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1.
Anticancer Res ; 41(8): 3933-3940, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281856

RESUMO

BACKGROUND: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. PATIENTS AND METHODS: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. RESULTS: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). CONCLUSION: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Idoso , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Carga Tumoral
2.
Tumour Biol ; 43(1): 115-127, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34219680

RESUMO

BACKGROUND: The widespread introduction of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) has led to durable responses but still many patients fail and are treated beyond progression. OBJECTIVE: This study investigated whether readily available blood-based tumor biomarkers allow accurate detection of early non-responsiveness, allowing a timely switch of therapy and cost reduction. METHODS: In a prospective, observational study in patients with NSCLC treated with nivolumab or pembrolizumab, five serum tumor markers were measured at baseline and every other week. Six months disease control as determined by RECIST was used as a measure of clinical response. Patients with a disease control <  6 months were deemed non-responsive. For every separate tumor marker a criterion for predicting of non-response was developed. Each marker test was defined as positive (predictive of non-response) if the value of that tumor marker increased at least 50% from the value at baseline and above a marker dependent minimum value to be determined. Also, tests based on combination of multiple markers were designed. Specificity and sensitivity for predicting non-response was calculated and results were validated in an independent cohort. The target specificity of the test for detecting non-response was set at >  95%, in order to allow its safe use for treatment decisions. RESULTS: A total of 376 patients (training cohort: 180, validation cohort: 196) were included in our analysis. Results for the specificity of the single marker tests in the validation set were CEA: 98·3% (95% CI: 90·9-100%), NSE: 96·5% (95% CI: 87·9-99·6%), SCC: 96·5% (95% CI: 88·1-99·6%), Cyfra21·1 : 91.8% (95% CI: 81·9-97·3%), and CA125 : 86·0% (95% CI: 74·2-93·7%). A test based on the combination of Cyfra21.1, CEA and NSE accurately predicted non-response in 32.3% (95% CI 22.6-43.1%) of patients 6 weeks after start of immunotherapy. Survival analysis showed a significant difference between predicted responders (Median PFS: 237 days (95% CI 184-289 days)) and non-responders (Median PFS: 58 days (95% CI 46-70 days)) (p <  0.001). CONCLUSIONS: Serum tumor marker based tests can be used for accurate detection of non-response in NSCLC, thereby allowing early and safe discontinuation of immunotherapy in a significant subset of patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Imunoterapia/mortalidade , Neoplasias Pulmonares/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Técnicas de Apoio para a Decisão , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
3.
Cancer Sci ; 112(9): 3437-3454, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34152672

RESUMO

Metastasis is the main cause of death in individuals with cancer. Immune checkpoint blockade (ICB) can potentially reverse CD8+ cytotoxic T lymphocytes (CTLs) dysfunction, leading to significant remission in multiple cancers. However, the mechanism underlying the development of CTL exhaustion during metastatic progression remains unclear. Here, we established an experimental pulmonary metastasis model with melanoma cells and discovered a critical role for melanoma-released exosomes in metastasis. Using genetic knockdown of nSMase2 and Rab27a, 2 key enzymes for exosome secretion, we showed that high levels of effector-like tumor-specific CD8+ T cells with transitory exhaustion, instead of terminal exhaustion, were observed in mice without exosomes; these cells showed limited inhibitory receptors and strong proliferation and cytotoxicity. Mechanistically, the immunosuppression of exosomes depends on exogenous PD-L1, which can be largely rescued by pretreatment with antibody blockade. Notably, we also found that exosomal PD-L1 acts as a promising predictive biomarker for ICB therapies during metastasis. Together, our findings suggest that exosomal PD-L1 may be a potential immunotherapy target, suggesting a new curative therapy for tumor metastasis.


Assuntos
Antígeno B7-H1/metabolismo , Exossomos/metabolismo , Tolerância Imunológica , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Melanoma/metabolismo , Melanoma/patologia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva/métodos , Idoso , Animais , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Masculino , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Esfingomielina Fosfodiesterase/deficiência , Esfingomielina Fosfodiesterase/genética , Resultado do Tratamento , Proteínas rab27 de Ligação ao GTP/deficiência , Proteínas rab27 de Ligação ao GTP/genética
4.
Nat Biomed Eng ; 5(6): 586-599, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34131323

RESUMO

The low abundance of circulating tumour DNA (ctDNA) in plasma samples makes the analysis of ctDNA biomarkers for the detection or monitoring of early-stage cancers challenging. Here we show that deep methylation sequencing aided by a machine-learning classifier of methylation patterns enables the detection of tumour-derived signals at dilution factors as low as 1 in 10,000. For a total of 308 patients with surgery-resectable lung cancer and 261 age- and sex-matched non-cancer control individuals recruited from two hospitals, the assay detected 52-81% of the patients at disease stages IA to III with a specificity of 96% (95% confidence interval (CI) 93-98%). In a subgroup of 115 individuals, the assay identified, at 100% specificity (95% CI 91-100%), nearly twice as many patients with cancer as those identified by ultradeep mutation sequencing analysis. The low amounts of ctDNA permitted by machine-learning-aided deep methylation sequencing could provide advantages in cancer screening and the assessment of treatment efficacy.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Aprendizado de Máquina/estatística & dados numéricos , Adulto , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , DNA Tumoral Circulante/sangue , Metilação de DNA , Detecção Precoce de Câncer/métodos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA/métodos
5.
Int J Cancer ; 149(6): 1385-1397, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-33961700

RESUMO

Detection of tumour-specific circulating cell-free DNA in plasma (ctDNA) fails in a significant number of cases depending on the clinical context. The primary aim was to investigate clinicopathological factors associated with detection of ctDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer (mCRC) prior to first-line therapy. A secondary aim was to evaluate the prognostic impact of ctDNA compared to other biomarkers. Patients were included from the NORDIC-VII study (N = 253). ctDNA was sampled prior to treatment and analysed for hotspot tissue mutations (KRAS, NRAS, and BRAF) using droplet digital PCR. Multivariable regression models were constructed to predict the probability of mutation detection and survival. Increasing radiological size of target lesions by increments of 1 cm (odds ratio [OR] = 1.18; 95% confidence interval [CI] 1.09-1.27; P < .001), intact primary tumour (OR = 3.17; 95% CI 1.22-8.22; P = .018) and more than one metastatic site (OR = 3.08; 95% CI 1.32-7.19; P = .009) were associated with mutation detection in plasma. Metastatic involvement of the lung was associated with non-detection (OR = 0.26; 95% CI 0.12-0.58; P = .001). Preanalytical and analytical factors modulated detection. High allele frequencies of ctDNA indicated poor prognosis independently of CEA and CA19-9 (hazard ratio [HR] = 2.38; 95% CI 1.74-3.26; P < .001; N = 206). Clinicopathological characteristics should be carefully considered when evaluating ctDNA results from mCRC patients, especially when confronted with a plasma negative result. ctDNA may prove to be a clinically useful marker in the evaluation of mCRC treatment.


Assuntos
Neoplasias Colorretais/genética , GTP Fosfo-Hidrolases/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Proteínas de Membrana/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Feminino , Frequência do Gene , Humanos , Modelos Logísticos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Análise de Sobrevida
6.
Chem Commun (Camb) ; 57(49): 6058-6061, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34037012

RESUMO

A dual-colorimetric miRNA detection kit that can simultaneously detect two miRNAs with high sensitivity and selectivity is developed, and the data can be read by the naked eye easily. The kit is able to distinguish the patients from healthy people and achieve lung cancer diagnosis using clinical serum samples in a short time.


Assuntos
MicroRNA Circulante/sangue , Colorimetria , Neoplasias Pulmonares/diagnóstico , Hibridização de Ácido Nucleico , Ouro/química , Humanos , Neoplasias Pulmonares/sangue , Nanopartículas Metálicas/química , Tamanho da Partícula , Propriedades de Superfície
7.
Aging (Albany NY) ; 13(9): 13264-13286, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952725

RESUMO

Exosomes are messengers for intercellular communication and signal transduction. Circular RNA (circRNA) abnormal expression and regulation are involved in the occurrence and development of a variety of tumors. In the present study, exosomes in the serum of five patients with non-small cell lung cancer (NSCLC) were isolated before and after EGFR-TKIs resistance, and the circRNA expression profile was screened using a circRNA microarray. The effects of the exosome circRNA_102481 on cell proliferation and apoptosis were analyzed. The interaction between miR-30a-5p and circRNA_102481 or ROR1 was predicted by starBase software, and was confirmed by RNA pull-down and dual-luciferase reporter assays. The results showed that exosomes containing circRNA_102481 were significantly up-regulated in NSCLC with EGFR-TKIs resistance (p<0.05), and that circRNA_102481 was mainly secreted by EGFR-TKIs resistance cell via exosomes (p<0.05). Both circRNA_102481 silencing and si-circRNA_102481 transported by exosomes could inhibit EGFR-TKIs resistance cell proliferation and promote cell apoptosis and circRNA_102481 overexpression could promote EGFR-TKIs sensitive cell proliferation and inhibit cell apoptosis in vitro (p<0.05). CircRNA_102481 served as a miR-30a-5p sponge to regulate ROR1 expression (p<0.05). Furthermore, the expression of circRNA_102481 in exosomes was associated with TNM stage, tumor differentiation status, brain metastasis, and PFS and OS duration. Therefore, it was concluded that tumor-derived exosomal circRNA_ 102481 could contribute to EGFR-TKIs resistance via the microRNA-30a-5p/ROR1 axis in NSCLC. Exosomal circRNA_102481 may serve as a novel diagnostic biomarker and a therapeutic target for EGFR-TKIs resistance in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/sangue , RNA Circular/sangue , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo
8.
Cancer Invest ; 39(6-7): 505-513, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33969786

RESUMO

Circulating long non-coding RNAs (lncRNA) are dysregulated in several diseases, especially cancers, e.g. non-small-cell lung cancer (NSCLC). Of specific notice in this regard is growth arrest-specific 5 gene (lncRNA GAS5), which is principally recognised as a tumor suppressor gene in numerous cancers. Functionally, GAS5 is involved in arresting cellular growth and induction of apoptosis. We analysed plasma GAS5 expression by qRT-PCR in 100 patients with NSCLC before and after tumour resection surgery. We reported a downregulation of GAS5 expression in NSCLC tissue and plasma, which showed elevation after surgery. Downregulation of GAS5 was associated with poor prognosis of NSCLC patients.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Regulação para Baixo , Neoplasias Pulmonares/cirurgia , RNA Longo não Codificante/sangue , Adulto , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
9.
Artigo em Inglês | MEDLINE | ID: mdl-33991955

RESUMO

In recent years, more than 50 tyrosine kinase inhibitors (TKIs) was indicated against numerous cancers, especially outstanding advantages in the treatment of non-small cell lung cancer (NSCLC), and several studies have shown that therapeutic drug monitoring (TDM) of TKIs can improve treatment efficacy and safety. The present study aimed to develop and validate a LC-MS/MS method for the TDM of 12 TKIs (gefitinib, erlotinib, afatinib, dacomitinib, icotinib, osimertinib, crizotinib, ceritinib, alectinib, dabrafenib, trametinib, anlotinib) in patients with NSCLC. The analytes of interest and internal standard were extracted from human plasma. Salting-out assisted liquid-liquid extraction (SALLE) with 5 M ammonium acetate solution was optimized for method validation and compared to simple protein precipitation (PPT). Chromatographic separation was conducted on Waters X bridge C18 column (100 × 4.6 mm, 3.5 µm) using a gradient elution of acetonitrile/5mM ammonium acetate in pure water with 0.1% (v/v) formic acid at 40 °C within 6 min. The total flow was maintained at 1 mL/min, 30% of the post column flow was split into the mass spectrometer and the rest to waste via a 3-way tee. The mass analysis was performed by positive ion electrospray ionization (ESI) in multiple-reaction monitoring (MRM) mode. The assay was validated based on the guidelines on bioanalytical methods by FDA. This quantification method was proved to be satisfactory in selectivity, accuracy, precision, linearity (r2 > 0.995), recovery, matrix effect and stability and the accuracy was further assessed in plasma with a degree of hemolysis of 4%. The described method to simultaneously quantify the 12 selected anticancer drugs in human plasma was successfully validated and applied to routine TDM of gefitinib, erlotinib, icotinib, osimertinib, crizotinib and anlotinib in cancer patients. TKIs plasma monitoring helps to individualize dose adjustment and manage adverse effects in NSCLC patients.


Assuntos
Antineoplásicos/sangue , Carcinoma Pulmonar de Células não Pequenas , Monitoramento de Medicamentos/métodos , Neoplasias Pulmonares , Inibidores de Proteínas Quinases/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Espectrometria de Massas em Tandem
10.
Biomed Res Int ; 2021: 8817898, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997043

RESUMO

Background: Genomic testing gives guidance to the treatment options in lung adenocarcinoma patients, but some patients are unable to obtain tissue samples due to lesion location or intolerance. Cell-free circulating tumor DNA (ctDNA) tested in plasma or pleural effusion is an advanced access to solve the problem. Our study descriptively identified the genetic variations of advanced Chinese lung adenocarcinoma patients and analyzed the overall survival of patients with EGFR mutations. Methods: A total of 152 patients' plasma samples were included, and gene mutations were detected by NGS using an Illumina Miseq tabletop sequencer. Results: Frequencies of altered were EGFR 46.05%, ALK 7.24%, KRAS 6.58%, PIK3CA 6.58%, PTEN 2.63%, HER2 1.97%, MET 1.97%, BRAF 1.32%, NF1 1.32%, and ROS1 0.66%. We identified 48 cases with double or triple driver gene mutations. Multiple mutations were more frequently observed in EGFR and PIK3CA genes. Patients harboring coexistent mutations with an EGFR mutation tended to have a shorter overall survival than those with exclusively EGFR mutations. Conclusion: EGFR, ALK, and KRAS were common driver gene in Chinese patients with stage IV lung adenocarcinoma. Multiple mutations were detected in the ctDNA samples and involve more EGFR and PIK3CA mutations. The existence of coexisting gene mutations may have adverse effects on the prognosis of patients with EGFR mutation. The unknown mutations discovered by NGS may provide new targets for gene targeting therapy, and ctDNA test by NGS is an effective method for making appropriate treatment choices.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA Tumoral Circulante/genética , Neoplasias Pulmonares/genética , Mutação/genética , Adenocarcinoma de Pulmão/sangue , Biomarcadores Tumorais/genética , China , DNA Tumoral Circulante/sangue , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade
11.
Medicine (Baltimore) ; 100(18): e25690, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950949

RESUMO

OBJECTIVE: We conducted this study to evaluate the efficacy and safety of traditional Chinese medicine (TCM) in advanced non-small cell lung cancer (NSCLC) patients who underwent chemotherapy. DESIGN: This was a prospective, open-label, randomized controlled trial. NSCLC patients at stage IIIA, IIIB, or IV were randomly assigned to either TCM plus chemotherapy or chemotherapy alone. The comprehensive TCM treatment consisted of Kang Ai injection, herbal decoction, and Zhenqifuzheng capsules. The primary endpoint was quality of life (QOL) measured by the Functional Assessment of Cancer Therapy-Lung version 4.0. The secondary endpoints were chemotherapy completion rate, tumor response, and adverse events. All assessments were done at baseline, the third week, and the sixth week. RESULTS: Thirty-nine participants were randomly assigned to the treatment group and 36 to the control group. The QOL scores were significantly improved in the treatment group compared with those of the control group in social well-being (cycle 1, P = .048; cycle 2, P = .015), emotional well-being (cycle 1, P = .047; cycle 2, P = 4.29E-05), and functional well-being (cycle 1, P = .030; cycle 2, P = .003), while the QOL scores in the above 3 domains declined in the control group (P < .05). Both groups had a decline in the physical well-being score (cycle 1, P = .042; cycle 2, P = .017) and lung cancer symptom score (cycle 1, P = .001; cycle 2, P = .001) after 2 courses of intervention. The deterioration in physical well-being and lung cancer symptoms was noticeably smaller in the treatment group (P < .05). There were significant differences between the 2 groups in social well-being, emotional well-being, functional well-being, lung cancer symptom domain, and the total score (P < .05). Patients in the treatment group had a significantly lower incidence of platelet reduction than the control group (P = .028) after 2 cycles of treatment. No significant difference in nonhematological adverse events (AEs) was observed. CONCLUSION: This study illustrated that comprehensive TCM treatment could promote the QOL of NSCLC patients, alleviate symptoms, and reduce the AEs caused by chemotherapy, verifying the synergistic and attenuating effects of TCM in NSCLC patients undergoing chemotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (www.chictr.org.cn): ChiCTR-TRC-13003637.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Qualidade de Vida , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Humanos , Incidência , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Contagem de Plaquetas , Estudos Prospectivos , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Trombocitopenia/prevenção & controle , Adulto Jovem
12.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33836566

RESUMO

Unlike other epithelial cancer types, circulating tumor cells (CTCs) are less frequently detected in the peripheral blood of non-small cell lung cancer (NSCLC) patients using epithelial marker-based detection approaches despite the aggressive nature of NSCLC. Here, we demonstrate hexokinase-2 (HK2) as a metabolic function-associated marker for the detection of CTCs. In 59 NSCLC patients bearing cytokeratin-positive (CKpos) primary tumors, HK2 enables resolving cytokeratin-negative (HK2high/CKneg) CTCs as a prevalent population in about half of the peripheral blood samples with positive CTC counts. However, HK2high/CKneg tumor cells are a minority population in pleural effusions and cerebrospinal fluids. Single-cell analysis shows that HK2high/CKneg CTCs exhibit smaller sizes but consistent copy number variation profiles compared with CKpos counterparts. Single-cell transcriptome profiling reveals that CK expression levels of CTCs are independent of their epithelial-to-mesenchymal transition (EMT) status, challenging the long-standing association between CK expression and EMT. HK2high/CKneg CTCs display metastasis and EGFR inhibitor resistance-related molecular signatures and are selectively enriched in patients with EGFR L858R driver oncogene mutation as opposed to EGFR 19Del , which is more frequently found in patients with prevalent CKpos CTCs in the blood. Consistently, treatment-naïve patients with a larger number or proportion of HK2high/CKneg CTCs in the blood exhibit poor therapy response and shorter progression-free survival. Collectively, our approach resolves a more complete spectrum of CTCs in NSCLC that can potentially be exploited to identify patient prognosis before therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Hexoquinase/sangue , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Transição Epitelial-Mesenquimal , Receptores ErbB/genética , Genótipo , Humanos , Queratinas/sangue , Biópsia Líquida , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/enzimologia , Prognóstico
13.
World Neurosurg ; 151: e324-e331, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33878466

RESUMO

OBJECTIVE: To investigate predictive value of preradiosurgery leukocyte-based prognostic ratios in a selected cohort of non-small cell lung cancer (NSCLC) patients with radiosurgery-treated brain metastases (BM) and concomitant immunotherapy (IT) or targeted therapy (TT). METHODS: We performed a retrospective analysis of 166 patients with NSCLC BM treated with Gamma Knife radiosurgery. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio were assessed within 14 days before radiosurgery. RESULTS: In radiosurgically treated patients with NSCLC BM with concomitant IT or TT, estimated median survival after first Gamma Knife radiosurgery treatment was significantly longer in patients with NLR cutoff value <5 (P = 0.038). Consequently, the Cox regression model for NLR cutoff value groups revealed a significant hazard ratio of 1.519 (95% confidence interval 1.020-2.265, P = 0.040). In addition, each increase in NLR of 1 equaled an increase of 5.4% in risk of death (hazard ratio 1.054, 95% confidence interval 1.024-1.085, P < 0.001). After adjusting for sex, age, Karnofsky performance scale, and presence of extracranial metastases, NLR remained a significant and independent predictor for survival (hazard ratio 1.047, 95% confidence interval 1.017-1.078, P = 0.002). In contrast, platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio did not exhibit the same predictive value among patients with radiosurgery-treated BM with concomitant IT or TT. CONCLUSIONS: In patients with NSCLC BM treated with radiosurgery with concomitant IT or TT, preradiosurgery NLR represents a simple prognostic predictor for survival and is superior to other leukocyte-based ratios. NLR may be relevant for clinical decision making, therapeutic evaluation, patient counseling, and appropriate stratification of future clinical trials among patients with radiosurgery-treated BM.


Assuntos
Neoplasias Encefálicas/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Linfócitos , Neutrófilos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Radiocirurgia , Estudos Retrospectivos , Taxa de Sobrevida
14.
Oncology ; 99(8): 539-546, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33902046

RESUMO

BACKGROUND: Several studies have shown that the non-small-cell lung cancer (NSCLC) genomic background among Hispanics differs from other populations. The finding of low-frequency genomic alterations in cell-free DNA (cfDNA) can increase diagnostic accuracy and could improve treatment in NSCLC. METHODS: Data from 54 Hispanic patients with advanced NSCLC with high clinical suspicion for ALK, EGFR, and ROS1 mutations were collected (including young age, female sex, and non-smokers). cfDNA was extracted from plasma and analyzed using a commercial next-generation sequencing test (Guardant360) which detects genomic alterations in 74 genes. RESULTS: The median age was 56 years (range 31-83). Most patients were female (661.1%) and never smokers (72.3%). Among the patients included, 96% (52/54) had cfDNA detectable alterations with a mean number of 3.37 cfDNA alterations per test (range 1-10). cfDNA was able to detect some genomic alterations previously undetected by tissue biopsy. Among patients with insufficient or unavailable tissue to perform testing, mutations in EGFR and ALK which led to a change in therapy were determined using cfDNA in 28.8 and 3.8% of cases, respectively. Among patients with cfDNA alterations, 46.1% (n = 24) were switched to a targeted therapy with a median progression-free survival of 11.1 months (95% CI 7.6-14.6) and an overall survival of 40.3 months (95% CI 27.1-53.6). Concurrent genetic mutations with TP53 and KRAS negatively impacted the prognosis. CONCLUSIONS: In a selected population of NSCLC Hispanic patients, comprehensive cfDNA analysis allowed a treatment change in 46.1% of the cases. Guardant360 allows the identification of genomic alterations to improve treatment selection and increase prognosis.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA Tumoral Circulante/genética , Hispano-Americanos/genética , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Colômbia , Receptores ErbB/genética , Feminino , Técnicas de Genotipagem , Humanos , Biópsia Líquida , Neoplasias Pulmonares/sangue , Masculino , México , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética
15.
Cancer Med ; 10(9): 3085-3100, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33826244

RESUMO

Lung cancer is the most common cause of cancer-related death in developed countries; therefore, the generation of effective targeted therapeutic regimens is essential. Recently, gene therapy approaches toward malignant cells have emerged as attractive molecular therapeutics. Previous studies have indicated that stanniocalcin-1 (STC-1), a hormone involved in calcium and phosphate homeostasis, positively regulates proliferation, apoptosis resistance, and glucose metabolism in lung cancer cell lines. In this study, we investigated if targeting STC-1 in tumor cells could be a promising strategy for lung cancer gene therapy. We confirmed that STC-1 levels in peripheral blood were higher in lung cancer patients than in healthy donors and that STC-1 expression was observed in five out of eight lung cancer cell lines. A vector expressing a suicide gene, uracil phosphoribosyltransferase (UPRT), under the control of the STC-1 promoter, was constructed (pPSTC-1 -UPRT) and transfected into three STC-1-positive cell lines, PC-9, A549, and H1299. When stably transfected, we observed significant cell growth inhibition using 5-fluorouracil (5-FU) treatment. Furthermore, growth of the STC-1-negative lung cancer cell line, LK-2 was significantly arrested when combined with STC-1-positive cells transfected with pPSTC-1 -UPRT. We believe that conferring cytotoxicity in STC-1-positive lung cancer cells using a suicide gene may be a useful therapeutic strategy for lung cancer.


Assuntos
Terapia Genética/métodos , Glicoproteínas/metabolismo , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular/métodos , Pentosiltransferases/metabolismo , Células A549 , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Fluoruracila/uso terapêutico , Genes Reporter , Genes Transgênicos Suicidas , Glucose/metabolismo , Glicoproteínas/sangue , Glicoproteínas/genética , Humanos , Luciferases/genética , Luciferases/metabolismo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pentosiltransferases/genética , Plasmídeos , Regiões Promotoras Genéticas/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telomerase/genética , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
16.
BMC Cancer ; 21(1): 441, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882890

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been incorporated into various clinical oncology guidelines for systemic treatment of advanced non-small cell lung cancers (aNSCLC). However, less than 50% (and 20%) of the patients responded to the therapy as a first (or second) line of therapy. PD-L1 immunohistochemistry (IHC) is an extensively studied biomarker of response to ICI, but results from this test have equivocal predictive power. In order to identify other biomarkers that support clinical decision-making around whether to treat with ICIs or not, we performed a retrospective study of patients with aNSCLC who underwent ICI-based therapy in the Mount Sinai Health System between 2014 and 2019. METHODS: We analyzed data from standard laboratory tests performed in patients as a part of the routine clinical workup during treatment, including complete blood counts (CBC) and a comprehensive metabolic panel (CMP), to correlate test results with clinical response and survival. RESULTS: Of 11,138 NSCLC patients identified, 249 had been treated with ICIs. We found associations between high neutrophil-to-lymphocyte ratio (NLR ≥ 5) and poor survival in ICI-treated NSCLC. We further observed that sustained high NLR after initiation of treatment had a more profound impact on survival than baseline NLR, regardless of PD-L1 status. Hazard ratios when comparing patients with NLR ≥ 5 vs. NLR < 5 are 1.7 (p = 0.02), 3.4 (p = 4.2 × 10- 8), and 3.9 (p = 1.4 × 10- 6) at baseline, 2-8 weeks, and 8-14 weeks after treatment start, respectively. Mild anemia, defined as hemoglobin (HGB) less than 12 g/dL was correlated with survival independently of NLR. Finally, we developed a composite NLR and HGB biomarker. Patients with pretreatment NLR ≥ 5 and HGB < 12 g/dL had a median overall survival (OS) of 8.0 months (95% CI 4.5-11.5) compared to the rest of the cohort with a median OS not reached (95% CI 15.9-NE, p = 1.8 × 10- 5), and a hazard ratio of 2.6 (95% CI 1.7-4.1, p = 3.5 × 10- 5). CONCLUSIONS: We developed a novel composite biomarker for ICI-based therapy in NSCLC based on routine CBC tests, which may provide meaningful clinical utility to guide treatment decision. The results suggest that treatment of anemia to elevate HGB before initiation of ICI therapy may improve patient outcomes or the use of alternative non-chemotherapy containing regimens.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Índices de Eritrócitos , Contagem de Leucócitos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Linfócitos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Neutrófilos , Razão de Chances , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do Tratamento
17.
J Immunol ; 206(10): 2412-2419, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33911005

RESUMO

Sepsis induces significant immune dysregulation characterized by lymphocyte apoptosis and alterations in the cytokine milieu. Because cancer patients exhibit a 10-fold greater risk of developing sepsis compared with the general population, we aimed to understand how pre-existing malignancy alters sepsis-induced immune dysregulation. To address this question, we assessed the impact of tumor-specific CD8+ T cells on the immune response in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. Tumor-bearing animals containing Thy1.1+ tumor-specific CD8+ T cells were subjected to CLP, and groups of animals received anti-Thy1.1 mAb to deplete tumor-specific CD8+ T cells or isotype control. Results indicated that depleting tumor-specific T cells significantly improved mortality from sepsis. The presence of tumor-specific CD8+ T cells resulted in increased expression of the 2B4 coinhibitory receptor and increased apoptosis of endogenous CD8+ T cells. Moreover, tumor-specific T cells were not reduced in number in the tumors during sepsis but did exhibit impaired IFN-γ production in the tumor, tumor draining lymph node, and spleen 24 h after CLP. Our research provides novel insight into the mechanisms by which pre-existing malignancy contributes to increased mortality during sepsis.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/imunologia , Melanoma Experimental/complicações , Melanoma Experimental/imunologia , Sepse/complicações , Sepse/imunologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/imunologia , Animais , Apoptose/imunologia , Linhagem Celular Tumoral , Citocinas/sangue , Interferon gama/metabolismo , Neoplasias Pulmonares/sangue , Linfonodos/imunologia , Masculino , Melanoma Experimental/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Sepse/sangue , Sepse/mortalidade , Neoplasias Cutâneas/sangue , Baço/imunologia , Antígenos Thy-1/genética
18.
J Int Med Res ; 49(4): 3000605211004229, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33823630

RESUMO

OBJECTIVE: To investigate the prognostic value of pretreatment haemoglobin-to-red cell distribution width radio (HRR) in predicting overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: This retrospective study analysed patients with advanced NSCLC. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were conducted to evaluate the predictive value of HRR for OS. A propensity matching analysis was used to reduce the impact of other confounding factors on the results. RESULTS: A total of 448 patients were enrolled in the study. The median HRR was 0.984, which was used as the cut-off value. Regardless of matching or not, a lower HRR was correlated with an unfavourable risk of death. After propensity matching, univariate and multivariate analysis showed that HRR was an independent factor for the prognosis of NSCLC (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.17, 2.04; HR 1.57, 95% CI, 1.17, 2.10; respectively). Kaplan-Meier analysis showed that low HRR was associated with shortened OS. The relationship between HRR and the risk of death was consistent across all patient subgroups after stratification by subgroup analysis. CONCLUSIONS: These findings showed that a lower pretreatment HRR could be a potentially valuable prognostic factor in patients with advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Índices de Eritrócitos , Hemoglobinas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Feminino , Hemoglobinas/análise , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Masculino , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos
19.
Medicine (Baltimore) ; 100(15): e25447, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847650

RESUMO

BACKGROUND: High pretreatment level of D-dimer in small cell lung cancer (SCLC) is commonly encountered, but the impact of high pretreatment D-dimer level on the prognosis of SCLC patients remains undetermined. Therefore, we conducted this meta-analysis focusing specifically on the prognostic value of high pretreatment D-dimer level in SCLC patients comprehensively. METHODS: We searched systematically in PubMed, Embase, and Web of Science for relevant studies published before January 28, 2019. Outcomes including 1-year overall survival (OS), progression-free survival (PFS) rates, and hazard ratios (HRs) of OS and PFS from multivariate analysis were extracted and analyzed. RESULTS: A total of 5 cohort studies consisting of 813 SCLC patients (473 patients with high pretreatment level of D-dimer and 340 with normal level of D-dimer) were finally included for meta-analysis. We found that patients with high pretreatment level of D-dimer had significantly shorter 1-year OS (47.6% vs 79.9%; fixed effects: risk ratio [RR] = 2.506; 95% confidence interval [CI] = [1.948, 3.224]; P < .001) and PFS (15.8% vs 34.0%; random effects: RR = 1.294; 95% CI = [1.060, 1.579]; P = .011) rates than those with normal level of D-dimer. Moreover, high pretreatment D-dimer level was further proved to remain as an unfavorable predictor of OS (fixed effects: HR = 1.865; 95% CI = [1.469, 2.367]; P < .001; I2 = 7.6%) and PFS (fixed effects: HR = 1.513; 95% CI = [1.183, 1.936]; P = .001; I2 = 0.0%) in patients with SCLC. CONCLUSION: High pretreatment level of D-dimer was found to be an independent unfavorable prognostic factor in SCLC patients. However, more studies with sufficient adjustment for confounding factors are encouraged to confirm our conclusions.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Carcinoma de Pequenas Células do Pulmão/terapia , Taxa de Sobrevida
20.
Mol Biol Rep ; 48(3): 2543-2552, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33837901

RESUMO

One of the most recent of tumor molecular characterization approaches is the microRNA (miR) expression profile. No single marker is sufficiently accurate for clinical use. Numerous biomarkers panels were created for three main purposes: tumor subtype, classification and, early detection, and prediction of tumor responses to treatment and prognosis of patients. miR-21-5p and miR-126-3p have received special attention because of their relationship with many cancer sites such as lung cancer, colorectal cancer, and renal cell carcinoma. We aimed to study their diagnostic and prognostic utility in lung cancer patients. Serum carcinoembryonic antigen (CEA) level was measured using an enzyme-linked immunosorbent assay (ELISA) technique. The expression levels of miR-21-5p and miR-126-3p were determined by real-time PCR in 60 non small cell lung cancer (NSCLC) patients and 40 healthy controls to detect diagnostic utility. Moreover, it was correlated with all disease clinicopathological characters and patient survival. Higher miR-21-5p and lower miR-126-3p levels were found in lung cancer patients than in controls. The sensitivity of CEA and miR-21-5p and miR-126-3p were 78.3, 96.7, and 90% at cutoff points 7.5, 2.35, and 2.175, respectively to distinguish NSCLC patients from controls. On combining both miR-21-5p and miR-126-3p, an improvement of sensitivity to 97% was noted. For patients, miR-21-5P increased significantly with metastatic stage and the highest grade (GIII). There was significantly longer overall survival (OS) among patients with early stages, lower grades GI&II, low miR-21-5p, and high miR-126-3p. miR-126-3p and presence of metastasis, the last two factors were the independent factors affecting OS with a hazard ratio of 0.26 (95% CI: 0.06-1.09) and 3.64 (95% CI: 1.22-16.5), respectively. Circulating miR-21-5p and miR-126-3p may play a significant role in diagnosis and prognosis in NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , MicroRNAs/sangue , Adolescente , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Adulto Jovem
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