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Efficacy and safety of apatinib alone or apatinib plus paclitaxel/docetaxel versus paclitaxel/docetaxel in the treatment of advanced non-small cell lung cancer: A meta-analysis.
Li, Z, Liu, Z, Wu, Y, Li, H, Sun, Z, Han, C, Zhang, X, Zhang, J
Thoracic cancer. 2021;(21):2838-2848
Abstract
BACKGROUND To investigate the efficacy and safety of apatinib alone or apatinib plus paclitaxel/docetaxel versus paclitaxel/docetaxel in the treatment of advanced non-small cell lung cancer (NSCLC) through pooling of open published data. METHODS The electronic databases of Medline (1960-2021.5), Cochrane central register of controlled trials (CENTRAL), EMBASE(1980-2021.5) and Wan fang (1986-2021.5) were systematically searched by two reviewers to identify the relevant clinical trials related to the above subject. The objective response rate (ORR), disease control rate (DCR) and drug relevant adverse reactions were pooled and demonstrated by risk ratio (RR) and 95% confidence interval (95% CI). The statistical heterogeneity across studies was assessed by I-square test. The publication bias was evaluated by Egger's line regression test and demonstrated by Begg's funnel plot. RESULTS Eleven prospective studies were included in the meta-analysis. The pooled results indicated that the ORR (RR = 1.62, 95% CI: 1.32-2.00, p < 0.05) and DCR (RR = 1.29, 95% CI: 1.18-1.41, p < 0.05) of apatinib alone or apatinib plus paclitaxel/docetaxel was significantly higher than that of the paclitaxel/docetaxel group for advanced NSCLC, respectively. The drug-related adverse reaction was not statistically different between apatinib alone or apatinib plus paclitaxel/docetaxel with regard to the hand-foot syndrome, gastrointestinal reaction, thrombocytopenia, anemia and leukocytopenia (pall > 0.05) except for hypertension (RR = 3.60, 95% CI: 1.26-10.31, p < 0.05). Subgroup analysis also indicated that the hypertension and hand-foot syndrome in apatinib + paclitaxel/docetaxel were higher than that of the paclitaxel/docetaxel group with a statistical difference (p < 0.05). CONCLUSIONS Apatinib alone or apatinib plus paclitaxel/docetaxel was superior to paclitaxel/docetaxel for ORR and DCR. However, combined treatment with apatinib appears to increase the risk of a patient developing an adverse reaction, especially hypertension and hand-foot syndrome.
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Risk factors for brain metastases from non-small-cell lung cancer: A protocol for observational study.
He, J, Wang, X, Xiao, R, Zuo, W, Zhang, W, Yao, H
Medicine. 2021;(9):e24724
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Brain metastasis is a common site of distant metastasis of non-small-cell lung cancer (NSCLC) that greatly reduces the prognosis of patients. In this study, we explored the correlation between different clinical factors and secondary brain metastases in NSCLC in an attempt to identify NSCLC patient populations at high risk of metastasis to the central nervous system.We collected data for 350 NSCLC patients from the medical record system of the First Affiliated Hospital of Nanchang University from June 2015 to June 2019, and these patients had pathologically verified diagnoses. The correlations between age at the time of diagnosis, sex, histological type, calcium concentration, hemoglobin (HB), fibrinogen (Fbg), activated partial thromboplastin time (APTT), alkaline phosphatase (ALP), carcinoembryonic antigen (CEA), CA125, and CA199 levels and brain metastasis were analyzed. Multivariate logistic regression analysis was used to identify risk factors for NSCLC brain metastasis. A receiver operating characteristic (ROC) curve was used to calculate the cutoff, sensitivity, and specificity of the independent related factors.Of the 350 patients, 57 were diagnosed with brain metastases. Univariate and multivariate logistic regression analysis indicated that lesion diameter, calcium concentration, and CEA level were independent risk factors correlated with brain metastasis (P < .05). There were no significant differences in age, sex, type of histopathology, presence or absence of mediastinal lymph node metastasis, HB, Fbg, APTT, ALP, cancer antigen 125 (CA-125), or cancer antigen 199 (CA-199) levels between patients with brain metastases and patients without brain metastases (P > .05, respectively). ROC curves demonstrated that these factors had comparable accuracy in predicting brain metastasis (area under the curve [AUCs] were 0.620, 0.661, and 0.729, respectively). The cutoff values for lesion diameter, calcium, and CEA were 5.050 cm, 2.295 mmol/L, and 11.160 ng/mL, respectively. The sensitivities for prediction brain metastasis were 59.6%, 64.9%, and 73.3%, with specificities of 63.1%, 59.2%, and 70.3%, respectively.According to our study, lesion diameter, calcium concentration, and CEA level are independent risk factors for brain metastases in NSCLC patients. Thus, we can strengthen the regular follow-up of NSCLC patients with tumor diameter > 5.050 cm, calcium > 2.295 mmol/L, CEA > 11.160 ng/mL, and use these factors as a reference for preventive treatments.
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Sorafenib and everolimus in patients with advanced solid tumors and KRAS-mutated NSCLC: A phase I trial with early pharmacodynamic FDG-PET assessment.
Nogova, L, Mattonet, C, Scheffler, M, Taubert, M, Gardizi, M, Sos, ML, Michels, S, Fischer, RN, Limburg, M, Abdulla, DSY, et al
Cancer medicine. 2020;(14):4991-5007
Abstract
BACKGROUND Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR. METHODS Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5-10.0 mg/d in a 14-day run-in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS-mutated non-small-cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG-PET. Efficacy was assessed by CT scans every 6 weeks of combination. RESULTS Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose-limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG-PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively. CONCLUSIONS Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG-PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS-mutant solid tumors.
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Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents.
Minnelli, C, Laudadio, E, Mobbili, G, Galeazzi, R
International journal of molecular sciences. 2020;(5)
Abstract
Non-small cell lung cancer (NSCLC) represents a difficult condition to treat, due to epidermal growth factor receptor (EGFR) kinase domain mutations, which lead to ligand-independent phosphorylation. Deletion of five amino acids (ELREA) in exon 19 and mutational change from leucine to arginine at position 858 (L858R) are responsible for tyrosine kinase domain aberrant activation. These two common types of EGFR-mutated forms are clinically associated with high response with Tyrosine Kinase Inhibitors (TKI); however, the secondary T790M mutation within the Tyrosine Kinase Domain (TKD) determines a resistance to these EGFR-TKIs. Using molecular dynamic simulation (MD), the present study investigated the architectural changes of wild-type and mutants EGFR's kinase domains in order to detect any conformational differences that could be associated with a constitutively activated state and thus to evaluate the differences between the wild-type and its mutated forms. In addition, in order to evaluate to which extent the EGFR mutations affect its inhibition, Epigallocatechin 3-Gallate (EGCG) and Erlotinib (Erl), known EGFR-TKI, were included in our study. Their binding modes with the EGFR-TK domain were elucidated and the binding differences between EGFR wild-type and the mutated forms were evidenced. The aminoacids mutations directly influence the binding affinity of these two inhibitors, resulting in a different efficacy of Erl and EGCG inhibition. In particular, for the T790M/L858R EGFR, the binding modes of studied inhibitors were compromised by aminoacidic substitution confirming the experimental findings. These results may be useful for novel drug design strategies targeting the dimerization domain of the EGFR mutated forms, thus preventing receptor activation.
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NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype.
Bocci, F, Tripathi, SC, Vilchez Mercedes, SA, George, JT, Casabar, JP, Wong, PK, Hanash, SM, Levine, H, Onuchic, JN, Jolly, MK
Integrative biology : quantitative biosciences from nano to macro. 2019;(6):251-263
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The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype - a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) - the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the 'metastatic sweet spot'.
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Chinese Herbal Medicine (Xiaoaiping) Injections for Chemotherapy-Induced Thrombocytopenia: A Randomized, Controlled, Multicenter Clinical Trial.
Qi, S, Li, X, Dong, Q, Lai, H, Porter, D, Tian, S, Hou, L, Chen, X, Li, X, Wang, K
Journal of alternative and complementary medicine (New York, N.Y.). 2019;(6):648-655
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Objectives: The study aims to evaluate the therapeutic efficacy and safety of Chinese herbal medicine (Xiaoaiping) injections for chemotherapy-induced thrombocytopenia (CIT) in nonsmall cell lung cancer (NSCLC) and gastric cancer. Design: A randomized, controlled, multicenter study from December 2013 to August 2015. Settings/Location: All patients are from China. Subjects: One hundred forty patients with either NSCLC or gastric cancer were enrolled in this trial. Interventions: The intervention group (n = 70) was given Xiaoaiping injections (1 dose/day for 10 days) with chemotherapy, whereas the control group (n = 70) was given chemotherapy only. The follow up period was 11 days after the final injection. Outcome measures: Platelet (PLT) count was tested at day 0, 7, 14, and 21 as the primary outcome for evaluation. Safety measurements, including red blood cells (RBC), hemoglobin (HBG), white blood cells (WBC), neutrophil (NE)#, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine (Cr), and blood urea nitrogen (BUN) were tested at day 0 and 21 as the secondary outcomes. Results: (1) Two patients in the intervention group and four patients in the control group were lost upon follow-up. (2) PLT count: there was no significant difference in PLT count between the two groups from baseline (day 0), day 7, and day 14. At day 21, the intervention group indicated an upward trend of PLT count with a statistically significant difference than that of the control group (p < 0.05). (3) NSCLC there was significant difference in PLT count between the two groups on day 21 (p < 0.01). (4) Gastric cancer: there was no significant difference in PLT count between the two groups during this trial (p > 0.05). (5) There was no statistically significant difference between the intervention group and the control group with the safety figures (secondary outcomes) RBC, HGB, WBC, NE#, AST, ALT, LDH, CK, Cr, and BUN measured (p > 0.05). (6) Adverse events: one gastric cancer patient in the control group was diagnosed with gastrointestinal bleeding on day 3. Conclusions: In conclusion, Xiaoaiping injections may provide a safe and effective option for CIT in patients with NSCLC.
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Acquired haemophilia A in a patient with breast cancer and lung carcinoma: a case report and literature review.
Biesheuvel, V, Hiddema, SM, Levenga, H, Eikenboom, J, van der Deure, WM
The Netherlands journal of medicine. 2019;(4):153-155
Abstract
Acquired haemophilia A is a rare disorder caused by spontaneous formation of auto-antibodies (inhibitors) against coagulation factor VIII. This can lead tolife-threatening haemorrhages. Six to twenty-two percent of patients with acquired haemophilia have an underlying malignancy. We describe a 69-year-old woman with metastatic breast cancer and non-small cell lung carcinoma who presented at the emergency room with spontaneous bruising, and who was using a vitamin K antagonist. She had a prolonged activated partial thromboplastin time (aPTT) due to a coagulation factor VIII deficiency caused by factor VIII antibodies. She was treated with prednisone and cyclophosphamide.
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CRISP-R/Cas9 Mediated Deletion of Copper Transport Genes CTR1 and DMT1 in NSCLC Cell Line H1299. Biological and Pharmacological Consequences.
Ilyechova, EY, Bonaldi, E, Orlov, IA, Skomorokhova, EA, Puchkova, LV, Broggini, M
Cells. 2019;(4)
Abstract
Copper, the highly toxic micronutrient, plays two essential roles: it is a catalytic and structural cofactor for Cu-dependent enzymes, and it acts as a secondary messenger. In the cells, copper is imported by CTR1 (high-affinity copper transporter 1), a transmembrane high-affinity copper importer, and DMT1 (divalent metal transporter). In cytosol, enzyme-specific chaperones receive copper from CTR1 C-terminus and deliver it to their apoenzymes. DMT1 cannot be a donor of catalytic copper because it does not have a cytosol domain which is required for copper transfer to the Cu-chaperons that assist the formation of cuproenzymes. Here, we assume that DMT1 can mediate copper way required for a regulatory copper pool. To verify this hypothesis, we used CRISPR/Cas9 to generate H1299 cell line with CTR1 or DMT1 single knockout (KO) and CTR1/DMT1 double knockout (DKO). To confirm KOs of the genes qRT-PCR were used. Two independent clones for each gene were selected for further studies. In CTR1 KO cells, expression of the DMT1 gene was significantly increased and vice versa. In subcellular compartments of the derived cells, copper concentration dropped, however, in nuclei basal level of copper did not change dramatically. CTR1 KO cells, but not DMT1 KO, demonstrated reduced sensitivity to cisplatin and silver ions, the agents that enter the cell through CTR1. Using single CTR1 and DMT1 KO, we were able to show that both, CTR1 and DMT1, provided the formation of vital intracellular cuproenzymes (SOD1, COX), but not secretory ceruloplasmin. The loss of CTR1 resulted in a decrease in the level of COMMD1, XIAP, and NF-κB. Differently, the DMT1 deficiency induced increase of the COMMD1, HIF1α, and XIAP levels. The possibility of using CTR1 KO and DMT1 KO cells to study homeodynamics of catalytic and signaling copper selectively is discussed.
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Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies.
Ahn, MJ, Tsai, CM, Shepherd, FA, Bazhenova, L, Sequist, LV, Hida, T, Yang, JCH, Ramalingam, SS, Mitsudomi, T, Jänne, PA, et al
Cancer. 2019;(6):892-901
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BACKGROUND Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is selective for both EGFR-TKI-sensitizing and T790M (threonine-to-methionine substitution at codon 790)-resistance mutations. The authors present long-term follow-up data from a preplanned, pooled analysis of phase 2 studies, the AZD9291 First Time in Patients Ascending Dose Study (AURA) extension trial (clincialtrials.gov identifier NCT01802632) and the AURA2 trial (NCT02094261). METHODS Patients with centrally confirmed, T790M mutation-positive, advanced non-small cell lung cancer received osimertinib 80 mg once daily until disease progression or study discontinuation. Response was assessed by a blinded, independent, central review using Response Evaluation Criteria in Solid Tumors, version 1.1. The primary endpoint was the objective response rate. RESULTS In total, 411 patients received osimertinib (second line, 129 patients; third line or later, 282 patients). At the data cutoff date of November 1, 2016, the median treatment exposure was 16.4 months (range, 0-29.7 months), the objective response rate was 66% (95% confidence interval [CI], 61%-70%), the median response duration was 12.3 months (95% CI, 11.1-13.8 months), and the median progression-free survival was 9.9 months (95% CI, 9.5-12.3 months). At the data cutoff date of May 1, 2018, 271 patients (66%) had died, and 140 patients (34%) had discontinued before death. The median overall survival was 26.8 months (95% CI, 24.0-29.1 months); and the 12-month, 24-month, and 36-month survival rates were 80%, 55%, and 37%, respectively. Grade ≥3 possibly causally related (investigator assessed) adverse events were reported in 65 patients (16%), and the most common were rash (grouped terms; 42%; grade ≥3, 1%) and diarrhea (39%; <1%). CONCLUSIONS This pooled analysis represents the most mature clinical trial data for osimertinib in patients with pretreated, T790M-positive, advanced non-small cell lung cancer, further establishing osimertinib as a standard of care for this patient population.
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Evidence of Astragalus injection combined platinum-based chemotherapy in advanced nonsmall cell lung cancer patients: A systematic review and meta-analysis.
Cao, A, He, H, Wang, Q, Li, L, An, Y, Zhou, X
Medicine. 2019;(11):e14798
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BACKGROUND Platinum-based chemotherapy is one of the standard treatments for advanced nonsmall cell lung cancer (NSCLC). Despite on an effective treatment for advanced NSCLC patients, its high toxicity and limited clinical effects have raised big concerns. Astragalus injection (AGI) has been commonly employed as an adjutant chemotherapy drug for NSCLC in China. This review was conducted to evaluate the beneficial of AGI in combination with platinum-based chemotherapy in advanced NSCLC. METHODS We collected all studies about AGI plus platinum-based chemotherapy for advanced NSCLC in the PubMed, EMBASE, China National Knowledge Infrastructure Database, the Cochrane Library, Wanfang Database, China Biological Medicine Database, and Chinese Scientific Journal Database established on July 2018 without language restriction. Cochrane handbook was applied to assess the quality of included trials. Stata (version 12.0) and RevMan (version 5.3) were employed for data analysis. The quality of the evidence was assessed with the GRADE approach. RESULTS Nineteen randomized controlled trials (RCTs) including 1635 patients were included to determine the effectiveness and safety of AGI combined with platinum-based chemotherapy in the treatment of NSCLC. The result of meta-analysis indicated that comparing with chemotherapy alone, AGI combined chemotherapy could significantly improve the objective response rate (relative risk [RR] = 1.19, 95% confidence interval [CI] [1.06, 1.33], P = .002), the Karnofsky performance status (RR = 2.28, 95% CI [1.63, 3.18], P < .00001), and 1-year survival rate (RR = 1.40, 95% CI [1.16, 1.70], P = .0005), meanwhile increase the percentages of CD3 (weighted mean differences [WMD] = 11.98, 95% CI [8.0, 15.96], P < .00001), CD4 (WMD = 2.98, 95% CI [0.45, 5.52], P = .02), CD4/CD8 (WMD = 0.33, 95% CI [0.20, 0.46], P < .00001), and NK cells (WMD = 9.5, 95% CI [7.25, 11.76], P < .00001), decrease the incidence of leukopenia (RR = 0.52, 95% CI [0.44, 0.61], P < .00001), platelet toxicity (RR = 0.62, 95% CI [0.50, 0.76], P < .00001), and vomiting (RR = 0.72, 95% CI [0.60, 0.87], P = .0006). Based on the system evaluation results, the GRADE system recommendation grading method was adopted to evaluate the evidence quality. The results showed that the level of evidence was low. CONCLUSIONS The AGI apparently has attenuation and synergistic efficacy to platinum-based chemotherapy patients. However, considering the limits of articles included in the present researches, the recommendation is likely to be weak. High-quality RCTs are urgently used to generate conclusive results.