetas/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Membrana Celular/química , Membrana Celular/metabolismo , Células Cultivadas , Femenino , Células HT29 , Humanos , Imidazoles/química , Imidazoles/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Ratones Endogámicos C57BL , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/patología , Resultado del Tratamiento , Microambiente Tumoral/inmunología
3.
Anticancer Res ; 41(4): 1997-2005, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813406

RESUMEN

BACKGROUND/AIM: We aimed to evaluate the clinical outcomes of oligometastatic colorectal cancer in the liver and lung treated with carbon-ion radiotherapy (C-ion RT). PATIENTS AND METHODS: Nineteen consecutive patients with oligometastatic colorectal cancer in the liver or lung who received C-ion RT were analyzed. The doses of C-ion RT were 60.0 Gy [relative biological effectiveness (RBE)] in 4 fractions, 60.0 Gy (RBE) in 12 fractions, or 64.8 Gy (BRE) in 12 fractions. RESULTS: The median follow-up duration was 19 months. There were 23 tumors in 19 patients. The 2-year overall survival and local control rates for the whole patient cohort were 100% and 67%, respectively. None of the patients developed grade 2 or higher acute or late toxicities. CONCLUSION: C-ion RT for oligometastatic colorectal cancer in liver and lung provides favorable clinical outcomes. These outcomes suggest C-ion RT is a treatment option for oligometastatic colorectal cancer in liver and lung.


Asunto(s)
Adenocarcinoma/radioterapia , Neoplasias Colorrectales/radioterapia , Radioterapia de Iones Pesados , Neoplasias Hepáticas/radioterapia , Neoplasias Pulmonares/radioterapia , Adenocarcinoma/patología , Adenocarcinoma/terapia , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Terapia Combinada/métodos , Femenino , Radioterapia de Iones Pesados/efectos adversos , Radioterapia de Iones Pesados/métodos , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Radioterapia Ayuvante/efectos adversos , Radioterapia Ayuvante/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Carga Tumoral/efectos de la radiación
4.
Cancer Radiother ; 25(2): 119-125, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33676829

RESUMEN

PURPOSE: To evaluate the safety and efficacy of Cyberknife® (CK) for the treatment of primary or recurring thymic tumours. MATERIALS AND METHODS: We retrospectively reviewed 12 patients (16 tumour lesions) with primary or recurring thymic tumours who were treated with CK between March 2008 and October 2017. Their data was stored in prospectively collected database. Kaplan-Meier method was used to calculate survival curves. RESULTS: Five patients (41.7%), who had inoperable disease or refused surgery, were treated with CK initially, and 7 patients (58.3%) were treated with CK when they had recurrence diseases. The disease sites treated with CK were primary tumour site (5), regional lymph nodes (4), tumour bed (3), chest wall (2), pleura (1), and bone (1). The median target volume was 43.8 cm3 (range, 13.1-302.5cm3) for the 16 tumour lesions. The median follow-up time was 69.3 months (range, 9.7-124.8 months). The median survival time was 48.2 months, and the 5-year and 10-year OS rates were 68.2% and 45.5%, respectively. A high response rate for the tumour lesions irradiated with CK was obtained. Only one patient (8%) experienced in-field recurrence, and the 5-year local recurrence free survival was 90.9%. A case indicated that CK may induce the abscopal effect, which provides the potential to combine CK and immunotherapy. No severe radiation related toxicities were observed, and no treatment related death occurred. CONCLUSION: CK treatment resulted in good outcomes, particularly local control, with minimal side effects, in highly selected patients with primary and recurring thymic tumours. More studies with larger sample are needed.


Asunto(s)
Recurrencia Local de Neoplasia/radioterapia , Radiocirugia/métodos , Radioterapia Guiada por Imagen/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Timoma/radioterapia , Neoplasias del Timo/radioterapia , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundario , Irradiación Linfática , Masculino , Neoplasias del Mediastino/radioterapia , Neoplasias del Mediastino/secundario , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Radiocirugia/efectos adversos , Radioterapia Guiada por Imagen/efectos adversos , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Seguridad , Tasa de Supervivencia , Timoma/mortalidad , Timoma/patología , Timoma/secundario , Neoplasias del Timo/mortalidad , Neoplasias del Timo/patología , Factores de Tiempo
5.
Anticancer Res ; 41(3): 1683-1691, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788766

RESUMEN

BACKGROUND/AIM: Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib. PATIENTS AND METHODS: Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions. RESULTS: Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (<42 mm) group. This result was more significant in patients with fast-growing tumours. BTS was an independent prognostic factor for both PFS and OS. CONCLUSION: Starting lenvatinib at BTS <42 mm should be recommended to achieve good treatment outcomes in patients with RR-DTC.


Asunto(s)
Radioisótopos de Yodo/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología
6.
Nat Commun ; 12(1): 1394, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33654093

RESUMEN

N6-methyladenosine (m6A) is a reversible mRNA modification that has been shown to play important roles in various biological processes. However, the roles of m6A modification in macrophages are still unknown. Here, we discover that ablation of Mettl3 in myeloid cells promotes tumour growth and metastasis in vivo. In contrast to wild-type mice, Mettl3-deficient mice show increased M1/M2-like tumour-associated macrophage and regulatory T cell infiltration into tumours. m6A sequencing reveals that loss of METTL3 impairs the YTHDF1-mediated translation of SPRED2, which enhances the activation of NF-kB and STAT3 through the ERK pathway, leading to increased tumour growth and metastasis. Furthermore, the therapeutic efficacy of PD-1 checkpoint blockade is attenuated in Mettl3-deficient mice, identifying METTL3 as a potential therapeutic target for tumour immunotherapy.


Asunto(s)
Adenosina/análogos & derivados , Reprogramación Celular , Macrófagos/metabolismo , Macrófagos/patología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , ARN Neoplásico/metabolismo , Adenosina/metabolismo , Animales , Secuencia de Bases , Línea Celular Tumoral , Polaridad Celular , Proliferación Celular , Citocinas/metabolismo , Eliminación de Gen , Regulación de la Expresión Génica , Neoplasias Pulmonares/secundario , Metilación , Metiltransferasas/metabolismo , Ratones Noqueados , Células Mieloides/metabolismo , FN-kappa B/metabolismo , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas Represoras , Factor de Transcripción STAT3/metabolismo , Linfocitos T Reguladores/inmunología , Microambiente Tumoral
7.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670758

RESUMEN

The incidence of cancers in atopic dermatitis (AD) is not increased, although the Th2-dominant environment is known to downregulate tumor immunity. To gain mechanistic insights regarding tumor immunity in AD, we utilized CCL17 transgenic (TG) mice overexpressing CCL17, which is a key chemokine in AD. Tumor formation and lung metastasis were accelerated in CCL17 TG mice when melanoma cells were injected subcutaneously or intravenously. Flow cytometric analysis showed increases in regulatory T cells (Tregs) in lymph nodes in CCL17 TG mice with high mRNA levels of IL-10 and Foxp3 in tumors, suggesting that Tregs attenuated tumor immunity. The frequency of myeloid-derived suppressor cells (MDSCs), however, was significantly decreased in tumors of CCL17 TG mice, suggesting that decreased MDSCs might promote tumor immunity. Expression of CXCL17, a chemoattractant of MDSCs, was decreased in tumors of CCL17 TG mice. Depletion of Tregs by the anti-CD25 antibody markedly reduced tumor volumes in CCL17 TG mice, suggesting that tumor immunity was accelerated by the decrease in MDSCs in the absence of Tregs. Thus, CCL17 attenuates tumor immunity by increasing Tregs and Th2 cells, while it decreases MDSCs through reductions in CXCL17, which may work as a "safety-net" to reduce the risk of malignant tumors in the Th2-dominant environment.


Asunto(s)
Quimiocina CCL17/metabolismo , Dermatitis Atópica/inmunología , Células Supresoras de Origen Mieloide/inmunología , Neoplasias/epidemiología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Factores Quimiotácticos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Humanos , Inmunidad , Incidencia , Neoplasias Pulmonares/secundario , Ratones Transgénicos , Modelos Biológicos , Neoplasias Cutáneas/patología , Células Th2/efectos de los fármacos , Células Th2/inmunología
8.
Medicine (Baltimore) ; 100(12): e25262, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761725

RESUMEN

INTRODUCTION: Myxofibrosarcoma (MFS) is a locally aggressive tumor and has the potential to be fatal because of distant metastasis. Immunotherapy targeting either programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) has recently shown a curative effect on multiple cancers including melanoma, non-small cell lung cancer, and renal cell carcinoma. Although the immunotherapy has been applied in sarcoma, there is little information about the efficiency to treat metastatic MFS. PATIENT CONCERNS: A 42-year-old male presented to the clinic with a mass in the left thigh. Mass resection and ligament replacement surgery were performed. DIAGNOSES: The patient was diagnosed as high-grade MFS (federation nationale des centres de lutte contre le cancer, Grade 3) with pulmonary metastasis. INTERVENTIONS: In the past few years, he was treated with surgery, chemoradiotherapy, and Anlotinib (an angiogenesis inhibitor), but the metastatic lesion continued to progress. About 40% to 50% of tumor cells in his pulmonary tissues were showed positive PD-L1 expression and his tumor mutational burden was 215Muts. Thus, he received Camrelizumab (PD-1 inhibitor). OUTCOMES: Six months after the initiating immunotherapy of Camrelizumab, the size of pulmonary lesions showed marked shrinkage, indicating a partial response. After a follow-up of 18 months, the patient remained in good condition without progressive disease. CONCLUSION: This case described here demonstrated that immunotherapy of PD-1 inhibitor is a promising treatment option for refractory MFS with PD-L1 positive or tumor mutational burden -high, which could contribute to effective tumor response.


Asunto(s)
Inmunoterapia/métodos , Neoplasias Pulmonares , Mixosarcoma , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias de los Tejidos Blandos , Adulto , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Disección/métodos , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Mixosarcoma/patología , Mixosarcoma/cirugía , Clasificación del Tumor , Estadificación de Neoplasias , Supervivencia sin Progresión , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/cirugía , Muslo/patología , Muslo/cirugía , Resultado del Tratamiento
9.
Methods Mol Biol ; 2265: 385-406, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704729

RESUMEN

Metastatic melanoma is one of the most aggressive types of cancers, diffused worldwide and with a significant percentage of lethality. The employment of animal models to test therapeutic strategies against melanoma growth and metastatic spread is of key relevance for cancer biologists. In this regard, the count of metastatic foci in murine lung tissue is one of the recognized methods to monitor macrometastases of melanoma. Here, we illustrate a clonogenic assay method to detect with high sensitivity the presence of single melanoma cells (micrometastases) at the pulmonary level when metastatic foci are still not detectable in the tissue. This method allows for high precision detection and quantification of melanoma metastatic spread to the lung at early stages.


Asunto(s)
Neoplasias Pulmonares/metabolismo , Melanoma Experimental/metabolismo , Ensayo de Tumor de Célula Madre , Animales , Línea Celular Tumoral , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Melanoma Experimental/patología , Ratones , Metástasis de la Neoplasia
10.
Medicine (Baltimore) ; 100(6): e24471, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578541

RESUMEN

BACKGROUND: In osteosarcoma, the lung is the most common metastatic organ. Intensive work has been made to illuminate the pathogeny, but the specific metastatic mechanism remains unclear. Thus, we conducted the study to seek to find the key genes and critical functional pathways associated with progression and treatment in lung metastasis originating from osteosarcoma. METHODS: Two independent datasets (GSE14359 and GSE85537) were screened out from the Gene Expression Omnibus (GEO) database and the overlapping differentially expressed genes (DEGs) were identified using GEO2R online platform. Subsequently, the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of DEGs were conducted using DAVID. Meanwhile, the protein-protein interaction (PPI) network constructed by STRING was visualized using Cytoscape. Afterwards, the key module and hub genes were extracted from the PPI network using the MCODE and cytoHubba plugin. Moreover, the raw data obtained from GSE73166 and GSE21257 were applied to verify the expression differences and conduct the survival analyses of hub genes, respectively. Finally, the interaction network of miRNAs and hub genes constructed by ENCORI was visualized using Cytoscape. RESULTS: A total of 364 DEGs were identified, comprising 96 downregulated genes and 268 upregulated genes, which were mainly involved in cancer-associated pathways, adherens junction, ECM-receptor interaction, focal adhesion, MAPK signaling pathway. Subsequently, 10 hub genes were obtained and survival analysis demonstrated SKP2 and ASPM were closely related to poor prognosis of patients with osteosarcoma. Finally, hsa-miR-340-5p, has-miR-495-3p, and hsa-miR-96-5p were found to be most closely associated with these hub genes according to the interaction network of miRNAs and hub genes. CONCLUSION: The key genes and functional pathways identified in the study may contribute to understanding the molecular mechanisms involved in the carcinogenesis and progression of lung metastasis originating from osteosarcoma, and provide potential diagnostic and therapeutic targets.


Asunto(s)
Neoplasias Óseas/patología , Neoplasias Pulmonares/secundario , Osteosarcoma/patología , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Genes Relacionados con las Neoplasias/genética , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteosarcoma/diagnóstico , Osteosarcoma/genética , Transducción de Señal/genética
11.
J Immunother Cancer ; 9(2)2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33574054

RESUMEN

By the beginning of the global pandemic, SARS-CoV-2 infection has dramatically impacted on oncology daily practice. In the current oncological landscape, where immunotherapy has revolutionized the treatment of several malignancies, distinguishing between COVID-19 and immune-mediated pneumonitis can be hard because of shared clinical, radiological and pathological features. Indeed, their common mechanism of aberrant inflammation could lead to a mutual and amplifying interaction.We describe the case of a 65-year-old patient affected by metastatic squamous head and neck cancer and candidate to an experimental therapy including an anti-PD-L1 agent. COVID-19 ground-glass opacities under resolution were an incidental finding during screening procedures and worsened after starting immunotherapy. The diagnostic work-up was consistent with ICIs-related pneumonia and it is conceivable that lung injury by SARS-CoV-2 has acted as an inflammatory primer for the development of the immune-related adverse event.Patients recovered from COVID-19 starting ICIs could be at greater risk of recall immune-mediated pneumonitis. Nasopharyngeal swab and chest CT scan are recommended before starting immunotherapy. The awareness of the phenomenon could allow an easier interpretation of radiological changes under treatment and a faster diagnostic work-up to resume ICIs. In the presence of clinical benefit, for asymptomatic ICIs-related pneumonia a watchful-waiting approach and immunotherapy prosecution are suggested.


Asunto(s)
/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neumonía/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Anciano , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , /inmunología , Diagnóstico Diferencial , Humanos , /efectos adversos , Inmunoterapia/efectos adversos , Lesión Pulmonar/diagnóstico , Lesión Pulmonar/diagnóstico por imagen , Lesión Pulmonar/patología , Lesión Pulmonar/virología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/virología , Masculino , Nasofaringe/metabolismo , Nasofaringe/patología , Metástasis de la Neoplasia , Pandemias , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Neumonía/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/virología
12.
BMJ Case Rep ; 14(2)2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33558380

RESUMEN

Cancers can develop the ability to evade immune recognition and destruction. Immune checkpoint inhibitors (ICIs) are drugs targeting these immune evasion mechanisms. ICIs have significantly improved outcomes in several cancers including metastatic melanoma. However, data on toxicities associated with allograft transplant recipients receiving ICI is limited. We describe a case of a 71-year-old woman who was diagnosed with metastatic melanoma 13 years after renal transplantation. She was commenced on the ICI nivolumab. She developed acute renal transplant rejection 15 days after administration of the first dose. She continues on haemodialysis but has demonstrated complete oncological response. This case demonstrates the risk of acute renal transplant rejection versus improved oncological outcomes. Patients and clinicians must consider this balance when initiating ICI therapy in allograft transplant recipients. Patients should be fully consented of the potential consequences of acute renal transplant rejection including lifelong dialysis.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Rechazo de Injerto/inducido químicamente , Trasplante de Riñón , Melanoma/tratamiento farmacológico , Nivolumab/efectos adversos , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Femenino , Humanos , Fallo Renal Crónico/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Metástasis Linfática , Melanoma/patología , Cuero Cabelludo/patología , Neoplasias Cutáneas/patología , Factores de Tiempo , Trasplante Homólogo
13.
N Z Med J ; 134(1529): 45-56, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33582707

RESUMEN

AIM: Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted radiation in a shorter time period than conventional radiotherapy. The aim of this study was to compare the outcomes of lung-based SABR in a New Zealand cohort to the global literature. METHODS: A single-institution retrospective analysis was performed on all patients who received lung-based SABR between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included both early stage lung cancer and lung oligometastases that measured less than 5cm. RESULTS: 102 patients received SABR to 116 lesions. Median follow-up was 19 months. The three-year rate of local control in the primary and metastatic cohorts was 85% and 82%, respectively. This reflects the three-year local control rate of 86% for primary lung cancer in the SPACE trial and the two-year local control rate of 81% for pulmonary oligometastases in a German study. Central primary lung cancer was associated with a higher risk of local recurrence (HR6.4 (1.3-31.5) p=0.02). The three-year progression-free survival rate in patients with early stage lung cancer and oligometastases was 56% and 26%, respectively. Maori patients with primary lung cancer had a significantly worse progression free survival (HR2.4 (1.1-5.1) p=0.03). There were no reported grade three toxicities. CONCLUSION: The use of lung-based SABR in a typical radiotherapy setting in New Zealand mirrors global outcomes.


Asunto(s)
Neoplasias Pulmonares/radioterapia , Radiocirugia/métodos , Anciano , Femenino , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Nueva Zelanda , Grupo de Ascendencia Oceánica , Radiocirugia/efectos adversos , Estudios Retrospectivos , Análisis de Supervivencia
14.
J Thorac Cardiovasc Surg ; 161(3): 856-868.e1, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33478834

RESUMEN

OBJECTIVE: Men with metastatic nonseminomatous germ cell tumors (NSGCTs) often present with residual chest tumors after chemotherapy. We examined the pathologic concordance of intrathoracic disease and outcomes based on the worst pathology of disease resected at first thoracic surgery. METHODS: A retrospective analysis was performed of consecutive patients undergoing thoracic resection for metastatic NSGCT in our institution between 2005 and 2018. RESULTS: Eighty-nine patients (all men) were included. The median age was 29 years (interquartile range [IQR], 23-35 years). Primary sites were testis (n = 84; 94.4%) and retroperitoneum (n = 5; 5.6%). Eighty-seven patients received chemotherapy before undergoing surgery. Nineteen patients (21.3%; group 1) had malignancy resected at first surgery (OR1), and the other 70 patients had benign disease at OR1 (78.7%; group 2). Concordant pathology between lungs was 85.2% in group 1 and 91% in group 2, and between lung and mediastinum was 50% in group 1 and 72.7% in group 2. Despite no teratoma at OR1, 3 patients (15.8%) in group 2 had resection of teratoma (n = 2) or malignancy (n = 1) at future surgery. After a mean follow-up of 65.5 months (IQR, 23.1-89.2 months) for group 1 and 47.7 months (IQR, 13.0-75.1 months) for group 2, overall survival was significantly worse for group 1 (68.4% vs 92.9%; P = .03). CONCLUSIONS: The wide range of pathology resected in patients with intrathoracic NSGCT metastases requires careful decision making regarding treatment. Pathologic concordance between lungs is better than that between lung and mediastinum in patients with intrathoracic NSGCT metastases. Aggressive surgical management should be considered for all residual disease due to the low concordance between sites and the potential for excellent long-term survival even in patients with chemotherapy-refractory disease.


Asunto(s)
Neoplasias Pulmonares/cirugía , Neoplasias del Mediastino/cirugía , Metastasectomía , Neoplasias de Células Germinales y Embrionarias/cirugía , Neoplasias Testiculares/cirugía , Procedimientos Quirúrgicos Torácicos , Adulto , Biopsia , Quimioterapia Adyuvante , Toma de Decisiones Clínicas , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Masculino , Neoplasias del Mediastino/mortalidad , Neoplasias del Mediastino/secundario , Metastasectomía/efectos adversos , Metastasectomía/mortalidad , Terapia Neoadyuvante , Neoplasia Residual , Neoplasias de Células Germinales y Embrionarias/mortalidad , Neoplasias de Células Germinales y Embrionarias/secundario , Selección de Paciente , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Neoplasias Testiculares/mortalidad , Neoplasias Testiculares/patología , Procedimientos Quirúrgicos Torácicos/efectos adversos , Procedimientos Quirúrgicos Torácicos/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
15.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-33513753

RESUMEN

Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type 1 susceptibility (BRCA1) gene in patients with a lifetime risk of developing breast and/or ovarian cancer. To model the BRCA1-deleted stroma, we first generated induced pluripotent stem cells (iPSCs) from patients carrying a germline deletion of exon 17 of the BRCA1 gene (BRCA1+/- who, based on their family histories, were at a high risk for cancer. Using peripheral blood mononuclear cells (PBMCs) of these two affected family members and two normal (BRCA1+/+) individuals, we established a number of iPSC clones via non-integrating Sendai virus-based delivery of the four OCT4, SOX2, KLF4, and c-MYC factors. Induced mesenchymal stem cells (iMSCs) were generated and used as normal and pathological stromal cells. In transcriptome analyses, BRCA1+/- iMSCs exhibited a unique pro-angiogenic signature: compared to non-mutated iMSCs, they expressed high levels of HIF-1α, angiogenic factors belonging to the VEGF, PDGF, and ANGPT subfamilies showing high angiogenic potential. This was confirmed in vitro through the increased capacity to generate tube-like structures compared to BRCA1+/+ iMSCs and in vivo by a matrigel plug angiogenesis assay where the BRCA1+/- iMSCs promoted the development of an extended and organized vessel network. We also reported a highly increased migration capacity of BRCA1+/- iMSCs through an in vitro wound healing assay that correlated with the upregulation of the periostin (POSTN). Finally, we assessed the ability of both iMSCs to facilitate the engraftment of murine breast cancer cells using a xenogenic 4T1 transplant model. The co-injection of BRCA1+/- iMSCs and 4T1 breast cancer cells into mouse mammary fat pads gave rise to highly aggressive tumor growth (2-fold increase in tumor volume compared to 4T1 alone, p = 0.01283) and a higher prevalence of spontaneous metastatic spread to the lungs. Here, we report for the first time a major effect of BRCA1 haploinsufficiency on tumor-associated stroma in the context of BRCA1-associated cancers. The unique iMSC model used here was generated using patient-specific iPSCs, which opens new therapeutic avenues for the prevention and personalized treatment of BRCA1-associated hereditary breast cancer.


Asunto(s)
Proteína BRCA1/genética , Neoplasias de la Mama/genética , Células Madre Pluripotentes Inducidas/metabolismo , Neoplasias Pulmonares/genética , Células Madre Mesenquimatosas/metabolismo , Neovascularización Patológica/genética , Animales , Proteína BRCA1/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias de la Mama/congénito , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Ontología de Genes , Haploinsuficiencia , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos NOD , Ratones SCID , ARN Interferente Pequeño , Transcriptoma/genética , Microambiente Tumoral/genética , Cicatrización de Heridas/genética , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Nat Cell Biol ; 23(1): 75-86, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33420490

RESUMEN

Nutrient availability is central for T-cell functions and immune responses. Here we report that CD8+ T-cell activation and anti-tumour responses are strongly potentiated by the non-essential amino acid Asn. Increased Asn levels enhance CD8+ T-cell activation and effector functions against tumour cells in vitro and in vivo. Conversely, restriction of dietary Asn, ASNase administration or inhibition of the Asn transporter SLC1A5 impairs the activity and responses of CD8+ T cells. Mechanistically, Asn does not directly alter cellular metabolic fluxes; it instead binds the SRC-family protein tyrosine kinase LCK and orchestrates LCK phosphorylation at Tyr 394 and 505, thereby leading to enhanced LCK activity and T-cell-receptor signalling. Thus, our findings reveal a critical and metabolism-independent role for Asn in the direct modulation of the adaptive immune response by controlling T-cell activation and efficacy, and further uncover that LCK is a natural Asn sensor signalling Asn sufficiency to T-cell functions.


Asunto(s)
Asparagina/farmacología , Linfocitos T CD8-positivos/inmunología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/prevención & control , Activación de Linfocitos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/inmunología , Melanoma Experimental/prevención & control , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Femenino , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Masculino , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Fosforilación , Transducción de Señal , Células Tumorales Cultivadas , Tirosina/metabolismo , Familia-src Quinasas/metabolismo
17.
J Surg Oncol ; 123(4): 1144-1156, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33497473

RESUMEN

BACKGROUND: The lungs are the second most common site of metastases in colorectal cancer (CRC). The aim of this study was to investigate prognostic factors, including RNA-binding motif protein 3 (RBM3) expression, in patients with CRC treated with pulmonary metastasectomy (PM). METHODS: The cohort included all patients treated with PM at Skåne University Hospital, Lund, Sweden, from 2000 to 2014. Clinicopathological, treatment, and survival data were collected. Immunohistochemical staining of RBM3 was evaluated on tissue microarrays with samples from all lung metastases and a subset of paired primary tumors. Kaplan-Meier analysis and Cox proportional hazards modeling were applied to examine the associations of investigative factors with overall survival (OS) and recurrence-free survival. RESULTS: In total, 216 patients with a primary tumor in the rectum (57%), left colon (34%), or right colon (9%) underwent PM. The 5-year OS rate was 56%. Age > 60 years, more than one metastasis, size of metastasis > 3 cm, disease-free interval < 24 months, low RBM3 score in the lung metastasis, and no adjuvant chemotherapy following PM were prognostic factors for shorter OS. CONCLUSIONS: Several prognostic factors, including RBM3 expression, may be of aid in selecting CRC patients with lung metastases for PM as well as adjuvant therapy.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/secundario , Metastasectomía/mortalidad , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Neumonectomía/mortalidad , Proteínas de Unión al ARN/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/cirugía , Neoplasias/metabolismo , Neoplasias/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
18.
BMJ Case Rep ; 14(1)2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33472808

RESUMEN

We report a rare case of cardiac angiosarcoma in a young boy who presented with cardiac tamponade. His initial symptoms were non-specific. He was initially being managed in the line of fungal infection, with a possibility of malignancy. Cardiac imaging was also not conclusive and he worsened on antibiotics and antifungals and succumbed to the illness. After his death tissue biopsy from heart and lung was done and histopathological examination revealed the diagnosis of metastatic angiosarcoma. The case highlights the importance of considering the diagnosis of cardiac angiosarcoma in the patients presenting with haemorrhagic pericardial effusion and non-specific symptoms.


Asunto(s)
Taponamiento Cardíaco/etiología , Neoplasias Cardíacas/complicaciones , Hemangiosarcoma/complicaciones , Derrame Pericárdico/etiología , Taponamiento Cardíaco/diagnóstico por imagen , Taponamiento Cardíaco/terapia , Drenaje , Ecocardiografía , Resultado Fatal , Atrios Cardíacos , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/patología , Hemangiosarcoma/diagnóstico por imagen , Hemangiosarcoma/patología , Hemangiosarcoma/secundario , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Imagen por Resonancia Magnética , Masculino , Derrame Pericárdico/diagnóstico por imagen , Derrame Pericárdico/terapia , Choque/etiología , Tomografía Computarizada por Rayos X , Adulto Joven
19.
AJR Am J Roentgenol ; 216(3): 769-775, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33405948

RESUMEN

OBJECTIVE. Pulmonary intravascular metastasis is a special type of pulmonary metastasis of malignancies; however, few relevant studies have been performed. This study aimed to determine the characteristics of pulmonary intravascular metastasis and improve understanding of the disease by retrospective analysis of FDG PET/CT and thin-layer high-resolution CT (HRCT) imaging of the chest in patients with tumors. MATERIALS AND METHODS. We identified all patients who underwent FDG PET/CT at two hospitals between January 2016 and February 2019 and conducted a comparative analysis of HRCT and PET/CT images. In total, 84 patients (38 women and 46 men) ranging in age from 35 to 82 years old (mean age, 54.7 ± 14.5 [SD] years) participated in the study. Patient characteristics were summarized, and diagnosis was confirmed by chest CT or PET/CT follow-up. RESULTS. A total of 260 pulmonary intravascular metastases were found, which were classified as type I (no significant abnormality, n = 5), type II (abrupt and uneven thickening of the pulmonary vessel, n = 118), type III (simultaneous invasion of adjacent pulmonary vessel, n = 121), and type IV (large strip-shaped high-density mass, n = 16). The majority were located in peripheral pulmonary vessels (94.2% [245/260]). FDG up-take was increased in 252 lesions, and the mean SUVmax was 4.6 ± 2.5. CONCLUSION. The combination of PET/CT and chest HRCT is an effective approach for detecting pulmonary intravascular metastasis. The linear pattern of FDG uptake, abnormal pulmonary blood vessel morphology, and location (below the lung segment) are specific indicators for the diagnosis of pulmonary intravascular metastasis and should be recognized by clinicians and radiologists.


Asunto(s)
Fluorodesoxiglucosa F18 , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Tomografía Computarizada Multidetector/métodos , Células Neoplásicas Circulantes , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Pulmón/irrigación sanguínea , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/metabolismo , Metástasis Linfática , Masculino , Persona de Mediana Edad , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/metabolismo , Radiografía Torácica/métodos , Radiofármacos/farmacocinética , Estudios Retrospectivos
20.
AJR Am J Roentgenol ; 216(3): 781-790, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33474982

RESUMEN

OBJECTIVE. The purpose of this article is to review currently available and emerging techniques for pediatric lung MRI for general radiologists. CONCLUSION. MRI is a radiation-free alternative to CT, and clearly understanding the strengths and limitations of established and emerging techniques of pediatric lung MRI can allow practitioners to select and combine the optimal techniques, apply them in clinical practice, and potentially improve early diagnostic accuracy and patient management.


Asunto(s)
Enfermedades Pulmonares/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Adolescente , Artefactos , Contencion de la Respiración , Niño , Preescolar , Fibrosis Quística/diagnóstico por imagen , Femenino , Análisis de Fourier , Humanos , Lactante , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Imagen por Resonancia Magnética/tendencias , Masculino , Atelectasia Pulmonar/prevención & control , Rabdomiosarcoma/diagnóstico por imagen , Rabdomiosarcoma/secundario
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