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BACKGROUND: The prognosis of non-small-cell lung cancer (NSCLC) with brain metastases is very poor. Currently, therapeutic methods for this patient population include whole-brain radiation therapy (WBRT), surgery, radiosurgery and systemic treatment. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) could be effective on cerebral metastases of mutated NSCLC. However, which EGFR-TKIs is more appropriate is still unknown. METHODS: We conducted a retrospective analysis of advanced NSCLC patients with brain metastases for EGFR targeted therapy from November 2013 to April 2018 at Dongguan People's Hospital, Southern Medical University, China. A total of 43 patients were recruit in this study. Among them, 21 cases received icotinib (125 mg, thrice a day) and 22 cases received gefitinib (250 mg, once a day) until disease progression or unacceptable toxicity. The primary end point of this study was intracranial PFS (iPFS). The relationships between therapeutic arms and patients characteristics were performed using Pearson's chi-square test or Fisher's exact test. The differences in PFS among the two arms were analyzed using Kaplan-Meier curves and log rank tests. RESULTS: There was no significant difference of intracranial ORR (66.6% versus 59.1%, P = 0.62) and DCR (85.7% versus 81.8%, P = 0.73) between the two arms. The median intracranial PFS (iPFS) for icotinib and gefitinib arms were 8.4 months (95% CI, 5.4 to 11.3 months) and 10.6 months (95% CI, 6.3 to 14.8 months), respectively (P = 0.17). Adverse events of the two study arms were generally mild. None of the patients experienced dose reduction of EGFR-TKIs. CONCLUSIONS: Our study showed that icotinib and gefitinib had similar efficacy for brain metastasis of EGFR mutated NSCLC. Large randomized studies are suggested to further illuminate the effect of these two EGFR-TKIs on cerebral lesions of NSCLC.
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Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Receptores ErbB/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Two rare strains of Proteus mirabilis with swarming migration deficiency were isolated from urine samples of two patients with urinary tract infections and were named as G121 and G137. Migration experiments showed that P. mirabilis HI4320 had typical migration on blood agar, while G121 and G137 had significantly weakened migration ability. Results of adhesion tests showed that the adhesion ability of G121 and G137 to the bladder epithelial cell line 5637 was significantly reduced. High-throughput sequencing and alignment analysis of the transcriptomes of the three P. mirabilis strains were conducted, with P. mirabilis HI4320 as the reference strain. Reverse transcription quantitative PCR (RT-qPCR) was used to verify differentially expressed genes. Results of transcriptome analysis and RT-qPCR showed that, compared to the HI4320 strain, genes related to flagellum and fimbria formation, dicarboxylate transport, and cystathionine and anthranilate metabolism were down-regulated in G121 and G137, while genes related to iron transport, molybdenum metabolism, and metalloprotease were up-regulated, suggesting that these genes may be involved in the migration ability and epithelial cell adhesion ability of P. mirabilis. These results provide important insight to the search for virulence genes and the screening of new antibacterial targets for P. mirabilis.
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Perfilação da Expressão Gênica , Infecções por Proteus/microbiologia , Infecções por Proteus/urina , Proteus mirabilis/genética , Infecções Urinárias/microbiologia , Idoso de 80 Anos ou mais , Aderência Bacteriana , Proteínas de Bactérias/genética , Linhagem Celular , Células Epiteliais/microbiologia , Feminino , Flagelos , Regulação Bacteriana da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Movimento , Proteus mirabilis/isolamento & purificação , VirulênciaRESUMO
In the present study, we found that Ginsenoside Rg3 attenuated the stemness of non-small cell lung cancer (NSCLC) cells, evident by decreasing spheroid formation ability, ALDH1 activity and stemness marker expression. Furthermore, osimertinib-resistant NSCLC cells displayed a stronger stemness than the parental cells. Ginsenoside Rg3 reduced the stemness and osimertinib resistance of osimertinib-resistant cells. RNA-sequencing revealed that Hippo signaling was shown on the top of the most upregulated pathways regulated by Ginsenoside Rg3 in NSCLC cells, and YAP/TAZ expression was suppressed by Ginsenoside Rg3. Notably, the inhibitor of Hippo signaling attenuated the effects of Ginsenoside Rg3 on the stemness of NSCLC cells. Therefore, Ginsenoside Rg3 attenuates the osimertinib resistance of NSCLC cells via suppressing the stemness, which is dependent on Hippo pathway.
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Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ginsenosídeos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Via de Sinalização Hippo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de SinaisRESUMO
The integrated landscape of ferroptosis regulatory patterns and their association with colon microenvironment have been demonstrated in recent studies. However, the ferroptosis-related immunotherapeutic signature for colon cancer (CC) remains unclear. We comprehensively evaluated 1623 CC samples, identified patterns of ferroptosis modification based on ferroptosis-associated genes, and systematically correlated these patterns with tumor microenvironment (TME) cell infiltration characteristics. In addition, the ferroptosis-regulated gene score (FRG-score) was constructed to quantify the pattern of ferroptosis alterations in individual tumors. Three distinct patterns of ferroptosis modification were identified, including antioxidant defense, iron toxicity, and lipid peroxidation. The characteristics of TME cell infiltration under these three patterns were highly consistent with the three immune phenotypes of tumors, including immune-inflamed, immune-excluded and immune-desert phenotypes. We also demonstrated that evaluation of ferroptosis regulatory patterns within individual tumors can predict tumor inflammatory status, tumor subtype, TME stromal activity, genetic variation, and clinical outcome. Immunotherapy cohorts confirmed that patients with low FRG-scores showed remarkable therapeutic and clinical benefits. Furthermore, the hub gene apolipoprotein L6 (APOL6), a drug-sensitive target associated with cancer cell ferroptosis, was identified through our proposed novel key gene screening process and validated in CC cell lines and scRNA-seq.
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Neoplasias do Colo , Ferroptose , Humanos , Ferroptose/genética , Microambiente Tumoral/genética , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Antioxidantes , ImunoterapiaRESUMO
BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.
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Importance: Use of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear. Objective: To investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases. Design, Setting, and Participants: This open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled. Interventions: The eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone. Main Outcomes and Measures: The primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed. Results: A total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P < .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3; 95% CI, 14.4-18.2 months vs 9.5; 95% CI, 8.3-10.8 months; P < .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0%; 95% CI, 77.0%-93.0% vs 63.0%; 95% CI, 52.2%-73.7%; P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable. Conclusions and Relevance: In this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT01951469.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Gefitinibe , Neoplasias Pulmonares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Gefitinibe/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Prospectivos , Inibidores de Proteínas Quinases , Adulto , Idoso , Idoso de 80 Anos ou maisRESUMO
Background: The abnormal expression of Alpha-1,3-mannosyltransferase (ALG3) has been implicated in tumor promotion. However, the clinical significance of ALG3 in Lung Adenocarcinoma (LUAD) remains poorly understood. Therefore, we aimed to assess the prognostic value of ALG3 and its association with immune infiltrates in LUAD. Methods: The transcriptional expression profiles of ALG3 were obtained from the Cancer Genome Atlas (TCGA), comparing lung adenocarcinoma tissue with normal tissues. To determine the prognostic significance of AGL3, Kaplan-Meier plotter, and Cox regression analysis were employed. Logistic regression was utilized to analyze the association between ALG3 expression and clinical characteristics. Additionally, a receiver operating characteristic (ROC) curve and a nomogram were constructed. To explore the underlying mechanisms, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA) was conducted. The relationship between AGL3A mRNA expression and immune infiltrates was investigated using the tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB). Furthermore, an in vitro experiment was performed to assess the impact of ALG3 mRNA on lung cancer stemness abilities and examine key signaling pathway proteins. Results: Our results revealed the ALG3 mRNA and protein expression in patients with LUAD was much higher than that in adjacent normal tissues. High expression of ALG3 was significantly associated with N stage (N0, HR = 1.98, P = 0.002), pathological stage (stage I, HR = 2.09, P = 0.003), and the number of pack years (<40, HR = 2.58, P = 0.001). Kaplan-Meier survival analysis showed that high expression of ALG3 was associated with poor overall survival (P < 0.001), disease-free survival (P < 0.001), and progression-free interval (P = 0.007). Through multivariate analysis, it was determined that elevated ALG3 expression independently impacted overall survival (HR = 1.325, P = 0.04). The Tumor Immune Estimation Resource discovered a link between ALG3 expression and tumor-infiltrating immune cells in LUAD. Additionally, ROC analysis proved that ALG3 is a reliable diagnostic marker for LUAD (AUC:0.923). Functional pathways analysis identified that ALG3 is negatively correlated with FAT4. We performed qRT-PCR to assess that knockdown ALG3 expression significantly upregulated FAT4 expression. Spheroid assay and flow cytometry analysis results showed that downregulated of ALG3 inhibited H1975 cell line stemness. Western blot analysis revealed that decreased ALG3 inhibited the YAP/TAZ signal pathway. Conclusion: High expression of ALG3 is strongly associated with poor prognosis and immune infiltrates in LUAD.
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Immune checkpoint inhibitors (ICIs) are widely used to treat local or metastatic lung cancer. However, the efficacy of ICI in patients with brain metastases (BM) from lung cancer is unknown. This study aimed to evaluate the efficacy of PD-1/PD-L1 ICIs compared with chemotherapy for patients with lung cancer with BM. Electronic databases (PubMed, Embase, The Cochrane Library, and Web of Science) were searched. The meta-analysis assessed overall survival (OS) and progression-free survival (PFS) of the PD-1/PD-L1 inhibitors axis and its relationship with pathological type, drug modality, and the treatment line number in patients with BM from lung cancer. We included 694 patients with BM from lung cancer from 11 randomized controlled trials. Statistical analysis showed that compared with chemotherapy, PD-1/PD-L1 inhibitors could significantly prolong OS (hazard ratio (HR) = 0.75, 95%confidence interval (95%CI) = 0.51-0.99) and PFS (HR = 0.65, 95%CI = 0.51-0.80). In the subgroup analysis, ICIs plus chemotherapy improved PFS (HR = 0.60, 95%CI = 0.40-0.80), but not OS (HR = 0.75, 95%CI = 0.30-1.19). The efficacy of ICI monotherapy in patients with BM was significantly different between OS and PFS: OS pooled HR = 0.81 (95%CI = 0.57-1.05) and PFS = 0.78 (95%CI = 0.62-0.94). Among different pathological types, the OS pooled HR was 0.67 (95%CI = 0.39-0.95) for non-small cell lung cancer (NSCLC) and 0.94 (95%CI = 0.56-1.33) for small cell lung cancer (SCLC); the PFS pooled HR was 0.58 (95%CI = 0.39-0.76) for NSCLC and 0.79 (95%CI = 0.65-0.93) for SCLC. Subgroups analysis of treatment line showed that no advantage for OS with ICIs as first-line or subsequent-line therapy, whereas ICIs as first-line (HR = 0.63, 95%CI = 0.53-0.74) and second-line (HR = 0.62, 95%CI = 0.62-0.96) benefitted PFS. This meta-analysis implied that compared with chemotherapy, PD-1/PD-L1 inhibitors significantly improved efficacy treatment of patients with BM from lung cancer. Further studies are needed to confirm the role of ICIs in different pathological types and drug treatment modalities.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1RESUMO
This work describes the enhancement of a novel antitumor therapeutic platform that combines advantages from small-molecule drug conjugates (SMDCs) and antibody drug conjugates (ADCs). Valine-citrulline (VCit) dipeptide linkers are commonly used cathepsin B cleavable linkers for ADCs. However, the instability of these linkers in mouse serum makes translating efficacy data from mouse to human more challenging. Replacing the VCit linker with glutamic acid-valine-citrulline (EVCit) has been reported to enhance the stability of ADCs in mouse serum. However, the effect of EVCit linker on the stability of SMDCs has not been reported. Here, we report that incorporating the EVCit linker in prostate-specific membrane antigen-targeting SMDCs, equipped with the transthyretin ligand AG10, resulted in conjugates with lower toxicity, an extended half-life, and superior therapeutic efficacy to docetaxel in a xenograft mouse model of prostate cancer. This should make SMDCs' preclinical toxicity and efficacy data from mice more reliable for predicting human results.
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Antineoplásicos , Imunoconjugados , Animais , Humanos , Camundongos , Anticorpos Monoclonais/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Linhagem Celular Tumoral , Citrulina/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunoconjugados/química , Ligantes , Pré-Albumina , ValinaRESUMO
INTRODUCTION: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. METHODS: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. RESULTS: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. CONCLUSIONS: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas/uso terapêutico , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
OBJECTIVE: To analyze the prognostic significance of the pretreatment platelet/lymphocyte ratio (PLR) for targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). METHODS: We conducted a retrospective study of 96 patients with EGFR-mutated advanced NSCLC who were treated at Dongguan People's Hospital, Southern Medical University from May 2014 to December 2017. All patients received EGFR-targeted therapy until disease progression, unacceptable toxicity, or other factors. Approximately 3 days before the initial treatment, data including a detailed clinical history, physical examination, radiographic results, pathological diagnosis, and laboratory parameters including complete blood cell counts and albumin levels were evaluated. RESULTS: Patients in the PLR ≥ 190 group had shorter progression-free survival (PFS) than those in the PLR < 190 group. Furthermore, the 1-year PFS rate was worse in the PLR ≥ 190 group than in the PLR< 190 group. Multivariate analysis indicated the possible role of PLR as a prognostic factor for patients with advanced NSCLC who received EGFR-targeted therapy. CONCLUSIONS: Pretreatment PLR may be an independent prognostic factor for patients with NSCLC receiving EGFR tyrosine kinase inhibitor treatment. Further studies are needed to identify the impact of PLR on EGFR-mutated NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Linfócitos , Mutação , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos RetrospectivosRESUMO
Background: In patients with anaplastic lymphoma kinase (ALK) rearrangement-positive advanced non-small-cell lung cancer (NSCLC), ALK inhibitors are now the standard treatment, but their clinical efficacy varies widely for each patient. In this multicenter retrospective study, we evaluated the clinical efficacy of crizotinib according to the ALK rearrangement variants and concomitant mutations present. Patients and Methods: A total 132 patients with ALK rearrangement advanced NSCLC from 4 centers in Guangdong province, China were evaluated. All patients received crizotinib treatment and their ALK rearrangement status was identified by next-generation sequencing (NGS). Results: The median progression-free survival (PFS) in patients with EML4-ALK rearrangement (n = 121), non-EML4-ALK rearrangement (n = 5), and EML4-ALK arrangement accompanied by non-EML4-ALK rearrangement (n = 6) was 12.8, 7.5, and 7.4 months, respectively, with no significant difference between them (p = 0.1554). Similarly, among patients with various EML4-ALK variants (variant 1, variant 3a/b, and other variants), the median PFS values were again comparable. According to baseline NGS data, the median PFS in patients who had ALK rearrangement only, ALK rearrangement and concomitant tumor-suppressor gene mutations, and ALK rearrangement and concomitant oncogene mutations was 14.2, 10.9, and 4.9 months, respectively; (p = 0.0002). A multivariable analysis indicated that concomitant oncogene mutations and tumor-suppressor gene mutations were both negative factors influencing the efficacy of crizotinib in ALK rearrangement NSCLC. Conclusion: Concomitant oncogene mutations and tumor-suppressor gene mutations had negative effects on the efficacy of crizotinib, while various ALK variants had a similar influence.
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Non-small cell lung cancer (NSCLC) is closely associated with inflammation and chronic infection. Antibiotics are frequently prescribed for NSCLC patients in combination with epidermal growth factor receptor (EGFR)-targeted treatment in the presence of infection. The association between antibiotic use and the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has not previously been thoroughly investigated. Therefore, the present study investigated whether antibiotics could affect the efficacy and toxicity of EGFR-TKI treatment, with the aim of restricting the use of antibiotics in combination with targeted therapy in patients with advanced NSCLC in the near future. All patients received treatment with EGFR-TKIs until disease progression, unacceptable toxicity or other factors, including death, pregnancy or unwillingness to further receive targeted therapy, were observed. Patients were retrospectively divided into two groups: Group A, which was treated with EGFR-TKIs and antibiotics; and Group B, which was treated with EGFR-TKIs alone. Patients having used antibiotics 6 months prior to EGFR-TKI therapy were also included in the study. Antibiotic use negatively affected the median progression-free survival (PFS) following EGFR-TKI treatment in NSCLC compared with that in patients not treated with antibiotics; median PFS in Group A was 6.6 months, whereas median PFS in Group B was 10.1 months. Antibiotics also increased the toxicity of targeted therapy for advanced NSCLC. There were significant statistical differences between the two groups in the occurrence of the adverse events of diarrhea and dyspnea. In conclusion, antibiotics decreased the efficacy of first-line targeted therapy in advanced NSCLC and increased incidences of diarrhea and dyspnea. Large randomized studies are needed to identify the impact of antibiotic use on EGFR-TKI treatment for NSCLC.
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OBJECTIVES: Sclerosing pneumocytoma (sclerosing hemangioma, SP) is a rare benign tumor of the lung with a low risk of recurrence. The genomic profile of SP is not well-known. Here we report gene mutation findings in a 17-year-old girl with SP. MATERIALS AND METHODS: Immunohistochemistry (IHC), next-generation sequencing (NGS), and sanger sequencing were performed on the tumor tissue of this patient for pathological diagnosis and gene mutation analysis. RESULTS AND CONCLUSION: Two mutations were identified in the tumor tissue by NGS and sanger sequencing: AKT1 E17K and BRAF (B-Raf proto-oncogene, serine/threonine kinase) V600E. This is the first case report of a BRAF V600E mutation in a patient with SP. This discovery extends our understanding of the pathogenesis of SP, and suggests the need for future testing of BRAF V600E in this rare tumor type.
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Biomarcadores Tumorais/genética , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Hemangioma Esclerosante Pulmonar/genética , Adolescente , Análise Mutacional de DNA , Feminino , Humanos , Neoplasias Pulmonares/patologia , Proto-Oncogene Mas , Hemangioma Esclerosante Pulmonar/patologiaRESUMO
The purpose of this study was to determine whether docetaxel increases the risk of severe infections in patients with non-small cell lung cancer. A thorough literature search of the PubMed, EMBASE and Cochrane Central Register of Controlled Trials databases was performed (up to February 28, 2017) without any language restrictions. In addition, we searched the www.clinicaltrials.gov website and checked each reference listed in the included studies, relevant reviews and guidelines. We also included randomized controlled trials that reported severe infections in patients with non-small cell lung cancer who were administered docetaxel. A meta- analysis was conducted using relative risk and random effects models in Stata 14.0 software. Sensitivity analysis and meta-regression were performed using Stata 14.0 software. We identified 354 records from the initial search, and this systematic review ultimately included 43 trials with 12,447 participants. The results of our meta- analysis showed that docetaxel increased the risk of severe infections [relative risk: 2.10, 95% confidence interval: 1.51-2.93, I2 = 69.6%, P = 0.000]. Meta-regression analysis indicated that the type of intervention was a major source of heterogeneity. Our systematic review and meta-analysis suggest that docetaxel is associated with the risk of severe infections.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , RNA Longo não Codificante , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , RNA Longo não Codificante/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Proteína HMGA1a/genética , MicroRNAs/genética , Fatores de Transcrição/genética , Proliferação de Células , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genéticaRESUMO
OBJECTIVE: We report a rare case of a multiple sarcomatoid carcinoma of the jejunum with postoperative lung and brain metastases. The patient underwent jejunum segmental resection for intussusception and gastrointestinal bleeding. Multiple metastasis ofbrain and lung occurred 4 months after the operation, and the patient died for multiple organ failure 8 months after the surgery. Primary sarcomatoid carcinoma was difficult to diagnose at an early stage, and the diagnosis relies on optical microscopic and immunohistochemical observations. Currently no guidelinesare established for treatment for sarcomatoid carcinoma of the jejunum, and surgical resection remains the optimal therapeutic approach. Previous reports documented a poor prognosis of the patients with a median survival time of 5.5 months (0.36-36months), and the primary causes of death were tumor recurrence and metastasis. Ki-67 as a potential prognostic marker and the value of PD-L1-targeted immunotherapy for the treatment await further investigation.