恶性胸腔积液的治疗现状

恶性胸液在临床上基本上都出现在肿瘤的中、晚期,治疗的主要目的是解决患者的痛苦、提高病人的生存质量、延长患者的生命,其治疗措施随着科技的进步也在不断地改进完善,远期效果将有待于进一步提高。     

恶性胸腔积液与结核性胸腔积液的诊断进展

胸腔积液分为渗出液和漏出液,而渗出性胸腔积液以结核性胸腔积液和恶性胸腔积液较为常见,这两种积液的治疗和预后差异很大。因此,及时而准确地找到胸腔积液的成因,才能使患者得到早期诊断和治疗,改善患者的预后。但目前,临床工作中两者的鉴别仍较为困难,因此需要从多方面入手。系统的询问病史、体格检查是判断患者是否存在胸腔积液的第一步,然后行X线、B超、CT检查判断积液的位置及积液量,后行胸腔穿刺检查明确积液的性质是渗出液或漏出液,结合肿瘤标志物、细胞因子检查进一步判断积液病因,最后通过胸腔穿刺胸膜活检、胸腔镜检查明确病理诊断而获得确诊,对于疑难性胸腔积液,PET/CT检查也具备较好的优势。本文就近年来恶性胸腔积液与结核性胸腔积液的鉴别诊断技术和方法进展作简要综述。     

恶性胸腔积液综合治疗进展

恶性胸腔积液是恶性肿瘤累及胸膜,或是发生胸膜转移所致。它是癌症晚期常见的并发症,治疗难度大,预后较差。约有一半以上的癌症患者晚期出现胸腔积液。大量胸腔积液可引起胸痛,咳嗽,呼吸困难等,影响病人生存质量,治疗不及时可危及生命。因此我们治疗恶性胸腔积液的主要目的是缓解症状,有效的清除胸腔积液并防止它的再次蓄积,改善患者的生存质量,延长生存时间。目前,恶性胸腔积液治疗的方法较多,但是没有标准的治疗方法,总体疗效有限。由于其预后不佳,临床上多以姑息治疗手段为主。常见的方法有胸腔穿刺术,胸腔置管引流术,化学胸膜固定术,及胸膜剥除术等。生物免疫制剂协同其他方法治疗恶性胸腔积液被广泛应用于临床,疗效满意,毒副反应小。本文综合性的回顾恶性胸腔积液的治疗方法,就恶性胸腔积液的治疗进展进行简要分析。     

Gene Alterations in Paired Supernatants and Precipitates from Malignant Pleural Effusions of Non-Squamous Non-Small Cell Lung Cancer

OBJECTIVE: This study investigated the feasibility of using malignant pleural effusion (MPE) supernatant and paired cell blocks (precipitate) for gene profiling in patients with non-small cell lung cancer (NSCLC) using next-generation sequencing (NGS) technique. METHODS: Stage IV non-squamous NSCLC patients with MPE were eligible in this prospective study and recruited from Zhejiang Cancer Hospital between May 2014 and October 2015. MPE supernatant and paired precipitate sample gene alterations were determined with NGS containing 14 cancer-related genes. Progression free survival (PFS) was evaluated using Kaplan–Meier method and compared using log-rank test. RESULTS: A total of 102 patients were enrolled in the present study. All pleural effusions were confirmed as malignant with cytological smears. A total of 77 paired MPE supernatant and precipitate samples were acquired from the 102 patients. The results revealed that there were no statistically significant differences in the detection rate and maximum allelic fraction between supernatant and precipitate samples (P = 1.0 and P = .6). Collectively, 172 and 158 genomic alterations with 112 shared mutations were identified in supernatant and precipitate samples, respectively. Comparable PFS was found in EGFR mutation patients according to the supernatant and precipitate sample results (14.0 vs.13.9 months, P = .90). CONCLUSIONS: These results demonstrated that MPE supernatants were comparable to precipitate samples for detection of genetic alterations. However, gene mutation heterogeneity was found between these two media types.     

结核分枝杆菌抗原特异反应性白细胞介素-22对结核性和恶性胸腔积液的鉴别诊断价值

目的:研究结核性胸膜炎与恶性胸水患者胸腔积液单个核细胞经结核分枝杆菌特异性抗原肽刺激后IL-22的表达特点,探索IL-22对结核性胸膜炎和恶性胸水的鉴别诊断价值。方法:采用eBioscience IL-22和IFN-γ试剂盒,利用流式细胞术微球阵列法检测52例结核性胸膜炎和35例恶性胸水患者胸水上清、PFMCs经结核分枝杆菌特异性抗原肽刺激培养后上清中IL-22和IFN-γ的浓度,并作统计学分析。结果:结核性胸膜炎组IL-22在刺激后上清中表达水平显著升高,且显著高于恶性胸水组(P0.05)。结核性胸膜炎组IL-22与IFN-γ在刺激后上清中表达水平显著相关(r=0.3485,P=0.0320)。结论:结核分枝杆菌抗原特异反应性IL-22可作为鉴别诊断胸腔积液病因的新指标。     

信息管理系统下胸腔镜胸膜固定术治疗恶性胸腔积液

目的:分析基于信息管理系统的胸腔镜滑石粉胸膜固定术控制恶性胸腔积液患者术后的并发症,死亡率及生存时间。方法:2011年9月至2014年10月,一共400个患者完成了胸腔镜辅下滑石粉胸膜固定术。对手术前后的患者的并发症,死亡率,成功率和中位生存时间进行评价。结果:中位随访时间为40个月(范围4-61月)。所有患者的呼吸困难症状都得到明显缓解。围手术期死亡率为0。患者对这一手术的耐受性良好,没有观察到明显的副作用。院内死亡率为2%,胸膜固定的成功率为85%。较差的KS评分及胸腔积液诊断到完成胸膜固定术之间的时间延误与院内死亡的发生明显相关。乳腺癌的生存情况最好,其次为卵巢癌,淋巴瘤和胸膜间皮瘤。结论:胸腔镜滑石粉胸膜固定术是一项安全有效的操作,胸膜固定的成功率较高,呼吸困难会能够得到长期有效的控制。     

Microfluidic Purification and Concentration of Malignant Pleural Effusions for Improved Molecular and Cytomorphological Diagnostics

Evaluation of pleural fluids for metastatic cells is a key component of diagnostic cytopathology. However, a large background of smaller leukocytes and/or erythrocytes can make accurate diagnosis difficult and reduce specificity in identification of mutations of interest for targeted anti-cancer therapies. Here, we describe an automated microfluidic system (Centrifuge Chip) which employs microscale vortices for the size-based isolation and concentration of cancer cells and mesothelial cells from a background of blood cells. We are able to process non-diluted pleural fluids at 6 mL/min and enrich target cells significantly over the background; we achieved improved purity in all patient samples analyzed. The resulting isolated and viable cells are readily available for immunostaining, cytological analysis, and detection of gene mutations. To demonstrate the utility towards aiding companion diagnostics, we also show improved detection accuracy of KRAS gene mutations in lung cancer cells processed using the Centrifuge Chip, leading to an increase in the area under the curve (AUC) of the receiver operating characteristic from 0.90 to 0.99. The Centrifuge Chip allows for rapid concentration and processing of large volumes of bodily fluid samples for improved cytological diagnosis and purification of cells of interest for genetic testing, which will be helpful for enhancing diagnostic accuracy.     

Lumican Is Overexpressed in Lung Adenocarcinoma Pleural Effusions

Adenocarcinoma (AdC) is the most common lung cancer subtype and is often associated with pleural effusion (PE). Its poor prognosis is attributable to diagnostic delay and lack of effective treatments and there is a pressing need in discovering new biomarkers for early diagnosis or targeted therapies. To date, little is known about lung AdC proteome. We investigated protein expression of lung AdC in PE using the isobaric Tags for Relative and Absolute Quantification (iTRAQ) approach to identify possible novel diagnostic/prognostic biomarkers. This provided the identification of 109 of lung AdC-related proteins. We further analyzed lumican, one of the overexpressed proteins, in 88 resected lung AdCs and in 23 malignant PE cell-blocks (13 lung AdCs and 10 non-lung cancers) using immunohistochemistry. In AdC surgical samples, lumican expression was low in cancer cells, whereas it was strong and diffuse in the stroma surrounding the tumor. However, lumican expression was not associated with tumor grade, stage, and vascular/pleural invasion. None of the lung cancer cell-blocks showed lumican immunoreaction, whereas those of all the other tumors were strongly positive. Finally, immunoblotting analysis showed lumican expression in both cell lysate and conditioned medium of a fibroblast culture but not in those of A549 lung cancer cell line. PE is a valid source of information for proteomic analysis without many of the restrictions of plasma. The high lumican levels characterizing AdC PEs are probably due to its release by the fibroblasts surrounding the tumor. Despite the role of lumican in lung AdC is still elusive, it could be of diagnostic value.     

Defining the Minimal Important Difference for the Visual Analogue Scale Assessing Dyspnea in Patients with Malignant Pleural Effusions

Background

The minimal important difference (MID) is essential for interpreting the results of randomised controlled trials (RCTs). Despite a number of RCTs in patients with malignant pleural effusions (MPEs) which use the visual analogue scale for dyspnea (VASD) as an outcome measure, the MID has not been established.

Methods

Patients with suspected MPE undergoing a pleural procedure recorded their baseline VASD and their post-procedure VASD (24 hours after the pleural drainage), and in parallel assessed their breathlessness on a 7 point Likert scale.

Findings

The mean decrease in VASD in patients with a MPE reporting a ‘small but just worthwhile decrease’ in their dyspnea (i.e. equivalent to the MID) was 19mm (95% CI 14-24mm). The mean drainage volume required to produce a change in VASD of 19mm was 760ml.

Interpretation

The mean MID for the VASD in patients with a MPE undergoing a pleural procedure is 19mm (95% CI 14-24mm). Thus choosing an improvement of 19mm in the VASD would be justifiable in the design and analysis of future MPE studies.     

Diagnostic and Prognostic Value of SHOX2 and SEPT9 DNA Methylation and Cytology in Benign,Paramalignant and Malignant Pleural Effusions

Pleural effusions (PE) are a common clinical problem. The discrimination between benign (BPE), malignant (MPE) and paramalignant (PPE) pleural effusions is highly important to ensure appropriate patient treatment. Today, cytology is the gold standard for diagnosing malignant pleural effusions. However, its sensitivity is limited due to the sometimes low abundance of tumor cells and the challenging assessment of cell morphology in cytological samples. This study aimed to develop and validate a diagnostic test, which allows for the highly specific detection of malignant cells in pleural effusions based on the DNA methylation biomarkers SHOX2 and SEPT9. A quantitative real-time PCR assay was developed which enabled the accurate and sensitive detection of SHOX2 and SEPT9 in PEs. Cytological and DNA methylation analyses were conducted in a case control study comprised of PEs from 114 patients (58 cases, 56 controls). Cytological analysis as well as SHOX2 and SEPT9 methylation resulted in 100% specificity. 21% of the cases were cytologically positive and 26% were SHOX2 or SEPT9 methylation positive. The combined analysis of cytology and DNA methylation resulted in an increase of 71% positively classified PEs from cancer patients as compared to cytological analysis alone. The absolute sensitivity of cytology and DNA methylation was not determinable due to the lack of an appropriate gold standard diagnostic for distinguishing between MPEs and PPEs. Therefore, it was unclear which PEs from cancer patients were malignant (containing tumor cells) and which PEs were paramalignant and resulted from benign conditions in cancer patients, respectively. Furthermore, DNA methylation analysis in PEs allowed the prognosis of the overall survival in cancer patients (Kaplan-Meier analysis, log rank test, p = 0.02 (SHOX2), p = 0.02 (SEPT9)). The developed test may be used as a diagnostic and prognostic adjunct to existing clinical and cytopathological investigations in patients with PEs of unclear etiology.