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BACKGROUND: We report the first study examining the clinical, numerical and biological properties of circulating tumor cells according to molecular subtypes of non-small-cell lung cancer. PATIENTS AND METHODS: 125 patients with treatment-naïve stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype, and survival were assessed. RESULTS: 51/125 patients (40.8%) were total CTC+ and 26/125 (20.8%) were vim CTC+ at baseline. Multivariate analysis showed patients with ≥5 total CTCs had significantly reduced OS (HR 0.55, 95% CI 0.33-0.92, P = 0.022) but not PFS (HR 0.68, 95% CI 0.42-1.1, P = 0.118) compared to patients with <5 total CTCs. No OS difference was evident between vim+ CTC and vim-negative CTC patients overall (HR 1.24, 95% CI 0.67-2.28, P = 0.494), but after subdivision according to NSCLC driver mutation, we found an increase of vim+ CTCs in the EGFR-mutated subgroup (N = 21/94 patients; mean 1.24 vs 1.22 vim+ CTCs, P = 0.013), a reduction of total CTCs in the ALK-rearranged subgroup (N = 13/90 patients; mean 1.69 vs 5.82 total CTCs, P = 0.029), and a total absence of vim+ CTCs in KRAS-mutated adenocarcinomas (N = 19/78 patients; mean 0 vs 1.4 vim+ CTCs, P = 0.006). CONCLUSIONS: We validate that the baseline presence of ≥5 total CTCs in advanced NSCLC confers a poor prognosis. CTCs from EGFR-mutant NSCLC express epithelial-mesenchymal transition characteristics, not seen in CTCs from patients with KRAS-mutant adenocarcinoma.
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Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Neoplasias Pulmonares/sangre , Células Neoplásicas Circulantes/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Transición Epitelial-Mesenquimal , Receptores ErbB/genética , Femenino , Reordenamiento Génico , Genotipo , Humanos , Separación Inmunomagnética , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Estadificación de Neoplasias , Células Neoplásicas Circulantes/patología , Fenotipo , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Tirosina Quinasas Receptoras/genética , Factores de Tiempo , Vimentina/sangreRESUMEN
Background: Approximately 50% of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) will acquire resistance by the T790M mutation. Osimertinib is the standard of care in this situation. The present study assesses the efficacy of osimertinib when T790M status is determined in circulating cell-free tumour DNA (ctDNA) from blood samples in progressing advanced EGFR-mutant NSCLC patients. Material and methods: ctDNA T790M mutational status was assessed by Inivata InVision™ (eTAm-Seq™) assay in 48 EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKIs without a tissue biopsy between April 2015 and April 2016. Progressing T790M-positive NSCLC patients received osimertinib (80 mg daily). The objectives were to assess the response rate to osimertinib according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, the progression-free survival (PFS) on osimertinib, and the percentage of T790M positive in ctDNA. Results: The ctDNA T790M mutation was detected in 50% of NSCLC patients. Among assessable patients, osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. All responses were confirmed responses. After median follow up of 8 months, median PFS by RECIST criteria was not achieved (95% CI: 4-NA), with 6- and 12-months PFS of 66.7% and 52%, respectively. Conclusion(s): ctDNA from liquid biopsy can be used as a surrogate marker for T790M in tumour tissue.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Piperazinas/uso terapéutico , Acrilamidas , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , ADN de Neoplasias/genética , Supervivencia sin Enfermedad , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
PURPOSE: Specific recommendations on screening modalities for paraganglioma (PGL) and phaeochromocytoma (PCC) in asymptomatic SDHx mutation carriers (relatives) are still lacking. We evaluated the added value of (18)F-FDG PET/CT in comparison with morphological imaging at initial diagnosis and 1 year of follow-up in this population. METHODS: The study included 30 consecutive relatives with a proven SDHx mutation who were investigated by (18)F-FDG PET/CT, gadolinium-enhanced magnetic resonance angiography of the head and neck, thoracic/abdominal/pelvic (TAP) contrast-enhanced CT and/or TAP MRI. (123)I-MIBG scintigraphy was performed in 20 subjects and somatostatin receptor scintigraphy (SRS) in 20 subjects. The gold standard was based on pathology or a composite endpoint as defined by any other positive imaging method and persistent tumour on follow-up. Images were considered as false-positive when the lesions were not detected by another imaging method or not confirmed at 1 year. RESULTS: At initial work-up, an imaging abnormality was found in eight subjects (27%). The final diagnosis was true-positive in five subjects (two with abdominal PGL, one with PCC and two with neck PGL) and false-positives in the other three subjects (detected with (18)F-FDG PET/CT in two and TAP MRI in one). At 1 year, an imaging abnormality was found in three subjects of which one was an 8-mm carotid body PGL in a patient with SDHD mutaion and two were considered false-positive. The tumour detection rate was 100% for (18)F-FDG PET/CT and conventional imaging, 80% for SRS and 60% for (123)I-MIBG scintigraphy. Overall, disease was detected in 4% of the subjects at the 1-year follow-up. CONCLUSION: (18)F-FDG PET/CT demonstrated excellent sensitivity but intermediate specificity justifying combined modality imaging in these patients. Given the slow progression of the disease, if (18)F-FDG PET/CT and MRI are normal at baseline, the second imaging work-up should be delayed and an examination that does not expose the patient to radiation should be used.
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Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Heterocigoto , Feocromocitoma/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos , Succinato Deshidrogenasa/genética , 3-Yodobencilguanidina , Adolescente , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Anciano , Enfermedades Asintomáticas , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Imagen Multimodal , Mutación , Linaje , Feocromocitoma/genética , Feocromocitoma/patología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Pancreatic neuroendocrine tumors (PNET) locally advanced may lead to significant local symptoms especially segmental portal hypertension (SPH) with risk of bleeding. The aim of our study was to evaluate the role of SPH on the PNET management in an expert center. METHODS: Forty-two patients treated for locally advanced PNET with SPH between January 1984 and December 2012 were retrospectively analyzed. RESULTS: The median age was 55 years (25-75). The median tumor size was 7.5 cm (3-20). Thirty four (80.9%) patients were metastatic mainly in the liver (n=33, 79%) with a frequent (n=16, 38.1%) involvement>20%. The surgery was impossible because of SPH in 7 (16.6%) cases. Pancreatic resection was performed in 28 (66.7%) cases by distal pancreatectomy. Neoadjuvant chemotherapy (n=24, 57%) had no impact on SPH with no modification of collateral circulation. Among operated on patients, complete macroscopic resection was obtained in 19 (67.8%) patients. The mortality and severe morbidity rate was respectively 3.6 and 18%. Five year overall survival (OS) was similar in operated and no operated patients. (61%; p=0.64). The 5-year OS was 77.9 or 55.4% in patients who underwent a complete or incomplete macroscopic resection of primary and metastases, respectively. CONCLUSION: PNET resection associated with SPH is feasible with a low morbimortality. SPH was not improved by chemotherapy. Prolonged survival was observed after complete macroscopic resection.
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Hipertensión Portal/etiología , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/cirugía , Adulto , Anciano , Quimioterapia Adyuvante , Estudios de Factibilidad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/secundario , Pancreatectomía/métodos , Neoplasias Pancreáticas/patología , Estudios RetrospectivosRESUMEN
Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development. Hyperglycemia is a major risk factor for endothelial dysfunction and vascular complication, which subsequently may trigger neurodegeneration. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C ßII (PKC ßII), which in turn leads to a higher expression of vascular endothelial growth factor (VEGF), via the mRNA-binding Hu-antigen R (HuR) protein. VEGF is a pivotal mediator of neovascularization and a well-known vasopermeability factor. Blocking the increase of VEGF via modulation of this cascade can thus represent a new pharmacological option to prevent DR progression. To this aim, proper in vitro models are crucial for drug discovery, as they allow to better identify promising effective molecules. Considering that endothelial cells are key elements in DR and that hyperglycemia triggers the PKCßII/HuR/VEGF pathway, we set up two distinct in vitro models applying two different stimuli. Namely, human umbilical vein endothelial cells were exposed to phorbol 12-myristate 13-acetate, which mimics diacylglycerol whose synthesis is triggered by diabetic hyperglycemia, while human retinal endothelial cells were treated with high glucose for different times. After selecting the optimal experimental conditions able to determine an increased VEGF production, in search of molecules useful to prevent DR development, we investigated the capability of troxerutin, an antioxidant flavonoid, to counteract not only the rise of VEGF but also the activation of the PKCßII/HuR cascade in both in vitro models. The results show the capability of troxerutin to hinder the hyperglycemia-induced increase in VEGF in both models through PKCßII/HuR pathway modulation. Further, these data confirm the key engagement of this cascade as an early event triggered by hyperglycemia to promote VEGF expression. Finally, the present findings also suggest the potential use of troxerutin as a preventive treatment during the early phases of DR.
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PURPOSE: The purpose of this study was to compare efficacy and tolerance between radiofrequency ablation (RFA) and surgery for the treatment of oligometastatic lung disease. MATERIALS AND METHODS: This retrospective study reviewed patients treated in two institutions for up to 5 pulmonary metastases with a maximal diameter of 4cm and without associated pleural involvement or thoracic lymphadenopathy. Patient demographics, tumor characteristics, treatment outcome, and length of hospital stay were compared between the two groups. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and pulmonary or local tumor progression rates. RESULTS: Among 204 patients identified, 78 patients (42 men, 36 women; mean age, 53.3±14.9 [SD]; age range: 15-81 years) were treated surgically, while 126 patients (59 men, 67 women; mean age, 62.2±10.8 [SD]; age range: 33-80 years) were treated by RFA. In the RFA cohort, patients were significantly older (P<0.0001), with more extra-thoracic localisation (P=0.015) and bilateral tumour burden (P=0.0014). In comparison between surgery and RFA cohorts, respectively, the 1- and 3-year OS were 94.8 and 67.2% vs. 94 and 72.1% (P=0.46), the 1- and 3-year PFS were 49.4% and 26.1% vs. 38.9% and 14.8% (P=0.12), the pulmonary progression rates were 39.1% and 56% vs. 41.2% and 65.3% (P>0.99), and the local tumour progression rates were 5.4% and 10.6% vs. 4.8% and 18.6% (P=0.07). Tumour size>2cm was associated with a significantly higher local tumor progression in the RFA group (P=0.010). Hospitalisation stay was significantly shorter in the RFA group (median of 3 days; IQR=2 days; range: 2-12 days) than in the surgery group (median of 9 days; IQR=2 days; range: 6-21 days) (P<0.01). CONCLUSION: RFA should be considered a minimally-invasive alternative with similar OS and PFS to surgery in the treatment of solitary or multiple lung metastases measuring less than 4cm in diameter without associated pleural involvement or thoracic lymphadenopathy.
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Ablación por Catéter , Neoplasias Hepáticas , Neoplasias Pulmonares , Ablación por Radiofrecuencia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To determine magnetic resonance imaging (MRI) signal and enhancement characteristics of endocrine pancreatic tumours (ETPs) and which MR sequences show them most consistently. METHODS: Fifty-five consecutive patients with 68 ETPs underwent 1.5-T abdominal MRI comprising T2-weighted, unenhanced T1-weighted and dynamic T1-weighted after injection of gadopentetate dimeglumine sequences. Twenty-one patients underwent diffusion-weighted imaging (DWI). Two radiologists identified the number, location, size, signal and enhancement patterns of ETPs, and determined a confidence scale indicating the presence of tumours on DWI. The results were compared with echo-endoscopy (endoscopic ultrasound) findings. RESULTS: The detection sensitivity was 95%, similar to that of echo-endoscopy. T2-weighted and T1-weighted sequences at the arterial phase had the highest contrast-to-noise ratio (CNR) median value. On DWI, the mean sensitivity was 65%. The mean apparent diffusion coefficient (ADC) value of ETP was significantly lower than in the normal parenchyma. CONCLUSION: In suspected ETP, MRI is a sensitive method, similar to echo-endoscopy and could be recommended as the first imaging technique. T2-weighted sequences and T1-weighted sequences in the arterial phase are the optimal pulse sequences. The quantitative assessment of ADC values is a promising tool for the characterisation of pancreatic lesions.
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Imagen por Resonancia Magnética , Neoplasias Pancreáticas/diagnóstico , Adulto , Anciano , Medios de Contraste , Imagen de Difusión por Resonancia Magnética , Endosonografía , Femenino , Gadolinio DTPA , Humanos , Masculino , Persona de Mediana Edad , Páncreas/diagnóstico por imagen , Páncreas/patología , Neoplasias Pancreáticas/diagnóstico por imagen , Sensibilidad y EspecificidadRESUMEN
The marrow contains a variable amount of yellow or fatty marrow and red or cellular marrow creating the signal intensity observed on MRI. Marrow replacement (by cells not normally present in bone marrow) typically is T1W hypointense. Marrow proliferation (by cells normally present in bone marrow) may be T1W hypointense (pseudo marrow replacement) or show intermediate T1W signal intensity due to red marrow redistribution. Marrow edema (reaction to an external process) show intermediate T1W hypointensity (mixture of water and marrow). Location will allow correct diagnosis. Bone marrow ischemia usually results in a necrotic fragment surrounded by a thin T1W hypointense rim.
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Enfermedades de la Médula Ósea/diagnóstico , Médula Ósea/patología , Aumento de la Imagen , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Enfermedades de la Columna Vertebral/diagnóstico , Adenocarcinoma/secundario , Factores de Edad , Anciano , Hematopoyesis/fisiología , Humanos , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/diagnóstico , Masculino , Neoplasias de la Próstata/diagnóstico , Valores de Referencia , Médula Espinal/patología , Compresión de la Médula Espinal/diagnóstico , Neoplasias de la Columna Vertebral/diagnóstico , Neoplasias de la Columna Vertebral/secundarioRESUMEN
Concomitant radiochemotherapy has been the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), irrespective of histological sub-type or molecular characteristics. Currently, only 15-30 % of patients are alive five years after radiochemotherapy, and this figure remains largely unchanged despite multiple phase III randomised trials. In recent years, immune-checkpoint blockades with anti-PD-(L)1 have revolutionised the care of metastatic NSCLC, becoming the standard front- and second-line strategy. Several preclinical studies reported an increased tumour antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumours. Immunotherapy has therefore recently been evaluated for patients with locally advanced stage III NSCLC. Following the PACIFIC trial, the anti-PD-L1 durvalumab antibody has emerged as a new standard consolidative treatment for patients with unresectable stage III NSCLC whose disease has not progressed following concomitant platinum-based chemoradiotherapy. Immunoradiotherapy therefore appears to be a promising association in patients with localised NSCLC. Many trials are currently evaluating the value of concomitant immunotherapy and chemoradiotherapy and/or consolidative chemotherapy with immunotherapy in patients with locally advanced unresectable NSCLC.
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Humanos , Neoplasias Pulmonares/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Radioterapia AdyuvanteRESUMEN
PURPOSE: The second edition of the artificial intelligence (AI) data challenge was organized by the French Society of Radiology with the aim to: (i), work on relevant public health issues; (ii), build large, multicentre, high quality databases; and (iii), include three-dimensional (3D) information and prognostic questions. MATERIALS AND METHODS: Relevant clinical questions were proposed by French subspecialty colleges of radiology. Their feasibility was assessed by experts in the field of AI. A dedicated platform was set up for inclusion centers to safely upload their anonymized examinations in compliance with general data protection regulation. The quality of the database was checked by experts weekly with annotations performed by radiologists. Multidisciplinary teams competed between September 11th and October 13th 2019. RESULTS: Three questions were selected using different imaging and evaluation modalities, including: pulmonary nodule detection and classification from 3D computed tomography (CT), prediction of expanded disability status scale in multiple sclerosis using 3D magnetic resonance imaging (MRI) and segmentation of muscular surface for sarcopenia estimation from two-dimensional CT. A total of 4347 examinations were gathered of which only 6% were excluded. Three independent databases from 24 individual centers were created. A total of 143 participants were split into 20 multidisciplinary teams. CONCLUSION: Three data challenges with over 1200 general data protection regulation compliant CT or MRI examinations each were organized. Future challenges should be made with more complex situations combining histopathological or genetic information to resemble real life situations faced by radiologists in routine practice.
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Inteligencia Artificial , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Humanos , RadiólogosRESUMEN
PURPOSE: The purpose of this study was to create an algorithm to detect and classify pulmonary nodules in two categories based on their volume greater than 100 mm3 or not, using machine learning and deep learning techniques. MATERIALS AND METHOD: The dataset used to train the model was provided by the organization team of the SFR (French Radiological Society) Data Challenge 2019. An asynchronous and parallel 3-stages pipeline was developed to process all the data (a data "pre-processing" stage; a "nodule detection" stage; a "classifier" stage). Lung segmentation was achieved using 3D U-NET algorithm; nodule detection was done using 3D Retina-UNET and classifier stage with a support vector machine algorithm on selected features. Performances were assessed using area under receiver operating characteristics curve (AUROC). RESULTS: The pipeline showed good performance for pathological nodule detection and patient diagnosis. With the preparation dataset, an AUROC of 0.9058 (95% confidence interval [CI]: 0.8746-0.9362) was obtained, 87% yielding accuracy (95% CI: 84.83%-91.03%) for the "nodule detection" stage, corresponding to 86% specificity (95% CI: 82%-92%) and 89% sensitivity (95% CI: 84.83%-91.03%). CONCLUSION: A fully functional pipeline using 3D U-NET, 3D Retina-UNET and classifier stage with a support vector machine algorithm was developed, resulting in high capabilities for pulmonary nodule classification.
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Inteligencia Artificial , Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Aprendizaje Profundo , Humanos , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/diagnóstico por imagen , Nódulos Pulmonares Múltiples/clasificación , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
INTRODUCTION: Innate immunity represents the first step of activation of the immune system and dictates the quality of adaptive immune responses. Studies have reported links between systemic inflammatory or innate immune markers and prognosis in patients with lung cancer. To our knowledge, the prospective and concomitant study of these systemic markers has never been performed. METHODS: Advanced treatment-naive non-small cell lung cancer (NSCLC) patients eligible for first-line platinum-based chemotherapy were prospectively included from December 2012 to July 2015 (N = 148). Blood samples of patients were collected before the first cycle for fresh NK cell phenotyping. Peripheral blood mononuclear cells were cryopreserved for natural cytotoxicity receptor (NCR) genotyping as well as sera for NCR's ligand quantification. Data on leukocytes, neutrophils and monocyte counts and lactate dehydrogenase (LDH) levels were extracted from electronic medical records. RESULTS: Among all studied markers, monocytosis, neutrophilia, leucocytosis, high LDH and sBAG6 levels and reduced levels of NCR3 transcripts were associated with poor overall survival (OS) in univariate analysis. The levels of NCR3 transcripts was linked to age, number of metastatic sites, monocyte counts, LDH and sBAG6 levels. Neutrophilia was associated to high sBAG6 levels. NCR3 was the unique innate immune parameter that remained as an independent factor associated with both OS (P = 0.003) and progression-free survival (P = 0.009) in the multivariate analysis. CONCLUSION: This study brought evidence that these biomarkers are entangled; parameters associated with an inflammatory process were related to reduced levels of NCR3 transcripts. Finally, the level of NCR3 transcripts was independently associated with outcomes in treatment-naive patients with advanced NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/inmunología , Inmunidad Innata/inmunología , Neoplasias Pulmonares/inmunología , Receptor 3 Gatillante de la Citotoxidad Natural/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Células Asesinas Naturales/inmunología , L-Lactato Deshidrogenasa/metabolismo , Recuento de Leucocitos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Chaperonas Moleculares/inmunología , Monocitos/inmunología , Receptor 3 Gatillante de la Citotoxidad Natural/genética , Neutrófilos/inmunología , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , ARN Mensajero/metabolismo , Tasa de SupervivenciaRESUMEN
PURPOSE: The goal of this data challenge was to create a structured dynamic with the following objectives: (1) teach radiologists the new rules of General Data Protection Regulation (GDPR), while building a large multicentric prospective database of ultrasound, computed tomography (CT) and MRI patient images; (2) build a network including radiologists, researchers, start-ups, large companies, and students from engineering schools, and; (3) provide all French stakeholders working together during 5 data challenges with a secured framework, offering a realistic picture of the benefits and concerns in October 2018. MATERIALS AND METHODS: Relevant clinical questions were chosen by the Société Francaise de Radiologie. The challenge was designed to respect all French ethical and data protection constraints. Multidisciplinary teams with at least one radiologist, one engineering student, and a company and/or research lab were gathered using different networks, and clinical databases were created accordingly. RESULTS: Five challenges were launched: detection of meniscal tears on MRI, segmentation of renal cortex on CT, detection and characterization of liver lesions on ultrasound, detection of breast lesions on MRI, and characterization of thyroid cartilage lesions on CT. A total of 5,170 images within 4 months were provided for the challenge by 46 radiology services. Twenty-six multidisciplinary teams with 181 contestants worked for one month on the challenges. Three challenges, meniscal tears, renal cortex, and liver lesions, resulted in an accuracy>90%. The fourth challenge (breast) reached 82% and the lastone (thyroid) 70%. CONCLUSION: Theses five challenges were able to gather a large community of radiologists, engineers, researchers, and companies in a very short period of time. The accurate results of three of the five modalities suggest that artificial intelligence is a promising tool in these radiology modalities.
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Inteligencia Artificial , Conjuntos de Datos como Asunto , Neoplasias de la Mama/diagnóstico por imagen , Comunicación , Seguridad Computacional , Humanos , Relaciones Interprofesionales , Corteza Renal/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Invasividad Neoplásica/diagnóstico por imagen , Cartílago Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/patología , Lesiones de Menisco Tibial/diagnóstico por imagen , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
The interaction between polyelectrolytes (PE) and oppositely charged drugs (D) results in complexes (PE-D) that can be exploited in controlled release drug delivery systems. The aim of this work is to better understand the relevance of some preparative parameters such as moisture content and particle size on the performance of two PE-D complexes to be used in oral controlled release tablets. PE-D complexes containing diltiazem HCL (DTZ) or metoprolol tartrate (MTP) and lambda carrageenan were obtained at two particle size levels (<45 microm and 75-105 microm), maintained at different values of relative humidity (RH) (11, 52, 75, and 93%), and compressed. The tablets were characterized for porosity, hardness, moisture content, and contact angle. Drug release profiles were fitted to the Weibull equation, and a factorial design was used to understand the relevance of particle size and RH% on release rate as a function of medium pH. The results indicated that the hydrophobic character of the complex between PE and D depended on the drug and in the present case was more pronounced for DTZ than for MTP. This in turn affected the possible release mechanism and therefore the importance of particle size and RH%.
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Carragenina/química , Carragenina/farmacocinética , Dureza , Humedad , Polímeros/química , Polímeros/farmacocinética , Química Farmacéutica/métodos , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Tamaño de la Partícula , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , ComprimidosRESUMEN
The aim of the present work was to develop a medication allowing for the combined delivery of platelet lysate (PL) and an anti-infective model drug, vancomycin hydrochloride (VCM), to chronic skin ulcers. A simple method was set up for the preparation of hyaluronic acid (HA) core-shell particles, loaded with PL and coated with calcium alginate, embedded in a VCM containing alginate matrix. Two different CaCl2 concentrations were investigated to allow for HA/PL core-shell particle formation. The resulting dressings were characterized for mechanical and hydration properties and tested in vitro (on fibroblasts) and ex-vivo (on skin biopsies) for biological activity. They were found of sufficient mechanical strength to withstand packaging and handling stress and able to absorb a high amount of wound exudate and to form a protective gel on the lesion area. The CaCl2 concentration used for shell formation did not affect VCM release from the alginate matrix, but strongly modified the release of PGFAB (chosen as representative of growth factors present in PL) from HA particles. In vitro and ex vivo tests provided sufficient proof of concept of the ability of dressings to improve skin ulcers healing.
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Alginatos/administración & dosificación , Antibacterianos/administración & dosificación , Vendajes , Plaquetas , Ácido Hialurónico/administración & dosificación , Úlcera Cutánea/tratamiento farmacológico , Vancomicina/administración & dosificación , Adulto , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Sistemas de Liberación de Medicamentos , Fibroblastos/efectos de los fármacos , Ácido Glucurónico/administración & dosificación , Ácidos Hexurónicos/administración & dosificación , Humanos , Piel , Cicatrización de Heridas/efectos de los fármacosRESUMEN
An amphiphilic chitosan salt, chitosan oleate (CS-OA), was previously proposed for the physical stabilization of lemongrass antimicrobial nanoemulsions (NE) through a mild spontaneous emulsification process. As both chitosan and oleic acid are described in the literature for their positive effects in wound healing, in the present study CS-OA has been proposed to encapsulate alpha tocopherol (αTph) in NEs aimed to skin wounds. A NE formulation was developed showing about 220â¯nm dimensions, 36% drug loading, and αTph concentration up to 1â¯mg/ml. Both CS-OA and αTph NE stimulated cell proliferation on keratinocytes and fibroblast cell cultures, and in ex vivo skin biopsies, suggesting the suitability of CS-OA and of the antioxidant agent for topical application in wound healing. αTph stability was further improved with respect of encapsulation, by spray drying the NE into a powder (up to about 90% αTph residual after 3â¯months). The spray drying process was optimized, to improve powder yield and αTph recovery, by a design of experiments approach. The powder obtained was easily re-suspended to deliver the NE and resulted able to completely release αTph.
Asunto(s)
Quitosano/química , Emulsiones/administración & dosificación , Nanopartículas/administración & dosificación , Nanopartículas/química , Ácido Oléico/química , Cicatrización de Heridas/efectos de los fármacos , alfa-Tocoferol/administración & dosificación , Antibacterianos/administración & dosificación , Antibacterianos/química , Antioxidantes/metabolismo , Biopsia , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Química Farmacéutica/métodos , Sistemas de Liberación de Medicamentos/métodos , Emulsiones/química , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Tamaño de la Partícula , Polvos/administración & dosificación , Polvos/química , alfa-Tocoferol/químicaRESUMEN
BACKGROUND: Immune checkpoint inhibitors are an important tool in the therapeutic strategy against metastatic non-small cell lung cancer (NSCLC); however, radiological evaluation is challenging due to the emergence of atypical patterns of responses. Several evaluation criteria have been proposed, such as the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, immune -related RECIST (irRECIST) and iRECIST, but have not been systematically compared in a homogeneous population. PATIENTS AND METHODS: We conducted a monocentric retrospective analysis of consecutive advanced NSCLC patients treated with an anti-programmed cell death-1 or anti-program death-ligand 1. Response patterns and the discordance between RECIST 1.1, irRECIST and iRECIST guidelines were described, and associations of response patterns and clinical outcome were explored. RESULTS: Overall, 160 patients treated between February 2013 and October 2016 were included. Atypical responses were observed in 20 patients (13%), including eight pseudoprogressions (PsPDs) (5%) and 12 dissociated responses (8%). Thirteen of the 20 patients demonstrated clinical benefit. Per the RECIST 1.1, 37 patients (23%) showed an objective response or stable disease, and 123 patients (77%) exhibited progression. Eighty progressive patients were assessable for irRECIST and iRECIST: 15 patients were assessed differently; however, only three (3.8%) mismatches with a theoretical impact on the therapeutic decision were identified. Patients with PsPD or dissociated response had higher overall survival than patients with true progression. CONCLUSION: Atypical responses (PsPD/dissociated response) occurred in 13% of NSCLC patients under immune checkpoint inhibitors. Based on survival analyses, the RECIST 1.1 evaluation underestimated the benefit of immune checkpoint inhibitors in 11% of the progressive patients. Immune-related RECIST and iRECIST identified these unconventional responses, with a 3.8% discrepancy rate.
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Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/metabolismo , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios RetrospectivosRESUMEN
The aim of the present work was the development of polymer films loaded with a carvacrol (CVR)/clay hybrid (HYBD) for the delivery of CRV in infected skin ulcer treatment. Different clays were considered: montmorrilonite, halloysite and palygorskite (PHC). CRV incorporation in PHC reduced its volatility. HYBD showed 20% w/w CRV loading capacity and was able to preserve CRV antioxidant properties. HYBD was characterized by improved antimicrobial properties against S. aureus and E. coli and cytocompatibility towards human fibroblasts with respect to pure CRV. Films were prepared by casting an aqueous dispersion containing poly(vinylalcohol) (PVA), poly(vinylpyrrolidone) (PVP), chitosan glutamate (CS), sericin and HYBD. Optimization of film composition was supported by a Design of Experiments (DoE) approach. In a screening phase, a full factorial design (FFD) was used and the following factors were investigated at two levels: PVA (12-14%w/w), PVP (2-4%w/w) and CS (0.134-0.5%w/w) concentrations. For the optimization phase, FFD was expanded to a "central composite design". The response variables considered were: elongation, tensile strength and buffer absorption of films, durability of the gels formed after film hydration. Upon hydration, the optimized film formed a viscoelastic gel able to protect the lesion area and to modulate CRV release.
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Silicatos de Aluminio/química , Antibacterianos/química , Sistemas de Liberación de Medicamentos , Monoterpenos/química , Células Cultivadas , Arcilla , Cimenos , Liberación de Fármacos , Escherichia coli/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Geles/química , Humanos , Staphylococcus aureus/efectos de los fármacosRESUMEN
The aim of the present work was to compare the penetration enhancement properties of chitosan hydrochloride (HCS) both as a polymeric solution and as a nanoparticulate system with that of trimethyl chitosan hydrochloride (TMC) on buccal mucosa. The hydrophilic high molecular weight fluorescein isothiocyanate dextran (FD4; 4400 Da) was used as a macromolecule model. The mechanism involved in the HCS (solution and nanoparticles) and TMC solution penetration enhancement was investigated on pig buccal mucosa, characterized by having stratified epithelium and lacking in tight junctions. The permeation/penetration of FD4 and the change in morphology and histology of the mucosa after contact with the polymers were assessed: the experiments were performed ex-vivo by applying the formulations on excised porcine buccal tissue. For the morphology and the histology studies, the epithelial cell layers from freshly excised pig buccal mucosa were analysed with light microscopy by means of routine histopathology analysis (haematoxylin and eosin staining and Toluidine blue staining) and immunohistochemistry reactions. The organization of desmosomal junctions was assessed by means of an immunochemical reaction on desmosomes and transmission electron microscopy. Confocal laser scanning microscopy (CLSM) was used to find evidence of the location of FD4 in the tissue. Furthermore, the increase of the FD4 apparent permeability coefficient was quantified by means of Franz diffusion cells using isolated buccal epithelium to demonstrate the penetration enhancement properties of the polymer systems. Morphological analysis, performed by light microscopy, transmission electron microscopy and CLSM, suggests a similar mechanism of penetration enhancement for both HCS and TMC solutions and for HCS nanoparticles. Such a mechanism probably involves a repackaging of the epithelial cells up to the basal membrane and a partial disarrangement of desmosomes. The cell viability and the nuclear integrity indicated on the semi-thin section stained with Toluidine blue and by CLSM analysis, respectively, suggest that HCS as a polymer solution and a nanoparticulate system, and TMC polymer solution, do not cause cell damage. Trimethyl chitosan and chitosan nanoparticulate systems were able to increase FD4 permeation across buccal epithelium to a greater extent than the chitosan solution.