Mikiko Asai-Sato

Prolactin inhibits apoptosis of ovarian carcinoma cells induced by serum starvation or cisplatin treatment

Prolactin, a peptide hormone essential for the development and function of reproductive organs, is involved in development of breast, prostate and colorectal cancers. However, the role of prolactin on the carcinogenesis of ovarian carcinomas is unclear. In this study, we show that mRNA of prolactin receptor is expressed in 5 out of 9 ovarian carcinoma cell lines, 15 out of 17 cases of surgical samples and all of normal ovarian surface epithelium, while prolactin transcript is detected only in 1 ovarian carcinoma cell line and in 1 of the surgical samples. For the prolactin receptor‐positive ovarian carcinoma cells, exogenous prolactin did not affect the proliferation but markedly inhibited apoptosis. Therefore, actual cell growth was enhanced by prolactin in a dose‐dependent manner. The blocking of prolactin receptor by antibody severely impaired the antiapoptotic and growth‐promoting effects of prolactin. Interestingly, the cisplatin‐induced cell death of the prolactin receptor‐positive cells was significantly inhibited by pretreatment with prolactin. These findings indicate a responsiveness of ovarian carcinomas to prolactin and suggest that the prolactin/prolactin receptor system may be a new therapeutic target of ovarian carcinomas.

Annexin A4 Is Involved in Proliferation, Chemo-Resistance and Migration and Invasion in Ovarian Clear Cell Adenocarcinoma Cells

Ovarian clear cell adenocarcinoma (CCC) is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca++-binding annexin A4 (ANXA4) protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs) that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO) resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

Anxiety and prevalence of psychiatric disorders among patients awaiting surgery for suspected ovarian cancer

Aim:  The goal of the current study was to determine the anxiety level and prevalence of psychiatric disorders among patients awaiting surgery for ovarian tumors. Also analyzed were the predictive factors for psychiatric disorders and changes after surgical diagnosis.

Web-based recruiting for a survey on knowledge and awareness of cervical cancer prevention among young women living in Kanagawa prefecture, Japan.

Objectives Cervical cancer (CC) incidence and mortality among young women have been increasing in Japan. To develop effective measures to combat this, we assessed the feasibility of using a social networking site (SNS) to recruit a representative sample of young women to conduct a knowledge and attitude study about CC prevention via an internet-based questionnaire. Methods From July 2012 to March 2013, advertising banners targeting women aged 16 to 35 years in Kanagawa Prefecture were placed on Facebook in a similar manner as an Australian (AUS) study conducted in 16- to 25-year-olds in 2010 and on a homepage to advertise our CC advocacy activities. Eligible participants were emailed instructions for accessing our secure Web site where they completed an online survey including demographics, awareness, and knowledge of human papillomavirus (HPV) and CC. Data for the study population were compared with the general Japanese population and the AUS study. Results Among 394 women who expressed interest, 243 (62%) completed the survey, with 52% completing it via Facebook. Women aged 26 to 35 years, living in Yokohama City, with an education beyond high school, were overrepresented. Participants had high awareness and knowledge of HPV and CC, comparable with the AUS study participants. However, the self-reported HPV vaccination rate (22% among participants aged 16–25 years) and the recognition rate of the link between smoking and CC (31%) were significantly lower than in the AUS study (58% and 43%, respectively) (P < 0.05). Significant predictors of high knowledge scores about HPV included awareness of HPV vaccine (P < 0.001) and self-reported HPV vaccination (P < 0.05). Conclusions The SNS and homepage are efficient methods to recruit young women into health surveys, which can effectively be performed online. A nationwide survey using SNSs would be an appropriate next step to better understand the current lack of uptake of the national HPV vaccine program by young women in Japan.

Post‐traumatic stress disorder in patients with gynecologic cancers

We present three cases of post‐traumatic stress disorder (PTSD) that occurred in patients with gynecologic cancers. Case 1 and 2 had ovarian cancer and case 3 had endometrial cancer. The patients developed anxiety, difficulty in sleeping, and complaints of various discomforts after their diagnosis. On consulting with psychiatrists, PTSD was diagnosed based upon the DSM‐IV classification. In cases 1 and 2, the symptoms worsened during the patients’ primary treatment and interfered with their ability to continue the treatment. Psychiatric interventions were provided making it possible to complete their treatment. In case 3, the patient needed psychiatric intervention because of her psychological distress during her treatment. She was finally diagnosed as having PTSD. There are few reports regarding PTSD occurring in gynecologic cancer patients. However, attention should be given to the symptoms of these disorders so that patients may complete their standard therapies.

Aberrant Expression of the Cell Polarity Regulator aPKCλ/ι is Associated With Disease Progression in Cervical Intraepithelial Neoplasia (CIN): A Possible Marker for Predicting CIN Prognosis.

Atypical protein kinase C &lgr;/&igr; (aPKC&lgr;/&igr;) is a regulator of epithelial cellular polarity. It is also overexpressed in several cancers and functions in cell proliferation and invasion. Therefore, we hypothesized that aPKC&lgr;/&igr; may be involved in development and progression of cervical intraepithelial neoplasia (CIN), the precancerous disease of cervical cancer induced by human papillomavirus. To do this, we investigated the relationship between aPKC&lgr;/&igr; expression and CIN. aPKC&lgr;/&igr; expression level and subcellular localization were assessed in 192 CIN biopsy samples and 13 normal epithelial samples using immunohistochemistry. aPKC&lgr;/&igr; overexpression (normal epithelium, 7.7%; CIN1, 41.7%; CIN2/3, 76.4%) and aPKC&lgr;/&igr; nuclear localization (normal epithelium, 0.0%; CIN1, 36.9%; CIN2/3, 78.7%) were higher in CIN samples than normal samples (P<0.05), suggesting that CIN grade is related to aPKC&lgr;/&igr; overexpression and nuclear localization. Then, 140 CIN cases were retrospectively analyzed for 4-yr cumulative disease progression and regression rates using the Cox proportional hazards model. CIN1 cases with aPKC&lgr;/&igr; overexpression or aPKC&lgr;/&igr; nuclear localization had a higher progression rate than CIN1 cases with normal aPKC&lgr;/&igr; expression levels or cytoplasmic localization (62.5% vs. 9.7% and 63.1% vs. 9.4%, respectively; P<0.001). Multivariate analysis indicated that human papillomavirus types 16 and 18, aPKC&lgr;/&igr; overexpression (hazard ratio=4.26; 95% confidence interval, 1.50–12.1; P=0.007), and aPKC&lgr;/&igr; nuclear localization (hazard ratio=3.59; 95% confidence interval, 1.24–10.4; P=0.019) were independent risk factors for CIN1 progression. In conclusion, aPKC&lgr;/&igr; could be useful for the therapeutic management of patients with CIN, particularly those with non-human papillomavirus 16/18 types.

Radiation therapy for pelvic lymph node metastasis from uterine cervical cancer

OBJECTIVES This study aimed to evaluate the efficacy of radiation therapy for pelvic lymph node metastasis from uterine cervical cancer and identify an optimal radiation regimen. METHODS A total of 111 metastatic pelvic lymph nodes, ranging from 11 to 56 mm (median, 25 mm) on CT/MRI, in 62 patients with uterine cervical cancer were treated initially with curative radiation therapy, with 46 patients receiving concurrent chemotherapy. Total radiation doses ranged from 45 to 61.2 Gy (median, 50.4 Gy) in 1.8-2 Gy (median, 1.8 Gy) fractions. RESULTS At a median follow-up of 33 months, 46 of the 62 patients survived. Only 2 irradiated lymph nodes, 24 and 28 mm in diameter, in 1 patient progressed after irradiation alone with 50.4 Gy in 1.8 Gy fractions. All 33 metastatic lymph nodes ≥ 30 mm in diameter were controlled by irradiation at a median dose of 55.8 Gy. The 3-year lymph node-progression free rates were 98.2% in all 62 patients and 98.0% in all 111 metastatic lymph nodes. Except for transient hematologic reactions, 2 patients developed grade ≥ 3 therapy-related toxicities, 1 with an ulcer and the other with perforation of the sigmoid colon. In addition, 2 patients experienced ileus after irradiation. CONCLUSIONS Radiation therapy effectively controlled pelvic lymph node metastases in patients with uterine cervical cancer, with most nodes <24 mm in diameter controlled by total doses of 50.4 Gy in 1.8 Gy fractions and larger nodes controlled by 55.8 Gy, particularly with concurrent chemotherapy. Higher doses to metastatic lymph nodes may increase intestinal toxicities.

Realistic fear of cervical cancer risk in Japan depending on birth year

ABSTRACT Objective: In Japan, the possible adverse events upon HPV vaccination was widely reported in the media. MHLW announced the suspension of aggressively encouraging HPV vaccination in 2013, and inoculation rate has sharply declined. The aim of the present study was estimation of future cervical cancer risk. Methods: The latest data on vaccination rate at each age in Sakai City were first investigated. The rate of experiencing sexual intercourse at the age of 12, 13, 14, 15, 16, 17 and throughout lifetime is assumed to be 0%, 1%, 2%, 5%, 15%, 25%, and 85% respectively. The cervical cancer risk was regarded to be proportional to the relative risk of HPV infection over the lifetime. The risk in those born in 1993 whom HPV vaccination was not available yet for was defined to be 1.0000. Results: The cumulative vaccination rates were 65.8% in those born in 1994, 72.7% in 1995, 72.8% in 1996, 75.7% in 1997, 75.0% in 1998, 66.8% in 1999, 4.1% in 2000, 1.5% in 2001, 0.1% in 2002, and 0.1% in 2003. The relative cervical cancer risk in those born in 1994–1999 was reduced to 0.56–0.70, however, the rate in those born in 2000–2003 was 0.98–1.0, almost the same risk as before introduction of the vaccine. Discussion: The cumulative initial vaccination rates were different by the year of birth. It is confirmed that the risk of future cervical cancer differs in accordance with the year of birth. For these females, cervical cancer screening should be recommended more strongly.

Radiation Therapy for Very Elderly Patients Aged 80 Years and Older With Squamous Cell Carcinoma of the Uterine Cervix.

Objectives: We carried out a retrospective review to determine the role played by radiation therapy in the treatment of very elderly patients with uterine cervical cancer. Materials and Methods: Thirty elderly patients aged 80 years and older with squamous cell carcinoma of the uterine cervix, at clinical stages IB-IVA, underwent radiation therapy. Of these 30 patients, 6 received external irradiation alone and 24 received external irradiation and intracavitary brachytherapy. A total median dose of 69.0 Gy (range, 45.6 to 75.4 Gy) was delivered to the cervical tumors. No patients underwent chemotherapy. Results: At a median follow-up time of 24 months, 7 patients had developed recurrences, including local recurrences in 3 and distant metastases in 5. The local control and distant metastasis-free rates were 88% and 79%, respectively, at 2 years. The disease-free, cause-specific, and overall survival rates were 69%, 77%, and 75%, respectively, at 2 years. Primary tumor size, T category, and clinical stage were found to be significant prognostic factors for distant metastasis. Age and primary tumor size were considered as being significant variables that affected survival. With the exception of a transient hematologic reaction, there were no therapy-related toxicities of grade ≥3. Conclusions: Radiation therapy was safe and effective regarding local control of uterine cervical cancer in elderly patients aged 80 years and older, and appeared to contribute to their prolonged survival. Curative radiation therapy should be considered as a viable treatment option, even in very elderly patients.

Endometrial adenocarcinoma without myometrial invasion metastasizing to the pancreas and masquerading as primary pancreatic neoplasm

Reported herein is a case of endometrial adenocarcinoma without myometrial invasion that metastasized to the pancreas in a 69‐year‐old Japanese woman who had a history of hysterectomy. Although systemic radiography could not detect any metastasis in the whole body before hysterectomy, imaging performed 2 months after the hysterectomy consisting of CT, magnetic resonance imaging, gallium scintigraphy and positron emission tomography identified a solitary pancreatic tumor. Imaging demonstrated an intracystic papillary growth in the pancreas, suggesting intraductal papillary mucinous neoplasm or mucinous cystic neoplasm. Excised in distal pancreatectomy, the tumor was diagnosed as a pancreatic primary, an invasive papillary adenocarcinoma at first, but both the endometrial tumor and the pancreatic tumor demonstrated similar morphology and immunohistochemistry. Furthermore, the identical nucleotide mutation of TP53 gene was observed from both the endometrial and pancreatic tumors. The pancreatic tumor was therefore confirmed to be a metastasis from the primary endometrial adenocarcinoma. Metastasis to the pancreas from endometrial carcinoma is extremely rare but must be considered even if the previous cancer was treated at an early stage. Histopathological comparison study and genetic analysis are important for the correct diagnosis of metastasis.