ADAR1 protein induces adenosine-targeted DNA mutations in senescent Bcl6 gene-deficient cells.

Somatic mutations accumulate in senescent cells. Bcl6, which functions as a transcriptional repressor, has been identified as a potent inhibitor of cell senescence, but a role of Bcl6 in the accumulation of somatic mutations has remained unclear. Ig class-switch recombination simultaneously induces somatic mutations in an IgM class-switch (Ig-Sµ) region of IgG B cells. Surprisingly, mutations were detected in the Ig-Sµ region of Bcl6-deficient IgM B cells without class-switch recombination, and these mutations were mainly generated by conversion of adenosine to guanosine, suggesting a novel DNA mutator in the B cells. The ADAR1 (adenosine deaminase acting on RNA1) gene was overexpressed in Bcl6-deficient cells, and its promoter analysis revealed that ADAR1 is a molecular target of Bcl6. Exogenous ADAR1 induced adenosine-targeted DNA mutations in IgM B cells from ADAR1-transgenic mice and in wild-type mouse embryonic fibroblasts (MEFs). These mutations accumulated in senescent MEFs accompanied with endogenous ADAR1 expression, and the frequency in senescent Bcl6-deficient MEFs was higher than senescent wild-type MEFs. Thus, Bcl6 protects senescent cells from accumulation of adenosine-targeted DNA mutations induced by ADAR1.

IgG antibodies to HPV16, 52, 58 and 6 L1-capsids and spontaneous regression of cervical intraepithelial neoplasia.

To identify the predictive markers for spontaneous regression of cervical intraepithelial neoplasia (CIN), we examined whether IgG antibody responses to common human papillomavirus (HPV) L1-capsids correlate with CIN regression. In a cohort study, a total of 116 Japanese women with CIN grade I/II were tested for cervical HPV DNA and serum IgG antibodies to HPV16/52/58/6 L1-capsids. Our data suggest that baseline IgG reactivities to HPV L1-capsids do not serve as a predictive marker of CIN regression, in contrast to histological CIN grades and HPV DNA status.

Oncolytic viral therapy for cervical and ovarian cancer cells by Sindbis virus AR339 strain.

PURPOSE: Recently, the application of replication-competent viruses has been studied as anticancer agents. Sindbis virus (SIN) is an RNA virus that belongs to the Alphavirus genus in the Togaviridae virus family. The AR339 strain of SIN has not been reported to induce any serious disease to humans. EXPERIMENTAL DESIGN: In this study, we evaluated the feasibility of the replication-competent SIN AR339 strain as an agent for cervical and ovarian cancer therapy. RESULTS: SIN infection was able to induce cytopathic effects and apoptosis in two cervical cancer cells (HeLaS3 and C33A) and three ovarian cancer cells (HOC-1, HAC-2, and OMC-3) but not in normal human keratinocytes in vitro. The analysis of cell viability, virus protein synthesis, and viral growth showed the cancer-specific cytotoxicity and virus growth of SIN. In nude mice, i.t. and i.v. inoculation of SIN resulted in significant regression of established cervical tumors implanted at their backs. Histologic studies revealed that systemic treatment with the single injection of SIN induces necrosis within tumors at a remote site. In the metastasis model of ovarian cancer, suppression of ascites formation was observed in nude mice with i.p. SIN treatment. By using an in vivo green fluorescent protein imaging system, we also showed that systemic treatment with SIN targeted tumors specifically. CONCLUSIONS: Our study suggested that SIN AR339 strain has a possibility as a novel agent for human cervical and ovarian cancer therapy.

Increased expression of GRP94 protein is associated with decreased sensitivity to X-rays in cervical cancer cell lines.

PURPOSE: Radiation therapy is one of the standard treatments for cervical cancer. Glucose regulated protein 94 (GRP94) is a molecular chaperone, which increases in amount after X-ray irradiation. This study examined the involvement of GRP94 in radio-resistance in human cervical cancer cells. MATERIALS AND METHODS: Seven human cervical carcinoma cell lines (HeLa, SKG-I, SKG-IIIb, QG-U, Caski, SiHa and C33A) were examined for basal levels of GRP94 protein by western blotting analysis. Sensitivity to X-ray irradiation of these cell lines was determined with a colony survival assay. The suppression of GRP94 expression was performed using specific small-interfering RNA (siRNA) in HeLa and Caski cells. RESULTS: HeLa cells and QG-U cells, with higher basal levels of GRP94, exhibited a low sensitivity to X-ray cell killing. In HeLa cells, the sensitivity increased when protein GRP94 levels were reduced by specific siRNA transfection. However, a reduction in GRP94 protein had little effect on the X-ray sensitivity of Caski cells, which expressed low basal GRP94 protein levels but showed a low sensitivity to X-rays. CONCLUSIONS: High basal protein levels of GRP94 were correlated with a modest decrease in sensitivity to X-ray cell death in some cervical cancer cell lines. These results suggest that higher GRP94 protein expression is one of the molecular mechanisms causing resistance to radiation, and therefore GRP94 siRNA might be useful in tumor-specific gene therapy by reversing radio-resistance prior to radiation in cervical cancer.

Genetic origin and imprinting in hydatidiform moles. Comparison between DNA polymorphism analysis and immunoreactivity of p57KIP2.

OBJECTIVE: To evaluate whether p57KIP2 expression is concordant with the result of DNA polymorphism analysis in molar pregnancy. STUDY DESIGN: Eleven molar pregnancies diagnosed by pathologic findings between October 2002 and April 2004 were studied. Histopathologic diagnosis, DNA polymorphism analysis and p57KIP2 immunohistochemistry were investigated. RESULTS: DNA polymorphism analysis identified 3 biparental conceptuses as well as 4 dispermic androgenetic complete moles (CMs) and 4 suggestive monospermic CMs. Distinctly positive nuclear immunoreactivity of p57KIP2 was observed in a significant proportion of the villous cytotrophoblast and mesenchyme (30-60% of cells positive) in 3 cases of biparental conceptuses proven by DNA polymorphism. In contrast, p57KIP2 expression was negative (< 5% positive cells) in either the villous cytotrophoblast or mesenchyme in 8 cases of androgenetic conceptuses proven by DNA polymorphism. In all 11, p57KIP2 immunostaining was observed in the nuclei of extravillous trophoblasts that served as internal positive controls. CONCLUSION: Negative p57KIP2 immunoreactivity (paternally imprinted, maternally expressed gene) was in perfect concordance with the androgenetic origin of molar pregnancies proven by DNA polymorphism. The results suggest that p57KIP2 immunoreactivity, which can be performed in routine pathologic examinations, is a promising ancillary diagnostic tool to differentiate androgenetic CM from biparental conceptuses.

Overexpression of the c-fos gene perturbs functional maturation of M1 cells into macrophages.

Expression of the proto-oncogene c-fos is induced in normal myelopoiesis. However, functions of c-Fos in the process of differentiation towards macrophages are still controversial. To explore the functions, we used the murine myeloblastic leukemia cell line M1. Stimulation of M1 cells with bacterial LPS promotes their terminal differentiation into functional macrophages. Overexpression of c-fos in M1 cells dramatically increased sensitivity of the cells for LPS-induced differentiation and generation of morphologically differentiated cells. However, the overexpression did not modulate phagocytotic functions, surface expression of macrophage markers such as CD16/CD32 (Fcgamma Receptor) and CD54 (ICAM-1), and expression of lysozyme, esterase and c-fms mRNA. Surprisingly, induction of the MHC class II expression on M1 cells after stimulation was inhibited by the overexpression. Expression of CIITA, as an essential transcription factor for the expression, was also reduced in the M1 cells. These results suggest that overexpression of c-fos in differentiating M1 cells perturbs their functional maturation.

HPV 16-E6-mediated degradation of intrinsic p53 is compensated by upregulation of p53 gene expression in normal cervical keratinocytes.

In this study we investigated the relationship between the development of either HSILs (high-grade squamous intraepithelial lesions) or invasive cancers of the uterine cervix and the p53 codon 72 polymorphisms consisting of arginine (Arg)- or proline (Pro)-encoded allele in Japanese populations. Furthermore, we determined if intrinsic p53 is affected by the p53-degradation activities of human papillomavirus type 16 (HPV 16)-E6 in normal cervical keratinocytes with each p53 codon 72 genotype. Using PCR with p53 codon 72 polymorphic allele-specific primers, p53 genotypes of 112 normal cervical specimens and 88 cervical lesions including 44 HSILs and 44 invasive cancers were determined. The expression levels of p53 proteins and mRNAs in keratinocytes following the expression of HPV 16-E6 from an HPV 16-E6-expressing recombinant adenovirus were analyzed. The frequencies of p53 genotypes, Pro/Pro, Arg/Pro and Arg/Arg were, respectively, 12, 49 and 39% in controls; and 18, 55 and 27% in HSILs; and 11, 41 and 48% in invasive cancers. The expression levels of the p53 proteins in normal human keratinocytes of each p53 codon 72 genotype were not affected by the introduction of HPV 16-E6, whereas the p53 mRNAs were found to be upregulated regardless of the p53 genotypes when HPV 16-E6 was expressed. In statistical analysis, no relationships between p53 genotypes and the development of cervical neoplasias were found. Furthermore, we demonstrated that p53 protein expression levels in normal cervical keratinocytes is not affected by the p53-degradation activities of HPV E6, probably due to a tight transcriptional regulation of p53.

Advances in the clinical laboratory detection of gestational trophoblastic disease.

BACKGROUND: Gestational trophoblastic disease (GTD) consists of a spectrum of disorders that are characterized by an abnormal proliferation of trophoblastic tissue. Gestational trophoblastic neoplasia (GTN) refers to a subset of GTD with a persistently elevated serum hCG in the absence of a normal pregnancy and with a history of normal or abnormal pregnancy. Although previously a lethal disease, GTN is considered today the most curable gynecologic cancer. However, a delay in the diagnosis may increase the patient's risk of developing malignant GTN, and therefore the prompt identification of GTN is important. SERUM MARKERS: hCG test is essential for detection of GTN. It has emerged that there are problems with hCG tests. In addition to regular hCG, at least five major variants of hCG are present in serum samples. False-positive hCG (phantom hCG) can occur in the absence of GTN. Low-level real hCG may occasionally persist in the absence of clinical evidence of pregnancy or GTD. Alternatively, low-level real hCG may be due to pituitary hCG. Other placental hormones, human placental lactogen (hPL), inhibin and activin, and progesterone have also been evaluated as tumor markers for GTD. CONCLUSION: hCG has high diagnostic sensitivity, approaching 100% sensitivity, for managing the treatment of GTN and for detecting recurrences of disease. It is recommended to use hCG test that recognizes all forms of the hCG molecule. In cases where low-level hCG persists, it must be differentiated whether it is real or false. Real-hCG may be due to quiescent gestational trophoblastic disease or pituitary hCG. It has not yet been established whether measurement of markers other than hCG (hPL, inhibin, activin, and progesterone) is useful in the detection and follow-up of GTD.

Adjuvant pelvic irradiation in patients with node-negative carcinoma of the uterine cervix.

BACKGROUND: To assess the role of post-operative pelvic radiotherapy in cervical cancer patients without lymph node metastases. MATERIALS AND METHODS: The records of 61 patients with cervical cancer treated with radical hysterectomy and bilateral pelvic lymphadenectomy followed by pelvic irradiation were reviewed. The distribution of FIGO stage was IB in 34, II4 in 5 and IIB in 22. The patients were treated with 10-18 MV X-rays using a fractional daily dose of 1.8-2.0 Gy to a median total dose of 50 Gy. RESULTS: The actuarial 5-year pelvic control rate was 95%. There was no isolated pelvic lymph node recurrence. The overall 5-year survival of the entire group was 89%. The mean age of the patients who developed recurrence was lower than the other patients (46 years vs. 53 years, p=0.07). CONCLUSION: The results indicated that post-operative pelvic irradiation was effective in preventing pelvic recurrence in patients with node-negative cervical cancer.

Salvage chemotherapy for high-risk gestational trophoblastic tumor.

OBJECTIVE: To evaluate the efficacy and safety of etoposide/methotrexate/actinomycin D (MEA regimen) as initial chemotherapy and 5-fluorouracil/actinomycin D (FA regimen) as salvage chemotherapy for high-risk gestational trophoblastic tumor (GTT). STUDY DESIGN: From 1985 to 2001, 36 patients with World Health Organization (WHO)--defined high-risk GTT were treated with MEA or FA at Chiba University Hospital. Thirty-three patients were initially treated with MEA. FA was administered to 11 patients; 1 had had no previous chemotherapy, 7 had developed drug resistance to MEA, 1 had relapsed following MEA, and 2 had relapsed following etoposide/methotrexate/actinomycin D/ cyclophosphamide/vincristine (EMA/CO) combination chemotherapy. RESULTS: The primary remission rate with MEA was 69.7% (23 of 33). With FA the survival rate was 81.8% (9 of 11) for a mean follow-up period of 11.5 years. Two patients died due to multidrug resistance, and 2 patients relapsed subsequently. The 2 relapse cases were successfully salvaged again with MEA. The toxicity of FA was evaluated in 89 cycles. Myelosuppression seemed to be the dose-limiting toxicity, and the incidence of WHO grade 4 leukocytopenia and thrombocytopenia were 5.6% and 3.4%, respectively. CONCLUSION: Although etoposide-containing chemotherapy is currently the most effective and well tolerated regimen for high-risk GTT, 20-30% of patients develop drug resistance to these regimens. Salvage combination chemotherapy with FA is effective for refractory patients, and the toxicity is predictable and manageable.

Early pregnancy outcomes after chemotherapy for gestational trophoblastic tumor.

OBJECTIVE: To analyze the outcome of the first pregnancy following chemotherapy for gestational trophoblastic tumor (GTT). STUDY DESIGN: A total of 393 patients with GTT (87 with high-risk and 306 with low-risk GTT) underwent chemotherapy at Chiba University Hospital between 1974 and 2000. Of them, 137 (19 with high-risk and 118 with low-risk GTT) who achieved primary remission and had at least 1 conception following chemotherapy were included in the study. RESULTS: The overall outcomes of the first subsequent pregnancies in the 137 women treated with chemotherapy were comparable to those in the general Japanese population. However, the incidence of abnormal pregnancies (spontaneous abortion, stillbirth, repeat mole) was significantly higher in women who conceived within 6 months of completing chemotherapy (6 of 16, 37.5%) than in those who conceived after the recommended waiting period, > 12 months (11 of 99, 10.5%) (P=.014). CONCLUSION: Patients who achieved primary remission with various kinds of chemotherapy may anticipate a normal future reproductive outcome. As pregnancies occurring within 6 months following remission are at risk of abnormality, a waiting period of at least 6 months after chemotherapy for GTT is recommended.

Efficient subtractive cloning of genes activated by lipopolysaccharide and interferon γ in primary-cultured cortical cells of newborn mice.

Innate immune responses play a central role in neuroprotection and neurotoxicity during inflammatory processes that are triggered by pathogen-associated molecular pattern-exhibiting agents such as bacterial lipopolysaccharide (LPS) and that are modulated by inflammatory cytokines such as interferon γ (IFNγ). Recent findings describing the unexpected complexity of mammalian genomes and transcriptomes have stimulated further identification of novel transcripts involved in specific physiological and pathological processes, such as the neural innate immune response that alters the expression of many genes. We developed a system for efficient subtractive cloning that employs both sense and antisense cRNA drivers, and coupled it with in-house cDNA microarray analysis. This system enabled effective direct cloning of differentially expressed transcripts, from a small amount (0.5 µg) of total RNA. We applied this system to isolation of genes activated by LPS and IFNγ in primary-cultured cortical cells that were derived from newborn mice, to investigate the mechanisms involved in neuroprotection and neurotoxicity in maternal/perinatal infections that cause various brain injuries including periventricular leukomalacia. A number of genes involved in the immune and inflammatory response were identified, showing that neonatal neuronal/glial cells are highly responsive to LPS and IFNγ. Subsequent RNA blot analysis revealed that the identified genes were activated by LPS and IFNγ in a cooperative or distinctive manner, thereby supporting the notion that these bacterial and cellular inflammatory mediators can affect the brain through direct but complicated pathways. We also identified several novel clones of apparently non-coding RNAs that potentially harbor various regulatory functions. Characterization of the presently identified genes will give insights into mechanisms and interventions not only for perinatal infection-induced brain damage, but also for many other innate immunity-related brain disorders.

Genetic variations within the insulin gene region are associated with accelerated fetal growth.

Size at birth has been proposed to be associated with the risk of type 2 diabetes and cardiovascular disease later in life. It is, however, unclear whether this association is attributed to an unfavorable intrauterine environment or to specific genotypes predisposing both altered fetal growth and common diseases in adult life. The aim of this study was to investigate the associations between the neonatal birth size and the genotypes of polymorphic loci within the insulin gene (INS) region, which is susceptible to diabetes mellitus. We analyzed the genotypes of two polymorphic loci; -23HphI and HUMTH01, in 520 pairs of normal Japanese mothers and their neonates, and compared with the somatoscopic characteristics at birth converted into standard deviation scores (SDS) according to sex, parity and gestational weeks at delivery. It was revealed that neonatal -23HphI T allele and HUMTH01 allele10, which are linked to the INS variable number of tandem repeats (VNTR) class III allele, were associated with increased weight, head circumstance, and length at birth. These associations confirmed that variation within the INS region, most probably at the INS-VNTR, influences fetal growth. Furthermore, the finding that the paternally transmitted -23HphI T allele was exclusively correlated with increased size at birth indicates the involvement of an imprinting mechanism. In conclusion, the INS-VNTR class III allele might accelerate fetal growth in a parent-specific manner.

Recent changes of the incidence of complete and partial mole in Chiba prefecture.

AIMS: To study the changes of the incidence of complete mole (CM) and partial mole (PM) by 10-year age groups in Chiba Prefecture. METHODS: All women registered as CM and PMs in Chiba Prefecture during these 18 years were included in this study. The diagnosis of CM and PM was based on the macroscopic and/or microscopic findings. The annual numbers of pregnancy were obtained from the Division of Statistics in Chiba Prefecture Government. RESULTS: The incidence of CM at the upper and lower extremes of maternal age is higher than that of PM. The incidence of CM has decreased constantly at all maternal ages and significantly decreased in women of middle reproductive age (20-39 years old) since 1991, while that of PM has stayed constant during these 18 years. CONCLUSIONS: The incidence of CM and PM in Chiba Prefecture has become as low as that in Europe or the USA. These recent changes suggest that Japanese women may have lost the increased risk to ovulate a nuclear or inactive oocytes, or the differential diagnosis between CM and PM may be obscured with the macroscopic and/or microscopic findings.

Tamoxifen and the risk of endometrial cancer in Japanese women with breast cancer.

PURPOSE: There is ongoing debate about whether tamoxifen for breast cancer is associated with a risk of endometrial cancer in Japanese women. We conducted a study to investigate this further. METHODS: We conducted a retrospective hospital-based cohort study. A total of 674 consecutive patients underwent surgery for primary breast cancer between January 1989 and December 1998. By December 2003, endometrial cancers had been diagnosed in six of these patients. Based on medical records, we evaluated the potential risk factors for endometrial cancer, including age, menopausal status, obesity, parity, diabetes mellitus, hypertension, and tamoxifen. The 674 patients were divided into three groups based on the cumulative duration of tamoxifen use (A, <2 years vs B, 2-5 years vs C, >5 years). To examine the relationships between endometrial cancer and tamoxifen (and other factors), the hazards ratio (HR), 95% confidence interval (CI), and two-sided P value for endometrial cancer associated with each variable were calculated by the Cox regression method. RESULTS: Endometrial cancer was found in 1/318 (0.31%) patients in group A, 3/247 in group B, and 2/109 in group C. In a multivariate analysis no variable was significant, but tamoxifen use for longer than 5 years (group C) was closely correlated with endometrial cancer (HR = 7.92, CI = 0.69-90.89, P = 0.096). CONCLUSION: Although our data did not reach significance, they support a link between long-term tamoxifen and the development of endometrial cancer in Japanese women with breast cancer.

Accelerated bone turnover in pregnant women with McCune-Albright syndrome.

Bone turnover in pregnant women with McCune-Albright syndrome may be affected by both the syndrome and pregnancy. This study evaluated changes in biochemical bone turnover markers in pregnant women with the syndrome. Serum calcium, phosphorus, 1,25-dihydroxyvitamin D (1,25-(OH)2D), intact osteocalcin (I-OC) and alkaline phosphatase (ALP), and urinary pyridinoline (Pyr), deoxypyridinoline (D-Pyr) and hydroxyproline (HPR) were measured during pregnancy and postpartum in 2 women with McCune-Albright syndrome. Serum calcitonin (CT), and plasma intact parathyroid hormone (I-PTH) and parathyroid hormone-related protein (PTHrP) were also measured in 1 patient. Serum corrected Ca levels were normal or low-normal; phosphorus levels were normal, and 1,25-(OH)2D levels increased toward term and decreased thereafter, similar to normal pregnant women. Urinary Pyr, D-Pyr and HPR were elevated during pregnancy compared to normal pregnant women, peaked just after delivery, and decreased thereafter. Serum I-OC and ALP levels were high during pregnancy and postpartum. Intact PTH levels were increased during pregnancy and postpartum compared to normal pregnant women, whereas serum CT and PTHrP levels were not elevated. Both bone formation and absorption appear to be more enhanced during pregnancy and postpartum in women with McCune-Albright syndrome than in normal pregnant women. Additional or amplified cyclic AMP synthesis in bone cells through activation of the alpha subunit of G protein, independent of hormonal control, may explain the high local bone turnover.

Relapse rate of patients with low-risk gestational trophoblastic tumor initially treated with single-agent chemotherapy.

OBJECTIVE: To determine the factors for relapse in patients with low-risk gestational trophoblastic tumor (GTT) treated with single-agent chemotherapy. METHODS: Between 1974 and 2000, 272 consecutive patients with low-risk GTT were initially treated with methotrexate (MTX), actinomycin D (Act-D) or etoposide chemotherapy. The primary remission rate, change of chemotherapy because of drug resistance or toxicity, and relapse rate were compared. RESULTS: Overall survival rate and primary remission rate for 272 patients were 100% and 75.7%, respectively. Primary remission rate was significantly higher in patients given etoposide than those given conventional MTX (P < 0.0001) or MTX-folinic acid (MTX-CF) (P = 0.0005). Twenty-four (8.8%) patients required a change of chemotherapy because of drug resistance. The frequency of drug resistance was significantly higher in patients treated with MTX-CF than those treated with etoposide (P = 0.006). Although maternal age, presence of metastasis, high pretreatment hCG titer, and planned hysterectomy did not influence the development of drug resistance, the new FIGO scores were significantly higher in patients who developed drug resistance. Relapse rate increased significantly in patients who had high FIGO scores and who required change of chemotherapy due to drug resistance. CONCLUSIONS: All patients with low-risk GTT eventually attained complete remission, even though some developed drug resistance to the first-line chemotherapy. The relapse rate was significantly higher in patients with drug resistance than those with primary remission. Chemotherapy regimen that induces little drug resistance is desirable from the viewpoint of long-term prognosis.

Serum vascular endothelial growth factor (VEGF) and VEGF-C levels as tumor markers in patients with cervical carcinoma.

BACKGROUND: Vascular endothelial growth factor (VEGF) and VEGF-C play a crucial role in the regulation of tumor growth and metastasis. The current study examined the significance of serum VEGF and VEGF-C levels in relation to conventional clinicopathologic parameters, response to treatment, and survival in patients with cervical carcinoma. METHODS: Between December 1999 and March 2004, serum VEGF and VEGF-C levels were analyzed in 78 patients with cervical carcinoma undergoing primary treatment (primary surgery [n=40] and radiotherapy [n=38]), as well as in 30 healthy controls. Serum VEGF and VEGF-C levels were assessed by enzyme-linked immunosorbent assay before and within 2 weeks after treatment. RESULTS: Serum VEGF and VEGF-C levels were higher in patients with cervical carcinoma than in the healthy control (P=0.0002 and P=0.0007, respectively). Both VEGF and VEGF-C concentrations increased significantly in patients with squamous cell carcinoma (SCC vs. normal control: P<0.0001 and P=0.0001, respectively), but not in adenocarcinoma (vs. normal control: P=0.2982 and P=0.7766, respectively). In an analysis of SCC, the pretherapeutic serum levels of VEGF and VEGF-C correlated significantly with advanced International Federation of Gynecology and Obstetrics stage and large tumor size, but not with lymph node metastasis. The pretherapeutic serum level of VEGF-C also correlated significantly with disease recurrence or persistence after treatment. Both serum VEGF and VEGF-C levels decreased significantly after treatment. CONCLUSIONS: The serum levels of both VEGF and VEGF-C have potential usefulness as biologic markers of SCC of the uterine cervix.

Discordance between serum level and tissue immunohistochemical staining of CA125 in endometrioid adenocarcinoma of the uterine corpus.

This study was designed to correlate tissue expression of CA125 with the corresponding serum value in endometrial cancer. The records of 52 endometrioid adenocarcinomas diagnosed were reviewed. Serum CA125 levels were examined before definitive surgery, and 20 U/ml was used as the cutoff value. Immunohistochemical staining for CA125 was assessed according to the ImmunoReactive Score. Statistical analyzes were performed to identify independent factor for high serum CA125 levels, including CA125 staining and the conventional pathologic features. Elevated serum CA125 levels were found in 15 of 52 patients (29%) (range, 0.1-172.1; mean 22.6 U/ml). The frequency of positive CA125 tissue staining (35/52, 67%) tended to be higher than that of elevated serum levels (p = 0.046). Fifteen patients with elevated serum CA125 levels statistically differed from the remaining 37 patients with normal serum CA125 level with respect to International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.027) and lymph node metastasis (p = 0.024), and tended to have positive washing cytology (p = 0.052). In multivariate analysis, elevated serum CA125 significantly correlated only with FIGO stage III, but not with tumor size or CA125 tissue staining. Intrauterine tumor may not be the main source of serum CA125 in endometrial cancer, and elevated serum level is closely related to the presence of disseminated cancer cells in the peritoneal cavity.