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Objectives: The aim of this study was to estimate the survival impact of adjuvant paclitaxel and carboplatin (TC) compared to cisplatin (CDDP)-based chemotherapies for early-stage ovarian clear-cell carcinoma (CCC)., Methods: Clinicopathologic information on 99 stage I-II CCC patients was obtained between 1987 and 2005. All patients underwent complete surgical staging including systemic lymphadenectomy, followed by TC or various CDDP-based regimens. In the present study, only CCC patients with no residual tumor were enrolled., Results: The median age was 53 years and ranged from 30 to 69 years. Fifty-three (53.5%) patients received TC and 46 (46.5%) patients underwent various CDDP-based chemotherapies after initial surgery. Five-year progression-free survival (PFS) rates of TC and various CDDP groups were 66.5 and 75.8%, respectively (n.s., p = 0.933). In addition, 5-year overall survival (OS) rates of TC and various CDDP groups were 82.4 and 82.3%, respectively (n.s., p = 0.583). In multivariate analyses of OS and PFS, the regimen of chemotherapywas not a significant prognostic factor (OS, p = 0.502; PFS, p = 0.977., Conclusions: In our current examination of the long-term survival of early-stage CCC patients, we did not identify a superiority of TC over various CDDP-based regimens as frontline adjuvant chemotherapy., (Copyright © 2011 S. Karger AG, Basel.)

Background: Cisplatin is used as a key drug for ovarian yolk sac tumor (YST), but relapse may occur. Details of the molecular mechanism responsible for cisplatin resistance remain unclear., Methods: We established cisplatin-resistant ovarian YST cells (NOY1-CR) from parent NOY1. To characterize these cells, we examined cross-resistance to other anticancer drugs. Then, cDNA microarray analysis was performed to quantify gene expression in NOY1 and NOY1-CR cells. The expression of several potential genes related to drug resistance was compared with parent cells by real-time PCR and Western blotting. Knockdown experiments using small interfering RNA (siRNA) were also performed to confirm the genetic association with drug resistance., Results: The IC(50) for cisplatin of NOY1-CR was 22.3-fold higher than that for parent cells. NOY1-CR cells showed cross-resistance to some drugs, but not to VP-16 and bleomycin. Microarray analysis identified 315 up-regulated and 412 down-regulated genes in NOY1-CR cells. Knockdown of GSTA1, which was up-regulated in resistant cells, by GSTA1 siRNA restored cisplatin sensitivity in NOY1-CR cells., Conclusions: Our data suggest the molecular mechanisms of cisplatin resistance and show the potential for GSTA1 to become a novel therapeutic target for cisplatin-resistant ovarian YST., (Copyright © 2010 S. Karger AG, Basel.)

Background/aims: In the present study, we investigated the participation of inflammatory cytokine-induced mediated matrix metalloproteinase (MMP) expressions and inhibition of interleukin (IL)-6-induced MMP secretion in amniotic epithelial cells by tocilizumab., Methods: To investigate the role of MMP expressions, immunohistochemical staining was performed using membranes obtained from 10 patients with preterm premature rupture of membranes (PPROM) and from 10 patients who underwent a nonlabor cesarean section. We also investigated the regulation of MMP expression by inflammatory cytokines in human amnion cells., Results: Immunohistochemical staining showed a significantly higher expression of MMP-2 and -9 in PPROM. Treatment of cultured WISH and primary amniotic epithelial cells with 10(-8) or 10(-7)M IL-6 or tumor necrosis factor (TNF)-alpha clearly increased the secretion of MMP-2 and -9. Treatment with 10(-8)M TNF-alpha or IL-6 significantly increased the invasion of WISH or primary amniotic epithelial cells, respectively, compared with the control. At a low concentration of 1 microg/ml, tocilizumab (anti-human IL-6 receptor monoclonal antibody) inhibited the IL-6-induced MMP secretion., Conclusions: This paper is the 1st report of tocilizumab inhibiting IL-6-induced MMP-2 and MMP-9 secretions from human amnion cells in PPROM.

Objective: Ovarian yolk sac tumor (YST) is rare and highly malignant. Up to the present, there have been no cell lines of human ovarian YST constructed and, therefore, no studies on their cell function. The purpose of this study was to establish a human ovarian YST cell line to be able to identify a target for novel molecular-based therapy., Methods: A 28-year-old woman underwent right salpingo-oophorectomy for right ovarian YST. YST cell lines (NOY1 and NOY2) were established from surgical specimens, and NOY1 cells were characterized. We also transfected them with small interfering RNA (siRNA) oligonucleotides specific for human Nkx2.5 and investigated cell proliferation compared to control siRNA-transfected cells., Results: The cell lines were successfully maintained both in culture and in nude mice. Histological examination showed that xenografted tumors were composed of cells in solid and glandular patterns of YST. These cells were positively immunostained for AFP. Nkx2.5 siRNA-transfected NOY1 cell viability decreased by 50% compared to that of control-siRNA-transfected cells., Conclusions: This is the first report of a cell line established from human YST. Analysis of this new cell line suggested that Nkx2.5 can be a new molecular target in the treatment of ovarian YST., (Copyright 2008 S. Karger AG, Basel.)

Twin pregnancy consisting of a complete hydatidiform mole (CHM) along with a live co-existing fetus is a rare entity and difficult to diagnose. A 37-year-old Japanese woman demonstrated a living fetus, a placenta and a multicystic mass within one gestational sac on ultrasound at 10 weeks. Termination of the pregnancy was performed, and the specimen was classified as partial mole by macro- and microscopic findings. The karyotype of the molar tissue was 46XX. DNA polymorphism analysis demonstrated that fetal DNA showed bi-parental origin while molar DNA showed paternal origin only. Thus, this case was erroneously classified by ultrasonography, macroscopic and pathologic findings, then correctly diagnosed as a twin pregnancy with a CHM and co-existing normal twin fetus by DNA polymorphism analysis. Immunohistochemistry of p57(KIP2), the paternally imprinted and maternally expressed gene, supported the genetic diagnosis. This case suggested that conventional diagnostic methods were inadequate for accurate diagnosis of CHM with a co-existing fetus. DNA polymorphism analysis should be requested for the diagnosis of hydatidiform mole, especially in cases where it is difficult to discriminate between partial hydatidiform mole and CHM with a co-existing fetus., (2007 S. Karger AG, Basel)

Objectives: Twist is a highly conserved basic helix-loop-helix transcription factor that regulates the expression of E-cadherin and promotes the epithelial-mesenchymal transition, which is critical for tumor infiltration. We examined the distribution and expression of this molecule in clear cell carcinoma of the ovary (CCC) to elucidate their clinical significance., Methods: Paraffin sections from CCC tissues (n = 27) were immunostained with Twist antibody and staining intensities were evaluated. Stratified with various clinicopathological factors, overall survival (OS) and progression-free survival (PFS) were evaluated., Results: In the 27 carcinomas, negative Twist immunoexpression was observed in 14 cases (51.9%), and positive immunoexpression in 13 (48.1%). Twist, when categorized into negative versus positive expression, was associated with FIGO stage and peritoneal cytology. In addition, positive Twist expression significantly predicted a poorer OS and PFS compared with negative expression (p < 0.0001). Furthermore, the multivariate analyses revealed that positive Twist expression was an independent prognostic factor for OS and PFS of patients with CCC in this study (p = 0.0077 and 0.0033, respectively)., Conclusion: The current findings suggest that the assessment of Twist immunoreactivity may be a useful prognostic indicator and that Twist may play a critical role in the progression of CCC., (Copyright 2006 S. Karger AG, Basel.)

Objectives: Neutral endopeptidase 24.11 (NEP) is known to play important roles in the maintenance of homeostasis or in neoplastic transformation and tumor progression in certain human malignancies through the enzymatic inactivation of bioactive peptides such as endothelin-1 (ET-1), angiotensin-II, and bombesin., Methods: In this study, we first investigated NEP expression in cervical carcinoma by immunohistochemical staining and Western blot analysis. Next, we examined NEP functions in vitro and in vivo by generating NEP-overexpressing cervical carcinoma cells., Results: We found a significant decrease in cellular proliferative and invasive abilities with a reduced ET-1 concentration in the conditioned medium by NEP overexpression in cervical carcinoma CaSki cells, which have an ET-1 autocrine loop. In addition, these potentials were cancelled by blockade of NEP activity with a specific inhibitor. Although vector-transfected CaSki cells could grow even in serum-free media, NEP-overexpressing cells failed to proliferate in these media. Furthermore, we demonstrated that NEP suppressed tumor formation of subcutaneous xenografts using nude mice., Conclusions: Our results indicated that NEP functions as a tumor-suppressor gene in cervical carcinoma cells, and its expression may have prognostic significance. Further elucidation of the mechanism underlying the observed effect of NEP will contribute to a better understanding of its role in the pathophysiology of cervical carcinoma.

Objective: Placental leucine aminopeptidase (P-LAP) is a cell surface aminopeptidase (oxytocinase). We cloned P-LAP cDNA and found a widespread tissue distribution of P-LAP. Since P-LAP can degrade several small peptide hormones such as oxytocin, this enzyme may affect many cellular functions of carcinoma cells as well as normal cells. This study investigated whether the expression of P-LAP correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma., Methods: Histologic sections of formalin-fixed, paraffin-embedded specimens from 99 primary endometrial carcinomas were stained for P-LAP using polyclonal P-LAP antibody. Disease-free survival and other clinicopathologic characteristics were analyzed according to the intensity of P-LAP staining., Results: Of 99 cases, 69 (69.7%) showed specific P-LAP immunostaining. We found a positive correlation between the expression of P-LAP and histological grade (p < 0.01), surgical stage of the disease (p = 0.02), myometrial invasion (p = 0.01), lymph node involvement (p < 0.01), and vascular infiltration (p < 0.01). In patients who had strongly positive P-LAP staining, the disease-free interval was significantly lower than in patients who had negative or weakly positive P-LAP staining (p < 0.01). Multivariate analysis demonstrated that strongly immunoreactive P-LAP (odds ratio, 12.8; 95% confidence interval, 2.84-58.8; p < 0.01) and surgical stage (odds ratio, 8.78; 95% confidence interval, 2.77-27.8; p < 0.01) are independent prognostic factors., Conclusions: This study suggests P-LAP as an independent prognosticator of clinical outcome in patients with endometrial carcinoma. Therefore, assessment of the P-LAP status provides clinically useful prognostic information in patients with endometrial carcinoma., (Copyright 2004 S. Karger AG, Basel)

This study investigated response rate, toxicity, and influence on intra- and postoperative complications of neoadjuvant concurrent chemoradiation in locally advanced (Figo IB2-IIIB) cervical carcinomas. Twenty-eight patients (median age 46.5 years, age range 29-73 years), diagnosed as having squamous cell carcinomas (n=21), adenocarcinomas (n=6), and undifferentiated carcinoma (n=1), entered this study. The chemoradiation protocol included external radiotherapy to the pelvis (39.6 Gy), intra-arterial or intravenous infusion of cisplatin (70 mg/m2 on days 1 and 22), and 24-hour continuous intravenous infusion of 5-fluorouracil (700 mg/m2 on days 1-4 and 22-25). Two weeks after the end of chemoradiotherapy, the patients underwent restaging followed by suitable operation including pelvic lymphadenectomy. The median follow-up period in the surviving patients was 13.1 months. The response rate for chemoradiation was 93% (26/28). The 2-year disease free survival was 85.2%. Grade 3-4 neutropenia was observed in 14 patients (50%), 4 patients (14%) showed grade 3 anemia, and 5 patients (17.8%) showed grade 3-4 thrombocytopenia. Nineteen patients (67.8%) could undergo surgery after concurrent chemoradiation. Pathological examination revealed a complete response (pT0) in 7 patients, and 5 patients showed only microscopic residual disease (pTmic). In 4 patients, there were intraoperative complications: vesical lesions in 2 (10%) and small intestine lesions in 2 (10%). Neoadjuvant therapy with concurrent chemoradiation for locally advanced cervical carcinoma is effective, safe, and useful for increasing operability rates as well as decreasing intra- and postoperative complications. Therefore, neoadjuvant concurrent chemoradiation should be considered for treatment in patients with locally advanced cervical carcinomas who could not undergo primary operation., (Copyright 2004 S. Karger AG, Basel)

Objective: There are a few long-term follow-up studies of patients with stage I ovarian carcinoma. The objective of this study was to evaluate prognostic factors for long-term survival., Methods: Two hundred fourteen stage I ovarian carcinomas (registered by the Tokai Ovarian Tumor Study Group from 1988 to 1999) were analyzed. Staging according to the International Federation of Gynecology and Obstetrics was set without considering the pathologic findings of the lymph nodes. Stage Ic was divided into Ic(b) and other Ic., Results: Seventy-four patients were stage Ia, 2 were stage Ib, and 138 were stage Ic, consisting of 75 Ic(b) and 63 other Ic patients. The ratios of stage Ic to Ia and stage Ic(b) to Ic were highest in clear-cell adenocarcinoma among histologies analyzed. There were significant differences in disease-free survival curves between each group. In clear cell adenocarcinoma, there was a significant difference in disease- free survival curves between stage Ic(b) and other Ic (p = 0.0373), while this tendency was also observed in other histologies except for mucinous carcinoma. Multivariate analysis demonstrated that substage was a significant prognostic factor of both disease-free and overall survival., Conclusions: Stage Ic(b) patients showed poorer survival than stage Ia patients but better than survival in other Ic. Thus, cautious treatment of ovarian tumor during surgery is quite important to avoid rupture., (Copyright 2003 S. Karger AG, Basel)

Objective: Although the ovaries are common sites of metastases from a variety of primary neoplasms excluding carcinomas of the genital tract, there were few reports concerning survival and prognostic factors. The objective of this study was to assess the clinical factors affecting survival., Methods: Fifty-three secondary ovarian carcinomas excluding metastases from genital tract carcinoma were registered by the Tokai Ovarian Tumor Study Group from 1989 to 1999. FIGO staging was set without considering the pathologic findings of the lymph nodes and the primary tumors., Results: Twenty-four patients were stage I, 11 were stage II, 16 were stage III, and 2 were stage IV. There were significant differences in the survival curves between the early stages (I and II) and advanced stages (III and IV). The 5-year survival rate for patients without residual tumors was 39.9%, while all patients with residual tumors after surgery died within 33 months. The most frequent primary tumor was large intestinal carcinoma, and the second was gastric carcinoma. The 5-year survival rate for patients with large intestinal primary tumors was significantly better than that with stomach tumors. Multivariate analysis demonstrated that tumor stage and primary tumor sites were significant prognostic factors., Conclusion: FIGO staging without considering lymph node involvement and the primary tumor was a significant prognostic factor, and prognostic factors for primary ovarian carcinomas can be applied to secondary ovarian carcinomas. Furthermore, the primary tumor site was also an important prognostic factor for survival., (Copyright 2002 S. Karger AG, Basel)

This study evaluated whether preoperative findings are useful prognostic indicators in patients with non-gynecologic carcinomas metastasizing to the ovaries. Fifty-three patients were analyzed. Primary sites of carcinoma were discovered after gynecologic surgery in 20 patients. In 10 patients, primary sites of carcinoma were discovered during gynecologic surgery. Thirty-one patients received surgery on the primary site before gynecologic surgery. The primary site could not be identified in 2 patients. The 5-year survival rate was 40.0% in patients, who underwent surgery on the primary site before gynecologic surgery. However, the 5-year survival rate was 12.2% in patients, who underwent surgery on the primary site during or after gynecologic surgery. The CEA level was significantly lower in the stomach primary group than in the intestine primary group. However, CA125 was the only marker significantly affecting survival. In comparison with primary ovarian carcinoma, the sensitivity of CEA was significantly higher for non-gynecologic ovarian carcinoma, while that of CA125 was significantly less sensitive for non-gynecologic ovarian carcinoma. In conclusion, the prognosis was better in patients, who had undergone resection of primary carcinoma before gynecologic surgery on non-gynecologic ovarian carcinoma. CEA is a useful marker to distinguish non-gynecologic from primary ovarian carcinoma, while CA125 is the only significant prognostic marker for non-gynecologic ovarian carcinoma., (Copyright 2002 S. Karger AG, Basel)

Cell surface aminopeptidases play an important role in biological processes through degradation of small peptides. There are many bioactive peptides in ascites and these peptides are involved in carcinoma cell dissemination and infiltration. In human mesothelial cells dipeptidyl peptidase IV (DPPIV) shows the highest expression mostly in four cell surface aminopeptidases: aminopeptidase A, neutral endopeptidase 24-11, aminopeptidase N and DPPIV. Since mesothelial cells are always in contact with ascites, we examined the influence of malignant ascites on DPPIV. DPPIV enzyme activity in mesothelial cells was enhanced by the addition of ascites obtained from ovarian carcinoma patients in a time- and concentration-dependent manner, and flow cytometry and immunocytochemistry also revealed an increased expression of DPPIV on the cell surface of mesothelial cells. The <3-kD fraction of malignant ascites increased the DPPIV enzyme activity to the same level as the total ascites. Northern hybridization demonstrated that DPPIV mRNA was increased 3-fold by the addition of the <3-kD malignant ascites. In conclusion, DPPIV is highly expressed in human mesothelial cells and was regulated by ascites., (Copyright 2002 S. Karger AG, Basel)

Objectives: Neutral endopeptidase 24.11 (NEP)/CD10 is a cell-surface peptidase that degrades various bioactive peptides including endothelin-1 (ET-1). This enzyme is known to play a role in maintaining ET-1-regulated vascular homeostasis in the normal human endometrium. The purpose of the present study was to investigate the expression and localization of NEP and ET-1 in neoplastic endometria, and also to clarify the correlation of their expression with the tumor grade of endometrial carcinoma., Methods: Immunohistochemical analysis for NEP and ET-1 expression was performed on paraffin-embedded tissue sections of 7 normal endometria (after menopause), 5 atypical endometrial hyperplasias (AEH), and 32 endometrial endometrioid adenocarcinomas., Results: In normal endometrium and AEH, NEP immunoreactivity was detected in stromal cells, but not in glandular cells. In contrast, ET-1 immunoreactivity was detected in both glandular and stromal cells. In the stromal cells of grade 1 endometrial adenocarcinoma, NEP was detected at high or moderate quantities. However, significantly decreased NEP immunoreactivity was observed in the stromal cells of grade 2 and 3 adenocarcinomas. However, NEP was not immunostained in adenocarcinoma cells except for the lesions of squamous differentiation. ET-1 immunoreactivity was weakly detected in the stromal cells of grade 1 adenocarcinoma, but the intensity of ET-1 staining increased with advancing tumor grade. The ratio of the staining scores of stromal ET-1 to stromal NEP was positively correlated with the tumor grade., Conclusions: These findings demonstrate that NEP expression in the stromal cells of endometrial adenocarcinoma is downregulated, while stromal ET-1 is upregulated, with increasing tumor grade. The present findings also suggest that NEP may play a role in the regulation of neoplastic transformation, tumor progression, and differentiation in endometrial neoplasms, possibly by degrading certain peptide growth factors such as ET-1., (Copyright 2001 S. Karger AG, Basel)

Using sonography, we classified the adnexal masses of 292 patients into 4 patterns. Pattern A was benign cystic tumors; B was benign mixed tumors (cysts with a smooth solid component); C was malignant mixed tumors (cysts with an irregular solid component or thickened septum), and D was solid tumors. We diagnosed tumors showing patterns A and B as benign, while patterns C and D represented tumors with low malignant potential or actual malignancy. The sensitivity and specificity of sonography was 82.2 and 82.1%, respectively, and these values were superior to those for tumor markers (CA125, CA19-9, CA72-4). Both the sensitivity and specificity of intraoperative frozen sections were the highest, showing that this is the most reliable examination. However, 15 of 191 patients undergoing frozen section were upgraded by the final pathological diagnosis. If sonography is performed by an experienced gynecologic oncologist, this examination is more reliable than tumor markers. However, intraoperative frozen section should still be performed during surgery for patients with ovarian tumors., (Copyright 2001 S. Karger AG, Basel)

Aminopeptidase A (AP-A) is a cell surface metallopeptidase which specifically cleaves the amino-terminal acidic residue from peptide substrates such as angiotensin II. AP-A is identical to the differentiation-related antigen, murine BP-1 or human kidney gp160, and is involved in regulating cell differentiation and/or neoplastic transformation of certain normal and transformed cells. We examined expression of AP-A in premalignant and malignant lesions of the uterine cervix, and investigated whether its expression was related to disease progression and neoplastic transformation. Formalin-fixed, paraffin-embedded tissue sections including 14 cervical intraepithelial neoplasms (CIN) and 23 invasive squamous cell carcinomas (SCC) were immunohistochemically evaluated. AP-A was localized in the basal cell layer in normal squamous epithelium. In CIN, AP-A expression was found on dysplastic cells, and increased with the severity of the precancerous lesions. In invasive cancer, 18 of 19 non-keratinizing-type SCCs and none of 4 keratinizing-type SCCs expressed AP-A. In addition, AP-A immunoreactivity was significantly correlated with proliferating cell nuclear antigen expression in both CIN and SCC cases. Furthermore, angiotensin II type 1 receptor was present in all AP-A-positive SCCs. These results indicate that AP-A is upregulated as the lesion progresses toward carcinoma in the cervical epithelium, and suggest that AP-A may play a regulatory role in neoplastic transformation and disease progression in cervical neoplasms and may serve as a potential tumor marker during cervical neoplasia development., (Copyright 2000 S. Karger AG, Basel)

The effect of human granulocyte colony stimulating factor (hG-CSF) was investigated on the proliferation of choriocarcinoma cells in vitro. No growth-stimulating effect was observed. Then, 22 patients with invasive mole and 9 patients with choriocarcinoma who received combination chemotherapy were treated with hG-CSF when white blood cell counts decreased below 2,000/mm3. The duration of neutropenia was reduced significantly by 3-4 days with the use of hG-CSF. No side effects were observed. These results indicate safety and usefulness of hG-CSF as an adjunct to chemotherapy in the treatment of gestational trophoblastic disease.