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1.
Lung Cancer ; 150: 240-246, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33249379

RESUMO

BACKGROUND: Patients with anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC) treated with crizotinib inevitably relapse, with brain as common site of progression. PATIENTS AND METHODS: ASCEND-6, a phase 1/2, single-arm study, included adult Chinese patients with stage IIIB or IV ALK+ NSCLC pretreated with crizotinib as the last therapy (irrespective of prior chemotherapies [≤2]). Primary endpoints were pharmacokinetics (PK), safety, and tolerability. Key secondary endpoint was overall response rate (ORR; investigator assessed). RESULTS: Of the 103 enrolled patients, all received prior crizotinib, 70 % received ≥1 prior chemotherapy regimen, and 63.1 % had brain metastases at baseline. In the phase 1 component, 20 patients completed a 5-day PK run-in period. Median Tmax (n = 16) was ∼6 h; geometric means of AUC0-24 h (n = 16) and Cmax (n = 16) at steady state were 22,000 ng*h/mL and 1080 ng/mL, respectively. In the final analysis, median follow-up time was 34 months (range: 27.8-40.6). The ORR was 41.7 % (95 % confidence interval [CI]: 32.1-51.9), and median progression-free survival was 7.2 months (95 % CI: 4.1-7.5). Median overall survival was 17.5 months (95 % CI: 10.8-24.3). Most frequent adverse events, regardless of study drug relationship (mostly grade 1/2), were diarrhea (74.8 %), vomiting (62.1 %), alanine transaminase increased (59.2 %), aspartate transaminase increased (58.3 %), and nausea (58.3 %). CONCLUSIONS: Ceritinib PK in Chinese patients is consistent with those observed in the global ASCEND-1 study. Ceritinib was well tolerated and showed durable responses in Chinese patients with ALK+ NSCLC who progressed after crizotinib and ≤2 prior lines of chemotherapy.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Preparações Farmacêuticas , Adulto , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , China , Crizotinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/uso terapêutico , Sulfonas
2.
Chin J Cancer ; 35: 30, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-27001083

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations, including a known exon 19 deletion (19 del) and exon 21 L858R point mutation (L858R mutation), are strong predictors of the response to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment in lung adenocarcinoma. However, whether patients carrying EGFR 19 del and L858R mutations exhibit different responsiveness to EGFR-TKIs and what are the potential mechanism for this difference remain controversial. This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes. METHODS: Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858R mutations, 532 received EGFR-TKI treatment and were included in this study. EGFR 19 del and L858R mutations were detected by using denaturing high-performance liquid chromatography (DHPLC). T790M mutation, which is a common resistant mutation on exon 20 of EGFR, was detected by amplification refractory mutation system (ARMS). Next-generation sequencing (NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858R mutations. RESULTS: Of the 532 patients, 319 (60.0%) had EGFR 19 del, and 213 (40.0%) had L858R mutations. The patients with EGFR 19 del presented a significantly higher overall response rate (ORR) for EGFR-TKI treatment (55.2% vs. 43.7%, P = 0.017) and had a longer progression-free survival (PFS) after first-line EGFR-TKI treatment (14.4 vs. 11.4 months, P = 0.034) compared with those with L858R mutations. However, no statistically significant difference in overall survival (OS) was observed between the two groups of patients. T790M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment, and there was no significant difference in the co-existence of T790M mutation with EGFR 19 del and L858R mutations before EGFR-TKI treatment (5.6% vs. 8.8%, P = 0.554) or after treatment (24.4% vs. 35.4%, P = 0.176). In addition, 24 patients with EGFR 19 del and 19 with L858R mutations were analyzed by NGS, and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes. CONCLUSIONS: Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858R mutations. Whether the heterogeneity of tumors with EGFR 19 del and L858R mutations contribute to a therapeutic response difference needs further investigation.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação Puntual , Inibidores de Proteínas Quinases/administração & dosagem , Deleção de Sequência , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Éxons , Feminino , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Análise de Sequência de DNA , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
3.
Mol Clin Oncol ; 2(6): 953-959, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25279180

RESUMO

Rechallenge chemotherapy with pemetrexed was shown to be efficient in malignant pleural mesothelioma; however, its role in non-small-cell lung cancer (NSCLC) has not been investigated. In this study, we retrospectively enrolled 31 patients with non-squamous NSCLC who had achieved disease control with initial pemetrexed treatment, followed by rechallenge with pemetrexed-based chemotherapy (PBC) upon disease progression. After the rechallenge, 5 patients (16.1%) achieved partial remission (PR), 17 (54.8%) achieved stable disease (SD) and 9 (29.1%) experienced progressive disease. The treatment was generally well tolerated, with a low rate of toxicity. The median progression-free survival (PFS) was 3.8 months with the rechallenge. Patients with a PFS of ≥10 months with initial PBC exhibited longer PFS and overall survival (OS) with the rechallenge compared to those with a PFS of <10 months with initial PBC (PFS: 6.2±0.33 vs. 3.1±0.26 months, respectively; P=0.011; and OS, 19.8±3.2 vs. 9.2±1.1 months, respectively; P=0.005). The time from the termination of initial PBC to disease progression was also associated with survival after the rechallenge. However, the response to initial PBC (PR vs. SD) did not affect PFS after the rechallenge. No significant differences were observed in thymidylate synthase expression, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase gene fusion, or epithelial growth factor receptor mutation status between pemetrexed-sensitive and pemetrexed-resistant patients. Our results demonstrated that rechallenge with PBC was well tolerated and survival after the rechallenge was associated with survival during initial PBC. Therefore, patients with a PFS of ≥10 months or time-to-disease progression ≥3 months may be considered as candidates for pemetrexed rechallenge.

4.
Thorac Cancer ; 5(6): 509-16, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26767045

RESUMO

BACKGROUND: Drug resistance significantly weakens the efficacy of cancer treatment, and the BIM (also known as the BCL2L11 gene) deletion polymorphism has been identified as a potential biomarker for drug resistance. In this retrospective study, we included a total of 290 patients with advanced non-small cell lung cancer (NSCLC) who received treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. METHODS: The BIM deletion polymorphism of each patient was detected by polymerase chain reaction. EGFR mutations were detected by denaturing high-performance liquid chromatography methods and the amplification refractory mutation system. RESULTS: The BIM deletion polymorphism was detected in 45/290 (15.5%) Chinese NSCLC patients. No associations were observed between the BIM deletion and clinic-pathologic characteristics of patients. The BIM deletion polymorphism was predictive of shorter progression-free survival in Chinese patients with EGFR-mutant adenocarcinoma and who were treated with EGFR-TKIs (7.30 vs. 9.53 months, P = 0.034). Additionally, we found that the BIM deletion polymorphism was an effective predictor of short progression-free survival in individuals with EGFR-mutant NSCLC and treated with chemotherapy containing pemetrexed (3.32 vs. 5.30, P = 0.012) or second-/beyond-line chemotherapy containing taxanes (1.53 vs. 2.61 months, P = 0.025). The BIM deletion was not correlated with overall survival. CONCLUSION: The BIM deletion polymorphism occurs in 15.5% of Chinese NSCLC patients, and is a biomarker for resistance to TKIs and chemotherapy. However, BIM deletion was not a decisive factor in overall survival.

5.
Zhonghua Jie He He Hu Xi Za Zhi ; 36(3): 162-8, 2013 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-23856136

RESUMO

OBJECTIVE: To identify potential prognosis related clinical and molecular factors in malignant pleural mesothelioma (MPM). METHODS: Seventy-nine patients with MPM treated in Beijing Cancer Hospital from June 1996 to May 2012 were enrolled in this study. Clinical and pathological data were collected, including age, gender, smoking status, treatment, response, and molecular biomarkers such as thymidylate synthetase (TS) expression, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene rearrangement. The primary endpoint was overall survival (OS). SPSS 16.0 statistical analysis software was used for univariate analysis. The expression of TS was detected by immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) was performed to detect EML4-ALK gene rearrangement. Efficacy of the chemotherapy regimen including pemetrexed was analyzed with these molecular biomarkers. RESULTS: The median survival time (MST) of all patients was 15.5 months (95% CI: 10.6 - 20.4). Univariate survival analysis revealed that treatment factors including receiving operation, systemic chemotherapy, pemetrexed-based chemotherapy and capability of receiving second (or above) line chemotherapy were significantly related with OS. The MST of patients receiving operation was 5.4 months (95% CI: 3.6 - 7.3), significantly shorter than the 17.7months (95% CI: 11.8 - 23.5) in those who didn't receive operation (P = 0.030). Patients receiving systemic chemotherapy had a longer MST of 18.0 months (95% CI: 12.3 - 23.8) as compared to the 7.9 months (95% CI: 1.1 - 14.7) in those who didn't (P = 0.001). The MST of pemetrexed-based chemotherapy was 21.9 months (95% CI: 14.1-29.7) compared with 8.8 months (95% CI: 4.2 - 13.4) of regimens without pemetrexed (P = 0.000). For patients capable of receiving second (or above) line chemotherapy the MST was longer (21.0 months, 95% CI: 12.7 - 29.3) than those who could not (12.1 month, 95% CI: 6.4 - 17.8 month), P = 0.022. For the 42 patients treated with pemetrexed-based chemotherapy, the objective response rate (ORR) was 33.3% (14/42), the disease control rate (DCR) was 78.6% (33/42), the median progression-free survival (PFS) was 4.8 months (95% CI: 3.6 - 6.0) and MST was 21.9 months (95% CI: 14.1 - 29.7). Twenty-nine patients provided adequate specimens for detection of TS expression and 6 cases (20.7%) were positive. EML4-ALK gene rearrangement was studied in 32 patients and 6 (18.8%) were positive. TS expression was found to be inversely related to PFS of pemetrexed-based chemotherapy (P = 0.041). The MST was 19.6 months (95% CI: 6.0 - 7.9) in EML4-ALK-positive patients and 9.57 months (95% CI: 2.7 - 4.3) in negative ones (P = 0.159). CONCLUSIONS: Systemic chemotherapy especially pemetrexed-based regimen was proved to be a superior option for MPM with a significantly prolonged OS. Correlation between TS expression or EML4-ALK rearrangement and outcome of pemetrexed-based chemotherapy for MPM may contribute to future individualized treatment, which needs further validation from large-scale prospective studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glutamatos/administração & dosagem , Guanina/análogos & derivados , Mesotelioma/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Neoplasias Pleurais/tratamento farmacológico , Timidilato Sintase/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Cisplatino/administração & dosagem , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Guanina/administração & dosagem , Humanos , Imuno-Histoquímica , Masculino , Mesotelioma/metabolismo , Mesotelioma/mortalidade , Mesotelioma/patologia , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Pemetrexede , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Prognóstico , Fatores de Risco , Adulto Jovem
6.
Zhonghua Jie He He Hu Xi Za Zhi ; 35(5): 323-8, 2012 May.
Artigo em Chinês | MEDLINE | ID: mdl-22883988

RESUMO

OBJECTIVE: To investigate the frequency of epidermal growth factor receptor (EGFR) mutations and their correlation with the efficacy of tyrosine kinase inhibitors (EGFR-TKI) in advanced squamous cell lung cancer. METHODS: This retrospective study enrolled 79 patients with advanced squamous cell lung cancer who received EGFR-TKI at Department of Thoracic Medical Oncology in Peking University Cancer Hospital from June 2004 to June 2011. Among them, 67 patients had tissue and/or plasma EGFR exon 19 and 21 mutation detection in order to make an analysis on the relationship between EGFR mutation and the TKI's effect. RESULTS: The disease control rate (DCR) was 56% in all the patients. The median progression free survival (mPFS) and median overall survival (mOS) was 3.7 months (95%CI: 2.0 - 5.0) and 11.5 months (95%CI: 6.6 - 14.2), respectively. Of the 67 patients who received EGFR mutation detection, there were 31 patients harboring EGFR-mutation, for whom the DCR was 71% (22/31), and mPFS and mOS was 6.3 months (95%CI: 2.2 - 10.0) and 13.5 months (95%CI: 7.3 - 18.6) respectively. 36 patients' EGFR status were wild type, for whom the DCR was 44% (16/36), mPFS and mOS was 2.2 months (95%CI: 1.1 - 4.0) and 6.4 months (95%CI: 4.0 - 12.0). There were 17 patients who received erlotinib and 7 patients who received gefitinib as second or more line treatment. mPFS and mOS were 7.9 months and 15.8 months in the erlotinib group, respectively; and the mPFS and mOS were both 6.3 months in gefitinib group; the difference between the 2 groups did not reach statistical significance. Cox-regression analysis showed that EGFR mutation was significantly correlated with PFS and OS (P < 0.05, respectively). EGFR mutation was significantly correlated with DCR by Chi-square test, P < 0.05. CONCLUSIONS: EGFR mutation was a predictor for advanced squamous cell lung cancer to EGFR-TKI. However, the effect was inferior in advanced squamous cell lung cancer as compared to lung adenocarcinoma. Erlotinib tended to be superior to gefitinib.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Quinazolinas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
7.
Zhonghua Jie He He Hu Xi Za Zhi ; 35(2): 97-101, 2012 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-22455964

RESUMO

OBJECTIVE: To evaluate the effect of pemetrexed plus platinum for chemotherapy-naive advanced non-small cell lung cancer (NSCLC), and to explore thymidylate synthetase (TS) expression as the predictive and prognostic factor for this treatment. METHODS: This retrospective study enrolled 51 patients with chemotherapy-naive advanced NSCLC (non-squamous) treated at Department of Thoracic Medical Oncology in Beijing Cancer Hospital from Jan 2008 to Oct 2009. All patients received pemetrexed plus platinum as first-line treatment. TS expression was detected in 30 patients who had enough tissue samples by immunohistochemistry. RESULTS: The objective response rate (ORR) was 37.3%. Median progression-free survival (PFS) was 5.3 months (95%CI: 3.9 - 6.7), and median overall survival (OS) was 19.0 months (95%CI: 11.6 - 26.4). Univariate analysis showed that gender, pathology, smoking status and response were significantly correlated with OS. Cox-regression analysis showed that pathology was an independent prognostic factor. Rate of Grade 3/4 adverse events was low. In 30 patients with enough tissue samples were available, TS expression positive rate was 33.3% (10/30). Chi-square test showed that TS expression was not associated with ORR. Multivariate analysis showed that pathology, response and TS expression (P = 0.003, 0.005 and 0.001, respectively) were the prognostic factors. CONCLUSION: The therapeutic effect and tolerance of pemetrexed plus platinum regiment were definite as first-line treatment for chemotherapy-naive advanced NSCLC, and TS expression was an independent prognostic factor.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Timidilato Sintase/análise , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Pemetrexede , Platina/administração & dosagem , Estudos Retrospectivos , Timidilato Sintase/metabolismo , Resultado do Tratamento , Adulto Jovem
8.
Chin Med J (Engl) ; 124(21): 3510-4, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22340169

RESUMO

BACKGROUND: The genotype of epidermal growth factor receptor (EGFR) is associated with tyrosine kinase inhibitor and effectiveness of therapy, but its role in cytotoxic chemotherapy is still unknown. Previous studies indicated that certain EGFR mutations were associated with response and progression free survival following platinum based chemotherapy. Our recent studies have identified that EGFR genotypes in the tumour tissues were not associated with response to the first-line chemotherapy in Chinese patients with advanced non-small cell lung cancer (NSCLC). In this study, we investigated associations of EGFR genotypes from plasma of patients with advanced NSCLC and response to first-line chemotherapy and prognosis. METHODS: We enrolled 145 advanced NSCLC patients who had received first-line chemotherapy in our department. We examined plasma EGFR genotypes for these patients and associations of EGFR mutations with response to chemotherapy and clinical outcomes. RESULTS: There were 54 patients with known EGFR mutations and 91 cases of wild types. No significant difference was detected in the response rate to first-line chemotherapy between mutation carriers and wild-type patients (37.0% vs. 31.9%). The median survival time and 1-, 2-year survival rates were higher in mutation carriers than wild-types (24 months vs. 18 months, 85.7% vs. 65.7% and 43.7% vs. 25.9%, P = 0.047). Clinical stage (IV vs. IIIb), response to the first-line chemotherapy (partial vs. no) and EGFR genotype were independent prognostic factors. CONCLUSION: Plasma EGFR mutations in the Chinese patients with advanced NSCLC is not a predictor for the response to first-line chemotherapy, but an independent prognostic factor indicating longer survival.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Plasmídeos/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
9.
Chin J Cancer Res ; 23(2): 112-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23483659

RESUMO

OBJECTIVE: To analyze the outcomes of patients who received TKI immediately after the first-line without progression as maintenance treatment (immediate group) vs. those received delayed treatment upon disease progression as second-line therapy (delayed group). METHODS: The study included 159 no-small-cell lung cancer (NSCLC) patients who received gefitinib or erlotinib as maintenance treatment in the immediate group (85 patients) or as second-line therapy in the delayed group (74 patients). The primary end point was progression-free survival (PFS). EGFR mutation status was detected using denaturing high-performance liquid chromatography (DHPLC). RESULTS: PFS was 17.3 and 16.4 months in the immediate and delayed groups, respectively (hazard ratio [HR], 0.99; 95% Confidence Interval [CI]: 0.69-1.42; P=0.947). In a subgroup analysis that included only patients with EGFR mutation, however, PFS was significantly longer in the immediate group than in the delayed group (HR, 0.48; 95% CI: 0.27-0.85; P=0.012). In patients with wild type EGFR, the risk for disease progression was comparable between the two groups (HR, 1.23; 95% CI: 0.61-2.51; P=0.564). No significant difference was demonstrated between the immediate and delayed group in terms of the overall survival (OS) (26.1 months vs. 21.6 months, respectively; HR=0.53; 95% CI: 0.27 to 1.06; P=0.072). There was also no difference in the incidence of adverse events between the two groups. CONCLUSIONS: EGFR TKI maintenance improves PFS in patients with EGFR mutation. Prospectively designed clinical studies that compare TKI immediate vs. delayed treatment after first-line chemotherapy upon disease progression are needed.

10.
J Clin Oncol ; 27(16): 2653-9, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19414683

RESUMO

PURPOSE: Mutations in the epidermal growth factor receptor (EGFR) kinase domain can predict tumor response to tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). However, obtaining tumor tissues for mutation analysis is challenging. We hypothesized that plasma-based EGFR mutation analysis is feasible and has value in predicting tumor response in patients with NSCLC. PATIENTS AND METHODS: Plasma DNA samples and matched tumors from 230 patients with stages IIIB to IV NSCLC were analyzed for EGFR mutations in exons 19 and 21 by using denaturing high-performance liquid chromatography. We compared the mutations in the plasma samples and the matched tumors and determined an association between EGFR mutation status and the patients' clinical outcomes prospectively. RESULTS: In 230 patients, we detected 81 EGFR mutations in 79 (34.3%) of the patients' plasma samples. We detected the same mutations in 63 (79.7%) of the matched tumors. Sixteen plasma (7.0%) and fourteen tumor (6.1%) samples showed unique mutations. The mutation frequencies were significantly higher in never-smokers and in patients with adenocarcinomas (P = .012 and P = .009, respectively). In the 102 patients who failed platinum-based treatment and who were treated with gefitinib, 22 (59.5%) of the 37 with EGFR mutations in the plasma samples, whereas only 15 (23.1%) of the 65 without EGFR mutations, achieved an objective response (P = .002). Patients with EGFR mutations had a significantly longer progression-free survival time than those without mutations (P = .044) in plasma. CONCLUSION: EGFR mutations can be reliably detected in plasma DNA of patients with stages IIIB to IV NSCLC and can be used as a biomarker to predict tumor response to TKIs.


Assuntos
Antineoplásicos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Idoso , Carcinoma Pulmonar de Células não Pequenas/etnologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , China , DNA/sangue , DNA de Neoplasias/análise , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Éxons , Estudos de Viabilidade , Feminino , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Seleção de Pacientes , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Tempo , Resultado do Tratamento
12.
Zhonghua Jie He He Hu Xi Za Zhi ; 31(12): 891-6, 2008 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-19134404

RESUMO

OBJECTIVE: To study the application of denaturing high performance liquid chromatography (DHPLC) as a screening tool in detecting plasma and matched tissue epidermal growth factor receptor (EGFR) mutations for advanced non-small-cell lung cancer (NSCLC). METHODS: Plasma DNA samples and matched tumors from 230 cases of NSCLC were analyzed for EGFR mutations in exons 19 and 21 using DHPLC. The mutations in the plasma samples and the matched tumors were compared, and the association between EGFR mutations and the clinicopathological features were evaluated. RESULTS: Mutation of EGFR was found by DHPLC to be 33.5% (77/230) in tissues and 34.3% (79/230) in matched peripheral blood samples. Consistency of EGFR mutation status between tissues and matched plasma DNA was confirmed (kappa is 0.74, P < 0.01). The sensitivity and specificity of DHPLC for detecting EGFR mutation were 96.9% and 91.9%, respectively (kappa is 0.88). EGFR mutations in both tissue and blood was correlated with histology type (OR = 3.38, 95% CI 1.81 - 6.36, P < 0.05) and smoking status (OR = 1.61, 95% CI 1.13 - 2.28, P < 0.05), but no association with age, sex and stage was found (P > 0.05). CONCLUSION: The detection of EGFR mutation is highly consistent in tissues and in plasma DNA samples. DHPLC may serve as a preliminary screening tool for detecting EGFR mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Receptores ErbB/sangue , Éxons , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Mutação
13.
Zhonghua Jie He He Hu Xi Za Zhi ; 30(2): 103-7, 2007 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-17445470

RESUMO

OBJECTIVE: In patients with resected early stage non-small cell lung cancer (NSCLC), intrapulmonary solitary tumor represents either second primary tumor (SPT) or a metastasis. This study is to discern SPT from lung metastasis in patients with postoperative NSCLC followed a solitary intrapulmonary tumor by microsatellite analysis. METHODS: Twenty-one patients with stage I - III(A) NSCLC resected by surgery during 1994.1 - 2002.8 were studied. Paired tumors from 21 patients with NSCLC and a solitary lung nodule were analyzed for their loss of heterozygosity (LOH) on chromosomal arms 3p, 9p and 17p. DNA from microdissected tumors and non-malignant lung tissues was subjected to polymerase chain reaction-based microsatellite analysis using 8 microsatellite markers. An effort was also made to distinguish SPT from lung metastasis on the basis of clinical and histopathologic features. RESULTS: The paired tumors from 7 patients had concordant patterns of LOH at all microsatellite loci suggesting the same clonal origin, and supporting metastatic spread, where 4 paired tumors had discordant patterns of at all loci suggesting independent tumor origin. These observations were supported by the clinical and pathologic findings. Additional 6 paired tumors had concordant allelic loss on 3p and discordant loss on the other, clinical characteristics supporting metastatic disease. In contrast, 2 paired tumors had concordant allelic loss on 9p or 17p but discordant loss on the 3p, clinical data supporting SPT. CONCLUSIONS: The paired tumors from 7 patients had concordant patterns of LOH at all microsatellite loci suggesting the same clonal origin, and supporting metastatic spread, where 4 paired tumors had discordant patterns of at all loci suggesting independent tumor origin. These observations were supported by the clinical and pathologic findings. Additional 6 paired tumors had concordant allelic loss on 3p and discordant loss on the other, clinical characteristics supporting metastatic disease. In contrast, 2 paired tumors had concordant allelic loss on 9p or 17p but discordant loss on the 3p, clinical data supporting SPT.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Diagnóstico Diferencial , Feminino , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico
14.
Zhonghua Zhong Liu Za Zhi ; 28(6): 474-7, 2006 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-17152500

RESUMO

OBJECTIVE: To investigate the efficacy, time to progression, survival time and toxicity of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor Gefitinib (Iressa), a target therapy agent, in the treatment of advanced non-small cell lung cancer (NSCLC), and to analyze the factors affecting the efficacy and patients' survival. METHODS: From Nov. 2003 to May 2005, 91 patients with advanced NSCLC who failed from previous first-line chemotherapy were treated by gefitinib in this trial with a median chemotherapy cycle of six. Sixty-eight of these 91 patients (74.7%) had received a second-line chemotherapy. Seventy-six (83.5%) of the 91 patients had stage IV disease, and 42 (46.2%) had developed metastases at least two sites. Gefitinib was administered orally at a dose of 250 mg daily until disease progressed or severe toxicity developed. Clinical data were analyzed using chi-square test, Log-lank test, Cox regression and Kaplan-Meier survival analysis in SPSS 11.5. RESULTS: (1) Overall response rate was 20.9% (19/91) and the disease control rate (response and stable disease) was 63.7% (58/91). Patients'symptoms were improved in 72.7% (40/55), and ECOG score was improved or remained stable in 71.4% (65/91). The disease control rate of those who had adenocarcinoma, or received second-line chemotherapy or developed skin toxicity was significantly better than the other patients (P value = 0.04, 0.02, 0.00, respectively). (2) Median time to progress (TIP) was 5.0 months (95% CI 3.26-6.74). (3) Median following-up duration was 7.5 months (1-18. 5 months), and 1-year survival rate was 56.4%. Of the 56 patients (61.5%) who were still alive when following-up ended, 29 (51.8%) had stable disease, 20 had survived more than one year (12-18. 5 months). Non-smoker, stable diseases, skin toxicities, and controlled metastatic diseases during the treatment of gefitinib were the favorable factors affecting the survival (P value = 0.00, 0.00, 0.00, 0.01, respectively). (4) The main toxicity of gefitinib was grade I or II skin toxicity. CONCLUSION: Gefitinib, a target therapy agent which may be an alternative, is effective and tolerable in the treatment for advanced NSCLC patients who have failed in the first-line or even second-line chemotherapy. It can remarkablely improve the disease control rate and disease-related symptoms, and also prolong survival in the responders.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Exantema/induzido quimicamente , Feminino , Seguimentos , Gefitinibe , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Quinazolinas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento
15.
Ai Zheng ; 23(11 Suppl): 1428-30, 2004 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-15566650

RESUMO

BACKGROUND & OBJECTIVE: Clinical trails showed that thymosin alpha1 offers protection from toxicities (nausea, vomiting, fatigue) of chemotherapy. This study was designed to investigate the protection of thymosin alpha1 to nervous system. METHODS: Twenty-two patients with advanced lung cancer, or advanced breast cancer were treated with vinorelbine (25 mg/m(2), d(1), d(8)) combined with cisplatin (80 mg/m(2), d(1)), or gemcitabine (1.25 g/m(2), d(1), d(8)) combined with cisplatin (80 mg/m(2), d(1)),or paclitaxel (80 mg/m(2), d(1), d(8), d(15)) combined with carboplatin (AUC=6 d(1)),or paclitaxel (80 mg/m(2), d(1), d(8), d(15)) combined with epirubicin (80 mg/m(2), d(1)). They all experienced grade 2 to 4 of neurotoxicities according to common toxicity criteria of National Cancer Institute after chemotherapy. The same chemotherapy regimens were combined with thymosin alpha1 (1.6 mg/d for 4 days before chemotherapy, and 1.6 mg twice weekly for 1-3 weeks after chemotherapy began) in the next cycle. Clinical neurologic evaluation was performed at baseline every week. RESULTS: In 10 patients (45.4%), neurotoxicities reduced from grade 2-4 before chemotherapy to less than grade 2 after chemotherapy. CONCLUSION: Thymosin alpha1 may prevent patients from chemotherapy-induced neurotoxicities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hipestesia/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Timosina/análogos & derivados , Timosina/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Feminino , Humanos , Hipestesia/induzido quimicamente , Hipocinesia/induzido quimicamente , Hipocinesia/tratamento farmacológico , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Timalfasina
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