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BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Adolescente , Adulto , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/uso terapêutico , Quinase do Linfoma Anaplásico/uso terapêutico , Proteínas Proto-Oncogênicas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents. METHODS: The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 µg, 2100 µg, and 2400 µg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 µg and rhG-CSF 5 µg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 µg, 1500 µg, and continuous rhG-CSF 5 µg/kg. RESULTS: Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 µg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 µg to 2400 µg, while the double delivery of HSA/G-CSF 2400 µg failed to meet the noninferiority in comparison with rhG-CSF. CONCLUSION: The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 µg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).
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Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/metabolismo , Albumina Sérica/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: FRESCO study demonstrated efficacy and safety of fruquintinib in metastatic colorectal cancer patients. Impact of prior targeted therapy (PTT) on efficacy and safety of fruquintinib was evaluated. Materials & methods: In this subgroup analysis of FRESCO trial, patients were divided into PTT and non-PTT subgroups, and efficacy and safety of fruquintinib were assessed, respectively. Results: In non-PTT subgroup, fruquintinib significantly prolonged overall survival (OS) and progression-free survival (PFS) of patients compared with placebo. In PTT subgroup, the median OS and PFS of patients in fruquintinib arm was significantly higher than those in placebo. Treatment-emergent adverse events (TEAEs) rates were similar in both subgroups. Conclusion: Fruquintinib demonstrated clinically meaningful improvement in OS, PFS, objective response rate, and disease control rate with manageable TEAEs in both subgroups. Clinical trial registration: NCT02314819 (ClinicalTrials.gov).
Lay abstract In this analysis of the FRESCO trial, we evaluated the efficacy and safety of fruquintinib in two different groups of patients (subgroups) with metastatic colorectal cancer - patients who received prior targeted therapy (PTT) and patients who did not (non-PTT). Of the 278 patients treated with fruquintinib, 111 patients received PTT. Patients treated with fruquintinib had longer overall survival and it took longer for their disease to worsen in both PTT and non-PTT subgroups compared with placebo. Patients in both subgroups treated with fruquintinib showed measurable reduction in their tumor size and disease control with similar side effects in patients of both the subgroups. These results suggest that fruquintinib is safe and effective in patients with metastatic colorectal cancer in both subgroups.
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Benzofuranos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Quinazolinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The tripartite motif containing 23 (TRIM23) gene is a member of the tripartite motif (TRIM) family that participates in many pathophysiological processes. However, the role of TRIM23 in lung adenocarcinoma (LUAD) remains unclear. In the present study, TRIM23 was first screened by next-generation sequencing between the cisplatin (DDP)-resistant A549/DDP cell line and the parental A549 cell line, combined with integrated analysis of the Gene Expression Omnibus (GEO) data (E-GEOD-43493 and E-GEOD-43494). The expression of TRIM23 was then verified to be upregulated in the DDP-resistant LUAD cells and tissues. The knockdown of TRIM23 expression in A549/DDP cells caused increased apoptosis, decreased IC50 values of DDP, NF-κB nuclear translocation, inhibition of cell proliferation in vitro and in vivo, inhibition of GLUT1/3 expression, glucose uptake, and lactate and ATP production. TRIM23 overexpression resulted in the opposite effects in A549 cells. In addition, the inhibition of proliferation in A549 cells caused by NF-κB signaling inhibitor PTDC or glycolysis inhibitor 3-BrPA could be weakened by TRIM23 overexpression. Furthermore, immunohistochemical analysis revealed that TRIM23 was upregulated in 46.1% (70/152) of LUAD cases, and elevated TRIM23 expression was correlated with high expression of NF-κB, poor cellular differentiation, and adverse overall survival (OS) and disease-free survival (DFS). In conclusion, our study demonstrates that TRIM23 acts as an oncogene in LUAD and promotes DDP resistance by regulating glucose metabolism via the TRIM23/NF-κB/ GLUT1/3 axis.
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Adenocarcinoma/genética , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteínas de Ligação ao GTP/genética , Neoplasias Pulmonares/genética , Regulação para Cima , Células A549 , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/uso terapêutico , Feminino , Proteínas de Ligação ao GTP/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transdução de Sinais , Análise de SobrevidaRESUMO
The long noncoding RNAs (lncRNAs) SBF2 antisense RNA 1 (SBF2-AS1) was found to act as an oncogenic lncRNA in non-small-cell lung cancer (NSCLC), but the role of SBF2-AS1 in small-cell lung cancer (SCLC) was still unclear. The purpose of this study was to provide the clinical significance and biological function of SBF2-AS1 in SCLC. In our results, SBF2-AS1 was found to be upregulated in SCLC tissues compared with NSCLC tissues or adjacent normal lung tissues. Besides, SBF2-AS1 expression was also elevated in SCLC cell lines compared with the normal bronchial epithelial cell line or NSCLC lines. Moreover, high expression of SBF2-AS1 was associated with clinical stage, tumor size, lymph node metastasis and distant metastasis in SCLC patients. Survival analysis showed SCLC patients with high expression of SBF2-AS1 had shorter overall survival than patients with low expression of SBF2-AS1, and high expression of SBF2-AS1 acted as an independent poor prognostic factor for overall survival in SCLC patients. The study in vitro suggested inhibition of SBF2-AS1 obviously depressed cell proliferation, migration, and invasion in SCLC. In conclusion, SBF2-AS1 acts as a novel oncogenic lncRNA in SCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , RNA Longo não Codificante/genética , Regulação para Cima , Células A549 , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de SobrevidaRESUMO
Lung cancer characterized with malignantâ¯cell growth is the leading cause of cancer-related deaths. In recent years, several circular RNAs (circRNAs) have been reported to participate in lung cancer progression. However, the correlation between circular RNA (circRNA) and lung cancer still remains to be further investigated. In this study, we screened out a highly expressed circular RNA hsa_circRNA_103809 in lung cancer tissues. We showed hsa_circRNA_103809 could serve as a prognostic biomarker for patients with lung cancer. Furthermore, we found that hsa_circRNA_103809 knockdown significantly suppressed lung cancer cell proliferation and invasion in vitro and delayed tumor growth in vivo. In mechanism, we identified hsa_circRNA_103809 as a sponge of miR-4302 targeting ZNF121. By sequestering miR-4302, hsa_circRNA_103809 promoted the expression of ZNF121 which consequently enhanced MYC protein level in lung cancer cells. Through rescue assays, we demonstrated hsa_circRNA_103809 contributed to lung cancer cell proliferation and invasion via facilitating ZNF121-dependent MYC expression by sponging miR-4302. In conclusion, our findings illustrated a novel hsa_circRNA_103809/miR-4302/ZNF121/MYC regulatory signaling pathway in lung cancer progression.
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Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA/genética , Fatores de Transcrição/genética , Células A549 , Animais , Apoptose , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA/metabolismo , RNA Circular , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recently, circular RNA (circRNA) is identified as a novel class of noncoding RNA with important roles in human diseases, such as cancer. However, how circRNA participates in colorectal cancer (CRC) remains unclear. In this study, we aimed to illustrate the role of circ_0026344 in CRC progression. We showed that circ_0026344 expression was downregulated in CRC tissues compared to adjacent normal tissues. Moreover, the level of circ_0026344 was inversely correlated with CRC advance and lymphoid node metastasis. Additionally, circ_0026344 low expression predicted poor prognosis in CRC patients. We identified circ_0026344 as a miRNA sponge for microRNA-21 (miR-21) and microRNA-31 (miR-31) whose expression levels were elevated in CRC tissues. And the level of circ_0026344 was reversely correlated with both miR-21 and miR-31 levels in CRC tissues. Functionally, we found that ectopic expression of circ_0026344 decreased the growth and invasion of CRC cells while promoting apoptosis in vitro. The xenograft experiment indicated that circ_0026344 overexpress led to CRC growth inhibition in vivo. Rescue assays further demonstrated that circ_0026344 exerted biological functions by sponging miR-21 and miR-31 in CRC. In conclusion, this study revealed that circ_0026344/miR-21/miR-31 regulatory signaling was implicated in CRC progression.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , MicroRNAs/genética , RNA Neoplásico/genética , RNA/genética , Animais , Sequência de Bases , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Camundongos Nus , Prognóstico , RNA Circular , Homologia de Sequência do Ácido Nucleico , Transplante HeterólogoRESUMO
Importance: Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. Objective: To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. Design, Setting, and Participants: FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Interventions: Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. Main Outcomes and Measures: The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Results: Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Conclusions and Relevance: Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. Trial Registration: ClinicalTrials.gov Identifier: NCT02314819.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzofuranos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Quinazolinas/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzofuranos/efeitos adversos , China , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Quinazolinas/efeitos adversos , Análise de Sobrevida , Adulto JovemRESUMO
Recently, long non-coding RNAs (lncRNAs) have been shown to play important roles in human cancer biology. The purpose of this study was to assess the biological role of lncRNA H19 in non-small-cell lung cancer (NSCLC). Quantitative reverse transcription PCR (qRT-PCR) was used to detect the expression of H19 in tumor tissues and corresponding non-tumor NSCLC tissues from 70 patients. The higher expression of H19 was positively correlated with advanced tumor-node-metastasis (TNM) stage and tumor size. Multivariate analyses found that H19 expression could serve as an independent prognostic factor for overall survival of NSCLC. Moreover, chromatin immunoprecipitation (ChIP) assays revealed that H19 was a direct transcriptional target of c-Myc. And, knockdown of H19 significantly inhibited NSCLC cell proliferation both in vitro and in vivo. In conclusion, our study demonstrated that H19 is involved in the oncogenesis of NSCLC, and H19 may be a potential diagnostic and target for new therapies in patients with NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Longo não Codificante/metabolismo , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Proliferação de Células , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Transplante de Neoplasias , RNA Longo não Codificante/genética , Carga TumoralRESUMO
OBJECTIVE: To investigate the different expressions of ER and ER gene status between primary and relapsed/metastatic lesions and their clinical significance. METHODS: ER and ER gene status of primary and relapse/metastatic breast cancer masked in 70 metastatic breast cancer patients were assessed by determination of methylation status by immunohistochemistry (IHC) and methylation specific polymerase chain reaction (MSP), respectively. RESULTS: Positive rate of ER in the primary breast cancers was 64.3%, and in the relapse/metastatic lesions was 41.4% (P < 0.05). There were six patients whose positive ER status was changed to negative, among them the ER gene status was changed from demethylation to hypermethylation in four cases. Another four patients with negative ER status changed to positive, and their ER gene hypermethylation changed to ER demethylation status. CONCLUSIONS: The discordance of ER expression status in primary and relapse/metastatic lesions of breast cancer might be related to DNA methylation status.
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Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Metilação de DNA , Receptores de Estrogênio/genética , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/metabolismo , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/secundário , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Receptores de Estrogênio/metabolismoRESUMO
This retrospective analysis compared standard regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with the dose-dense ABVD regimen (ABVD-21) in terms of efficacy and toxicity. Patients who had early-stage unfavorable or advanced Hodgkin's lymphoma (HL) according to German Hodgkin Study Group criteria from March 1999 to February 2011 were analyzed for treatment response, long-term survival and hematological toxicity. There were 85 patients in the ABVD-21 group and 118 patients in the ABVD group respectively. The complete remission rates after completion of treatment were 92.9% and 90.7% for ABVD-21 and ABVD, respectively. During a median follow-up period of 62 months, no significant difference was found in projected 10-year progression-free survival (PFS) and overall survival (OS) rates (84.7% and 94.1% respectively for ABVD-21; 81.4% and 91.5% for ABVD). Subgroup analyses showed that ABVD-21 was significantly better than ABVD for patients with IPS≥3 in terms of PFS and OS rates. Grade 3 to 4 leukopenia (51.8% vs. 28.8%, P=0.001) and neutropenia (57.6% vs. 39.0%, P=0.009) were more common with ABVD-21. We were led to conclude that dose-dense ABVD did not result in better tumor control and overall survival than did ABVD for early-stage unfavorable HL. However, patients at high risk, for example, with IPS≥3, may benefit from dose-dense ABVD.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Terapia Combinada/métodos , Doença de Hodgkin/tratamento farmacológico , Adulto , Bleomicina/administração & dosagem , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Feminino , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona , Estudos Retrospectivos , Vimblastina/administração & dosagemRESUMO
Tumor-associated macrophages (TAM) are considered as crucial influencing factors of lung adenocarcinoma (LUAD) carcinogenesis and metastasis. Profilin 1 (PFN1) has been proposed as a potent driver of migration and drug resistance in LUAD. The focus of this work was to figure out the functional mechanism of PFN1 in macrophage polarization in LUAD. PFN1 expression and its significance in patients' survival were detected by ENCORI and Kaplan-Meier Plotter. RT-qPCR and western blotting examined PFN1 expression in LUAD cells. CCK-8 assay and colony formation assay detected cell proliferation. Flow cytometry detected cell apoptosis. Relevant assay kit tested caspase3 concentration. Western blotting analyzed the expression of proliferation- and apoptosis-related proteins. RT-qPCR and immunofluorescence staining measured M1 and M2 macrophages markers. Mitophagy was assessed by MitoTracker Red staining, immunofluorescence staining, and western blotting. PFN1 expression was increased in LUAD tissues and cells and correlated with the poor survival rate of LUAD patients. Deficiency of PFN1 hindered the proliferation, whereas facilitated the apoptosis of LUAD cells. Additionally, PFN1 interference impaired M2 macrophage polarization. Moreover, PFN1 knockdown exacerbated the mitophagy in LUAD cells and mitophagy inhibitor mitochondrial division inhibitor 1 (Mdivi-1) notably reversed the effects of PFN1 down-regulation on the proliferation, apoptosis as well as macrophage polarization in LUAD cells. To sum up, activation of mitophagy initiated by PFN1 depletion might obstruct the occurrence and M2 macrophage polarization in LUAD.
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BACKGROUND: Recent studies have suggested that microRNA-10b (miR-10b) acts as a promoter of metastasis in breast cancer, although the underlying mechanism remains largely unknown. In this study, we provide the first evidence that E-cadherin (E-cad) is a potential target of miR-10b. MATERIAL/METHOD: By applying gain-of-function and loss-of-function approaches in the metastatic breast cancer cell line MDA-MB-231, we demonstrated that miR-10b is necessary and sufficient to regulate the cellular expression of E-cad and in vitro tumor cell invasion. RESULTS: Comparative expression analysis of miR-10b in benign breast lesions (N=16), primary breast cancers (N=21), and metastatic breast carcinomas (N=23) revealed that miR-10b transcription was uniquely up-regulated in metastatic cancers. The expression level of miR-10b positively correlated with tumor size, pathological grading, clinical staging, lymph node metastasis, Her2-positivity and tumor proliferation, but was negatively associated with estrogen receptor-positivity, progesterone receptor-positivity and E-cad mRNA and protein levels. CONCLUSIONS: These findings indicate the existence of a novel E-cadherin-related mechanism by which miR-10b modulates breast cancer metastasis. In addition, miR-10b may be a useful biomarker of advanced progression and metastasis of breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/metabolismo , MicroRNAs/metabolismo , Adulto , Idoso , Antígenos CD , Sequência de Bases , Caderinas/genética , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Lineares , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise Multivariada , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Regulação para Cima/genéticaRESUMO
Introduction: Savolitinib has been found to have encouraging antitumor activity and a favorable safety profile in Chinese patients with pulmonary sarcomatoid carcinoma and other NSCLCs with MET exon 14 skipping alterations (MET ex14 positive) at the primary analysis of a phase 2 study. Here, we present the long-term efficacy and safety data of savolitinib, including subgroup analyses. Methods: This multicenter, single-arm, open-label, phase 2 study in the People's Republic of China enrolled MET inhibitor-naive adults with locally advanced or metastatic METex14-positive NSCLC (NCT02897479). Oral savolitinib at a dose of 400 or 600 mg was administered once daily (body weight dependent). The primary objectives of the final analysis were long-term overall survival (OS) and subgroup analyses by previous systemic treatment, NSCLC subtypes, and brain metastases. Results: At the final analysis cutoff date (June 28, 2021), a total of 70 patients were enrolled and receiving savolitinib, and median follow-up was 28.4 (interquartile range: 26.2-36.3) months. The median OS was 12.5 months (95% confidence interval [CI]: 10.5-21.4 [18- and 24-mo OS rates, 42.1% and 31.5%, respectively]). Median OS in pretreated or treatment-naive patients was 19.4 (95% CI: 10.5-31.3) and 10.9 (95% CI: 7.5-14.0) months, respectively; it was 10.6 months (95% CI: 4.6-14.0) in patients with pulmonary sarcomatoid carcinoma, 17.3 months (95% CI: 10.6-23.6) in other NSCLC subtypes, and 17.7 months (95% CI: 10.5-not evaluable) in patients with brain metastases. No new safety signals emerged with prolonged follow-up and exposure. Conclusions: The updated results further confirm the favorable benefit and acceptable safety of savolitinib in Chinese patients with METex14-positive NSCLC.
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Background: Savolitinib, a selective MET inhibitor, showed efficacy in patients with non-small cell lung cancer (NSCLC), including pulmonary sarcomatoid carcinoma (PSC), harbouring MET exon 14 skipping alteration (METex14). Objective: To analyse post hoc, the association between circulating tumour DNA (ctDNA) biomarkers and clinical outcomes, including resistance, with savolitinib. Design: A multicentre, single-arm, open-label phase 2 study. Methods: All enrolled patients with baseline plasma samples were included. Outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) by baseline METex14 and post-treatment clearance, coexisting gene alterations at baseline and disease progression. Results: Among 66 patients with baseline ctDNA sequencing, 46 (70%) had detectable METex14. Frequent coexisting baseline gene alterations included TP53 and POT1 mutations. Patients with detectable baseline METex14 exhibited worse PFS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 0.88-3.57; p = 0.108] and OS (HR, 3.26; 95% CI, 1.35-7.89; p = 0.006) than those without, despite showing a numerically higher ORR. Among 24 patients with baseline detectable METex14 and evaluable postbaseline samples, 13 achieved METex14 clearance post-treatment. Median time to first clearance was 1.3 months (range, 0.7-1.5). METex14 post-treatment clearance was associated with better ORR (92.3%; 95% CI, 64.0-99.8 versus 36.4%; 95% CI, 10.9-69.2; p = 0.0078), PFS (HR, 0.44; 95% CI, 0.2-1.3; p = 0.1225) and OS (HR, 0.31; 95% CI, 0.1-1.0; p = 0.0397) versus non-clearance. Among 22 patients with disease progression, 10 acquired pathway alterations (e.g. in RAS/RAF and PI3K/PTEN) alone or with secondary MET mutations (D1228H/N and Y1230C/H/S). Conclusion: ctDNA biomarkers may allow for longitudinal monitoring of clinical outcomes with savolitinib in patients with METex14-positive PSC and other NSCLC subtypes. Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib. Registration: The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.
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Background: Trastuzumab is the recommended first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients in China, but therapeutic resistance to trastuzumab and other early-line treatments is common and late-line treatment options are limited. Derived from the same murine precursor antibody, margetuximab has enhanced anti-tumor activity compared with trastuzumab and may be an effective late-line treatment. However, data regarding the use of margetuximab in pre-treated Chinese patients are scarce. This study aimed to evaluate the efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients, and to determine whether the results are consistent with the clinical benefit of margetuximab observed in the pivotal global phase III study. Methods: In this randomized, open-label, multicenter, phase II bridging study, eligible Chinese patients pretreated with ≥2 lines of anti-HER2 therapies were randomized 1:1 by stratified block randomization to margetuximab (15 mg/kg over at least 120 minutes) or trastuzumab (6 mg/kg over at least 30 minutes), each administered intravenously once every 21-day cycle and plus chemotherapy. Disease assessment was conducted once every two treatment cycles (6 weeks ± 7 days). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), and the incidence and severity of treatment-emergent adverse events (TEAEs). Results: Between February 4, 2020 and February 23, 2021, 123 patients were randomized to the margetuximab (n=62) and trastuzumab (n=61) arms. Among them, 15 and 7 patients, respectively, were still on study treatment as of data cut-off (September 3, 2021). Overall, 99.2% were female, median age was 53 years old. All patients were pretreated with trastuzumab, and 83.7% and 25.2%, respectively, were pretreated with tyrosine kinase inhibitors (TKIs) and pertuzumab. Baseline characteristics were numerically balanced between arms. BICR-assessed median PFS (mPFS) was 5.5 months in the margetuximab arm and 4.1 months in the trastuzumab arm, with a hazard ratio (HR) of 0.69 [95% confidence interval (CI): 0.43-1.12], which met the consistency criterion (HR <0.88) for bridging success. Median investigator-assessed PFS was 5.5 months in the margetuximab arm and 4.0 months in the trastuzumab arm (HR =0.63; 95% CI: 0.41-0.96). Median OS (mOS) was not yet reached. Both ORR and CBR were greater in the margetuximab arm (25.5% vs. 12.5%; 32.7% vs. 14.3%). Safety results were numerically comparable between the two arms. Anti-HER2 treatment-related infusion-related reactions (IRRs) were more common in the margetuximab arm than in the trastuzumab arm (12.9% vs. 1.7%). All IRRs could be resolved. Conclusions: Margetuximab was effective and well-tolerated in this study, supporting its clinical use in pretreated HER2-positive MBC patients in China. Trial Registration: ClinicalTrials.gov Identifier: NCT04262804.
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BACKGROUND: Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC. METHODS: ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. RESULTS: Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001)ï¼for sintilimab treatment. CONCLUSIONS: Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Docetaxel/efeitos adversos , Neoplasias Pulmonares/patologia , Taxoides/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Fatores de TranscriçãoRESUMO
BACKGROUND: Savolitinib is a selective MET tyrosine-kinase inhibitor. We investigated the activity and safety of savolitinib in patients with pulmonary sarcomatoid carcinoma and other non-small-cell lung cancer (NSCLC) subtypes positive for MET exon 14 skipping alterations (METex14-positive). METHODS: We did a multicentre, single-arm, open-label, phase 2 study across 32 hospitals in China. Eligible patients were 18 years or older with locally advanced or metastatic METex14-positive pulmonary sarcomatoid carcinoma or other NSCLC subtypes, had either presented with disease progression or toxicity intolerance towards one or more standard treatments or were deemed clinically unsuitable for standard treatment, were MET inhibitor-naive, and had measurable disease. Patients received either 600 mg (bodyweight ≥50 kg) or 400 mg (bodyweight <50 kg) of oral savolitinib once daily until disease progression, death, intolerable toxicity, initiation of other anti-tumour therapy, non-compliance, patient withdrawal, or patient discontinuation. Radiographic tumour evaluation was done at baseline, every 6 weeks within 1 year of the first dose, and every 12 weeks thereafter. The primary endpoint was objective response rate, defined as the proportion of patients with confirmed complete or partial responses by independent review committee (IRC) assessment. The primary endpoint was assessed in the tumour response evaluable set, which comprised all treated patients with a measurable lesion at baseline and at least one adequate scheduled post-baseline tumour assessment or the presence of radiological disease progression, with a sensitivity analysis done in the full analysis set, which comprised all patients who received at least one dose of savolitinib. Safety was also evaluated in the full analysis set. This study is registered with ClinicalTrials.gov, NCT02897479, and recruitment is complete, with treatment and follow-up ongoing. FINDINGS: From Nov 8, 2016, to Aug 3, 2020, 84 patients with METex14 skipping alterations were screened for eligibility, of whom 70 were enrolled, received savolitinib, and comprised the full analysis set. The IRC-assessed tumour response evaluable set comprised 61 patients. At a median follow-up of 17·6 months (IQR 14·2-24·4), the IRC-assessed objective response rate was 49·2% (36·1-62·3; 30 of 61 patients) in the tumour response evaluable set and 42·9% (95% CI 31·1-55·3; 30 of 70 patients) in the full analysis set. All 70 patients reported at least one treatment-related adverse event. Treatment-related adverse events of grade 3 or more occurred in 32 (46%) patients, the most frequent of which were increased aspartate aminotransferase (n=9), increased alanine aminotransferase (n=7), and peripheral oedema (n=6). Treatment-related serious adverse events occurred in 17 (24%) patients, the most common being abnormal hepatic function (n=3) and hypersensitivity (n=2). One death due to tumour lysis syndrome in a patient with pulmonary sarcomatoid carcinoma was assessed to be probably related to savolitinib by the investigator. INTERPRETATION: Savolitinib yielded promising activity and had an acceptable safety profile in patients with pulmonary sarcomatoid carcinoma and other NSCLC subtypes positive for METex14 skipping alterations. Savolitinib could therefore be a novel treatment option in this population. FUNDING: Hutchison MediPharma and AstraZeneca. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Éxons , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Pirazinas , TriazinasRESUMO
OBJECTIVE: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy. METHODS: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups. RESULTS: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45-0.77, P<0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17-0.30; P<0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group. CONCLUSION: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM. CLINICALTRIALSGOV IDENTIFIER: NCT02314819.