Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.

The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2017 for the Treatment of Uterine Cervical Cancer are for the purpose of providing standard treatment strategies for cervical cancer, indicating treatment methods currently considered appropriate for cervical cancer, minimizing variances in treatment methods among institutions, improving the safety of treatment and prognosis of diseases, reducing the economic and psychosomatic burden of patients by promoting performance of appropriate treatment, and enhancing mutual understanding between patients and healthcare professionals. The guidelines were prepared through consensus of the JSGO Guideline Committee, based on careful review of evidence gathered through the literature searches and in view of the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise eight chapters and five algorithms. The main features of the 2017 revision are as follows: (1) evidence was collected using a search formula and with cooperation of the Japan Library Association. The bibliographical search formula was placed at the end of the book; (2) regarding clinical questions (CQs) where evidence or clinical inspection in Japan was lacking, opinions of the Guidelines Committee were described as "proposals for future directions"; (3) cervical intraepithelial neoplasia (CIN) 3 and adenocarcinoma in situ (AIS) were treated as a cervical precancerous lesion; (4) the CQs of endoscopic surgery, radical trachelectomy, and sentinel node biopsy were newly added in Chapter 3, "primary treatment for stage IB-II cervical cancer"; and (5) the CQ about hormone replacement therapy after cancer treatment was newly established. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2017 for the Treatment of Uterine Cervical Cancer.

Multicenter Clinicopathological Study of High-Grade Serous Carcinoma Presenting as Primary Peritoneal Carcinoma.

OBJECTIVE: We conducted a multicenter clinicopathological study to characterize patients with high-grade serous carcinoma presenting as primary peritoneal carcinoma (clinical PPC). METHODS: At 9 sites in Japan, patients with clinical PPC diagnosed according to Gynecologic Oncology Group criteria were enrolled retrospectively. The Gynecologic Oncology Group criteria allow for minor ovarian involvement by high-grade serous carcinoma. There was no systematic detailed histopathological review of the fallopian tubes to determine whether they were involved by serous carcinoma. RESULTS: There were 139 patients and 64% were aged 60 years or older. Median pretreatment serum CA-125 was 1653.5 IU/mL. Pretreatment performance status was poor in more than 50%, endometrial cytology was positive in 40.3%, and the preoperative clinical diagnosis was correct in 72.7%. Primary debulking surgery was performed in 36% of patients, whereas 64% underwent neoadjuvant chemotherapy (NAC) with interval debulking surgery (IDS). The main tumor sites were the upper abdomen (greater omentum), extrapelvic peritoneum, mesentery, and diaphragm. Lymph node metastasis was found in 46.8% of patients undergoing systematic retroperitoneal node dissection. The optimal surgery rate was 32.0% with primary debulking surgery versus 53.9% with NAC and IDS (P = 0.0139). The response rate was 82.0% with NAC and 80.6% with postoperative chemotherapy. Median progression-free survival was 19.0 months and median overall survival was 41.0 months. Multivariate analysis showed that prognostic factors for progression-free survival were NAC and residual tumor diameter after debulking surgery, whereas the only prognostic factor for overall survival was the residual tumor diameter. CONCLUSIONS: This study identified various characteristics of clinical PPC. Neoadjuvant chemotherapy with IDS is a reasonable treatment strategy, and complete debulking surgery is optimum.

Japan Society of Gynecologic Oncology guidelines 2015 for the treatment of vulvar cancer and vaginal cancer.

BACKGROUND: Vulvar cancer and vaginal cancer are relatively rare tumors, and there had been no established treatment principles or guidelines to treat these rare tumors in Japan. The first version of the Japan Society of Gynecologic Oncology (JSGO) guidelines for the treatment of vulvar cancer and vaginal cancer was published in 2015 in Japanese. OBJECTIVE: The JSGO committee decided to publish the English version of the JSGO guidelines worldwide, and hope it will be a useful guide to physicians in a similar situation as in Japan. METHODS: The guideline was created according to the basic principles in creating the guidelines of JSGO. RESULTS: The guidelines consist of five chapters and five algorithms. Prior to the first chapter, basic items are described including staging classification and history, classification of histology, and definition of the methods of surgery, radiation, and chemotherapy to give the reader a better understanding of the contents of the guidelines for these rare tumors. The first chapter gives an overview of the guidelines, including the basic policy of the guidelines. The second chapter discusses vulvar cancer, the third chapter discusses vaginal cancer, and the fourth chapter discusses vulvar Paget's disease and malignant melanoma. Each chapter includes clinical questions, recommendations, backgrounds, objectives, explanations, and references. The fifth chapter provides supplemental data for the drugs that are mentioned in the explanation of clinical questions. CONCLUSION: Overall, the objective of these guidelines is to clearly delineate the standard of care for vulvar and vaginal cancer with the goal of ensuring a high standard of care for all women diagnosed with these rare diseases.

Assessing the effect of guideline introduction on clinical practice and outcome in patients with endometrial cancer in Japan: a project of the Japan Society of Gynecologic Oncology (JSGO) guideline evaluation committee.

OBJECTIVE: The Japan Society of Gynecologic Oncology (JSGO) published the first practice guideline for endometrial cancer in 2006. The JSGO guideline evaluation committee assessed the effect of this guideline introduction on clinical practice and patient outcome using data provided by the Japan Society of Obstetrics and Gynecology (JSOG) cancer registration system. METHODS: Data of patients with endometrial cancer registered between 2000 and 2012 were analyzed, and epidemiological and clinical trends were assessed. The influence of guideline introduction on survival was determined by analyzing data of patients registered between 2004 and 2009 using competing risk model. RESULTS: In total, 65,241 cases of endometrial cancer were registered. Total number of patients registered each year increased about 3 times in the analyzed period, and the proportion of older patients with type II endometrial cancer rapidly increased. The frequency of lymphadenectomy had decreased not only among the low-recurrence risk group but also among the intermediate- or high-recurrence risk group. Adjuvant therapy was integrated into chemotherapy (p<0.001). Overall survival did not significantly differ before and after the guideline introduction (hazard ratio [HR]=0.891; p=0.160). Additional analyses revealed patients receiving adjuvant chemotherapy showed better prognosis than those receiving adjuvant radiation therapy when limited to stage I or II (HR= 0.598; p=0.003). CONCLUSION: It was suggested that guideline introduction influenced the management of endometrial cancer at several aspects. Better organized information and continuous evaluation are necessary to understand the causal relationship between the guideline and patient outcome.

Japan Society of Gynecologic Oncology guidelines 2015 for the treatment of ovarian cancer including primary peritoneal cancer and fallopian tube cancer.

The fourth edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer including primary peritoneal cancer and fallopian tube cancer was published in 2015. The guidelines contain seven chapters and six flow charts. The major changes in this new edition are as follows-(1) the format has been changed from reviews to clinical questions (CQ), and the guidelines for optimal clinical practice in Japan are now shown as 41 CQs and answers; (2) the 'flow charts' have been improved and placed near the beginning of the guidelines; (3) the 'basic points', including tumor staging, histological classification, surgical procedures, chemotherapy, and palliative care, are described before the chapter; (4) the FIGO surgical staging of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer was revised in 2014 and the guideline has been revised accordingly to take the updated version of this classification into account; (5) the procedures for examination and management of hereditary breast and ovarian cancer are described; (6) information on molecular targeting therapy has been added; (7) guidelines for the treatment of recurrent cancer based on tumor markers alone are described, as well as guidelines for providing hormone replacement therapy after treatment.

Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms.

The third version of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine body neoplasms was published in 2013. The guidelines comprise nine chapters and nine algorithms. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. This revision was intended to collect up-to-date international evidence. The highlights of this revision are to (1) newly specify costs and conflicts of interest; (2) describe the clinical significance of pelvic lymph node dissection and para-aortic lymphadenectomy, including variant histologic types; (3) describe more clearly the indications for laparoscopic surgery as the standard treatment; (4) provide guidelines for post-treatment hormone replacement therapy; (5) clearly differentiate treatment of advanced or recurrent cancer between the initial treatment and the treatment carried out after the primary operation; (6) collectively describe fertility-sparing therapy for both atypical endometrial hyperplasia and endometrioid adenocarcinoma (corresponding to G1) and newly describe relapse therapy after fertility-preserving treatment; and (7) newly describe the treatment of trophoblastic disease. Overall, the objective of these guidelines is to clearly delineate the standard of care for uterine body neoplasms in Japan with the goal of ensuring a high standard of care for all Japanese women diagnosed with uterine body neoplasms.

Japanese Society of Clinical Oncology clinical practice guidelines 2010 for antiemesis in oncology: executive summary.

The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT3) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT3 receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT3 receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.

Japan Society of Gynecologic Oncology guidelines 2011 for the treatment of uterine cervical cancer.

The second edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine cervical cancer was published in 2011. The guidelines comprise eight chapters and five algorithms. They were prepared by consensus among the members of the Japan Society of Gynecologic Oncology Guidelines Formulation Committee and Evaluation Committee and are based on a careful review of the evidence obtained from the literature, health insurance system, and actual clinical settings in Japan. The highlights of the 2011 revision are (1) the recommended grades have been changed to five stages--A, B, C1, C2, and D; (2) the revisions are consistent with the new International Federation of Gynecology and Obstetrics staging system; (3) the roles are shared between the 'Japanese classification of cervical cancer' and the new guidelines; (4) clinical questions related to adenocarcinoma have been revised; and (5) a clinical question regarding cervical cancer in pregnant patients has been added. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. Each recommendation is accompanied by a classification of recommendation categories. The objective of these guidelines is to update the standard treatment strategies for cervical cancer, thus eliminating unnecessary and insufficient treatment.

Cytological scoring and prognosis of poorly differentiated endometrioid adenocarcinoma.

OBJECTIVE: Histopathological variation has been demonstrated in grade 3 endometrioid adenocarcinomas. We attempted to evaluate the clinicopathological features of grade 3 tumors by endometrial cytological features using a scoring system. STUDY DESIGN: Twenty-one endometrial cytological samples were evaluated using 5 cytological features: rates of cluster formation in tumor cells; nuclear pleomorphism; nuclear dimension; size of nucleoli, and chromatin structure and distribution. The relationships between cytological scores and clinicopathological factors or prognosis were investigated. RESULTS: The median cytological score was 6 (range 4-14); therefore, samples with scores of 4-5 were defined as having low scores, while those with scores of 6-14 were defined as high scores. The accuracy of the cytological diagnosis for grade 3 tumors in the high score group (8/10 patients, 80.0%) was significantly higher than that of the low score group (2/11 patients, 18.2%; p=0.009). Significant relationships between cytological scores and lymph node metastases or positive peritoneal cytology were observed (p=0.03 and 0.035, respectively). The overall survival rate was significantly worse in the high score group (30.0%) than the low score group (88.9%; p=0.02). CONCLUSIONS: Grade 3 endometrioid adenocarcinomas varied in cytological features; according to the scoring system used, high scores were associated with worse clinicopathological factors and poorer prognosis than low scores.

Factors affecting platinum sensitivity in cervical cancer.

The present study aimed to investigate the association between nedaplatin (NDP) sensitivity and the expression of biological factors in cervical cancer. A total of 45 cervical cancer specimens, including 18 pretreatment biopsies and 27 surgical specimens, were used in histoculture drug response assays to determine the chemosensitivity of cervical cancer specimens to NDP. Each specimen was assessed for immunohistochemical expression of Ki-67, p53, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved caspase-3, cyclooxygenase-2 (COX-2), and excision repair cross-complementation group 1 (ERCC1). The results revealed that low or negative expression of p53, Bcl-2 and COX-2, and high or positive expression of cleaved caspase-3 were significantly correlated with high sensitivity to NDP. However, there were no significant differences in Ki-67, Bax or ERCC1 expression between the low and high sensitivity groups. These findings indicate that sensitivity to platinum may be easily predicted by immunostaining for the detection of these specific factors in pretreatment biopsies or surgical specimens. The expression profiles of these targets may therefore provide additional information for planning individualized chemotherapy in the treatment of cervical cancer.

Retrospective comparative study of irinotecan and pegylated liposomal doxorubicin for platinum-resistant or -refractory epithelial ovarian and primary peritoneal carcinoma.

PURPOSE: This study was conducted to retrospectively compare the efficacy and safety of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma. METHODS: Nineteen patients who received CPT-11 and eleven patients who received PLD were enrolled. CPT-11 was intravenously administered at a starting dose of 60-100 mg/m(2) on day 1, 8, and 15 every 28 days, and PLD was administered at a starting dose of 40-50 mg/m(2) on day 1 every 28 days. Primary outcomes were overall response rate (complete response [CR] + partial response [PR]), disease control rate (CR + PR + stable disease), and progression-free survival (PFS) in each group. Clinical response was evaluated every two or three cycles using the Response Evaluation Criteria in Solid Tumors criteria; CA125 analysis was not performed. RESULTS: The overall response rate was 21.1 % (PR, four cases) and 0 % (p = 0.10) in the CPT-11 and PLD groups, respectively, and the disease control rate was 73.7 and 45.5 % (p = 0.12), respectively. Median PFS was 25.3 (range 5.4-69.9) weeks and 12.7 (range 4.0-43.1) weeks in the CPT-11 and PLD groups, respectively; however, this difference was not statistically significant (p = 0.064). Major adverse events in the CPT-11 group were neutropenia, nausea, and diarrhea, whereas those in the PLD group included thrombocytopenia, anemia, stomatitis, and hand-foot syndrome. CONCLUSIONS: This retrospective study demonstrated comparable efficacy outcomes for CPT-11 and PLD. The overall response rate, disease control rate, and median PFS were more favorable in the CPT-11 group compared to the PLD group, although the difference was not significant. The adverse event profiles were different between groups. These results suggest that CPT-11 might be a feasible choice as single-agent salvage chemotherapy for platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma beside established regimen like PLD.

ERCC1 expression and chemosensitivity in uterine cervical adenocarcinoma cells.

UNLABELLED: BACKGROUD/AIM: We previously demonstrated that high protein expression of excision repair cross-complementation group-1 (ERCC1) was associated with poor disease-free survival in patients who received adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin, and was shown to be an independent prognostic factor. In the present study, we evaluated ERCC1 expression levels in uterine cervical adenocarcinoma cell lines to assess whether they are affected by treatment with cisplatin with and without 5-fluorouracil (5-FU). MATERIALS AND METHODS: Firstly, half-maximal (50%) inhibitory concentration (IC50) values for cisplatin or 5-FU were calculated in cervical adenocarcinoma, HCA-1, and TCO-2 cell lines by 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, yellow tetrazole (MTT) assay. ERCC1 mRNA and protein levels were investigated by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. Secondly, cisplatin-resistant HCA-1 cells, designated HCA-1R cells were established, and IC50 values for cisplatin and 5-FU were calculated by the MTT assay. ERCC1 mRNA expression levels were investigated using quantitative RT-PCR following treatment with cisplatin with and without 5-FU. RESULTS: HCA-1 and TCO-2 cells exhibited similar sensitivity to cisplatin, and 5-FU, and comparable expression of ERCC1 mRNA and protein levels. HCA-1R cells exhibited two-fold higher resistance to cisplatin and a significantly higher level of ERCC1 mRNA expression compared to native HCA-1 cells. ERCC1 expression was significantly elevated by cisplatin treatment, which was reduced by co-administration of 5-FU in HCA-1, TCO-2 and HCA-1R cells. CONCLUSION: The current study demonstrated an association between ERCC1 expression and sensitivity to cisplatin in cervical adenocarcinoma cells. Co-administration of cisplatin and 5-FU revealed synergistic or additive effects through inhibition of ERCC1 expression in cervical adenocarcinoma cells. Therefore, it is possible that a combination therapy of cisplatin and 5-FU or 5-FU derivatives constitutes an ideal treatment regimen, from the ERCC1 inhibition point of view in cervical adenocarcinoma.

Relationship between detection of the cervical gland area during the late third trimester and necessity for induction of labor to prevent post-term delivery.

OBJECTIVES: With the maturation of the cervical canal during pregnancy, the cervical gland area (CGA) as observed on transvaginal ultrasonography is gradually obscured. The aim of this study was to elucidate the significance of CGA in the late third trimester as a determinant of the outcome of labor. METHODS: We investigated 123 primiparous women with singleton pregnancies at 36-41 weeks' gestation. The women were divided into two groups: a normal delivery group (93 women), which had vaginal delivery without medical intervention, and an induction of labor group (30 women), which required induction of labor after 41 weeks and 0 day. At outpatient prenatal checkups, the Bishop score (BS) was assessed by pelvic examination, and cervical length (CL) and CGA were evaluated by transvaginal ultrasonography. The relationship between each parameter and induction of labor was retrospectively determined and compared. RESULTS: Time-dependent assessment of each outcome determinant showed that the CGA detection rate was higher and the CL was longer in the induction of labor group from 3 weeks to 1 week before delivery at a significant level (P < 0.05); however, the BS was significantly lower in the induction of labor group only at 1 week before delivery (P < 0.05). When multiple logistic regression analysis of the necessity of induction of labor was conducted using BS, CL, and CGA parameters as explanatory variables at 1 week before delivery, CGA alone was shown to be an independent predictor of induction of labor (OR = 6.1, 95 % CI 2.3-16.2). CONCLUSION: The present study suggests that in the late third trimester, evaluation of CGA with transvaginal ultrasonography is most useful in predicting the necessity of induction of labor to prevent post-term delivery.

Effect of ursolic acid on MAPK in cyclin D1 signaling and RING-type E3 ligase (SCF E3s) in two endometrial cancer cell lines.

Cyclin D1 regulates G1 progression and is important in the development and proliferation of various human cancers. Cyclin D1 gene expression is activated by the Ras kinase cascade. Nuclear cyclin D1 levels are dependent on cytoplasmic degradation of cyclin D1 via ubiquitin-mediated proteolysis. We sought to determine whether the important MAPK signaling pathway, in the cyclin D1 cascade, including FBXW8, Cullin1, and the ubiquitination pathway mediated these effects. Ursolic acid (UA) treatment of SNG-2 cells, an endometrial cancer cell line, decreased cyclin D1, pERK1/2, FBXW8, and Cullin1 levels in a dose- and time-dependent manner. RING-type E3 ligase consists of CulIin1, Rbx, Skp1, and a member of the F-box protein family. In SNG-2, both dose- and time-dependent inhibition of Rbx 1 were observed following treatment with UA. Moreover, in HEC108 cells, another endometrial cancer cell line, UA treatment decreased cyclin D1, pERK1/2, and Cullin1 levels in a dose- and time-dependent manner and UA markedly inhibited FBXW8. Treatment of HEC108 cells moderately decreased Rbx1 in a dose- and-time-dependent fashion. In contrast, UA treatment increased ubiquitinated proteins in a dose- and time-dependent manner in both cell lines. RING-type E3 ligase accumulated in the cytoplasm following UA treatment of SNG-2cells. That in turn prevented cytoplasmic degradation of cyclin D1 via RING-type E3 (SCF E3s) ligase. In conclusion, our study found inhibition of the MAPK- cyclin D1 pathway and RING type E3 ligase (SCF E3s) in both endometrial cancer cell lines. Furthermore, CD36 was noted as a cell surface receptor for UA.

Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor.

Cyclooxygenase (COX)-2 inhibitors have been reported to potentially modulate the resistance of cancer cells to chemotherapeutic drugs by affecting multidrug resistance 1 (MDR1) expression. In the present study, we investigated the association between COX-2 and MDR1 expression in endometrial cancers and evaluated the effects of the COX-2 inhibitor, etodolac, in combination with paclitaxel on paclitaxel-resistant endometrial cancer cells. The relationship between COX-2 and MDR1 mRNA expression was examined by quantitative PCR in 36 endometrial cancer specimens. The paclitaxel-resistant cell line OMC-2P was established from OMC-2 cells. Paclitaxel (1 µg/ml) with or without etodolac (10 µg/ml) was added to OMC-2 and OMC-2P cells, and COX-2 and MDR1 mRNA expression levels were examined. The concentration of prostaglandin E2 (PGE2) in the supernatant of each cell line was examined by enzyme-linked immunosorbent assay. The function of MDR1 was determined by intracellular accumulation of rhodamine 123 using flow cytometry, and the concentration of intracellular paclitaxel was determined by high-performance liquid chromatography. We found a positive relationship between COX-2 and MDR1 mRNA expression in endometrial cancer. Both COX-2 mRNA expression and PGE2 production were elevated in resistant OMC-2P cells when compared to non-resistant OMC-2 cells. Additionally, MDR1 mRNA expression was markedly upregulated in OMC-2P cells. In OMC-2 cells, COX-2 and MDR1 mRNA levels were significantly upregulated by paclitaxel treatment and downregulated by co-administration with etodolac. In OMC-2P cells, COX-2 mRNA expression was also significantly upregulated by paclitaxel treatment and tended to be downregulated by co-administration with etodolac. Moreover, co-administration of paclitaxel and etodolac suppressed the induction of MDR1 mRNA. Rhodamine 123 efflux was increased in OMC-2P cells when compared to the efflux in the OMC-2 cells and was increased in response to paclitaxel treatment. Co-administration of paclitaxel and etodolac in both cell lines resulted in decreased rhodamine 123 efflux. The actual concentration of intracellular paclitaxel in OMC-2P cells was significantly lower than that in OMC-2 cells treated with paclitaxel alone and was significantly increased after co-administration of paclitaxel and etodolac. These findings suggest that paclitaxel resistance may be associated with COX-2 and MDR1 expression in cancer cells. Co-administration of COX-2 inhibitors and paclitaxel may have a key role in modulating or overcoming paclitaxel resistance in endometrial cancers.

Human epidermal growth factor receptor-2 overexpression and amplification in metastatic and recurrent high grade or type 2 endometrial carcinomas.

INTRODUCTION: Human epidermal growth factor receptor (HER)-2 overexpression or gene amplification is more common in high-grade or type 2 endometrial carcinomas. We assessed the discordance of HER-2 expression between primary and metastatic or recurrent endometrial carcinomas. MATERIALS AND METHODS: Thirty-six primary, along with 14 metastatic and five recurrent tumors (matched to primaries), pathologically confirmed as high-grade or type 2 endometrial carcinomas, were submitted for immunohistochemistry (IHC) for HER-2. Fluorescence in situ hybridization was performed when the tumors showed HER-2 overexpression (≥2+ IHC score). The results of the IHC and fluorescence in situ hybridization assays were compared between the primary and metastatic or recurrent tumors. The relationships between HER-2 expression and clinicopathological factors or prognosis were investigated. RESULTS: HER-2 overexpression and HER-2 amplification (a ratio of HER-2 copies to chromosome 17 [CEP17] copies ≥2.2) were detected in 33.3% (twelve of 36 patients) and 5.6% (two of 36 patients) of primary tumors, respectively. HER-2 overexpression was not associated with clinicopathological factors or prognosis. In 19 tumor specimens obtained from metastatic or recurrent tumors, HER-2 overexpression and HER-2 amplification were detected in 57.9% (eleven patients) and 15.8% (three patients), respectively. HER-2 overexpression tended to predict a worse prognosis. CONCLUSION: HER-2 expression in metastatic or recurrent tumors was more frequent than in matched primary high-grade or type 2 endometrial carcinomas. Trastuzumab in combination with cytotoxic chemotherapy may represent an alternative therapeutic option for these tumors.

Decreased expression of apelin in placentas from severe pre-eclampsia patients.

OBJECTIVE: It is well documented that anti-angiogenic factors are likely to play essential roles in the etiology of pre-eclampsia. Apelin is a small peptide that may potentially act as an angiogenic factor. The expression of apelin was examined at the RNA and protein levels in this study. METHODS: We compared the expression of apelin, examined using quantitative reverse-transcription polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay and immunostaining, between pre-eclamptic patients and normotensive controls. RESULTS: Apelin messenger RNA is significantly decreased in pre-eclamptic placentas compared with normotensive pregnancies (p<0.05). Apelin protein levels are also lower in pre-eclamptic placentas than the controls but higher in the maternal circulation in pre-eclampsia patients. Immunohistochemical signals for apelin and its receptor APJ were detected mainly in the cytoplasm of syncytiotrophoblasts in chorionic villi and trophoblast-lineage cells in the decidua of term placentas. In early gestation, stronger APJ signals were observed at the cellular membrane. CONCLUSIONS: A functional role of the apelin--APJ system is likely in early gestation, and this raises the possibility that a dysfunctional apelin--APJ system contributes to the onset of pre-eclampsia via decreased angiogenic activity in placental implantation.