人附睾分泌蛋白4(HE4)对卵巢上皮性癌的预测价值

卵巢癌是妇女生殖系统中常见的恶性肿瘤,早期诊断卵巢癌可明显改善患者预后。人附睾分泌蛋白4(human sapiens epididymis specific protein4,HE4)作为一种新型的肿瘤标记物,其在卵巢癌的早期诊断及疾病监测方面均具有很好的临床价值。     

血清HE4和CA125联合检测预测盆腔包块患者卵巢癌的风险

目的:探讨新型肿瘤标记物人附睾分泌蛋白4(HE4)和CA125联合检测预测盆腔包块患者上皮性卵巢癌(EOC)风险的价值。方法:将诊断为盆腔包块拟行手术的患者纳入本研究。测定患者术前血清HE4和CA125水平,分别用绝经后和绝经前预测模型(ROMA)将患者划分至高危组和低危组,评估预测模型的应用价值。结果:评估了191例患者,其中138例盆腔良性疾病,53例盆腔恶性肿瘤,包括36例EOC。绝经后组盆腔良性疾病12例,8例划分至低危组,特异性66.7%(95%CI=40.0～93.3),恶性肿瘤37例,35例划分至高危组,敏感性94.6%(95%CI=87.0～101.9),EOC28例(含9例早期),全划分至高危组,敏感性100.0%。绝经前组良性疾病126例,103例划分至低危组,特异性81.7%(95%CI=75.0～88.5),16例恶性肿瘤,12例划分至高危组,敏感性75.0%(95%CI=54.0～96.2),EOC8例(含2例早期),全划分至高危组,敏感性100.0%。结论:ROMA成功地将盆腔恶性肿瘤患者划分至高危组,其中EOC患者全被正确地划分至高危组,可用于将恶性肿瘤患者尤其是EOC患者分流至有治疗经验的肿瘤医师及治疗中心。     

血清CA199、CA125、HE4水平表达与卵巢癌的相关性分析

目的 探究血清糖类抗原199(CA199)、糖类抗原125(CA125)、人附睾蛋白4(HE4)水平表达与卵巢癌的相关性。方法 选取60例卵巢癌患者纳入研究组;另选取同期健康体检者60例纳入对照组。两组均采用全自动化学发光免疫分析仪测定血清CA199、CA125、HE4水平以及卵巢癌不同分期患者的血清水平,并分析血清CA199、CA125、HE4水平与卵巢癌的相关性。结果 研究组血清CA199、CA125、HE4水平高于对照组（P<0.05）。研究组卵巢癌Ⅲ～Ⅳ期患者的血清CA199、CA125、HE4水平高于Ⅰ～Ⅱ期患者（P<0.05）。血清CA199、CA125、HE4水平与卵巢癌成正相关（r=0.387、0.379、0.383,P<0.05）。结论 血清CA199、CA125、HE4水平高表达与卵巢癌发病及进展有关,可作为临床预测、诊断、评估病情的关键指标。     

血清HE4及CA125对子宫内膜癌宫外转移的预测价值

目的:评估术前血清HE4和CA125联合检测在子宫内膜癌(EC)的子宫外转移的诊断价值。方法:回顾分析327例EC患者的临床病理资料,检测血清HE4和CA125水平,分析HE4及CA125与临床病理参数的关系,计算诊断评价指标,绘制受试者工作特征(ROC)曲线,计算AUC值。结果:患者血清HE4和CA125水平与病灶范围大小、肌层浸润深度、肿瘤分化程度、临床分期、有无子宫外转移等有关,差异有统计学意义(P0.01)。血清HE4、CA125单项检测子宫外转移时,HE4敏感度最高,为57.81%,联合诊断能显著提高敏感度达79.68%。两项单独检测的ROC-AUC值分别为0.740、0.714,而联合诊断的ROC-AUC值为0.810,差异有统计学意义(P0.001)。结论:血清HE4和CA125联合预测EC患者的子宫外转移比单项检测更具优势。     

血清CA125及HE4诊断卵巢癌的研究进展

目前临床用于卵巢癌早期诊断的主要肿瘤标记物是血清糖链抗原125(CA125),CA125诊断卵巢癌的敏感性及特异性低。血清人附睾蛋白4(HE4)在卵巢癌中呈高表达,尤其是浆液性卵巢癌,其与CA125联合检测可有效提高卵巢癌的早期诊断率。本文就血清CA125和HE4单独及联合检测诊断卵巢癌的研究进展做一综述。     

血清CA125、HE4以及ROMA指数在卵巢癌早期诊断中的应用价值

目的:探讨人附睾蛋白4(HE4)、糖类抗原125(CA_(125))及卵巢癌风险预测模型(ROMA)在卵巢癌早期诊断中的应用价值。方法:采用酶联免疫吸附试验及化学发光法检测53例国际妇产科联合会(FIGO)2014年卵巢癌分期Ⅰ、Ⅱ期卵巢癌患者及54例卵巢良性肿瘤患者血清HE4及CA_(125)水平,根据受试者绝经情况,通过计算ROMA指数,绘制受试者工作特征(ROC)曲线并计算曲线下面积(AUC)。结果:卵巢癌检测HE4、CA_(125)水平及ROMA指数分别为416.19±134.04 pmol/L、895.97±252.16 U/ml及(59.10±4.49)%;卵巢良性肿瘤组分别为33.61±3.07 pmol/L、33.98±4.99 U/ml及(20.08±5.07)%,卵巢癌组血清HE4、CA_(125)水平及ROMA指数高于卵巢良性肿瘤组,差异有统计学意义(P0.05)。血清HE4、CA_(125)水平和ROMA指数对卵巢癌诊断的敏感度分别为92.45%、69.81%、96.23%,特异度分别为79.63%、70.37%、81.48%,ROC-AUC分别为0.943、0.803、0.975。结论:联合检测HE4和CA_(125)计算ROMA指数对卵巢癌早期诊断敏感度和特异度较高。     

血清miR-222、HE4及CA125水平联合ROMA指数对上皮性卵巢癌的诊断价值

目的:探讨血清miR-222、血清人附睾蛋白4(HE4)及糖类抗原125(CA125)水平联合ROMA指数对上皮性卵巢癌(EOC)的诊断价值.方法:选取2016年1月至2019年12月海南西部中心医院收治的120例EOC患者、100例上皮性卵巢良性肿瘤患者和50例正常健康女性作为研究对象.实时定量PCR法检测miR-2...     

HE4、CA125、Atg5水平在不同级别浆液性卵巢癌患者组织内表达水平变化意义分析

目的 探讨浆液性卵巢癌组织中人附睾蛋白4(HE4)、人自噬相关蛋白5(Atg5)、血清糖类抗原125(CA125)的表达及其临床意义。方法 选取沧州市中心医院2021年8月至2022年7月收治的112例浆液性卵巢癌患者作为病例组、因子宫肌瘤妇科手术获取的正常卵巢组织标本60例作为对照组;检测两组患者的卵巢组织中的HE4、Atg5表达及血清CA125水平差异,并分别比较不同病理学分级、FIGO分期、是否发生淋巴结转移的浆液性卵巢癌患者上述指标的差异。结果 病例组患者卵巢组织标本中的HE4阳性表达率为60.71%,显著高于对照组的31.67%,差异有统计学意义（P <0.05）;病例组患者卵巢组织标本中的Atg5阳性表达率为34.82%,显著低于对照组的78.33%,差异有统计学意义（P <0.05）;病例组血清CA125水平显著高于对照组,差异有统计学意义（P <0.05）;不同FIGO分期、不同病理学分级、是否发生淋巴结转移的浆液性卵巢癌组织中HE4蛋白阳性表达率进行比较,差异有统计学意义（P <0.05）;不同FIGO分期的浆液性卵巢癌组织中Atg5蛋白阳性表...     

913例健康体检女性血清HE4水平分布的初步观察

目的:探讨上海地区不同年龄健康体检女性血清人附睾蛋白4(HE4)水平的分布情况,为建立女性血清HEA水平的参考区间提供参考.方法:对913例健康体检女性以60岁为界,分为＜60岁组835例,≥60岁组78例;再将＜60岁组以10岁一年龄段分4个亚组.采用ELISA法测定血清HE4水平.结果:913例健康体检女性血清HEA平均水平为40.96±10.81pmoL/L,其中＜60岁组血清HE4水平40.05±9.88 pmol/L,≥60岁组为50.73 ± 14.87 pmol/L,两组比较差异有高度统计学意义(P＜0.01).在＜60岁组中,20 ～ 29岁组(148例)血清HE4水平为38.04±8.87 pmol/L,30 ～ 39岁组(182例)为39.21 ±9.02 pmol/L,40～49岁组(326例)为40.97±10.82 pmol/L,50 ～ 59岁组(179例)为40.89 ±9.46pmol/L,60岁以下各年龄组间血清HEA水平比较,差异无统计学意义(P＞0.05).以(x)+2s为参考上限,健康体检女性血清HEA水平参考区间:60岁以下＜59.81 pmol/L,60岁以上＜80.47 pmol/L.结论:年龄是影响人血清HE4水平的重要生理因素.建议按照60岁以下和60岁以上分别建立女性血清HE4水平的参考区间.     

上皮性卵巢肿瘤患者血清中YKL-40、HE4的表达及临床意义

目的:探讨血清甲壳质酶蛋白40(YKL-40)、人附睾蛋白4(HE4)在上皮性卵巢肿瘤的表达及临床意义。方法:用酶联免疫吸附试验,检测健康妇女、上皮性良性卵巢肿瘤、交界性卵巢肿瘤及卵巢癌患者血清中YKL-40、HE4的水平。结果:(1)健康妇女、上皮性良性卵巢肿瘤、交界性卵巢肿瘤及卵巢癌患者术前血清中,YKL-40表达中位数分别为35.56、41.42、44.34和130.25μg/L;HE4的表达中位数分别为41.10、43.98、65.21和260.90pmol/L;在术前卵巢癌组YKL-40、HE4的表达水平均高于前3组,差异有统计学意义(P<0.05),前3组之间差异无统计学意义;卵巢癌患者术后血清中YKL-40、HE4中位数分别为58.57μg/L、124.32pmol/L,术前血清水平明显高于术后(P<0.05);(2)卵巢癌患者术前血清YKL-40浓度与FIGO分期、血清CA125浓度呈正相关(P<0.05);术前血清HE4浓度与病理类型、血清CA125浓度、年龄相关。结论:血清YKL-40、HE4有望成为卵巢癌标志物,用于早期诊断和预后分析。     

Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125

Objective

Evaluate and compare the effectiveness of CA125, HE4, Mesothelin and MMP7 marker levels to monitor ovarian cancer patients after surgery and chemotherapy. Evaluate the lead time of a rise of marker levels before recurrence.

Methods

The study consists of 23 patients with advanced stage ovarian/fallopian tube cancer. Blood was drawn after front line surgery and chemotherapy treatment and at 3 month intervals thereafter. One patient had chemoresistant disease, two patients remained in remission and 20 patients had recurring disease and were used for marker evaluation.

Results

In five patients HE4 was the only marker to elevate before recurrence with a lead time of up to 4½ months including one patient who did not have a CA125 response at all. In a further two patients, HE4 increased before CA125 did. In four of these seven patients, HE4 levels were consistently at or above threshold during remission when both CA125 and imaging results were negative. MMP7 elevated before recurrence in one patient who was negative for the other markers. Mesothelin elevated in two patients who were also positive for CA125 and HE4.

Conclusions

HE4 can predict ovarian cancer recurrence earlier than CA125 and it can be elevated in patients that do not express CA125 at sufficient levels to make a clinical decision. MMP7 and Mesothelin have lower potential as markers for ovarian cancer recurrence to complement CA125. A failure of HE4 levels to normalize at completion of standard therapy may indicate a poor prognosis.     

血清人附睾分泌蛋白4（HE_4）和CA_（125）在卵巢癌患者手术及化疗前后的变化

目的检测卵巢癌患者手术及化疗前后HE4和CA125的血清值,探讨卵巢癌患者治疗前后HE4、CA125的变化情况。方法采用酶联免疫吸附试验（ELISA法）检测21例卵巢癌患者治疗过程中血清HE4和CA125水平。数据使用SPSS13.0进行统计学分析。结果卵巢癌患者术后行常规化疗,血清HE4及CA125的水平基本下降到正常。术前HE4中位数水平为796.32pmol/L,第2次后基本恢复正常,为135.61pmol/L;患者术前CA125中位数水平为1280kU/L,第3次化疗后为30.4kU/L,恢复正常。卵巢癌患者治疗过程中HE4与CA125具有较强的相关性,相关系数为0.811。结论 HE4可能作为有助于评判疗效的另一种血清学标志物。     

HE4 is an independent prognostic marker in endometrial cancer patients

Objective

To evaluate the prognostic value of pretherapeutic serum HE4 in endometrial cancer in comparison to CA125.

Methods

HE4 and CA125 serum levels were analyzed by means of chemiluminescent microparticle immunoassays in 183 patients with endometrial cancer treated at the Department of Obstetrics and Gynecology, Innsbruck Medical University, between 1999 and 2009. The Kaplan-Meier method and Cox's proportional hazards analysis were performed to determine the prognostic significance of HE4, CA125 and the combination of both markers.

Results

In univariate analysis both markers, HE4 and CA125, were of prognostic value for overall survival (p < 0.001 and p = 0.028) and disease-free survival (p = 0.015 and p = 0.045). In multivariate analysis HE4 was seen to have independent prognostic value in overall survival (HR 2.407, p = 0.017) in contrast to CA125. The combination of both markers showed a higher hazard ratio (HR 4.04, p = 0.023) for overall survival in comparison to HE4 alone. In the subgroup endometrioid histological type (n = 132) only HE4 was of prognostic value for overall survival in univariate (p = 0.001) and multivariate analysis (p = 0.023).

Conclusions

Pretherapeutic serum HE4 levels alone and in combination with CA125 are an independent prognostic marker in endometrial cancer patients.     

CA125 regression in ovarian cancer patients treated with intravenous versus intraperitoneal platinum-based chemotherapy: a gynecologic oncology group study

Objective

CA125 is a non-specific marker of peritoneal irritation which has the potential for false elevation during intraperitoneal treatment. The purpose of this study is to identify the rate of CA125 regression during intraperitoneal (IP) versus intravenous (IV) chemotherapy for ovarian cancer.

Methods

GOG 114, a randomized control trial evaluating IP and IV treatment, includes an intensive CA125 measurement schema with weekly CA125 levels until ≤ 35 units/ml for both IP- and IV-treated patients. Rate of CA125 normalization, median CA125 values for each treatment cycle, as well as clinical and pathologic features were compared between the treatment groups. Baseline CA125 levels and rate of CA125 decline were evaluated with respect to overall survival.

Results

CA125 data were available for 223 patients who received IV cisplatin/paclitaxel and for 231 patients who received IV carboplatin followed by IP cisplatin/paclitaxel. Standard prognostic criteria and baseline CA125 values were similar between the treatment groups. For treatment cycles in which IP-treatment was administered, there was no statistically significant difference in CA125 levels between IV- and IP-treated patients. The rate of CA125 normalization was similar between IV- and IP-treated patients (p = 0.55). Patients with low pre-chemotherapy CA125 levels which rapidly declined during treatment demonstrated a survival advantage (p < 0.0001).

Conclusions

No difference in CA125 decline was identified between IP- and IV-treated patients undergoing a weekly CA125 monitoring schedule. This data supports the utilization of standard CA125 response criteria in the therapeutic monitoring for patients receiving IP treatment.     

Diagnostic performance of the biomarkers HE4 and CA125 in type I and type II epithelial ovarian cancer

Objective

To evaluate the diagnostic performance of HE4 and CA125 in patients presenting with suspicious malignant ovarian cysts. We especially wanted to investigate the levels of HE4 and CA125 with regard to the gene and histology-unifying model of type I and type II epithelial ovarian cancer (EOC).

Methods

Plasma from 373 women presenting with a suspicious malignant ovarian cyst was collected prior to surgery. Histology, grade, and stage were determined according to FIGO-classification. HE4 and CA125 were analyzed using ELISA, and the markers were evaluated for significance separately and in combination. Receiver operating curves, the area under the curve, sensitivity and specificity were estimated.

Results

The combination of HE4 and CA125 resulted in the best diagnostic power in comparing benign tumors to EOC (ROC AUC 0.93, sensitivity 94.4% at 75% specificity) for type II. Diagnostic power in type I (ROC AUC 0.79, sensitivity 61.9% at 75% specificity) was less impressive. In particular, mucinous benign vs. malignant tumors could not significantly be separated by the dual marker combination. Impressively high ROC AUC 0.99 was found for the late stage type II EOC with 100% sensitivity at 75% specificity.

Conclusions

HE4 and CA125 have a good ability to diagnose the more aggressive type II tumors but a poor diagnostic ability when patients are presenting with slow-growing type I in the early stage. Our results support the hypothesis that EOC should be looked upon as several different diseases, and that we lack biomarkers for sub-groups of EOC.     

血清CA125预测卵巢上皮癌治疗后复发的Meta分析

目的:系统评价血清CA125对卵巢上皮癌综合治疗(手术+化疗)后复发的诊断价值。方法:计算机检索Pub Med、EMBASE、Cochrane Library、Web of Science、中国生物医学文献数据库(CBM)、中国期刊全文数据库(CJFD)、中国科技期刊数据库(CSJD)、中国知网(CNKI)数据库,检验医学专业数据库:IFCC循证实验医学数据库、Medion、CRDdatabase、Bandlier Knowledge library等;灰色文献检索:中国学术会议论文库(CACP)、ISTP,检索期限自建库至2015年12月31日。收集有关血清CA125诊断卵巢上皮癌综合治疗后复发的前瞻性或回顾性队列研究。使用诊断性试验准确性质量评价工具(QUADAS)评价文献质量并提取数据,采用Meta-Disc1.4版软件进行Meta分析。结果:共纳入33篇文献,共2188例患者。Meta分析结果显示,血清CA125对卵巢上皮癌治疗后复发的诊断优势比DOR为11.77(95%Cl为7.16~19.37),灵敏度为67%(95%Cl为65%~70%),特异度为83%(95%Cl为80%~85%),阳性似然比为3.83(95%Cl为2.70~5.43),阴性似然比为0.41(95%Cl为0.35~0.49)。结论:血清CA125阴性排除"卵巢癌复发"的价值较大,而阳性诊断"卵巢癌复发"的价值有待进一步确证。     

Prognostic significance and predictors of the neutrophil-to-lymphocyte ratio in ovarian cancer

Objective

To investigate the neutrophil-to-lymphocyte ratio (NLR) from peripheral blood, a general measure of inflammation, in ovarian cancer.

Methods

White cell counts and CA125 levels before treatment, tumor features, and questionnaire data on 519 women with ovarian cancer at two Boston hospitals were recorded. Counts were log-transformed and effects on these by tumor features and epidemiologic variables assessed by analysis of variance and generalized linear models. Cox proportional hazards models were used to assess effects on overall survival.

Results

Greater NLR was associated with higher tumor stage and grade, presence of ascites, and bilateral disease and correlated with risk factors including Jewish ethnicity, taller height, more ovulatory cycles, and family history of cancer in premenopausal women and talc use in all women. CA125 was positively correlated with neutrophil count, monocyte count, and NLR and inversely correlated with lymphocyte count. In a multivariate adjusted analysis, high NLR predicted poorer survival and high lymphocyte count better survival.

Conclusion

An elevated NLR before treatment signals more aggressive disease and correlates with risk factors for ovarian cancer. CA125 directly correlates with neutrophils which may reflect secretion of both CA125 and neutrophilic growth factors by the tumor. CA125 inversely correlates with lymphocytes which may reflect the ability of some neutrophilic factors to induce lymphopenia and/or binding of CA125 to lymphocytes removing CA125 from the serum pool. Links between NLR, CA125, and epidemiologic factors may provide new clues about the pathogenesis and progression of ovarian cancer.     

Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass

Objective

Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes.

Methods

Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI.

Results

809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI = 200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI).

Conclusion

HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.