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1.
Lung ; 202(2): 197-210, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480620

RESUMO

PURPOSE: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC). METHODS: Seventy-nine patients eligible to pembrolizumab regimens-alone or in combination with chemotherapy-as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS). RESULTS: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [-4.46 to -1.01]) and time-to death (-0.13 [-0.20 to -0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = -0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses. CONCLUSION: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Osteopontina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores
2.
Int J Mol Sci ; 24(5)2023 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-36901733

RESUMO

Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600- subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF/PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.


Assuntos
Ácidos Nucleicos Livres , Melanoma , Humanos , Variações do Número de Cópias de DNA , Sequenciamento do Exoma , Melanoma/genética , Melanoma/terapia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética
3.
Eur J Clin Invest ; 52(1): e13668, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34390488

RESUMO

BACKGROUND: High circulating levels of cellular adhesion molecules (CAMs) in non-small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre-treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC. MATERIALS AND METHODS: Seventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow-up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival ≥2 years or absence of disease progression at the end of the follow-up, and the overall survival. RESULTS: Composite outcome and overall survival were positively associated with VCAM-1 baseline levels and with the reduction of VCAM-1 during the treatment. After adjustment for potential confounders, the change in VCAM-1 serum levels during the treatment was an independent predictor of overall survival. CONCLUSIONS: High baseline serum levels of VCAM-1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Nivolumabe/uso terapêutico , Molécula 1 de Adesão de Célula Vascular/sangue , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Taxa de Sobrevida
4.
Int J Mol Sci ; 23(11)2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35682999

RESUMO

The study of circulating cancer-derived components (circulome) is considered the new frontier of liquid biopsy. Despite the recognized role of circulome biomarkers, their comparative molecular profiling is not yet routine. In advanced breast cancer (BC), approximately 40% of hormone-receptor-positive, HER2-negative BC cases harbor druggable PIK3CA mutations suitable for combined alpelisib/fulvestrant treatment. This pilot study investigates PIK3CA mutations in circulating tumor DNA (ctDNA), tumor cells (CTCs), and extracellular vesicles (EVs) with the aim of determining which information on molecular targetable profiling could be recollected in each of them. The in-depth molecular analysis of four BC patients demonstrated, as a proof-of-concept study, that it is possible to retrieve mutational information in the three components. Patient-specific PIK3CA mutations were found in both tissue and ctDNA and in 3/4 cases, as well as in CTCs, in the classical population (large-sized CD45-/EpCAM+/- cells), and/or in the "non-conventional" sub-population (smaller-sized CD44+/EpCAM-/CD45- cells). Consistent mutational profiles of EVs with CTCs suggest that they may have been released by CTCs. This preliminary evidence on the molecular content of the different circulating biomaterials suggests their possible function as a mirror of the intrinsic heterogeneity of BC. Moreover, this study demonstrates, through mutational assessment, the tumor origin of the different CTC sub-populations sustaining the translational value of the circulome for a more comprehensive picture of the disease.


Assuntos
Neoplasias da Mama , DNA Tumoral Circulante , Células Neoplásicas Circulantes , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , DNA Tumoral Circulante/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Molécula de Adesão da Célula Epitelial/genética , Feminino , Humanos , Mutação , Células Neoplásicas Circulantes/patologia , Projetos Piloto
5.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807876

RESUMO

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal-epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo
6.
Eur Radiol ; 30(12): 6808-6817, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32623505

RESUMO

OBJECTIVES: To correlate a CT-based semi-quantitative score of pulmonary involvement in COVID-19 pneumonia with clinical staging of disease and laboratory findings. We also aimed to investigate whether CT findings may be predictive of patients' outcome. METHODS: From March 6 to March 22, 2020, 130 symptomatic SARS-CoV-2 patients were enrolled for this single-center analysis and chest CT examinations were retrospectively evaluated. A semi-quantitative CT score was calculated based on the extent of lobar involvement (0:0%; 1, < 5%; 2:5-25%; 3:26-50%; 4:51-75%; 5, > 75%; range 0-5; global score 0-25). Data were matched with clinical stages and laboratory findings. Survival curves and univariate and multivariate analyses were performed to evaluate the role of CT score as a predictor of patients' outcome. RESULTS: Ground glass opacities were predominant in early-phase (≤ 7 days since symptoms' onset), while crazy-paving pattern, consolidation, and fibrosis characterized late-phase disease (> 7 days). CT score was significantly higher in critical and severe than in mild stage (p < 0.0001), and among late-phase than early-phase patients (p < 0.0001). CT score was significantly correlated with CRP (p < 0.0001, r = 0.6204) and D-dimer (p < 0.0001, r = 0.6625) levels. A CT score of ≥ 18 was associated with an increased mortality risk and was found to be predictive of death both in univariate (HR, 8.33; 95% CI, 3.19-21.73; p < 0.0001) and multivariate analysis (HR, 3.74; 95% CI, 1.10-12.77; p = 0.0348). CONCLUSIONS: Our preliminary data suggest the potential role of CT score for predicting the outcome of SARS-CoV-2 patients. CT score is highly correlated with laboratory findings and disease severity and might be beneficial to speed-up diagnostic workflow in symptomatic cases. KEY POINTS: • CT score is positively correlated with age, inflammatory biomarkers, severity of clinical categories, and disease phases. • A CT score ≥ 18 has shown to be highly predictive of patient's mortality in short-term follow-up. • Our multivariate analysis demonstrated that CT parenchymal assessment may more accurately reflect short-term outcome, providing a direct visualization of anatomic injury compared with non-specific inflammatory biomarkers.


Assuntos
Betacoronavirus , Infecções por Coronavirus/diagnóstico , Pulmão/diagnóstico por imagem , Pandemias , Pneumonia Viral/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Adulto , COVID-19 , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/epidemiologia , Prognóstico , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença
7.
Mol Med ; 25(1): 15, 2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-31029076

RESUMO

BACKGROUND: The demonstration of EGFR T790M gene mutation in plasma is crucial to assess the eligibility of Non Small Cell Lung Cancer (NSCLC) patients, who have acquired resistance to first or second generation Tyrosine Kinase Inhibitors (TKIs), to receive a subsequent treatment with osimertinib. Since circulating tumor DNA (ctDNA) is present in very low amounts in plasma, high sensitive and specific methods are required for molecular analysis. Improving sensitivity of T790M mutation detection in plasma ctDNA enables a larger number of NSCLC patients to receive the appropriate therapy without any further invasive procedure. METHODS: A tag-based next generation sequencing (NGS) platform capable of tagging rare circulating tumor DNA alleles was employed in this study for the identification of T790M mutation in 42 post-TKI NSCLC patients. RESULTS: Compared to Real Time PCR, tag-based NGS improved the T790M detection rate (42.85% versus 21.4%, respectively), especially in those cases with a low median mutation abundance (i.e. 0.24, range 0.07-0.78). Moreover, the tag-based NGS identified EGFR activating mutations more efficiently than Real Time PCR (85.7% versus 61.9% detection rate, respectively), particularly of the L858R variant type (0.06-0.75 mutation abundance range). Patients in whom the T790M mutation was detected in plasma, achieved an objective response to osimertinib (9/14, 64.28%). CONCLUSIONS: Tag-based NGS represents an accurate and sensitive tool in a clinical setting for non-invasive assessment and monitoring of T790M variant in NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/genética , Receptores ErbB/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Feminino , Humanos , Masculino , Mutação/genética
8.
Cancer Immunol Immunother ; 68(8): 1351-1358, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31327024

RESUMO

Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Imunoterapia/métodos , Neoplasias Pulmonares/diagnóstico , Nivolumabe/uso terapêutico , Pró-Proteína Convertase 9/sangue , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Itália , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento
9.
Eur Radiol ; 29(5): 2369-2377, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30552479

RESUMO

OBJECTIVES: To investigate the prognostic role of early post-infarction cardiac magnetic resonance (CMR) on long-term risk stratification of ST segment elevation myocardial infarction (STEMI) patients with preserved left ventricular ejection fraction (LVEF). METHODS: Seventy-seven STEMI patients treated by primary percutaneous coronary intervention (PCI) and LVEF > 50% at CMR were included. The median time between STEMI and CMR was 5 days (IQR 2-8). LV volumes and function, area at risk (on T2 weighted images), infarcted myocardium (on late enhanced images), intramyocardial hemorrhage, and early and late microvascular obstruction (MVO) were detected and measured. CMR tissue determinants were correlated with the incidence of major adverse cardiovascular events (MACEs) over a 5-year follow-up. RESULTS: During median follow-up of 4 years (range 3 to 5 years), eight (10%) patients experienced MACE, yielding an annualized event rate of 2.1%. All CMR tissue markers were not significantly different between MACE and no-MACE patients, except for the presence of late MVO (50% vs. 16%, respectively; p = 0.044) and its extent (2.30 ± 1.64 g vs. 0.18 ± 0.12 g, respectively; p = 0.000). From receiver-operating characteristic (ROC) curve (area under the curve 0.89; 95% confidence interval, 0.75-1.0; p = 0.000), late MVO extent > 0.385 g was a strong independent predictor of MACE at long-term follow-up (sensitivity = 87%, specificity = 90%; hazard ratio = 2.24; 95% confidence interval, 1.51-3.33; p = 0.000). CONCLUSIONS: Late MVO extent after primary PCI on CMR seems to be a strong predictor of MACE at 5-year follow-up in patients with LVEF > 50%. Noticeably, late MVO extent > 0.385 g provided relevant prognostic insights leading to improved long-term risk stratification. KEY POINTS: • Tissue markers provided by cardiac magnetic resonance aid in prognostic stratification after myocardial infarction • The occurrence of late microvascular obstruction after acute myocardial infarction increases risk of major adverse events at 5-year follow-up. • The greater microvascular obstruction extent on late gadolinium enhanced images is related to an increased risk of adverse events in patients with myocardial infarction and preserved left ventricular function.


Assuntos
Circulação Coronária/fisiologia , Estenose Coronária/diagnóstico , Microcirculação/fisiologia , Complicações Pós-Operatórias , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Estenose Coronária/epidemiologia , Estenose Coronária/fisiopatologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Itália/epidemiologia , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Prognóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Taxa de Sobrevida/tendências , Fatores de Tempo
10.
Nature ; 488(7409): 100-5, 2012 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-22832583

RESUMO

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.


Assuntos
Neoplasias Cerebelares/genética , Genoma Humano/genética , Meduloblastoma/genética , Envelhecimento/genética , Sequência de Aminoácidos , Transformação Celular Neoplásica , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/patologia , Criança , Cromatina/metabolismo , Cromossomos Humanos/genética , RNA Helicases DEAD-box/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Genômica , Proteínas Hedgehog/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Histona Desmetilases/genética , Humanos , Meduloblastoma/classificação , Meduloblastoma/diagnóstico , Meduloblastoma/patologia , Metilação , Mutação/genética , Taxa de Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Receptores Patched , Receptor Patched-1 , Fosfoproteínas Fosfatases/genética , Poliploidia , Receptores de Superfície Celular/genética , Análise de Sequência de RNA , Transdução de Sinais , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/metabolismo , beta Catenina/genética
12.
Int J Mol Sci ; 18(5)2017 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-28492516

RESUMO

Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma cfDNA quantification was performed by quantitative PCR (qPCR) whereas CTCs were isolated by the ScreenCell Cyto (ScreenCell, Paris, France) device and enumerated according to malignant features. Patients with baseline cfDNA higher than the median value (96.3 hTERT copy number) had a significantly worse overall survival (OS) and double the risk of death (hazard ratio (HR): 2.14; 95% confidence limits (CL) = 1.24-3.68; p-value = 0.006). Conversely, an inverse relationship between CTC median baseline number (6 CTC/3 mL of blood) and OS was observed. In addition, we found that in patients reporting stable disease (SD), the baseline cfDNA and CTCs were able to discriminate patients at high risk of poor survival. cfDNA demonstrated a more reliable biomarker than CTCs in the overall population. In the subgroup of SD patients, both biomarkers identified patients at high risk of poor prognosis who might deserve additional/alternative therapeutic interventions.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ácidos Nucleicos Livres/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Estudos de Coortes , Tratamento Farmacológico , Feminino , Humanos , Estimativa de Kaplan-Meier , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
13.
BMC Cancer ; 16: 692, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27578032

RESUMO

BACKGROUND: Next Generation Sequencing (NGS) has become a valuable tool for molecular landscape characterization of cancer genomes, leading to a better understanding of tumor onset and progression, and opening new avenues in translational oncology. Formalin-fixed paraffin-embedded (FFPE) tissue is the method of choice for storage of clinical samples, however low quality of FFPE genomic DNA (gDNA) can limit its use for downstream applications. METHODS: To investigate the FFPE specimen suitability for NGS analysis and to establish the performance of two solution-based exome capture technologies, we compared the whole-exome sequencing (WES) data of gDNA extracted from 5 fresh frozen (FF) and 5 matched FFPE lung adenocarcinoma tissues using: SeqCap EZ Human Exome v.3.0 (Roche NimbleGen) and SureSelect XT Human All Exon v.5 (Agilent Technologies). RESULTS: Sequencing metrics on Illumina HiSeq were optimal for both exome systems and comparable among FFPE and FF samples, with a slight increase of PCR duplicates in FFPE, mainly in Roche NimbleGen libraries. Comparison of single nucleotide variants (SNVs) between FFPE-FF pairs reached overlapping values >90 % in both systems. Both WES showed high concordance with target re-sequencing data by Ion PGM™ in 22 lung-cancer genes, regardless the source of samples. Exon coverage of 623 cancer-related genes revealed high coverage efficiency of both kits, proposing WES as a valid alternative to target re-sequencing. CONCLUSIONS: High-quality and reliable data can be successfully obtained from WES of FFPE samples starting from a relatively low amount of input gDNA, suggesting the inclusion of NGS-based tests into clinical contest. In conclusion, our analysis suggests that the WES approach could be extended to a translational research context as well as to the clinic (e.g. to study rare malignancies), where the simultaneous analysis of the whole coding region of the genome may help in the detection of cancer-linked variants.


Assuntos
Adenocarcinoma/genética , DNA de Neoplasias/análise , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Kit de Reagentes para Diagnóstico , Adenocarcinoma de Pulmão , Exoma , Formaldeído , Humanos , Inclusão em Parafina , Fixação de Tecidos
14.
Int J Mol Sci ; 16(12): 28765-82, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26633390

RESUMO

Next-generation sequencing (NGS) is a cost-effective technology capable of screening several genes simultaneously; however, its application in a clinical context requires an established workflow to acquire reliable sequencing results. Here, we report an optimized NGS workflow analyzing 22 lung cancer-related genes to sequence critical samples such as DNA from formalin-fixed paraffin-embedded (FFPE) blocks and circulating free DNA (cfDNA). Snap frozen and matched FFPE gDNA from 12 non-small cell lung cancer (NSCLC) patients, whose gDNA fragmentation status was previously evaluated using a multiplex PCR-based quality control, were successfully sequenced with Ion Torrent PGM™. The robust bioinformatic pipeline allowed us to correctly call both Single Nucleotide Variants (SNVs) and indels with a detection limit of 5%, achieving 100% specificity and 96% sensitivity. This workflow was also validated in 13 FFPE NSCLC biopsies. Furthermore, a specific protocol for low input gDNA capable of producing good sequencing data with high coverage, high uniformity, and a low error rate was also optimized. In conclusion, we demonstrate the feasibility of obtaining gDNA from FFPE samples suitable for NGS by performing appropriate quality controls. The optimized workflow, capable of screening low input gDNA, highlights NGS as a potential tool in the detection, disease monitoring, and treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares/genética , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Biologia Computacional/normas , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Controle de Qualidade , Sensibilidade e Especificidade , Fluxo de Trabalho
15.
Pediatr Blood Cancer ; 61(10): 1867-70, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24391119

RESUMO

While a polymorphism located within the promoter region of the MDM2 proto-oncogene, SNP309 (T > G), has previously been associated with increased risk and aggressiveness of neuroblastoma and other tumor entities, a protective effect has also been reported in certain other cancers. In this study, we evaluated the association of MDM2 SNP309 with outcome in 496 patients with neuroblastoma and its effect on MDM2 expression. No significant difference in overall or event-free survival was observed among patients with neuroblastoma with or without MDM2 SNP309. The presence of SNP309 does not affect MDM2 expression in neuroblastoma.


Assuntos
Neuroblastoma/genética , Neuroblastoma/mortalidade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-mdm2/genética , Intervalo Livre de Doença , Predisposição Genética para Doença , Genótipo , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Regiões Promotoras Genéticas/genética , Proto-Oncogene Mas
16.
Future Oncol ; 10(1): 79-90, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24328411

RESUMO

After several decades of modest results with nonspecific immune stimulants, immunotherapy has become an exciting approach in the treatment of cancer. Although non-small-cell lung cancer has not been considered an immunogenic disease for very long, a better understanding of tumor immunology and the identification of new targets have led to the development of many clinical trials of immune-based therapies for this neoplasm. Promising results from many clinical trials suggest that immunotherapy could be an effective strategy in the management of advanced non-small-cell lung cancer. Further studies are required to help clinicians in the selection of patients who are more likely to benefit from immunotherapy strategies by the identification of biomarkers and to understand when the combination of immunotherapy with other agents should be recommended.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/imunologia , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Ipilimumab , Neoplasias Pulmonares/metabolismo , Terapia de Alvo Molecular/métodos , Nivolumabe , Oligodesoxirribonucleotídeos/farmacologia , Oligodesoxirribonucleotídeos/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismo
17.
Expert Opin Pharmacother ; 25(8): 1051-1069, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38935538

RESUMO

INTRODUCTION: The treatment landscape of non-small cell lung cancer (NSCLC) has seen significant advancements in recent years, marked by a shift toward target agents and immune checkpoint inhibitors (ICIs). However, chemotherapy remains a cornerstone of treatment, alone or in combination. Microtubule-targeting agents, such as taxanes and vinca alkaloids, play a crucial role in clinical practice in both early and advanced settings in NSCLC. AREA COVERED: This review outlines the mechanisms of action, present significance, and prospective advancements of microtubule-targeting agents (MTAs), with a special highlight on new combinations in phase 3 trials. The online databases PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'Microtubule-targeting agents' and 'non-small cell lung cancer' or synonyms, with a special focus over the last 5 years of publications. EXPERT OPINION: Despite the emergence of immunotherapy, MTA remains crucial, often used alongside or after immunotherapy, especially in squamous cell lung cancer. Next-generation sequencing expands treatment options, but reliable biomarkers for immunotherapy are lacking. While antibody-drug conjugates (ADCs) show promise, managing toxicities remain vital. In the early stages, MTAs, possibly with ICIs, are standard, while ADCs may replace traditional chemotherapy in the advanced stages. Nevertheless, MTAs remain essential in subsequent lines or for patients with contraindications.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Moduladores de Tubulina , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Antineoplásicos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
18.
Int J Mol Sci ; 14(4): 7492-505, 2013 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-23567267

RESUMO

Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum consisting of four distinct subgroups: WNT, SHH, Group 3 and Group 4, which exhibit different molecular phenotypes. We studied the expression of Dickkopf (DKK) 1-4 family genes, inhibitors of the Wnt signaling cascade, in MB by screening 355 expression profiles derived from four independent datasets. Upregulation of DKK1, DKK2 and DKK4 mRNA was observed in the WNT subgroup, whereas DKK3 was downregulated in 80% MBs across subgroups with respect to the normal cerebellum (p < 0.001). Since copy number aberrations targeting the DKK3 locus (11p15.3) are rare events, we hypothesized that epigenetic factors could play a role in DKK3 regulation. Accordingly, we studied 77 miRNAs predicting to repress DKK3; however, no significant inverse correlation between miRNA/mRNA expression was observed. Moreover, the low methylation levels in the DKK3 promoters (median: 3%, 5% and 5% for promoter 1, 2 and 3, respectively) excluded the downregulation of gene expression by methylation. On the other hand, the treatment of MB cells with Trichostatin A (TSA), a potent inhibitor of histone deacetylases (HDAC), was able to restore both DKK3 mRNA and protein. In conclusion, DKK3 downregulation across all MB subgroups may be due to epigenetic mechanisms, in particular, through chromatin condensation.


Assuntos
Montagem e Desmontagem da Cromatina , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Meduloblastoma/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Quimiocinas , Criança , Pré-Escolar , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Metilação , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese
19.
Drug Discov Today ; 28(7): 103616, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37196761

RESUMO

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Circulating elements have gained significant interest in the diagnosis and prognosis of NSCLC patients. Among these, platelets (PLTs) and their derived extracellular vesicles (P-EVs) are emerging eligible biosources both in terms of number and carriers of genetic materials (RNA, proteins, and lipids). PLTs are mainly produced by the shedding of megakaryocytes and together with P-EVs, participate in a variety of pathological processes including thrombosis, tumor progression, and metastasis. Here, we performed an extensive literature review focusing on PLTs and P-EVs as potential diagnostic, prognostic, and predictive markers for NSCLC patient management.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Vesículas Extracelulares , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Plaquetas/metabolismo , Plaquetas/patologia , Neoplasias Pulmonares/metabolismo , Vesículas Extracelulares/metabolismo , Prognóstico
20.
Cancers (Basel) ; 15(17)2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37686579

RESUMO

BACKGROUND: Oncolytic viruses (OVs) have been utilized since 1990s for targeted cancer treatment. Our study examined the Measles-Mumps-Rubella (MMR) vaccine's cancer-killing potency against Glioblastoma (GBM), a therapy-resistant, aggressive cancer type. METHODOLOGY: We used GBM cell lines, primary GBM cells, and normal mice microglial cells, to assess the MMR vaccine's efficacy through cell viability, cell cycle analysis, intracellular viral load via RT-PCR, and Transmission Electron Microscopy (TEM). RESULTS: After 72 h of MMR treatment, GBM cell lines and primary GBM cells exhibited significant viability reduction compared to untreated cells. Conversely, normal microglial cells showed only minor changes in viability and morphology. Intracellular viral load tests indicated GBM cells' increased sensitivity to MMR viruses compared to normal cells. The cell cycle study also revealed measles and mumps viruses' crucial role in cytopathic effects, with the rubella virus causing cell cycle arrest. CONCLUSION: Herein the reported results demonstrate the anti-cancer activity of the MMR vaccine against GBM cells. Accordingly, the MMR vaccine warrants further study as a potential new tool for GBM therapy and relapse prevention. Therapeutic potential of the MMR vaccine has been found to be promising in earlier studies as well.

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