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1.
Bioanalysis ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32186405

RESUMO

Aim: To investigate the clinical pharmacokinetic profiles of FCN-411, a new EGFR tyrosine kinase inhibitor, an ultra-performance LC-MS/MS method was developed. Methods & results: The method was suitable to determine FCN-411 in plasma due to the fast sample preparation (protein precipitation procedure), a good linear range of 2-500 ng/ml, low amount of sample volume (5 µl) and less run time (4.5 min) for analysis. And it was demonstrated to be acceptable according to the guidelines for bioanalytical assay validation. Conclusion: The method was robust, sensitive and repeatable, and it is ready to be applied to measure FCN-411 in a Phase I clinical pharmacokinetic study.

2.
J Thorac Oncol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007598

RESUMO

INTRODUCTION: Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M-resistant mutations. We assessed the safety, efficacy, and pharmacokinetics of alflutinib in patients with advanced NSCLC with confirmed EGFR T790M mutation, whose status progressed after the first- or second-generation EGFR tyrosine kinase inhibitor therapy. METHODS: In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. The primary end points were safety, tolerability, and pharmacokinetics for the dose-escalation study and the objective response rate (assessed by an independent radiological review committee) for the dose-expansion study. RESULTS: Between November 30, 2016, and July 24, 2018, a total of 130 patients (14 in dose escalation, 116 in dose expansion) received alflutinib treatment (20 mg, 40 mg, 80 mg, 160 mg, or 240 mg once daily). On October 30, 2018, 79 patients (61%) remained on the treatment. No dose-limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40-240 mg), the overall objective response rate was 76.7% (89 of 116), and it was 70.6% in patients with central nervous system metastases (12 of 17). A total of 79% of all patients had possibly treatment-related adverse events (AEs) (103 of 130); 8% had treatment-related grade 3 or higher AEs (11 of 130). Serious AEs were reported in 15% of patients (20 of 130), and two serious AEs were related to treatment. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state. CONCLUSIONS: Alflutinib was clinically effective with an acceptable toxicity profile in patients with advanced NSCLC (including those with central nervous system metastases) with EGFR T790M mutation. Further investigation is ongoing.

3.
Clin Biochem ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32087138

RESUMO

BACKGROUND: Recently, a series of studies have been published to examine the possible diagnostic and prognostic values of glypican-3 (GPC3) in liver cancer with conflicting results observed. Thus, the present study aimed to assess the values of preoperative serum GPC3 alone and in combination with AFP for the diagnosis of liver cancer. METHODS: An enzyme-linked immunoassay was used to quantify serum GPC3 in hepatocellular carcinoma group (HCC, n = 210), intrahepatic cholangiocarcinoma group (ICC, n = 36), combined hepatocellular cholangiocarcinoma group (cHCC-CC, n = 8), metastatic liver cancer group (MLC, n = 10) and normal controls (NC, n = 134). RESULTS: The area under the curve (AUC) of GPC3 for HCC versus NC was 0.879, with a sensitivity of 79.52% at an optimal cutoff value of 0.0414 ng/mL; when GPC3 was combined with AFP, the AUC and sensitivity were increased to 0.925 and 88.10%, respectively. In addition, 43 of 68 AFP-negative patients had elevated GPC3 levels. Furthermore, the positive rate of GPC3 was significantly higher than the that of AFP for HCC in early stage. CONCLUSIONS: Serum GPC3 was superior to AFP for the diagnosis of early-stage HCC, and may be complementary to AFP for distinguishing HCC from NC.

4.
Scand J Immunol ; 91(2): e12829, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31536647

RESUMO

Serum autoantibodies against tumour-associated antigens are promising biomarkers for diagnosis of cancer. This review summarizes the available evidence pertaining to the diagnostic potential of autoantibodies studied in the context of colorectal cancer (CRC). A systematic literature search was conducted in three databases (PubMed, Cochrane Library and Embase). Data pertaining to a total of 145 autoantibodies published in 80 articles were reviewed. Of these, anti-p53 antibody was the most commonly studied autoantibody; thus, we performed a meta-analysis on anti-p53 antibody in 24 articles. According to the cut-off values used to determine positivity for anti-p53 antibody, we divided the included studies into five groups. Owing to the presence of threshold effect in groups 4 and 5 and non-threshold effect in groups 1 and 2, pooled analysis focused on group 3 using a fixed-effects model (Mantel-Haenszel). Group 3, determining the cut-off value based on the value of p53 antibody titre index, was comprised of five articles including 733 patients with CRC and 172 controls (126 healthy individuals and 46 benign diseases). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and summary area under the receiver operating characteristic curves were 0.21, 0.99, 12.26, 0.80, 15.46 and 0.87, respectively. Serum anti-p53 autoantibody may potentially help distinguish CRC from healthy controls or benign diseases; however, it should be used in combination with other indicators due to the low sensitivity. Our study provides insights for further exploration of the optimal combination of different tumour-associated antigens or autoantibodies for diagnosis of CRC.


Assuntos
Neoplasias do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Neoplasias Retais/diagnóstico , Proteína Supressora de Tumor p53/imunologia , Animais , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Humanos
5.
Rapid Commun Mass Spectrom ; 34(5): e8603, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31756778

RESUMO

RATIONALE: Chlorogenic acid (CA) is well known for its various biological activities. Here, a clinical study was performed in patients with advanced malignant cancer to explore its therapeutic effects. We aimed to develop a method to quantify CA in human plasma and urine to assist the clinical pharmacokinetic study. METHODS: Ultra-performance liquid chromatography (UPLC) coupled with a triple quadruple mass spectrometry was used to separate and detect CA, with puerarin serving as the internal standard. RESULTS: The method presents an excellent linearity ranging from 5 to 2000 ng/mL for plasma analysis and 50 to 20 000 ng/mL for urine analysis. Intra- and inter-day precision and accuracy were both less than 15% for plasma and urine. CONCLUSIONS: These results showed that the novel UPLC method was robust and sensitive, and fulfilled the requirements for a clinical pharmacokinetic study of CA in patients with advanced cancer.

6.
Insects ; 10(12)2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31835398

RESUMO

Dendrolimus houi Lajonquiere is a phytophagous caterpillar infesting many economically important coniferous tree species in China, causing serious economic and ecological environment losses. Based on previous research, it has one generation per year in South China and East China in contrast to two generations per year in Yunnan province in southwestern China. The species is potentially resilient to climatic extremes in these regions with the eggs and 1st instar larvae surviving in the winter (5 °C), older instar larvae and pupae surviving high temperatures in the summer (35 °C), suggesting some temperature stress tolerance during different developmental stages. However, little is known in this species at the genetic and genomic level. In this study, we used high throughput sequencing to obtain transcriptome data from different developmental stages (eggs, 1st-3rd instar larvae, 4th-5th instar larvae, 6th-7th instar larvae, pupae, male and female adults), which were collected from Fujian province. In total, we obtained approximately 90 Gb of data, from which 33,720 unigenes were assembled and 17,797 unigenes were annotated. We furtherly analyzed the differentially expressed genes (DGEs) across all stages, the largest number between the eggs and 1st instar larvae stage and gene expression varied significantly in different developmental stages. Furthermore, 4138 SSR genes and 114,977 SNP loci were screened from transcriptome data. This paper will be a foundation for further study towards improved integrated pest management strategies for this species.

7.
Life Sci ; : 117218, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31884093

RESUMO

Prostate cancer (PCa) is the second most frequently diagnosed cancer in men. However, its genetic characteristics in the Chinese population have not been extensively profiled. Here we screened 27 Chinese patients and preformed whole-genome sequencing to dissect their genomic patterns. We found that 18.5% (5/27) tumors harbored non-protein coding mutations on FOXA1. Besides, novel focal amplifications/deletions involving ZBTB7B, SLC4A4, TBX18, CYSLTR2 and EFNA5 were frequently present in tumors. Notably, group specificity of base substitution signature B displayed a strong link to hotspot mutations on SPOP gene. Furthermore, based on six rearrangement signatures, tumors were assigned to five subgroups that revealed different biological mechanisms. Of which, tandem duplicator subgroup harbored all CDK12 mutations, small deletor subgroup owned 75% TP53 changes, and large deletor subgroup had 66.7% SPOP mutations. Taken together, we provide a comprehensive view of genomic patterns which affect the critical cell regulators of PCa in the Chinese population. Our findings may provide valuable insights for designing specific treatments for Chinese patients with PCa.

8.
J Transl Med ; 17(1): 339, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597567

RESUMO

INTRODUCTION: Pemetrexed combined with platinum complexes can be used as first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC), however, the efficacy and safety is varying from individuals. There is a need to better understand the genetic variations associated with platinum response. MATERIALS AND METHODS: We performed next-generation sequencing (NGS) based on BGI Oseq-ctDNA panel to analyze 98 longitudinal plasma samples from 32 lung adenocarcinoma patients during platinum-based chemotherapy, and a bioinformatic pipeline was developed to detect point mutations. RESULTS: We found that mutation burden was decreased after chemotherapy, which reflected chemotherapy sensitivity, especially the frequency of C>G and C>A substitutions. Moreover, neoplastic cells carrying a specific set of somatic mutations, such as EGFR(L858R), KRAS (p.G12C) were obviously correlated with platinum treatment. In addition, the MAPK pathway was found to have a pivotal role in NSCLC and platinum based response. Finally, we found that smokers benefit less from platinum-based chemotherapy. CONCLUSIONS: Collectively, this work described the dynamic changes of ctDNA mutation status during platinum-based treatment, which may contribute to advanced lung adenocarcinoma patients stratification and precision treatment.

9.
J Cell Mol Med ; 23(10): 6812-6821, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31393074

RESUMO

Osimertinib is designed to target the secondary resistant EGFR T790M mutant and has shown outstanding clinical efficacy. However, the prognostic prediction of osimertinib patients is a big problem in clinical practice. The resistance mechanism of osimertinib is also not fully understood. NGS and a 1021 gene capture panel were used to analyse the somatic mutation profile of thirty-six lung adenocarcinoma patients' serial ctDNA samples. Progression-free survival of subgroup patients is analysed. Patients harbour TP53 mutations and patients with higher TMB value in pre-treatment samples showed a shorter PFS. Moreover, compared to CT evaluation, ctDNA changes generally correlated with treatment responses in most patients. Novel resistance mechanisms are discovered including EGFR mutations and alternative activation pathway. Our results implied a broad potential of ctDNA as an adjuvant tool in practical clinical management of NSCLC patients. ctDNA could help with clinical practice during osimertinib treatment, regarding monitoring tumour response, detecting development of heterogeneity, identifying potential resistance mechanisms, predicting treatment efficacy and patient outcome.

10.
Front Oncol ; 9: 556, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448219

RESUMO

Background: Lung adenocarcinoma (LUAD) possesses a poor prognosis with a low 5-year survival rate even for stages I-III resected patients, it is thus critical to understand the determinants that affect the survival and discover new potentially prognostic biomarkers. Somatic copy number alterations (CNAs) are major source of genomic variations driving tumor evolution, CNAs screening may identify prognostic biomarkers. Methods: Oncoscan MIP array was used to analyze the patterns of CNAs on formalin fixed paraffin embedded(FFPE) tumor specimens from 163 consecutive stage I-III resected LUAD patients, 145 out of which received platinum-based adjuvant chemotherapy. Results: Of the 163 patients, 91(55.8%) were recurred within 3 years after surgery. The most common aberrations in our cohort were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q, 18q for losses. The GISTIC2 analysis produced 45 amplification peaks and 40 deletion peaks, involving some reported genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, and CDKN2A, most of which were consistent with TCGA database. The amplifications of 12p12.1 (CMAS, GOLT1B, YS2, LDHB, RECQL, ETNK1, IAPP, PYROXD1, KRAS) and KDM5A were correlated with worse prognosis in our cohort, this result was further validated in 506 LUAD patients from TCGA. In addition, 163 patients could be well-classified into five groups, and the clinical outcomes were significantly different based on threshold copy number at reoccurring alteration peaks. Among the 145 patients who received adjuvant chemotherapy, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients, this result was validated in an independent group of Imielinski et al., demonstrating these two CNAs may contribute to resected LUAD recurrence after adjuvant chemotherapy. Conclusion: This study suggests that CNAs profiling may be a potential prognostic classifier in resected LAUD patients. Amplifications of 12p12.1 and KDM5A might be prognostic biomarkers for LUAD, and amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after adjuvant chemotherapy. These novel findings may provide implication for better implementation of precision therapy for lung cancer patients.

11.
J Thorac Dis ; 11(5): 1779-1787, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31285870

RESUMO

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become important treatment options for non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. However, the detection of EGFR driver mutation is impeded by the lack of adequate tumor tissues, histopathological type, long detection period, and the heterogeneity of a tumor. Therefore, it is necessary to develop a more convenient method to guide the clinical use of EGFR-TKI. Circular RNAs (circRNAs) are characterized as a closed structure with covalently joined ends resistant to exonucleases may be a potential biomarker. In the present study, we aimed to screen circRNAs that may be associated with the efficacy of EGFR-TKI. Methods: The expression of circRNAs sequenced by circular microarray in plasma samples between gefitinib effective and ineffective groups were compared. RT-qPCR further validated the results in an independent cohort. Kaplan-Meier curves were used to analyze the association between circRNA and progression-free survival (PFS) of NSCLC patients treated with gefitinib. Results: In total, 52 NSCLC patients treated with gefitinib were included for analysis. 1,377 circRNAs were differentially expressed in gefitinib effective and ineffective groups, among which 989 circRNAs were up-regulated, and 388 circRNAs were down-regulated in the effective group. Furthermore, two differentially expressed circRNAs, hsa_circ_0109320 and hsa_circ_0134501, were validated by RT-qPCR in an independent cohort of 38 gefitinib-treated NSCLC patients. Elevated hsa_circ_0109320 was associated with longer PFS in gefitinib-treated NSCLC patients. Conclusions: Taken together, hsa_circ_0109320 may be a potential biomarker for the efficacy of EGFR-TKI in NSCLC patients. This provides a new molecular typing method for individualized precision treatment.

12.
Cancer Manag Res ; 11: 4449-4459, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191007

RESUMO

Purpose: The aim of this phase Ib study (clinicaltrials.gov: NCT01772732) was to assess safety, tolerability, and pharmacokinetics (PKs) of simotinib (a novel EGFR tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer (NSCLC) and EGFR gene mutation. Patients and methods: 41 patients with EGFR gene mutations were enrolled and received simotinib orally administered twice daily with dose escalating from 100 to 650 mg in 28 days cycle. Safety and tolerability were assessed through the study. Blood samples were collected for PK analysis on Days 1, 8, 9, 10, 15, 22 and 29. Tumor response was assessed at baseline, on Day 29 and every 8 weeks thereafter. Results: Simotinib was well tolerated, with no dose-limiting toxicities. Maximum tolerated dose (MTD) was not found. 95.1% of patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequently reported AEs. Simotinib was rapidly absorbed and eliminated with average T max ranging from 1 to 4 hrs and T 1/2 ranging between 6.2 and 13.0 hrs after multiple-dose administration. No dose-response relationship between dose and exposure was observed after multiple-dose administration. 39.3% of the enrolled patients achieved a partial response and 46.3% had stable disease. Median progression-free survival and overall survival were 9.9 (CI% 4.7; 12.1) months and 14.6 (95%CI 12.3; 22.5) months, respectively. Conclusion: Simotinib was well tolerated, with manageable AEs at doses of up to 650 mg and MTD was not reached. Further studies to explore higher doses are ongoing.

13.
J Cancer ; 10(5): 1275-1287, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854137

RESUMO

The study was performed to investigate the antitumor efficacy of histone deacetylase inhibitor (HDACi) chidamide alone or with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) icotinib in non-small cell lung cancer (NSCLC). The cell viability, cell cycle, apoptosis, protein expression, and the molecular mechanisms were explored among ten NSCLC cell lines with chidamide and icotinib alone or in combination, and further validated in xenograft models of nude mice. Chidamide significantly reduced the viability of A549, HCC827, HCC827IR (icotinib resistant) cells, increased the sensitivity of icotinib synergistically in EGFR-TKI resistant cell line, especially in H1975 cells. Chidamide alone or combined with icotinib induced cell cycle arrest by inhibiting the activation of RAS/MAPK, PI3K/AKT and/or JAK/STAT pathways, and caused apoptosis by activating caspase 3 and PARP. Chidamide alone or with icotinib suppressed ß-catenin expression in HCC827, HCC827IR, and H1975 cells. The sensitivity of H1975 cells to icotinib was increased by chidamide through restoring E-cadherin expression. Furthermore, chidamide alone or in combination with icotinib inhibited HCC827IR and H1975 xenograft growth in athymic nude mice, respectively, with no appreciable side effects. Chidamide or combinating with icotinib exhibits antitumor activity in NSCLC cells, and has potential clinical implication for the treatment of NSCLC.

14.
J Clin Lab Anal ; 33(5): e22877, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30843281

RESUMO

BACKGROUND: To establish and validate an laboratory information system (LIS)-based auto-verification (AV) system by using large amounts of biochemical test results in cancer patients. METHODS: An algorithm of the AV process was designed for pre-analysis, analysis, and post-analysis. The limit range check was adjusted three times, while the delta check criteria were first replaced by the same patients' historical extremum results. AV rules of 51 biochemical test items were tested by using data of 121 123 samples (6 177 273 tests) in 2016 that were manually reviewed through the simulative i-Vertification software of Roche. The improved and optimal AV rules were programed into our LIS and validated by using 140 113 clinical specimens in 2018. RESULTS: The AV passing rate for samples tested in our laboratory increased from 15.57% to the current overall passing rate of 49.70%. The passing rate of each item for rule 3 was between 71.16% and 99.91%. Different cancer groups had different passing rate, while the disease group of liver, gallbladder, and pancreas always had the lowest passing rate. A total of 9420 reports (6.72%) were not verified by AV but could be verified by MV in 2018, while there were no reports that were verified by AV but not by MV. The TAT of March 2018 decreased with increase in sample size compared with the same time in 2017. CONCLUSION: We have firstly established an LIS-based AV system and implemented it in actual clinical care for cancer patients.


Assuntos
Sistemas de Informação em Laboratório Clínico , Técnicas de Laboratório Clínico , Neoplasias/química , Algoritmos , Bioquímica/métodos , Bioquímica/normas , Análise Química do Sangue/métodos , Análise Química do Sangue/normas , Técnicas de Laboratório Clínico/métodos , Técnicas de Laboratório Clínico/normas , Humanos , Neoplasias/sangue
15.
PLoS One ; 14(3): e0212204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30861008

RESUMO

The spatial numerical association of response codes effect, referred to as the SNARC effect, reveals that small numbers elicit faster left than right responses, and conversely, large numbers elicit faster right responses. Here, we explored the development of this number-space association by assessing how 7-, 9-, 11-year-olds, and adults differed in spatial orienting of attention on Posner' paradigm. Compared with the previous research, we examined how the cues would affect the level and strength of the SNARC effect in children under the different attentional conditions. Subjects made parity decisions for endogenous attention (Experiment 1) and exogenous attention (Experiment 2). The results showed that adults displayed the SNARC effect in both experiments, relatively speaking, 7- to 11-year-old Chinese children's ability of spatial numerical association progressed gradually. With endogenous attention, the SNARC effect appeared in all age groups except for 7-year-olds for invalid cues. Compared with the endogenous attention condition, the SNARC effect was more significantly affected by cues in the exogenous attention condition. This result might be owing to the fact that the SNARC effect was not demonstrated in 7-year-olds with either valid or invalid cues. Our results suggest that the differences in the spatial orienting of attention are based on the cognitive load associated with processing number information and that this process can be affected by cues. Further, there may be cross-cultural influences on the SNARC effect, as early family training may explain the results seen in this sample of Chinese 7-year-olds. Thus, reaction times decreased with increasing age in the parity judgment task, and reaction times for valid cues were faster than for invalid cues regardless of the age group in both experiments. The SNARC effect was only present for 7-year-olds for valid cues, for endogenous attention.


Assuntos
Atenção/fisiologia , Tempo de Reação/fisiologia , Comportamento Espacial/fisiologia , Adulto , Criança , Cognição , Sinais (Psicologia) , Tomada de Decisões , Feminino , Lateralidade Funcional/fisiologia , Humanos , Julgamento/fisiologia , Masculino , Orientação Espacial/fisiologia , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologia , Percepção Espacial/fisiologia
16.
Curr Cancer Drug Targets ; 19(8): 655-665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30381078

RESUMO

BACKGROUND: Crizotinib established the position of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI) in the treatment of non-small cell lung cancer (NSCLC) while the therapy- resistance hindered those patients from benefitting continuously from the treatment. CT-707 is an inhibitor of ALK/focal adhesion kinase (FAK) and IGFR-1. H2228CR (crizotinib resistance, CR) and H3122CR NSCLC cell lines were generated from the parental cell line H2228 (EML4-ALK, E6a/b:A20, variant 3) and H3122(EML4-ALK, E13:A20, variant 1), respectively. METHODS: We investigated the antitumor effects CT-707 exerted against H3122CR in vitro /vivo. RESULTS: Importantly, our study provided evidence that CT-707 overcomes resistance to crizotinib through activating PDPK1-AKT1 pathway by targeting FAK. Meanwhile, by using an in-vivo H3122CR xenograft model, we found CT-707 inhibited tumor growth significantly without obvious side effects. CONCLUSION: These findings indicate that CT-707 may be a promising therapeutic agent against crizotinib- resistance in NSCLC.

17.
Curr Cancer Drug Targets ; 19(8): 666-673, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30332963

RESUMO

BACKGROUND: Leptomeningeal metastases (LM) are much more frequent in patients of non-small lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFRTKI) shows promising efficacy for LM. OBJECTIVE: The aim of this study was to analyze the concentration of osimertinib and gene variation of circulating tumor DNA (ctDNA) in human plasma and cerebrospinal fluid (CSF). Furthermore, we explored whether ctDNA in CSF might be used as a biomarker to predict and monitor therapeutic responses. METHODS: The dynamic paired CSF and blood samples were collected from the NSCLC patient with LM acquired EGFR-TKI resistance. A method based on ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) was developed and validated for detecting osimertinib in CSF and plasma samples. Gene variations of ctDNA were tested by next-generation sequencing with a panel of 1021 genes. RESULTS: The concentrations of osimertinib in CSF were significantly lower than that in plasma (penetration rate was 1.47%). Mutations included mTOR, EGFR, CHECK1, ABCC11, and TP53 were explored in ctDNA from plasma and CSF samples. The detected mutation rate of CSF samples was higher than that of plasma samples (50% vs. 25%). Our data further revealed that the variations allele frequency (VAF) and molecular tumor burden index (mTBI) of ctDNA derived from CSF exhibited the negative correlation with efficacy of treatment. CONCLUSION: ctDNA from CSF might be a useful biomarker for monitoring the efficacy of treatment and an effective complement to nuclear magnetic resonance imaging (MRI) for LM.

18.
Thorac Cancer ; 9(10): 1220-1230, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30151899

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the clinical treatment of multiple cancers. Recent studies revealed the potential prognostic value of the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in patients receiving ICIs; however, the results were inconsistent. We conducted a meta-analysis to identify the prognostic significance of baseline NLR and PLR in cancer patients treated with ICIs. METHODS: We conducted a thorough literature search of PubMed, Embase, and Cochrane databases for studies dealing with the prognostic impact of pretreatment NLR and/or PLR levels in cancer patients treated with ICIs. The clinical outcomes were progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and sensitivity and subgroup analyses were performed to investigate heterogeneity. RESULTS: Seventeen articles involving 2092 patients were included in the final analysis. The pooled HRs of PFS and OS for NLR were 1.81(95% CI 1.36-2.41) and 2.26 (95% CI 1.68-3.03), respectively, suggesting that patients with higher baseline NLRs had significantly poorer PFS and OS. Similar results were detected in sensitivity and subgroup analyses. However, no significant relevance was found between PLR and clinical endpoints in patients treated with ICIs (HR = 1.14, 95% CI 0.88-1.48 for PFS; HR = 1.35, 95% CI 0.86-2.12 for OS). CONCLUSION: These results indicate that high pretreatment NLR but not PLR level, as a routinely obtained hematological parameter, is a potential prognostic predictor for poor PFS and OS in cancer patients receiving ICIs.


Assuntos
Biomarcadores/sangue , Neoplasias/sangue , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Prognóstico
19.
BMC Immunol ; 19(1): 14, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29661145

RESUMO

BACKGROUND: Hu-rhEGF-rP64k/Mont is a biotechnology product for the treatment of advanced non-small cell lung cancer (NSCLC). The vaccine induces a neutralizing antibody-mediated immune response, against the normal circulating self-protein antigen epidermal growth factor (EGF), which prevents its binding to and activation of the EGF receptor, inhibiting the transduction of the signals that drive cancer cell proliferation, survival and spread. This phase I study aimed to evaluate the safety and the immunological response of Hu-rhEGF-rP64k vaccine in NSCLC patients. RESULTS: The Hu-rhEGF-rP64k/Mont vaccine showed to be safe and well tolerated, with dizziness, injection-site reactions and tremors being the most commonly reported adverse event. No severe adverse events or death were related to the vaccination. Immune monitoring demonstrated the generation of anti-EGF antibody titers and as a consequence the patients exhibited a decrease in the EGF concentration. In 80% of the vaccinated patients stable disease was achieved. CONCLUSION: Hu-rhEGF-rP64k/Mont elicited a valuable immune response, with good safety profile assuring further clinical development of the vaccine in this population to further confirm the potential benefits on survival. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-OID-17014048 , date 2017/12/20 (retrospectively registered); Chinese Food and Drug Administration, CFDA 2009 L02105, date 2009/04/03; China Drug Trial, CTR20131039 .


Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia Ativa/métodos , Neoplasias Pulmonares/terapia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Vacinas Anticâncer/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , China , Fator de Crescimento Epidérmico/imunologia , Feminino , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
20.
Thorac Cancer ; 9(4): 498-501, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29411527

RESUMO

Osimertinib is a novel, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR-mutated lung adenocarcinoma who, after 23-month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c-Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism. Our findings revealed the underlying multiple and heterogeneous mechanisms in resistance to osimertinib, suggesting combination strategies should be considered post-osimertinib progression.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Acrilamidas , Compostos de Anilina , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Mutação , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem
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