A randomized clinical study to compare intrapleural infusion with intravenous infusion of bevacizumab in the management of malignant pleural effusion in patients with non-small-cell lung cancer.
- 作者列表："Nie K","Zhang Z","You Y","Zhuang X","Zhang C","Ji Y
BACKGROUND:To compare the efficiency and toxicity of bevacizumab by intrapleural or intravenous infusion in the management of malignant pleural effusion in patients with non-small-cell lung cancer (NSCLC). METHODS:Sensitizing mutation negative NSCLC patients with malignant pleural effusion were randomized into two groups in 1:1 ratio. The pleural effusion was completely drained in 24 hours; one group received intrapleural infusion and the second group received intravenous infusion of bevacizumab at a dose of 7.5 mg per kg bodyweight. The serum vascular endothelial growth factor (VEGF) was tested before and 72 hours after injection of bevacizumab. Computerized tomography (CT) scan to evaluate pleural effusions was carried out at four weeks for each patient and their survival followed-up. RESULTS:A total of 67 patients were screened and 43 enrolled into the study. The response rate was 80% (16 of 20) in the intrapleural group and 66.7% (14 of 21) in the intravenous group. The median duration of response (DoR) of pleural effusion was 4.50 months and 3.70 months, respectively. The median serum VEGF level at 72 hours decreased 67.25% in the intrapleural group and 57.19% in the intravenous group compared to baseline level (P = 0.276). The median serum VEGF level at 72 hours decreased 52.02% compared to baseline level in patients' DoR less than three months and 68.33% in patients' DoR longer than three months, respectively (P = 0.014). The main side effects noted were mild to moderate hypertension, proteinuria and epistaxis. CONCLUSIONS:Bevacizumab intrapleural infusion had higher efficiency and higher safety than intravenous infusion in the management of malignant pleural effusion caused by NSCLC. The decreased level of serum VEGF at 72 hours after bevacizumab treatment was closely related to the response rate and duration of the response of pleural effusion.
背景: 比较贝伐单抗胸腔内或静脉输注治疗非小细胞肺癌 (NSCLC) 患者恶性胸腔积液的疗效和毒性。 方法: 选择敏感突变阴性的 NSCLC 恶性胸腔积液患者，按 1:1 比例随机分为两组。胸腔积液在 24 小时内完全引流; 一组接受胸腔内输注，第二组接受贝伐单抗静脉输注，剂量为 7.5 mg/kg 体重。在注射贝伐单抗前及注射后 72 小时检测血清血管内皮生长因子 (VEGF)。每例患者在 4 周时进行计算机断层扫描 (CT) 评估胸腔积液，并随访其生存情况。 结果: 共筛选出 67 例患者，43 例入组研究。胸腔内组有效率为 80% (16/20)，静脉组有效率为 66.7% (14/21)。胸腔积液的中位缓解时间 (DoR) 分别为 4.50 个月和 3.70 个月。与基线水平相比，胸腔内组 72 小时的中位血清 VEGF 水平降低了 67.25%，静脉组降低了 57.19% (P = 0.276)。72 小时的中位血清 VEGF 水平较基线水平分别下降 52.02% (患者 DoR 小于 3 个月) 和 68.33% (患者 DoR 大于 3 个月) (P = 0.014)。主要不良反应为轻中度高血压、蛋白尿和鼻出血。 结论: Bevacizumab 胸腔内灌注治疗非小细胞肺癌所致的恶性胸腔积液比静脉内灌注具有更高的疗效和安全性。Bevacizumab 治疗后 72h 血清 VEGF 水平下降与胸腔积液的缓解率和缓解时间密切相关。
METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.
METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.
METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.