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1.
JCO Precis Oncol ; 52021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34632253

RESUMEN

Comprehensive molecular profiling (CMP) plays an essential role in clinical decision making in metastatic non-small-cell lung cancer (mNSCLC). Circulating tumor DNA (ctDNA) analysis provides possibilities for molecular tumor profiling. In this study, we aim to explore the additional value of centralized ctDNA profiling next to current standard-of-care protocolled tissue-based molecular profiling (SoC-TMP) in the primary diagnostic setting of mNSCLC in the Netherlands. METHODS: Pretreatment plasma samples from 209 patients with confirmed mNSCLC were analyzed retrospectively using the NGS AVENIO ctDNA Targeted Kit (Roche Diagnostics, Basel, Switzerland) and compared with paired prospective pretreatment tissue-based molecular profiling from patient records. The AVENIO panel is designed to detect single-nucleotide variants, copy-number variations, insertions or deletions, and tyrosine kinase fusion in 17 genes. RESULTS: Potentially targetable drivers were detected with SoC-TMP alone in 34.4% of patients. Addition of clonal hematopoiesis of indeterminate potential-corrected, plasma-based CMP increased this to 39.7% (P < .001). Concordance between SoC-TMP and plasma-CMP was 86.6% for potentially targetable drivers. Clinical sensitivity of plasma-CMP was 75.2% for any oncogenic driver. Specificity and positive predictive value were more than 90% for all oncogenic drivers. CONCLUSION: Plasma-CMP is a reliable tool in the primary diagnostic setting, although it cannot fully replace SoC-TMP. Complementary profiling by combined SoC-TMP and plasma-CMP increased the proportion of patients who are eligible for targeted treatment.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante/genética , Neoplasias Pulmonares/genética , Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/aislamiento & purificación , Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico , Países Bajos , Estudios Prospectivos
2.
JTO Clin Res Rep ; 2(7): 100195, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34590040

RESUMEN

INTRODUCTION: Treatment patterns in stage III NSCLC can vary considerably between countries. The PACIFIC trial reported improvements in progression-free and overall survival with adjuvant durvalumab after concurrent chemoradiotherapy (CCRT). We studied treatment decision-making by three Dutch regional thoracic multidisciplinary tumor boards between 2015 and 2019, to identify changes in practice when adjuvant durvalumab became available. METHODS: Details of patients presenting with stage III NSCLC were retrospectively collected. Both CCRT and multimodality schemes incorporating planned surgery were defined as being radical-intent treatment (RIT). RESULTS: Of 855 eligible patients, most (95%) were discussed at a thoracic multidisciplinary tumor board, which recommended a RIT in 63% (n = 510). Only 52% (n = 424) of the patients finally received a RIT. Predictors for not recommending RIT were age greater than or equal to 70 years, WHO performance score greater than or equal to 2, Charlson comorbidity index greater than or equal to 2 (excluding age), forced expiratory volume in 1 second less than 80% of predicted value, N3 disease, and period of diagnosis. Between 2015 to 2017 and 2018 to 2019, the proportion of patients undergoing CCRT increased from 34% to 42% (p = 0.02) and use of sequential chemoradiotherapy declined (21%-16%, p = 0.05). Rates of early toxicity and 1-year mortality were comparable for both periods. After 2018, 57% of the patients who underwent CCRT (90 of 159) received adjuvant durvalumab. CONCLUSIONS: After publication of the PACIFIC trial, a significant increase was observed in the use of CCRT for patients with stage III NSCLC with rates of early toxicity and mortality being unchanged. Since 2018, 57% of the patients undergoing CCRT went on to receive adjuvant durvalumab. Nevertheless, approximately half of the patients were still considered unfit for a RIT.

3.
J Clin Med ; 9(6)2020 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-32575869

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease, characterized by fibroblast proliferation and extracellular matrix deposition. CC-chemokine ligand 18 (CCL18) upregulates the production of collagen by lung fibroblasts and is associated with mortality. This study was designed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the CCL18 gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in the CCL18 gene were analyzed in 77 Dutch IPF patients and 349 healthy controls (HCs). CCL18 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 18 healthy subjects. Survival analysis was conducted, dependent on CCL18-levels and -genotypes and validated in two German IPF cohorts (Part B). IPF patients demonstrated significantly higher serum CCL18 levels than the healthy controls (p < 0.001). Both in IPF patients and HCs, serum CCL18 levels were influenced by rs2015086 C > T genotype, with the highest CCL18-levels with the presence of the C-allele. Constitutive CCL18 mRNA-expression in PBMCs was significantly increased with the C-allele and correlated with serum CCL18-levels. In IPF, high serum levels correlated with decreased survival (p = 0.02). Survival was worse with the CT-genotype compared to the TT genotype (p = 0.01). Concluding, genetic variability in the CCL18-gene accounts for differences in CCL18 mRNA-expression and serum-levels and influences survival in IPF.

4.
Lung Cancer ; 134: 52-58, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31319995

RESUMEN

OBJECTIVES: Mediastinal lymph node staging of NSCLC by initial endosonography and confirmatory mediastinoscopy is recommended by the European guideline. We assessed guideline adherence on mediastinal staging, whether staging procedures were performed systematically and unforeseen N2 rates following staging by endosonography with or without confirmatory mediastinoscopy. MATERIAL AND METHODS: We performed a multicentre (n = 6) retrospective analysis of NSCLC patients without distant metastases, who were surgical candidates and had an indication for mediastinal staging in the year 2015. All patients who underwent EBUS, EUS and/or mediastinoscopy were included. Surgical lymph node dissection was the reference standard. Guideline adherence was based on the 2014 ESTS guideline. RESULTS: 330 consecutive patients (mean age 69 years; 61% male) were included. The overall prevalence of N2/N3 disease was 42%. Initial mediastinal staging by endosonography was done in 84% (277/330; range among centres 71-100%; p < .01). Confirmatory mediastinoscopy was performed in 40% of patients with tumour negative endosonography (61/154; range among centres 10%-73%; p < .01). Endosonography procedures were performed 'systematically' in 21% of patients (57/277) with significant variability among centres (range 0-56%; p < .01). Unforeseen N2 rates after lobe-specific lymph node dissection were 8.6% (3/35; 95%-CI 3.0-22.4) after negative endosonography versus 7.5% (3/40; 95% CI 2.6-19.9) after negative endosonography and confirmatory mediastinoscopy. CONCLUSION: Although adherence to the European NSCLC mediastinal staging guideline on initial use of endosonography was good, 30% of endosonography procedures were performed insufficiently. Confirmatory mediastinoscopy following negative endosonography was frequently omitted. Significant variability was found among participating centres regarding staging strategy and systematic performance of procedures. However, unforeseen N2 rates after mediastinal staging by endosonography with and without confirmatory mediastinoscopy were comparable.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Adhesión a Directriz , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Mediastino/patología , Estadificación de Neoplasias/métodos , Anciano , Anciano de 80 o más Años , Endosonografía/métodos , Femenino , Humanos , Masculino , Mediastinoscopía/métodos , Mediastino/diagnóstico por imagen , Persona de Mediana Edad , Países Bajos/epidemiología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Guías de Práctica Clínica como Asunto , Estudios Retrospectivos
5.
PLoS One ; 7(1): e30442, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22291954

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a devastating and progressive lung disease. Its aetiology is thought to involve damage to the epithelium and abnormal repair. Alveolar epithelial cells near areas of remodelling show an increased expression of proapoptotic molecules. Therefore, we investigated the role of genes involved in cell cycle control in IPF. Genotypes for five single nucleotide polymorphisms (SNPs) in the tumour protein 53 (TP53) gene and four SNPs in cyclin-dependent kinase inhibitor 1A (CDKN1A), the gene encoding p21, were determined in 77 IPF patients and 353 controls. In peripheral blood mononuclear cells (PBMC) from 16 healthy controls mRNA expression of TP53 and CDKN1A was determined. Rs12951053 and rs12602273, in TP53, were significantly associated with survival in IPF patients. Carriers of a minor allele had a 4-year survival of 22% versus 57% in the non-carrier group (p = 0.006). Rs2395655 and rs733590, in CDKN1A, were associated with an increased risk of developing IPF. In addition, the rs2395655 G allele correlated with progression of the disease as it increased the risk of a rapid decline in lung function. Functional experiments showed that rs733590 correlated significantly with CDKN1A mRNA expression levels in healthy controls. This is the first study to show that genetic variations in the cell cycle genes encoding p53 and p21 are associated with IPF disease development and progression. These findings support the idea that cell cycle control plays a role in the pathology of IPF. Variations in TP53 and CDKN1A can impair the response to cell damage and increase the loss of alveolar epithelial cells.


Asunto(s)
Genes cdc/genética , Fibrosis Pulmonar Idiopática/genética , Anciano , Estudios de Casos y Controles , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Frecuencia de los Genes , Genes p53 , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Fibrosis Pulmonar Idiopática/epidemiología , Fibrosis Pulmonar Idiopática/mortalidad , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Análisis de Supervivencia
6.
Respir Med ; 105(1): 106-13, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20888745

RESUMEN

BACKGROUND: The chitinase-like protein YKL-40 is a serum biomarker in diseases with fibrosis, inflammation and tissue remodelling. Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that is hallmarked by these processes. The aim of this study was to investigate the potential of YKL-40 as a prognostic biomarker for survival in IPF patients. METHODS: Serum and bronchoalveolar lavage fluid (BALF) levels of YKL-40 at the time of diagnosis and a promoter polymorphism in CHI3L1, the gene encoding YKL-40, were determined in 85 IPF patients and 126 controls. The relationship between YKL-40 levels and clinical parameters was evaluated. Kaplan-Meier and Cox regression analyses were used to examine the association between YKL-40 levels and survival. RESULTS: Serum and BALF YKL-40 levels were significantly higher in patients than in healthy controls (p < 0.001). The - 329 A/G polymorphism had a significant influence on BALF YKL-40 levels and the influence on serum YKL-40 levels showed a trend towards significance in IPF patients. IPF patients with high (> 79 ng/ml) serum or high BALF YKL-40 (> 17 ng/ml) levels had significantly shorter survival than those with low YKL-40 levels in serum or BALF. In patients with both low serum and low BALF YKL-40 levels no IPF related mortality was observed. Cox regression modelling showed that there were no confounding factors. CONCLUSIONS: The - 329 polymorphism was associated with serum and BALF YKL-40 levels in IPF patients. High serum and BALF YKL-40 levels are associated with poor survival in IPF patients and could be useful prognostic markers for survival in IPF.


Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Glicoproteínas/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Lectinas/metabolismo , Adipoquinas , Adulto , Anciano , Biomarcadores/análisis , Biomarcadores/metabolismo , Proteína 1 Similar a Quitinasa-3 , Femenino , Glicoproteínas/análisis , Glicoproteínas/genética , Humanos , Fibrosis Pulmonar Idiopática/mortalidad , Lectinas/análisis , Lectinas/genética , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Modelos de Riesgos Proporcionales
7.
Am J Respir Crit Care Med ; 182(11): 1419-25, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-20656946

RESUMEN

RATIONALE: Familial clustering of adult idiopathic interstitial pneumonias (IIP) suggests that genetic factors might play an important role in disease development. Mutations in the gene encoding surfactant protein C (SFTPC) have been found in children and families with idiopathic pneumonias, whereas cocarriage of a mutation in ATP-binding cassette subfamily A member 3 (ABCA3) was postulated to have a disease-modifying effect. OBJECTIVES: To investigate the contribution of SFTPC mutations to adult familial pulmonary fibrosis (FPF) and the disease-modifying effect of mutations in ABCA3 within their families. METHODS: Twenty-two unrelated patients with FPF (10%) were identified within our single-center cohort of 229 patients with IIP. SFTPC was sequenced in 20 patients with FPF and 20 patients with sporadic IIP. In patients with an SFTPC mutation, sequencing of ABCA3 was performed. Discovered variants were typed in more than 100 control subjects and 121 additional patients with sporadic IIP. MEASUREMENTS AND MAIN RESULTS: In 5/20 unrelated patients with FPF (25%; confidence interval, 10-49) a mutation in SFTPC was detected: M71V, IVS4+2, and three times I73T. No mutations were detected in the sporadic or control cohort. Patients with SFTPC mutations presented with a histopathological pattern of usual interstitial pneumonia and nodular septa thickening and multiple lung cysts in combination with ground glass or diffuse lung involvement on chest high-resolution computed tomography. Two variants in ABCA3 were found in adult patients with FPF but not in affected children. CONCLUSIONS: Mutations in SFTPC are a frequent cause of FPF in adult patients in our cohort. Nonclassifiable radiological patterns with cystic changes and histopathological patterns of usual interstitial pneumonia are characteristics of adult SFTPC mutation carriers.


Asunto(s)
Mutación/genética , Fibrosis Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Familia , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Neumonías Intersticiales Idiopáticas/complicaciones , Neumonías Intersticiales Idiopáticas/genética , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Genético/genética , Fibrosis Pulmonar/etiología , Estadísticas no Paramétricas
9.
Ned Tijdschr Geneeskd ; 153: B425, 2009.
Artículo en Holandés | MEDLINE | ID: mdl-19785823

RESUMEN

OBJECTIVE: To describe the clinical presentation, diagnosis, and prognosis of a cohort of Dutch patients with idiopathic pulmonary fibrosis (IPF), a serious and rapidly progressive lung disease belonging to the idiopathic interstitial pneumonias. DESIGN: Retrospective study of patient records. METHOD: The data from the clinical presentation, diagnosis, treatment and survival of all patients with IPF, diagnosed in the St. Antonius Hospital in Nieuwegein and University Medical Center Utrecht (UMCU), both in the Netherlands, during the period 1998-2007 were investigated. For the diagnosis, the criteria of the American Thoracic Society and the European Respiratory Society from 2002 were adhered to. RESULTS: The records of 113 patients satisfied the inclusion criteria. Mean age at the time of presentation was 61.9 (SD: 12.7) years and a strong male predominance was observed (90 men vs. 23 women). The most common complaints and symptoms at presentation were dyspnoea, cough, basal crepitations and clubbing of the nails. Lung function tests revealed restrictive lung function impairment and a reduced diffusing capacity. In 72% of cases the diagnosis IPF was histologically confirmed by open lung biopsy, which revealed a pattern of usual interstitial pneumonia (UIP). In 17% of patients it concerned a familial form of the disease with diagnosis at a younger age (average 52 years; SD: 14.8). The medical treatment mostly consisted of corticosteroids, which for half of the patients were administered in combination with an immunosuppressant such as azathioprine or cyclophosphamide. After screening, 28 patients were eligible for lung transplantation. Of these, 12 patients underwent a lung transplantation in the study period, 9 died and 7 are still on the waiting list. The median survival period was 3.9 years. CONCLUSION: In the cohort studied, IPF presented as a rapidly progressive disease with only a marginal response to medical treatment and a poor prognosis. It is important to differentiate IPF from other fibrotic interstitial lung diseases and to refer to a specialist centre, especially in the case of patients who could be eligible for a lung transplant or for participation in trials with new drugs.


Asunto(s)
Trasplante de Pulmón , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/terapia , Corticoesteroides/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Pronóstico , Fibrosis Pulmonar/mortalidad , Pruebas de Función Respiratoria , Estudios Retrospectivos , Factores Sexuales , Fumar/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Listas de Espera
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