野村 弘行

Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) :lad cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non-LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation.

The Werner (WRN) gene codes for a DNA helicase that contributes to genomic stability and has been identified as the gene responsible for progeria. Recent studies have shown reduced WRN expression due to aberrant DNA hypermethylation in cancer cells. Furthermore, WRN expression is thought to affect sensitivity to DNA topoisomerase I inhibitors in cancer therapy. In this study, we examined the relationship between aberrant DNA hypermethylation of WRN and the sensitivity of cervical cancer cells to anticancer drugs. DNA was extracted from samples from 22 patients with primary cervical cancer and 6 human cervical cancer-derived cell lines. Aberrant DNA hypermethylation was analyzed by methylation-specific PCR. WRN expression in cultured cells before and after addition of 5-aza-2-deoxycytidine, a demethylating agent, was examined using RT-PCR. The sensitivity of cells to anticancer drugs was determined using a collagen gel droplet embedded culture drug sensitivity test (CD-DST). siRNA against WRN was transfected into a cervical cancer-derived cell line with high WRN expression. Changes in drug sensitivity after silencing WRN were determined by CD-DST. Aberrant DNA hypermethylation and decreased expression of WRN were detected in 7/21 cases of primary cervical cancer and in two cervical cancer-derived cell lines. These two cell lines showed high sensitivity to CPT-11, a topoisomerase I inhibitor, but became resistant to CPT-11 after treatment with 5-aza-2-deoxycytidine. Transfection of siRNA against WRN increased the sensitivity of the cells to CPT-11. Aberrant DNA hypermethylation of WRN also increased the sensitivity of cervical cancer cells to CPT-11. Therefore, epigenetic inactivation of this gene may be a biomarker for selection of drugs for the treatment of cervical cancer. This is the first report to show a relationship between the methylation of the WRN gene and sensitivity to CPT-11 in gynecological cancers.

Epimutation is defined as abnormal transcriptional repression of active genes and/or abnormal activation of usually repressed genes caused by errors in epigenetic gene repression. Epimutation arises in somatic cells and the germline, and constitutional epimutation may also occur. Epimutation is the first step of tumorigenesis and can be a direct cause of carcinogenesis. Cancers associated with epimutation include Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC), chronic lymphocytic leukemia, breast cancer and ovarian cancer. Epimutation has been shown for many tumor suppressor genes, including RB, VHL, hMLHI, APC and BRCA1, in sporadic cancers. Methylation has recently been shown in DNA from normal tissues and peripheral blood in cases of sporadic colorectal cancer and many studies show constitutive epimutation in cancers. Epimutation of DNA mismatch repair (MMR) genes (BRCA1,hMLH1 and hMSH2) involved in development familial cancers has also been found. These results have led to a focus on epimutation as a novel oncogenic mechanism.

The number of cases of endometrial cancer has shown a tendency to increase in recent years. Endometrial cancer originates from the endometrium and is classified, based on the development mechanism, into types 1 and 2, which are responsive and non-responsive to estrogen, respectively, and have significantly different gene expression profiles. Studies of genes with abnormal expression in endometrial cancer have identified multiple oncogenes, tumor suppressors, mismatch repair genes, apoptosis-associated genes, levels of hormone receptors and DNA ploidy and aneuploidy as biomarkers of endometrial cancer. The use of these molecules and genes may facilitate accurate diagnosis and prognostic prediction and contribute to individualized treatment. Trials of drugs which target these biomarkers and searches for new biomarkers using cDNA microarrays and RT-qPCR are ongoing and it is likely that these findings can be translated to clinical use.

Progestin preparations are made of synthetic progesterone and have often been used for hormone therapy in gynecological patients with endometriosis or endometrial cancer. Hormone therapy using progestin is considered to be one of the effective means of treatment particularly when dealing with endometrial cancer (an estrogen-dependent tumor). Numerous reports have been published concerning its efficacy in advanced or recurrent cases of atypical endometrial hyperplasia or endometrial cancer. Dienogest has been developed as a fourth-generation progestin for hormone therapy for endometriosis that can be used with high safety for long periods of time. In Japan, dienogest has been recommended as a first-line drug for endometriosis-associated pain. However, its antitumor activity has also been attracting close attention following a report that this drug suppressed the proliferation in vitro of endometrial cancer-derived cell lines which failed to respond to other progestins such as medroxyprogesterine acetate (MPA). The mechanism for antitumor activity of dienogest is considered to differ from the mechanism for antitumor activity of conventional progestin preparations used for treatment of endometrial cancer. This drug is expected to be clinically applicable as a new drug for the treatment of endometrial cancer.

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and alpha-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC.

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and a-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC. (c) 2011 Wiley Periodicals, Inc.

Uterine carcinosarcoma (CS) is usually classified as uterine endometrial carcinoma (EC). However, CS is more aggressive even compared with high grade EC. CS is also reported to undergo epithelial to mesenchymal transition (EMT). In this study, we compared the gene expression profiles of CS, EC, and uterine sarcoma (US) and evaluated the role of EMT and chromosomal aberrations in CS tumor formation. Frozen tissues of 46 patients (14 CS, 24 EC, and 8 US) were included. The similarity was examined by Gene Set Enrichment Analysis (GSEA), Fisher's exact test, and clustering using intrinsic gene set. We examined the expression of 39 EMT-related genes and evaluated TGF-beta signaling by phospho-SMAD2/3 (p-SMAD2/3) staining. Chromosomal regions differing between CS and EC were identified by chromosomal GSEA and comparative genomic hybridization (CGH) microarrays. Three statistical methods confirmed that CS resembled US rather than EC. Acquired markers of EMT were upregulated and attenuated markers of EMT were downregulated in CS. Immunohistochemistry showed that carcinomatous region of CS have higher expression of p-SMAD2/3 than EC (P = 0.008). Chromosomal GSEA showed that genes located at 19q13 had higher expression in CS. Furthermore, CGH microarray indicated that the TGFB1 locus at 19q13.1 was amplified in 4 of 7 samples. Based on the expression profile, CS resembles US rather than EC. TGF-beta signaling is activated in CS and chromosomal gains at 19q13, which includes the TGFB1 locus, suggest that this may contribute to high expression of TGF-beta and thereby EMT phenotype of CS. (c) 2011 Wiley Periodicals, Inc.

Background: Endometrial cancer (EC) is the most common cancer of the female genital tract. However, no screening method for EC has been established yet. In this study, we evaluated the cell-free DNA in EC. Methods: Fifteen healthy individuals, 9 with benign gynecologic diseases, and 53 with ECs were included in this study. Alu sequences in free DNA fragments were used as surrogate markers, and cell-free DNA density was measured by quantitative real-time polymerase chain reaction. Results: The cell-free DNA levels in ECs tended to be higher than in benign condition (healthy individuals + benign gynecologic diseases, n = 24; P = 0.095). There was no significant difference in cell-free DNA among stage or histological grade of EC, and no significant change in cell-free DNA before and after operation (P = 0.25): Moreover, in 19 ECs, cell-free DNA decreased after operation, however, in 6 ECs, cell-free DNA did not decrease. Three ECs recurred, and cell-free DNA did not decrease in these cases. Conclusions: Measurement of cell-free DNA is not useful for EC screening; however, the change of cell-free DNA in a patient may be a prognostic biomarker of EC.

Purpose: The standard regimen for platinum-resistant/refractory recurrent epithelial ovarian cancer (EOC) remains to be determined. In this study, we retrospectively compared the effect of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in the treatment of platinum-resistant recurrent EOC. Methods: Thirty patients who received salvage chemotherapy with CPT-11 or PLD were included in the study. CPT-11 (100 mg/m(2)) was administered intravenously on days I, 8 and 15 every four weeks. PLD (50 mg/m2) was administered on day 1 every four weeks. Treatment was repeated, provided that no disease progression or intolerable toxicity occurred. Results: Response rate in the CPT-11 group and PLD group showed no difference at 26.7% (p=0.66) in both, while non-PD rate was 73.3% vs 33.3% (p<0.05). respectively. Progression-free survival after CPT-11 treatment and PLD treatment was 28.4 weeks and 16.8 weeks (p=0.07), respectively. Hand-foot syndrome and mucositis were more common in the PLD group than in the CPT-II group (p<0.05). Conclusions: The results indicate that CPT-11 is a promising drug for the treatment of platinum-resistant recurrent EOC.

Endometrial cancer is the seventh most common cancer in women worldwide. Therefore elucidation of the pathogenesis and development of effective treatment for endometrial cancer are important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic variation and mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, in recent years, epigenetic mechanisms that do not involve changes in DNA sequences have been examined. Studies aimed at detection of aberrant DNA hypermethylation in cancer cells present in microscopic amounts in vivo and application of the results to cancer diagnosis have also started. Breakdown of the DNA mismatch repair mechanism is thought to play a large role in the development of endometrial cancer, with changes in the expression of the hMLH1 gene being particularly important. Silencing of genes such as APC and CHFR, Sprouty 2, RASSF1A, GPR54, CDH1, and RSK4 by DNA hypermethylation, onset of Lynch syndrome due to hereditary epimutation of hMLH1 and hMSH2 mismatch repair genes, and regulation of gene expression by microRNAs may also underlie the carcinogenic mechanisms of endometrial cancer. Further understanding of these issues may permit development of new therapies. © Copyright 2012 Kouji Banno et al.

若年発症の卵巣胚細胞腫瘍に対する妊孕性温存治療、特に術後化学療法の妊孕性への影響について明らかにすることを目的とし、1985年より2011年までに当院で、妊孕性温存手術および術後化学療法を施行した11症例を対象として検討を行った。対象症例の年齢は中央値25歳(19〜31歳)であり、未熟奇形腫8例、卵黄嚢腫瘍1例、ディスジャーミノーマ1例、悪性転化を伴う成熟嚢胞性奇形腫1例が含まれ、進行期はI期9例、III期2例であった。治療後の再発は認められなかった(追跡期間4〜146ヵ月、中央値77ヵ月)。全症例で化学療法に伴う一過性の無月経が認められ、化学療法終了から月経再開までの期間は1〜6ヵ月(中央値3ヵ月)であった。挙児希望のあった8例中6例で治療後の正常分娩が得られた。若年の卵巣胚細胞腫瘍に対する術後化学療法による卵巣機能障害は比較的軽度であると考えられた。(著者抄録)

Narrow band imaging (NBI) has been used in the gastrointestinal endoscopy field as a novel endoscopic imaging technique and has contributed to improved qualitative diagnosis and detection of lesions. However, there are only a few studies of use of NBI in the gynecology field. We applied NBI in flexible hysteroscopy at our outpatient clinic and evaluated the utility of NBI hysteroscopy for diagnosis of malignant endometrial lesions by comparison of the sensitivity and specificity between white light alone and white light+NBI using hysteroscopic video images. The subjects were 65 patients with a suspected endometrial lesion in the uterine cavity. These patients underwent flexible hysteroscopy using NBI in addition to conventional white light. Video images from 65 patients were edited into two groups, white light alone (WL group) and white light+NBI (NBI group) (130 images in total). Computerized block randomization of the order was then performed. Four raters independently diagnosed the images without use of other clinical information. Using the pathological diagnosis as the gold standard, we evaluated the sensitivity and specificity of diagnosis of atypical endometrial hyperplasia (AEH) or endometrial carcinoma compared between the WL and NBI groups. The sensitivity of diagnosis of A EH or endometrial carcinoma was numerically higher in the NBI group for all raters, and the average sensitivity was significantly higher in the NBI group compared to the WL group (78.6% vs. 63.7%, P<0.001). The specificity for each rater and the average specificity were comparable between the two groups. Compared to white light hysteroscopy, NBI hysteroscopy had a higher sensitivity for diagnosis of AEH or endometrial carcinoma without loss of specificity. This suggests that NBI hysteroscopy may be more useful than white light hysteroscopy for endoscopic diagnosis of malignant endometrial lesions.

40歳。子宮がん検診で子宮筋腫を指摘された。経腟超音波および骨盤MRIで子宮前壁より隆起する径11cm、表面やや不整の充実性腫瘍を認め、漿膜下筋腫と診断した。下腹部膨満感などの症状があることから、腹腔鏡下子宮筋腫核出術を施行した。筋腫核出後、広範囲に腹膜が欠損したが、縫合修復は困難と判断し癒着予防にインターシードを貼付するのみとした。術後出血のインフォメーションとして右下腹部5mmトロッカー挿入部より10mm径のペンローズドレーンを挿入し、他のトロッカー挿入部は閉鎖した。第1病日にドレーンを抜去し、抜去部に皮膚テープを貼付した。第3病日より離床が進み、翌日の退院診察で右トロッカー挿入部の皮膚テープを除去したところ、大網の脱出を認め、緊急手術を施行した。トロッカー挿入部を約4cmに延長切開し、腹膜を全周性に把持しながら大網を完全に腹腔内に還納し、腹膜、筋膜を順次縫合閉鎖した。術後創部や全身状態に異常はなく、5日後に退院した。

The aim of this study was to examine the relation between cofilin I expression and progression-free survival in advanced epithelial ovarian cancer. We performed quantitative. reverse transcriptase polymerase chain reaction and immunohistochemical analysis in 78 patients with advanced epithelial ovarian cancer (excluding those with mucinous and clear-cell types). All patients received the standard therapy, including staging laparotomy and adjuvant chemotherapy consisting of carboplatin and paclitaxel. Of 78 samples, RNA from 62 samples was available for reverse transcriptase polymerase chain reaction analysis. We defined cofilin I high expression as relative gene expression equal to or higher than the median and low expression as gene expression lower than median. The progression-free survival was longer in cofilin I low-expression cases than in high-expression cases (P = .039). Multivariate analysis demonstrated that stage and cofilin 1 expression were significant predictors of progression-free survival. Of the 78 samples, 54 were appropriate for immunohistochemical study. In 35 of those 54 cases. cofilin 1 protein expression was detected. The progression-free survival was longer in cofilin I protein-negative cases than in protein-positive cases (P = .042). Expression of cofilin I may predict the progression-tree survival of patients with advanced epithelial ovarian cancer receiving standard therapy. (C) 2011 Elsevier Inc. All rights reserved.

Background: The purpose of this study is to assess the efficacy and safety of treatment with taxane plus platinum in combination therapies for advanced or recurrent endometrial carcinoma. Patients and methods: Patients with measurable disease derived from histologically confirmed stage III/IV or recurrent endometrial carcinoma were randomly assigned to receive docetaxel plus cisplatin (DP), docetaxel plus carboplatin (DC), or paclitaxel plus carboplatin (TC) every 3 weeks until disease progression or adverse events prohibited further therapy. Among these regimens, the study evaluated the tumor response rate as the primary end point as well as toxicity. Results: Ninety patients were enrolled. Of them, 88 were eligible and consequently 29, 29, and 30 patients were randomly assigned to DP, DC, and TC, respectively. Tumor response rates were 51.7%, 48.3%, and 60.0% in DP, DC, and TC, respectively (P = 0.65). The following toxic effects were observed: grade 3/4 neutropenia in 83.3%, 90.0%, and 76.6%; febrile neutropenia in 10.0%, 6.7%, and 3.3%; grade 3/4 thrombocytopenia in 6.7%, 10.0%, and 10.0%; grade 3/4 diarrhea in 13.3%, 3.3%, and 0%, respectively; and grade 3 neurotoxicity in 10.0% of TC. These toxicity profiles were not significantly different. Conclusion: The taxane plus platinum combination therapies could be candidates in further phase III trials for endometrial carcinoma.

Endometrial cancer arises from the uterine body and fundus in many cases, but can also originate from the lower region of the uterine body through the upper region of the cervix. Such tumors are referred to as carcinoma of the lower uterine segment (LUS) or isthmus, and account for 3-6.3% of all cases of endometrial cancer. This relatively low incidence has permitted performance of only small-scale studies, but the clinical and pathological characteristics of carcinoma of the LUS in all these reports have differed from those of other endometrial cancers. Generally, endometrial cancer is classified into estrogen-dependent endometrioid adenocarcinoma (designated as type I), and non-endometrioid types that are less associated with estrogen and include poorly differentiated adenocarcinoma (type II). In some reports, carcinoma of the LUS has been found to have type II characteristics. Carcinoma of the LUS has also been associated with Lynch syndrome, a hereditary disease with frequent development of colorectal, endometrial, and ovarian cancers. Lynch syndrome is thought to be induced by mismatch repair gene mutation. The frequency of Lynch syndrome in cases of general endometrial cancer is 1-2%. In contrast, the frequency in patients with carcinoma of the LUS is much higher, with up to 29% of cases diagnosable with Lynch syndrome and a high frequency of hMSH2 mutation found in one study. This suggests that further investigation of the clinical and pathological characteristics of carcinoma of the LUS and the association with Lynch syndrome is required through performance of a large-scale survey.

Narrow band imaging (NBI) for detection of blood vessels and microstructures on the mucosal surface is used in gastrointestinal endoscopy since it can improve qualitative diagnosis and detection of lesion. However, there are no studies on flexible hysteroscopy using NBI. We performed flexible hysteroscopy with NBI for outpatients to investigate the sensitivity and specificity of endoscopic diagnosis of malignant endometrial lesions. Of patients who attended our hospital for suspected lesions in the uterine cavity between April 2009 and May 2010, 104 subjects underwent hysteroscopy with NBI, in addition to white light. Using the pathological diagnosis as the gold-standard, we evaluated the sensitivity and specificity of NBI hysteroscopy for detecting atypical endometrial hyperplasia (AEH) or carcinoma. The results were also compared with historical data (n=209) for conventional hysteroscopy using white light only in 2008. The sensitivities were 97.2% [95% confidence interval (95% CI): 90.3-99.7%] and 82.6% (95% Cl: 74.4-89.0%) for NBI hysteroscopy and conventional hysteroscopy, respectively. The 95% CIs for the two methods did not overlap and the sensitivity of lesion detection was higher with NB! hysteroscopy. Specificities were comparable, 90.6% (95% CI: 75.0-98.0%) and 85.1% (95% CI: 76.3-91.6%) between the methods. NBI hysteroscopy has increased sensitivity for detection of atypical endometrial hyperplasia (AEH) or carcinoma. A comparison with historical data suggested that NBI may be useful for diagnosis of malignant endometrial lesions. As far as we are aware, this is the first evaluation of flexible hysteroscopy with NBI for diagnosis of malignant endometrial lesions.

Purpose: In this study, we compared second-line chemotherapy effects of nodal metastases with other metastases sites. Methods: The medical records of 44 women with recurrent ovarian cancer who received second-line chemotherapy were retrospectively reviewed. Results: Median age at the time of second-line chemotherapy was 55 years (range: 31-74). Recurrent sites were as follows: 29 patients had a solitary site (abdominal cavity: 8; lymph node: 3; pelvic cavity: 10; liver: 4; lung: 4) and 15 patients had multiple sites In total, the response rate was 30% (CR: 8, PR: 5). The response rate in sensitive cases was higher than in refractory/resistant cases (50% vs 5% p = 0.002). However, age, chemotherapy regimen, histologic type and number of diseases were not related with chemotherapy effect. In all diseases, response rate tended to be higher in lymph node disease than in the others (44% vs 27%). In both sensitive and refractory/resistant cases, response rate tended to be higher in lymph node disease. Conclusion: The response rate for lymph node diseases tended to be relatively high. Further study analyzing survival will be required to conclude the chemotherapy effect.

For both cervical cancer (UCC) and endometrial cancer (EMC) there are no effective prognostic markers. In this study, we evaluated 14102 protein expression in 332 uterine cancers (186 UCCs and 146 EMCs) and examined the relationship between HIG2 protein expression and clinical factors, including prognosis. Totally, HIG2 expression was detected in 58% of UCC and 66% of EMC. However, there was no significant relationship between HIG2 expression and age, clinical stage and histology in either UCC or EMC. In addition, HIG2 protein expression was not related to prognosis of UCC or EMC. The positivity rate of HIG2 protein was 56% and 61% in early-stage UCC and EMC, respectively and 67% in non-squamous cell carcinoma of UCC. The positivity rate of HIG2 protein was high even in early-stage UCC and EMC

MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 base pairs that regulate the expression of genes by targeting messenger RNA with complementarity with the miRNA base sequence. Regulation of gene expression by miRNAs is crucial in cellular development and differentiation, and recent studies suggest a relationship between human diseases and the breakdown of gene silencing mechanisms induced by miRNA abnormalities. In particular, abnormal miRNA expression has been detected in various types of cancer and the target genes have been identified. These results indicate that miRNAs act in a manner equivalent to oncogenes or tumor suppressors. miRNAs may also serve as diagnostic biomarkers and therapeutic targets. In this review, we introduce the latest findings on miRNAs in human endometrial cancer, a common malignancy, and discuss the potential of miRNAs as biomarkers and targets for molecular therapy.

Objectives. The purpose of this study was to identify genes that predict progression-free survival (PFS) in advanced epithelial ovarian cancer (aEOC) receiving standard therapy. Methods. We performed microarray analysis on laser microdissected aEOC cells. All cases received staging laparotomy and adjuvant chemotherapy (carboplatin + paclitaxel) as primary therapy. Results. Microarray analysis identified 50 genes differentially expressed between tumors of patients with no evidence of disease (NED) or evidence of disease (ED) (p<0.001). Six genes (13%) were located at 8q24, and 9 genes (19.6%), at 20q11-13. The ratio of selected gene set/analyzed gene set in chromosomes 8 and 20 are significantly higher than that in other chromosome regions (6/606 vs. 32/13656, p 0.01) and (12/383 vs. 32/13656, p = 1.3 x 10(-16)). We speculate that the abnormal chromosomal distribution is due to genomic alteration and that these genes may play an important role in aEOC and choose GNAS (GNAS complex locus, NM__000516) on 20q13 based on the p value and fold change. Genomic PCR of aEOC cells also showed that amplification of GNAS was significantly correlated with unfavorable PFS (p = 0.011). Real-time quantitative RT-PCR analysis of independent samples revealed that high mRNA expression levels of the GNAS genes, located at chromosome 20q13, was significantly unfavorable indicators of progression-free survival (PFS). Finally, GNAS amplification was an independent prognostic factor for PFS. Conclusions. Our results suggest that GNAS gene amplification may be an independent, qualitative, and reproducible biomarker of PFS in aEOC. (C) 2010 Elsevier Inc. All rights reserved.

Objectives: Incidence of lymph node metastasis is relatively high even in early-stage epithelial ovarian cancers (EOC). Lymphadenectomy is important in the surgical treatment of EOC; however, the exact role of lymphadenectomy in the management of EOC remains unclear. In this study, we evaluated lymph node metastasis in stages I and II EOC patients. Patients and Methods: Seventy-nine patients with stage I/II EOC underwent initial surgery, and 68 patients received adjuvant platinum and taxane chemotherapy after surgery at Keio University Hospital. The patients were evaluated with respect to age at diagnosis, clinical stage, histology, histological grade, and tumor laterality. Results: Of the 79 patients, 10 (12.7%) had lymph node metastasis. Of these, 4 (5.1%) had lymph node metastasis in paraaortic lymph node (PAN) only, 1 (1.3%) in pelvic lymph node (PLN) only, and 5 (6.3%) in both PAN and PLN. The incidence of serous-type lymph node metastasis in PAN, PAN + PLN, and total was higher than nonserous type (25% vs 1.5%, P < 0.0001; 25% vs 3.0%, P = 0.001; 50% vs 5.9%, P < 0.0001). However, there was no significant difference between lymph node status and T factor or histological grade. In 78% of patients (7/9), metastases in contralateral lymph nodes were present (contralateral, 2; bilateral, 5). There was no significant difference in progression-free survival between node-positive and node-negative groups (P = 0.47). Conclusions: Based on diagnostic value, the result suggests that the role of lymphadenectomy might differ by histological type, as its therapeutic effect might be unclear. A multicenter analysis is essential for confirmation.

Objectives: Endometrioid type adenocarcinoma sometimes occupies both endometrium and ovary and in some cases the origin cannot be determined. Study design: In this study, we established a formula to distinguish ovarian endometrioid cancer (ECC) from endometrioid type endometrial cancer (EEC), based on our previous report of cyclin and KI67 expression pattern by immunohistochemistry of 36 EECc and 37 OECc by the logistic regression. We calculated the diagnostic accuracy using 92 test samples retrospectively and finally could diagnose the origin of 16 cases in whom endometrioid type adenocarcinoma arose in both ovary and endometrium and could be determined by Scully's criteria, and 15 cases in whom endometrioid type adenocarcinoma arose in both ovary and endometrium and Scully's criteria were not usuful retrospectively. Results: The estimated formula is as follows: Logit(Prob(EOC)) = -1.1437 - 0.0853 CNA + 0.0423 CNB + 0.173 CND1 + 0.0129 CNE + 0.0224 CNF + 0.0508 KI67, where Prob(EOC) is the probability that a clinical sample is EOC. If Prob(EOC) is larger than 0.5, the diagnosis is ovarian cancer; if less than 0.5 it is endometrial cancer. Finally, using the formula, 37 of 48 EECs (77.1%) and 33 of 44 EOCs (75.0%) were correctly classified, with an accuracy of 76.1% (p < 0.0001), retrospectively. In 12 of the 16 cases (75%) who could be determined by Scully's criteria, the origin determined by Scully's criteria was concordant with the origin determined by the formula retrospectively. In the other 15 cases, 12 cases were judged as ovary/ovary, 2 cases were judged as uterus/uterus and 1 case was judged as uterus/ovary. Conclusion: The formula we established was thought to be useful to distinguish the origin of the cases in whom endometrioid type adenocarcinoma arises in both ovary and endometrium. (C) 2009 Elsevier Ireland Ltd. All rights reserved.