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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.
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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 , FormaldehídoRESUMEN
Rosai-Dorfman-Destombes histiocytosis is a rare histiocytosis characterized by an accumulation of histiocytes within the tissues. It is a heterogeneous entity with various clinical phenotypes: isolated lymph nodes, in association with extranodal involvement, autoimmune disease or neoplasm. These extra nodal lesions mainly affect the skin, the nasal cavity, orofacial sinuses, or are lytic bone lesions or even damage to the central nervous system. The diagnosis is histopathological. We present here the case of a histiocytosis of Rosai-Dorfman-Destombes in a 46-year-old patient with a lesion of the left palate. Our observation discuss the diagnostic hypotheses in front of a lytic lesion of the ENT sphere predominantly histiocytic.
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Histiocitosis Sinusal , Histiocitosis , Histiocitos/patología , Histiocitosis/patología , Histiocitosis Sinusal/diagnóstico , Histiocitosis Sinusal/patología , Humanos , Ganglios Linfáticos/patología , Piel/patologíaRESUMEN
INTRODUCTION: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. METHODS: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). RESULTS: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations. CONCLUSION: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.
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Tumor Carcinoide/genética , Tumor Carcinoide/patología , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genómica , Humanos , Masculino , Persona de Mediana Edad , Mutación , Clasificación del TumorRESUMEN
BACKGROUND: Choroidal metastases are the most common eye metastatic site. The prevalence of choroidal metastases in NSCLC patients has been reported to vary from 0.2 to 7% in historical series. Although previously reported, little is known about choroidal metastasis in Epidermal Growth Factor Receptor (EGFR)-mutant Non-small cell lung cancer (NSCLC). This study sought to describe the prevalence of choroidal metastases among patients with EGFR-mutated NSCLC and their characteristics, and to estimate their impact on prognosis. METHODS: We conducted a single-center retrospective study including all consecutive metastatic EGFR-mutant NSCLC patients, from Sept. 2015 to Oct. 2018. The EGFR-mutant NSCLC patients were identified via the Department of Genetics' files. Patients who exhibited choroidal metastases were compared to patients without choroidal metastases. Kaplan-Meier analysis and log-rank test were conducted to assess median overall survival (OS) from diagnosis for the two groups. The study was approved by the IRB as CEPRO number #2020-010. RESULTS: Prevalence of choroidal metastases in EGFR-mutated NSCLCs was 8.4% (7/83). Five were women, and four current or former smokers. Molecular analysis showed three tumors with exon 19 deletion, three with L858R mutation, and one with complex exon 21 mutation. The choroidal metastases were symptomatic in six/seven patients. Visual disturbances decreased in all but one symptomatic cases upon EGFR TKI, and the choroidal response was maintained over time. Median follow-up was 42.2 mo (95%CI [37.2-47.1]). Median OS in the choroidal metastasis group was 23.4 mo (95%CI [0.1-51.4]) versus 27.9 mo (95%CI [16.9-38.9]) in the non-choroidal metastasis group (p = 0.32). In the choroidal metastasis group, 2-year and 5-year OS were 47.6 and 0%, respectively, versus 55.8 and 26.3% in the non-choroidal metastasis subset. CONCLUSIONS: Choroidal metastases in NSCLC EGFR-mutant patients are rare but should be systematically suspected in case of visual disturbance. TKIs are efficient for treating visual symptoms. Whether choroidal metastases confer a worse prognosis remains unclear owing to the third-generation EGFR TKI osimertinib first-line registration.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/farmacología , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Hiperplasia , Células Neuroendocrinas , Humanos , Hiperplasia/patología , Pulmón/patología , Pulmón/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico por imagen , Células Neuroendocrinas/patología , Pleura/patología , Pleura/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Acinic cell carcinoma (ACC) is a low grade malignant tumor of the salivary glands. Primary ACC affects most frequently the parotid gland and can rarely arise in the minor salivary glands of the oral cavity, pharynx and larynx. It is extremely rare in the nasal cavity; to our knowledge only 18 cases of primary ACC of the nasal cavity are reported in the English-written literature. Herein we report a case of acinic cell carcinoma of the nasal cavity, describe the clinical, radiological and microscopic features of this uncommon presentation and finally provide a discussion in the light of relevant literature.
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Carcinoma de Células Acinares , Cavidad Nasal , Tabique Nasal , Neoplasias Nasales , Neoplasias de las Glándulas Salivales , Adulto , Biopsia , Carcinoma de Células Acinares/diagnóstico por imagen , Carcinoma de Células Acinares/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Cavidad Nasal/diagnóstico por imagen , Cavidad Nasal/patología , Tabique Nasal/diagnóstico por imagen , Tabique Nasal/patología , Neoplasias Nasales/diagnóstico por imagen , Neoplasias Nasales/patología , Neoplasias de las Glándulas Salivales/diagnóstico por imagen , Neoplasias de las Glándulas Salivales/patologíaRESUMEN
BACKGROUND: Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). METHODS: Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. RESULTS: Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. CONCLUSIONS: This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.
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Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Estudios RetrospectivosAsunto(s)
Anemia Aplásica , Timoma , Neoplasias del Timo , Anemia Aplásica/complicaciones , Anemia Aplásica/diagnóstico , Anemia Aplásica/epidemiología , Humanos , Encuestas y Cuestionarios , Timoma/complicaciones , Timoma/diagnóstico , Timoma/epidemiología , Neoplasias del Timo/complicaciones , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/epidemiologíaRESUMEN
Pulmonary hypertension (PH) is associated with pulmonary vasoconstriction and endothelial dysfunction leading to impaired nitric oxide (NO) and prostacyclin (PGI2) pathways. Metformin, the first line treatment for type 2 diabetes and AMP-activated protein kinase (AMPK) activator, has been recently highlighted as a potential PH treatment. AMPK activation has been reported to improve endothelial function by enhancing endothelial NO synthase (eNOS) activity and to have relaxant effects in blood vessels. In this study, we examined the effect of metformin treatment on PH as well as on NO and PGI2 pathways in monocrotaline (MCT)-injected rats with established PH. Moreover, we investigated the anti-contractile effects of AMPK activators on endothelium-denuded human pulmonary arteries (HPA) from Non-PH and Group 3 PH patients (due to lung diseases and/or hypoxia). Furthermore, we explored the interaction between treprostinil and the AMPK/eNOS pathway. Our results showed that metformin protected against PH progression in MCT rats where it reduced the mean pulmonary artery pressure, pulmonary vascular remodeling and right ventricular hypertrophy and fibrosis compared to vehicle-treated MCT rats. The protective effects on rat lungs were mediated in part by increasing eNOS activity and protein kinase G-1 expression but not through the PGI2 pathway. In addition, incubation with AMPK activators reduced the phenylephrine-induced contraction of endothelium-denuded HPA from Non-PH and PH patients. Finally, treprostinil also augmented eNOS activity in HPA smooth muscle cells. In conclusion, we found that AMPK activation can enhance the NO pathway, attenuate vasoconstriction by direct effects on smooth muscles, and reverse established MCT-induced PH in rats.
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Diabetes Mellitus Tipo 2 , Hipertensión Pulmonar , Metformina , Ratas , Humanos , Animales , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/prevención & control , Arteria Pulmonar , Metformina/efectos adversos , Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Monocrotalina/efectos adversosAsunto(s)
Enfermedades de los Genitales Masculinos/patología , Granuloma de Células Plasmáticas/patología , Enfermedad Relacionada con Inmunoglobulina G4/patología , Adulto , Fibrosis , Enfermedades de los Genitales Masculinos/diagnóstico por imagen , Granuloma de Células Plasmáticas/diagnóstico por imagen , Humanos , Inmunoglobulina G/análisis , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico por imagen , Masculino , Células Plasmáticas/química , Células Plasmáticas/patología , Escroto/patologíaRESUMEN
Walking speed (WS) has emerged as a potential predictor of mortality in elderly cancer patients, yet data involving non-small-cell lung cancer (NSCLC) patients are scarce. Our prospective exploratory study sought to determine whether WS would predict early death or toxicity in patients with advanced NSCLC receiving first-line systemic intravenous treatment. Overall, 145 patients of ≥70 years were diagnosed with NSCLC over 19 months, 91 of whom displayed locally-advanced or metastatic cancer. As first-line treatment, 21 (23%) patients received best supportive care, 13 (14%) targeted therapy, and 57 (63%) chemotherapy or immunotherapy. Among the latter, 38 consented to participate in the study (median age: 75 years). Median cumulative illness rating scale for geriatrics (CIRS-G) was 10 (IQR: 8−12), and median WS 1.09 (IQR: 0.9−1.31) m/s. Older age (p = 0.03) and comorbidities (p = 0.02) were associated with Grade 3−4 treatment-related adverse events or death within 6 months of accrual. Overall survival was 14.3 (IQR: 6.1-NR) months for patients with WS < 1 m/s versus 17.3 (IQR: 9.2−26.5) for those with WS ≥ 1 m/s (p = 0.78). This exploratory study revealed WS to be numerically, yet not significantly, associated with early mortality in older metastatic NSCLC patients. Following these hypothesis-generating results, a larger prospective, multicenter study appears to be required to further investigate this outcome.
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BACKGROUND: Computed tomography (CT) screening has improved lung cancer survival, yet increasingly detects small lung lesions. Thus, the number of transthoracic lung biopsies (TTLB) for small nodules is expected to rise significantly. The aim of the present study was to evaluate the diagnostic accuracy and safety of CT-guided TTLB for nodules ≤20â mm versus nodules >20â mm. STUDY DESIGN AND METHODS: Data for CT-guided TTLBs from 474 consecutive patients were prospectively collected over a 3-year period (198 lesions ≤20â mm and 276 lesions >20â mm) in a teaching hospital and analysed in terms of diagnostic performance and complications. RESULTS: There were more conclusive biopsies in the >20â mm lesion group (n=236, 85.5%) than in ≤20â mm lesion group (n=140, 70.7%; p<0.001). The overall accuracy, sensitivity, specificity and negative predictive value for diagnosing malignant lesions after first TTLB were 88.4%, 84%, 100% and 70.1%, respectively, for ≤20â mm lesions, and 94.2%, 93%, 100% and 74.6%, respectively, for >20â mm lesions. Pneumothorax requiring drainage was significantly more common for ≤20â mm lesions, compared to TTLB of larger lesions (9.6% versus 4.3%; p=0.02). Prolonged hospital stay due to pneumothorax occurred in 27 (17.4%) TTLBs of ≤20â mm lesions and 15 (7%) TTLBs of >20â mm lesions (p=0.002). There were no deaths. The only variable significantly associated with diagnostic failure in the ≤20â mm lesion group was the radiologist's experience. INTERPRETATION: TTLBs for lesions ≤20â mm were associated with slightly lower diagnostic performance, whereas the higher rate of major complications was still inferior to that extrapolated from United States insurance databases.
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BACKGROUND: Diagnosis of interstitial lung disease is based on the analysis of clinical, biological, radiological, and pathological findings during a multidisciplinary discussion (MDD). When a definitive diagnosis is not possible, guidelines recommend obtaining lung samples through surgical lung biopsy (SLB). We sought to determine morbidity, mortality, diagnostic yield, and therapeutic impact of SLB in the management of patients with interstitial lung disease. METHODS: We retrospectively analyzed morbidity, mortality, diagnostic yield, and therapeutic changes after SLB for interstitial lung disease performed electively from January 2015 to May 2019 in a reference center. Each case was reviewed during 2 MDDs, first without and then with the result of the SLB. RESULTS: The study group included 73 patients (56% male, age 66 [interquartile range (IQR), 57-70] years, forced vital capacity 79% [IQR, 69%-91%], diffusing capacity of the lungs for carbon monoxide 52% [IQR, 46%-63%]). Median postoperative hospital length of stay was 2 (IQR, 0-11) days. Thirteen (17%) patients experienced at least 1 complication, including pain at 1 month (n = 8) and residual pneumothorax (n = 6). No serious complication or postoperative death was noticed. After the first retrospective MDD, the working diagnosis was idiopathic nonspecific interstitial pneumonia in 20 (27%), idiopathic pulmonary fibrosis in 18 (25%), fibrotic hypersensitivity pneumonitis in 15 (21%), unclassifiable interstitial lung disease in 5 (7%), and other diagnosis in 15 (21%) patients. After SLB and second retrospective MDD, the final diagnosis was modified in 35 (48%) patients and led to therapeutic changes in 33 (45%) patients. CONCLUSIONS: SLB is associated with no serious complication or death and notably changes the diagnosis and treatment of interstitial lung disease.
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Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Anciano , Biopsia/efectos adversos , Femenino , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/cirugía , Pulmón/cirugía , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/cirugía , Masculino , Estudios RetrospectivosRESUMEN
Lysosomes are intracellular organelles that are responsible for degrading and recycling macromolecules. Lysosomal storage diseases (LSDs) are a group of inherited diseases caused by mutations affecting genes that encode the function of the lysosomal enzymes. Three LSDs are associated with lung involvement and/or interstitial lung disease (ILD): Gaucher disease (GD); Niemann-Pick disease, also known as acid sphingomyelinase deficiency (ASMD); and Fabry disease (FD). In GD and in ASMD, analysis of bronchoalveolar lavage fluid and lung biopsy can be informative, showing foamy cells. In GD, ILD is rare. Enzyme replacement therapy (ERT) has been available since 1991 and has greatly changed the natural history of GD, with pulmonary failure and death reported before the ERT era. In ASMD, ILD is frequent and is usually associated with spleen enlargement, low platelet cell count and low level of high-density lipoprotein-cholesterol. Results of ERT are promising regarding preliminary results of olipudase alfa in paediatric and adult ASMD populations. The most frequent respiratory manifestation in FD is COPD-like symptoms regardless of smoking habit and dyspnoea due to congestive heart failure. Early diagnosis of these three LSDs is crucial to prevent irreversible organ damage. Early initiation of ERT can, at least in part, prevent organ failure.
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Enfermedades Pulmonares Intersticiales , Enfermedades por Almacenamiento Lisosomal , Enfermedad de Niemann-Pick Tipo A , Enfermedades de Niemann-Pick , Niño , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , LisosomasRESUMEN
INTRODUCTION: Prostacyclin (PGI2) is synthetized by PGI2 synthase (PGIS) and induces vasorelaxation via activation of cyclic AMP (cAMP) generating IP-receptor. Several components of the PGI2 signaling pathway are reduced in patients with pulmonary hypertension (PH). AIM: To study the effect of 17ß-estradiol (E2) on the PGI2 signaling pathway in human pulmonary arteries (HPA) and in their smooth muscle cells (hPASMC) derived from Group-3 PH and non-PH patients. METHODS: Following E2-treatments of isolated HPA and cultured hPASMC, we measured: 6-keto-Prostaglandin F1α (PGI2 stable metabolite) by ELISA, PGIS and IP protein levels by Western blot and HPA vasorelaxations with an organ bath system. RESULTS: Incubation with E2 (24/48 h, doses ≥ 10 nM) significantly increased the expression of PGIS in hPASMC derived from both PH (65-98%) and non-PH (21-33%) patients, whereas incubation with E2 (2 h, 0.1 and 1 µM) increased 6-keto-PGF1α production in HPA from Group-3 PH patients only, and did not affect 6-keto-PGF1α production in hPASMC from either non-PH or Group-3 PH patients. Increases in IP receptor expression were observed following 10 mM E2-treatment of hPASMC from non-PH (33% after 48 h) and Group-3 PH (23% after 24 h) patient lungs. Finally, preincubation with 100 nM E2 significantly increased arachidonic acid-induced vasorelaxation of HPA from non-PH patient lungs but not of HPA from Group-3 PH patient lungs. CONCLUSION: E2-treatment may help to restore the PGI2-pathway in Group-3 PH.
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6-Cetoprostaglandina F1 alfa/metabolismo , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Estradiol/farmacología , Estrógenos/farmacología , Hipertensión Pulmonar/metabolismo , Oxidorreductasas Intramoleculares/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Antihipertensivos/farmacología , Ácido Araquidónico/farmacología , Estudios de Casos y Controles , Sistema Enzimático del Citocromo P-450/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Epoprostenol/análogos & derivados , Epoprostenol/farmacología , Femenino , Humanos , Hipertensión Pulmonar/fisiopatología , Oxidorreductasas Intramoleculares/metabolismo , Masculino , Persona de Mediana Edad , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/metabolismo , Arteria Pulmonar/citología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatologíaRESUMEN
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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Pulmonary hypertension (PH) is a progressive and life-threating lung disorder characterized by elevated pulmonary artery pressure and vascular remodeling. PH is classified into five groups, and one of the most common and lethal forms, PH Group-III is defined as PH due to lung diseases and/or hypoxia. Due to the lack of studies in this group, PH-specific drug therapies including prostacyclin (PGI2) analogues have not been approved or recommended for use in these patients. PGI2 is synthesized by the PGI2 synthase (PGIS) enzyme, and its production is determined by measuring its stable metabolite, 6-keto-PGF1α. An impaired PGI2 pathway has been observed in PH animal models and in PH Group-I patients; however, there are contradictory results. The aim of this study is to determine whether PH Group-III is associated with altered expression of PGIS and production of PGI2 in humans. To explore this hypothesis, we measured PGIS expression (by western blot) and PGI2 production (by ELISA) in a large variety of preparations from the pulmonary circulation including human pulmonary artery, pulmonary vein, distal lung tissue, pulmonary artery smooth muscle cells (hPASMC), and bronchi in PH Group-III (n = 35) and control patients (n = 32). Our results showed decreased PGIS expression and/or 6-keto-PGF1α levels in human pulmonary artery, hPASMC, and distal lung tissue derived from PH Group-III patients. Moreover, the production of 6-keto-PGF1α from hPASMC positively correlated with PGIS expression and was inversely correlated with mean pulmonary artery pressure. On the other hand, PH Group-III pulmonary veins and bronchi did not show altered PGI2 production compared to controls. The deficit in PGIS expression and/or PGI2 production observed in pulmonary artery and distal lung tissue in PH Group-III patients may have important implications in the pathogenesis and treatment of PH Group-III.
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Sistema Enzimático del Citocromo P-450/metabolismo , Epoprostenol/metabolismo , Hipertensión Pulmonar/metabolismo , Oxidorreductasas Intramoleculares/metabolismo , Arteria Pulmonar/metabolismo , Bronquios/enzimología , Bronquios/metabolismo , Hipoxia de la Célula/fisiología , Células Cultivadas , Dinoprost/metabolismo , Regulación hacia Abajo , Femenino , Humanos , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/fisiopatología , Pulmón/enzimología , Pulmón/metabolismo , Masculino , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/metabolismo , Arteria Pulmonar/enzimología , Venas Pulmonares/enzimología , Venas Pulmonares/metabolismoRESUMEN
A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFß signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGFß-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance. SIGNIFICANCE: Our work provides a significant advance in characterizing and understanding FAP+ CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies.This article is highlighted in the In This Issue feature, p. 1241.
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Fibroblastos Asociados al Cáncer/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias/tratamiento farmacológico , Escape del Tumor , Microambiente Tumoral/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Línea Celular Tumoral , Conjuntos de Datos como Asunto , Resistencia a Antineoplásicos/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/cirugía , Cultivo Primario de Células , RNA-Seq , Análisis de la Célula Individual , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
BACKGROUND: The development of pulmonary hypertension (PH) during the course of COPD is a well-known phenomenon, with the prevalence depending on the severity of airway obstruction. When mean pulmonary pressure (mPAP) level at rest is ≥ 35 mm Hg or ≥ 25 mm Hg with low cardiac index, the term severe PH is used. For these patients, little is known on the underlying histologic lesions. Our objective was to describe these lesions. METHODS: From the explants of patients undergoing lung transplantation, we compared retrospectively three groups of patients with COPD: severe PH-COPD (n = 10), moderate PH-COPD (mPAP between 25 and 34 mm Hg without low cardiac index) (n = 10), and no PH (mPAP < 25 mm Hg) (n = 10). Histologic analysis of the explanted lungs examined the wall of medium-size arteries, the remodeling of microvessels, and the pulmonary capillary density using morphometric measurements performed on three sections per patient. RESULTS: Compared with the moderate PH group, the remodeling score of the microvessels was significantly higher (P = .0045) and the capillary density was lower (P = .0049) in the severe PH-COPD group. The alterations of the medium-size arteries, important in group 1 PH, seemed less discriminating. CONCLUSIONS: Patients with severe PH-COPD appear to have a specific histologic pattern, different from that observed in patients with COPD with moderate PH or without PH.
Asunto(s)
Hipertensión Pulmonar/patología , Arteria Pulmonar/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Femenino , Humanos , Hipertensión Pulmonar/etiología , Trasplante de Pulmón , Masculino , Microcirculación , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/cirugía , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Anaplastic lymphoma kinase (ALK) rearrangement is reported in 3% to 8% of patients with lung adenocarcinoma and can be detected by fluorescent in situ hybridization (FISH) or indirectly by immunohistochemistry. In FISH assay, isolated 5' signal (loss of 3' signal) is usually considered negative. We report three young nonsmoking patients with stage IV lung adenocarcinoma. Strong ALK expression in tumor cells detected by immunohistochemistry was observed in all cases, but FISH revealed an isolated 5' signal pattern. Massive parallel "next-generation" sequencing was performed in two patients and confirmed ALK rearrangement. The three patients were treated and responded to crizotinib after 14, 10, and 31â¯months.