Evaluation of soluble intracellular adhesion molecule-1 (sICAM-1) in benign and malignant ovarian masses

PURPOSE: To evaluate serum ICAM-1 levels preoperatively in patients with ovarian masses. METHODS: Estimation by ELISA assay in 101 women with pelvic tumours and 16 healthy controls was performed. Correlations of sICAM-1 levels with CA-125, Tumour Volume Index, morphological score and pathological findings were studied. RESULTS: Fifty-one ovarian tumours were malignant, five were borderline and 45 benign. Mean levels of sICAM-1 were respectively, 311.1 +/- 182.9 ng/ml, 172.6 +/- 40.1 ng/ml, 241.8 +/- 74.1 ng/ml and 195.6 +/- 68.7 ng/ml for controls. The area under ROC curve for sICAM-1 was 0.72 (95% CI 0.58-0.82), the cut-off 250 ng/ml, corresponding to 81.3% sensitivity and 52.9% specificity. Serum ICAM-1 correlated with morphological score (r = 0.51, p < 0.001), but not with FIGO stage, tumour grade, Tumour Volume Index and CA-125. CONCLUSION: sICAM-1 concentrations are higher in patients with malignant tumours, but poorly correlate with clinical status. The clinical use alone in ovarian malignancy detection and tumour differentiation seems to have limited application. Combinations of CA-125 and sICAM-1 could improve the test characteristics.     

Mutational analysis of TP53 and p21 in familial and sporadic ovarian cancer in Japan

OBJECTIVE: To investigate whether somatic mutations in cell cycle checkpoint genes, TP53 and p21, are involved in the development of ovarian cancer with or without BRCA1 germline mutation. METHODS: We analyzed somatic genetic alterations of TP53 and p21 in 46 ovarian cancer patients with BRCA1 germline mutations and 93 sporadic patients, using direct sequencing for the entire coding sequences in TP53 and p21. RESULTS: TP53 somatic mutations were detected in 25 of the 46 BRCA1 cases and 40 of the 93 sporadic cases (54.3% vs. 43.0%). In contrast, p21 somatic mutations were detected in 1 of the 46 BRCA1 cases and 2 of the 93 sporadic cases (2.2% vs. 2.2%). TP53 mutations in sporadic cases more frequently occurred in exons 6-11 than those in cases with germline BRCA1 mutations (84.4% vs. 56.3%: P = 0.013). The proportion of sporadic cases with TP53 mutations in non-serous tumors (e.g. endometrioid, clear cell, or mucinous) was significantly lower than that in serous tumors (18.5% vs. 53.0%: P = 0.0038). However, there was no significant difference between the proportion of BRCA1 cases with TP53 mutation in non-serous and in serous tumors (37.5% vs. 57.9%). CONCLUSIONS: Our results suggest that somatic mutation of TP53 plays less of a role in the carcinogenesis of sporadic non-serous tumors than in that of sporadic serous tumors or BRCA1-related tumors. Furthermore, p21 somatic mutation appears to be less involved in the development of ovarian cancer than TP53 somatic mutation.     

Comparison of candidate serologic markers for type I and type II ovarian cancer

Objective

To examine the value of individual and combinations of ovarian cancer associated blood biomarkers for the discrimination between plasma of patients with type I or II ovarian cancer and disease-free volunteers.

Methods

Levels of 14 currently promising ovarian cancer-related biomarkers, including CA125, macrophage inhibitory factor-1 (MIF-1), leptin, prolactin, osteopontin (OPN), insulin-like growth factor-II (IGF-II), autoantibodies (AAbs) to eight proteins: p53, NY-ESO-1, p16, ALPP, CTSD, B23, GRP78, and SSX, were measured in the plasma of 151 ovarian cancer patients, 23 with borderline ovarian tumors, 55 with benign tumors and 75 healthy controls.

Results

When examined individually, seven candidate biomarkers (MIF, Prolactin, CA-125, OPN, Leptin, IGF-II and p53 AAbs) had significantly different plasma levels between type II ovarian cancer patients and healthy controls. Based on the receiver operating characteristic (ROC) curves constructed and area under the curve (AUC) calculated, CA125 exhibited the greatest power to discriminate the plasma samples of type II cancer patients from normal volunteers (AUC 0.9310), followed by IGF-II (AUC 0.8514), OPN (AUC 0.7888), leptin (AUC 0.7571), prolactin (AUC 0.7247), p53 AAbs (AUC 0.7033), and MIF (AUC 0.6992). p53 AAbs levels exhibited the lowest correlation with CA125 levels among the six markers, suggesting the potential of p53 AAbs as a biomarker independent of CA125. Indeed, p53 AAbs increased the AUC of ROC curve to the greatest extent when combining CA125 with one of the other markers. At a fixed specificity of 100%, the addition of p53 AAbs to CA125 increased sensitivity from 73.8% to 85.7% to discriminate type II cancer patients from normal controls. Notably, seropositivity of p53 AAbs is comparable in type II ovarian cancer patients with negative and positive CA125, but has no value for type I ovarian cancer patients.

Conclusions

p53 AAbs might be a useful blood-based biomarker for the detection of type II ovarian cancer, especially when combined with CA125 levels.     

Mutation and expression of the TP53 gene in early stage epithelial ovarian carcinoma

OBJECTIVE: The early natural history of epithelial ovarian carcinoma remains poorly understood. Mutation of the TP53 gene is common in advanced-stage (III-IV) ovarian cancers, but less well described in early stage (I-II) tumors. The purpose of this study was to perform a comprehensive analysis of TP53 mutation and p53 expression status in early stage ovarian carcinomas. METHODS: Seventy-three cases of various histologic types, including 46 stage I and 27 stage II tumors, were subjected to direct sequence analysis of the entire TP53 coding region and exon-intron junctions as well as immunohistochemical assessment of p53 expression. RESULTS: Overall, mutations were identified in 24 of 73 (34%) cases. However, a significant difference in the distribution of mutations among histologic types was observed; TP53 mutations were present in 14 of 21 (67%) serous cancers and 11 of 52 (21%) non-serous cancers (P = 0.0002). Mutations were equally common between stage I and stage II tumors of serous histology. With respect to the correlation between TP53 mutation and p53 immunopositivity, the sensitivity (58%), specificity (71%), positive predictive value (64%), and negative predictive value (83%) were not sufficiently robust to justify use of p53 expression as a surrogate or screen for mutation. CONCLUSIONS: These data indicate that TP53 mutation is common in early stage ovarian carcinomas of serous histology, with a mutation frequency comparable to that reported for advanced-stage tumors, and is therefore likely to occur early in the progression of the most common histologic variant of ovarian carcinoma.     

Macrophage-colony stimulating factor and ovarian cancer]

BACKGROUND: In this study the use of macrophage-colony stimulating factor (M-CSF) as tumor marker for ovarian cancer is evaluated. METHODS: Serum samples were obtained from 74 patients, 43 of these were affected by ovarian carcinoma and 31 by benign ovarian tumors. The M-CSF levels were assayed with an ELISA method and compared with those of 148 healthy women. CA 125 levels were also evaluated. RESULTS: In healthy women the M-CSF levels were 770.4 +/- 145.9 U/ml, the upper limit of normal level was considered 1056 U/ml. Serum M-CSF levels were significantly high in patients with ovarian cancer (1425.3 +/- 1007.1 U/ml; p < 0.001) and in 29 of the 43 patients exceeded the limit of 1056 U/ml. No differences were observed among the histologic types. There were no significant differences between patients with benign ovarian pathology and healthy women. No definite relationship was found with CA 125, but evaluating at the same time M-CSF and CA 125 positive results were found in 95.3% of cases. CONCLUSIONS: Therefore M-CSF can be considered a marker for ovarian cancer, and the assay of its serum levels can be particularly useful in association with those of CA 125.     

No differences in p53 mutation frequencies between BRCA1-associated and sporadic ovarian cancers

OBJECTIVE: Mutation of the BRCA1 gene, which has incomplete penetrance, is involved in ovarian cancer development. Cell cycle check point inactivation via acquired somatic mutations in the check point regulatory genes, particularly p53, may be required for BRCA1-linked ovarian tumorigenesis. In the few studies directly comparing p53 mutations in BRCA1-linked and sporadic ovarian cancers, data have been contradictory. This study aimed to clarify the role of p53 mutation in BRCA1-associated and sporadic ovarian cancer by comparing two, large, matched cohorts from two different populations who developed BRCA1-linked or sporadic ovarian cancers. METHODS: Forty-eight BRCA1-associated ovarian tumor samples (22 from Australia and 26 from Norway) were collected and matched with 48 sporadic ovarian cancers for tumor stage, grade, histological subtype, and patient age. Expression of p53 protein was measured by immunohistochemistry (IHC). RESULTS: Consistent with the presence of a mutated p53 protein, the majority of BRCA1-associated (79%) and sporadic (73%) ovarian carcinomas from Australia and Norway overexpressed p53 protein. There was no significant difference between BRCA1-linked ovarian cancers and their sporadic counterparts with regard to p53 protein expression (P = 0.5). CONCLUSION: Our results suggest that p53 inactivation is associated with both BRCA1-associated and sporadic ovarian tumorigenesis, and that BRCA1-linked and sporadic ovarian cancers may develop through a similar carcinogenic pathway.     

Evaluation of Preoperative Serum Levels of CA 125 and Expression of p53 in Ovarian Neoplasms: A Prospective Clinicopathological Study in a Tertiary Care Hospital

Objectives

To assess the preoperative serum levels of CA 125 with its diagnostic role and to evaluate the p53 expression in patients of primary ovarian neoplasms. We also wished to judge their relationship with other parameters like clinical staging and histopathologic tumor type.

Materials and Methods

The present study was conducted on 86 patients during the study period of 2.5 years. Preoperative CA 125 levels were evaluated by an automated immunoassay analyzer. p53 expression was judged immunohistochemically with pre-diluted monoclonal antibody. An objective scoring was done depending on distinct nuclear immunopositivity.

Results

Median value of preoperative CA 125 levels was 32 U/mL in benign surface epithelial-stromal tumors (BSEST), 53 U/mL in borderline surface epithelial-stromal tumors (BOT), 346 U/mL in malignant surface epithelial-stromal tumors (MSEST) and 560 U/mL in serous adenocarcinomas (SAC). Most of ovarian tumors were in the FIGO stage I (64 cases, 74.4%), but higher stages (II, III, IV) were observed mostly in MSESTs. SACs displayed the maximum p53 expression. Considering the cut-off value of more than 35 U/mL in CA 125 levels, the sensitivity to diagnose MSESTs was 94.7%. Preoperative CA 125 levels strongly and positively correlated with FIGO staging and p53 expression. Similarly p53 expression strongly and positively correlated with FIGO staging and histopathological categories.

Conclusion

Higher values of preoperative CA 125 levels and higher expression p53 are associated with MSESTs and BOTs especially of serous type. They strongly correlate with each other and with tumor stage. But there is no serum CA 125 concentration that can clearly differentiate benign and malignant ovarian masses.     

Loss of Expression of the p16 Tumor Suppressor Gene Is More Frequent in Advanced Ovarian Cancers Lacking p53 Mutations

OBJECTIVE: The aim of this study was to test the hypothesis that p53 mutations are less frequent in ovarian cancers with alterations in other genes that regulate G1 progression. METHODS: Expression of G1 stimulatory (cyclins D1 and E, cdk4, Ki67) and inhibitory (p16, Rb, p27, p14) genes was analyzed using Western blots in 84 primary ovarian cancers and seven cell lines of known p53 mutation status. Expression of p16 and Rb also was determined using immunohistochemistry and the p16 gene was examined for homozygous deletions and mutations. RESULTS: Loss of p16 protein was more frequent in ovarian cancers with wild-type p53. All four cell lines with wild-type p53 had lost p16 compared to only one of three with mutant p53 genes. p16 expression was absent in 34% (28/82) of primary ovarian cancers, and this was significantly more common in cases with wild-type p53 (14/28, 50%) compared to those with p53 mutations (14/54, 26%, P = 0.03). Homozygous deletion of the p16 gene was found in cell lines lacking p16, but not in any primary cancers. p16 loss was more common in serous (21/52, 40%) than nonserous cancers (4/23, 17%, P = 0.07). Cases that expressed p16 were more likely to express high levels of Rb (47/55, 85%) than p16-negative cases (12/28, 43%, P < 0.001). Loss of Rb occurred in 5/30 (17%) ovarian cancers lacking p53 mutations compared to 5/54 (9%) cases with p53 mutations (P = 0.48). Expression of G1 stimulatory proteins (cyclins D1 and E, cdk4, Ki67) did not correlate with p53 mutation status. CONCLUSIONS: Loss of expression of the p16 tumor suppressor occurs more often in ovarian cancers lacking p53 mutations. These data are consistent with the paradigm that inactivation of p53 is less of a requisite event in ovarian carcinogenesis when another G1 regulatory gene such as p16 already has been inactivated.     

术前测定血清CA125、CA199、CA724、CEA和GM-CSF在鉴别附件包块性质中的作用

探讨术前测定患者血清CA12 5、CA19 9、CA72 4、CEA和GM -CSF水平在鉴别附件包块良恶性质中的作用。方法 :74例附件包块患者术前 1周内采外周血 ,用固相免疫放射法测定各种肿瘤标志物浓度 ,并与术后组织学诊断比较。计算各标志物单独和联合应用诊断卵巢癌的相应诊断参数。结果 :( 1)CA12 5(临界值 70U/ml)鉴别卵巢肿瘤性质的敏感性和特异性分别为 85 71%和 82 61% ,CA19 9(临界值 30U/ml)分别为 4 2 86%和 73 33% ,CA72 4 (临界值 3 8U/ml)分别为 53 57%和 90 90 % ,CEA(临界值 5ng/ml)分别为 4 6 4 3%和 4 8 89% ;( 2 )联合应用肿瘤标志物 :CA12 5联合CA19 9的敏感性和特异性分别为 89 2 9%和 73 33% ;CA12 5联合CA72 4的敏感性和特异性分别为 89 2 9%和 75 56% ;CA12 5联合CEA的敏感性和特异性分别为 92 86%和 4 0 0 0 % ;( 3)如果去除 9例子宫内膜异位症 ,CA12 5、CA19 9、CA72 4和CEA的特异性分别增至 89 19% ,80 55% ,94 2 9%和4 7 2 2 %。结论 :此项研究应用的肿瘤标志物中以CA12 5最为敏感。将CA12 5临界值定为 70U/ml时诊断效果最佳。CA72 4的特异性最高 ,但诊断卵巢癌的敏感性低。CEA的诊断价值有限 ,GM -CSF则无价值。CA12 5与其他肿瘤标志物联合检测时诊断的特异性会部分丧失。?     

Preoperative discrimination between ovarian carcinoma, non-ovarian gynecological malignancy and benign adnexal masses using serum levels of CA125 and the polymorphic epithelial mucin antigens CASA, OSA and MSA

Serum levels of the tumor associated antigens CA125, CASA, OSA and MSA were determined preoperatively in a non-consecutive series of patients with: invasive epithelial ovarian cancer (OC, n = 87), ovarian tumors of low malignant potential (LMP, n = 9), benign adnexal masses (BAM, n = 48) and other peritoneal and pelvic malignancies ( n = 48). In addition, serum levels of CASA, OSA, and MSA were determined in 3477 asymptomatic well women. Ninety-eight percent of the asymptomatic women had CASA levels < 6.0 U ml⁻¹, OSA levels < 5.5 U ml⁻¹ and MSA levels < 80.0 U ml⁻¹. Serum CA125 levels were> 35 U ml⁻¹ in 89% of OC, in 44% of LMP, and in 23% of BAM. Serum CASA levels were> 6.0 U ml⁻¹ in 58% of OC, in 0% of LMP, and in 0% of BAM. Serum OSA levels were> 5.5 U ml⁻¹ in 61% of OC in 0% of LMP and in 4% of BAM. Serum MSA levels were> 80.0 U ml⁻¹ in 56% of OC, in 11% of LMP, and in 10% of BAM. When cut-off levels were set to exclude all patients with BAM, the best discrimination from OC using a single assay was achieved using CASA (58%). However, a combination of CASA and CA125 gave positive levels in 69% of OC at levels which precluded BAM. All markers were also elevated in some colon cancers, cervical cancers, uterine cancers and other peritoneal malignancies. A combination of CA125 and CASA levels, obtained preoperatively may assist the general gynecologist in avoiding potentially difficult oncologic surgery.     

Clinical significance of new tumor marker CA 125 in gynecological cancer--particularly usefulness in diagnosis of ovarian cancer

A concentration in sera of a new antigen CA125 related to cancer of the ovary was measured by radioimmunoassay which used a monoclonal antibody, and its usefulness as a tumor marker in the diagnosis of cancer of the ovary was investigated. The mean values for CA125 in sera of healthy controls (80 females) were 14.2 +/- 12.2 U/ml. Mean values for CA125 in sera of various patients were 29.0 +/- 39.6 for myoma uteri (30 cases), 26.7 +/- 30.1 for benign ovarian tumors (10 cases), 64.4 +/- 146.2 for cervical carcinoma (14 cases), and 31.5 +/- 19.8 for endometrial carcinoma (6 cases), whereas the mean values for ovarian cancers (23 cases) were as high as 311.3 +/- 250.4. On the other hand, positive rates for CA125, when the cut-off value was set to 65 U/ml, were 1.3% for healthy controls (1 out of 80 cases), 10.0% for myoma uteri (3 out of 30 cases), 10.0% for benign ovarian tumors (1 out of 10 cases), 14.3% for cervical carcinoma (2 out of 14 cases), and 16.7% for endometrial carcinoma (1 out of 6 cases), whereas the positive rate for ovarian cancers was 78.3% (18 out of 23 cases). Especially for serous cystadenocarcinoma, the positive rate was 100% (10 out of 10 cases). From the above, the measurement of CA125 in sera was considered to be significant in the diagnosis of ovarian cancer.     

Assessment of soluble intracellular adhesion molecule-1 (sICAM-1) in women with benign ovarian tumors

OBJECTIVES: Overexpression of intracellular adhesion molecule-I (ICAM-1) was observed in many benign and malignant tumors. The aim of our study was to evaluate its serum concentrations as well as CA-125 in women with benign ovarian tumors. MATERIALS AND METHODS: Forty-five women treated surgically because of benign ovarian mass. RESULTS: Mean concentrations of sICAM-1 in benign tumors was 241.8+/-74.1 ng/ml and 195.6+/-68.7 ng/ml in healthy controls. No correlations between sICAM-1 concentrations and leukocyte count, tumor volume, BMI and obstetrical history. Efficiency in tumor differentiation was higher for CA-125 than sICAM-1 (area under Receiver Operating Characteristic curve 0.78 and 0.63 respectively). We observed higher sICAM-1 concentrations in fibrothecomas and lower in endometrial and dermoid cysts. CONCLUSIONS: Serum ICAM-1 concentrations correlate with some histological types of benign tumors, but not with tumor volume. Levels of CA-125 are more effective than ICAM-1 in ovarian tumors differentiation.     

Prognostic significance of p53 and p21(waf1/cip1) immunoreactivity in epithelial cancers of the ovary

OBJECTIVES: Theprognostic value of p53 expression in epithelial ovarian cancer remains unresolved. We hypothesized that prognosis may relate more to expression of p21(waf1/cip1), the major downstream effector of p53, which can also be induced through p53-independent mechanisms. We therefore studied the relationship of p53 and p21(waf1/cip1) expression in epithelial ovarian cancers to clinicopathological variables and prognosis. METHODS: Fixed, embedded tumors from 85 patients with untreated, primary epithelial ovarian cancer were immunostained with antibodies to p53 and p21(waf1/cip1). Expression was correlated with clinicopathological features and prognosis. Survival curves were calculated by the Kaplan-Meier method and compared using the log-rank test for p53, p21(waf1/cip1), and all combinations of expression of the two markers. RESULTS: Sixty-two percent of tumors expressed p53, and 42% expressed p21(waf1/cip1). There was no correlation between p53 and p21(waf1/cip1) expression. Advanced stage, grade, age >/=50, and p53 expression were associated with worse disease-free survival. Patients whose tumors were p53(+)/waf1(-), however, had a particularly strong association with poorer disease-free survival when compared with other combinations of p53 and p21(waf1/cip1) expression (P = 0.003). Neither p53, nor p21(waf1/cip1), nor combinations of expression were independently related to survival when histology, age, stage, and differentiation were considered. CONCLUSIONS: p53 expression in the absence of p21(waf1/cip1) expression is a better marker of poor prognosis than either p53 or p21(waf1/cip1) expression status alone in univariate analysis. Absence of independent prognostic significance may be related to the paucity of early stage cases in the current study.     

Potential markers that complement expression of CA125 in epithelial ovarian cancer

BACKGROUND: When ovarian carcinoma is diagnosed in stage I, up to 90% of patients can be cured with surgery and currently available chemotherapy. At present, less than 25% of cases are diagnosed at this stage. To increase the fraction of ovarian cancers detected at an early stage, screening strategies have been devised that utilize a rising serum CA125 level to trigger the performance of transvaginal sonography. One limitation of CA125 as an initial step in such a screening strategy is that up to 20% of ovarian cancers lack expression of the antigen. Serum tumor markers that can be detected in ovarian cancers that lack CA125 expression might improve the sensitivity for early detection. METHODS: From 296 ovarian cancers, 65 (22%) were found to have weak or absent CA125 expression on immunoperoxidase staining. Tissue expression of CA125 was compared to serum CA125 levels. Using immunoperoxidase staining of tissue arrays, we have assessed expression of 10 potential serum tumor markers in the 65 epithelial ovarian cancers with little or no CA125 expression and in ovarian cystadenomas, tumors of low malignant potential, normal ovaries, and 16 other normal tissues. RESULTS: Low or absent expression of CA125 in surgical specimens of epithelial ovarian cancer was associated with low levels of serum CA125 in pre-operative serum specimens. In ovarian cancers that lacked CA125, all specimens (100%) expressed human kallikrein 10 (HK10), human kallikrein 6 (HK6), osteopontin (OPN), and claudin 3. A smaller fraction of CA125-deficient ovarian cancers expressed DF3 (95%), vascular endothelial growth factor (VEGF) (81%), MUC1 (62%), mesothelin (MES) (34%), HE4 (32%), and CA19-9 (29%). When reactivity with normal tissues was considered, however, MES and HE4 showed the greatest specificity. Differential expression was also found for HK10, OPN, DF3, and MUC1. CONCLUSIONS: At the level of tissue expression, each of 10 potential serum markers could be detected in 29-100% of ovarian cancers that had low or absent expression of CA125. Several markers exhibited more intense expression in cancers than in normal organs. Further investigation is needed to demonstrate complementary expression of markers in serum.     

Increased prevalence of p53 overexpression from typical endometriosis to atypical endometriosis and ovarian cancer associated with endometriosis

OBJECTIVE: To evaluate the expression of p53, c-erb-B-2, MIB1 and Bcl-2 in normal endometrium, endometriosis, atypical endometriosis and ovarian cancer associated with endometriosis, looking for immunohistochemical markers that may help determine endometriosis with premalignant potential. STUDY DESIGN: Between 1948 and 1999, 410 epithelial ovarian cancers and 521 cases of endometriosis were surgically treated at Fundación Jiménez Díaz. Pathology reports and slides were reviewed. Four groups were defined: (1) endometriosis/cancer (n=17); (2) atypical endometriosis (n=6); (3) endometriosis (n=17); (4) endometrium (n=7). Tumors and controls were immunostained and evaluated for expression of p53, c-erb-B-2, MIB1 and Bcl-2. Statistical analysis was performed using Chi-square for linear trends, Fisher exact and Kruskal-Wallis tests. RESULTS: Of the 410 cancers, 17 (4.1%) had associated endometriosis and of the 521 endometriosis, 6 (1.2 %) had atypical changes. Fourteen of 17 (82.4%) cancers associated with endometriosis and all atypical endometriosis had p53 overexpression. Only 2 of 17 (11.8%) endometriosis and none of the endometriums had mutant p53 (P<0.01). We found a trend towards increased expression of MIB1 (0.073) in the cancer and atypical endometriosis groups, and no differences in expression of Bcl-2 or c-erb-B-2. The sensitivity and specificity of p53 as a marker for the diagnosis of atypical endometriosis and cancer associated with endometriosis were 87%; CI 95% (73.2-100%) and 92% (80.6-100%), respectively. When comparing all groups, the mean positive p53 and MIB1 cell count was statistically significant (P=0.01). CONCLUSIONS: Overexpression of p53 in atypical endometriosis and cancer associated with endometriosis is a common finding and may be used to identify endometriosis with premalignant potential.     

Correlations of serum CA125 level and computerized tomography (CT) imaging with laparotomic findings following intraperitoneal chemotherapy in patients with ovarian cancer

The aim of this study was to evaluate the role of serum CA125 levels and computerized tomography (CT) scans in predicting pathologic response of intraperitoneal chemotherapy in patients with ovarian cancer. We prospectively analyzed serum CA125 levels and abdominopelvic CT scans obtained after the completion of intraperitoneal chemotherapy in 52 patients with ovarian cancer and compared the results with subsequent laparotomic findings, which served as the gold standard for statistical analysis. Laparatomy revealed either microscopic or macroscopic residual disease in 20 patients, while 32 patients were completely tumor-free. CA125 levels correlated significantly with laparotomic findings (p=0.003, u=1405). Median CA125 values in patients with residual tumors and in tumor-free patients following intraperitoneal chemotherapy were 14.6 (1-775) and 7.2 (1-37) U/ml, respectively. Although CT-imaging and CA 125 levels had a high specificity (100% and 96.9%, respectively), they showed a low sensitivity rate (50% and 40%, respectively). Similarly, despite high positive predictive values (100% and 88.9%, respectively), the negative predictive values were 76.2% and 72.1%, respectively. Conclusion: Although highly specific, CT scans and CA125 levels do not accurately indicate the presence of disease. Due to a high false-negative rate, a normal CT scan or a normal CA125 value is not sufficient to replace a laparotomy.     

Preoperative serum vascular endothelial growth factor (VEGF) in ovarian masses

PURPOSE OF THE INVESTIGATION: To determine the diagnostic value of serum vascular endothelial growth factor (VEGF) in the preoperative assessment of the nature of ovarian masses. MATERIALS AND METHODS: A prospective cohort study was conducted from August 2001 to September 2002 on 40 premenopausal and 23 postmenopausal patients with ovarian masses. During preoperative workup, patient age, serum Ca-125 levels, serum VEGF levels, and tumor volume based on ultrasonographic examination were determined. Laparoscopic (n=23) or laparotomic (n=39) approaches were undertaken to obtain the final pathologic result. According to the final ovarian pathology, follicular cysts, corpus luteum cysts and endometriomas were grouped as non-neoplastic ovarian masses (n=40, group I). Serous or mucinous cyctadenomas, dermoid tumors and fibromas were allocated into the neoplastic benign ovarian mass group (n=10, group II). Primary malignant ovarian neoplasms were categorized into the neoplastic-malign group (n=12, group III). RESULTS: Mean ages of cases among groups I, II and III were 39.0 +/- 2.0, 42.2 +/- 5.2 and 56.9 +/- 4.2, respectively. As age of the cases enrolled in this sudy increased, the more likely was the occurrence of neoplastic malign ovarian pathologies (p < 0.001). Among postmenopausal cases diagnosed with an ovarian mass, serum Ca-125 levels were 113.5 +/- 20 IU/ml compared to those in premenopausal cases (85.8 +/- 16.0, p = 0.05). The values for serum VEGF values among pre- and postmenopausal ovarian masses were 46.2 +/- 6.7 pg/ml and 68.2 +/- 7.9, respectively (p = 0.04). In group I, serum VEGF levels of endometriomas (56.5 +/- 1.5 pg/ml) were higher compared to those of follicular or corpus luteum cysts (30.6 +/- 2.8, p = 0.05). In contrast, tumor size appeared to be larger in non-endometriotic. non-neoplastic cysts (10.1 +/- 2.0 cm), compared to endometriomas (6.4 +/- 0.6 cm, p < 0.01). Serum VEGF levels of group III were higher than other groups (p < 0.001). With respect to the discriminating benign or malign nature of the mass, with a specific cut-off value of serum VEGF level of 68.7 pg/ml, the sensitivity, specificity, positive and negative likelihood ratios were 92.3%, 88.0%, 3.3 and 0.1, respectively. For serum Ca-125 levels, the sensitivity, specificity, positive and negative likelihood ratio with a statistically relevant cut-off value of 102 IU/ml were, 76.9%, 76.0%, 3.21 and 0.3, respectively. Area under curve (AUC) for serum VEGF and Ca-125 values were 0.938 (95% CI: 0.81-0.96) and 0.769 (95% CI: 0.64-0.86), respectively (p = 0.02). Among the postmenopausal group, AUC for serum VEGF and Ca-125 was detected as 0.902 (95% CI: 0.70-0.98) and 0.873 (95% CI: 0.66-0.91) (p = 0.14). CONCLUSION: Serum VEGF has the potential to be considered as a tumor marker with a good diagnostic relevance in differentiating the nature of ovarian masses.     

血清人附睾分泌蛋白4和CA125水平检测在卵巢恶性肿瘤中的诊断价值

目的 探讨血清人附睾分泌蛋白4(HE4)和CA125水平检测在卵巢恶性肿瘤诊断中的价值.方法 用酶联免疫吸附试验方法 对卵巢恶性肿瘤组(30例)、盆腔良性疾病组(110例,其中卵巢良性肿瘤45例、子宫内膜异位症和子宫腺肌病57例和盆腔炎8例)和正常组(137例)妇女血清中HFA和CA125水平进行双盲检测,结果 以中位数表示,分析两指标单独或联合检测诊断卵巢恶性肿瘤的价值.血清HF4和CA125正常值分别为0～150 pmoVL和0～35 kU/L,单独或联合检测时,其中任一指标高于正常值即定为阳性.结果 (1)卵巢恶性肿瘤组血清HE4和CA125水平分别为244 pmol/L 和601 kU/L,分别与盆腔良性疾病组(分别为32 pmoVL和22 kU/L)和正常组(分别为32 pmol/L和11 kU/L)比较,差异均有统计学意义(P<0.05).卵巢恶性肿瘤组血清HE4单项检测的阳性率为63.3%,明显低于血清CA125项榆测的阳性率(86.7%,P=0.036).(2)单项检测时,以盆腔良性疾病组作参照人群时,HE4和CA125单项检测的受试者工作特征曲线下面积(ROC-AUC)分别为0.900和0.840,其特异度为100%时的敏感度分别为70%和7%,两者比较,差异有统计学意义(P=0.000);以正常组作参照人群时,HE4和CAl25单项检测的ROC-AUC分别0.904和0.914,其特异度为100%时的敏感度分别为67%和87%,两者比较,差异有统计学意义(P=0.031).(3)联合检测时,以盆腔良性疾病组作参照人群时,HE4+CA,笛联合检测和CA125单项检测的ROC-AUC分别为0.894和0.840,其特异度为100%时的敏感度分别为50%和7%,两者比较,差异有统计学意义(P=0.000).以正常组作参照人群时,HE4+CA125联合榆测和HE4单项检测的ROC-AUC分别为0.914和0.904,其特异度为100%时的敏感度分别为87%和67%,两者比较,差异有统计学意义(P=0.031).以盆腔良性疾病组作参照人群时,HE4+CA125联合检测在特异度为100%时的敏感度(50%)虽然低于HE4单项检测(70%),但两者比较,差异无统计学意义(P=0.070).(4)以ROC曲线最左上方的点86 pmol/L、正常组95%参考值50 pmoVL和正常值的上限150 pmol/L为界值点,比较HE4单项检测对卵巢恶性肿瘤的诊断能力,结果 显示,界值点为50 pmol/L时的特异度和阳性预测值分别为95%和63%,明显低于界值点为86(分别为100%和95%)和150 pmoVL(均为100%)时的特异度和阴性预测值(P<0.01).结论 HE4单项检测诊断卵巢恶性肿瘤的特异度优于CA125单项检测,两者联合检测可以提高诊断能力.以150 pmol/L为界值点,对卵巢恶性肿瘤的诊断正确率更高,而以86 pmol/L为界值点有利于卵巢恶性肿瘤的筛查、降低漏诊率.     

Vascular endothelial growth factor (VEGF) improves the sensitivity of CA125 for differentiation of epithelial ovarian cancers from ovarian cysts

Background

The present study aimed to compare the diagnostic value of preoperative serum levels of CA125 and vascular endothelial growth factor (VEGF), and the combination of both biomarkers for differentiating early stage epithelial ovarian cancers from ovarian cysts.

Materials and methods

In this study, preoperative and postoperative serum levels of CA125 and VEGF of 30 patients with epithelial ovarian cancers (cancer arm) compared with that of 30 patients with benign ovarian cysts (cyst arm). Initial eligibility included having an ovarian cystic or solid mass detected by transvaginal ultrasonography at the hospital clinic. Included patients had to have localized pelvic disease and no clinical or imaging evidence of extrapelvic disease, ascites and distant metastasis. Initial exclusion criteria included prior history of malignancy or any type of cancer treatment. After surgery, only patients with pathologic diagnosis of early stage epithelial ovarian cancer and ovarian cyst were included.

Results

Preoperative serum levels of CA125 (P < 0.001) and VEGF (P < 0.001) were significantly higher in the study arm compared to the control arm. In addition, postoperative serum levels of CA125 (P < 0.001) and VEGF (P < 0.001) in study arm were significantly decreased compared to preoperative serum levels. At usual clinical cut-off levels of 17.6 pg/ml for VEGF and 35 U/ml for CA125, the sensitivity and specificity for detecting early stage epithelial ovary cancer were 90 and 57 % for VEGF and 66.6 and 73 % for CA125, respectively. At 100 % specificity for each test, the addition of VEGF to CA125 increased the sensitivity of early ovarian cancer detection from 60 to 73.3 %.

Conclusion

This study indicates that the addition of VEGF serum value improves the specificity and the sensitivity of CA125 to detect early stage epithelial ovarian cancers, and to differentiate these neoplasms from ovarian cyst.     

Preoperative evaluation of CA 125 and CA 19-9 serum levels in patients with ovarian masses

Serum CA 125 and CA 19-9 were presurgically measured in 40 patients with ovarian carcinoma and in 108 with benign ovarian pathologies. The sensitivity for ovarian carcinoma of CA 125 (cut-off value = 65 U/ml) and CA 19-9 (cut-off value = 40 U/ml) were 67.5% and 37.5% respectively. In particular serum CA 125 was elevated in 71.9% of non-mucinous and in 50% of mucinous carcinomas, while serum CA 19-9 was high in 25% of non-mucinous and in 87.5% of mucinous malignancies. The correlation of CA 19-9 with mucinous histotype was significant. Elevated serum levels of CA 125 and CA 19-9 were observed respectively in 14.7% and in 13.8% of benign adnexal masses. The percentages of elevated serum marker levels were significantly higher in patients with ovarian carcinoma than in women bearing benign ovarian pathology (P less than 0.001 for CA 125; P less than 0.01 for CA 19-9). Serum CA 125 and CA 19-9 alone cannot clarify the nature of an adnexal mass. However, the measurement of serum levels of these markers could give additional information to other diagnostic methods, such as ultrasonography, for discriminating benign from malignant ovarian pathologies.