OBJECTIVES ARID1A is a recently identified tumor suppressor participating in chromatin remodeling. Somatic inactivating mutations of ARID1A and loss of its expression occur most frequently in ovarian clear cell and endometrioid carcinomas and uterine endometrioid carcinomas. Since endometriosis is thought to be a precursor of most ovarian clear cell and endometrioid carcinomas, we undertook an analysis of ARID1A expression of these tumors arising within an endometriotic cyst (endometrioma). MATERIALS/METHODS Our immunohistochemical study set consisted of 47 endometriotic cysts containing clear cell carcinoma in 24 cases, well-differentiated ovarian endometrioid carcinoma in 20 and mixed clear cell and endometrioid carcinoma in 3. RESULTS ARID1A loss was observed in 31 (66%) of 47 carcinomas and therefore these cases were informative for determining the temporal sequence of loss of ARID1A expression in tumor progression. In 16 of the 47 cases, ARID1A immunoreactivity was retained in both the endometriotic cyst and the carcinoma and thus these cases were not informative. All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor. CONCLUSIONS The findings in this study provide cogent evidence that loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event, occurring before malignant transformation, in the development of the majority of ovarian clear cell and endometrioid carcinomas arising in endometriomas.

Recent reports have shown that peroxisome proliferatoractivated receptor (PPAR

Objective: The aim of this study was to investigate the prognostic role of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a predictive marker prior to treatment of cervical cancer with radiation therapy (RT) alone or concurrent chemoradiation therapy (CCRT).Methods: Fifty-six patients with squamous cell carcinoma (SCC) of the uterine cervix who underwent RT or CCRT from 2005 to 2013 at this Hospital were retrospectively identified using electronic databases.Patients were divided into a high NLR group (≥ 2.5) and a low NLR group (< 2.5). The efficacy of RT and CCRT in the two groups was compared.Result: Of the 56 patients, 35 were in the high NLR group and 21 were in the low NLR group. In comparison to a high NLR, a low NLR was significantly associated with a complete response (P < 0.001).When cancer was divided into stages I/II and III/IV, patients with a low NLR had a significantly better therapeutic outcome than those with a high NLR (P < 0.05). Multivariate analysis showed that only the NLR was a significant prognostic factor for progression-free survival (PFS). Patients with a high NLR had a significantly shorter PFS and overall survival than those with a low NLR.Conclusion: Results showed that a low NLR before treatment can predict a good response to RT or CCRT by all stages of uterine cervical cancer. The NLR may be a promising parameter on which to base the choice of a therapeutic strategy to treat SCC of the uterine cervix.

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BACKGROUND.It was recently reported that high expression of peroxisome proliferator‐activated receptor γ (PPARγ) and low expression of cyclooxygenase‐2 (COX‐2) might be involved in the inhibition of ovarian tumor progression and confirmed that PPARγ activation could suppress COX‐2 expression via the nuclear factor‐κB pathway in ovarian cancer cells.METHODS.The current study investigated whether meloxicam, a selective COX‐2 inhibitor, and ciglitazone, a ligand for PPARγ, inhibit the growth of human ovarian cancer cell lines and aimed to elucidate the molecular mechanism of their antitumor effect. Tumor growth and survival were examined in female nu/nu mice xenografted with subcutaneous OVCAR‐3 tumors or with intraperitoneal DISS tumors and treated with meloxicam (162 ppm in diet, every day) or ciglitazone (15 mg/kg intraperitoneally once a week).RESULTS.Both meloxicam and ciglitazone treatments significantly suppressed the growth of OVCAR‐3 tumors xenotransplanted subcutaneously and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with controls. Meloxicam treatment decreased COX‐2 expression in tumors by 2.5‐fold compared with that observed in untreated tumors. Although ciglitazone treatment did not alter COX‐2 expression in tumors, it reduced the expression of microsomal prostaglandin (PG) E synthase, which converts COX‐derived PGH2 to PGE2. Both meloxicam and ciglitazone decreased PGE2 levels in serum as well as in ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR‐3 tumors treated with either meloxicam or ciglitazone.CONCLUSIONS.These results indicate that both meloxicam and ciglitazone produce antitumor effects against ovarian cancer in conjunction with reduced angiogenesis and induction of apoptosis. Cancer 2007; 110:791–800. © 2007 American Cancer Society.

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ObjectiveLoss of ARID1A is related to oncogenic transformation of ovarian clear cell adenocarcinoma. The present study was conducted in epithelial ovarian cancer of all tissue types to investigate whether an increased or decreased expression level of ARID1A can be a prognostic factor for ovarian cancer or can influence the sensitivity to anticancer drugs.MethodsThe expression level of ARID1A was investigated in 111 patients with epithelial ovarian cancer who received initial treatment at the Hirosaki University Hospital between 2006 and 2011. The expression level of ARID1A was immunohistochemically graded using staining scores, which were calculated by multiplying the staining intensity of the nuclei by the stain-positive area.ResultsThe level of ARID1A was significantly lower in clear cell adenocarcinoma than in other histologic types. Among the patients with stage III, IV cancer (n=46), the level of ARID1A was significantly lower (p=0.026) in patients who did not achieve complete response (CR; n=12) than in patients who achieved CR (n=34). The level of ARID1A was relatively lower (p=0.07) in patients who relapsed after achieving CR (n=21) than in patients who did not relapse (n=13). When the staining score of 0 was defined as ARID1A-negative and other staining scores were defined as ARID1A-positive, there was significant difference in progression-free survival between ARID1A-negative (n=11) and ARID1A-positive (n=35) patients in stage III, IV disease.ConclusionThe result suggests that decreased ARID1A expression is correlated with chemoresistance and may be a predictive factor for the risk of relapse of advanced cancer after achieving CR.

Expression of cyclooxygenase (COX)-2 plays a key role in tumorigenesis and development and peroxisome proliferator-activated receptor g (PPARg) has been implicated in the control of COX-2 expression in some tissues. The aim of this study is to investigate (1) whether expression of COX-2 and PPARg is associated with ovarian carcinogenesis and progression of ovarian tumours and (2) whether COX-2 expression is controlled through ligand-mediated activation of PPARg in ovarian carcinoma cells. For this purpose, the presence of COX-2 and PPARg was immunohistochemically examined in 71 epithelial ovarian carcinomas, 18 borderline tumours and 23 benign tumours and the levels of COX-2 and PPARg proteins were determined by enzyme immunoassay in four benign tumours, three borderline tumours and 12 carcinomas. The frequency of COX-2 and PPARg detection was significantly increased and decreased as lesions progressed to carcinoma, respectively. The COX-2 protein was not detected in the three borderline tumours, whereas PPARg protein was detected in all of them. COX-2 protein was detected in eight of the 12 carcinomas, whereas PPARg protein was detected in only two cases. In addition, PPARg protein was not detected in all of the eight carcinomas in which COX-2 protein was detected, suggesting that expression of PPARg and COX-2 was in a reciprocal relationship. Furthermore, in cultured ovarian carcinoma cells, Western blot revealed that PPARg and COX-2 expression was regulated conversely as a result of stimulation by 15-deoxy-D 12, 14 PGJ 2 (15-PGJ 2 ), a PPARg activator. In addition, 15d-PGJ 2 suppressed tumour necrosis factor-ainduced-COX-2 expression, confirming the reciprocal correlation between COX-2 and PPARg. From these results, it was suggested that PPARg activation might suppress COX-2 expression via the nuclear factor-kB pathway in the ovarian carcinoma cells and that low expression of PPARg and high expression of COX-2 might be involved in carcinogenesis and progression of ovarian tumours.