Motoki Matsuura

Osteopontin is a new target molecule for ovarian clear cell carcinoma therapy.

Recent studies have demonstrated overexpression of osteopontin (OPN) in ovarian clear cell carcinoma. Here, we revealed the role of OPN in invasiveness in ovarian clear cell carcinoma. We used immunofluorescence analysis to detect OPN in a total of 160 patient‐derived specimens. Ovarian clear cell carcinoma cell lines, RMG‐1 and TOV‐21G, were used to monitor changes in OPN and integrin levels, and cell invasiveness following treatment with OPN, simvastatin, and transfection with siRNA. Immunofluorescence analysis revealed statistically significant differences among the histological groups, and ovarian clear cell carcinoma expressed a strong OPN signal. The OPN receptors, alpha v and 5, and beta 1 and 3 integrins, were increased after treatment with OPN. Invasion assays indicated that OPN enhanced in vitro extracellular matrix invasion dose‐dependently in ovarian clear cell carcinoma. Simvastatin significantly reduced expression of OPN and the integrins, and decreased ECM invasion. RNA interference also suppressed ECM invasion. These results suggest that down‐ or up‐regulation of OPN is involved in carcinoma cell invasion. We thus conclude that OPN regulation could have a crucial role in ovarian clear cell carcinoma therapy. (Cancer Sci 2010)

Analgesic efficacy of controlled-release oxycodone in patients with uterine or ovarian cancer.

Treatment with opioid analgesics often causes adverse reactions that may make continuous use of such drugs difficult. We investigated the efficacy and safety of controlled-release oxycodone in the treatment of gynecologic cancer pain. The patients included 14 with cervical cancer, 6 with corpus cancer, and 17 with ovarian cancer. Treatment with controlled-release oxycodone was started at 5 mg/dose when pain control using nonsteroidal anti-inflammatory drugs became ineffective. The dose was titrated to the optimal level over a mean duration of 2.34 ± 1.13 days, and the initially optimal dose was 18.92 ± 5.23 mg/day. Although no patients experienced confusion, vomiting, or respiratory depression, 17 patients experienced adverse events, including constipation in 14 patients and nausea in 9 patients. The incidence of nausea was low in patients receiving oxycodone and prochlorperazine. In the present study, patients with moderate to severe pain caused by gynecologic cancer could successfully be treated with controlled-release oxycodone.

Successful Uterus-Preserving Surgery for Treatment of Chemotherapy-Resistant Placenta Increta

Treatment of placenta increta often entails abdominal total hysterectomy. We present a case of placenta increta in which 3-dimensional computed tomography shows very high blood flow to the placenta, even after chemotherapy with methotrexate. Nonetheless, we were able to remove the region of the uterus that had been invaded by chorionic villi. Massive bleeding during the operation was prevented by ligation of the hypogastric artery and local injection of vasopressin. The combination of chemotherapy and partial resection of the uterus is quite a unique treatment for placenta increta patients. This approach enabled preservation of the uterus and the patient’s fertility. We suggest this procedure could be one of the treatments for patients who have placenta increta and wish to retain their fertility.

Rap1GAP inhibits tumor progression in endometrial cancer

OBJECTIVE Endometrioid adenocarcinoma (EAC) is a common endometrial cancer with recent dramatic increases in incidence. Previous findings indicate that Rap1GAP acts as a tumor suppressor inhibiting Ras superfamily protein Rap1 in multiple aggressive carcinomas; however, Rap1GAP expression in EAC has not been investigated. In this study, the tumor suppressing activity of Rap1GAP in EAC was explored. METHODS EAC cell lines were used to examine Rap1GAP levels by real-time RT-PCR and western blotting and the effects of Rap1GAP on cancer cell invasion and migration. Rap1GAP expression was analyzed by immunohistochemical staining for Rap1GAP, E-cadherin in surgically resected tumors of 114 EAC patients scored according to EAC differentiation grade. Prognostic variables such as age, stage, grade, tumor size, and immunostaining for Rap1GAP, E-cadherin were evaluated using Cox regression multivariate analysis. RESULTS Low Rap1GAP expression was detected in poorly differentiated EAC cells. Rap1GAP deficiency significantly accelerated while Rap1 deficiency decreased cancer cell migration and invasion. Patients with higher Rap1GAP, E-cadherin, and especially combined Rap1GAP/E-cadherin levels had better overall survival than EAC patients with no or weak expression. In addition, Rap1GAP expression was an independent prognostic factor in EAC. CONCLUSIONS Inhibition of Rap1GAP expression increases EAC cell migration and invasion through upregulation of Rap1. Low expression of Rap1GAP correlates with poor EAC differentiation. Our findings suggest that Rap1GAP is an important tumor suppressor with high prognostic value in EAC.

Prediction of Histologic Type and Lymph Node Metastasis for Advanced Ovarian Cancer on Uterine Cervical and Endometrial Cytology

OBJECTIVE To evaluate usefulness of uterine cervical and endometrial cytology for detecting ovarian cancer and predicting histologic type. STUDY DESIGN Retrospective analysis was performed on uterine cervical and endometrial cytology data on 163 patients with ovarian cancer. RESULTS Cervical and endometrial abnormalities were detected in 10 and 19 of the patients evaluated. Patients whose cervical and endometrial cytology revealed abnormal cells were classified as having ovarian cancer at International Federation of Gynecology and Obstetrics (FIGO) stages III and IV Peritoneal cytology proved positive in many of the patients with abnormal findings on uterine cytologic analysis. Of the 19 patients with positive uterine cytologic findings, 12 had recurrence of ovarian cancer after radical therapies. Lymph node metastases were detected in 9 of 19 patients. Our findings indicated that it is possible to predict histologic type in ovarian cancer in 90% of cases of positive cervical smears and 79% ofabnormal endometrial smears. CONCLUSION Our study showed that most of the ovarian cancer cases that had abnormalities in uterine cervical and endometrial cytologic tests exhibited progression of disease. As a consequence, our findings indicate that it is possible to predict development of ovarian cancer and its histologic type using cytology screening.

Analysis of A Single Para-Aortic Lymph Node Metastasis in Endometrial Cancer

Objective: To determine the indication for lymph node dissection in patients with endometrial cancer, we investigated the incidence and distribution of single metastatic lymph nodes in patients who underwent systematic pelvic and para-aortic lymph node dissection.Methods: This study involved 910 patients with endometrial cancer who were treated at the Cancer Institute Hospital, Japan, between January 1994 and December 2015. All patients underwent an open hysterectomy with bilateral salpingo-oophorectomy and pelvic and para-aortic lymph nodes dissection.Results: Lymph node metastasis was observed in 199 patients (21.9%), 45 (5%) of whom had single lymph node metastasis. Single lymph node metastasis accounted for 22.6% of all metastatic cases. Myometrial invasion >50% was observed in 30 patients, whereas 15 patients had <50% myometrial invasion. When mapping single lymph node metastatic sites, the para-aortic area had a frequency of 31.1% (14 cases). The distribution of single metastatic lymph nodes spanned a wide area between the pelvic and para-aortic regions. Considering single metastatic nodes and myometrial invasion, 8 patients (53.3%) who had myometrial invasion <50% had a single metastatic node in the para-aortic region. Four of 9 patients (45%) considered low-risk (endometrioid Grade 1-2, invasion depth <50%, no lymphovascular space invasion) showed metastasis to the para-aortic areas.Conclusion: Single metastatic lymph nodes were widely distributed between the pelvic and para-aortic regions, suggesting that detection of a sentinel lymph node in patients with endometrial cancer could be problematic.

Prediction of the therapeutic effect of dienogest in ovarian endometrial cysts using the apparent diffusion coefficient

Abstract The purpose of this study was to investigate whether apparent diffusion coefficient (ADC) mean values can be used for predicting the treatment response in ovarian endometrial cyst patients with dienogest (DNG) administration. Eighteen patients received DNG (2 mg/day, orally) for 60 days, among whom 26 ovarian endometrial cysts were retrospectively identified. Mean ADC values of individual ovarian endometrial cysts were obtained by ADC maps inside the tumor. There was a significant correlation between ADC values and reduction ratio. When calculating the mean ADC values for three groups; more than 50%, 50–25% and less than 25%, ADC values significantly increased with increasing reduction ratio; 2.05 × 10−3 mm2/s, 1.28 × 10−3 mm2/s and 0.94 × 10−3 mm2/s, respectively (p = 0.0180). Multiple regression analysis by reduction ratio (%), ADC mean values (×10−3 mm2/s), tumor longest diameter (cm) and CA125 (U/ml) revealed that tumor reduction ratio by DNG administration could be predicted by the following equation; R = 19.3 + 24.0x – 0.4y + 0.1z (R: Reduction ratio, x: ADC mean, y: Longest diameter, z: CA125). In conclusion, the ADC mean value is useful for the prediction of the treatment response in ovarian endometrial cyst patients with DNG administration. Chinese abstract 该研究目的是探讨表面扩散系数（ADC）均值是否可以用来预测卵巢子宫内膜异位囊肿对地诺孕素（DNG）治疗的反应。对18位患者(每天口服DNG 2mg),进行了为期60天的治疗,其中对26个卵巢子宫内膜异位囊肿进行回顾性分析。通过每个肿瘤内的ADC图获得单个卵巢子宫内膜异位囊肿的ADC均值。发现ADC值和减速比（reduction ratio）有显著相关性。把平均ADC值分为三组；超过50%，50-25%，和不到25%时，ADC值随着减速比的增加而明显增加，分别为2.05×103mm2/s，1.28×103mm2/s和0.94×103mm2/s（p=0.0180）。通过对减速比，ADC均值（×103mm2/s），肿瘤最长径（cm）和CA125(U/ml) 水平的多重线性回归分析发现，使用DNG治疗的肿瘤减速比可以用以下公式表示：R=19.3+24.0x-0.4y+0.1z(R:减速比，x：平均ADC，y:最长经线，z:CA125)。总之，ADC均值对使用DNG治疗卵巢子宫内膜异位囊肿的疗效预测是非常有用的。

Evaluation of cervical conization as a definitive treatment for microinvasive cervical carcinoma and cervical intraepithelial neoplasia grade 3.

PurposeThe aim of the study was to evaluate disease persistence after conization of CIN3 and microinvasive cervical carcinoma.MethodsMedical records from a total of 231 patients were reviewed. The prevalence of CIN3 and cervical carcinoma diagnosed by means of conization were analyzed. All conizations were performed under lumbar anesthesia using a laser technique.ResultsOf the 231 patients, 25 had margin involvement with CIN3 or microinvasive carcinoma. Among these 25 patients, 10 underwent hysterectomy. Two of these 10 patients had CIN3 and eight had microinvasive carcinoma. Residual disease was observed in hysterectomy specimens from 9 of the 10 patients. Of the eight patients diagnosed with microinvasion from post-cone hysterectomy specimens, four had CIN3 and three had microinvasive carcinoma. The three patients with microinvasion were found to have a larger area of residual disease as compared with other patients with margin involvement.ConclusionsConization alone seems to be a reasonable treatment for patients with CIN1, 2, 3, and microinvasive carcinoma. For adenocarcinoma, in situ treatment with conization alone is possible but requires careful follow-up. Hysterectomy appears to be a safe treatment option for microinvasive adenocarcinoma, although follow-up by cytology is sometimes possible in cases with negative surgical margins.

Efficacy of liquid-based genetic diagnosis of endometrial cancer

Although liquid‐based cytology (LBC) has increased the sensitivity of cytological diagnosis of endometrial cancer (EC) compared with conventional smear cytology, the sensitivity of LBC for the detection of EC is between 70% and 96% and remains unsatisfactory. In the present study, we compared the efficacy of LBC with liquid‐based genetic diagnosis (LBGDx) by amplicon sequencing of five genes including PTEN, PIK3CA, CTNNB1, KRAS, and TP53 in 48 LBC subjects who underwent endometrial screening. Consequently, LBC classified 15 samples as “positive or suspicious for malignancy” and the 15 were later confirmed as EC. However, LBC failed to identify five cases who were diagnosed as EC by additional transvaginal ultrasound and endometrial curettage, indicating that the sensitivity of cytology alone was 75% (15/20). LBGDx identified 11 pathogenic PTEN variants in 10 subjects, six PIK3CA variants in nine, three CTNNB1 variants in five, two KRAS variants in four, and three TP53 variants in three. Collectively, at least one pathogenic variant was identified in 19 subjects, which included 17 EC (15 endometrioid carcinoma and 2 endometrial carcinosarcomas), and one cervical adenocarcinoma. However, LBGDx did not identify any pathogenic mutations in three of the 20 EC, indicating that the sensitivity of LBGDx alone was 85% (17/20). Although five EC were negative for malignancy by LBC and three were negative for pathogenic mutations by LBGDx, the combination of LBC and LBGDx would successfully diagnose all 20 EC. These data suggested that LBGDx is a useful strategy to improve the sensitivity of screening of EC by LBC.

Comparison of human papillomavirus genotyping and cytology triage, COMPACT Study : Design, methods and baseline results in 14 642 women

Although cytology‐based screening programs have significantly reduced mortality and morbidity from cervical cancer, the global consensus is that primary human papillomavirus (HPV) testing for cervical screening increases detection of high‐grade cervical intraepithelial neoplasia (CIN) and invasive cancer. However, the optimal triage strategy for HPV‐positive women to avoid over‐referral to colposcopy may be setting specific. As Japan requires data that have been generated domestically to modify screening guidelines, we conducted a 3‐year prospective study, COMparison of HPV genotyping And Cytology Triage (COMPACT), to evaluate the potential role of HPV16/18 partial genotyping and cytology for primary HPV screening. In total, 14 642 women aged 20 to 69 years undergoing routine screening at 3 centers in Hokkaido were enrolled. Conventional cytology and HPV testing were carried out. Women with abnormal cytology or HPV16/18 positivity underwent colposcopy. Those with 12 other high‐risk (hr) HPV types underwent repeat cytology after 6 months. Primary study endpoints were detection of high‐grade cervical disease defined as CIN2/CIN3 or greater as determined by consensus pathology. Prevalence of cytological abnormalities was 2.4%. hrHPV, HPV 16, and HPV 18 were detected in 4.6%, 0.9%, and 0.3% of women, respectively. HPV16/18 were detected in all (8/8) invasive cervical cancers and in all (2/2) adenocarcinomas in situ. Both cytological abnormalities and hrHPV positivity declined with increasing age. This is the first Japanese study to investigate the role of partial genotyping and cytology in an HPV‐based screening program. Results should help policy‐makers develop guidelines for future cervical screening programs and management of cervical abnormalities based on HPV genotype.