An approach for immunoradiometric assay with metallic radionuclides: gallium-67-deferoxamine-dialdehyde starch-IgG

Radiogallium (Ga) labeling of an immunoglobulin-G-deferoxamine conjugate (DF-IgG) to a high-specific radioactivity was performed to allow the development of a radiometallic immunoradiometric assay (IRMA) system. To increase the specific radioactivity of Ga-DF-IgG, we used dialdehyde starch (DAS) as a multi-site spacer for the binding of DF to IgG. Six DF molecules bound to each IgG molecule after DAS conjugation. DF-DAS-IgG was then labeled with the previously reported 67Ga labeling solution, producing labeled IgG with a specific radioactivity of 11,766 MBq/mg IgG. Using this method, we labeled an anti-CA125 tumor-associated antigen monoclonal antibody (130-22), allowing the first application of 67Ga-DF-DAS-IgG to an IRMA system. With this system, a higher sensitivity could be obtained than with 125I IRMA. In addition, a very high correlation (r = 0.995) was obtained between serum CA125 levels as determined by 67Ga IRMA and 125I IRMA. Gallium-67-labeled antibodies with a high-specific radioactivity appear to hold promise for use in highly sensitive radioassay systems.     

Volume rendering and bicolour scale in double isotope studies: application to immunoscintigraphy and bone landmarking.

Combining the volume rendering and bicolour visualization techniques is proposed as an aid in interpreting single photon emission tomography (SPET) immunoscintigraphy (IS) recorded simultaneously with SPET bone landmarking (BL). The combination helps in localizing abnormal monoclonal uptake and in differentiating it from a physiological radioactivity distribution. The so-called rendered images (RIs) are obtained in both IS and BL studies according to a depth- weighted maximum activity projection algorithm. Fused BL and IS RIs are constructed by a simple, pixel by pixel addition. They are displayed using a bicolour grey-red scale, which makes it possible to visualize both studies by a transparency effect. This method was applied to patients suspected of suffering colorectal or ovarian cancer recurrences, in whom monoclonal antibodies against carcinoembryonic antigen, B72-3 or OC125 labelled with indium-111 were used.     

Volume rendering and bicolour scale in double isotope studies: application to immunoscintigraphy and bone landmarking

Combining the volume rendering and bicolour visualization tehniques is proposed as an aid in interpreting single photon emission tomography (SPET) immunoscintigraphy (IS) recorded simultaneously with SPET bone landmarking (BL). The combination helps in localizing abnormal monoclonal uptake and in differentiating it from a physiological radioactivity distribution. The so-called rendered images (RIs) are obtained in both IS and BL studies according to a depth- weighted maximum activity projection algorithm. Fused BL and IS RIs are constructed by a simple, pixel by pixel addition. They are displayed using a bicolour grey-red scale, which makes it possible to visualize both studies by a transparency effect. This method was applied to patients suspected of suffering colorectal or ovarian cancer recurrences, in whom monoclonal antibodies against carci-noembryonic antigen, B72-3 or OC125 labelled with indium-111 were used. Offprint requests to: A. Loboguerrero     

人附睾蛋白4单克隆抗体与免放试剂盒的制备及其对卵巢癌诊断的临床价值探讨

目的 制备人附睾蛋白4(HE4)单克隆抗体并研制免放分析试剂盒, 探讨其在卵巢癌临床诊断中的价值。 方法 用重组人HE4免疫小鼠, 通过细胞融合杂交瘤技术制备并筛选可以配对的HE4单抗, 用125I标记其中一株单抗, 研制HE4免放试剂盒, 并评价其检测的灵敏度。通过检测临床血清标本来评价其对卵巢癌诊断的灵敏度和特异度。 结果 筛选出了一对亲和力与特异性高的HE4单抗, 其免放试剂盒检测的灵敏度为3.65 pmol/L, 其对卵巢癌的临床诊断的灵敏度可达90.83%, 特异度为99.17%。 结论 制备的单克隆抗体亲和力高, 研制的免放试剂盒各项指标较好, 可用于卵巢癌的早期临床诊断和疗效观察, 降低卵巢癌患者的病死率。     

A fundamental study of immunoscintigraphy with 131I-labeled anti-CA 19-9 and anti-CEA monoclonal antibodies--imaging of tumor-bearing mice by IMACIS-1 and cell ELISA with human tumor cells

A study was made on 2 types of 131I-labeled anti-CA 19-9 and anti-CEA mouse monoclonal antibodies (IMACIS-1) against human cancer related antigen as to their usefulness in radioimmunoimaging. Tumor-bearing nude mice were used for comparison. The transplanted tumors (SW948, COLO 201) were clearly visualized 48-72 hours after administration of IMACIS-1. Tumor/blood ratio 72 hours after administration: 8.69 in COLO 201 and 5.70 in SW948, showing ca. 10-15 times as high as those in PC-3 and HEp-2. IMACIS-1 therefore is considered useful in radioimmunoimaging of cancer. Analysis was made by in vitro cell ELISA. As a result, both of the cells specifically reacted with anti-CA 19-9 but not anti-CEA.     

Semiquantitative in vitro binding assay of indium-111-labeled monoclonal antibodies to human cancer and normal tissues

We have developed a simple in vitro method for the semiquantitative assessment of the radiolabeled antibody binding to cancer and normal tissues. Indium-111-labeled F(ab')2 fragments of 17-1A and 19-9 monoclonal antibodies with well-characterized specificity for gastrointestinal cancer demonstrated similar binding properties between cultured cancer cells and membrane fractions of homogenates prepared from tumor tissues. All of the 17 colon cancer specimens and seven (64%) of 11 gastric cancer specimens obtained by surgery showed positive binding with 17-1A. Specific binding of 19-9 was observed in 9 (53%) colon cancers and 4 (36%) gastric cancers. However, some normal colon tissues were also positive with 111In-labeled 17-1A. Relative levels of CA 19-9 antigen expression, determined by the binding with radiolabeled antibodies, correlated with percent positive cells determined by the immunohistochemical assays. Furthermore, membrane fractions could be cryopreserved without losing antibody-binding activity. These results indicate that this assay can be used for testing the immunoreactivity of radiolabeled anti-tumor antibodies and in vitro binding properties to cancer and normal tissues.     

彩色多普勒超声联合肿瘤标志物检测对卵巢恶性肿瘤的诊断价值

目的：探讨彩色多普勒超声联合肿瘤标志物CA125、CA199对卵巢恶性肿瘤的诊断价值。方法：选取2009年1～12月在本院治疗的卵巢恶性肿瘤患者85例,回顾性分析二维超声、彩色多普勒血流显像及血清CA125、CA199水平,并将术前结果与术后病理进行对照。结果：单一的彩色多普勒超声阳性率为88.23%,CA125阳性率91.76%,CA199阳性率21.18%,彩色多普勒超声联合肿瘤标志物的诊断阳性率96.47%,联合检查较单项检查有统计学差异（P〈0.05）。结论：彩色多普勒超声联合血清CA125、CA199检查对卵巢恶性肿瘤诊断临床价值较高,大大提高了卵巢恶性肿瘤阳性诊断率。     

5种血清肿瘤标志物测定对诊断老年人肺癌的临床应用价值

目的了解5项肿瘤标志物与肺癌的相关性,从而为多指标联合诊断提供依据。方法取确诊肺癌老年患者治疗前后血清测定CEA、CA125、NSE、CA199、CA242与非肺癌患者对照。结果肺癌各组的CEA、CA125均值均高于正常参考值,肺腺癌组与健康对照组比较有显著统计学差异(P<0.01)。健康对照组及肺癌各组CA199、CA242的检测值均在正常范围内。健康对照组及肺癌、肺鳞癌的NSE在正常参考值内,只有小细胞肺癌的NSE明显高于正常参考值,与健康对照组比较,有显著统计学差异(P<0.01)。各项标志物的特异性均较高,但灵敏度不同。肺腺癌的CEA、CA125、CA242的灵敏度较高,小细胞肺癌的CEA、CAl25、NSE的灵敏度较高。选择两项阳性作为诊断指标,则肺癌、肺腺癌、小细胞肺癌的阳性率均达50%以上,与健康对照组比较均有显著统计学差异(P<0.01)。结论CEA、CA125、CA242可作为肺腺癌;NSE、CA125、CEA可作为小细胞肺癌较好的肿瘤标志物。联合检测中两项阳性率对肺癌诊断最有价值。     

^18FDG—PET诊断卵巢癌术后复发

目的 :评价18FDG PET诊断卵巢癌治疗后复发的价值。材料和方法 :对 2 0例临床疑有复发的卵巢癌患者进行了18FDG PET全身及腹部成像 ,并与CT、B超及CA12 5等进行比较。结果 :9例PET与CT、B超显示为阴性 ,且CA12 5正常。11例经病理证实肿瘤复发 :8/11例血清CA12 5升高 ;B超及CT等常规影像检查 9/11例阳性 ;10 /11例18FDG PET显示阳性。结论 :18FDG PET全身显像作为无创伤性检查技术 ,能及时探测到复发或扩散肿瘤的代谢变化 ,可以为卵巢癌术后随访提供一种有效的非侵入性影像学诊断方法。     

High-Grade Serous Ovarian Cancer: Use of Machine Learning to Predict Abdominopelvic Recurrence on CT on the Basis of Serial Cancer Antigen 125 Levels

PurposeThe aim of this study was to use machine learning to predict abdominal recurrence on CT on the basis of serial cancer antigen 125 (CA125) levels in patients with advanced high-grade serous ovarian cancer on surveillance.MethodsThis institutional review board–approved, HIPAA-compliant, retrospective, hypothesis-generating study included all 57 patients (mean age, 61 ± 11.2 years) with advanced high-grade serous ovarian cancer who underwent cytoreductive surgery from January to December 2012, followed by surveillance abdominopelvic CT and corresponding CA125 levels. A blinded radiologist reviewed abdominopelvic CT studies until recurrence was noted. Four measures of CA125 were assessed: actual CA125 levels at the time of CT, absolute change since prior CT, relative change since prior CT, and rate of change since prior CT. Using machine learning, support vector machine models were optimized and evaluated using 10-fold cross-validation to determine the CA125 measure most predictive of abdominal recurrence. The association of the most accurate CA125 measure was further analyzed using Cox proportional-hazards model along with age, tumor size, stage, and degree of cytoreduction.ResultsRate of change in CA125 was most predictive of abdominal recurrence in a linear kernel support vector machine model and was significantly higher preceding CT studies showing abdominal recurrence (median 13.2 versus 0.6 units/month; P = .007). On multivariate analysis, a higher rate of CA125 increase was significantly associated with recurrence (hazard ratio, 1.02 per 10 units change; 95% confidence interval, 1.0006-1.04; P = .04).ConclusionA higher rate of CA125 increase is associated with abdominal recurrence. The rate of increase of CA125 may help in the selection of patients who are most likely to benefit from abdominopelvic CT in surveillance of ovarian cancer.     

Modern trends in radioimmunotherapy of cancer: pretargeting strategies for the treatment of ovarian cancer.

A review of published data on some of the problems associated in treating cancer using radioimmunotherapy is presented. Potential improvements for this type of therapy using pretargeting strategies are discussed and preliminary results on a novel multistep regimen to treat human ovarian cancer are presented. A pretargeting strategy using a biotinylated, anti-CA125 monoclonal antibody (MAb) to attract biotinylated long-circulating liposomes to the surface of CA125-expressing ovarian cancer cells, was employed. Confocal laser scanning microscopy and fluorescent labels were used to establish the biodistribution patterns in NIH:OVCAR-3 (CA-125 positive) and SK-OV-3 (CA-125 negative) human ovarian cancer cells. Shedding kinetics of the pretargeted stage were measured using 125I labeled MAbs. No significant internalization of the MAb used in the pretargeting step was observed by 4 hrs. The antibody was gradually internalized starting at 6 hrs, and most of the labelled MAb was detected in cytoplasm by 24 hrs. Shedding and exocytosis of the antigen-MAb complex was not significant for up to 6-hours following administration of the iodinated MAb. Biotinylated liposomes were shown to specifically target the biotinylated MAb/streptavidin complex on the cell surface. We have demonstrated that by a three-step pretargeting approach, biotinylated liposomes can be specifically delivered to cells pretargeted with biotinylated MAb/SAv complex. The slow internalization and shedding properties of the two MAbs are ideal for multistep pretargeting methods. A successful multistep linkage was established with the biotinylated MAb B27.1, streptavidin and biotinylated liposomes to OVCAR-3 cells, but not to SK-OV-3 cells.     

18F-脱氧葡萄糖PET/CT显像在卵巢癌术后复发诊断及治疗中的价值

目的 探讨全身18F-脱氧葡萄糖(FDG) PET/CT显像在卵巢癌术后患者复发诊断和治疗中的价值.资料与方法 46例患者,行全身显像及局部延迟显像;以病灶最大标准摄取值(SUVmax)＞2.5伴密度异常为阳性,检测血清糖类抗原-125 (CA125).10个月内随访.结果 60例次全身显像,阳性48例次,30例次延迟显像SUVmax增加大于20％;CA125升高39例次.34例病灶在腹盆腔内,12例伴有其他部位转移.检查后化疗22例次,再手术12例次,放疗8例次,未治疗13例次.切除26处病灶中,25处肿瘤转移,准确率为96.2％.结论 PET/CT发现卵巢癌术后转移灶主要位于腹盆腔内;手术切除病例,CA125明显降低;多灶性病例行全身化疗或局部放疗;CA125正常病例,显像可提前发现转移病灶.     

卵巢恶性上皮性肿瘤化疗期间血清CA_(125)水平动态监测价值的初步探讨

目的　探讨血清CA12 5在评估卵巢恶性上皮性肿瘤化疗效果及预后方面的价值。方法　对 2 5例卵巢恶性上皮性肿瘤患者术前、后的化疗期间以及 8例存活率≥ 5年的患者 2次探查术前、后的血清CA12 5值进行了动态监测。结果　首次化疗期间 ,血清CA12 5值≥ 6 5U /ml者占 80 % (2 0 / 2 5 )。在化疗期间疗程之前 ,6 3.3% (14/ 2 2 )患者血清CA12 5值降至≤ 35U/ml;6例血清CA12 5值≥ 6 5U/ml患者中 ,5例盆腔内有癌肿持续存在。化疗第 3疗程以后各疗程期间 ,血清CA12 5值≥ 35U/ml者 6例 ,5例盆腔内有癌肿的复发或持续存在。存活时间≥ 5年 ,2次探查术组织病理学检查结果阴性的 5例中 ,4例血清CA12 5值持续 <2 0U/ml;癌肿复发者 3例 ,其血清CA12 5值均 >6 5U/ml。化疗期间 ,8例癌肿复发者中 ,有 6例血清CA12 5值的升高较临床发现平均早 4个月。结论　提示血清CA12 5值是监测卵巢恶性上皮性肿瘤临床病理变化的敏感肿瘤标记物 ;化疗第 3疗程之前 ,动态监测血清CA12 5值下降幅度是评价化疗效果及预后的重要依据。     

Superimposition of computed tomography and single photon emission tomography immunoscintigraphic images in the pelvis: validation in patients with colorectal or ovarian carcinoma recurrence.

A method of superimposing computed tomography (CT) and immunoscintigraphic (IS) single photon emission tomography (SPET) slices is presented and has been applied to 10 patients with suspected cancer recurrence. IS was performed with carcinoembryonic antigen (CEA)-specific indium-111 monoclonal antibodies (MoAbs) in 5 patients with colorectal cancer, and with OC125 111In-MoAbs in 5 patients with ovarian cancer. All patients had an abnormal CT image result in the pelvis, which was interpreted 5 times as recurrence, once as doubtful and four times as scar fibrosis. Recurrence was subsequently proven in all patients. Bone scintigraphy (BS) SPET was recorded at the same time as IS. No special technique was used during BS, IS or CT acquisition. CT images were fed into a computer using a CCD camera. Using the internal anatomical landmarks provided by the pelvic bone structures seen on CT and BS, an operator had to select corresponding fiducial points, which were used by the software to register the images. The final results were CT-BS and CT-IS superimposed images. CT-BS images were used for quality control. In all patients, the inspection of CT-BS and CT-IS showed that the registration process is accurate and assists in the co-interpretation of CT and IS images.     

血浆CYFRA21-1和CA125、CA199、CA153联合检测对肺癌的辅助诊断价值

目的：探讨血浆细胞角蛋白19片段（CYFRA21-1）和糖链抗原肿瘤标志物水平测定对肺癌诊断的临床意义。方法采用放射免疫分析法和化学发光免疫法检测了184例肺癌患者（包括81例肺鳞癌、68例肺腺癌和35例小细胞肺癌患者）的血浆CYFRA21-1和糖链抗原125、199和153（CA125、CA199和CA153）水平,并与51例肺部良性疾病患者和60名正常对照者进行了比较性分析;进行了肿癌标志物诊断肺癌的不同联合测定情况下的灵敏度、特异度和准确率的比较。结果与51例肺部良性疾病患者相比,184例肺癌患者的血浆CYFRA21-1、CA125、CA199和CA153水平显著升高（tCYFRA21-1=5.637, P〈0.001;tCA125=3.106, P〈0.01;tCA199=4.456, P〈0.001;tCA153=3.763, P〈0.01）。与60名正常对照者相比,184例肺癌患者的血浆CYFRA21-1、CA125、CA199和CA153水平显著升高（tCYFRA21-1=8.612,tCA125=4.067,tCA199=4.872, tCA153=8.673,P均〈0.001）。与60名正常对照者相比,51例肺部良性疾病患者的血浆CYFRA21-1水平显著升高（tCYFRA21-1=6.327,P〈0.001）;CA125和CA153水平升高（tCA125=2.264,tCA153=2.343,P均〈0.05）;CA199水平差异无统计学意义（tCA199=1.761,P〉0.05）。在184例肺癌中,81例肺鳞癌患者的血浆CYFRA21-1水平升高最为显著,68例肺腺癌患者的血浆CA125、CA199和CA153水平升高最为明显。单项肿瘤标志物检测CYFRA21-1的灵敏度（59.78%）和准确率（70.17%）最好,CA199的特异度（28.83%）最高。而四项联合检测肺癌的灵敏度（93.48%）和准确率（86.44%）为最高,明显高于单项和两项的检测。结论血浆CYFRA21-1、CA125、CA199和CA153水平测定是诊断肺癌的有价值肿瘤标志物,它们的联合测定可以提高诊断灵敏度和准确率。     

COX-1在卵巢癌组织中的表达及其意义

目的探讨环氧化酶-1（COX-1）在卵巢癌组织中的表达及其意义。方法应用免疫组化SP法检测37例卵巢癌和31例卵巢囊肿组织中COX-1和CA125蛋白的表达;应用ELISA法检测40例卵巢癌和31例卵巢囊肿以及60例正常体检者血清中COX-1和CA125的浓度。结果COX-1、CA125在卵巢癌组织的表达率分别为78%和57%,在卵巢囊肿的阳性表达率仅为7%和3%;卵巢癌患者血清COX-1、CA125的阳性率分别为65%和93%。结论COX-1蛋白表达可作为卵巢癌的辅助诊断指标。     

糖类抗原和癌胚抗原联合检测对肺癌的诊断价值

目的探讨联合测定患者血清和胸水中糖类抗原(CA125、CA199、CA153)和癌胚抗原(CEA)对肺癌的诊断价值。方法采用化学发光免疫法测定68例肺癌患者和38例肺结核患者血清以及胸水中CA125、CA199、CA153和CEA的含量。结果肺癌组患者血清中CEA、CA199、CA153的含量均明显增高且明显高于肺结核组患者血清中CEA、CA199、CA153的含量,有显著性差异(P<0.01)。而肺癌组患者和肺结核组患者血清中CA125的含量均明显增高,无显著性差异(P>0.05)。肺癌组患者胸水中CEA、CA125、CA199、CA153的含量均明显增高且明显高于肺结核组患者胸水中CEA、CA125、CA199、CA153的含量,CEA有显著性差异(P<0.01),CA125、CA199、CA153有显著性差异(P<0.05)。结论 CEA、CA125、CA199、CA153的血清和胸水联合检测可以提高肺癌诊断水平。     

CT diagnosis of intrasplenic metastasis from ovarian carcinoma

Intrasplenic metastases from ovarian carcinoma cannot be always demonstrated intraoperatively. CT is the most important imaging modality of choice for staging and follow-up ovarian cancer; in this study we searched CT appearances of intrasplenic metastases from ovarian carcinoma. We retrospectively reviewed imaging histories of the patients with ovarian cancer from the radiology information system, and found 12 patients with intrasplenic metastasis. All patients underwent abdominal CT with 16-MDCT. We searched number, density and maximum diameters of splenic metastasis. The growing rate of three lesions, which were followed up by CT, was calculated. Serum cancer antigen (CA) 125 levels were noted. We also evaluated clinical history and pathology reports of all patients. Splenic metastases, solitary or multiple, were detected most frequently during the follow-up (1-14 years after initial diagnosis) and most were associated with other sites of recurrence. The diameters of lesions ranged from 4 to 85mm. All lesions appeared hypodense except for one lesion with dense calcification. Densities of lesions ranged from 12 to 208 Hounsfield units (mean, 49±51HU). Most lesions appeared as solid well-defined nodules; however some lesions had lobulated and irregular contours with an infiltrative pattern. The growing rates of three lesions were 0.72mm/month, 1.75mm/month and 2.70mm/month. Eight patients had elevated serum CA 125 levels (40-1256U/mL). We concluded that CT can demonstrate intraparenchymal and infiltrative splenic metastasis in patients with ovarian cancer even in the absence of increased CA 125 levels.     

乳腺癌骨转移临床相关因素的研究

目的 研究乳腺癌骨转移的临床和影像学资料,寻找影响骨转移的相关因素,为早期诊断提供依据.方法 对334例乳腺癌患者全身骨显像、临床分期、病理、免疫组织化学及血清学检-查结果进行回顾性分析,并对数据行χ2检验.结果 有淋巴结转移者骨转移率71.0%（152/214）,没有淋巴结转移者骨转移率为22.5%（27/120）,两者比较差异有统计学意义（χ2=72.80,P=0.000） 浸润性非特殊性癌骨转移率69.0%（203/294）,浸润性特殊性癌骨转移率41.7%（5/12）,两者比较差异有统计学意义（χ2=3.97,P=0.046） 骨转移中碱性磷酸酶（ALP）升高者占28.5%（51/179）,非骨转移中ALP升高者占14.9%（11/74）,两者比较差异也有统计学意义（χ2=5.25,P=0.022） 而骨转移中肿瘤标志物[癌胚抗原（CEA）、糖类抗原（CA）15-3、CA125、CA19-9]升高者占68.7%（123/179）,非骨转移中肿瘤标志物升高者占27.0%（20/74）（χ2=37.03,P=0.000）.结论 乳腺癌骨转移的发生率与原发灶的病理类型、发病时有无淋巴结转移有关,浸润性非特殊性癌或有淋巴结转移者骨转移率较高.动态监测血清ALP、CEA、CA15-3、CA125、CA19-9有助于早期诊断.     

B超引导下术中125I粒子植入治疗晚期胰腺癌的疗效评价

目的 探讨B超引导下125I粒子组织间植入治疗晚期胰腺癌的临床价值。 方法 97例晚期胰腺癌患者在B超引导下术中植入125I粒子,采用疼痛数字分级法、实体瘤的疗效评价标准和肿瘤标志物糖类抗原242、19-9（CA242、CA19-9）的水平进行疗效评价,随访中观察患者的并发症及不良反应等。 结果 术前与术后1周、2周、1个月、3个月的患者疼痛评分比较,差异具有统计学意义（χ2=0.018、0.022、0.034、0.045,P均 < 0.05）;肿瘤完全缓解患者8例、部分缓解46例、稳定34例、疾病进展9例,总有效率为55.67%（54/97）;术前与术后1个月、3个月CA242、CA19-9的水平比较,差异具有统计学意义（χ2=0.027、0.029、0.017、0.022,P均 < 0.05）;治疗后中位生存时间为（8.0±4.5）个月,未出现严重并发症及不良反应。 结论 B超引导下125I粒子植入治疗晚期胰腺癌,疗效确切,安全性高,癌痛缓解明显。