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Outcomes with and without bevacizumab as first-line chemotherapy in Japanese-only ovarian cancer patients have not been reported. In this study, we report a retrospective study conducted at the Tohoku Gynecologic Cancer Unit.The study included 453 patients with stage III/IV ovarian, fallopian tube, and primary peritoneal cancer who received first-line platinum-based chemotherapy. The patients were divided into two groups: bevacizumab (168 patients) and without bevacizumab (285 patients). The primary endpoint was the rate of platinum-resistant recurrence and the secondary endpoints were the antitumor response, progression-free survival, overall survival, and adverse events.The objective response rates for patients with measurable diseases treated with and without bevacizumab were 84.5% and 73.0%, respectively (P = 0.0066). Platinum-resistant recurrence in the groups treated with and without bevacizumab was noted in 31 (18.4%) and 111 (38.6%) patients, respectively (P 0.0001). The median progression-free survival for the bevacizumab and without bevacizumab groups was 23 and 15 months, respectively (P = 0.0002), and the median overall survival was not reached and 49 months, respectively (P = 0.0005). Hypertension of grade 3 or higher was observed in 21 patients (12.5%) in the bevacizumab group (P 0.001), and proteinuria was observed in 18 patients (10.7%) and 1 patient (0.3%) in the bevacizumab and without bevacizumab groups, respectively (P 0.001). Intestinal perforation was observed in only one patient (0.6%) in the bevacizumab group.Combination and maintenance with bevacizumab in primary chemotherapy for advanced ovarian, fallopian tube, and primary peritoneal cancer was effective in reducing platinum-resistant recurrence rates and prolonging progression-free and overall survival.

Background: Although tortuosity of the internal carotid artery (ICA) can pose a significant challenge when performing mechanical thrombectomy, few studies have examined the impact of ICA tortuosity on mechanical thrombectomy outcomes. Methods: In a registry-based hospital cohort, consecutive patients with anterior circulation stroke in whom mechanical thrombectomy was attempted were divided into 2 groups: those with tortuosity in the extracranial or cavernous ICA (tortuous group) and those without (nontortuous group). The extracranial ICA tortuosity was defined as the presence of coiling or kinking. The cavernous ICA tortuosity was defined by the posterior deflection of the posterior genu or the shape resembling Simmons-type catheter. Outcomes included first pass effect (FPE; extended Thrombolysis in Cerebral Infarction score 2c/3 after first pass), favorable outcome (3-month modified Rankin Scale score of 0–2), and intracranial hemorrhage. Results: Of 370 patients, 124 were in the tortuous group (extracranial ICA tortuosity, 35; cavernous ICA tortuosity, 70; tortuosity at both sites, 19). The tortuous group showed a higher proportion of women and atrial fibrillation than the nontortuous group. FPE was less frequently achieved in the tortuous group than the nontortuous group (21% versus 39%; adjusted odds ratio, 0.45 [95% CI, 0.26–0.77]). ICA tortuosity was independently associated with the longer time from puncture to extended Thrombolysis in Cerebral Infarction ≥2b reperfusion (β=23.19 [95% CI, 13.44–32.94]). Favorable outcome was similar between groups (46% versus 48%; P =0.87). Frequencies of any intracranial hemorrhage (54% versus 42%; adjusted odds ratio, 1.61 [95% CI, 1.02–2.53]) and parenchymal hematoma (11% versus 6%; adjusted odds ratio, 2.41 [95% CI, 1.04–5.58]) were higher in the tortuous group. In the tortuous group, the FPE rate was similar in patients who underwent combined stent retriever and contact aspiration thrombectomy and in those who underwent either procedure alone (22% versus 19%; P =0.80). However, in the nontortuous group, the FPE rate was significantly higher in patients who underwent combined stent retriever and contact aspiration (52% versus 35%; P =0.02). Conclusions: ICA tortuosity was independently associated with reduced likelihood of FPE and increased risk of postmechanical thrombectomy intracranial hemorrhage. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02251665.

Glutathione is an antioxidant that has an important role in chemotherapeutic drug resistance in cancer. Cysteine is synthesized from cystine and is transported into the cell via the xCT antiporter. Another pathway for synthesizing cysteine involves intracellular methionine. We determined whether targeting the xCT represents a promising strategy for the treatment of endometrial cancer and identified factors that predict efficacy of this treatment strategy. In uterine serous carcinoma (USC) cell lines, the combination of cisplatin and the xCT inhibitor, sulfasalazine, significantly inhibited cell growth compared with single-agent cisplatin or sulfasalazine. Sulfasalazine treatment significantly decreased intracellular glutathione levels and induced apoptosis when combined with cisplatin in USC cell lines. On the one hand, the effectiveness of combined cisplatin and sulfasalazine was not evident in endometrioid carcinoma. USC cell lines exhibited increased expression of xCT and decreased expression of cystathionine gamma lyase (CGL), which is an enzyme involved in the synthesis of cysteine from methionine. On the other hand, endometrioid carcinoma cell lines exhibited increased CGL expression or decreased xCT expression. These findings suggest that using a glutathione synthesis pathway-based approach for selecting subjects for sulfasalazine treatment may be an effective strategy for circumventing glutathione-related chemotherapeutic drug resistance in endometrial carcinoma.

The aim of this study was to review the clinicopathological characteristics of small cell neuroendocrine cervical cancer (SCNEC) and to identify the optimal treatment.The Japanese Society of Gynecologic Oncology conducted a retrospective cohort study of SCNECs enrolled in the Gynecological Tumor Registry of the Japan Society of Obstetrics and Gynecology between 2004 and 2015. All cases were modified and unified by International Federation of Gynecology and Obstetrics 2008 (Union for International Cancer Control 7th edition).There were 822 registered patients diagnosed with SCNEC from 2004 to 2015 which comprised 1.1% (822/73,698) of all uterine cervical cancer cases. Rates of lymph-node and distant metastasis were significantly higher in T1b2 (38.9% and 13.7%, respectively) than T1b1 (14.2% and 4.4%, respectively) (p0.01). In IB2 and T1bN1M0 SCNEC, the 5-year survival rate with surgery followed by chemotherapy was significantly higher than that with surgery followed by radiation therapy/concurrent chemoradiation therapy (p0.01).SNCEC tumors4 cm in size had greater rates of lymph-node and distant metastasis when compared with tumors ≤4 cm. Adjuvant chemotherapy, rather than radiotherapy, may improve prognosis after surgery in T1bN1M0 SCNEC.

Nuclear receptor coactivator 6 (Ncoa6), a modulator of several nuclear receptors and transcription factors, is essential for the decidualization of endometrial stromal cells in mice. However, the function of Ncoa6 in the human endometrium remains unclear. We investigated its function in the decidualization of human endometrial stromal cells (HESCs) isolated from resected uteri. Knockdown of Ncoa6 was performed using two independent small interfering RNAs. Decidualization was induced in vitro via medroxyprogesterone and cyclic adenosine monophosphate. We compared decidualized cellular morphology between the Ncoa6 knockdown cells and control cells. Messenger RNA (mRNA) sequencing was performed to determine the Ncoa6 target genes in undecidualized HESCs. We found that the knockdown of Ncoa6 caused the failure of morphological changes in decidualized HESCs compared to that in the control cells. mRNA sequencing revealed that Ncoa6 regulates the expression of genes associated with the regulation of actin fibers. Ncoa6 knockdown cells failed to reorganize actin fibers during the decidualization of HESCs. Ncoa6 was shown to play an essential role in decidualization via the appropriate regulation of actin fiber regulation in HESCs. Herein, our in vitro studies revealed a part of the mechanisms involved in endometrial decidualization. Future research is needed to investigate these mechanisms in women with implantation defects.

Background Group A streptococcus infection during pregnancy can be concerning. It may cause toxic shock syndrome, which can be fatal. Here, we report a rare case of a pregnant woman who developed infectious sacroiliitis due to group A streptococcus infection. To the best of our knowledge, this case is the first of its kind to be reported. Case presentation A 32-year-old multiparous Japanese woman presented with fever and right buttock pain at 28 weeks of gestation. Based on our clinical findings and investigations, she was diagnosed with group A streptococcus bacteremia and infectious sacroiliitis caused by group A streptococcus. A cardiotocography performed to assess the fetal status showed fetal tachycardia. To prevent the patient from progressing to toxic shock syndrome caused by group A streptococcus, we performed an emergency cesarean section. The patient and her infant had a good course after the cesarean section. Conclusion A pregnant woman diagnosed with group A streptococcus infection needs to be monitored closely because a timely decision to deliver the fetus before rapid deterioration to toxic shock syndrome is crucial.

To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2018 and the Annual Treatment Report for 2013, on the outcomes of patients who started treatment in 2013. The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry, where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment with gynecologic malignancies was initiated in 2018 were analyzed retrospectively. Survival of the patients who started treatment with cervical, endometrial, and ovarian cancer in 2013 was analyzed by using the Kaplan-Meier, log-rank, and Wilcoxson tests. Treatment was initiated in 2018 for 7304 patients with cervical cancer; 11 230 with endometrial cancer; 7031 with ovarian, tubal, and peritoneal cancer; 2072 with ovarian borderline tumors; and with the others (222 vulvar cancer, 159 vaginal cancer, 413 uterine sarcoma, 54 uterine adenosarcoma, and 135 trophoblastic diseases). This clinicopathological information was summarized as the Patient Annual Report. The 5-year survival rates of the patients with cervical cancer were 93.1%, 75.9%, 59.1%, and 31.2% for Stages I, II, III, and IV, respectively. The 5-year survival rates for the patients with endometrial cancer were 94.1%, 89.2%, 73.6%, and 25.8% for Stages I, II, III, and IV, respectively. The 5-year survival rates for the patients with ovarian cancer (surface epithelial-stromal tumors) were 89.7%, 76.8%, 49.1%, and 32.4% for Stages I, II, III, and IV, respectively. The annual report is important to provide knowledge on gynecological malignancy trends in Japan.

Objective Periprocedural thromboembolic events are a serious complication associated with coil embolization of unruptured intracranial aneurysms. However, no established clinical rule for predicting thromboembolic events exists. This study aimed to clarify the significance of adding preoperative clopidogrel response value to clinical factors when predicting the occurrence of thromboembolic events during/after coil embolization and to develop a nomogram for thromboembolic event prediction. Methods In this prospective, single-center, cohort study, we included 345 patients undergoing elective coil embolization for unruptured intracranial aneurysm. Thromboembolic event was defined as the occurrence of intra-procedural thrombus formation and postprocedural symptomatic cerebral infarction within 7 days. We evaluated preoperative clopidogrel response and patients’ clinical information. We developed a patient-clinical-information model for thromboembolic event using multivariate analysis and compared its efficiency with that of patient-clinical-information plus preoperative clopidogrel response model. The predictive performances of the two models were assessed using area under the receiver-operating characteristic curve (AUC-ROC) with bootstrap method and compared using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results Twenty-eight patients experienced thromboembolic events. The clinical model included age, aneurysm location, aneurysm dome and neck size, and treatment technique. AUC-ROC for the clinical model improved from 0.707 to 0.779 after adding the clopidogrel response value. Significant intergroup differences were noted in NRI (0.617, 95% CI: 0.247–0.987, p < .001) and IDI (0.068, 95% CI: 0.021–0.116, p = .005). Conclusions Evaluation of preoperative clopidogrel response in addition to clinical variables improves the prediction accuracy of thromboembolic event occurrence during/after coil embolization of unruptured intracranial aneurysm.

The purpose of our study was to conduct a detailed survey of radical hysterectomy in Japanese patients with early-stage cervical cancer, and to compare oncologic outcomes between open and minimally invasive radical hysterectomy. In Japan during 2015, the medical records of 929 patients with FIGO stage IB1 and IIA disease treated with radical hysterectomy were retrospectively reviewed. We assessed patients’ characteristics, disease-free survival (DFS), overall survival (OS) and prognostic factors for survival. The median patient age was 44 (20–80) years. Most patients (94.4%) had stage IB1 disease. Of the patients who underwent radical hysterectomy, 91.2% underwent open surgery and 8.8% underwent minimally invasive surgery (MIS). The median follow-up period was 40.8 months (range, 0.49–51.1 months). The rate of DFS and OS at 4 years in all patients was 88.3% and 96.4%, respectively. Multivariate analysis identified age (≥ 47), adenocarcinoma histology, tumor size (≥ 2 cm), parametrial invasion, positive lymph node metastasis and institutional accreditation as independent predictors of recurrence, and adenocarcinoma, other cell types, and positive lymph node metastasis as independent predictors of death. Oncologic outcomes in all patients were similar between open and MIS, including DFS and OS. The survival rate of the Japanese patients underwent radical hysterectomy for early-stage cervical cancer was favorable. No significant differences were observed for DFS and OS between open and MIS performed by a limited number of surgeons at a limited number of facilities in Japan. Further investigations are required to identify the appropriate patients might benefit from MIS.

Background and purpose The impact of the paraoxonase-1 (PON1) polymorphism, Q192R, on platelet inhibition in response to clopidogrel remains controversial. We aimed to investigate the association between carrier status of PON1 Q192R and high platelet reactivity (HPR) with clopidogrel in patients undergoing elective neurointervention. Methods Post-clopidogrel platelet reactivity was measured using a VerifyNow® P2Y12 assay in P2Y12 reaction units (PRU) for consecutive patients before the treatment. Genotype testing was performed for PON1 Q192R and CYP2C19*2 and *3 (no function alleles), and *17. PRU was corrected on the basis of hematocrit. We investigated associations between factors including carrying ≥1 PON1 192R allele and HPR defined as original and corrected PRU ≥208. Results Of 475 patients (232 men, median age, 68 years), HPR by original and corrected PRU was observed in 259 and 199 patients (54.5% and 41.9%), respectively. Carriers of ≥1 PON1 192R allele more frequently had HPR by original and corrected PRU compared with non-carriers (91.5% vs 85.2%, P = 0.031 and 92.5% vs 85.9%, P = 0.026, respectively). In multivariate analyses, carrying ≥1 PON1 192R allele was associated with HPR by original (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.03–3.76) and corrected PRU (OR 2.34, 95% CI 1.21–4.74) after adjustment for age, sex, treatment with antihypertensive medications, hematocrit, platelet count, total cholesterol, and carrying ≥1 CYP2C19 no function allele. Conclusions Carrying ≥1 PON1 192R allele is associated with HPR by original and corrected PRU with clopidogrel in patients undergoing elective neurointervention, although alternative results related to other genetic polymorphisms cannot be excluded.

Aim To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2017 and the Annual Treatment Report for 2012, on the outcomes of patients who started treatment in 2012. Methods The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry, where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment with gynecologic malignancies was initiated in 2017 were analyzed retrospectively. Survival of the patients who started treatment with cervical, endometrial and ovarian cancer in 2012 was analyzed by using the Kaplan-Meier, log-rank and Wilcoxon tests. Results Treatment was initiated in 2017 for 7710 patients with cervical cancer; 11 120 with endometrial cancer; 7029 with ovarian, tubal and peritoneal cancer; 2164 with ovarian borderline tumors; and with the others (213 vulvar cancer, 139 vaginal cancer, 366 uterine sarcoma, 41 uterine adenosarcoma and 131 trophoblastic diseases). This clinicopathological information was summarized as the patient annual report. The 5-year survival rates of the patients with cervical cancer were 92.9, 75.5, 58.2 and 26.7% for stages I, II, III and IV, respectively. The 5-year survival rates for the patients with endometrial cancer were 93.6, 85.6, 72.6 and 27.3% for stages I, II, III and IV, respectively. The 5-year survival rates for the patients with ovarian cancer (surface epithelial-stromal tumors) were 92.5, 83.5, 49.5 and 30.8% for stages I, II, III and IV, respectively. Conclusion The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan.

Patients receiving vinca alkaloids for hematological malignancies frequently experience constipation that is unresponsive to laxatives. Research on treatment of vinca alkaloid-induced constipation is limited. This study aimed to determine whether the chloride channel activator lubiprostone ameliorates vinca alkaloid-induced constipation in patients with hematological malignancies. In this retrospective cohort study, vinca alkaloid-induced constipation (grade ≥ 3 using the Common Terminology Criteria for Adverse Events) was investigated in patients treated for hematological malignancies between July 2014 and June 2019 who had already been prescribed osmotic laxatives and additionally received either a stimulant laxative or lubiprostone. Univariate and multivariate analyses were performed to identify the risk factors for persistent constipation after introduction of the second laxative. A propensity score model was used to match 67 patients taking a stimulant laxative and 67 treated with lubiprostone, and the occurrence of intractable constipation was compared between groups. Overall, 203 patients were included, among whom 50 (25%) had constipation. On multivariate analysis, body mass index, opioid use, and addition of lubiprostone were independently associated with constipation. Patients treated with lubiprostone were significantly less likely to experience intractable constipation than did those treated with stimulant laxatives (10% vs. 34%, P = 0.002). Moreover, post-constipation diarrhea was significantly less frequent among patients treated with lubiprostone (42% vs. 63%, P = 0.024). Lubiprostone was more effective than stimulant laxatives at treating vinca alkaloid-induced intractable constipation in patients with hematological malignancies, and its use could enable safe vinca alkaloid chemotherapy.

The purpose of this study was to investigate whether patients with low preoperative Diffusion-weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) could benefit from mechanical thrombectomy for acute anterior circulation occlusion. This was a retrospective, non-blinded, cohort study. From September 2012 to August 2016, 83 consecutive patients of acute anterior circulation occlusion were treated with thrombectomy using second-generation devices or medical management. The DWI-ASPECTS was scored after the first MRI. Patient characteristics and clinical outcomes were compared between the treatment groups. Significant dependence was defined as a modified Rankin scale score ≥3 at 90 days. As a result, 33 patients underwent mechanical thrombectomy and 50 received medical management. In the mechanical thrombectomy group, the variable of lower DWI-ASPECTS (5, 4–6 vs. 8, 7–8, P < 0.001), especially ≤6, was significantly associated with poor prognosis. However, compared with patients of DWI-ASPECTS ≤ 6 who received medical management, there were significantly fewer patients with poor outcomes in thrombectomy (dependent in 11 of 15 vs. 23 of 23, respectively; P = 0.019). Although patients with lower pretreatment DWI-ASPECTS could benefit less from thrombectomy, their outcomes were still better than medical management. Therefore, mechanical thrombectomy could be considered in some patients with low pretreatment DWI-ASPECTS.

Purpose We report a phase II clinical study of the combination of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in platinum- and taxane-resistant recurrent ovarian cancer, based on the recommended doses determined in a phase I trial. Methods PLD was administered intravenously at a dose of 30 mg/m2 on day 3. CPT-11 was administered intravenously at a dose of 80 mg/m2 on days 1 and 15, according to the recommendations of the phase I study. A single course of chemotherapy lasted 28 days, and patients underwent at least 2 courses until disease progression. The primary endpoint was antitumor efficacy, and the secondary endpoints were adverse events, progression-free survival (PFS), and overall survival (OS). Results The response rate was 32.3% and the disease control rate was 64.5%. Grade 3 and 4 neutropenia, anemia, and a decrease in platelet count were observed in 17 (54.9%), 3 (9.7%), and 1 patient (3.2%), respectively. In terms of grade 3 or higher non-hematologic toxicities, grade 3 nausea occurred in 1 patient (3.2%), vomiting in 3 patients (9.7%), and grade 3 diarrhea and fatigue in 1 patient (3.2%). The median PFS and OS rates were 2 months and not reached, respectively. Of the 11 patients with a treatment-free interval (TFI) of ≥3 months, the response rate was 63.3%, and the median PFS was 7 months. Conclusions The treatment outcomes for the 31 patients enrolled in this study were unsatisfactory. However, sub-analysis suggested that patients with a TFI of ≥3 months had a good response rate and PFS. This suggests that CPT-11/PLD combination therapy may be a chemotherapy option for platinum-resistant recurrent ovarian cancer.

Background Globally, cervical cancer is the fourth most common cancer in women. Here, we report a case of cutaneous lymphangitis carcinomatosa arising from cervical cancer, an extremely rare and treatment-resistant condition. Case presentation A 64-year-old Japanese woman presented with genital bleeding. She was diagnosed as having stage IB1 squamous cell cervical cancer and subsequently treated with radiotherapy. Approximately 2 years after the curative radiotherapy, she developed itching, skin rash, and small nodules on her left femoral and pubic area. Slight 18F-fluorodeoxyglucose uptake was detected at her left femoral skin on positron emission tomography with computed tomography. A histopathological examination was performed on a biopsy sample from an erythematous macule on her left femoral skin and vulva. Consequently, she was diagnosed as having cutaneous lymphangitis carcinomatosa arising from cervical cancer. Paclitaxel (135 mg/m2), cisplatin (50 mg/m2), and bevacizumab (15 mg/kg) combination therapy was administered every 21 days. Both itching and rash improved after three treatment cycles. After the completion of six cycles, skin erythema in the femoral and vulval area disappeared completely. Our patient experienced a 25-month symptom-free interval after the last chemotherapy session. Conclusion Our findings suggest that combination chemotherapy plus bevacizumab is an effective therapeutic option in patients with cutaneous lymphangitis carcinomatosa arising from cervical cancer.

ObjectiveTo identify a proximal anterior circulation occlusion for effectively administering immediate mechanical thrombectomy by developing a novel, simple diagnostic scale to predict the occlusion, to compare its validity with available scales, and to assess its utility.MethodsTo develop a novel clinical scale, we retrospectively analyzed a cohort of 429 patients with acute ischemic stroke from a single center. The novel scale GAI2AA was applied to a prospective cohort of 259 patients from 3 stroke centers for external validation. The utility of the scale as an in-hospital triage was compared for the temporal factors of 158 patients with the occlusion.ResultsIn a scale-developmental phase, those with a proximal anterior circulation occlusion had significantly more frequent signs of hemispheric symptoms, including gaze palsy, aphasia, inattention, arm paresis, and atrial fibrillation. The GAI2AA scale was developed using consolidated hemispheric symptoms and was scored as follows: score = 2, arm paresis score = 1, and atrial fibrillation score = 1. A cutoff value ≥3 was optimal for the correlation between sensitivity (88%) and specificity (81%), with a C statistic of 0.90 (95% confidence interval 0.87–0.93). External validation indicated that discrimination was significantly better than or not different from that of available complex scales. Door-to-puncture time was significantly reduced (91 [82–111] vs 52 [32–75] minutes, p < 0.001).ConclusionThe GAI2AA scale showed high sensitivity and specificity when an optimal cutoff score was used and was useful as an in-hospital triage tool.

Intravenous nicardipine is generally used to treat hypertension in acute stroke patients but is associated with frequent phlebitis. We aimed to identify the incidence and risk factors of phlebitis in such patients.The incidence and risk factors of phlebitis were investigated in 358 acute stroke patients from July 2014 to June 2015.In total, 138 patients received intravenous nicardipine. Of 45 (12.6%) phlebitis patients in 358 acute stroke patients, 42 (93.3%) were administered nicardipine, which was significantly associated with phlebitis occurrence (P .01). Other candidate risk factors of phlebitis of acute stroke patients in univariate analysis were intracerebral hemorrhage (P .01), nicardipine injection to paralyzed limbs (P = .023), dilution of nicardipine with normal saline (P .01), higher maximum flow rate of nicardipine (7.2 ± 4.1 mg/h versus 1.6 ± 3.1 mg/h; P .01), and higher maximum concentration of nicardipine (271.5 ± 145.0 µg/mL versus 37.6 ± 75.0 µg/mL; P .01). The only statistically significant independent factor following multivariate logistic regression analysis, according to the optimal cutoff values defined from receiver operating characteristic curve analyses, was the maximum concentration of nicardipine greater than 130 µg/mL (OR 57.9; 95% CI 21.5-156; P .01). A gradual decline of pH below 4.3 was observed when the concentration of nicardipine solution increased to greater than or equal to 130 µg/mL in vitro.Nicardipine-related phlebitis is frequently observed in acute stroke patients and is significantly associated with administration of a maximum concentration of nicardipine greater than 130 µg/mL.

Objective We conducted this study to evaluate the efficacy and safety of adjuvant chemotherapy using taxane plus carboplatin (CBDCA) for high-risk stage IB–IIB patients with uterine cervical non-squamous cell carcinoma after radical hysterectomy. Methods Thirty-seven patients were eligible. Pelvic lymph node involvement and/or parametrial invasion were defined as high-risk factors. The patients were treated with 6 cycles of paclitaxel (PTX, 175 mg/m2) or docetaxel (DTX, 60 mg/m2) followed by CBDCA (area under the curve, 6) every 3 weeks. The primary end point was 2-year progression-free survival (PFS) rate, and the secondary end point was the assessment of adverse events. Results Twenty-two patients received PTX/CBDCA (TC) chemotherapy, and the remaining 15 patients underwent DTX/CBDCA (DC) chemotherapy. The 2-year PFS rate was 62.1% (95% confidence interval, 44.6%–75.5%). Patients receiving DC chemotherapy showed a better 2-year PFS rate compared to those with TC chemotherapy, but the difference was not statistically significant (80.0% vs 50.0%, P = 0.1400). The most common grade 3/4 adverse events were hematologic toxicities, which were generally well tolerable. Nonhematologic toxicity was generally mild. Conclusions Taxane and CBDCA combination chemotherapy, especially DC chemotherapy, may be one of the useful adjuvant treatments for high-risk stage IB–IIB patients with uterine cervical non-squamous cell carcinoma after radical hysterectomy.

Delirium in acute stroke is associated with poor clinical outcome. The purpose of this study was to examine the effect of sleep medications on sleep quality and delirium in acute stroke.In this retrospective cohort study, sleep disturbances, and delirium were investigated in acute stroke patients treated in April 2013-March 2017 who were prescribed ramelteon plus either an alpha-aminobutyric acid receptor (GABAR) agonist or a selective dual orexin receptor antagonist (suvorexant).Of the patients included, 104 received a GABAR agonist and 128 received suvorexant in addition to ramelteon. Patient characteristics did not differ significantly between the groups, except for a higher proportion of cerebral infarction in suvorexant group (P = .033). Subjective sleep quality was significantly improved in suvorexant group compared to GABAR agonist group (difficulty staying asleep: 6.3% versus 34%, P.001; daytime sleepiness: 33% versus 63%, P.001). Delirium was significantly less frequent in suvorexant group than GABAR agonist group (7.0% versus 31%, P.001). The length of hospital stay was significantly shorter in suvorexant group than in GABAR agonist group (in days, 21 [15-29] versus 25 [18-33]; P = .019). Multivariable logistic regression analysis revealed that the addition of suvorexant was significantly associated with a reduced occurrence of delirium (odds ratios .19, 95% confidence interval .085-.43, P.001).Addition of suvorexant to ramelteon therapy, rather than a GABA receptor agonist, can improve subjective sleep quality without inducing delirium in acute stroke patients.

To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2015 and the Annual Treatment Report for 2010 on the outcomes of patients who started treatment in 2010.The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment was initiated in 2015 were analyzed retrospectively. Survival of the patients who started treatment in 2010 was analyzed by using the Kaplan-Meier, log-rank and Wilcoxson tests.Treatment was initiated in 2015 for 7527 patients with cervical cancer, 10 119 with endometrial cancer, 6424 with ovarian cancer and 2181 with ovarian borderline tumors. This clinicopathological information was summarized as the Patient Annual Report. Prognoses were analyzed across 4309 patients with cervical cancer, 5054 with endometrial cancer and 3423 with ovarian cancer, whose treatment was initiated in 2010. The 5-year survival rates of the patients with cervical cancer were 92.1%, 74.2%, 52.0%, and 29.8% for stages I, II, III, and IV, respectively. The 5-year survival rates for the patients with endometrial cancer were 94.3%, 88.8%, 74.0% and 26.6% for stages I, II, III and IV, respectively. The 5-year survival rates for the patients with ovarian cancer (surface epithelial-stromal tumors) were 88.5%, 80.1%, 46.3% and 36.2% for stages I, II, III and IV, respectively.The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan.

Object The purpose of this study was to investigate the safety and efficacy of intravenous low-dose alteplase for acute ischemic stroke patients with relative contraindications. Methods The consecutive series of patients admitted within 4.5 hours of ischemic stroke onset between September 2012 and April 2017 were retrospectively evaluated. A good outcome at 90 days and symptomatic intracerebral hemorrhage were evaluated to determine the association with intravenous low-dose alteplase, especially in the presence of relative contraindications. Results Intravenous low-dose alteplase was administered to 219 of 315 patients (70%). A significantly higher number of patients treated with intravenous low-dose alteplase achieved a good outcome compared with those treated without alteplase (60% versus 44%; P = .014). The incidence of symptomatic intracerebral hemorrhage was not significantly different between the treatment groups. Multivariable logistic regression analysis of good outcome revealed that the significant independent factors were age of 81 years or older (odds ratio, .33; 95% confidence interval, .18-.60), National Institutes of Health Stroke Scale (NIHSS) of 4 or less (compared with NIHSS, 5-25; odds ratio, 3.3; 95% confidence interval, 1.8-6.4), modified Rankin scale score of 1 before stroke (odds ratio, .32; 95% confidence interval, .14-.73), and large changes on first brain imaging (odds ratio, .16; 95% confidence interval, .058-.44). Even with these relative contraindications, intravenous low-dose alteplase was still associated with good outcome (odds ratio, 3.1; 95% confidence interval, 1.6-5.8). Conclusions Intravenous low-dose alteplase treatment can be safe and effective in relative contraindication patients with acute ischemic stroke.

Background and purposeHemorrhagic complications during neurointerventional procedures have various etiologies and can result in severe morbidity and mortality. This study investigated the possible association between low platelet reactivity measured by the VerifyNow assay and increased hemorrhagic complications during elective neurointervention under dual antiplatelet therapy.MethodsFrom May 2010 to April 2013 we recorded baseline characteristics, P2Y12 reaction units (PRU), and aspirin reaction units using VerifyNow. The primary endpoint was post-procedural hemorrhagic complications.ResultsA total of 279 patients were enrolled and 31 major hemorrhagic complications (11.1%) were identified. From receiver-operating characteristic curve analysis, PRU values could discriminate between patients with and without major hemorrhagic complications (area under the curve 0.63). Aspirin reaction unit values had no association with the primary outcome. The optimal cut-off for the primary outcome (PRU ≤175) was used to identify the low platelet reactivity group. The incidence of hemorrhagic complications was 20.0% in this group and 8.9% in the non-low platelet reactivity group. Multivariate analysis identified low platelet reactivity as an independent predictor for hemorrhagic complications.ConclusionsThe risk of hemorrhagic complications during elective neurointervention including cerebral aneurysm coil embolization and carotid artery stenting under dual antiplatelet therapy is associated with the response to clopidogrel but not to aspirin. A PRU value of ≤175 discriminates between patients with and without hemorrhagic complications. Future prospective studies are required to validate whether a specific PRU value around 170–180 is predictive of hemorrhagic complications.

This multi-institutional study was conducted to clarify the clinicopathological features of squamous cell carcinomas of the vulva.The medical records of vulvar cancer patients treated between 2002 and 2012 were retrospectively reviewed following approval by the Institutional Review Board of each institution.One hundred and eleven patients with vulvar malignancies were included. Of these, 63 patients had squamous cell carcinoma (57 %). Initial treatment was surgery, radiation therapy (RT), and concurrent chemoradiotherapy (CCRT) in 34 (54 %), 15 (24 %), and 11 (17 %) patients, respectively. Nineteen, 11, 26, and 7 patients had stage I, II, III, and IV disease, respectively. Of the 34 patients who had surgical treatment, 50 % had stage I disease, while 74 % of those who received CCRT had stage III or IV disease. Complete response (CR) rates for the surgery, RT, and CCRT groups were 73, 60, and 64 %, respectively. The 5-year survival rates for stage I/II and III/IV disease were 64 and 39 %, respectively (P = 0.019). The 5-year survival rates for the surgery, RT, and CCRT groups were 53, 38, and 50 %, respectively, and the prognosis of patients treated with surgery or CCRT was significantly better than that of patients who received RT (P0.05). In multivariate analysis, clinical response to initial treatment was an independent prognostic factor (P0.001).Although many patients had advanced-stage disease in the CCRT group, the therapeutic outcome for the surgery and CCRT groups was similar. Thus, CCRT may be a promising treatment for squamous cell carcinoma of the vulva.

Nicardipine is frequently used in the treatment of hypertension for patients with acute stroke; however, its dosing is complicated by a high risk of phlebitis. In the present study, we examined whether restricting nicardipine concentration under a specific value could reduce the incidence of nicardipine-related phlebitis in patients with acute stroke.Intravenous nicardipine-related phlebitis was retrospectively analyzed. From July 2015, a simple proposition was made to dilute maximum intravenous nicardipine concentration to lower than 130 µg/mL. The maximum intravenous nicardipine concentration and the incidence of phlebitis were compared between patients treated from July 2014 to June 2015 (preproposition group) and patients treated from July 2015 to June 2016 (postproposition group).A total of 300 patients (preproposition group, 138; postproposition group, 162) were included. The postproposition group demonstrated significantly lower maximum intravenous nicardipine concentration (in µg/mL, 76.9, 47.6-104.5 versus 130.4, 69.8-230.8; P .001) and incidence of phlebitis (9.9%, 16/162 vs. 30%, 42/138; P .001) than the preproposition group. Multivariable logistic regression analysis revealed that the maximum intravenous nicardipine concentration lower than 130 µg/mL (odds ratio [OR] .15; 95% confidence interval [CI] .06-.35; P .001) and National Institutes of Health Stroke Scale on admission (OR .95; 95% CI .91-.99; P = .007) were the statistically significant independent factors for phlebitis, which indicated the usefulness of the proposition to dilute maximum intravenous nicardipine concentration to lower than 130 µg/mL.The simple and appropriate proposition about nicardipine administration lowered maximum nicardipine concentration and reduced the incidence of nicardipine-related phlebitis in patients with acute stroke.

Objectives: This study aimed to evaluate differences in oxidative stress of visceral fat between premenopausal and postmenopausal women and clarify the antioxidant effect of estrogen on adipocytes. Materials and Methods: Abdominal subcutaneous and omental visceral adipose tissues were obtained from 38 patients who underwent gynecological surgery. We measured the sizes of the adipocytes and evaluated the lipid peroxidation levels in the adipose tissues. We investigated whether estrogen inhibited the intracellular reactive oxygen species (ROS) production that was induced by hydrogen peroxide (H2O2) in 3T3-L1 adipocytes. Results: The visceral adipocytes were 1162.4 μm2 and 1881.9 μm2 in premenopausal and postmenopausal women, respectively; hence they were significantly larger in the latter (p

BACKGROUND AND PURPOSE: The risk factors of early hemorrhagic complications after endovascular coiling are not well-known. We identified the factors affecting early hemorrhagic complications, defined as any expansion or appearance of hemorrhage shown by head CT in the initial 48 hours after coiling. MATERIALS AND METHODS: We retrospectively reviewed a series of 93 patients who underwent coiling for a ruptured saccular aneurysm between 2006 and 2012 at our hospital. RESULTS: Five patients showed early hemorrhagic complications, and all involved an expansion of the existing intracerebral hematoma immediately after coiling. The associated risk factors were accompanying intracerebral hemorrhage at onset (P < .001), postoperative antiplatelet therapy (P < .001), and thromboembolic complications (P = .044). In the accompanying intracerebral hemorrhage group, the associated risk factors were postoperative antiplatelet therapy (P = .044) and earlier initiation of coiling (9.8 ± 6.5 versus 28.1 ± 24.0 hours, P = .023). Early hemorrhagic complications were significant risk factors for worse clinical outcome (modified Rankin Scale, 2.02 ± 2.21 versus 4.4 ± 2.30, P = .022). None of the 93 patients showed further hemorrhage after the initial 48 hours after coiling. CONCLUSIONS: The accompanying intracerebral hemorrhage at onset, thromboembolic complications, postoperative antiplatelet therapy, and earlier initiation of coiling were the risk factors for early hemorrhagic complications.

A male neonate was referred to our hospital for the treatment of myelomeningocele and hydrocephalus related to Chiari malformation type 2. After the placement of ventriculoperitoneal (VP) shunt for hydrocephalus, an intracranial cyst, which was asymptomatic at first, expanded and caused clinical symptoms due to increased intracranial pressure. The expansion of the cyst was confirmed dominantly in the right lateral ventricle where the VP shunt was inserted. Intraoperative findings through a neuroendoscope suggested that the expanded cyst was an isolated lesion. The pressure reduction in the lateral ventricle through the shunt tube, not the malfunction of the VP shunt, might have attributed to increased intracranial pressure with the expanded cyst. The authors present this rare case, speculating the cause of the expansion of the cyst.

Global increase in the trimethylation of histone H3 at lysine 27 (H3K27me3) has been associated with the differentiation of normal stem cells and cancer cells, however, the role of H3K27me3 in the control of cancer stem cells (CSCs) remains poorly understood. We investigated the impact of increased H3K27me3 on CSCs using a selective H3K27 demethylase inhibitor GSKJ4.The effect of GSKJ4 on the viability as well as on the self-renewal and tumor-initiating capacity of CSCs derived from the A2780 human ovarian cancer cell line was examined.GSKJ4 induced cell death in A2780 CSCs at a concentration non-toxic to normal human fibroblasts. GSKJ4 also caused loss of self-renewal and tumor-initiating capacity of A2780 CSCs surviving GSKJ4 treatment.Our findings suggest that H3K27 methylation may have an inhibitory role in the maintenance of CSCs and that GSKJ4 may represent a novel class of CSC-targeting agents.

OBJECTIVE We investigated the effects of dienogest (DNG), which has a profile similar to that of natural progesterone (P4), on the favorable effects of estrogen in endothelial function. METHODS (1) Human umbilical vein endothelial cells were treated with medroxyprogesterone acetate (MPA), DNG, or P4 with or without estradiol (E2), and then we examined nitric oxide (NO) production, phosphorylation of Akt, ERK, and endothelial NO synthase. (2) Twenty women with surgical menopause were randomly allocated to four groups: control (no treatment), E2 alone, E2 + MPA, and E2 + DNG. The treatment groups were treated with transdermal E2 (0.72 mg) for 2 days or E2 + MPA (2.5 mg/d) or E2 + DNG (2 mg/d) for a week starting 1 week after the operation; the control group did not use hormone. We examined the changes in the flow-mediated dilatation (FMD) of the brachial artery using ultrasonography. RESULTS (1) Although MPA attenuated E2-induced NO production and phosphorylation of Akt, extracellular signal-regulated kinase, and endothelial NO synthase, neither DNG nor P4 inhibited E2 effects. (2) A significant decrease in FMD was observed 1 week after the operation in all groups. E2 significantly ameliorated endothelial impairment (FMD, 3.4% +/- 0.9% to 7.6% +/- 1.3%) in the E2-alone group (P < 0.05), but E2 + MPA could not ameliorate endothelial impairment (3.3% +/- 1.1% to 3.5% +/- 1.0%). However, FMD in the E2 + DNG group significantly increased (2.9% +/- 0.5% to 8.7% +/- 1.0%; P < 0.05). CONCLUSIONS These results suggest that DNG did not inhibit the restoration of vasodilatation by E2. DNG may have an advantage compared with MPA on the endothelial function in postmenopausal women receiving hormone therapy.

We examined the molecular mechanisms of the antiestrogenic effects of clomiphene citrate (CC) in the endometrium using two types of cell lines, Ishikawa and EM-E6/E7/hTERT cells. CC or ICI182780 inhibited 17beta-estradiol (E2)-induced endometrial cell proliferation and transcriptional activation of the estrogen response element (ERE) gene. We directly visualized the ligand-estrogen receptor (ER)alpha interaction using green fluorescent protein (GFP)-tagged ER alpha in a single living cell. Whereas E2 changed the nuclear localization of GFP-ER alpha to a punctate distribution within 5 min, CC or ICI182780 changed the slower and less mobilization of GFP-ER alpha compared with E2. Pretreatment with CC or ICI182780 partly prevented the E2-induced nuclear redistribution of GFP-ER alpha. Fluorescence recovery after photobleaching revealed that GFP-ER alpha mobility treated with E2 was more rapid than that treated by CC or ICI182780. As coactivator recruitment to the ER is essential for ER-dependent transcription, we examined the interaction between ER alpha and steroid receptor coactivator-1 (SRC-1). The complex formation between ER alpha and SRC-1 was significantly increased by E2 but was prevented in the presence of CC or ICI182780 by coimmunoprecipitation. Moreover, the E2-induced colocalization of GFP-ER alpha and SRC-1 was prevented in the presence of CC or ICI182780 according to an immunofluorescence assay. We also observed that the reduction of SRC-1 using small interfering RNA for SRC-1 resulted in the inhibition of E2-induced cell proliferation and transcriptional activation of the ERE gene. Collectively, these results suggest that CC may inhibit E2-induced endometrial epithelial cell proliferation and ERE transactivation by inhibiting the recruitment of SRC-1 to ER alpha.

Mayer-Rokitansky-Küster-Hauser syndrome is a rare congenital anomaly characterized by congenital aplasia or hypoplasia of the uterus and vagina. We report a case of Mayer-Rokitansky-Küster-Hauser syndrome with multiple large pelvic masses diagnosed by three-dimensional computed tomography (CT) angiography.A 40-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome presented with an abdominal mass that had grown for 3 months. Magnetic resonance imaging (MRI) confirmed several solid masses, and normal bilateral ovaries were detected; three-dimensional CT revealed that these tumors were supplied from the right ovarian and uterine arteries, suggesting that they arose from the uterus. Accordingly, leiomyoma was suspected. Laparoscopic surgery was contraindicated, and the patient therefore underwent laparotomy. The masses were resected with the bilateral rudimentary uteri and fallopian tubes, and pathologic evaluation confirmed leiomyoma.Combined MRI and three-dimensional CT angiography can accurately evaluate the origin and anatomic properties of leiomyomas in patients with Mayer-Rokitansky-Küster-Hauser syndrome.

Cancer stem cells (CSCs) are considered to contribute to the poor prognosis of ovarian cancer as a major cause of fatal recurrence. Identification of effective measures to eliminate ovarian CSCs through induction of cell death and/or loss of self-renewal capacity would, therefore, be key to successful management of ovarian cancer.The effects of resveratrol on the viability and self-renewal capacity of CSCs derived from A2780 human ovarian cancer cells were examined. The involvement of reactive oxygen species (ROS) was also investigated.At a non-toxic to normal human fibroblasts concentration, resveratrol effectively killed ovarian CSCs independently of ROS, while ROS-dependently impaired the self-renewal capacity of ovarian CSCs that survived resveratrol treatment.Our findings not only shed light on a novel mechanism of action for resveratrol but also suggest that resveratrol, or its analogs, may be useful for CSC-directed therapy against ovarian cancer.

Ovarian cancer remains the most lethal gynecologic cancer and new targeted molecular therapies against this miserable disease continue to be challenging. In this study, we analyzed the expressional patterns of Interleukin-6 (IL-6) and its receptor (IL-6R) expression in ovarian cancer tissues, evaluated the impact of these expressions on clinical outcomes of patients, and found that a high-level of IL-6R expression but not IL-6 expression in cancer cells is an independent prognostic factor. In in vitro analyses using ovarian cell lines, while six (RMUG-S, RMG-1, OVISE, A2780, SKOV3ip1 and OVCAR-3) of seven overexpressed IL-6R compared with a primary normal ovarian surface epithelium, only two (RMG-1, OVISE) of seven cell lines overexpressed IL-6, suggesting that IL-6/IL-6R signaling exerts in a paracrine manner in certain types of ovarian cancer cells. Ovarian cancer ascites were collected from patients, and we found that primary CD11b+CD14+ cells, which were predominantly M2-polarized macrophages, are the major source of IL-6 production in an ovarian cancer microenvironment. When CD11b+CD14+ cells were co-cultured with cancer cells, both the invasion and the proliferation of cancer cells were robustly promoted and these promotions were almost completely inhibited by pretreatment with anti-IL-6R antibody (tocilizumab). The data presented herein suggest a rationale for anti-IL-6/IL-6R therapy to suppress the peritoneal spread of ovarian cancer, and represent evidence of the therapeutic potential of anti-IL-6R therapy for ovarian cancer treatment.

Activation of the c-JUN N-terminal kinase (JNK) signaling pathway has been associated with poor survival of ovarian cancer patients, but the role(s) and significance of JNK signaling in ovarian cancer cells remain poorly understood. In the present study, we aimed to investigate the role of JNK specifically in ovarian cancer stem cells (CSCs).The effect of JNK inhibition on the self-renewal (CSC marker expression, sphere-forming ability) and tumor-initiating capacity was examined in CSCs derived from the A2780 human ovarian cancer cell line. JNK inhibition was achieved either pharmacologically or genetically by use of RNA interference.Both pharmacological and genetic targeting of JNK resulted in loss of self-renewal and tumor-initiating capacity of A2780 CSCs.Our findings demonstrate, to our knowledge for the first time, that JNK has a pivotal role in the maintenance of ovarian CSCs.

This study aimed to evaluate surgical, pregnancy, and prognostic outcomes of radical abdominal trachelectomy (RAT) for Japanese patients with early-stage cervical cancer.This was a multicenter prospective cohort study conducted in member facilities of Tohoku Gynecologic Cancer Unit. Patients with FIGO 1A-1B1 squamous cell carcinoma were included.A total of 42 patients were registered in this study, and all patients underwent planned RAT. The median stromal invasion and median horizontal spread of resected specimens were 4.6 (range 1.0-10.0) and 12.4 mm (range 3.0-28.0), respectively. The median surgical time and median blood loss were 304 min (range 233-611) and 848 mL (range 250-3984), respectively. Five patients (11.9 %) received blood transfusion. Five of 18 (27.8 %) patients who attempted to conceive achieved pregnancy, and 3 patients had healthy babies. However, all pregnancies required assisted reproductive technology with in-vitro fertilization and embryo transfer. Four patients (9.5 %) received postoperative adjuvant therapy, and 3 patients (7.1 %) developed disease recurrence.RAT may be safely performed for Japanese patients with FIGO 1A-1B1 squamous cell carcinoma of the cervix, even in educational medical facilities. However, less-invasive surgery should be considered more often to improve pregnancy outcomes.

The prolongation of progression-free survival (PFS) in patients with advanced ovarian cancer by antiangiogenic therapy has been shown in several clinical trials. However, although an anti-VEGF antibody (bevacizumab) is the only option currently available, its efficacy is limited and it is not cost effective for use in all patients. Therefore, the development of a novel antiangiogenic drug, especially composed of small-molecule compounds, could be a powerful armament for ovarian cancer treatment. As NF-κB signaling has the potential to regulate VEGF expression, we determined to identify whether VEGF expression is associated with NF-κB activation and to investigate the possibility of a novel IKKβ inhibitor, IMD-0354 (IMMD Inc.), as an antiangiogenic drug. Tissue microarrays from 94 ovarian cancer tissues were constructed and immunohistochemical analyses performed. We revealed that IKK phosphorylation is an independent prognostic factor (PFS: 26.1 vs. 49.8 months, P = 0.011), and is positively correlated with high VEGF expression. In in vitro analyses, IMD-0354 robustly inhibited adhesive and invasive activities of ovarian cancer cells without impairing cell viabilities. IMD-0354 significantly suppressed VEGF production from cancer cells, which led to the inhibition of angiogenesis. In a xenograft model, the treatment of IMD-0354 significantly inhibited peritoneal dissemination with a marked reduction of intratumoral blood vessel formation followed by the inhibition of VEGF expression from cancer cells. IMD-0354 is a stable small-molecule drug and has already been administered safely to humans in other trials. Antiangiogenic therapy targeting IKKβ is a potential future option to treat ovarian cancer. Mol Cancer Ther; 14(4); 909–19. ©2015 AACR.

BACKGROUND AND PURPOSE: Despite major progress in treating aneurysms by coil embolization, the complete occlusion of aneurysms of >10 mm in diameter (large/giant aneurysms) remains challenging. We present a novel endovascular treatment method for large and giant cerebral aneurysms called the “maze-making and solving” technique and compare the short-term follow-up results of this technique with those of conventional coil embolization. MATERIALS AND METHODS: Eight patients (65 ± 11.5 years of age, 7 women) with large/giant unruptured nonthrombosed cerebral aneurysm (mean largest aneurysm dimension, 19 ± 4.4 mm) were treated by the maze-making and solving technique, a combination of the double-catheter technique and various assisted techniques. The coil-packing attenuation, postoperative courses, and recurrence rate of this maze group were compared with 30 previous cases (conventional group, 65.4 ± 13.0 years of age; 22 women; mean largest aneurysm dimension, 13.4 ± 3.8 mm). RESULTS: Four maze group cases were Raymond class 1; and 4 were class 2 as indicated by immediate postsurgical angiography. No perioperative deaths or major strokes occurred. Mean packing attenuation of the maze group was significantly higher than that of the conventional group (37.4 ± 5.9% versus 26.2 ± 5.6%). Follow-up angiography performed at 11.3 ± 5.4 months revealed no recurrence in the maze group compared with 39.2% in the conventional group. CONCLUSIONS: The maze-making and solving technique achieves high coil-packing attenuation for efficient embolization of large and giant cerebral aneurysms with a low risk of recurrence.

The aim of this study was to evaluate prognostic factors including efficacy of postoperative chemotherapy in Japanese patients with uterine carcinosarcoma.We conducted a retrospective survey of seven medical facilities in the Tohoku Gynecologic Cancer Unit.A total of 45 patients who had undergone hysterectomy and bilateral salpingo-oophorectomy were enrolled. No significant difference was observed in overall survival according to patient age (≤ 50 years vs50 years) or retroperitoneal lymphadenectomy (performed vs. not performed). However, the International Federation of Gynecology and Obstetrics stage (stage I/II vs stage III/IV) and postoperative chemotherapy (provided vs not provided) were significant prognostic factors in both univariate and multivariate analyses for the 25-month median follow-up period.Our results revealed that postoperative chemotherapy should be considered for all uterine carcinosarcoma stages in Japanese patients.

Changes in bone mineral density with age were measured in the distal radius of healthy adults using dual energy X-ray absorptiometry. A total of 2789 healthy women (20–95 years old) and 1255 healthy men (20–87 years old), and 72 women (52–94 years old) and 23 men (51–79 years old) with fractures of the distal radius were assessed. Bone mineral density remains relatively stable in men despite aging, and was significantly higher than in women in every decade. In women aged 70 years and more, the bone mineral density was significantly lower in the fracture group than the nonfracture group. In men with fractures of the distal radius, there were no significant differences between bone mineral density and age. In the fracture groups loss of radial inclination after reduction correlated with decreased bone mineral density, but there was no significant regression between bone mineral density and the decrease in radial length or palmar tilt.

We investigated whether the estrogen released from non-sex cord-stromal ovarian tumors has biological effects on bone and endometrial tissue in postmenopausal women.A total of 132 patients with malignant (n = 112) or benign (n = 20) gynecological disease with normal postmenopausal ovaries were recruited as a control group (group C). The 75 patients with ovarian tumors were divided into 2 groups: group L (serum estradiol [E2] level of20 pg/ml; n = 42) and group H (serum E2 level of20 pg/ml; n = 33). The subjects' serum E2 levels, bone mineral density, urinary levels of the N-telopeptide of type I collagen, and serum levels of bone-specific alkaline phosphatase were measured before and after surgery. Histological examinations of the endometrium were carried out in the 75 patients with non-sex cord-stromal ovarian tumors.High serum E2 levels were detected in 33 (44%) of 75 patients with ovarian tumors. The serum E2 levels of group H were significantly decreased after surgery. In the other subjects, there were no significant differences between the serum E2 levels observed before and after surgery. The mean preoperative N-telopeptide of type I collagen and bone-specific alkaline phosphatase levels of group H were significantly lower than those of group C. The bone mineral density values of groups L and H were significantly decreased after surgery. Five (6.7%) of 75 patients with non-sex cord-stromal ovarian tumors displayed abnormal endometrial histology, including 4 patients with grade 1 endometrioid cancer.The E2 released from ovarian tumors might have biological effects on bone metabolism and the incidence of abnormal endometrial histology.

We evaluated neurotization after transplantation with lyophilized nerves, muscles, and arteries, and examined the possibility of practical application of long bridging grafts. Grafts of 10 mm and 25 mm of lyophilized nerves, muscles, and arteries harvested from Fisher rats were transplanted to the sciatic nerves of recipient Lewis rats. The histological changes undergone by short grafts were observed at weekly intervals. The sham-operated and isograft groups were used to compare the results of long grafts. In both the nerve and muscle-graft group, regenerated axons grew out through the residual basement membrane tube. But in the muscle graft group, phagocytosis of myofibril debris took longer than that of degenerated axons. No statistical differences were found between results of TSI, induced EMG, and quantitative analysis of myelinated axons in the nerve and muscle graft groups. No neurotization was noted in the long artery graft. In long grafts, laminin found on the basement membrane may not be sufficient to accelerate neurotization, and arteries should not be used for tubulization.

Background Delirium is considered to worsen life prognosis in elderly patients with stroke. We examined the effects of the melatonin receptor agonist ramelteon for treating delirium in elderly stroke patients with insomnia in comparison to the other drugs. Methods Elderly patients with delirium and insomnia after acute stroke who were treated with ramelteon (7 patients; mean age 76 years) and the other drugs (21 patients; mean age 77.3 years) between July 2011 and March 2012 at our hospital were retrospectively examined. Results All patients treated with ramelteon had a significant improvement within a week and were started on early and aggressive rehabilitation. No patient experienced oversedation, neurologic deterioration, or any other worsening effect associated with ramelteon treatment. Conclusions Melatonin receptor agonists may be effective for the treatment of delirium in elderly patients with acute stroke.

Rho, a Ras-related small GTPase, and Rho-associated coiled coil-containing protein kinase (Rho kinase, ROCK1 and ROCK2) are key regulators of focal adhesion, actomyosin contraction, and thus cell motility. Rho/ROCK kinases also play roles in proliferation, differentiation, apoptosis and oncogenic transformation. In the present study, we have shown that Rho/ROCK pathway inhibition by fasudil, an orally administered inhibitor of Rho kinases, enhanced cisplatin-induced growth inhibition and apoptosis in human ovarian cancer cell lines. Fasudil inhibited hypoxia inducible factor (HIF)-1α protein expression. Knockdown of RhoA, ROCK1 or ROCK2 also attenuated the expression of HIF-1α. Furthermore, knockdown of HIF-1α using small interfering RNA enhanced cisplatin-induced growth inhibition and apoptosis as did inhibition of the Rho/ROCK pathway by fasudil, the Rho/ROCK inhibitor Y27632, or by Rho/ROCK knockdown. Therefore, the Rho/ROCK pathway may modulate HIF-1α signal transduction and blockade of Rho/ROCK enhances the efficacy of cisplatin by inhibiting HIF-1α in ovarian cancer cells. Our findings suggested that the Rho/ROCK pathway may be a new target for molecular targeting therapies against ovarian cancer.

To investigate the phosphatidylinositol 3-kinase (PI3K)-Akt and extracellular signal regulated protein kinase (ERK) activation by chemotherapy, and the relationship between the activation of them and patient outcomes. The effect of chemotherapy on the cell proliferation and apoptosis markers and their role in the biology of ovarian cancer were also investigated.This study was carried out in a series of 10 ovarian (or tubal) cancer patients whose specimens were obtained before and after chemotherapy. PI3K-Akt and ERK activation were evaluated by immunohistochemical staining for phosphorylated Akt and ERK. Their correlation with patient outcome was investigated by survival curves using the Kaplan-Meier method. Cell proliferation was evaluated by Ki-67 expression using immunofluorescent staining. Apoptosis was examined by caspase-3 and cleaved Poly ADP ribose polymerase (PARP) using immunofluorescent staining.An increase in Akt and ERK phosphorylation after chemotherapy was observed in 5 and 8 patients, respectively out of 10 patients examined. Akt and ERK activation by chemotherapy were associated with a favorable overall survival. In almost all patients, Ki-67 expression was initially high and largely decreased after chemotherapy. An increase in apoptotic marker expression was observed in almost all patients exposed to chemotherapy.Our findings suggest that Akt and ERK activation by chemotherapy may be associated with favorable prognosis.

A 70-year-old woman with a history of end-stage renal disease secondary to anti-neutrophil cytoplasmic autoantibody-associated vasculitis had been receiving hemodialysis for 5 years. The patient underwent attempted right internal jugular vein cannulation for temporary hemodialysis catheter placement. Pulsating mass developed in the neck and angiography revealed a subclavian artery pseudoaneurysm 4 days later. The pseudoaneurysm disappeared spontaneously during the interval between the diagnosis and the planned surgical procedure. Such delayed onset and spontaneous resolution of subclavian artery pseudoaneurysm is uncommon. Close observation may be optimal if delayed onset of pseudoaneurysm occurs after small needle puncture with cessation of antiplatelet/anticoagulant administration.

Small cell carcinoma of the ovary is a rare type of ovarian carcinoma with a very poor prognosis.We report here a case of a 55-year-old woman with small cell carcinoma of the left ovary. The patient underwent cytoreductive surgery with residual tumors of 6 cm at the cul-de-sac and was found to have stage IIIc disease. After six courses of irinotecan (CPT-11) and cisplatin (CDDP) combination therapy, secondary cytoreductive surgery was performed. The patient showed no evidence of residual tumors. After an additional three courses of chemotherapy, the patient is still alive and well without evidence of disease.CPT-11 and CDDP combination chemotherapy may be effective and safe for patients with small cell carcinoma of the ovary.

Objective: To examine the effect of raloxifene on the endothelial dysfunction caused by surgical menopause. Design: Ten premenopausal women who underwent gynecological surgery with ovariectomy were divided into two groups. Five participants used raloxifene (60 mg/d) for 7 days staring 1 week after the surgery, and the other five participants did not use raloxifene. We examined the changes in flow-mediated dilatation (FMD) of the brachial artery using ultrasonography. Vasodilation in response to nitroglycerin was also studied. We also measured the brachial-ankle pulse wave velocity to examine the change in arterial stiffness in these participants before and after surgical menopause. Results: In both the raloxifene and control groups, a significant decrease in FMD was observed 1 week after the surgery. Although no further changes in FMD were observed in the control group at 2 weeks after surgery, FMD was significantly increased in the raloxifene group. No remarkable changes in nitroglycerin or brachial-ankle pulse wave velocity were observed after surgery in either group. Conclusions: Raloxifene rapidly restored FMD that was impaired after surgical menopause. Therefore, raloxifene may be effective for ameliorating and maintaining endothelial function in premenopausal women who undergo ovariectomy.

The mechanism of medroxyprogesterone acetate (MPA)-induced cell proliferation in human breast cancer cells remains elusive. We examined the mechanism by which MPA affects the cyclin D1 expression in progesterone receptor (PR)-positive T47D human breast cancer cells. MPA (10 nM) treatment for 48 h induced proliferation of the cells (1.6-fold induction). MPA induced cyclin D1 expression (3.3-fold induction), and RU486, a selective PR antagonist, blocked the MPA-induced cell proliferation and cyclin D1 expression (23% inhibition). MPA increased both the protein level (2.2-fold induction) and promoter activity (2.7-fold induction) of cyclin D1 in MCF-7 cells transfected with PRB but not with PRA. Although MPA transcriptionally activated cyclin D1 expression, cyclin D1 promoter does not have progesterone-responsive element-related sequence. We further examined the mechanism for the regulation of the cyclin D1 expression. Because the cyclin D1 promoter contains three putative nuclear factor-kappaB (NFkappaB)-binding motifs and NFkappaB is a substrate of Akt, we investigated the effect of the phosphatidylinositol 3-kinase (PI3K)/Akt/NFkappaB cascade on the responses of cyclin D1 to MPA. MPA induced the transient phosphorylation of Akt (2.7-fold induction at 5 min), and treatment with PI3K inhibitor (wortmannin) attenuated the MPA-induced up-regulation of cyclin D1 expression (40% inhibition) and cell proliferation (40% inhibition). MPA also induced phosphorylation of inhibitor of NFkappaBalpha (IkappaBalpha) (2.3-fold induction), and treatment with wortmannin attenuated the MPA-induced IkappaBalpha phosphorylation (60% inhibition). Treatment with an IkappaBalpha phosphorylation inhibitor (BAY 11-7085) or a specific NFkappaB nuclear translocation inhibitor (SN-50) attenuated the MPA-induced up-regulation of both cyclin D1 expression (80 and 50% inhibition, respectively) and cell proliferation (55 and 34% inhibition, respectively). Because MPA induced a transient phosphorylation of Akt and the cyclin D1 promoter contains no progesterone-responsive element-related sequence, the MPA-induced cell proliferation through PRB by up-regulation of cyclin D1 expression via the PI3K/Akt/NFkappaB cascade may be a nongenomic mechanism.

Torsion of a nongravid uterus is extremely rare. Most cases of uterine torsion occur during pregnancy. Here we report a case of nongravid uterus torsion with a large adnexal mass. A 73-year-old woman presented at the emergency room with acute abdominal pain. A preoperative diagnosis of torsion of an ovarian cyst was made and laparotomy was performed. The left ovary was twisted 360° in a clockwise rotation, and the uterine corpus had also undergone a 360° rotation. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were carried out. Although a preoperative diagnosis of uterine torsion was not possible, it is noteworthy that in the contrast-enhanced magnetic resonance images the uterine cervix was intensely enhanced, while the uterine corpus was not. This is the first report to show the magnetic resonance imaging findings of a twisted uterus.