Serum interleukin-6 levels correlate with malnutrition and survival in patients with advanced non-small cell lung cancer

AIM: To investigate the level of interleukin-6 in advanced non-small cell lung cancer and to analyze the relationship with malnutrition and survival. METHODS AND STUDY DESIGN: Seventy-one newly diagnosed advanced non-small cell lung cancer patients were enrolled in this prospective study. Malnutrition was defined by using subjective global assessment. Performance status was assessed by the Karnofsky scale. Serum levels of albumin, transferrin, C-reactive protein, lymphocytes/mm3, lactate dehydrogenase and growth hormone were determined before treatment. The patients were followed, and the factors affecting survival were analyzed. RESULTS: The mean follow-up after diagnosis was 180 days. IL-6 levels increased in 48 (68%) of 71 patients. According to the subjective global assessment, 28 (39%) patients were well nourished and 43 (61%) were malnourished. Of the 43 malnourished patients, 29 (41%) were moderately malnourished or suspected of being malnourished and 14 (20%) were severely malnourished. The IL-6 level was related to impaired performance status (P = 0.0001), severe malnutrition (P = 0.004), increased C-reactive protein (P = 0.013), higher growth hormone (P = 0.025) and transferrin (P = 0.03) levels. On univariate analysis, impaired performance status, moderate and severe malnutrition, decreased serum albumin and transferrin, a raised IL-6 and lactate dehydrogenase levels were the significant prognostic factors for survival. Multivariate analysis indicated that a raised IL-6, severe malnutrition and a low serum level of albumin were independent prognostic factors for survival in patients with advanced non-small cell lung cancer. CONCLUSIONS: IL-6 secretion may play a role in the pathophysiology of malnutrition in advanced lung cancer. Results show a relation between elevated IL-6 serum levels and malnutrition, poor performance status, acute phase response and shorter survival in patients affected by advanced non-small cell lung cancer.     

盐酸埃克替尼治疗EGFR突变型老年非小细胞肺癌的临床疗效与安全性分析

目的:探讨盐酸埃克替尼治疗EGFR突变型老年非小细胞肺癌的临床疗效及安全性。方法:选择2015年4月至2017年6月接受治疗的EGFR突变型老年非小细胞肺癌患者110例,随机数字法分为对照组（n=55例）和观察组（n=55例）。对照组采用吉非替尼治疗,观察组采用盐酸埃克替尼治疗,采用酶联免疫吸附试验测定两组患者血清C反应蛋白（CRP）、血清淀粉样蛋白A（SAA）、白细胞介素-6（IL-6）及白细胞介素-2受体（IL-2R）水平,比较两组患者临床疗效及安全性。结果:观察组治疗4周后有效率为34.55%,高于对照组25.45%（P<0.05）;两组患者治疗前炎症因子水平差异无统计学意义（P>0.05）;两组化疗后CRP、SAA、IL-6及IL-2R水平均得到提高;观察组治疗4周后CRP、SAA、IL-6及IL-2R水平,均低于对照组（P<0.05）;观察组治疗4周后药物毒副反应发生率为21.82%,低于对照组的32.73%（P<0.05）。结论:将盐酸埃克替尼用于治疗EGFR突变型老年非小细胞肺癌患者有助于提高临床疗效,降低炎症因子水平,安全性较高,值得推广应用。     

IL-2, TNF-alpha, and leptin: local versus systemic concentrations in NSCLC patients

One recent line of cancer research shows increasing interest for biological factor such as IL-2, TNF-alpha, and leptin, which have been found to participate in the development and progression of non-small cell lung cancer (NSCLC). The aim of this study was to measure IL-2, TNF-alpha, and leptin concentrations in the airways and in the systemic circle of patients with NSCLC, investigating the role of these factors in the lung tumors. We enrolled 32 patients (17 men, 71 +/- 7 years) with a histological diagnosis of NSCLC and 20 healthy ex-smoker controls, negative for computed tomography of the chest (14 men, 69 +/- 8 years). IL-2, TNF-alpha, and leptin levels were measured in the serum, the urine, the bronchoalveolar lavage, the induced sputum, and exhaled breath condensate (EBC) of patients enrolled by means of a specific enzyme immunoassay kit. Higher concentrations of IL-2, TNF-alpha and leptin were found in NSCLC patients than in controls (p < 0.0001). A statistically significant increase of IL-2, TNF-alpha, and leptin concentrations was observed in patients from stage I to stage III of NSCLC. These findings suggest that IL-2, TNF-alpha, and the leptin play an important role in the cancerogenesis of NSCLC. Their measure in the EBC could be proposed as noninvasive markers for an early detection of NSCLC and in the follow-up of this tumor.     

The value of serum levels of IL-6, TNF-alpha, and erythropoietin in metastatic malignant melanoma

In order to study the relation to the metastatic profile and survival, we evaluated the association between pretreatment serum levels of IL-6, TNF-alpha, and erythropoietin (EPO) and metastatic distribution and survival in 16 patients with metastatic malignant melanoma. IL-6 and TNF-alpha immunoassay (R&D Systems, Inc. Minneapolis, USA) employs the quantitative sandwich enzyme immunoassay technique. The Quantikine IVD EPO ELISA (R&D Systems, Inc.) is based on the double-antibody sandwich method. The baseline serum IL-6 and EPO levels were significantly higher in patients with metastatic malignant melanoma than in the control group (p=0.009 and p=0.033, respectively). Serum IL-6 levels were higher in patients with weight loss (p=0.02), who were anemic (p=0.026), with elevated serum LDH levels (p=0.028), and who were chemotherapy nonresponding (p=0.016). The relationship of serum IL-6 concentration to the tumor burden was not determined. Only serum EPO level was influenced by hemoglobin status (p=0.001). No difference was shown among these three parameters. Elevated serum IL-6 concentration (p=0.002) was found to be an adverse prognostic factor in patients with poor performance status, weight loss, low serum hemoglobin, elevated serum LDH, and unresponsive to chemotherapy. On the other hand, both serum TNF-alpha and EPO levels were of no prognostic value. Serum levels of IL-6 were found to be prognostic factors as valuable as serum LDH levels in patients with metastatic malignant melanoma. Their prognostic value should be further evaluated in a larger patient population.     

Elevations of serum C-reactive protein occur independently of circulating interleukin-6 concentrations in patients with lung-cancer

It has been suggested that a proportion of patients with cancer have an ongoing acute phase response indicated by a raised C-reactive protein (CRP). To examine whether an acute phase protein response is associated with circulating interleukin-6 (IL-6) concentrations in patients with lung cancer, we measured serum levels of CRP and interleukin (IL)-6 in 176 patients with lung cancer and 48 patients with other pulmonary diseases (28 diffuse pulmonary infiltrates, 15 benign lung tumors, and 5 bronchial asthmas). Serum CRP was detectable (greater-than-or-equal-to 2.5 mg/liter) in 57.4% of patients with lung cancer, 78.6% of patients with diffuse pulmonary infiltrates, 46.7% of patients with benign lung tumors, and 40.0% of patients with bronchial asthma. Serum IL-6 was detectable in all patients by a highly sensitive enzyme-immunoassay, the concentration ranging from 0.126 to 35.115 pg/ml. Although there was no significant difference in serum IL-6 levels among the histologic types of lung cancer, the IL-6 concentration was significantly higher in patients with advanced cancers than in those with early ones. Correlation analyses showed that there was no significant relationship between the CRP and IL-6 concentrations in the 176 patients with lung cancer (r=0.212, P=0.1243), while a highly significant correlation between both levels was observed in the 28 patients with diffuse pulmonary infiltrates (r=0.783, P=0.0005). These results indicate that the serum IL-6 level in patients with lung cancer is closely associated with the disease stage, but that a raised CRP concentration occurs independently of circulating IL-6 concentrations in patients with lung cancer.     

Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort.

BACKGROUND: Chronic inflammation is associated with processes that contribute to the onset or progression of cancer. This study examined the relationships between circulating levels of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha) and total as well as site-specific cancer incidence. METHODS: Study subjects (n = 2,438) were older adults (ages 70-79 years) participating in the Health Aging and Body Composition study, who did not report a previous cancer diagnosis (except for nonmelanoma skin cancer) at baseline. Incident cancer events (n = 296) were ascertained during an average follow-up of 5.5 years. Inflammatory markers were measured in stored baseline fasting blood samples. RESULTS: The adjusted hazard ratios (95% confidence intervals) for incident cancer associated with a 1-unit increase on the natural log-scale were 1.13 (0.94-1.37), 1.25 (1.09-1.43), and 1.28 (0.96-1.70) for IL-6, CRP, and TNF-alpha, respectively. Markers were more strongly associated with cancer death: hazard ratios were 1.63 (1.19-2.23) for IL-6, 1.64 (1.20-2.24) for CRP, and 1.82 (1.14-2.92) for TNF-alpha. Although precision was low for site-specific analyses, our results suggest that all three markers were associated with lung cancer, that IL-6 and CRP were associated with colorectal cancer, and that CRP was associated with breast cancer. Prostate cancer was not associated with any of these markers. CONCLUSIONS: These findings suggest that (a) the associations between IL-6, CRP, and TNF-alpha and the risk of cancer may be site specific and (b) increased levels of inflammatory markers are more strongly associated with the risk of cancer death than cancer incidence.     

Serum cytokine levels in patients with advanced non-small cell lung cancer: correlation with treatment response and survival

To investigate whether expression of several cytokines affected clinical outcome in non-small cell lung cancer patients. A total of 86 stage IIIB/IV non-small cell lung cancer patients, treated with platinum-based doublets, were examined expression levels of IL-1, IL-2R, IL-5, IL-6, IFN-γ, TNF-α pre- and post-chemotherapy. Enzyme-linked immunosorbent assay technique was performed. Kaplan–Meier analysis and Cox regression analyses were used to adjust for possible confounding variables. IL-6 expression levels were significantly decreased due to chemotherapy in patients with stable disease (P = 0.041). IL-2R expression levels were significantly increased due to chemotherapy in patients with progression disease (P = 0.010). Patients with high concentrations of TNF post-chemotherapy had a significantly longer survival (P = 0.009, 17 months versus 11 months) than low levels. Multivariate analysis showed that sex, response rate, IL-1 and TNF-α were significantly predictive of the survival. Serum IL-6 and IL-2R levels correlated with chemoresponse in advanced non-small cell lung cancer, serum IL-1 and TNF-α can be predictive factors in advanced non-small cell lung cancer.     

晚期肺癌患者癌症相关性疲乏的发生及其与血清炎性因子的关系

目的 本研究拟评估晚期肺癌患者癌症相关性疲乏（cancer-related fatigue, CRF）发生情况,测定血清中CRP、CORT、IL-6的水平,探究该指标与CRF之间的相关性。方法 应用FACIT-F量表对51例晚期肺癌患者进行CRF评估。采用免疫比浊法测定血清CRP水平,免疫微粒电发光法测定CORT水平,采用双抗体夹心酶联免疫吸附ELISA法测定IL-6水平。采用Spearman相关分析方法分析量表得分与血清炎性因子水平的相关程度。应用Logistic回归分析进行危险因素分析。结果 27例患者附加关注子量表得分≤34分,CRF发生率为52.9%。存在疼痛的患者身体状况及附加关注得分低于无疼痛患者（P=0.009, P=0.018）。睡眠障碍显著影响身体状况、附加关注及总分值得分,存在睡眠障碍者三项得分均明显低于无睡眠障碍患者（P<0.01）。血清CRP水平与身体状况、功能状况、附加关注、总得分呈负相关（P值分别为0.004、0.027、0.007、0.013）。IL-6水平与身体状况、附加关注及总分值呈负相关（P值分别为0.044、0.029、0.023）。CORT水平与量表得分无显著相关。睡眠障碍和疼痛是CRF的独立危险因素,OR值分别为6.167、7.405（P=0.010, P=0.005）。结论 血清IL-6、CRP水平高低与患者疲乏程度显著相关,血清IL-6、CRP水平越高与患者疲乏程度相关性越显著,IL-6、CRP可作为临床监测疲乏程度的指标。合并疼痛、睡眠障碍的患者更容易发生疲乏、疲乏程度更严重。     

Quantitative evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status

In advanced cancer patients, the oxidative stress could take place either at the onset of disease or as a function of disease progression. To test this hypothesis, the following parameters were investigated: the erythrocyte activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the serum activity of glutathione reductase (GR) and the serum total antioxidant status (TAS). The total antioxidant capacity of plasma LMWA was evaluated by the cyclic voltammetry methodology. We further determined the serum levels of proinflammatory cytokines (IL-6 and TNFalpha), IL-2, leptin and C-reactive protein (CRP). All of these parameters have been correlated with the most important clinical indices of patients such as Stage of disease, ECOG PS and clinical response. Eighty-two advanced stage cancer patients and 36 healthy individuals used as controls were included in the study. Our findings show that SOD activity was significantly higher in cancer patients than in controls and GPx activity was significantly lower in cancer patients than in controls. Serum values of IL-6, TNFalpha and CRP were significantly higher in patients than in controls. Serum leptin values of cancer patients were significantly lower than controls. SOD activity increased significantly from Stage II/ECOG 0-1 to Stage IV/ECOG 0-1, whereas it decreased significantly in Stage IV/ECOG 3. GPx activity decreased significantly in Stage IV/ECOG 2-3. An inverse correlation between ECOG PS and serum leptin levels was found. Serum levels of IL-2 decreased from Stage II/ECOG 0-1 to Stage IV/ECOG 2-3. A direct correlation between Stage/ECOG PS and serum levels of both IL-6 and CRP was observed. Cisplatin administration induced a significant increase of GPx after 24 hr. In conclusion, this is the first study that shows that several "biological" parameters of cancer patients such as antioxidant enzyme activity, cytokines, leptin and CRP strictly correlate with the most important clinical parameters of disease such as Stage and ECOG PS.     

Research on the Relationship Between Serum Levels of Inflammatory Cytokines and Non-small Cell Lung Cancer

Aims: This study was conducted to evaluate the levels of TNF-α, IL-6, IL-8 and VEGF in serum of patientswith non- small cell lung cancer, for assessing their possible diagnostic and prognostic roles. Methods: Weenrolled 48 patients newly diagnosed with non-small cell lung cancer and 40 healthy controls. TNF- α, IL-6and IL-8 levels were measured in the serum of all the subjects with specific radioimmunoassay kits, while EGFwas analyzed by sandwich enzyme immunoassay techniques. Results: A statistically significant difference wasobserved between lung cancer patients and the control group regarding the values of TNF-α, IL-6, IL-8 andVEGF in serum. Moreover, TNF-α, IL-8 and VEGF levels were higher in patients with advanced stages comparedto early stages. In addition, higher serum levels of TNF-α, IL-6, IL-8 and VEGF were found in smokers than innon-smokers, both in patients and controls. Conclusion: Serum levels of TNF-α, IL-6, IL-8 and VEGF were allelevated in lung cancer patients, suggesting that inflammatory cytokines could be jointly used as a screening tool.Though TNF-α, IL-8 and VEGF levels were related to advanced disease, long-term survival studies of NSCLCpatients should be performed to confirm whether they can act as biomarkers of advanced disease. In addition,smoking would be an important contributor to the processes of inflammation and lung cancer.     

化疗对晚期非小细胞肺癌外周血Th1/Th2细胞因子表达的影响

目的探讨化疗对非小细胞肺癌患者外周血Th1/Th2细胞因子表达的影响。方法应用ELISA方法,检测患者化疗前、化疗3个周期后和化疗6个周期后Th1/Th2细胞因子的表达水平。结果晚期非小细胞肺癌患者外周血Th1型细胞因子IL-2、IFN-γ表达水平低于正常组(P<0.05),而Th2型细胞因子IL-6和IL-10表达水平显著高于正常组(P<0.05)。化疗3个周期后血IL-2、IFN-γ水平明显高于化疗前,差异有统计学意义(P<0.05),IL-6和IL-10水平明显低于化疗前(P<0.05)。化疗6个周期后血IL-2、IFN-γ表达水平明显低于化疗3个周期,差异有统计学意义(P<0.05),而化疗6个周期后血IL-6和IL-10水平稍低于化疗3个周期,差异无统计学意义(P>0.05)。结论晚期非小细胞肺癌患者存在免疫相关因子紊乱,3个周期的化疗对改善机体的免疫平衡有效;6个周期的化疗未能进一步改善机体免疫功能,甚至出现免疫功能恶化。     

Association of serum IL-6 levels with comprehensive geriatric assessment variables in a population of elderly cancer patients

The primary aim of this study was to find whether any association exists between serum levels of proinflammatory cytokines, mainly IL-6, and the most important comprehensive geriatric assessment (CGA) variables such as functional status, cognitive functions and nutrition in a population of elderly cancer patients. The secondary aims were to find whether any difference existed between: i) age groups, ii) performance status scores, iii) patients who had lost weight versus those who had not. Eighty-four elderly patients with advanced cancer were included in the study (stage III 15.4%, and stage IV 72.6%). Serum levels of IL-6 and CRP were significantly higher in elderly than in the other adult cancer patients. Among the CGA variables investigated, the most affected were functional status assessed by IADL, cognitive functions by MMSE and nutrition. The ECOG PS was shown to be significantly associated with all the dimensions of CGA investigated: poor PS (>/=2) corresponded to severe disabilities. As for the relationship of serum IL-6 with CGA variables, the strongest correlations were between IL-6 and functional status assessed by both Katz ADL (p=0.0003), IADL (p=0.0070) and nutrition (p=0.0013). Moreover, we observed an association, although not statistically significant, between functional disability (ADL and IADL) and high IL-6 levels in individuals with weight loss. IL-6 levels seem to be independently associated with all CGA variables investigated in the present study in a population of elderly cancer patients. Because the most important CGA variables, in particular functional status, have been observed to be strongly associated with survival, the present study, confirming our previously reported ones, suggests that IL-6 may be a reliable marker of disease outcome and supports the feasibility of using IL-6 as a sensitive outcome marker in studies based on novel approaches aiming at modifying age- and cancer-related biologic mechanisms.     

Serum levels of interleukin-6 in patients with primary head and neck squamous cell carcinoma

Interleukin (IL)-6 plays a central role as a differentiation and growth factor of tumor cells. IL-6 has been identified in a wide variety of malignancies, including head and neck squamous cell carcinomas (HNSCC). The aim of this study was to investigate the association between the serum levels of IL-6 in HNSCC patients and the biological characteristics of the tumor as well as the clinicopathological status of the patients. The circulating level of IL-6 in sera from patients with various HNSCC (n = 90) as well as from healthy normal controls (n = 39) was investigated. Serum IL-6 concentrations were determined as serum immunoreactivity using a quantitative sandwich enzyme immunoassay technique. For statistical analysis, the Kruskal-Wallis test was performed. The majority of the patients with HNSCC were found to have high serum IL-6 concentrations. The IL-6 levels in the sera of patients with cancer ranged from below the detection limit to 312.8 pg/ml (mean, 19.5 pg/ml). In contrast, the IL-6 serum levels in 39 healthy individuals ranged from below the detection limit to 52.2 pg/ml (mean, 6.0 pg/ml), with the concentration being significantly higher in HNSCC patients (p < 0.001). Furthermore, the correlation of the IL-6 serum concentration with tumor stage was significant (p = 0.04). Accordingly, there was a significant difference of IL-6 serum concentration of tumors with positive and negative lymph nodes (p = 0.045), with concentration being significantly higher in lymph node-positive tumors. Our data on elevated IL-6 serum levels in the majority of HNSCC cancer patients and its correlation with tumor stage and lymph node status suggest that serum IL-6 reflects the proliferative activity of the tumor in patients with head and neck cancer. IL-6 serum determinations might serve as a biological marker and help to identify advanced head and neck tumors.     

Serum vascular endothelial growth factor (VEGF) and bcl-2 levels in advanced stage non-small cell lung cancer

The characteristic changes in cancer process are assumed to be genetic alterations about the imbalance of cell proliferation and apoptotic cell death. This study was conducted to determine the value of the circulating vascular endothelial growth factor (VEGF) and Bcl-2 in patients with advanced stage non-small cell lung cancer (NSCLC). These serum factors were measured of 52 NSCLC patients pathologically verified on before and after chemotherapy in comparison with 16 healthy controls by using ELISA method. Both of the serum levels of VEGF (p = 0.015) and Bcl-2 (p < 0.001) were increased significantly in NSCLC patients compared with the healthy controls. No statistically significant relationships between investigated elevated serum parameters and various characteristics of patients and disease such as stage and tumor burden were determined. Likewise, we also found no correlation between serum VEGF and Bcl-2. Cytotoxic therapy of patients was accompanied by unchanged serum levels of serum factors. The median survival of all patients was 27 weeks and one-year survival rate was 22.4 percent. With the median serum levels as the cut-off value, patients were divided into high- and low-serum parameter groups. While we found that patients' performance status (p < 0.0001), serum LDH level (p = 0.0002), response to chemotherapy (p = 0.0023), and stage of the disease (p = 0.0085) were prognostic factors for survival, serum VEGF (p = 0.48) and Bcl-2 (p = 0.91) levels were determined as ineffective on survival in patients with advanced NSCLC. In conclusion, our data suggest that these serum factors, VEGF and Bcl-2, are useful diagnostic factors, not predictive and prognostic markers for overall survival in advanced NSCLC patients.     

Serum HE4 as a diagnostic and prognostic marker for lung cancer

We evaluated the diagnostic and prognostic efficacy of human epididymis protein 4 (HE4) for lung cancer patients by using our novel enzyme-linked immunosorbent assay (ELISA) system. We measured serum HE4 levels of cancer patients including 49 lung cancer and 18 ovarian cancer patients. Furthermore, we evaluated the relationship between serum HE4 levels and overall survival after chemotherapy of 24 lung cancer patients. Serum HE4 levels were significantly higher for non-small, small cell lung cancer and ovarian cancer patients than for healthy controls. The area under the receiver operating characteristic curve (AUC) was calculated for differentiation of lung cancer patients and healthy controls. AUC for serum HE4 was 0.988 for differentiating lung cancer patients from healthy controls, with a cutoff value of 6.56 ng/ml (sensitivity = 89.8%, specificity = 100%). Serum HE4 levels were elevated in 36/40 (90.0%) non-small cell lung cancer patients, 8/9 (88.9%) small cell lung cancer patients and 8/18 (44.4%) ovarian cancer patients. High levels of serum HE4 (>15 ng/ml) after chemotherapy were significantly correlated with worse overall survival after the treatment. These findings suggest that serum HE4 is a potential diagnostic and prognostic marker for lung cancer patients.     

Prognostic and Predictive Role of Angiogenic Markers in Non- Small Cell Lung Cancer

Objective: Despite the existence of detailed consensus guidelines, challenges remain regarding the role angiogeneticfactors on non-small cell lung cancer (NSCLC). This study was conducted to determine the role of the vascular endothelialgrowth factor (VEGF), interleukin-8 (IL-8) and angiopoietin2 (Ang2) in patients with NSCLC. Methods: This studyincluded 64 consecutive patients with non-small cell lung cancer, who admitted to clinic. Pre-treatment serum VEGF, IL-8and Ang2 levels were evaluated. Patients were treated according to internationally accepted guidelines. Results: VEGFand IL-8 serum levels of patients with both squamous cell carcinoma and adenocarcinoma were significantly higherthan controls (p<0.05). In addition, IL-8 levels were lower among treatment-responders than non-responders (p:0.031).Impact of elevated or decreased levels of VEGF, Ang2 and IL-8 on survival was evaluated, accepting median level asreference. There was no correlation between the serum levels of VEGF, Ang2, IL-8 and survival. Conclusion: We foundthat the levels of angiogenic markers were significantly different between non-small cell lung cancer patients andcontrols. These markers could elicit more information related to stage and prognosis.     

A phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer

BACKGROUND: Bryostatin-1 is a macrocyclic lactone, which exhibits pleiotropic biological effects via protein kinase C and has shown preclinical synergy with paclitaxel for enhanced tumor cell apoptosis. PATIENTS AND METHODS: Patients had stage IIIB (pleural effusion)/IV non-small cell lung cancer, measurable disease, performance status 0-2 Eastern Cooperative Oncology Group, adequate organ function, and no prior chemotherapy. Patients received dexamethasone premedication followed by paclitaxel at a dose of 90 mg/m(2) on days 1, 8, and 15 along with bryostatin-1 50 microg/m(2) on days 2, 9, and 16 every 28 days until disease progression. Correlative assays measuring serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and T-lymphocyte numbers were performed based on a previous study showing cytokine induction in vivo by bryostatin-1. Fifteen patients were enrolled. RESULTS: Thirty cycles of the bryostatin-1 and paclitaxel were delivered with a median of 2 per patient (range 1-4). Myalgia was the predominant non-hematologic toxicity encountered as 3 patients developed grade 4 and 1 patient developed grade 3 myalgia. Four patients were removed from the study during cycle 1 for rapid disease progression or myalgia. Eleven patients could be evaluated for response. Five patients had stable disease, two had a mixed response, and four had progressive disease. Ten patients received second-line chemotherapy after leaving the study. Median survival was 31 weeks (95% confidence interval: 5.4-49.3). Correlative data showed a trend towards decreased plasma IL-6 and TNF-alpha after each cycle of therapy presumably due to the dexamethasone premedication and/or paclitaxel. CONCLUSIONS: This drug combination showed no significant clinical response and was associated with reproducible toxicity. The predominance of myalgia in the absence of elevated serum cytokines suggests a non-inflammatory etiology of this toxicity.     

Prognostic factors in patients with inoperable non-small cell lung cancer--an analysis of long-term survival patients

A survival benefit of patients with inoperable non-small cell lung cancer has been reported since a development of new therapeutic agents in the 1990's. However, multivariate analyses of patients have not been evaluated. The aim of this study is to identify prognostic factors in the long-term survivors who had been treated with chemotherapy using these new agents and/or radiotherapy. A retrospective study and clinical analysis of 121 inoperable nonsmall cell lung cancer patients were conducted. Fifteen cases (male: 9, female: 6) with a survival of more than 2 years were revealed. Regarding clinical variables between the 15 cases and others, an early nodal (N) status, a high serum protein level, a good performance status (PS) and those having first-line chemotherapy or radiotherapy were all identified as significant prognostic factors for the long-term survivors. Multivariate analyses also revealed that an early N status, a good PS, female gender and chemotherapy and/or radiotherapy were associated with the long-term survivors. These results suggest that patients with inoperable non-small cell lung cancer should be considered for appropriate treatments including new chemotherapeutic agents.     

VEGF, TNF-alpha and 8-isoprostane levels in exhaled breath condensate and serum of patients with lung cancer

The aim of the present study was to evaluate the levels of VEGF, 8-isoprostane and TNF-alpha in EBC and serum of patients with primary lung cancer prior to the initiation of any treatment, in order to evaluate their possible diagnostic role. Furthermore, associations between VEGF, 8-isoprostane and TNF-alpha levels in EBC and serum with clinicopathologic factors were investigated. We enrolled 30 patients with lung cancer (mean age 65.2+/-10.5 years) and 15 age and gender-matched healthy smokers as controls. Serum and EBC were collected before any treatment. TNF-alpha, VEGF and 8-isoprostane levels in EBC and serum were analyzed by an immunoenzymatic method (ELISA). A statistically significant difference was observed between lung cancer patients and the control group regarding the values of TNF-alpha, both in EBC (52.9+/-5.0 pg/ml vs. 19.4+/-3.9 pg/ml, p<0.0001) and serum (44.5+/-6.3 pg/ml vs. 22.2+/-4.3 pg/ml, p=0.035). Moreover, EBC VEGF levels were higher in patients with T3-T4 tumor stage compared to T1-T2 (9.3+/-2.8 pg/ml vs. 2.3+/-0.7pg/ml, p=0.047). A statistically significant correlation was also observed between serum and EBC values of VEGF (r=0.52, p=0.019). In addition, serum levels of VEGF were higher in lung cancer patients than in controls (369.3+/-55.1 pg/ml vs. 180.5+/-14.7 pg/ml, p=0.046). VEGF serum levels were also found higher in patients with advanced stage of disease (IIIB-IV) and distant nodal metastasis (N2-N3). No differences were observed in 8-isoprostane in EBC between lung cancer patients and controls. In contrast, serum 8-isoprostane levels were higher in lung cancer patients compared to controls (24.9+/-3.6 pg/ml vs. 12.9+/-1.6 pg/ml, p=0.027) and were higher in patients with advanced disease. All three biomarkers presented acceptable reproducibility in the EBC on two consecutive days. In conclusion, we have shown that TNF-alpha, VEGF and 8-isoprostane are elevated in the serum of lung cancer patients and increased serum VEGF and 8-isoprostane levels are related to advanced disease. In EBC, increased TNF-alpha levels were observed in lung cancer patients, whereas increased VEGF levels were observed in advanced T-stage. Further longitudinal studies are warranted for the evaluation of the prognostic role of these biomarkers in lung cancer.     

Anaemia in patients with cancer: role of inflammatory activity on iron metabolism and severity of anaemia

Hepcidin has been proposed as an important factor in the pathogenesis of the anaemia of chronic disease (ACD). The aim of this study was to assess the relationship between anaemia and inflammatory activity in patients with solid tumours. Patients were classified as having iron deficiency anaemia (IDA) (hypoferremia and hypoferretinemia), ACD (hypoferremia, normal or increased serum ferritin) and anaemia related to cancer (ARC) (no abnormalities in iron status). Serum pro-hepcidin, IL-6, C-reactive protein (CRP) and iron status parameters were measured using commercial kits. CRP and IL-6 levels were significantly higher in patients with ACD when compared to IDA, ARC and non anaemic patients (P < 0.005). Serum pro-hepcidin levels were not different among all studied groups (P = 0.138). A negative correlation was observed between haemoglobin and serum ferritin, CRP and IL-6 levels only in group of ACD. Serum pro-hepcidin concentrations were not correlated with degree of anaemia or iron metabolism parameters. According to our results the inflammatory activity represented by high levels of IL-6 and CRP are involved in the pathogenesis of ACD, probably due to the action of inflammation on iron metabolism, but not in ARC. It was not possible to demonstrate a significant effect of pro-hepcidin on the anaemia in cancer patients.