Novel Strategy for the Management of Cervical Multicystic Diseases.

PURPOSE: To investigate the clinical practices of diagnosing multicystic cervical lesions as a means to develop a more appropriate diagnostic algorithm for gastric-type adenocarcinoma (GAS) and its precursors. METHODS: Clinical information for 159 surgically treated patients for multicystic disease of the uterine cervix was collected from 15 hospitals. We performed a central review of the MRI and pathological findings. The MRI findings were categorized into four types including two newly proposed imaging features based on the morphology and distribution of cysts, and the diagnosis accuracy was assessed. Among the four MRI types, types 1 and 2 were categorized as benign lesions that included LEGH; type 3 were precancerous lesions (with an assumption of atypical LEGH); and type 4 were malignant lesions. RESULTS: The central pathological review identified 56 cases of LEGH, seven with GAS, four with another form of carcinoma, and 92 with benign disease. In clinical practice, over-diagnosis of malignancy (suspicion of MDA) occurred for 12/19 cases (63.2%) and under-diagnosis of malignancy occurred for 4/11 (36%). Among the 118 patients who had a preoperative MRI and underwent a hysterectomy, type 3 or 4 MRI findings in conjunction with abnormal cytology were positively indicative of premalignancy or malignancy, with a sensitivity and specificity of 61.1% and 96.7%, respectively. CONCLUSIONS: Although the correct preoperative diagnosis of cervical cancer with a multicystic lesion is challenging, the combination of cytology and MRI findings creates a more appropriate diagnostic algorithm that significantly improves the diagnostic accuracy for differentiating benign disease from premalignancy and malignancy.

Unexpected diagnosis of stage IIA dysgerminoma in streak gonad in a patient with Swyer syndrome: a case report.

Patients with Swyer syndrome, which is also known as 46,XY pure gonadal dysgenesis, are at an increased risk of gonadoblastoma and germ cell tumor. Prophylactic gonadectomy is recommended for these patients. We report a case of stage IIA dysgerminoma arising in a streak gonad in a patient with Swyer syndrome, which was not diagnosable preoperatively and intraoperatively. The patient was primarily amenorrheic and identified as female phenotypically. She underwent gonadectomy at 27 years of age. Preoperative image analysis showed a relatively small uterus without adnexal masses. Laparoscopic findings showed bilateral streak gonads. Postoperatively, histopathological examination revealed that the patient had dysgerminoma in her left streak gonad. Preoperative and intraoperative diagnosis of dysgerminoma in normal size ovaries is thought to be difficult. Although it is rare, considering the occurrence of dysgerminoma in streak gonad with extension to the mesosalpinx, prompt prophylactic gonadectomy is strongly recommended for these patients regardless of the size of the ovaries.

Ovarian insufficiency following allogeneic hematopoietic stem cell transplantation.

Ovarian insufficiency is a serious complication for young women who undergo hematopoietic stem cell transplantation (HSCT). Reduced-intensity conditioning (RIC) has been utilized more widely due to its reduced toxicity; however, there is a lack of data concerning ovarian function after HSCT with RIC. We investigated the ovarian function in patients who received HSCT with RIC, compared to those who received myeloablative conditioning (MAC). The records of 69 female patients who received allogeneic HSCT at the institution under 40 years of age at transplantation from 1991 to 2012 were retrospectively analyzed. Prevalence of ovarian insufficiency was significantly lower in patients conditioned with RIC than in those conditioned with MAC (4/27 = 14.8% for RIC and 36/42 = 85.7% for MAC, p < 0.0001). A younger age at HSCT was associated with a lower risk of ovarian insufficiency. Among the 40 patients with ovarian insufficiency, four patients recovered ovarian function, and two conceived following hormone-replacement therapy (HRT). A higher serum E2 level prior to HRT was a significant predictor for the restoration of ovarian function (p = 0.0028). In conclusion, RIC was significantly less toxic to ovarian function compared with MAC. HSCT-associated ovarian insufficiency is not irreversible, and a higher E2 level may predict the restoration of ovarian function.

Efficacy of dienogest in thinning the endometrium before hysteroscopic surgery.

STUDY OBJECTIVE: To investigate the efficacy of administration of dienogest to thin the endometrium before hysteroscopic surgery and to evaluate the surgical outcome. DESIGN: Retrospective clinical study (Canadian Task Force classification III). SETTING: Community hospital. PATIENTS: Twenty-six patients who underwent hysteroscopic surgery for treatment of endometrial polyps or submucous myomas <25 mm. INTERVENTIONS: Before hysteroscopic surgery, 13 patients (dienogest group) received 2 mg dienogest orally for 2 weeks, and 13 patients (GnRH group) received a gonadotropin-releasing hormone agonist subcutaneously 1 to 3 times every 4 weeks, and 4 of those received hormone therapy after surgery. Endometrial thickness, serum estradiol and progesterone concentrations, duration of surgery, weight of tissue removed, surgical field visualization, and time to resumption of spontaneous menstruation were recorded. MEASUREMENTS AND MAIN RESULTS: Endometrial thickness decreased from approximately 7.0 mm to 3.9 mm in the dienogest group. Duration of surgery and weight of tissue removed were similar between groups. The surgical field was clearly visualized in 12 patients in each group. Spontaneous menstruation resumed at approximately 22.0 days after hysteroscopic surgery in the dienogest group; in contrast, no resumption of spontaneous menstruation was observed within the first postoperative month in the GnRH group. No patients had perioperative complications, and none exhibited any residual tumor. CONCLUSION: Administration of dienogest for 2 weeks thinned the endometrium and yielded favorable surgical outcomes, similar to those with GnRH agonists. Administration of dienogest may be an effective and convenient treatment before hysteroscopy.

Total laparoscopic hysterectomy in patients with previous abdominal surgery.

PURPOSE: To evaluate the effects of previous abdominal surgery on the feasibility and the safety of total laparoscopic hysterectomy (TLH). METHODS: One hundred seventy-four consecutive patients who underwent TLH in private hospital between February 2008 and December 2009 were retrospectively reviewed. Surgical history, operation time, blood loss, transfusion, conversion to an open surgery, complications and hospital stay were assessed in each patient. The patients were classified into two groups; patients with or without a history of abdominal surgery. RESULTS: Group 1 included patients with a history of abdominal surgery (n = 44) and Group 2 included patients without a history (n = 130). The complication rate was 6.8% in patients with (Group 1) and 5.4% in patients without (Group 2) a history of abdominal surgery, respectively. No bladder, bowel, ureteral, or vascular injuries occurred in either group. Transfusion was required in one patient without a history of abdominal surgery (Group 2; 0.8%). Three patients with (Group 1; 6.8%) and two patients without (Group 2; 1.5%) a history of abdominal surgery were converted to laparotomy. No statistically significant difference was noted between the groups with respect to the complication and conversion rates. CONCLUSIONS: In our study, TLH can be performed successfully in patients with a history of abdominal surgery.

Efficacy of hormone therapy for osteoporosis in adolescent girls after hematopoietic stem cell transplantation: a longitudinal study.

OBJECTIVE: To assess changes in bone mineral density of adolescent girls diagnosed with hypogonadism after hematopoietic stem cell transplantation (HSCT) during continuous hormone therapy (HT). DESIGN: Retrospective study. SETTING: Department of Obstetrics and Gynecology, Osaka Medical Center and Research Institute for Maternal and Child Health. PATIENT(S): Twenty-eight adolescent girls with hormone deficiency after HSCT. INTERVENTION(S): All patients were treated with HT. MAIN OUTCOME MEASURE(S): Bone mineral density and markers of bone metabolism were evaluated. RESULT(S): Twenty-eight patients were enrolled. The girls underwent HSCT at 10.2 ± 4.0 years of age (median ± SD).The first evaluation was performed at 15.1 ± 1.9 years of age, 3.8 ± 3.4 years after HSCT. Bone mineral density increased significantly from -2.7 ± 1.1 (Z-score) to -2.3 ± 1.2 during HT administration for 5.7 ± 2.5 years. Twenty-four of 28 patients (86%) showed a good response to HT. The levels of urinary N-telopeptides of type 1 collagen and serum osteocalcin were high at the first evaluation in 76% and 53% of patients and at the last in 76% and 18%, respectively, thereafter. CONCLUSION(S): Significant effects on bone metabolism resulting from HSCT were observed; however, HT increased bone mineral density of the hypogonadal patients.

Concurrent weekly nedaplatin, external beam radiotherapy and high-dose-rate brachytherapy in patients with FIGO stage IIIb cervical cancer: a comparison with a cohort treated by radiotherapy alone.

OBJECTIVES: The aim of this study was to evaluate whether nedaplatin-based concurrent chemoradiotherapy (CCRT) using high-dose-rate intracavitary brachytherapy (HDR-ICBT) is superior to radiotherapy (RT) alone in patients with FIGO stage IIIb cervical cancer. METHODS: The records of 41 consecutive women treated either with nedaplatin-based CCRT using HDR-ICBT (n = 20) or RT alone (nonrandomized control group, n = 21) for stage IIIb cervical cancer were retrospectively reviewed. The activity and toxicity were compared between the two treatment groups. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. RESULTS: The 5-year overall survival rates in the CCRT and RT groups were 65 and 33.3%, respectively. The median OS of the CCRT and RT groups were 60 and 29 months, respectively. CCRT was significantly superior to RT alone with regard to PFS (p = 0.0015) and OS (p = 0.0364). The frequency of acute grade 3-4 toxicity was significantly higher in the CCRT group than in the RT group. However, no statistically significant difference was observed with regard to severe late toxicity. CONCLUSIONS: Nedaplatin-based concurrent chemoradiotherapy was safely performed and significantly improved the prognosis of patients with FIGO stage IIIb cervical cancer. This treatment can be considered as an alternative to cisplatin-based chemoradiotherapy in this patient population.

Novel bioactive compound from the Sparassis crispa mushroom.

A novel compound (2) and a known one (1) were isolated from the mushroom, Sparassis crispa. Both compounds inhibited melanin synthesis and MRSA growth.

Estrogen and raloxifene inhibit the monocytic chemoattractant protein-1-induced migration of human monocytic cells via nongenomic estrogen receptor alpha.

OBJECTIVE: To investigate the effects of estradiol (E2) and raloxifene on the migration of human monocytic THP-1 cells to endothelium. DESIGN: A prospective comparative study. THP-1 cells, a human acute monocytic leukemia cell line, were used for the study. Migration assays were performed using transwell inserts. THP-1 cells were exposed to E2 or raloxifene in the presence of monocytic chemoattractant protein-1 (MCP-1), a major chemoattractant for monocytes. The cells were transfected with small interfering RNA (siRNA) against estrogen receptor (ER) alpha and ERbeta for gene silencing. ER expression was evaluated by Western blot analysis. RESULTS: MCP-1 induced the migration of the cells for 90 minutes. The addition of E2 or raloxifene significantly inhibited the MCP-1-induced migration for 90 minutes. Preincubation of THP-1 cells with an ER antagonist, ICI 182780, significantly attenuated the inhibitory effects of E2 and raloxifene. Whereas transfection with siRNA of ERalpha significantly attenuated the inhibition by E2 of MCP-1-induced monocyte migration, transfection with control siRNA or siRNA of ERbeta had no effect on the rapid inhibitory action of E2. Moreover, preincubation of THP-1 cells with a transcriptional inhibitor, actinomycin D, had no effect on the rapid inhibitory action of E2. CONCLUSIONS: Our findings suggest that both E2 and raloxifene inhibited the MCP-1-induced monocyte migration through nongenomic ERalpha. This result may explain one of the antiatherosclerotic effects of E2 and raloxifene on vasculature.

Inhibition of inhibitor of nuclear factor-kappaB phosphorylation increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models.

We investigated whether inhibition of nuclear factor-kappaB (NFkappaB) increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Treatment of paclitaxel-sensitive Caov-3 cells with paclitaxel transiently activated the phosphorylation of Akt, the phosphorylation of IkappaB kinase (IKK), and the phosphorylation of inhibitor of NFkappaB (IkappaBalpha). Paclitaxel also caused a transient increase in NFkappaB activity, followed by a decrease in NFkappaB activity. We show an association between Akt and IKK and show that the phosphorylation of IKK induced by paclitaxel is blocked by treatment with a phosphatidylinositol 3-kinase inhibitor (wortmannin or LY294002). Furthermore, interference of the Akt signaling cascade inhibits the transient induction of IkappaBalpha phosphorylation and NFkappaB activity by paclitaxel. Inhibition of NFkappaB activity by treatment with an IkappaBalpha phosphorylation inhibitor (BAY 11-7085) attenuated both basal and transient induction of IkappaBalpha phosphorylation by paclitaxel. Treatment with BAY 11-7085 also enhanced the inhibition of NFkappaB activity by paclitaxel for up to 24 hours. In addition, treatment with BAY 11-7085 decreased the viability of cells treated with paclitaxel. Moreover, treatment with BAY 11-7085 increased the efficacy of paclitaxel-induced inhibition of intraabdominal dissemination and production of ascites in athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that paclitaxel transiently induces NFkappaB activity via the phosphatidylinositol 3-kinase/Akt cascade and that combination therapy with paclitaxel and an NFkappaB inhibitor would increase the therapeutic efficacy of paclitaxel.

Inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models.

Whether or not inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models was investigated. We compared the basal levels of phosphorylation of IkappaBalpha and activity of NFkappaB between cisplatin-sensitive A2780 cells and cisplatin-resistant Caov-3 cells. The basal levels of phosphorylation of IkappaBalpha and activity of NFkappaB in Caov-3 cells were significantly higher than those in A2780 cells. Cisplatin caused a more marked decrease in the phosphorylation of IkappaBalpha and activity of NFkappaB in A2780 cells than in Caov-3 cells. Thus, high basal levels of phosphorylation of IkappaBalpha and activation of NFkappaB and less marked inhibition of the phosphorylation of IkappaBalpha and activation of NFkappaB by cisplatin seem to reduce the sensitivity of cells to cisplatin. Inhibition of NFkappaB activity either by treatment with the IkappaBalpha phosphorylation inhibitor (BAY 11-7085) or a specific NFkappaB nuclear translocation inhibitor (SN-50) or by transfection of p50DeltaNLS (which lacks the nuclear localization signal domain) increased the efficacy of both the cisplatin-induced attenuation of IkappaBalpha phosphorylation and NFkappaB activity and the cisplatin-induced apoptosis. In addition, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced attenuation of both the expression of X-linked inhibitor of apoptosis protein (XIAP) and cell invasion through Matrigel. Moreover, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced inhibition of the intra-abdominal dissemination and production of ascites using athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that combination therapy of cisplatin with the NFkappaB inhibitor should increase the therapeutic efficacy of cisplatin.

Estrogen inhibits paclitaxel-induced apoptosis via the phosphorylation of apoptosis signal-regulating kinase 1 in human ovarian cancer cell lines.

The influence of postoperative estrogen replacement therapy on the sensitivity of ovarian cancer to paclitaxel remains elusive. We examined whether estrogen affects paclitaxel-induced apoptosis in the Caov-3 human ovarian cancer cell line, which expresses estrogen receptor. 17beta-Estradiol (E2) significantly reversed the paclitaxel-induced apoptosis and reduction of cell viability, and a highly selective estrogen receptor antagonist, ICI182,780, and a phosphatidylinositol 3-kinase inhibitor, LY294002, attenuated the reversal effect of E2 on paclitaxel-induced apoptosis and reduction of cell viability. E2 significantly induced the phosphorylation of Akt. Akt and apoptosis signal-regulating kinase 1 (ASK1) were physically associated, and E2 induced the phosphorylation of ASK1 at serine-83, which is a consensus Akt phosphorylation site. We confirmed a previous report showing that paclitaxel induces cell damage via the ASK1-c-Jun N-terminal protein kinase (JNK) cascade. E2 inhibited the paclitaxel-induced JNK activation, and the E2-induced inhibition of the paclitaxel-induced JNK activation was attenuated in cells treated with either ICI182,780 or LY294002 or transfected with ASK1S83A, in which a consensus Akt phosphorylation site at serine-83 was converted to alanine. The inhibitory effect of E2 on the paclitaxel-induced reduction of cell viability and apoptosis was diminished in cells transfected with ASK1S83A. These results indicate that E2 inhibits paclitaxel-induced cell damage by inhibiting JNK activity via phosphorylation of Akt-ASK1. Thus, treatment of ovarian cancer with paclitaxel might be less effective in the setting of postoperative estrogen replacement therapy.

Metastatic ovarian tumors: a review of 64 cases.

OBJECTIVE: The goal was to review cases of metastatic ovarian tumor with respect to their clinical features. METHODS: Sixty-four patients with pathologically confirmed metastatic ovarian carcinoma, who were treated between 1978 and 2002 at Osaka Medical Center for Cancer and Cardiovascular Diseases (OMCC), were reviewed and the clinical features examined. RESULTS: We found that metastatic tumors accounted for 21.1% (64/304) of malignant ovarian tumors. Of 64 metastatic ovarian tumors, 26 originated from gynecologic organs, and 38, from nongynecologic organs. Gynecologic primary sites were the uterine body (23%), uterine cervix (14%), and fallopian tube (3%). Eight of nine cervical cancers with ovarian metastases were adenocarcinomas. Adenocarcinoma of the uterine cervix metastasized to the ovaries more frequently than squamous cell carcinoma (5.6% vs 0.1%, respectively; P < 0.01). Among 38 cases of metastatic ovarian tumors from nongynecologic organs, Krukenberg tumors, pathologically characterized by the presence of typical signet-ring cells, were found in 11 patients (29%). Most (8/11) had originated in the stomach. Half (19/38) were preoperatively diagnosed as metastases. The 5-year survival rate after resection of metastatic ovarian tumors from gynecologic organs was significantly higher than the rate after resection of such tumors from nongynecologic organs (47% vs 19%, respectively; P = 0.026). CONCLUSIONS: Metastatic ovarian tumors are likely to be relatively common in Japan because of the high incidence of gastric cancer. In cases of pelvic tumor, metastatic ovarian tumor should always be included in the differential diagnoses. As the 5-year survival after resection of metastatic ovarian tumor is 19%, even for tumors from nongynecologic organs, it seems worthwhile to consider tumorectomy as the second cytoreduction.