Cerebrospinal fluid interleukin-10 is a potentially useful biomarker in immunocompetent primary central nervous system lymphoma (PCNSL)

The diagnosis of primary central nervous system lymphoma (PCNSL) by radiographical examination is often difficult because of its similarity to other brain tumors. To test whether interleukin-10 (IL-10) and IL-6 can be used to distinguish PCNSL from other brain tumors that are radiographically similar, cerebrospinal fluid (CSF) levels of IL-10 and IL-6 were measured in 66 patients with intracranial tumors (PCNSLs: 26 cases; other brain tumors: 40 cases). In the patients with PCNSLs, the median CSF levels of IL-10 and IL-6 were 27 pg/mL and 5.4 pg/mL, respectively. The CSF IL-10 and IL-6 levels were significantly higher in PCNSLs than in the other brain tumors. To validate the diagnostic value of CSF IL-10 in PCNSL, we prospectively examined 24 patients with brain lesions that were suspected to be PCNSL. We observed that the CSF IL-10 levels were significantly higher in PCNSLs than in other brain tumors. At an IL-10 cutoff level of 9.5 pg/mL, the sensitivity and specificity were 71.0% and 100%, respectively. After therapy, the CSF IL-10 levels were decreased in all patients and were increased at relapse in most of these patients. Immunohistochemically, all PCNSLs, except for 1 unclassified PCNSL, expressed both IL-10 and IL-10 receptor-A. In the patients with high CSF IL-10, IL-10 expression levels in tumor were relatively higher, compared with low CSF IL-10; however, there was no significant difference between these groups. In addition, elevated CSF level of IL-10 was significantly associated with having a shorter progression-free survival (hazard ratio, 3.37; 95% confidence interval, 0.985-11.528; log-rank, P= .038). These results indicate that the CSF level of IL-10 may be a useful diagnostic and prognostic biomarker in patients with PCNSLs.     

Elevated Serum IL-17A but not IL-6 in Glioma Versus Meningioma and Schwannoma

Background: There is a Th1/Th2 cytokine imbalance and expression of IL-17 in patients with brain tumours.We aimed to compare the levels of IL-17A and IL-6 in sera of glioma, meningioma and schwannoma patientsas well as in healthy individuals. Materials and Methods: IL-17A and IL-6 levels were measured in sera of 38glioma, 24 meningioma and 18 schwannoma patients for comparison with 26 healthy controls by commercialELISA assays. Results: We observed an increase in the IL-17A in 30% of glioma patients while only 4% and5.5% of meningioma and schwannoma patients and none of the healthy controls showed elevated IL-17A in theirsera (0.29±0.54, 0.03±0.15 and 0.16±0.68 vs. 0.00±0.00pg/ml; p=0.01, p=0.01 and p=0.001, respectively). Therewas also a significant decrease in the level of IL-6 in glioma patients compared to healthy controls (2.34±4.35 vs.4.67±4.32pg/ml; p=0.01). There was a direct correlation between the level of IL-17A and age in glioma patients(p=0.005). Glioma patients over 30 years of age had higher IL-17A and lower IL-6 in their sera compared tothe young patients. In addition, a non-significant grade-specific inverse trend between IL-17A and IL-6 wasobserved in glioma patients, where high-grade gliomas had higher IL-17A and lower IL-6. Conclusions: Ourdata suggest a Th17 mediated inflammatory response in the pathogenesis of glioma. Moreover, tuning of IL-6and IL-17A inflammatory cytokines occurs during progression of glioma. IL-17A may be a potential biomarkerand/or immunotherapeutic target in glioma cases.     

血清IL-9、IL-17及IL-23水平对多发性骨髓瘤患者肾损伤的诊断价值

目的:探讨血清白细胞介素-9（IL-9）、白细胞介素-17（IL-17）及白细胞介素-23（IL-23）水平对多发性骨髓瘤（multiple myeloma,MM）患者肾损伤的诊断价值。方法:选取2015年01月至2019年12月我院收治的82例MM患者,依据国际分期系统（ISS）分为I期（n=16）、Ⅱ期（n=25）和Ⅲ期（n=41）,根据肾功能情况,将其分为肾损伤组（n=27）和无肾损伤组（n=55）。另选取同期55例正常者作为对照组。检测各组血清IL-9、IL-17及IL-23水平。应用受试者工作特征（ROC）曲线分析血清IL-9、IL-17及IL-23水平诊断MM患者肾损伤的价值。采用Pearson相关分析MM患者血清IL-9、IL-17及IL-23水平之间的相关性。结果:MM组血清IL-9（66.72±18.50 vs 21.95±6.84,pg/mL）、IL-17（52.70±12.16 vs 24.36±5.73,pg/mL）及IL-23（81.60±22.75 vs 36.25±8.46,pg/mL）水平均明显高于对照组（P＜0.001）。随着ISS分期的增加,MM患者血清IL-9、IL-17及IL-23水平增加,Ⅲ期＞Ⅱ期＞Ⅰ期,差异有统计学意义（P＜0.001）。肾损伤组血清IL-9（93.60±24.65 vs 48.20±12.73,pg/mL）、IL-17（74.80±19.42 vs 35.26±8.50,pg/mL）及IL-23（116.48±40.25 vs 62.70±15.24,pg/mL）水平均明显高于无肾损伤组（P＜0.001）。ROC曲线分析显示,IL-9、IL-17及IL-23三项联合诊断MM患者发生肾损伤的曲线下面积（0.927,95%CI:0.865～0.983）最大,其灵敏度最高。相关分析显示,MM患者血清IL-9、IL-17及IL-23水平之间均呈正相关（P＜0.001）。结论:血清IL-9、IL-17、IL-23水平在MM中明显升高,且与MM患者的病情分期及肾损伤有关,三项联合诊断肾损伤的价值较高。     

宫颈癌及癌前病变中IL-10和IL-18的表达及临床意义

目的 探讨白细胞介素(IL)-10、IL-18在宫颈上皮内瘤变(CIN)及宫颈癌患者血清及组织中的表达及其临床意义.方法 收集108例(68例CIN、40例宫颈癌)患者的血液及临床组织标本,其中浸润性宫颈鳞状细胞癌(SCC) 40例,CIN Ⅰ期25例,CINⅡ～Ⅲ期43例,同时收集正常女性宫颈组织20例.通过酶联免疫吸附试验检测血清中IL-10和IL-18的表达,聚合酶链反应法检测宫颈组织中IL-10和IL-18的表达,第2代杂交捕获检测宫颈涂片中人乳头瘤病毒(HPV) DNA的表达情况,分析IL-10和IL-18表达与临床预后及HPV的关系.结果 IL-10和IL-18在正常对照组血清中的表达分别为(212.75±62.09)、(187.84 ±81.03) pg/ml,IL-10在CIN Ⅰ期、CINⅡ～Ⅲ期、SCC患者血清中的表达为(324.71 ±75.87)、(397.43±68.56)、(482.77±104.05) pg/ml;IL-18在CIN Ⅰ期、CINⅡ～Ⅲ期、SCC患者血清中的表达分别为(305.53±64.08)、(392.74±87.38)、(499.86±92.04) pg/ml,差异均有统计学意义(F=17.657,P=0.001;F =13.309,P=0.003).IL-10在正常对照组、CIN Ⅰ期、CINⅡ～Ⅲ期、SCC患者组织中的相对表达量分别为0.99 ±0.01、3.24 ±0.68、7.32 ±0.99、13.24±1.03;IL-18在正常对照组、CIN Ⅰ期、CINⅡ～Ⅲ期、SCC患者组织中的相对表达量分别为0.98±0.01、2.02±0.84、7.01±1.59、14.38±2.10;差异均有统计学意义(F=21.694,P=0.000;F=19.912,P=0.001).IL-10、IL-18的表达与HPV的感染呈正相关(r=0.696,P=0.001;r=0.852,P=0.001).高表达IL-10的患者其中位生存时间为9.74个月,较低表达者(24.47个月)明显缩短,差异有统计学意义(x2=21.363,P=0.001);高表达IL-18患者的中位生存时间为12.32个月,较低表达者(22.88个月)明显缩短,差异有统计学意义(x2 =7.457,P=0.006).结论 IL-10和IL-18在宫颈癌前病变及宫颈癌血清、组织中呈高表达,可作为早期预测宫颈病变的生物标志物.     

The balance of serum IL-18/IL-37 levels is disrupted during the development of oral squamous cell carcinoma

Growing evidences have demonstrated a pivotal role of chronic inflammation in oral squamous cell carcinoma (OSCC) through the modulation of inflammatory cells and cytokine production. IL-37 is newly discovered anti-inflammatory member of IL-1 family and can bind to IL-18 receptor to inhibit IL-18 (pro-inflammatory member of IL-1 family) function. Investigation on the balance of IL-18/IL-37 would provide new insights into the function of IL-1 family in OSCC. Thus, serum IL-18 and IL-37 levels of OSCC patients (n = 108), leukoplakia patients (n = 40), and healthy donors (n = 36) were collected to analyze the balance of IL-18 and IL-37, and also determine their diagnostic value and prognostic significance in OSCC. The results showed that OSCC patients had high IL-18 and low IL-37 levels in serum and peripheral blood mononuclear cell (PBMC). The ratio of IL-18/IL-37 in serum efficiently distinguished non-cancer individuals from OSCC patients (cut off value: 2.15). Moreover, patients with high IL-18 and low IL-37 were susceptible to develop advanced tumor stage and lymph node metastasis (Odd ratios of IL-18/IL-37 is 4.903 and 12.613, respectively). Meanwhile, higher IL-18/IL-37 ratio could predict shorter overall survival and disease-free survival of OSCC patients, although it was not an independent prognostic factor. We further analyze the correlations of serum IL-18/IL-37 with immunocytes in peripheral blood and found that high IL-18 level was associated with more CD19⁺ B cells, while serum IL-37 seem to be associated with reduced percentage of CD3⁺CD8⁺ T cells, indicating its balance could change the adaptive immune response. Unexpectedly, we first revealed the different function of IL-18/IL-37 in serum and tumor tissues. High mRNA expression of IL-18 in tumor tissues correlated with low lymph node metastasis rate and low tumor stage, which was contradictory to the pro-tumor role of IL-18 in serum. In conclusion, enhanced ratio of IL-18/IL-37 level in serum could be an efficient biomarker for OSCC. Its balance might regulate CD19⁺ B cells and CD3⁺ CD8⁺ T cells for OSCC progression.     

Preoperative serum interleukin-18 level as a postoperative prognostic marker in patients with gastric carcinoma

BACKGROUND: Interleukin-18 (IL-18), a recently described cytokine produced mainly by macrophages, stimulates interferon-gamma (IFN-gamma) production by natural killer cells and T cells. Although it has been reported that serum IL-18 levels are higher in patients with advanced tuberculosis and acute graft-versus-host disease compared with normal controls, the authors found no reports regarding serum IL-18 levels in patients with malignant solid tumors. The purpose of this study was to determine serum IL-18 levels and their clinical significance in patients with gastric carcinoma. METHODS: Peripheral blood samples were obtained from 94 patients with gastric carcinoma who underwent curative surgery and from 50 healthy volunteers. The serum IL-18 level, the IFN-gamma, level, and the Helicobacter pylori (HP) serology status were determined in each sample with an enzyme-linked immunosorbent assay. RESULTS: The mean serum IL-18 level for all patients was significantly higher compared with the mean level in healthy volunteers (P < 0.01). IFN-gamma titers were below the level of detection in all samples tested. When the patients were subdivided into groups, it was found that the serum IL-18 level in patients with Stage II and III disease was significantly higher compared with the level found in healthy volunteers (P < 0.01). The serum IL-18 level decreased after patients underwent surgical resection. However, there was no significant difference in the serum IL-18 level between healthy controls and patients with Stage I or IV disease. Patients with IL-18 levels >or= 310 pg/mL (i.e., equal to or greater than the mean levels +/- 1 standard deviation in the healthy volunteers) experienced a significantly lower survival rate compared with patients who had IL-18 levels < 310 pg/mL after undergoing surgery (P < 0.05) despite a lack of any discernible difference in clinicopathologic factors between the two groups. The serum IL-18 level was identified as an independent postoperative prognostic factor in multivariate survival analysis using a Cox proportional hazards model (hazard ratio, 4.89; P = 0.01). There was no significant correlation between HP serology status and serum IL-18 levels. CONCLUSIONS: The preoperative serum IL-18 level may represent a significant postoperative prognostic determinant in patients with gastric carcinoma. Its function in the host immune system remains to be elucidated.     

血清白细胞介素18在前列腺癌患者中的临床价值

Objective: To determine serum interleukin-18 (IL-18) levels and their clinical significance in patients with prostate cancer. Methods: Peripheral blood samples were obtained from 38 nonmetastatic and 18 metastatic prostate cancer patients who underwent curative surgery and from 25 healthy volunteers. The serum IL-18 level was determined in each sample with the enzyme-linked immunosorbent assay. Results: The levels of serum IL-18 were increased significantly in prostate cancer patients compared with control subjects (P ＜ 0.05). Serum IL-18 levels were significantly higher in the metastatic patients compared with the nonmetastatic patients (P ＜ 0.01). Patients with bone metastasis had higher serum IL-18 levels compared with patients with liver and lung metastasis (P ＜ 0.01). When the patients were subdivided into groups, it was found that the serum IL-18 levels in patients with T2, T3 and T4 stage were significantly higher than that of T1 stage patients (P ＜ 0.01). Patients with IL-18 levels ≥ 316 pg/mL experienced a significantly lower survival rate compared with the patients who had IL-18levels ＜ 316 pg/mL after undergoing surgery (P ＜ 0.05). The serum IL-18 level was identified as an independent postoperative prognostic factor in multivariate survival analysis using a Cox proportional hazards model (hazard ratio, 4.21; P = 0.02).Conclusion: The serum IL-18 level may be a useful marker in monitoring prostate cancer patients. IL-18 activity in prostate cancer patients with bone metastasis may be more valuable in the follow-up.     

Serum Levels of G-CSF and IL-7 in Iranian Breast Cancer Patients

Introduction: Breast cancer cells and tumor stroma produce different cytokines and soluble factors. Cytokines,while playing crucial roles in immune responses to tumors, also favour tumor growth and progression. IL-7and G-CSF are two cytokines that may exert influences on the pathophysiology of breast cancer. Materials andMethods: Sera were collected from 136 females with breast cancer before receiving chemotherapy or radiotherapy.The control group comprised of 60 healthy age-matched females without any acute or chronic diseases withno family history of breast cancer. Serum levels of IL-7 and G-CSF were measured by commercial enzymelinked immunosorbent assay. Results: While there was no significant difference in the level of G-CSF betweenpatients (92.81±594.54 pg/ml) and controls (0.00 pg/ml), G-CSF level in sera of patients with advanced stagesof breast cancer was elevated compared to early stages (p=0.0001). Moreover, the highest level of G-CSF wasseen in patients with N3 phase tumors (p=0.0001). IL-7 was slightly but not significantly higher in the controlgroup (0.04±0.11 pg/ml) in comparison with patients (0.02±0.10 pg/ml). Interestingly, a significant increase inthe level of IL-7 in patients with skin involvement was observed (p=0.001). Conclusion: Our results showed anelevation of G-CSF in sera of patients with advanced stages of tumor, while IL-7 elevation correlated with skininvolvement of breast cancer. IL-7 can be produced by keratinocytes in skin tissue and may be involved in thepathologic establishment of metastatic tumor cells in skin.     

Serum interleukin-10 levels in patients with advanced gastrointestinal malignancies

BACKGROUND: Interleukin-10 (IL-10) is a cytokine with immunosuppressive properties. In this study, the authors investigated the prognostic significance of IL-10 levels in the sera of 58 patients with advanced gastric or colorectal carcinoma. METHODS: IL-10 serum levels were measured before chemotherapy, on completion of chemotherapy, and at follow-up by means of a commercially available enzyme-linked immunoadsorbent assay kit. The results then were analyzed in comparison with other prognostic variables and a model predicting overall survival (OS) and time to disease progression (TTP) was generated. RESULTS: Elevated levels of serum IL-10 were found in carcinoma patients compared with healthy controls (19.6 +/- 6.8 pg/mL vs. 9.2 +/- 1.5 pg/mL; P < 0.0001), with those patients with metastatic disease showing significantly higher levels than patients with undisseminated disease (21.9 +/- 6. 7 pg/mL vs. 15.5 +/- 3.6 pg/mL; P = 0.0003). Retrospective analysis of prechemotherapy IL-10 serum levels showed a significant difference between responders and nonresponders (15.8 +/- 2.5 pg/mL vs. 21.6 +/- 7.6 pg/mL; P < 0.0001). Moreover, a further significant increase in IL-10 serum levels was observed in nonresponders at the end of therapy (21.6 +/- 7.6 pg/mL prechemotherapy vs. 31.3 +/- 11.6 pg/mL postchemotherapy; P < 0.0001) whereas no significant differences were observed in responders. Using univariate analysis, both OS and TTP were shown to be affected by the median pathologic levels of IL-10; multivariate analysis related to OS and TTP identified performance status and IL-10 serum level as the relevant prognostic factors, respectively. Finally, stepwise regression analysis identified IL-10 serum level and metastases as the prognostic factors related to both OS and TTP. CONCLUSIONS: The results of the current study show that measurement of pretreatment serum levels of IL-10 is of independent prognostic utility in patients with advanced gastrointestinal carcinoma and may be useful for the detection of disease progression.     

乳腺癌患者血清内IL-6和CCL-18的表达及临床意义

目的:定量检测乳腺癌患者血清内IL-6和CCL-18的表达,并分析其表达与临床病理因素的相关性,以评估IL-6和CCL-18作为乳腺癌诊断和预后指标的可行性。方法:ELISA定量检测来自于58名乳腺癌患者,41名乳腺良性肿瘤患者和30名健康人血清内IL-6和CCL-18的表达。Wlicoxon test检测各组间差异。结果:与健康组相比,肿瘤组IL-6和CCL-18表达水平明显升高,但与良性肿瘤组相比,肿瘤组CCL-18表达水平则处于边界值（P=0.05）。而良性肿瘤组与健康组相比,CCL-18和IL-6的表达水平均明显升高。此外,两种细胞因子的表达水平与病人年龄、肿瘤大小、组织学类型、淋巴结转移及组织学分级均无关。IL-6在ER阳性及发生转移的乳腺癌患者血清内表达明显升高,而CCL-18在晚期乳腺癌患者血清内表达明显升高。结论:IL-6和CCL-18可以用来区别乳腺癌患者和健康人群。IL-6的高度表达可能导致ER阳性乳腺癌患者预后较差,而CCL-18的表达与另一个预后参数Ki67的高表达相关。     

结直肠癌患者IL-35和IL-37水平表达与其病理学特征及预后的相关性

目的探讨结直肠癌术后患者白细胞介素35(IL-35)和白细胞介素37(IL-37)水平表达与其病理学特征及预后的相关性。方法选取60例结直肠癌患者作为研究对象,所有患者均行手术治疗,另取同期60例良性结直肠肿瘤手术患者进行比较分析,分析良性肿瘤患者与恶性肿瘤患者IL-35和IL-37水平表达。通过对60例结直肠癌患者的IL-35和IL-37检测,分析IL-35、IL-37水平与结直肠癌临床病理特征的关系,并分析其预后价值。结果与良性肿瘤患者相比,恶性肿瘤患者IL-35水平显著升高,IL-37水平降低(P<0.05);IL-37高表达与低表达的结直肠癌患者TNM分期、分化程度以及有无淋巴结转移情况具有明显差异(P<0.05)。Spearman相关分析结果显示:IL-35与结直肠癌TNM分期和淋巴结节转移均呈显著正相关,与分化程度呈显著负相关(P<0.05);IL-37与结直肠癌TNM分期和淋巴结节转移均呈显著负相关,与分化程度呈显著正相关(P<0.05);多因素分析显示:肿瘤侵袭深度和IL-35为结直肠癌患者术后生存预测的独立指标(P<0.05),其他因素分析对比无显著差异(P>0.05);单因素生存分析显示,TNM、肿瘤侵袭深度、淋巴结转移可作为结直肠癌患者预后预测指标(P<0.05),IL-35不可以作为结直肠癌患者预后预测指标(P>0.05)。结论IL-35和IL-37的水平表达与结直肠癌患者的疾病发展有着明显相关性,在预后相关性上,IL-35水平可能可以作为结直肠癌患者术后预测的独立指标。     

Serum soluble interleukin-2 receptor (IL-2R) and immunohistochemical staining of IL-2R/Tac antigen in colorectal cancer

Background: In the present study, we investigated the significance of serum soluble interleukin-2 receptor (IL-2R) as a tumor marker, and examined the existence and localization of cells positive for IL-2R/Tac antigen in colorectal cancer tissues and their regional lymph nodes. Methods: The study included 155 patients with colorectal cancer. Levels of serum soluble IL-2R were measured by an enzyme-linked immunosorbent assay. In the tissues obtained from 18 patients, immunohistochemical staining was performed, with the use of the avidin-biotin-peroxidase complex technique, in which mouse anti-human IL-2R antibody was used. Results: The preoperative levels of serum soluble IL-2R in patients with colorectal cancer were significantly higher than those of normal controls (P = 0.0065). The levels of serum soluble IL-2R in patients with metastatic lymph nodes were also significantly higher than the levels in those without metastatic lymph nodes (P = 0.0258). Concerning tumor markers, there were significant differences in serum soluble IL-2R levels between patients who were positive and those who were negative for carcinoembryonic antigen (CEA) and between these who were positive and those who were negative for immunosuppressive acidic protein (IAP). In the immunohistochemical staining of IL-2R, 16 of the 18 patients (88.8%) showed IL-2R-positive cells in the colorectal cancer tissues. In regard to the metastatic lymph nodes, all of 5 patients (100%) showed IL-2R-positive cells. On the other hand, IL-2R-positive cells were not recognized in normal colorectal tissues and non-metastatic lymph nodes. Conclusion: These results suggest that activated T lymphocytes infiltrating into cancer tissues to play an antitumor role may release a large amount of the α-chain of IL-2R, resulting in the high levels of serum soluble IL-2R in patients with colorectal cancer. Received: October 18, 2001 / Accepted: June 12, 2002 Acknowledgments This study was supported in part by a Grant-in Aid for Scientific Research (11671269) from the Japanese Ministry of Education, Science, and Culture. Correspondence to:S. Murakami     

Trends of IL-6 and IL-8 levels in patients with recurrent breast cancer: preliminary report

BACKGROUND: We reported that IL-6 and IL-8 levels at the beginning of treatment are predictive indicators of response to therapy and prognosis of patients with recurrent breast cancer. The aim of this study was to investigate the trend of IL-6 and IL-8 levels in heavily pretreated patients with recurrent breast cancer. METHODS: Cytokine level trends in 12 patients heavily pretreated with anthracyclines were studied. Patients were divided into two groups according to the objective response. There were 5 partial response (PR)/no change (NC), and 7 progressive disease (PD) patients. Blood was taken every four weeks. IL-6 was measured by chemiluminescent enzyme immunoassay. IL-8 was measured by ELISA. RESULTS: The pretreatment level of IL-6 in the PR/NC group (11.0+/-2.1 pg/ml) was significantly lower than that (15.3+/-2.7 pg/ml) in the PD group. However, there was no difference in IL-8 level between the PR/NC group (12.5+/-5.5 pg/ml) and the PD group (11.5+/-1.1 pg/ml). IL-6 levels in the PR/NC group were maintained within normal levels or decreased to within normal levels after treatment, while levels of IL-6 in the PD group gradually increased until the time of patient death. A decrease in IL-8 level after treatment was observed in only one patient in the PR/NC group. Mild increase of IL-8 levels was observed in the PD group. CONCLUSION: Continuous elevation of IL-6 levels indicates poor prognosis in heavily pretreated patients with recurrent breast cancer. Combination therapy including agents that reduce IL-6 levels will be a new strategy for aggressively treating recurrent breast cancer.     

Th1 cytokine pattern (IL-12 and IL-18) in bronchoalveolar lavage fluid (BALF) before and after treatment with interferon gamma-1b (IFN-gamma-1b) or colchicine in patients with idiopathic pulmonary fibrosis (IPF/UIP)

BACKGROUND AND AIM: Characterization of the biologic effects of Th1 cytokines will enhance the understanding of idiopathic pulmonary fibrosis (IPF) pathogenesis and treatment selection. Th1 response is characterized by increased expression of IFN-gamma, interleukin (IL)-12 and IL-18. The present study aims to evaluate the role of Th1 cytokines and their possible changes in the bronchoalveolar lavage fluid (BALF), before and after treatment with IFN-gamma-1b or colchicine. PATIENTS AND METHODS: We studied prospectively 10 patients (8 male, 2 female) of median age 67 yr with histologically confirmed IPF/UIP. Patients were randomly assigned to receive either IFN-gamma-1b 200 microg sc (5 patients) or colchicine 1 mg qd (5 patients) plus prednisone 10 mg qd. BALF IL-12 and IL-18 levels were measured before and after treatment. RESULTS: BALF IL-12 levels before and after treatment did not differ significantly between the two treatment groups. However, BALF IL-18 levels were significantly decreased after treatment with IFN-gamma-1b (mean +/- SD, 58.4 +/- 15.6 pg/mL vs 42.8 +/- 4.90 pg/mL, p < 0.05). A significant difference was also found after treatment with colchicine (mean +/- SD, 66.8 +/- 36.9 pg/mL vs 42.6 +/- 1.08 pg/mL, p < 0.01). A significant correlation was found between IL-18 BALF levels and the BALF neutrophils (r = 0.75, p = 0.024). CONCLUSION: Our data suggest the potential role of IL-18 as an inflammatory marker in the pathogenetic pathway of IPF such as its possible downregulation by IFN-gamma-1b treatment. Further studies are needed in a higher number of patients in order to define the precise role of both cytokines during the immunoregulatory response with IFN-gamma-1b.     

Serum IL-6 and Micrometry of Pap Smears in Women with Cervical Low-Grade Intraepithelial Lesions

Objective: To assess serum IL-6 in women with or without low-grade squamous intraepithelial lesions (LSILs) in Pap smears and correlate with the nucleo/cytoplasmic (N/C) ratio. Methods: Manual micrometry was carried out on Pap smears for N/C ratios: Group A, negative findings (N=15); Group B, inflammation without abnormality (N=14); Group C, LSIL with inflammation (N=13). Serum IL-6 was measured in Groups B and C after treatment of nonviral genital infections. Women with pelvic inflammatory or systemic diseases were excluded. Results: The N/C ratio was significantly higher in Group C vs Group B , both before and after treatment of nonviral infections and also vs group A (p < 0.001, Students t test). After treatment for non-viral infections serum IL-6 levels were >50pg/ml in 5/13 cases of Group C and significantly higher than levels in Group B (p<0.05), correlating positively with the N/C ratio in the 13 cases of LSIL (Pearson’s coefficient r=0.659, p<0.05). Conclusions: High peripheral circulating level of IL-6, despite prior treatment of nonviral infections, was observed in more than one third of women with persistent LSIL in Pap smears, and may serve as an additional biomarker for early cervical neoplasia. Long term follow up is indicated.     

Serum interleukin-6 level but not genotype predicts survival after resection in stages II and III gastric carcinoma

PURPOSE: It has been suggested that interleukin-6 (IL-6) is a prognostic indicator for survival in patients with gastric carcinoma, but this has not been proved using survival analysis. In Asians, the -634G allele is associated with increased IL-6 production. The objective of this study was to evaluate the association between serum IL-6 levels, -634G/C polymorphism, and overall survival after resection for gastric carcinoma. EXPERIMENTAL DESIGN: A total of 155 consecutive patients with gastric carcinoma were evaluated. Serum IL-6 levels were analyzed using an enzyme-linked immunoabsorbent assay. Genotype was determined by PCR and restriction fragment length polymorphism. Serum levels and survival were correlated with genotype and clinicopathologic factors. RESULTS: Age and stage, but not -634G/C genotype, were associated with serum IL-6 levels. The median survival for patients with stage II or stage III gastric carcinoma was 1,418 days in patients with low (< or =13 pg/mL) versus 618 days in patients with high (>13 pg/mL) serum IL-6 levels (P = 0.038). Results of a multivariate analysis showed that serum IL-6 level of >13 pg/mL was a significant predictor of poor survival (hazard ratio, 1.77; 95% confidence interval, 1.07-2.92; P = 0.026). CONCLUSIONS: Serum IL-6 level of >13 pg/mL correlates with tumor progression and is an independent predictor of poor survival after resection. In patients with stage II and III gastric carcinoma, serum IL-6 level is more effective than stage as a prognostic indicator. By measuring IL-6, these patients can be divided into two groups with significant differences in survival. The -634G/C polymorphism is not associated with serum IL-6 level or survival.     

Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients

Serum and plasma concentrations of vascular endothelial growth factor (sVEGF and pVEGF), serum concentrations of interleukin 6 (IL-6), and VEGF platelet load (VEGF/pl) in the blood of healthy controls (n = 26), breast cancer patients with locoregional disease (n = 31), and patients with progressive advanced disease (n = 73) have been compared. The 95th percentile values for the control population were 250 pg/mL for sVEGF, 30 pg/mL for pVEGF, and 1.6 pg/mL for IL-6. The 95th percentile value of the calculated VEGF/pl was 1.0 pg/10(6) platelets in the control population. Serum VEGF concentrations correlated with platelet number in all the groups. Patients with thrombocytosis had a median sVEGF concentration of 833 pg/mL, compared to 249 pg/mL in other patients (P = 0.018). Serum IL-6 levels correlated with sVEGF levels and with the calculated VEGF/pl. Serum IL-6 concentration was significantly higher in patients with breast cancer compared to healthy controls (P < 0.0001). Median IL-6 serum levels were nearly 10 times higher in patients with metastatic breast cancer as compared to the those with locoregional disease (6.0 pg/mL versus 0.7 pg/mL, respectively). Plasma VEGF and the VEGF/pl were also significantly different in the 3 groups. The ratio between sVEGF and pVEGF tended to be smaller in the metastatic breast cancer group compared to the patients with locoregional disease (median, 7.5 versus 10.1, respectively; P = 0.066), suggestive of more intravasal platelet degranulation in the former group. Serum IL-6 level is the most discriminative factor separating healthy controls and the locoregional and metastatic breast cancer patient groups. These results suggest a role for tumor-derived IL-6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF.     

IL-2、IL-6及TNF-α在结外NK/T细胞淋巴瘤鼻型患者血清中的表达及临床意义

背景与目的：结外NK/T细胞淋巴瘤鼻型(extranodal NK/T-cell lymphoma,nasal type,ENKTL)属于非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)的一种少见类型,在亚洲国家发病率较欧美国家强。该病侵袭性强,发病机制至今仍尚未明确,但其与EB病毒(epstein-barr virus,EBV)感染密切相关。到目前为止ENKTL尚无标准治疗指南,其治疗效果不佳,患者预后极差,因此,探索ENKTL的发病机制势在必行。本研究探讨ENKTL患者血清中白细胞介素-2(interleukin,IL-2)、白细胞介素-6(interleukin-6,IL-6)和肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)表达水平及其临床意义。方法：通过Luminex液相芯片技术检测67例ENKTL患者及26名正常人血清中的IL-2、IL-6和TNF-α的表达水平。结果：ENKTL患者血清中IL-2、IL-6和TNF-α的表达水平分别为(564.1±387.6)、(293.3±191.6)和(181.3±91.8)pg/mL;正常人血清中的IL-2、IL-6和TNF-α的表达水平分别为(1 097.0±365.7)、(417.5±289.6)和(291.3±89.4)pg/mL。和正常人相比,ENKTL患者血清中IL-2、IL-6和TNF-α的表达水平明显降低,差异有统计学意义(P<0.05)。进一步研究表明,经化疗达到完全缓解(complete response,CR)的5例ENKTL患者血清中TNF-α水平明显高于初治患者,分别为(162.7±10.3)和(125.2±7.3)pg/mL,差异有统计学意义(P<0.05)。结论：IL-2、IL-6和TNF-α在ENKTL患者血清中的表达水平降低,并且TNF-α的表达水平与化疗疗效密切相关。     

IL-17R deletion predicts high-grade colorectal cancer and poor clinical outcomes

The IL-17 receptor (IL-17R) has a perplexing role in cancer, which may be explained by its yin-yang signaling pathways. Recently, the critical role of IL-17R in maintaining basal levels of A20—a key negative regulator of NF-κB and JNK-c-Jun pathways has been demonstrated in cancer cell lines. Cross-cancer analyses of somatic copy number alterations in IL-17RA, IL-17RC and A20 genes reveal that IL-17RA-deletion is common in colorectal cancer (CRC) patients, representing 24, 26, 37 and 49% of stage I, II, III and IV of patients, respectively, and mutually exclusive with patients displaying microsatellite instability. Importantly, patients with IL-17R-deletion or concurrent deletions of A20 show significantly reduced overall survival. Analysis of multiple published microarray studies confirms that IL-17RA expression is significantly reduced in CRC samples compared to normal counterparts, and its level is closely associated with A20 expression. Analyses of RNAseq data indicate that tumors with IL-17R-deletion express strong molecular markers of tumor invasion, growth and metastasis. Notably, approximately 20 genes responsible for protein synthesis and mitochondrial metabolism are inversely correlated with both IL-17RA and A20. Immunohistochemistry staining in human colorectal tissue arrays further reveals that high-grade tumors have significantly reduced IL-17RA staining compared to low-grade tumors. Thus, collective evidence strongly supports a previously unrecognized CRC-promoting mechanism triggered by IL-17RA-deletion and highlights its utility as a prognostic marker in CRC.