血清细胞角蛋白19片段检测对肺癌的临床意义

目的确定我国肺癌患者血清细胞角蛋白１９片段（ＣＹＦＲＡ２１－１）浓度阈值，探讨其临床应用价值。方法应用单克隆抗体（Ｋｓ１９．１和ＢＭ１９．２１）检测７２例初次确诊肺癌患者和５０例肺良性疾病患者以及３３例治疗后肺癌患者血清ＣＹＦＲＡ２１－１水平。采用ＲＯＣ曲线确定ＣＹＦＲＡ２１－１浓度阈值。结果（１）肺癌患者血清ＣＹＦＲＡ２１－１水平显著高于肺良性疾病患者（Ｐ＜０．００１），鳞癌显著高于其它病理类型，且其浓度随临床分期升高而升高。（２）当阈值定为５．５μｇ／Ｌ时，ＣＹＦＲＡ２１－１检测肺癌的敏感性、特异性分别为６３％和９４％。鳞癌敏感性最高为７８％。（３）ＣＹＦＲＡ２１－１检测非小细胞肺癌的敏感性随临床分期升高而升高。（４）ＣＹＦＲＡ２１－１是监测肺癌病情、提示疗效的良好指标。（５）当ＣＹＦＲＡ２１－１作为筛检肺癌的指标时，阈值宜取非小细胞肺癌Ｉ－ＩＩ期ＲＯＣ曲线拐点，但对非小细胞肺癌早期诊断作用有限。结论ＣＹＦＲＡ２１－１是一较好的非小细胞肺癌肿瘤标记物，尤其适用于肺鳞癌     

Development and verification of a prediction model using serum tumor markers to predict the response to chemotherapy of patients with metastatic or recurrent breast cancer

Purpose  The aim of this study was to develop a prediction model using serum tumor markers to predict the response to chemotherapy of patients with metastatic or recurrent breast cancer. Methods  We retrospectively analyzed a training set of 105 patients with metastatic or recurrent breast cancer. Their chemotherapeutic response had been evaluated according to the World Health Organization (WHO)’s response criteria. Our model for predicting response using carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 15-3, and NCC-ST-439 was determined using the area under the receiver operating characteristic curve (ROC-AUC) and the overall misclassification rate (OMR) in a random cross-validation. The prediction model was then verified in a consecutive set of 64 patients. Their response had been evaluated using the response evaluation criteria in solid tumors (RECIST) criteria. Results  The best prediction model consisted of the serum CEA, CA15-3, and NCC-ST-439 levels, but the prediction formula varied according to the baseline CA15-3 level (elevated or normal). The overall ROC-AUC and OMR in the training set were 0.83 and 0.19, respectively. The overall ROC-AUC and OMR in the verification set were 0.72 and 0.28, respectively. When the verification set was stratified according to either the objective response or the predicted response, the time-to-progression, but not the overall survival, was significantly different. Conclusion  Our model for predicting the response to first-line chemotherapy of patients with metastatic or recurrent breast cancer may be valid because it predicted the outcome of more than 70% of the patients in an independent verification set.     

Serum KL-6 as a novel tumor marker for hepatocellular carcinoma in hepatitis C virus infected patients.

The up-regulation of MUC1 protein is associated with malignant phenotype of cancer. We investigated the significance of KL-6, one of the MUC1 antigens, as a tumor marker in hepatitis C virus positive hepatocellular carcinoma (HCC). Serum KL-6 was determined in 203 patients with chronic hepatitis (CH), 47 patients with liver cirrhosis (LC) and 78 patients with HCC. KL-6 was higher in HCC compared to non-HCC (p=0.0005) and was higher in patients with multiple HCC nodules compared to a single nodule (p=0.02). There was no correlation between KL-6 and existent tumor markers for HCC such as alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein or des-gamma-carboxyprothrombin. In the prospective analysis, the cumulative incidence of HCC was significantly greater in CH and LC patients with high initial KL-6 (above 400U/ml) compared to the others (p=0.02). Moreover, in the prospective observation of 25 patients whose HCC was completely cured by radiofrequency ablation therapy, the cumulative incidence of distant recurrences was significantly greater in patients with high initial KL-6 compared to the others (p=0.005). These results suggest that serum KL-6 could be a novel tumor marker in the diagnosis and the prediction of prognosis of HCC that may have additive value to the existent markers.     

CEA (carcinoembryonic antigen): Its role as a marker in the management of cancer

Summary A Consensus Development Conference was held at the National Institutes of Health from September 29-October 1, 1980, to address issues concerning the role of carcinoembryonic antigen (CEA) as a marker in the management of cancer. The panel met following formal presentations and discussions to assess the issues based on the evidence presented. These issues included: Should CEA be used in cancer screening? Is CEA helpful in cancer diagnosis? What does CEA tell about the extent and outcome of cancer? Is CEA helpful in monitoring cancer treatment? This paper constitutes the panel's findings.The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author. The EditorsThis paper is the official report of the panel members, listed above, resulting from the National Institutes of Health Consensus Development Conference on CEA (Carcinoembryonic Antigen): Its Role as a Marker in the Management of Cancer. This consensus conference was sponsored by the National Cancer Institute, assisted by the Office for Medical Applications of Research, Office of the Director, National Institutes of Health, Bethesda, MD, USA. The conference was organized by Dr. K. R. McIntire and Mr. L. P. Greenberg, Diagnosis Branch, National Cancer Institute, Bethesda, MD     

肿瘤标志物对肺癌分期和骨转移诊断的价值

目的探讨肿瘤标志物癌胚抗原（CEA）、细胞角蛋白19的片段（CYFRA21—1）、神经稀醇酶（NSE）、糖类抗原（CA153）血清水平对肺癌分期及肺癌骨转移的辅助诊断价值。方法检测206例肺癌患者血清4种标志物水平,比较各期肺癌之间、骨转移组和无骨转移组之间的肿瘤标志物表达水平和阳性率的差异。结果骨转移组4项标志物水平均高于无骨转移组（P均〈0．05）;肺癌分期越晚,4项标志物阳性率越高;4项联检时灵敏度、准确率等均优于单项检查。结论肿瘤标志物水平的检测对肺癌骨转移的诊断、肺癌分期（特别是肺癌后期）诊断有辅助价值,联合检查优于单项检查：     

肺癌血清肿瘤标志物的研究现状

血清肿瘤标志物的检测,对肺癌的早期诊断、组织学分型、临床分期、预后判断和疗效监测都具有重要应用价值.本文对癌胚抗原、细胞角蛋白19片段、胃泌素释放肽前体、基质金属蛋白酶和肿瘤M2型丙酮酸激酶等肺癌相关血清肿瘤标志物的研究现状作一综述.     

Circulating soluble cytochrome c in liver disease as a marker of apoptosis

OBJECTIVES: To measure levels of soluble cytochrome c, a clinical marker of apoptosis in patients with liver disease; determine whether soluble cytochrome c is derived from the liver; and correlate soluble cytochrome c level with histology and disease activity. DESIGN: Laboratory research study with comparison group. SETTING: Liver Institute, at the Rabin Medical Center, Israel, and In Vitro Toxicology Laboratory, Canada. SUBJECTS: A total of 108 patients with liver disease and 30 healthy controls. INTERVENTIONS: Paired hepatic and portal vein samples were taken via the transjugular vein in patients after liver biopsy and transjugular intrahepatic portacaval shunt, and bile from patients with external biliary drainage. Soluble cytochrome c was measured with an enzyme-linked immunosorbent assay in peripheral blood. Apoptotic cells in liver tissue were identified by morphological criteria and quantitated with the dUTP nick-end-labelling (TUNEL) assay. MAIN OUTCOME MEASURES: Soluble cytochrome c level by type of liver disease by clinical and histological findings. RESULTS: Soluble cytochrome c concentration (mean 187.1 +/- 219.5 ng x mL(-1)) was significantly higher in patients with liver disease than in controls (39.8 +/- 35.1 ng x mL(-1); P = 0.0001), with highest levels in the primary sclerosing cholangitis group (mean 1041.0 +/- 2844.8 ng x mL(-1); P = 0.001). Cytochrome c levels were correlated with serum bilirubin, alkaline phosphatase, creatinine levels, necroinflammatory score and apoptotic index, but not with serum alanine aminotransferase and synthetic liver function tests. In the 16 paired samples, soluble cytochrome c level was higher in the hepatic (mean 267.9 +/- 297.0 ng x mL(-1)) than the portal vein (mean 169.2 +/- 143.3 ng x mL(-1)), and it was highly detectable in bile (mean 2288.0 +/-4596.0 ng x mL(-1)) (P = 0.001). Untreated patients with chronic viral hepatitis (B and C) had significantly higher levels (mean 282.8 +/-304.3 ng x mL(-1)) than treated patients (77.9 +/- 35.8 ng x mL(-1); P = 0.001). CONCLUSIONS: Soluble cytochrome c levels are increased in different types of liver disease. Soluble cytochrome c is probably derived from the liver and secreted into the bile. Levels correlate with the apoptotic index and are affected by antiviral treatment. Soluble cytochrome c may serve as a serum marker of apoptosis.     

Neuron-specific enolase in medullary thyroid carcinoma: immunohistochemical demonstration,but no significance as serum tumor marker

Summary Neuron-specific enolase (NSE) is an enzyme detectable in nervous and neuroendocrine tissue. Increased serum levels of NSE are found in small cell lung cancer and in patients with neuroblastoma, in whom NSE is used as a serum tumor marker. We have investigated 32 patients with histologically proven medullary thyroid carcinoma, a tumor of neuroendocrine origin, in which the classical tumor marker calcitonin (CT) was pathologically elevated. Positive immunocytochemistry for NSE and CT in C-cells was obtained in all cases. Increased serum NSE levels were found in only 5 of 32 patients, there was no correlation between NSE and CT concentrations. We also compared NSE and CT serum levels during long-term follow-up and again found no correlation between NSE and CT. After i.v. stimulation tests with pentagastrin and calcium, no correlation was found between NSE and CT serum levels. We conclude, therefore, that in medullary thyroid carcinoma NSE is useful for immunocytochemistry but not a reliable serum tumor marker.This study was supported by Tumorzentrum Heidelberg/Mannheim; Schwerpunkt Schilddrüsencarcinom.     

食管癌血清肿瘤标志物诊断价值的研究

为探讨肿瘤标志物联合检测在食管癌诊断中的临床意义,分别用酶免法（EIA）、酶法、高效液相色谱法（HPLC）等测定了49例食管癌及272例非肿瘤患者的29种血清肿瘤标志物,应用特异性、阳性预期值、敏感性、阴性预期值、总有效率、5项平均值6个指标综合评价各种肿瘤标志物的价值。结果29种肿瘤标志物中,平均排序前6位的是糖类抗原242（CA^242)、精眯（SPM）、腐胺（PU）、肿瘤相关物质群（TSGF）、谷胱甘肽转移酶（GST）、角蛋白－19（CYFRA211）,TSGF、GST和癌胚抗原（CEA）的敏感性为84．62％。其中前二项敏感性为75．51％,三项中任一项阳性所致的特异性为48．68％。提示TSGF、GST、CEA联合检测对食管癌诊断有实用价值。     

克山病人心肌细胞色素氧化酶的性质研究

本文对一例慢型克山病和一例亚急型克山病人心肌线粒体进行了还原氧化差光谱分析和细胞色素氧化酶动力学研宄。结果表明,克山病人细胞色素 aa_3吸收峰向短皮方向偏移,峰形有所改变。酶动力学参数 Km_1、Km_2,Vm_1、Vm_2均明显低于正常对照。说明克山病人心肌细胞色素氧化酶活性不仅有量的减少,而且酶分子本身催化功能也有改变。这些工作从酶的稳态动力学角度为克山病心肌坏死提供了分子损害的证据。     

Assessment of KL-6 as a tumor marker in patients with hepatocellular carcinoma

AIM: To investigate the clinical significance of KL-6 as a tumor marker of HCC in two different ethnic groups with chronic liver disease consecutively encountered at outpatient clinics. METHODS: Serum KL-6 was measured by the sandwich enzyme immunoassay method using the KL-6 antibody (Ab) as both the capture and tracer Ab according to the manufacturer's instructions (Eisai, Tokyo, Japan). Assessment of alpha fetoprotein (AFP) and protein induced vitamin K deficiency or absence (PIVKA-Ⅱ) was performed in both groups using commercially available kits. RESULTS: A significantly higher mean serum KL-6 (556±467 U/L) was found in HCC in comparison with non-HCC groups either with (391±176 U/L; P<0.001) or without (361±161 U/L; P<0.001) liver cirrhosis (LC). Serum KL-6 level did not correlate with either AFP or PIVKA-Ⅱ serU/Levels. Using receiver operating curve analysis for KL-6 as a predictor for HCC showed that the area under the curve was 0.574 (95%CI = 0.50-0.64) and the KL-6 level that gave the best sensitivity (61%) was found to be 334 U/L but according to the manufacturer's instructions; a cut-off point of 500 U/L was used that showed the highest specificity (80%) in comparison with AFP and PIVKA-Ⅱ (78% vs 72% respectively). Combining the values of the three markers improved specificity of AFP for HCC diagnosis from 78% for AFP alone; 93% for AFP plus PIVKA-Ⅱ to 99% for both plus KL-6 value (P<0.001). Mean serum alkaline phosphatase level was significantly higher in KL-6 positive (564±475) in comparison with KL-6 negative (505±469) HCC patients (P = 0.021), but such a difference was not found among non-HCC corresponding groups. CONCLUSION: KL-6 is suggested as a tumor for HCC. Its positivity may reflect HCC-associated cholestasis and/ or local tumor invasion.     

Characterization of adducts of ethanol metabolites with cytochrome c

Cytochrome c (cyt c) is found in the mitochondria of all mammalian cells where hydrogen peroxide is produced as a byproduct of the electron transport chain. In the presence of peroxide cyt c generates a ferryl heme and radicals at Tyr residues (Barr et al., 1996). These radicals can be transferred to Trp residues within the protein or to Tyr- and Trp-containing peptides (Deterding et al., 1998). We report that addition of ethanol to this system of cyt c plus peroxide results in replacement of the Tyr/Trp radicals by 1-hydroxyethyl radicals (HER), and covalent binding of up to 10 mol of ethanol per mol of cyt c. In the absence of exogenously added peroxide, ethanol incorporation to cyt c is attained also with a reconstituted system of the ethanol-inducible cytochrome P-4502E1 isozyme. Comparative studies with myoglobin and apomyoglobin suggest that the heme is necessary for ethanol adduction of the protein to occur. Structural analysis by mass spectrometry of the tryptic digestion fractions of adducted cyt c is consistent with several peptides bearing one-to-three acetaldehyde moieties on Lys residues, and three distinct Tyr/Trp-containing peptides: P[28-53], P[56-73], P[73-91] carrying one-to-two HER. The x-ray crystallographic structure of cyt c shows that the Tyr/Trp residues in the adducted peptides are in close proximity to the heme. In conclusion, our data show that ethanol metabolites alkylate cyt c under oxidative stress and point to HER-Tyr/Trp adducts as plausible markers of alcoholism.     

肿瘤标志物在肺癌引起胸腔积液诊断中的应用进展

胸腔积液是一个常见的临床表现.其良恶性的判断与治疗、预后密切相关.许多方法和指标都曾尝试用于恶性胸腔积液的诊断,各有利弊.随着分子生物学和实验技术的迅速发展,新的诊断指标和检测方法不断涌现.肿瘤标志物包括肿瘤相关抗原,肿瘤相关蛋白等,对于肺癌引起的胸腔积液的鉴别诊断具有重要的意义.     

Formation of malondialdehyde adducts in livers of rats exposed to ethanol: role in ethanol-mediated inhibition of cytochrome c oxidase

BACKGROUND: Previous studies in our laboratory demonstrated that short-term ethanol consumption by maternal rats increased the hepatic levels of 4-hydroxynonenal (HNE) in both the adult and the fetus. Additionally, HNE inhibited cytochrome c oxidase (COX) by forming adducts with the enzyme subunits. The present study examined modification of COX by another major aldehydic lipid peroxidation product, malondialdehyde (MDA), and its role in COX inhibition by ethanol. METHODS AND RESULTS: It is demonstrated in vitro that MDA inhibits the activity of purified COX while forming adducts with the enzyme. Compared with HNE, MDA is a more potent inhibitor of COX. Overnight incubation at room temperature caused an 80% decrease in COX activity by MDA versus a 67% decrease by HNE. MDA produced marked inhibition of COX activity at physiologically relevant concentrations, e.g., 43% inhibition at 10 microM. Although our previous studies documented that HNE formed adducts primarily with subunit IV of COX via histidine residues, the current report showed that MDA forms adducts with both subunit IV and subunit V via lysine residues. Furthermore, both aldehydes induce carbonyl formation in subunit IV. The in vivo role of MDA in the impairment of COX by ethanol is assessed in both adult and fetal liver after maternal ethanol consumption. CONCLUSIONS: The results showed that: (1) there are significant increases in MDA levels in liver homogenate as well as mitochondria in both adult and fetal livers after ethanol exposure; (2) these MDA levels are in the nanomole/mg protein range, in contrast to picomole/mg protein range of HNE in identical setting; and (3) ethanol-induced production of MDA is accompanied by enhanced formation of MDA adducts with COX. These findings suggest that MDA may play at least as equally an important role as HNE in ethanol-induced inhibition of COX.     

肺癌患者血清中血管生成素-2水平及其临床意义

目的 通过检测肺癌患者血清中血管生成素-2（Ang-2）水平并进行分析.方法 检测90例肺癌患者、60例良性肺部疾病患者和102名健康体检者血清Ang-2水平,并进行比较分析.结果 肺癌组血清Ang-2水平明显高于良性肺疾病组和健康对照组 （P〈0.05）;随病程进展肺癌患者Ang-2的阳性率逐步升高,肺癌Ⅲ、Ⅳ期患者Ang-2阳性率（82.8% 、87.5%）明显高于Ⅰ、Ⅱ期患者（46.2%、56.5%）（均P〈0.05）;有淋巴结转移的患者Ang-2阳性率（79.2%）明显高于未转移患者（38.9%）（P〈0.05）.Ang-2诊断肺癌的灵敏度为71.0%,特异性为97.5%,准确性为 88.1%.结论 Ang-2对肺癌的辅助诊断有一定的临床价值,可以作为一项新的肺癌标志物应用.     

Tumor budding as a prognostic marker in stage-III rectal carcinoma

Background and aim Tumor budding along the invasive margin is known to be associated with biological behavior in colorectal carcinoma. The aims of this study were to explore if the semiquantitative assessment of tumor budding in rectal cancers correlates with oncological behavior and to appraise if the tumor budding is valid as a pathological parameter in distinguishing tumors with higher malignancy potential from those with lower one for prognostic stratification. Materials and methods Surgical specimens from 244 patients with well- or moderately differentiated rectal carcinoma were retrieved to assess the intensity of tumor budding at the invasive margin. Intensities were divided semiquantitatively into four groups based on quartiles, and the 5-year disease-free survivals (DFS) were analyzed to search for a cutoff point of prognostic stratification. Results The cutoff of the intensity considered to be the best indicator for dividing patients into subgroups with different DFS was between quartiles 3 and 4, but this survival difference in subgroups in either side of the cutoff was significant only in stage-III disease [5-year DFS, 62.1 vs 35.1%; p = 0.0023; 95% confidence interval (CI), 0.1824–0.6919]. Based on multivariate analysis, the intensity of budding proved to be an independent variable associated with DFS (hazard ratio, 2.005; p = 0.0086; 95% CI, 1.021–3.934). When scores were given to grade of budding (lower, 0; higher, 1) and N stage (N1, 0; N2, 1) in stage III, a better prognostic stratification in terms of the 5-year DFS was obtained than the American Joint Committee on Cancer nodal staging only (0 vs 1 vs 2, 66.5 vs 42.6 vs 29.2%; p = 0.0101). Conclusions Quantitative assessment of tumor budding is a reliable biological prognostic variable to identify higher malignancy potential. Scoring system using tumor budding and N stage showed better prognostic stratification in stage-III rectal carcinoma. A prospective evaluation would confirm the clinical significance of tumor budding for prognostic stratification.     

糖尿病患者糖化血红蛋白与血清CA199水平的相关性研究

目的 观察糖尿病患者HbA1c对血清CA199水平的影响. 方法 选取糖尿病住院患者198例,分为血清CA199＜39 U/ml组和CA199≥39 U/ml组,比较两组各项指标.行多元逐步回归分析,探讨各变量对血清CA199水平的影响. 结果 CA199≥39 U/ml组WC、BMI、FPG和HbA1c水平高于CA199＜39 U/ml组,2 hC-P低于CA199＜39 U/ml组（P＜0.05或P＜0.01）.多元逐步回归分析显示,HbA1c进入回归方程. 结论 HbA1c与CA199呈正相关,血清CA199水平升高的原因之一是HbA1c水平升高.     

血清CEA、NSE、CYFRA21-1水平与肺癌近期疗效的相关性研究

目的 评价癌胚抗原（CEA）、细胞角蛋白19片段（CYFRA21-1）、神经元特异性烯醇化酶（NSE）三项肿瘤标志物在肺癌化疗前后的表达意义.方法 97例确诊肺癌患者化疗前后,常规检查血清CEA、NSE和CYFRA21-1水平,评估变化.结果 三种病理类型肺癌化疗后,疗效评价有效者,腺癌患者CEA显著下降（P〈0.05）,小细胞癌患者NSE显著下降（P〈0.05）,而疗效评价稳定或恶化者,化疗前后其值无明显变化或升高.结论 三项肿瘤标志物水平对肺癌化疗疗效有一定判断价值.     

肺癌患者血清肿瘤标志物水平变化与化疗疗效及生存时间的相关性

目的探讨晚期肺癌患者化疗前后血清癌胚抗原（CEA）、细胞角质蛋白（CYFRA21-1）、鳞状细胞癌抗原（SCC）和神经烯醇化酶（NSE）水平变化与化疗疗效及生存时间的相关性。方法分别采集2006年1月至2012年6月确诊肺癌（Ⅲb-Ⅳ期）116例患者的化疗前及四疗程化疗后的血清标本,检测每份标本CEA、CYFRA21-1、SCC和NSE四种肿瘤标记物水平,探讨它们之间的差值差异及与化疗效果和生存时间的关系。结果四疗程化疗有效及进展的患者中位生存时间为16个月及9个月;结合生存曲线显示化疗有效的晚期肺癌患者较进展者生存时间更长。化疗前后肿瘤标志物水平变化与化疗疗效密切相关。化疗有效者相应肿瘤标志物下降;进展者标志物上升。其中不同疗效组的鳞癌患者CYFRA21-1及SCC水平,腺癌患者CEA水平,小细胞癌患者CEA及NSE差值差异明显（P〈0．05）。通过比较不同生存时间组的患者化疗前后肿瘤标志物的差值差异发现患者生存时间越长,化疗后相应的肿瘤标志物下降幅度越大;生存时间越短标志物上升越明显。其中鳞癌患者CYFRA21—1及SCC,腺癌患者CEA和小细胞癌患者CEA及NSE指标变化有统计学意义。结论CEA、CYFRA21—1,SCC和NSE这四种肿瘤标志物化疗前后差值可作为反映化疗疗效及评估一年生存时间的重要指标,且具有病理类型的特异性。