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1.
Cell Rep Med ; 5(5): 101549, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38703767

RESUMEN

There is a compelling need for approaches to predict the efficacy of immunotherapy drugs. Tumor-on-chip technology exploits microfluidics to generate 3D cell co-cultures embedded in hydrogels that recapitulate simplified tumor ecosystems. Here, we present the development and validation of lung tumor-on-chip platforms to quickly and precisely measure ex vivo the effects of immune checkpoint inhibitors on T cell-mediated cancer cell death by exploiting the power of live imaging and advanced image analysis algorithms. The integration of autologous immunosuppressive FAP+ cancer-associated fibroblasts impaired the response to anti-PD-1, indicating that tumors-on-chips are capable of recapitulating stroma-dependent mechanisms of immunotherapy resistance. For a small cohort of non-small cell lung cancer patients, we generated personalized tumors-on-chips with their autologous primary cells isolated from fresh tumor samples, and we measured the responses to anti-PD-1 treatment. These results support the power of tumor-on-chip technology in immuno-oncology research and open a path to future clinical validations.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Medicina de Precisión , Receptor de Muerte Celular Programada 1 , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Medicina de Precisión/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Dispositivos Laboratorio en un Chip , Inmunoterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Línea Celular Tumoral
2.
Cancer Control ; 30: 10732748231167257, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37386758

RESUMEN

INTRODUCTION: Gene copy number variations have theranostic impact and require reliable methods for their identification. We aimed to evaluate the reliability of combined next-generation sequencing (NGS) and digital droplet PCR (ddPCR) method for gene amplification evaluation. METHODS: We conducted a retrospective multicentric observational study. MET/ERBB2 amplifications were assessed in patients with lung or colorectal carcinoma (cohort A), from 2016 to 2020, by fluorescence in situ hybridization (FISH)/immunohistochemistry (IHC), NGS and ddPCR. NGS-based script and ddPCR were then used to detect amplifications of 7 additional oncogenes (EGFR, KRAS, BRAF, FGFR1, FGFR2, FGFR3, PIK3CA) in a cohort of patients (cohort B). RESULTS: 55 patients (9 control, 25 ERBB2-amplified and 21 MET-amplified) out of 3779 patients tested were included in cohort A. Correlation coefficient between NGS-based script and FISH/IHC results were .88 for MET (P < .001) and .89 (P < .001) for ERBB2. Using a threshold ratio of 1.56 with the NGS-based script, the sensitivity was 100% for both genes and the specificity 69% for MET and 90% for ERBB2, respectively. With an alternative 1.76 threshold, sensitivity was 94% for MET and 96% for ERBB2, while specificity was 85% for MET and 90% for ERBB2. Correlation coefficient between FISH and ddPCR ratio was .90 for MET and .88 for ERBB2. In both cohorts, NGS-based script and ddPCR results were significantly correlated regarding all genes (P < .001). CONCLUSION: Combined NGS-based script and ddPCR method is reliable and easily feasible for the detection of gene amplifications, providing useful data for guided therapy in cancer.


Asunto(s)
Neoplasias Colorrectales , Variaciones en el Número de Copia de ADN , Humanos , Hibridación Fluorescente in Situ , Adhesión en Parafina , Reproducibilidad de los Resultados , Estudios Retrospectivos , Oncogenes , Reacción en Cadena de la Polimerasa , Secuenciación de Nucleótidos de Alto Rendimiento , Pulmón , Neoplasias Colorrectales/genética , Formaldehído
3.
Eur Respir J ; 61(5)2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37080573

RESUMEN

Several reports have highlighted a potential role of autoreactive B-cells and autoantibodies that correlates with increased disease severity in patients with idiopathic pulmonary fibrosis (IPF). Here we show that patients with IPF have an altered B-cell phenotype and that those subjects who have autoantibodies against the intermediate filament protein periplakin (PPL) have a significantly worse outcome in terms of progression-free survival. Using a mouse model of lung fibrosis, we demonstrate that introducing antibodies targeting the endogenous protein PPL (mimicking naturally occurring autoantibodies seen in patients) directly in the lung increases lung injury, inflammation, collagen and fibronectin expression through direct activation of follicular dendritic cells, which in turn activates and drives proliferation of fibroblasts. This fibrocyte population was also observed in fibrotic foci of patients with IPF and was increased in peripheral blood of IPF patients compared to aged-matched controls. This study reiterates the complex and heterogeneous nature of IPF, identifying new pathways that may prove suitable for therapeutic intervention.


Asunto(s)
Autoanticuerpos , Fibrosis Pulmonar Idiopática , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Pulmón/metabolismo , Progresión de la Enfermedad , Fibroblastos/metabolismo
4.
Ann Pathol ; 43(3): 222-235, 2023 Jun.
Artículo en Francés | MEDLINE | ID: mdl-36997440

RESUMEN

The recent context of COVID-19 has renewed the interest of pathologists in diseases of infectious origin. This interest is even stronger in the gastrointestinal tract where symptoms are aspecific, often frustrating with a normal endoscopic appearance sometimes leading to diagnostic erraticity. In this context, systematic biopsies performed by the clinician are sometimes the only way to reach a diagnosis. Nevertheless, the precise diagnosis of these pathologies requires a good knowledge of the context in which they occur, the histopathological aspect and a rigorous analysis using special stains and/or immunohistochemical analyses. Some infectious diseases of the gastrointestinal tract are well known to pathologists who are widely called upon to diagnose them (Helicobacter pylori gastritis, Candida albicans oesophagitis or CMV colitis), but others are more difficult to diagnose. In this article, we will present, after having recalled the various useful special stains, rare or difficult to diagnose bacterial or parasitic pathologies "not to be missed" in the digestive tract.


Asunto(s)
COVID-19 , Enfermedades Transmisibles , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Humanos , Biopsia , Gastritis/patología , Colorantes , Infecciones por Helicobacter/diagnóstico
5.
Ann Pathol ; 43(3): 266-279, 2023 Jun.
Artículo en Francés | MEDLINE | ID: mdl-36828723

RESUMEN

Intra-epithelial lymphocytosis is an elementary lesion frequently observed in the gastrointestinal tract, which can be found from the esophagus to the colon. Many conditions of a varied nature (dysimmunitary diseases, drugs, infections…) are associated with intra-epithelial lymphocytosis, and the etiological diagnosis most often requires an anatomo-clinical correlation. The pathologist will have to identify histological lesions associated with intra-epithelial lymphocytosis allowing the diagnosis to be oriented in order to propose appropriate treatment. In this review, the main entities associated with digestive intra-epithelial lymphocytosis will be presented, detailing the key elements allowing their diagnosis.


Asunto(s)
Enfermedad Celíaca , Linfocitosis , Humanos , Linfocitosis/etiología , Linfocitosis/complicaciones , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/patología , Colon/patología , Linfocitos/patología , Esófago/patología
7.
ERJ Open Res ; 7(1)2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33816604

RESUMEN

ERBB4 fusion is a rare, novel oncogenic event involved in the development of lung adenocarcinoma that is not routinely looked for, although ERBB4 fusion is a potential target for existing pan-ErbB tyrosine kinase and must be implemented in the laboratory https://bit.ly/3nYmGQ9.

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