Volumetric Modulated Arc Therapy After Lung Sparing Surgery for Malignant Pleural Mesothelioma: A Single Institution Experience.
- 作者列表："Franceschini D","De Rose F","Cozzi S","Renna I","Franzese C","Di Brina L","Navarria P","D'Agostino GR","Mancosu P","Tomatis S","Scorsetti M
INTRODUCTION:We investigated the possible role of volumetric modulated arc therapy (VMAT) in the setting of adjuvant treatment of malignant pleural mesothelioma (MPM) after lung-sparing surgery with pleurectomy and decortication. MATERIALS AND METHODS:Patients affected by MPM who had undergone pleurectomy and decortication and adjuvant radiotherapy with VMAT were included. The endpoints of the present analysis were local control, progression-free survival, and overall survival. Assessment of the variables affecting survival was performed using univariate and multivariate Cox proportional hazard models. RESULTS:A total of 49 patients were included in the present study. Of the 49 patients, 96% had been treated with a trimodality approach. Radiotherapy was delivered to a median dose of 44 Gy in 22 fractions (range, 22-59.4 Gy). The treatment was well tolerated, with just 2 grade 3 acute toxicities, 1 grade 5, and 2 grade 4 toxicities recorded during the follow-up period. The median follow-up period was 27.4 months. The local control rate at 12, 24, and 36 months was 75.2%, 67.4%, and 56.5%, respectively. The median progression-free survival was 14.9 months (95% confidence interval [CI], 7.5-25.2). The median overall survival was 21.5 months (95% CI, 15.3-37.1). On multivariate analysis, the administration of carboplatin- instead of cisplatin-based chemotherapy (hazard ratio, 2.97; 95% CI, 1.22-7.26; P = .017) and R2 resection (hazard ratio, 1.95; 95% CI, 1.27-2.99; P = .002) showed a negative correlation with overall survival. On univariate analysis, the percentage of the heart receiving >20 Gy and >30 was associated with the occurrence of late pneumonitis (P = .018 and P = .077). CONCLUSION:VMAT is feasible in the setting of MPM after lung-sparing surgery. The toxicity rates were reduced with this technique compared with historical data of older techniques. Local and distant failure remain a major issue to be addressed in future trials.
简介: 我们研究了容积调制弧形治疗 (VMAT) 在恶性胸膜间皮瘤 (MPM) 保留肺手术后辅助治疗中的可能作用。 材料和方法: 包括接受胸膜切除术和去皮术以及 VMAT 辅助放疗的 MPM 患者。本分析的终点是局部控制、无进展生存期和总生存期。使用单变量和多变量 Cox 比例风险模型对影响生存的变量进行评估。 结果: 本研究共纳入 49 例患者。在 49 例患者中，96% 例采用三联方法治疗。22 个分数 (范围 22-59.4 Gy) 的中位放疗剂量为 44 Gy。治疗耐受性良好，随访期间仅记录到 2 个 3 级急性毒性、 1 个 5 级和 2 个 4 级毒性。中位随访时间为 27.4 个月。12 、 24 和 36 个月时的局部控制率分别为 75.2% 、 67.4% 和 56.5%。中位无进展生存期为 14.9 个月 (95% 可信区间 [CI]，7.5-25.2)。中位总生存期为 21.5 个月 (95% CI，15.3-37.1)。在多变量分析中，以卡铂代替以顺铂为基础的化疗 (风险比，2.97; 95% CI，1.22-7.26; P =。 017) 和 R2 切除 (风险比，1.95; 95% CI，1.27-2.99; P =。 002) 显示与总生存期呈负相关。在单变量分析中，心脏接受> 20 Gy 和> 30 的百分比与晚期肺炎的发生相关 (P =.018 和 P =.077)。 结论: VMAT 在保留肺手术后的 MPM 中是可行的。与旧技术的历史数据相比，该技术的毒性率降低。局部和远处的失败仍然是未来试验中需要解决的主要问题。
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.