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1.  Does the presence of coexisting diseases modulate the effectiveness of a low-dose estrogen/progestin, ethinylestradiol/drospirenone combination tablet in dysmenorrhea? Reanalysis of two randomized studies in Japanese women 
The purpose of this study was to investigate the effectiveness of a combination of ethinylestradiol (EE) and 0.02 mg/drospirenone (DRSP) 3 mg in Japanese women with dysmenorrhea and in particular to determine whether or not the presence of specific coexisting organic diseases (eg, endometriosis, uterine fibroids, uterine adenomyosis) has an impact on treatment.
Methods and results
Four hundred and ten patients with dysmenorrhea aged 20 years or older (315 without coexisting organic disease, 28 with endometriosis, 37 with uterine fibroids, and 46 with uterine adenomyosis [some patients had multiple coexisting organic diseases]) were enrolled and treated with EE/DRSP in either a 16-week comparator study or a 52-week long-term safety study. Evaluations included changes in total dysmenorrhea score, visual analog scale for dysmenorrhea, severity of symptoms, hormone levels, endometrial thickness, and safety outcomes. In both studies, the total dysmenorrhea score was significantly (P<0.001) decreased from baseline during treatment with EE/DRSP. Time-dependent changes in visual analog score for dysmenorrhea and alleviation of symptoms, such as lower abdominal pain, low back pain (lumbago), headache, and nausea/vomiting, were similar in all patient groups with and without any specific coexisting organic diseases. These improvements with EE/DRSP were observed for both short-term (16 weeks) and long-term (52 weeks) use. These effects were associated with suppressed increases in serum estradiol and progesterone levels and decreased endometrial thickness. The safety profile of EE/DRSP was similar in all patients, irrespective of the presence of coexisting organic diseases.
EE/DRSP may be prescribed for patients with dysmenorrhea irrespective of the presence of any specific coexisting organic diseases.
PMCID: PMC4259553  PMID: 25506249
dysmenorrhea; organic disease; ethinylestradiol; drospirenone; oral contraceptive
2.  The level of RECQL1 expression is a prognostic factor for epithelial ovarian cancer 
The human RECQ DNA helicase family is involved in genomic stability. Gene mutations of RECQL2, RECQL3, and RECQL4 are associated with genetic disorders and induce early aging and carcinogenesis. Although previous studies have reported that the level of RECQL1 expression is correlated with the prognosis of some of malignancies, the function of RECQL1 is not yet clarified. The present study aimed to examine the relationship between prognosis and the level of RECQL1 expression in epithelial ovarian cancer (EOC), and to identify the role of RECQL1 in EOC cells.
The level of RECQL1 expression was determined immunohistochemically in 111 patients with EOC who received initial treatment at Hirosaki University hospital between 2006 and 2011. Effects of RECQL1 on cell growth or apoptosis were examined in vitro using wild-type and OVCAR-3 cells (RECQL1(+) cells) and similar cells transfected with RECQL1 siRNA transfected (RECQL1(−) cells).
The level of RECQL1 expression was not related to histological type, clinical stage, or retroperitoneal lymph node metastasis, but the expression level was significantly higher (P = 0.002) in patients with recurrence than those without recurrence, and progression-free survival and complete response rate to chemotherapy were also improved in patients with RECQL1-low expression (n = 39) stage III/IV EOC (P = 0.02 and P <0.05 vs RECQL1-high expression patients (n = ), respectively). A cell proliferation and colony formation assays revealed significantly less growth of RECQL1(−) cells compared to RECQL1(+) cells. A flow cytometry using annexin V -FITC and propidium iodide (PI) staining revealed a significant increase in apoptotic RECQL1(−) cells. Cell cycle analysis showed a significantly greater distribution in subG1 phase indicating apoptotic cells in RECQL1(−) cells than in RECQL1(+) cells.
These results suggest that RECQL1 is a prognostic factor for EOC and that RECQL1 contributes to potential malignancy by inhibiting apoptosis.
PMCID: PMC4255635  PMID: 25424877
Ovarian cancer; RECQL1; siRNA; Apoptosis
3.  4-Methylumbelliferone inhibits ovarian cancer growth by suppressing thymidine phosphorylase expression 
4-Methylumbelliferone (4-MU), a hyaluronan (HA) synthesis inhibitor, has antitumor activity in cancer cells. However, few studies have focused on its effects on ovarian cancer. The aim of this study was to investigate the effects of 4-MU on ovarian cancer and to elucidate its mechanism of action.
The HRA human ovarian serous adenocarcinoma cell line was used in this study. The effects of 4-MU on cell proliferation, migration, and invasion were determined by using in vitro assays as well as an in vivo rat peritoneal carcinomatosis model. The expression of HA synthase (HAS), CD44 HA receptor, vascular endothelial growth factor (VEGF), and thymidine phosphorylase (TP) mRNA in HRA cells was analyzed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).
4-MU administration inhibited the growth of peritoneal tumors and significantly prolonged survival. In vitro experiments showed that 4-MU inhibited HRA cell proliferation in a dose-dependent manner, while it did not affect HRA cell invasion and migration. 4-MU significantly decreased TP mRNA expression in HRA cells. On the other hand, since HAS2, CD44, and VEGF endogenous mRNA expression levels were very low in HRA cells, it was impossible to evaluate the effect of 4-MU treatment.
These results suggest that 4-MU exerts its antitumor effect on ovarian cancer through suppressing TP expression.
PMCID: PMC4198731  PMID: 25304388
4-Methylumbelliferone; Ovarian cancer; Peritonitis carcinomatosa; Hymidine phosphorylase; HRA cells
4.  The prophylactic effects of a traditional Japanese medicine, goshajinkigan, on paclitaxel-induced peripheral neuropathy and its mechanism of action 
Molecular Pain  2014;10(1):61.
This study aimed to evaluate the prophylactic effect of goshajinkigan (GJG) on paclitaxel (PTX)-induced neuropathy and to elucidate the mechanism of action.
There was a time-dependent irreversible decrease in pain threshold in PTX group. In PTX/GJG group, pain threshold showed changes in the same level as control. Electron microscope showed that although the ganglion cells of control and PTX/GJG groups were normal, degeneration of the nucleus and swelling of the mitochondria were observed in PTX group. Expression of transient receptor potential vanilloid 4 (TRPV4) gene in PTX group significantly increased compared with that in control and PTX/GJG groups. In TRPV4 knock-out mice, no PTX-induced hyperalgesia was observed, and there was no significant difference in pain threshold between the 3 groups.
These results showed that PTX induced hyperalgesia by enhancing TRPV4 expression, and suggested that GJG might alleviate hyperalgesia by preventing degeneration of the ganglion cells and suppressing TRPV4 expression.
PMCID: PMC4176860  PMID: 25240613
Paclitaxel; Goshajinkigan; Peripheral neuropathy; Degeneration of the ganglion cells; TRPV4
5.  A phase I study of irinotecan and pegylated liposomal doxorubicin in recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study) 
A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan hydrochloride (CPT-11) in CPT-11/pegylated liposomal doxorubicin (PLD) combination therapy, a novel treatment regimen for platinum- and taxane-resistant recurrent ovarian cancer.
Pegylated liposomal doxorubicin was administered intravenously on day 3 at a fixed dose of 30 mg/m2. CPT-11 was administered intravenously on days 1 and 15, at a dose of 50 mg/m2 on both days. One course of chemotherapy was 28 days, and patients were given a maximum of six courses, with the CPT-11 dose being increased in increments of 10 mg/m2 (level 1, 50 mg/m2; level 2, 60 mg/m2; level 3, 70 mg/m2; level 4, 80 mg/m2) to determine MTD and RD.
During the period from April 2010 to March 2013, three patients were enrolled for each level. In the first course, no dose-limiting toxicity occurred in any of the patients. Grade 4 neutropenia was observed in two of three patients at level 4. At level 4, the antitumor effect was a partial response (PR) in two of the three patients and stable disease (SD) in one. At level 3, one of the three patients showed PR and two had SD. At level 4, the start of the next course was postponed in two of three patients. In addition, one patient at level 4 experienced hemotoxicity that met the criteria for dose reduction in the next course. The above results suggested that administration of CPT-11 at dose level 5 (90 mg/m2) would result in more patients with severe neutropenia and in more patients requiring postponement of the next course or a dose reduction. Based on the above, the RD of CPT-11 was determined to be 80 mg/m2.
The results suggest that CPT-11/PLD combination therapy for recurrent ovarian cancer is a useful treatment method with a high response rate and manageable adverse reactions. In the future phase II study, the safety and efficacy of this therapy will be assessed at 80 mg/m2 of CPT-11 and 30 mg/m2 of PLD.
PMCID: PMC4000409  PMID: 24585045
Recurrent ovarian cancer; Chemotherapy; CPT-11; PLD
6.  Inhibitory effects of aromatase inhibitor on estrogen receptor-alpha positive ovarian cancer in mice 
Estrogen causes proliferation of ovarian cancer cells. Although hormone therapy with an anti-estrogen agent is an optional therapy for recurrent epithelial ovarian cancers, both basic and clinical researches are insufficient. We here examine the efficacy of an aromatase inhibitor (AI) for peritonitis carcinomatosa, the late stage of ovarian cancer.
Estrogen receptor (ER)α was assayed in four ovarian cancer cell lines by the RT-PCR method. Using ovariectomized nude mice, peritonitis carcinomatosa consisting of OVCAR-3 cells with the strongest ERα expression or DISS cells with weaker ERα expression was prepared. The survival period was compared between the letrozole group (5 mg/kg/day orally; n = 10) and the control group (n = 10). In addition, the degree of angiogenesis and occurrence of apoptosis were compared using tumor tissue from the abdominal cavity. The expression of aromatase and the protein involving in ERα signaling were examined in tumors immunohistochemically.
Survival period in OVCAR-3 tumors was significantly prolonged in the letrozole group, compared with the control group (P < 0.05), whereas that in DISS tumors was not different between the both groups. The microvessel density in tumors and expression of VEGF decreased significantly in the letrozole group compared to the control group. The incidence of apoptosis did not differ significantly between these groups. No adverse event was observed accompanying the administration of letrozole. The expressions of aromatase, ERα and FOXP1 that is associated with ERα signaling were reduced in tumors by letrozole administration.
Letrozole was effective for ovarian cancers with abundant expression of ERα. Inhibition of angiogenesis and of ascites production appeared to contribute to prolongation of the survival period.
PMCID: PMC3895704  PMID: 24410765
Recurrent ovarian cancer; Letrozole; Estrogen receptor alpha; Aromatase inhibitor; Anti-angiogenesis
7.  Decreased ARID1A expression is correlated with chemoresistance in epithelial ovarian cancer 
Loss 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.
The 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.
The 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.
The 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.
PMCID: PMC3893676  PMID: 24459582
ARID1A; Chemoresistance; Epithelial ovarian cancer; Relapse
8.  Redistribution of resistance and sensitivity to platinum during the observation period following treatment of epithelial ovarian cancer 
Molecular and Clinical Oncology  2013;2(2):212-218.
The standard postoperative chemotherapy for epithelial ovarian cancer is a combination therapy including platinum and taxanes. The aim this study was to investigate the degree of platinum sensitivity in patients with relapsed epithelial ovarian cancer according to the treatment-free interval (TFI) and the histological tumor type. The medical records of 405 patients diagnosed with stage III/IV ovarian cancer, including 107 patients who relapsed after attaining a clinical complete response with first-line treatment, were retrospectively reviewed. The degree of platinum sensitivity was assessed by comparing the progression-free survival (PFS) following the second-line treatment. In patients with serous/endometrioid adenocarcinoma who were treated with platinum following relapse, there were significant differences in the PFS between the following groups of patients: those who relapsed within 6 months and those who relapsed between 6 and 12 months; those who relapsed between 6 and 12 months and those who relapsed between 12 and 18 months; and those who relapsed between 12 and 18 months and those who relapsed after 18 months. By contrast, in patients with clear cell/mucinous adenocarcinoma who were treated with platinum following a relapse, there were no significant differences in the PFS between patients who relapsed within 6 months and those who relapsed between 6 and 12 months, while there were significant differences in the PFS between those who relapsed between 6 and 12 months and those who relapsed after 12 months. With regard to the patients who relapsed after 12 months, the PFS of those with clear cell/mucinous adenocarcinoma was significantly shorter compared with the PFS of those with serous/endometrioid adenocarcinoma. Therefore, we considered it justified to classify patients with clear cell/mucinous adenocarcinoma who relapsed within 12 months as platinum-resistant and those who relapsed after 12 months as platinum-sensitive.
PMCID: PMC3917783  PMID: 24649335
relapsed epithelial ovarian cancer; platinum sensitivity; treatment-free interval; progression-free interval; histological type
9.  A Case of Small Cell Carcinoma of the Vagina 
Rare Tumors  2013;5(4):e58.
Primary small cell carcinoma of the vagina is quite rare, and a standard treatment has not been established yet. Herein, we report a case of an 81-year-old woman who was diagnosed with a vaginal tumor without continuity with the uterine cervix. Histopathological diagnosis indicated alveolar solid growth of nuclear chromatin-rich atypical cells with a high N/C ratio and a partially recognized rosette-like structure, suggesting a differentiated neuroendocrine system. Chromogranin A and synaptophysin were positive. Stage I vaginal small cell carcinoma localized to the vagina was diagnosed. The tumor disappeared by radiation monotherapy with external beam irradiation and endocavitary irradiation. The patient remains alive without any disease 1 year and 8 months after the treatment, suggesting the efficacy of radiotherapy in small cell carcinoma of the vagina.
PMCID: PMC3882930  PMID: 24416492
small cell carcinoma of the vagina; radiotherapy
10.  Recurrent epithelial ovarian cancer and hormone therapy 
The role of hormone therapy in the treatment of ovarian cancer is not clear. Data on the efficacy and safety of antiestrogens and aromatase inhibitors in recurrent ovarian cancer have been accumulated through phase II clinical studies. Most of these studies were conducted in platinum-resistant recurrent ovarian cancer, and although complete response rates were not high, reported adverse events were low. If administered to patients who are positive for estrogen receptors, hormone therapy may become a viable option for the treatment of recurrent ovarian cancer.
PMCID: PMC3845958  PMID: 24303498
Recurrent ovarian cancer; Hormone therapy; Letrozole; Anastrozole; Tamoxifen; Fulvestrant
11.  Clinical Efficacy on Fracture Risk and Safety of 0.5 mg or 1 mg/month Intravenous Ibandronate Versus 2.5 mg/day Oral Risedronate in Patients with Primary Osteoporosis 
Calcified Tissue International  2013;93(2):137-146.
This randomized, double-blind study assessed the antifracture efficacy and safety of intermittent intravenous (IV) ibandronate versus oral daily risedronate in Japanese patients with primary osteoporosis. Ambulatory patients aged ≥60 years were randomized to receive 0.5 or 1 mg/month IV ibandronate plus oral daily placebo or 2.5 mg/day oral risedronate, the licensed dose in Japan, plus IV placebo. The primary end point was noninferiority of ibandronate versus risedronate for first new or worsening vertebral fracture over 3 years. A total of 1,265 patients were randomized. A total of 1,134 patients formed the per-protocol set. Both ibandronate doses were noninferior to risedronate: 0.5 mg, hazard ratio (HR) 1.09 [95 % confidence interval (CI) 0.77–1.54]; 1 mg, HR 0.88 (95 % CI 0.61–1.27). The rate of first new vertebral fracture over 3 years was 16.8 % (95 % CI 12.8–20.8) for 0.5 mg ibandronate, 11.6 % (95 % CI 8.2–15.0) for 1 mg ibandronate, and 13.2 % (95 % CI 9.6–16.9) for risedronate. Significant increases in bone mineral density relative to baseline were observed with all treatments after 6 months, with substantial reductions in bone turnover markers after 3 months. Greatest efficacy was obtained with 1 mg ibandronate. Analyses in women only showed similar results to the overall population. No new safety concerns were identified. This study demonstrated the noninferiority of IV ibandronate to the licensed Japanese dose of oral risedronate and suggested that 1 mg/month is an effective dose in Japanese patients with primary osteoporosis.
PMCID: PMC3717162  PMID: 23644930
Ibandronate; Intravenous; Osteoporosis; Risedronate; Vertebral fracture
12.  Presentation of two patients with malignant granulosa cell tumors, with a review of the literature 
Granulosa cell tumors (GCTs) of the ovary account for 2 to 5 of ovarian malignancies. We present two patients with malignant ovarian adult GCT. In one patient, a combination of bleomycin, etoposide, and cisplatin was effective after initial surgery for malignant GCT. In the other, an aromatase inhibitor was effective for recurrent malignant GCT. We also review the literature for further management of this tumor. Because GCT of the ovary is rare, it will be necessary to elucidate the clinical phenotype and establish treatment protocols by accumulating and analyzing more patients.
PMCID: PMC3490972  PMID: 22963202
Ovarian malignant granulosa cell tumor; BEP combination therapy; Aromatase inhibitor
13.  Secular trends in age at menarche and time to establish regular menstrual cycling in Japanese women born between 1930 and 1985 
BMC Women's Health  2012;12:19.
Early life-stage exposure to estrogen increases the risk of breast cancer. The objective of this study was to investigate the age at menarche and time to onset of regular menstrual cycles for Japanese women born between 1930 and 1985.
A cross-sectional study was designed using data from the baseline survey of the Japan Nurses’ Health Study. The data from 48,104 female nurses were analyzed. To view trends in age at menarche, the distribution of age at menarche was calculated for each birth year cohort. The distribution of time to onset of regular menstrual cycles was calculated for each birth year cohort. To estimate whether high-risk group of the estrogenic dependent disorders increase with succeeding generations, we defined the women who experienced menarche at ten years old or younger and started a regular cycle within one year as early age onset of ovulatory cycles.
Average ages at menarche were as follows: 13.8 years for those born in the 1930s (n = 113), 13.3 years for the 1940s (n = 4,751), 12.8 years for the 1950s (n = 15,844), 12.3 years for the 1960s (n = 20,547), 12.2 years for the 1970s (n = 6,568), and 12.2 years for the 1980s (n = 281). The proportion of women who experienced the onset of regular menstrual cycles 1 year after menarche was 29.3% for those born in the 1930s, but decreased to 11.9% for the 1980s. On the other hand, the proportion of women who did not have regular menstrual cycles was 10.4% for those born in the 1930s, but rose to 19.8% in 1980s. The proportion of women who experienced menarche at 10 years old and started regular menstrual cycles within one year increased over time: the percentage was 0.0%, 0.4%, 0.6%, 1.1%, 1.3%, and 2.1% for the women born in 1930s, 1940s, 1950s, 1960s, 1970s, and 1980s, respectively.
The age at menarche of Japanese women born between 1930 and 1985 decreased, but the onset of regular menstrual cycling is delayed; so that the distribution of the start time of ovulatory cycles may have spread for younger generations. Those suggest that the high-risk group of estrogenic dependent diseases among Japanese women may increase in the near future.
PMCID: PMC3434095  PMID: 22800445
14.  Malignant Ovarian Tumors with Induced Expression of Carbonyl Reductase Show Spontaneous Regression 
The present study investigated tumor proliferation in a tumor model using murine ovarian cancer cells with increased carbonyl reductase (CR) expression.
CR cDNA was transfected into murine T-Ag-MOSE ovarian cancer cells by lipofection. CR-transfected cells (CR induction group) or empty vector-treated cells (control group) were injected into the backs of 8-week-old nude mice at a concentration of 0.5 × 106 per 0.2 mL. Subsequent tumor proliferation in both groups was observed for 5 weeks.
The control group showed an increase in tumor volume during the 5 weeks of observation. However, tumor volume in the CR induction group increased up to the second week but then decreased continuously until the fifth week of observation. The tumor growth curves for the two groups showed a significant difference (Mann-Whitney U test, P < 0.001). Histological and biochemical experiments were performed using tumor tissues isolated in the third week. Necrosis and inflammatory cell infiltration were noted for tumors in the CR induction group. Also, the number of apoptotic cells was significantly increased in the CR induction group compared with the control group (P < 0.001). Milk fat globule EGF factor 8, an “eat-me” signal for phagocytes such as macrophages, was expressed extensively in the tumor cytoplasm and interstitial cells of the CR induction group, and engulfment of apoptotic cells by macrophages was observed. Vascular endothelial growth factor expression in tumors was notably decreased in the CR induction group compared with the control group.
Increased necrosis due to engulfing of apoptotic cells by phagocytes attracted by increased milk fat globule EGF factor 8 was considered to be the mechanism of spontaneous tumor regression in the CR induction group.
PMCID: PMC3290113  PMID: 22408375
apoptosis; carbonyl reductase; ovarian tumor; phagocytosis

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