Involvement of interleukin-6 in the elevation of plasma fibrinogen levels in lung cancer patients

BACKGROUND: Involvements of interleukin-6 (IL-6) and fibrinogen in cancer development have been independently studied. However, the association of these molecules in cancer patients remains uncertain. This study was conducted to clarify the association according to the clinicopathological characteristics of lung cancer patients. METHODS: Serum IL-6 levels assayed in 339 patients without pleural effusion were assessed according to clinical stage, histological type of the cancer and levels of fibrin (ogen) degradation products (FDP), and C-reactive protein (CRP). RESULTS: Elevations of serum IL-6 levels more than 4 pg/ml were found in 37.8% of all patients. According to the clinical stage and histological type, the elevations were significantly more frequent in the advanced stage (44.7%), in squamous cell (49.1%) and large cell carcinomas (63.6%). Similarly, the frequency of the elevated cases (> 400 mg/dl) and the mean value of the fibrinogen level were also higher in the advanced stage (54.2%, 455.0 mg/dl) and large cell carcinoma (54.6%, 459.3 mg/dl), respectively. The elevations of fibrinogen, FDP and CRP levels were found to be related to those of the IL-6 level. CONCLUSION: In lung cancer, serum IL-6 elevations are particularly frequent in the advanced stages of patients with squamous cell and large cell carcinoma, which are associated with the elevated levels of fibrinogen, suggesting a possibility that IL-6 was involved not only directly, but also indirectly, through regulating plasma fibrinogen with promotion of cancer development in vivo.      

Tumor markers in pleural effusion diagnosis

In order to discriminate between malignant and benign effusions, the values of carcinoembryonic antigen (CEA), ferritin, beta2-microglobulin (BMG), acid-soluble glycoprotein (ASP), tissue polypeptide antigen (TPA), adenosine deaminase (ADA), and immunosuppressive acidic protein (IAP) were measured in the pleural fluid of 54 patients with lung cancer, 20 with malignancies other than lung cancer, 18 with tuberculous pleurisy, and 22 with benign diseases other than tuberculosis. CEA levels in malignant effusions were significantly higher than those in benign effusions. At a cutoff level of 5 ng/ml, 68% of the patients with lung cancer and 44% of the patients with other malignancies showed elevated pleural fluid CEA levels. In 13 lung cancer cases with negative pleural fluid cytology, nine cases had elevated pleural fluid CEA levels. The mean pleural fluid BMG level of patients with benign diseases was significantly higher than that of patients with malignant diseases, but there was a marked overlap between those with malignant and benign diseases. No significant differences were found in the pleural fluid ferritin, ASP, TPA, and IAP levels between malignant and benign conditions. ASP and IAP pleural fluid levels showed significant correlations with the pleural fluid C-reactive protein (CRP) concentrations suggesting that they also reflect inflammatory activity. The mean ADA activity in tuberculous effusion was significantly higher than that resulting from other causes of pleural effusion.     

An analysis of cytokine status in the serum and effusions of patients with tuberculous and lung cancer

The present study was designed to ascertain whether or not the pleural effusion and serum cytokine levels (granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-10 [IL-10], and interferon-gamma [IFN gamma]) in lung cancer patients differ from tuberculous (TB) pleural effusion, in which a strong cellular immune reaction is found; and, whether cytokine levels are a prognostic factor in lung cancer patients with malignant effusion. A total of 202 lung cancer patients with malignant pleural effusion and 26 patients with TB pleural effusion were studied consecutively between 1995 and 1998. Serum and effusion cytokine levels were analyzed with ELISA assays. The results showed that pleural effusion GM-CSF and IL-10 levels were significantly higher than serum levels in both cancer and TB patients. Pleural effusion IFN gamma levels were significantly higher than serum levels in TB patients. IFN gamma levels in both pleural effusion and serum were significantly higher in TB patients than in those with cancer. No significant difference was found, between TB and cancer patients, in the serum or pleural effusion levels of either IL-10 or GM-CSF. The ratio of pleural effusion IFN gamma to serum IFN gamma, effusion IFN gamma to effusion IL-10, and effusion IL-10 to serum IL-10, were all significantly higher in TB than in cancer patients, suggesting a higher cellular activity and T-helper 1 (Th1) reaction in TB pleural effusion than in malignant effusions, which were predominantly Th2 type. Survival analysis showed no significant difference in lung cancer patients with different levels of these cytokines. It was concluded that lung cancer patients with malignant pleural effusion had poorer immune profiles than those with TB pleurisy, both locally and systemically; and the cytokine profiles were not prognostic factors for lung cancer patients with malignant pleural effusion.     

Induction of lymphokine-activated killer cells by intrapleural instillations of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer

Intrapleural instillations of recombinant interleukin 2 (RIL-2) were performed in 11 patients with malignant pleurisy due to lung cancer. Kinetic studies on RIL-2 concentration in the pleural effusion and serum revealed relatively long-term maintenance of detectable levels of RIL-2 (over 24 h in the pleural effusion and over 8 h in the serum). Clinically, pleural effusions and cancer cells in the effusions disappeared in 9 of the 11 patients 4 to 10 days after the start of the treatment. Lymphokine-activated killer cells were induced in the effusions of responders who exhibited the disappearance of pleural effusion and cancer cells from the effusion, but not in those of the nonresponders. This induction of lymphokine-activated killer cells may result in the disappearance of cancer cells and pleural effusions. Cytological examination of pleural effusions revealed increases of lymphoblasts, immunoblastic large lymphocytes, and eosinophiles in number and proportion in the responder, although such a phenomenon could not be observed in the nonresponders. Main and frequent side effects of intrapleural instillations of RIL-2 were fever up to 39 degrees C, transient increase of pleural effusion, and eosinophilia. No serious side effect was encountered in our experience.     

NSCLC 恶性胸腔积液患者存活率的影响因素分析

目的：探讨非小细胞肺癌恶性胸腔积液患者存活率的影响因素。方法回顾性分析199例非小细胞肺癌恶性胸腔积液患者的临床资料,将患者年龄、性别、吸烟史、转移位点、病理形态、乳酸脱氢酶、血小板、血清C反应蛋白、顺铂胸腔内灌注这9个因素作为研究对象,采用COX多因素回归分析NSCLC恶性胸腔积液存活率的独立影响因子。结果单因素分析显示病理形态、乳酸脱氢酶、血清C反应蛋白、顺铂胸腔内灌注是患者预后影响因素,COX多因素回归分析显示血清C反应蛋白和顺铂胸腔内灌注为预后独立的影响因子。结论血清反应蛋白和顺铂胸腔内灌注为预后独立的影响因子。     

Interleukin 6 and its relationship to clinical parameters in patients with malignant pleural mesothelioma.

The relationship between interleukin 6 (IL-6) levels and clinical parameters was studied in 25 patients with malignant pleural mesothelioma. The serum levels of IL-6, C-reactive protein, alpha1-acid glycoprotein and fibrinogen were significantly higher in mesothelioma than in lung adenocarcinoma with cytology-positive pleural effusion. Serum IL-6 levels correlated with the levels of the acute-phase proteins. We demonstrated a high incidence of thrombocytosis (48%) and a significant correlation between platelet count and the serum IL-6 level. The level of IL-6 in the pleural fluid of patients with mesothelioma was significantly higher than in the pleural fluid of patients with adenocarcinoma, and was about 60-1400 times higher than in the serum. However, even higher levels of IL-6 in the pleural fluid and of thrombocytosis were found in patients with tuberculous pleurisy. These results indicate that large amounts of IL-6 from the pleural fluid of patients with mesothelioma leak into the systemic circulation and induce clinical inflammatory reactions. These profiles are not specific to mesothelioma as similar profiles are found in patients with tuberculous pleurisy. However, the detection of a markedly increased level of IL-6 in pleural fluid argues against a diagnosis of adenocarcinoma.     

Presence and potent immunosuppressive role of interleukin-10 in malignant pleural effusion due to lung cancer

The presence and possible role of interleukin (IL)-10 were examined in malignant pleural effusion due to lung cancer. In 37 out of 55 cases examined, IL-10 was detectable in pleural effusion and the mean level with standard error was 62.1+/-12.1 pg/ ml. Spontaneous and lipopolysaccharide-induced production of anti-tumor cytokines such as IL-1beta and tumor necrosis factor (TNF)-alpha, by pleural macrophages, obtained from five patients with malignant pleurisy, were suppressed by IL-10. These findings suggest that IL-10 is present in the tumor-growing site and acts as a suppressive factor of local anti-tumor immunity in humans.     

恶性胸腔积液来源树突状细胞对自体肿瘤 浸润性淋巴细胞的作用

 目的探讨恶性胸腔积液来源DCs（dentritic cells,DCs）对自体肿瘤浸润性淋巴细胞（tumor infiltration lymphocytes, TILs）增殖及杀伤肿瘤细胞能力的影响。方法用体外培养方法从16例肺癌患 者恶性胸腔积液来源分离单个核细胞,再用密度梯度离心辅以免疫磁珠分选细胞,用白细胞介素4（IL-4 ）、肿瘤坏死因子-α（TNF-α）、粒-单核细胞刺激因子（GM-CSF）等诱导出DCs,用流式细胞仪和电子 显微镜鉴定分离DCs;用IL-2、植物血凝素诱导同一患者胸腔积液单个核细胞中的TILs,用HEA-125磁珠分 选纯化肿瘤细胞,3H-TdR渗入法检测DCs对TILs增殖能力;MTT法检测TILs对肿瘤细胞杀伤活性。结果从肺 癌患者恶性胸腔积液单个核细胞中可诱导成熟DCs,电镜和光镜观察结果显示,这类DCs具有典型的DC形态 ,高表达HLA-ABC、HLA-DR、CD86,较高表达CD80、CD54,也表达CD83、CD1a。DCs可明显促进TILs增殖能 力（增加约1.7倍）。以TILs本身为对照,DCs激活的TILs对肿瘤细胞杀伤活性明显增加［从（31.80± 14.05）%提高到（51.89±13.27）%,P<0.05］。结论肺癌患者恶性胸腔积液单个核细胞中可诱导成熟DCs ,这种DCs可刺激自体TILs扩增,增加TILs杀伤肿瘤细胞的活性。     

Pharmacokinetics of intrapleural versus intravenous etoposide (VP 16) and teniposide (VM 26) in patients with malignant pleural effusion

The pharmacokinetics of etoposide (VP 16) and teniposide (VM 26) were studied after intrapleural administration to 3 patients with lung cancer and malignant pleural effusion. Comparison with the kinetic behavior of intravenously infused VP 16 and VM 26 in the same patients suggests that intrapleural drug delivery achieves higher and longer-lasting pleural concentrations, thus providing a theoretical basis for the palliative treatment of malignant pleural effusions. Although no systemic toxicity was observed after intrapleural administration of either drug, 1 of the 3 patients developed a transient asymptomatic hemorrhagic pleurisy during the first 2 days after the drug, alerting to the possible local toxicity of such treatment.     

Diagnostic value of carbohydrate antigens in supernatants and sediments of pleural effusions

A panel of tumour markers including carcinoembryonic antigen (CEA), carbohydrate antigen (Ca)15-3, Ca125 and Ca19-9 were measured in the lysate of sediments and in the supernatants of pleural effusions of patients with benign and malignant disease. The tumour markers were also measured in the serum of the same patients. Of these patients, 32 had benign diseases (12 trasudative effusions associated with cirrhosis and 20 with non-malignant exudates: 12 pleuritis and 8 other inflammations) and 103 had malignant effusions (37 breast cancers, 29 lung cancers, 10 ovary cancers, 6 kidney cancers, 11 mesotheliomas and 10 lymphomas). We showed the highest level of CEA in pleural effusions of lung cancer followed by that in pleural effusions of breast cancer; whereas Ca15-3 was very high in the pleural effusions of breast and lung cancer. Concerning the lysate of sediment, CEA was high in the pleural effusions of patients with lung cancer and Ca15-3 in those of patients with breast cancer. The other markers are much less useful. For the remaining tumours, none of the markers tested appear to aid in the diagnosis of disease. In conclusion, our data suggest that the combined determination of tumour markers on supernatants and sediments of pleural effusion may provide additional information on the nature of pleural effusion, especially for cases with negative cytology.     

Microsatellite DNA analysis does not distinguish malignant from benign pleural effusions

Distinguishing malignant from benign pleural effusions using routine cytology is a common diagnostic problem. Recently, genetic alterations, including microsatellite instability (MSI) and loss of heterozygosity (LOH), have been described in malignant pleural effusions and proposed as methods improving diagnostics. The purpose of this study was to evaluate a panel of molecular markers for the detection of genetic alterations of cells in pleural effusions and to determine their diagnostic value as an additional test to cytologic examination. Pleural fluid and peripheral blood from 48 patients (36 male and 12 female, median age 71 years) were analyzed. Twenty-six patients had malignant pleural effusion, including 23 lung cancer and three metastatic non-pulmonary carcinoma. The control group consisted of 22 patients with benign pleural effusions. Only 14 malignancy-associated pleural effusions were cytology-positive for malignant cells (54%), whereas all benign pleural effusions were negative. DNA was extracted from all the samples and analysed for MSI and/or LOH using the following microsatellite markers: D3S1234, D9S171, D12S363, D17S250, D5S346 and TP53Alu, located at five chromosomal regions: 3p, 9p, 12q, 17q, 5q. Microsatellite analysis of the pleural fluid pellet exhibited genetic alterations in two neoplastic pleural fluid cases and in one inflammatory case. Two out of 26 (7.6%) patients with malignant pleural effusion showed genetic alterations. One exhibited MSI in three different microsatellite markers (D17S250, D9S171, D3S134) and the other showed LOH in marker D3S134. One out of 22 (4.5%) patients with benign pleural effusion showed LOH in marker D3S134. In conclusion, genetic alterations at the level of microsatellite DNA, were detected only in very few cases of malignant pleural effusions, and in one case of benign pleural effusion. Thus, our data suggest that microsatellite DNA analysis does not facilitate the diagnosis of malignant pleural effusion.     

自体不成熟树突状细胞胸腔内注射治疗化疗耐药的肿瘤患者恶性胸腔积液

目的:观察体外扩增的不成熟树突状细胞(dendritic cells,DC)胸腔内注射对恶性胸腔积液的疗效和安全性。方法:从6例对化疗耐药的恶性胸腔积液患者采集外周血单个核细胞,体外细胞因子诱导培养获得不成熟DC,每4周患者胸腔内注射DC(5~10)×107个,连续3次为一疗程,观察治疗后患者胸腔积液的变化及治疗的不良反应,流式细胞仪检测胸水中T细胞、NK细胞亚群。结果:总体疗效为:CR 2例,PR 1例,SD 1例,PD 2例,有效率为50%(3/6),获益率(CR+PR+SD)为66.7%。2例CR均为肾癌患者,缓解时间达26周和147周;3例肺癌患者中1例PR、1例SD及1例PD;1例恶性胸膜间皮瘤PD;治疗中无严重不良反应发生。DC治疗后6例患者胸水中的T细胞百分率均较治疗前上升,但差异无统计学意义;NK细胞百分率较治疗前明显上升(P<0.05)。结论:采用无抗原加载的自体不成熟DC胸腔内注射治疗恶性胸腔积液的疗效肯定,可能主要是通过NK细胞介导,是一种安全、有效的治疗方法。     

Lymphokine-activated Killer Induction and Its Regulation by Macrophages in Malignant Pleural Effusions

Mononuclear cells (MNC) from pleural effusions and peripheral blood of 18 patients with primary lung cancer with malignant pleural effusion were studied. Pleural and blood MNC generated lymphokine-activated killer (LAK) activity similarly when cultured for 4 days with an optimal concentration of interleukin 2 (IL-2). Highly purified lymphocytes (>98%) and monocyte-macrophages (>90%) were isolated by discontinuous Percoll gradient centrifugation from pleural and blood MNC. Pleural macrophages, as well as blood monocytes, showed significant augmenting effects on in vitro LAK cell induction from pleural and blood lymphocytes by IL-2. During daily intrapleural administration of IL-2, significant induction of LAK activity in vivo was observed after 3 days, but then this LAK activity in pleural MNC decreased almost to zero by day 15. Daily injections of IL-2 resulted in reduction in the up-regulation of LAK induction by pleural macrophages and also in increase in the levels of soluble IL-2 receptors in pleural effusions. These findings indicate that in vivo LAK induction of lymphocytes in malignant effusions by IL-2 may be regulated by macrophages in the effusions.     

胸腔积液中肿瘤坏死因子、癌胚抗原和神经元特异性烯醇化酶的检测及诊断价值研究

目的探讨检测胸水中肿瘤坏死因子（TNF-α）、癌胚抗原（CEA）和神经元特异性烯醇化酶（NSE）对胸腔积液的诊断价值。方法采用电化学发光酶免疫分析法检测59例结核性胸水和48例肺癌性胸水患者胸水中TNF-α、CEA和NSE水平。结果结核性胸水中TNF-α水平显著高于肺癌性胸水（P〈0.05）。肺癌性胸水中CEA和NSE明显高于结核性胸水（P〈0.01）。肺腺癌胸水中CEA升高最明显,非小细胞肺癌胸水中NSE升高最显著。联合检测CEA及NSE,诊断敏感度92.0%,准确度86.3%。结论检测TNF-α、CEA和NSE对结核性胸水和肺癌性胸水的诊断及鉴别诊断有较高的临床价值,联合检测胸水CEA和NSE可提高肺癌诊断敏感度。     

Lymphokine-activated killer induction and its regulation by macrophages in malignant pleural effusions

Mononuclear cells (MNC) from pleural effusions and peripheral blood of 18 patients with primary lung cancer with malignant pleural effusion were studied. Pleural and blood MNC generated lymphokine-activated killer (LAK) activity similarly when cultured for 4 days with an optimal concentration of interleukin 2 (IL-2). Highly purified lymphocytes (greater than 98%) and monocyte-macrophages (greater than 90%) were isolated by discontinuous Percoll gradient centrifugation from pleural and blood MNC. Pleural macrophages, as well as blood monocytes, showed significant augmenting effects on in vitro LAK cell induction from pleural and blood lymphocytes by IL-2. During daily intrapleural administration of IL-2, significant induction of LAK activity in vivo was observed after 3 days, but then this LAK activity in pleural MNC decreased almost to zero by day 15. Daily injections of IL-2 resulted in reduction in the up-regulation of LAK induction by pleural macrophages and also in increases in the levels of soluble IL-2 receptors in pleural effusions. These findings indicate that in vivo LAK induction of lymphocytes in malignant effusions by IL-2 may be regulated by macrophages in the effusions.     

Evaluation of pleural fluid human epididymis 4 (HE4) as a marker of malignant pleural effusion

Pleural effusion is a commonly encountered problem in clinical practice, and pleural fluid analysis is usually the first step towards identifying the underlying etiology. Numerous studies have been published analyzing the potential utility of measuring biomarkers in pleural fluid as possible indicators of a malignant effusion; however, there are no studies that have examined the presence of human epididymis 4 (HE4) in pleural effusions. The aims of this study were to assess pleural effusion and serum concentrations of HE4 in patients with different types of pleural effusions and to evaluate the diagnostic performance of HE4 in detecting malignant pleural effusion. A prospective cohort study was carried out of 88 consecutive patients presenting with pleural effusions. The patients were divided into three groups: 22 patients with transudative effusions, 32 patients with non-malignant exudative effusions, and 34 patients with malignant pleural effusions. Blood and pleural fluid HE4 levels were measured using immunoassay. Both serum HE4 levels and pleural effusion HE4 levels were significantly higher in patients with malignant effusions than in patients with transudative or non-malignant exudative effusions. A pleural fluid HE4 cutoff value of 1,675?pmol/L was found to predict malignant pleural effusions with a diagnostic sensitivity of 85.3?% and specificity of 90.7?%. The current study reports a novel finding of increased serum and pleural fluid HE4 levels in patients with malignant effusions compared to non-malignant effusions. This finding has the potential to strengthen the diagnostic performance of tumor markers in detecting malignant pleural effusions.     

冀东满族肺腺癌患者胸液与相应肿瘤组织EGFR基因突变检测对比分析

目的:分析冀东满族肺腺癌患者胸液与相应肿瘤组织EGFR基因突变检测结果。方法:选取2010年9月至2014年9月间在我院胸外科治疗的74例有胸液的冀东满族肺腺癌患者为研究对象,采用变性高效液相色谱法(DHPLC)检测肺腺癌患者胸液及相应肿瘤组织样本中是否发生EGFR基因突变。结果:肿瘤组织EFGR基因突变检出率为50.00%,胸液样本EGFR基因突变检出率为52.70%,两者间无统计学差异(P＞0.05)。胸液上清、胸液沉淀、胸液上清与沉淀以及肿瘤组织EGFR基因检测结果一致性均良好。结论:肺腺癌患者胸液与相应肿瘤组织EGFR基因突变检测结果一致性良好,临床可通过胸液检测代替肿瘤组织检测,以期能够持续监测患者EGFR基因突变状态,以指导患者添加或者实施EGFR-TKIs治疗。     

电视胸腔镜诊治恶性胸腔积液18例报告

[目的]评价电视胸腔镜手术（VATS）在恶性胸腔积液诊治中的应用价值,［方法］18例恶性胸腔积液患者行胸腔镜胸膜活检和滑石粉胸膜固定术,术后加低负压胸腔引流。［结果］18例均获病理确诊,其中恶性胸膜间皮瘤2例,乳腺癌胸膜转移6例,肺癌胸膜转移8例,卵巢癌和胃癌胸膜转移各1例。胸膜固定成功16例;失败2例,其原因为肺癌伴有肺不张。［结论］VATS可以大大提高恶性胸腔积液的确诊率和胸膜固定术的效果,术后低负压胸腔引流有利于胸腔粘连形成,缩短引流时间。     

高聚金葡素与顺铂治疗恶性胸腔积液的疗效观察

 目的　观察高聚金葡素对晚期肺癌合并恶性胸腔积液的疗效。方法　32例设为对照组,常规全身行EP方案化疗并顺铂胸腔内注射;观察组32例 , 在作上述常规治疗的同时,加用肌注和胸腔内注入高聚金葡素。结果　观察 组胸水吸收的有效率达71.9%,karnofsky评分上升率为78.1%均优于对照组的43.8%和40 .6%(P<0.01),而白细胞减少和胃肠道反应的发生率均比对照组低(P<0.01)。结论　在全身和胸腔内应用抗癌药治疗晚期肺癌合并恶性胸腔积液的基础 上加用高聚金葡素可提高胸水吸收的有效率,改善生活质量,减少化疗毒副作用。     

置管引流并注入白介素-2联合顺铂治疗恶性胸腔积液疗效分析

目的探讨中央静脉导管胸腔闭式引流后注入白介素-2联合顺铂治疗恶性胸腔积液的疗效。方法 48例恶性胸腔积液患者随机分为2组,均经皮胸腔穿刺,置入中心静脉导管,联合治疗组（A组）25例,胸腔内注200万单位白介素-2和40 mg顺铂;单用顺铂组（B组）23例,胸腔内注入40 mg顺铂。A、B组均接受3次化疗,每次间隔1周。观察2组疗效和不良反应。结果所有患者均获得满意引流效果;A和B组治疗总有效率分别为84.0%和60.9%,差异有统计学意义（P〈0.05）。A组总不良反应发生率高于B组,但差异无统计学意义（P〉0.05）。结论中心静脉置管行胸腔闭式引流术具有创伤小、活动不受限以及引流效果满意等特点。白介素-2不良反应轻,耐受性好,是治疗恶性胸腔积液较好的选择。