Evaluation of cytokeratin 19 fragment (CYFRA 21-1) as a tumor marker in malignant pleural effusion

BACKGROUND: The aim was to investigate the diagnostic utility of CYFRA 21-1 (cytokeratin 19 fragment) as a tumor marker in pleural effusion and evaluate the value of combining CYFRA 21-1 and carcinoembryonic antigen (CEA) assays as a diagnostic aid in the malignant pleural effusion. METHODS: One hundred and twenty-six patients (72 malignant and 54 benign pleural effusion) were included in this retrospective study. The effusion levels of CYFRA 21-1 and CEA were measured using radioimmunometric assay. RESULTS: The median values of CYFRA 21-1 in benign and malignant pleural effusion are 15 and 70 ng/ml, respectively. Using a cut-off value of 50 ng/ml, defined at 94% specificity, the diagnostic sensitivity of CYFRA 21-1 for non-small cell lung carcinoma (n = 61), squamous cell carcinoma (n = 21), adenocarcinoma (n = 40) and small cell lung cancer (n = 11) was 64, 71, 60 and 18%, respectively. Regardless of cell types, the diagnostic sensitivity of CYFRA 21-1 and CEA in malignant pleural effusion (n = 72) was 57 and 60%, respectively (cut-off value of 10 ng/ml in CEA assay). Combining CEA with CYFRA 21-1, the diagnostic sensitivity may increase up to 72%, which was defined at 89% specificity. CONCLUSION: CYFRA 21-1 assay may be a useful tumor marker for discriminating benign from malignant pleural effusion, especially in those of non-small cell lung cancer. The combined use of CEA and CYFRA 21-1 assay in the malignant effusion may increase the diagnostic yield compared with CEA or CYFRA 21-1 alone.     

Serum level of cytokeratin 19 fragment (CYFRA 21-1) indicates tumour stage and prognosis of squamous cell carcinoma of the oesophagus

To determine the clinical efficacy of serum concentration of cytokeratin 19 fragment (CYFRA 21-1), sera from 66 patients with oesophageal squamous cell carcinoma were examined, and 54 surgically resected specimens were immunohistochemically stained for cytokeratin 19 (CK-19). The patients with positive CK-19 staining in the tissues of their carcinomas had significantly higher serum CYFRA 21-1 levels compared with those with negative CK-19 staining. When the cut-off value was defined as 2.0 ng/mL, CYFRA 21-1 had a higher positive ratio than that of either squamous cell carcinoma antigen (SCC-Ag) or carcinoembryonic antigen (CEA). Serum CYFRA 21-1 level increased significantly along with the clinical stages. In addition, serum CYFRA 21-1 level served as a prognostic factor for patients with oesophageal carcinoma after surgery, whilst SSC-Ag and CEA is not connected with the outcome. These findings suggest that the serum CYFRA 21-1 probably originated from the tumour tissue is an important marker for determining the stage and outcome of oesophageal carcinoma.     

肺癌患者血清中癌胚抗原和细胞角蛋白片段19的检测与临床价值

目的 探讨血清癌胚抗原(CEA)和细胞角蛋白片段19( CYFRA21-1)检测对肺癌的诊断价值.方法 采用电化学发光法对102例肺癌患者、78例肺部良性病患者和104例健康人血清进行分析,检测CEA和CYFRA21-1水平.结果 肺癌组患者血清中CEA水平及阳性率[(25.77±15.34) ng/ml,47.1％]均明显高于肺良性病组[(4.67±2.21)ml,7.7％]和健康组[(3.98±3.00)ng/ml,3.8％],差异有统计学意义(P＜0.05).肺癌组患者血清中CYFRA21-1水平及阳性率[(14.08±8.34)ng/ml,62.7％]也同样高于肺良性病组[(3.27±2.87)ml,7.7％]和健康组[(2.69±2.02)ng/ml,3.8％],差异有统计学意义(P＜0.05),而良性病组和健康组间差异无统计学意义(P＞0.05).肺癌组患者经TNM分期后,随着肿瘤分期级别的升高,CEA水平[Ⅱ～Ⅳ期分别为(17.78±8.71)ng/ml、(25.84±7.34)ng/ml和(34.85±6.99) ng/ml]和CYFRA21-1水平[Ⅱ～Ⅳ期分别为(10.05±6.76)ng/ml、(15.93±6.66) ng/ml和(22.78±4.12)ng/ml]也升高.CEA和CYFRA21-1联合检测后,灵敏度增高,特异度降低,准确率基本不变.结论 CEA和CYFRA21-1对肺癌有一定的辅助诊断价值,并且对肺癌的分期有一定诊断价值,联合检测可提高对肺癌的阳性诊断.     

Cytokeratin-19 fragments in serum (CYFRA 21-1) as a marker in primary liver cancer

Using an electrochemiluminescence immunoassay, CYFRA 21-1 concentrations were measured in sera from 187 patients with primary liver cancer (164 with hepatocellular carcinoma (HCC) and 23 with intrahepatic cholangiocarcinoma (ICC)) and 87 patients with benign liver diseases. Concentrations of CYFRA 21-1 were significantly higher in patients with ICC (5.0; interquartile range 3.1-10.7 ng ml(-1)) than in those with benign liver disease (1.4; 1.0-1.9; Mann-Whitney U-test, P<0.0001) or HCC (1.7; 1.1-2.7; Mann-Whitney U-test, P<0.0001). Using cutoff values selected for 95% specificity in the benign group (3.0 ng ml(-1)), CYFRA 21-1 showed higher sensitivity for ICC (87.0%) than three commonly used markers including alpha-fetoprotein (17.4%), carcinoembryonic antigen (34.8%), and carbohydrate antigen 19-9 (60.9%). Serum CYFRA 21-1 increased in ICC from stages I/II to IV (Kruskal-Wallis test, P=0.0102). CYFRA 21-1 concentration increased with extent of local invasion, but not nodal status. Serum CYFRA 21-1 represents a useful diagnostic test for ICC that offers high sensitivity. CYFRA 21-1 reflected differences in tumour burden, suggesting applicability to staging and follow-up.     

Mucin-like carcinoma-associated antigen (mca) serum levels in breast-cancer - a critical-appraisal

MCA serum levels were determined in 196 patients with benign breast disease (BD) and in 371 patients with breast cancer. MCA values were abnormal in 30.6% of the patients with BD. In breast cancer patients, significant increases were only found in metastatic disease (89.1%). MCA levels were not correlated with tumor size; on the contrary, the tumor marker showed a strict relation to axillary lymph node involvement. Moreover, the location of metastases and the number of sites involved seem to increase MCA concentrations. The MCA antigen seems to be a promising tool only for monitoring patients with advanced breast cancer.     

血清细胞角蛋白19片段抗原21-1、神经元特异性烯醇化酶在结肠癌中的表达情况及与预后的关系

目的 探讨血清细胞角蛋白19片段抗原21-1(CYFRA21-1)、神经元特异性烯醇化酶(NSE)在结肠癌中的表达情况及与预后关系.方法 检测78例结肠癌患者手术前后CYFRA21-1、NSE的表达水平,术后进行为期1年的随访,统计复发转移情况,比较不同临床特征结肠癌患者术后的血清CYFRA21-1、NSE表达水平,分析影响结肠癌患者术后复发转移的危险因素.结果 结肠癌患者术后血清CYFRA21-1、NSE水平均明显低于手术前(P﹤0.01).术后随访1年,有复发转移25例(32.05%),无复发转移53例(67.95%).单因素分析结果显示,淋巴结转移情况、分化程度、CYFRA21-1水平、NSE水平均可能是结肠癌患者术后复发转移的影响因素(P﹤0.05),肿瘤部位、性别、年龄、饮酒史、吸烟史均可能不是结肠癌患者术后复发转移的影响因素(P﹥0.05).将可能的影响因素带入Logistic回归模型进一步分析,结果显示,有淋巴结转移、分化程度低、术后CYFRA21-1高表达及NSE高表达均是结肠癌患者术后发生复发转移的危险因素(P﹤0.01).结论 血清CYFRA21-1、NSE水平在结肠癌患者中呈高表达,术后血清CYFRA21-1、NSE表达水平则明显下降,且血清CYFRA21-1、NSE表达与患者术后复发转移关系密切,对判断患者预后有重要临床价值.     

Measurement of cytokeratin 19 fragments as a marker of lung cancer by CYFRA 21-1 enzyme immunoassay.

Soluble cytokeratin fragment 19 levels were measured with an enzyme immunoassay method developed by Boehringer Mannheim (Enzymun-Test CYFRA 21-1) in the serum of 185 patients with lung cancer [149 with non-small-cell lung cancer (NSCLC) and 36 with small-cell lung cancer (SCLC)] and 97 patients with benign lung diseases in order to determine its clinical usefulness in the diagnosis of lung cancer and follow-up of treatment. We used the cut-off value of 3.5 ng ml-1, established by the Japan CYFRA research group. This cut-off value is based on calculations using the receiver operating characteristic approach instead of using the 95% specificity approach recommended by other authors. The resulting sensitivity and specificity for the group of all lung cancer patients were 65.4% and 84.5% respectively. The sensitivity was highest (76.1%) for squamous cell carcinoma and lowest (44.4%) for SCLC. For NSCLC patients, when CYFRA 21-1 levels were analysed by node (N) factor, patients who presented with mediastinal lymph node metastasis (N2 or N3) demonstrated higher serum CYFRA 21-1 levels (5.6; interquartile range 3.2-11.5 ng ml-1) than patients without mediastinal node metastasis (N0 or N1, 3.9; interquartile range 2.2-10.0 ng ml-1; Mann-Whitney U-test, P = 0.0373). We compared the discriminatory power of CYFRA 21-1 with that of other tumour markers including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). The area under the curve (AUC) of each ROC curve was calculated using the CLABROC program for statistical analysis. CYFRA 21-1 appeared to have the most discriminatory power of the markers tested in the diagnosis of lung cancer. In serial measurements of 14 patients receiving chemotherapy or radiotherapy, a high degree of correlation was noted between serum levels of CYFRA 21-1 and extent of clinical response (Wilcoxon, P = 0.0093).     

Serum markers casa, cea, cyfra-21-1, msa, nse, tpa and tps in lung-cancer

Serum CASA, CEA, CYFRA 21-1, NSE, MSA, TPA, and TPS were determined in patients with lung cancer (LC), benign lung disease (BL), and healthy control (HC) donors. Using predefined cutpoints, the cytokeratin-related markers TPA, TPS, and CYFRA showed the highest sensitivity in non-small cell lung cancer (TPA 69%, TPS 63%, CYFRA 54%), while NSE gave the highest sensitivity in small cell lung cancer (50%), indicating that these markers may be most appropriate in monitoring the course of disease and the patients response to therapy. Receiver-operator analysis was performed to compare assays at the same specificity. At high specificities (greater than or equal to 95%), CYFRA was significantly better than all assays except CASA in the LC vs. HC and LC vs. non-infectious BL comparisons (p<0.05), while CEA was the only assay which was not significantly different to CYFRA in the LC vs. BL comparison. CASA was of particular value when used in combination with these markers, as the sensitivity was increased. In addition, pretreatment CASA was the best indicator of patient survival (one year survival of 83% for patients with CASA <5 units/ml and 10% for patients with CASA greater than or equal to 5 units/ml).     

血清细胞角蛋白19片段与晚期非小细胞肺癌患者化疗疗效及预后关系的研究

目的:探讨晚期非小细胞肺癌(NSCLC)患者化疗前后血清细胞角蛋白19片段(CYFRA21-1)变化水平与影像学疗效哪个因素与预后的关系最密切。方法:采用电化学发光免疫法检测112例晚期NSCLC患者化疗前后血清CYFRA21-1水平变化,并将其变化水平与临床反应类型进行比较。结果:经过2个周期化疗后,112例患者中有80例可行影像学和血清学疗效评价,其中,影像学客观缓解率为26.3%,疾病控制率为65.0%。80例患者的中位生存期(MST)为9.9个月。影像学缓解(OR)与疾病控制(DC)患者的MST相似(P=0.094),但均长于PD患者(P均<0.001)。化疗后血清CYFRA21-1水平下降幅度与临床疗效相符。血清CYFRA21-1水平下降幅度≥30%和≥60%对于诊断DC和OR有最佳灵敏度和特异度。血清CY-FRA21-1水平下降幅度≥30%与DC(P<0.001)及生存期(P<0.001)密切相关。多因素分析表明,DC(RR=0.450,P=0.017)及血清CYFRA21-1水平下降幅度≥30%(RR=0.429,P=0.002)是影响预后的独立因素,而OR与生存期无关。结论:DC较OR更适合作为判定NSCLC化疗疗效的指标,血清CYFRA21-1水平下降幅度≥30%有望成为评价NSCLC化疗疗效的替代指标。     

Cytokeratin 19-fragments (CYFRA 21-1) as a novel serum biomarker for response and survival in patients with advanced pancreatic cancer

Background:

CYFRA 21-1 serves as biomarker in several epithelial malignancies. However, its role in pancreatic cancer (PC) has not yet been investigated.

Methods:

Within a prospective single-centre study serial blood samples were collected from patients with confirmed advanced PC. Pre-treatment values and weekly measurements of CYFRA 21-1, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (assessed by Elecsys 2010, Roche Diagnostics) during palliative first-line chemotherapy were obtained. Biomarker data were correlated with objective response (determined by RECIST) as well as time to progression (TTP) and overall survival (OS) using uni- and multivariate analyses.

Results:

Seventy-eight patients were included, 45% of these received treatment in prospective clinical trials. Median TTP was 3.9 months, median OS 7.7 months. Pre-treatment CYFRA 21-1 levels were significantly associated with performance status (P=0.0399) and stage of disease (P=0.0001). Marker values before chemotherapy and at the 2-month staging of all three markers were considered significant predictors for objective treatment response. Pre-treatment CYFRA 21-1 levels, as well as CA 19-9 values, could be applied to define subgroups (categorised by tertiles) with a different OS outcome (CYFRA: 14.8 vs 7.1 vs 4.8 months, CA 19-9: 14.2 vs 7.1 vs 5.2 months; P<0.0001). CYFRA 21-1 and CA 19-9 (both as categorised and as continuous variables) showed a highly significant correlation with TTP and OS at nearly all-time points assessed in univariate analysis. In multivariate analysis, only CYFRA 21-1 and performance status were independent predictors for OS.

Conclusions:

CYFRA 21-1 may serve as a valuable tool for monitoring treatment response and assessing prognosis in advanced PC.     

血清细胞角蛋白19在预测进展期非小细胞肺癌患者化疗疗效及预后中的临床意义

背景与目的由于RECIST(Response Evaluation Criteria in Solid Tumors, RECIST)标准不能对存活肿瘤组织进行检测,也不能对所有无法测量病灶的非小细胞肺癌(non-small cell lung cancer, NSCLC)患者的疗效进行准确评估,本研究通过检测进展期NSCLC患者化疗前后血清细胞角蛋白19片段(cytokeratin 19 fragment, CYFRA21-1) 表达水平的变化以评价其在预测进展期NSCLC患者化疗疗效及预后中的临床价值。方法采用全自动生化分析仪电化学发光免疫法检测112例初治的NSCLC患者化疗前和化疗2周期后血清CYFRA21-1表达水平的变化,应用受试者特征工作曲线(receiver operating characteristics curve, ROC)评价血清CYFRA21-1反应在诊断影像学缓解(objective response, OR)中的效能及其与预后的相关性。结果经一线铂类为基础的两药联合方案化疗2周期后,血清CYFRA21-1水平较化疗前基线水平明显下降。80例可评价影像学和血清学疗效的患者中,26...     

血清癌胚抗原和细胞角蛋白19片段对食管癌患者放疗效果及生存状况的评估

目的探讨联合检测食管癌患者放疗前后血清癌胚抗原(CEA)、细胞角蛋白19片段(CYFRA21-1)水平变化及其对患者生存预后的评估价值。方法选取125例食管癌患者(研究组)与45例健康对照者(对照组)。采用常规放疗方案对食管癌患者进行治疗,并采用酶联免疫吸附法(ELISA)检测食管癌患者放疗前后的CEA、CYFRA21-1水平,分析其与病情预后的相关性。结果研究组患者CEA、CYFRA21-1水平明显高于对照组(P<0.05)。经放疗后,食管癌患者的CEA、CYFRA21-1水平明显下降(P<0.05);CEA下降率为21.0%时,敏感度和特异度分别为87.3%和63.2%;CYFRA21-1下降率为43.0%时,敏感度和特异度均分别为82.3%和76.4%。血清CEA、CYFRA21-1水平下降组及未下降组间的生存率的差异均有统计学意义(P<0.05)。结论联合检测血清CEA和CYFRA21-1水平对食管癌患者的放疗疗效及生存预后的判定具有重要参考价值。     

电化学发光法检测尿Cyfra21-1对膀胱癌诊断的临床性能评价

目的:评估电化学发光法检测尿Cyfra21-1对膀胱癌的临床诊断价值。方法:收集2020年02月至2022年01月到深圳市罗湖区人民医院就诊的泌尿系统炎症疾病(尿路结石、尿路感染)患者尿液66例、膀胱癌患者尿液58例,收集深圳市众循精准医学研究院健康志愿者尿液37例和健康体检者尿液样本83例作为健康对照样本。参考美国临床和实验室标准协会(Clinical and Laboratory Standards Institute,CLSI)颁布的系列文件使用细胞角蛋白19片段(Cyfra21-1)测定试剂盒(电化学发光法)检测尿Cyfra21-1的最低检出限、线性范围、准确度、批内精密度、干扰试验进行性能,并初步建立正常参考区间,确定Cyfra21-1的阳性判断值,最后纳入新的外部验证队列对结果进行盲测验证。采用SPSS 25.0版本软件进行实验数据分析。结果:Cyfra21-1试剂盒的最低检出限为0.01 ng/mL;在0.1~500 ng/mL范围内,线性良好(r=0.995);每台仪器测得的高、低浓度水平样本相对偏差均不超过±10%;高、低浓度水平的批内精密度变异系数(CV)分别为1.47%与1.28%;干扰实验表明,尿液中含有生物素(≤30 ng/mL)、总蛋白(≤10 g/dL)、HAMA(≤100 ng/mL)、吉西他滨(≤380 μg/mL)、酒石酸·长春瑞滨,98％(≤1.23 μg/mL)、厄洛替尼(≤17 μg/mL)、紫杉醇(≤67 μg/mL)、阿霉素(≤40 μg/mL)、异环磷酰胺(≤800 μg/mL)、依托泊苷(≤12 μg/mL)、碳铂(卡铂)(≤500 μg/mL)时,测定结果的相对偏差均在±10％范围内;尿液中含有类风湿因子(≤1 000 IU/mL)时,测定结果的相对回收率为108.47%;建立的正常参考区间为≤10.809 ng/mL;尿Cyfra21-1的阳性判断值为7.678 ng/mL,敏感度和特异性分别为67.20%和92.50%。盲测样本经检测,23份结果正确,正确率为63.89%。膀胱癌组与健康对照组和泌尿系统炎症疾病组检测结果比较,差异具有统计学意义(P＜0.01);各组内性别比较,差异无统计学意义(P＞0.05),膀胱癌组内TNM各分期比较,差异无统计学意义(P＞0.05),膀胱癌组内肿瘤各分级比较,差异具有统计学意义(P＜0.01),膀胱癌组内肿瘤浸润程度比较,差异具有统计学意义(P＜0.05)。结论:细胞角蛋白19片段(Cyfra21-1)测定试剂盒(电化学发光法)性能良好,符合临床检测尿Cyfra21-1要求。电化学发光法检测尿Cyfra21-1能有效区分膀胱癌和非膀胱癌样本,具备精密度高、时间短、操作自动化等优势,适合于临床应用。     

低剂量穿刺活检联合癌胚抗原、细胞角质蛋白19片段抗原21-1检测对肺癌的诊断价值

目的 探讨低剂量穿刺活检联合癌胚抗原(CEA)、细胞角质蛋白19片段抗原21-1(CYFRA21-1)检测对肺癌的诊断价值.方法 选择150例疑似肺癌患者,所有患者均进行低剂量穿刺活检联合CEA、CYFRA21-1检测,观察患者的射线剂量、图像质量及CEA、CYFRA21-1水平.以病理诊断结果为金标准,采用Kappa...     

Decline in serum carcinoembryonic antigen and cytokeratin 19 fragment during chemotherapy predicts objective response and survival in patients with advanced nonsmall cell lung cancer

BACKGROUND: The authors assessed the predictive and prognostic role of decline in the serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) during chemotherapy in patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Changes in serum levels of CEA and CYFRA 21-1 during first-line, conventional chemotherapy were studied prospectively with an immunometric assay at baseline and every 2 courses in 117 patients with advanced NSCLC. Data were correlated with radiologic objective response (OR) and survival. RESULTS: One hundred seven patients were evaluable for radiologic and serologic response assessment after 2 chemotherapy courses. The radiologic OR rate was 44% overall. The CEA and CYFRA 21-1 responses (> or =20% reduction over baseline level; assessed after the second course of chemotherapy) were 38% and 61%, respectively. Statistically significant correlations were observed between CEA and CYFRA 21-1 responses and OR (P = .01 and P = .004, respectively). The median survival from response assessment (landmark analysis) was 9 months. In a univariate analysis, disease stage, performance status, baseline lactate dehydrogenase level (LDH), OR, CEA response, and CYFRA 21-1 response were correlated significantly with survival. In particular, the median survival was 13 months for patients who had a CEA response and 11 months for patients who had a CYFRA 21-1 response compared with 8 months and 6 months for patients who did not respond, respectively. In a multivariate analysis, performance status (P = .005), baseline LDH level (P = .02), CEA response (P = .03) and CYFRA 21-1 response (P = .01) were confirmed as independent prognostic factors for survival. CONCLUSIONS: CEA and CYFRA 21-1 responses appeared to be reliable surrogate markers of chemotherapy efficacy in patients with advanced NSCLC.     

Serum fragment of cytokeratin subunit 19 (Cyfra) as a tumor marker in diagnosis and monitoring of treatment of oral squamous cell carcinoma

Background. There have been no reports describing effective methods for diagnosing, assessing prognosis, or monitoring the treatment of oral squamous cell carcinoma (O-SCC). However, fragment of cytokeratin subunit 19 (Cyfra) has been reported to be a new marker in non-small cell carcinoma of the lung. Cytokeratins are intermediate filaments which make up the cytoskelton of normal epithelia and their malignant counterparts. We undertook this study to determine the value of measuring serum Cyfra levels in patients with O-SCC. Methods. Cyfra was determined by a solid-phase immunoradiometric assay, based on a two-sandwich method, of sera from 50 patients with O-SCC, 20 patients with benign oral diseases, and 10 healthy controls. The O-SCC patients were allocated to two groups: a good-prognosis group (32 patients who were completely tumor-free for more than 3 years after primary treatment) and a poor-prognosis group (18 patients who all died due to either local recurrence or regional lymph node or distant metastasis). Serial measurements of Cyfra were available before treatment as well as during individual therapy and follow-up in 20 patients. Serum samples were obtained at the time of primary diagnosis and after treatment, and at least once postoperatively. Results. The mean serum concentration of Cyfra in patients with O-SCC (2.24 ± 2.55 ng/ml) was significantly higher than that in the 20 patients with benign oral diseases (1.38 ± 0.77 ng/ml) and in the 10 healthy controls (1.17 ± 0.41 ng/ml) (P < 0.01). The mean serum concentration of Cyfra was significantly lower in the good-prognosis group (1.76 ± 1.25 ng/ml) than in the poor-prognosis group (3.08 ± 3.83 ng/ml) (P < 0.01). When good control of the cancers was achieved, the serum level of Cyfra returned to normal. In most patients with a poor prognosis, serum Cyfra levels decreased after primary treatment, but still remained higher than the cut-off level (i.e., upper limit of normal, 2.0 ng/ml). Conclusion. Based on the above findings, Evaluation of Cyfra in O-SCC patients appears to be a valuable tool as a tumor marker for assessing prognosis and monitoring treatment of O-SCC. Received: November 28, 1996 / Accepted: June 29, 1998     

Evaluation of the soluble fragments of cytokeratin 19 (CK19) in non-small cell lung cancer (NSCLC)

This study compared the diagnostic efficacy of serum CK19 determination (Cyfra 21-1) with other tumour markers, such as CEA, SCC, NSE, TPA, in patients with resected non-small lung cancer. Tumour marker levels were tested in 90 patients with benign lung disease and at diagnosis in 72 patients with proven NSCLC, 39 squamous cell carcinoma and 33 adenocarcinoma. At presentation baseline levels of all tumor markers were significantly higher (p<0.05) in lung cancer patients than in control subjects, except for NSE. A significant increase (p<0.05) in serum concentrations was observed from stage I to stage IIIb only for Cyfra 21-1 (stage I/II, median=2.7 ng/ml; stage IIIb, median=6.3 ng/ml) and TPA (stage I/II, median=89.8 IU/ml; stage IIIb, median=170.7 IU/ml). Receiver operating characteristic (ROC) analysis was performed to evaluate the best threshold values and the global accuracy of each marker. The highest global sensitivity for NSCLC was reached by TPA (70.8%), whereas that of Cyfra 21-1 was 50%. According to tumour histology, significant difference (p<0.05) in serum levels were found only for CEA (adenocarcinomas, median=5.6 ng/ml; squamous cell carcinoma, median=3.2 ng/ml) and SCC (adenocarcinomas, median=1.0 ng/ml; squamous cell carcinoma, median=1.5 ng/ml). As regards squamous cell carcinoma histotype, the highest sensitivity was obtained by TPA (74.4% at a specificity of 62.2%) and for adenocarcinomas by CEA (78.8% at a specificity of 85.6%). Tumour marker levels were also determined during the follow-up of 10 patients. The best sensitivity in detecting relapses was shown by CEA (90%), followed by TPA (70%), SCC (50%), Cyfra 21-1 (40%) and NSE (10%), even though the CEA test displayed a high percentage of false positive results (98.1%) in patients with no evidence of disease (NED).     

Fenretinide in breast-cancer chemoprevention (review)

Fenretinide (4-HPR), a synthetic amide derivative of retinoic acid, has proven effective in preventing chemically induced mammary carcinoma in rodents. During the past years, our group has made a particular effort with regard to this molecule in clinical studies aimed at evaluating its pharmacology, toxicity and efficacy in breast cancer prevention. We have demonstrated that 4-HPR blood levels remain constant during administration for as long as 5 years, that the drug accumulates in the human breast, and that it induces a significant decline of plasma retinol and insulinlike growth factor-I (IGF-I) levels. Accrual of the phase III study was closed on July 31, 1993 including 2,972 Stage I breast cancer patients. The aim is to evaluate the efficacy of a 5-year administration of 4-HPR to prevent new contralateral primary breast cancers. Compliance to protocol and treatment is high and tolerability of the drug is good; only 51 women out of 1,397 (3.6%) have interrupted drug intake due to toxicity. The only remarkable adverse effect of 4-HPR administration is diminished dark adaptation, which occurs in about one-fourth of the patients and is dependent on the decline of plasma retinol below the threshold level of 100 ng/ml. However, about 50% of the patients with altered dark-adaptometry are asymptomatic and the alterations of dark adaptation are promptly reversible upon drug discontinuation. Plasma level of N-(4-methoxyphenyl) retinamide (4-MPR), the principal metabolite of 4-HPR, which tends to be higher in women over 55 years with a high percentage of adipose tissue, is the major determinant of both retinol and IGF-I decrease. Since the combination of 4-HPR with the antioestrogen tamoxifen has shown a synergistic activity in preclinical models, it is currently an important avenue of clinical investigation in an attempt to prevent breast cancer. Moreover, a dose reduction of one or both agents in an effort to minimise toxicity while maintaining activity, would represent a major improvement in cancer chemoprevention.