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The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in the malignant transformation of human tumors and their subsequent growth, proliferation, and metastasis. Preclinical investigations have suggested that the PI3K/AKT/mTOR pathway is frequently activated in ovarian cancer, especially in clear cell carcinoma and endometrioid adenocarcinoma. Thus, this pathway is regarded as an attractive candidate for therapeutic interventions, and inhibitors targeting different components of this pathway are in various stages of clinical development. Here, we highlight the recent progress that has been made in our understanding of the PI3K/AKT/mTOR pathway and discuss the potential of therapeutic agents that target this pathway as treatments for ovarian cancer and the obstacles to their development., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A 39-year-old man developed fulminant myocarditis and was transferred on mechanical ventilation and a ventricular-assist device to our hospital. On Hospital Day 10, he was weaned from all medical engineering devices, and bedside rehabilitation was initiated. Although a multidisciplinary cardiac rehabilitation team had intervened since Hospital Day 3, he could not be encouraged to begin ambulation because of hypotension and tachycardia. Moreover, he complained of loss of self-confidence and anxiety regarding physical strength, and expansion of activities was difficult. Exercises reflecting his immediate desires and daily activities were used as activity goals, and we developed an individualized exercise program with stepwise increase in load to motivate him to perform rehabilitation. At the time of discharge, his cardiac function recovered to nearly normal levels; however, muscle strength and respiratory function had not recovered. While the intervention was continued at the cardiac rehabilitation outpatient unit, improvement was observed in physical health and mental health-related scale scores. The patient returned to work 4 months after onset of his myocarditis. Moreover, the cardiac rehabilitation team provided support to him for his long-term overseas assignment in the fifth year after myocarditis onset. Long-term comprehensive support by the cardiac rehabilitation team was feasible and useful. < Learning objective: Comprehensive intervention by a cardiac rehabilitation team from the acute phase may be helpful for motivating patients not only to participate in rehabilitation during hospitalization, but also to continue it on an outpatient basis after discharge. Moreover, continuous outpatient intervention can lead to recovery of physical/mental function in patients that is not achievable with only inpatient intervention, and support can be provided to patients for setting new life goals.>.

The purpose of this study was to determine the outcomes and optimal practice patterns of definitive radiotherapy for primary vaginal cancer. Between 1993 and 2012, 49 patients were treated with definitive radiotherapy for primary vaginal cancer in three hospitals. Of these, 15 patients (31%) had clinically positive regional lymph node metastasis. A total of 34 patients (70%) received external beam radiotherapy with high-dose-rate brachytherapy (interstitial or intracavitary), and 8 (16%) (with small superficial Stage I tumors) were treated with local radiotherapy. The median follow-up was 33 months (range: 1-169 months). The 3-year overall survival (OS), disease-free survival (DFS), and loco-regional control (LRC) rates were 83%, 59% and 71%, respectively. In multivariate analysis, the histological type (P = 0.044) was significant risk factors for LRC. In Federation of Gynecology and Obstetrics (FIGO) Stage I cases, 3 of 8 patients (38%) who did not undergo prophylactic lymph node irradiation had lymph node recurrence, compared with 2 of 12 patients (17%) who underwent prophylactic pelvic irradiation. For Stage III-IV tumors, the local recurrence rate was 50% and the lymph node recurrence rate was 40%. Patients with FIGO Stage I/II or clinical Stage N1 had a higher recurrence rate with treatment using a single modality compared with the recurrence rate using combined modalities. In conclusion, our treatment outcomes for vaginal cancer were acceptable, but external beam radiotherapy with brachytherapy (interstitial or intracavitary) was needed regardless of FIGO stage. Improvement of treatment outcomes in cases of FIGO Stage III or IV remains a significant challenge., (© The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Cisplatin-based concurrent chemoradiotherapy (CCRT) is a standard treatment for cervical cancer, but nedaplatin-based CCRT is not routinely administered. We evaluated the efficacy and safety of nedaplatin-based CCRT (35 mg/m(2) weekly) and analyzed prognostic factors for survival among 52 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB2-IVA cervical cancer treated from 1999 to 2009. Patients were treated with a combination of external beam radiotherapy of 40-56 Gy (in 20-28 fractions) and 13.6-28.8 Gy (in 2-4 fractions) of high-dose-rate (HDR) intracavitary brachytherapy or 18 Gy (in 3 fractions) of HDR interstitial brachytherapy. Overall survival (OS), progression-free survival (PFS), and local control (LC) were estimated using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis. Acute and late toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. The median follow-up period was 52 months. The median patient age was 63 years. The 5-year OS, PFS and LC rates were 78%, 57% and 73%, respectively. Multivariate analysis showed that histologic type, maximum tumor diameter, and pretreatment hemoglobin level were independent risk factors for PFS. Regarding adverse effects, 24 patients (46%) had acute Grade 3-4 leukopenia and 5 (10%) had late Grade 3 gastrointestinal toxicities. No patient experienced renal toxicity. Nedaplatin-based CCRT for FIGO Stage IB2-IVA cervical cancer was efficacious and safe, with no renal toxicity. Histologic type, maximum tumor diameter, and pretreatment hemoglobin level were statistically significant prognostic factors for PFS., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

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.

Objective: Removal of the ovaries is common during surgery for endometrial cancer. However, because loss of the ovaries can cause several health problems in patients, strategies for the prevention of such problems need to be established. Hence, we decided to conduct a multicenter randomized clinical trial to assess the effect of raloxifene on bone mineral density (BMD), bone metabolism, and the lipid profile of patients who had undergone surgery for patients with endometrial cancer., Materials and Methods: Patients with endometrial cancer were enrolled after treatment. The participants were randomized into 2 groups: group 1 included 39 women who received alfacalcidol (1 μg/d) alone and group 2 included 37 women who received alfacalcidol and the test drug, raloxifene hydrochloride, at a dose of 60 mg/d. The BMD of lumbar spine and femoral neck, serum bone markers, as well as lipid profile parameters were evaluated at enrollment as well as 6, 12, and 24 months after the enrollment. The primary efficacy end point was the percentage change from baseline to 24 months in lumbar spine (L2-L4) and femoral neck BMD., Results: Sixty-four women completed the 24-month study. At 24 months, the lumbar and femoral neck BMDs were significantly increased in group 2 compared with group 1 (3.5% vs -0.8% and 2.3% vs -2.8%, respectively). In group 2, low-density lipoprotein-cholesterol levels were significantly reduced by 13.6% and serum N-terminal telopeptide of type I collagen as well as bone-specific alkaline phosphatase values were significantly reduced by 16.7% and 25.7%, respectively. The patients who received adjuvant therapy for endometrial cancer showed a significantly higher response to raloxifene (5.8% vs 1.9%). Recurrence was detected in 2 (2.6%) patients in group 1. No severe adverse events were noted in any patient during the study period., Conclusions: Raloxifene exerts positive effects on BMD, bone metabolism, and lipid profile parameters and could provide an improved therapeutic option for patients with endometrial cancer.

Objective: Presence of high-risk factor in cervical cancer is known to be associated with decreased survival outcomes. However, the significance of multiple high-risk factors in early-stage cervical cancer related to survival outcomes, recurrence patterns, and treatment implications is not well elucidated., Methods: A retrospective study was conducted for surgically treated cervical cancer patients (stage IA2-IIB, n=540). Surgical-pathological risk factors were examined and tumors expressing ≥1 high-risk factors (nodal metastasis, parametrial involvement, or positive surgical margin) were eligible for analysis (n=177, 32.8%). Survival analysis was performed based on the number of high-risk factors and the type of adjuvant therapy., Results: There were 68 cases (38.4%) expressed multiple high-risk factors (2 high-risk factors: n=58, 32.8%; 3 high-risk factors: n=10, 5.6%). Multiple high-risk factors remained an independent prognosticator for decreased survival outcomes after controlling for age, histology, stage, and treatment type (disease-free survival: hazard ratio [HR], 2.34; p=0.002; overall survival: HR, 2.32; p=0.007). Postoperatively, 101 cases (57.1%) received concurrent chemoradiotherapy (CCRT) and 76 cases (42.9%) received radiotherapy (RT) alone. CCRT was beneficial in single high-risk factor cases: HRs for CCRT over RT alone for cumulative risk of locoregional and distant recurrence, 0.27 (p=0.022) and 0.27 (p=0.005), respectively. However, tumor expressing multiple high-risk factors completely offset the benefit of CCRT over RT alone for the risk of distant recurrence: HR for locoregional and distant recurrence, 0.31 (p=0.071) and 0.99 (p=0.980), respectively., Conclusion: Special consideration for the significance of multiple high-risk factors merits further investigation in the management of surgically treated early-stage cervical cancer.

Purpose: We retrospectively analyzed oncologic and reproductive outcomes of fertility-seeking premenopausal women with complex atypical hyperplasia (CAH) or Grade 1 endometrial adenocarcinoma (G1EA) who underwent medical management with high-dose medroxyprogesterone acetate (MPA) therapy., Methods: Patients were given a dose of 400-600 mg of MPA orally on a daily basis. They had histologically confirmed CAH or G1EA at presumed stage IA and wished to preserve fertility. Endometrial tissue sampling was carried out by dilation and curettage before and after the treatment and the pathologic response to MPA treatment was assessed., Results: A total of 27 premenopausal patients received MPA therapy. The median follow-up time was 39.2 months (3.4-153.8 months). Complete response was achieved in 81.8 % (9/11) of CAH cases and 68.8 % (11/16) of G1EA. Although no recurrences were found in CAH patients, nine G1EA patients (81.8 %) eventually recurred and underwent total hysterectomy. Neither therapeutic death nor irreversible toxicities were observed during the follow-up periods. Five patients (4 CAH and 1 G1EA) became pregnant and had nine live births., Conclusion: The high efficacy of fertility-sparing treatment with MPA was shown demonstrated. MPA therapy can be considered acceptable for the purpose of enabling patients to preserve their fertility. However, the rate of recurrence was high in patients with G1EA. Even in responders, close follow-up is required and a total hysterectomy needs to be considered without delay. Patients should be aware of the risks and limitations of this conservative treatment.

Aim: The present study aimed at evaluating the usefulness and adverse effects of duloxetine treatment for paclitaxel-induced peripheral neuropathy in gynecological cancer patients., Patients and Methods: Medical records of gynecological cancer patients treated with duloxetine were retrospectively studied to evaluate the drug's efficacy for paclitaxel-induced peripheral neuropathy., Results: RESULTS from 25 patients showed that an improved response was observed in 14 (56%). By univariate and multivariate analysis, the patient's age, tumor origin, regimen of chemotherapy, accumulated doses of paclitaxel or carboplatin, previous medication, maintenance dosage and timing of treatment with duloxetine were found not to be associated with the effectiveness of duloxetine treatment. Adverse effects with duloxetine were mild and well-tolerated., Conclusion: As an option, duloxetine can be effectively used for paclitaxel-induced peripheral neuropathy in patients with gynecological cancers, irrespective of patients' age, origin of the tumor, regimen of chemotherapy, or previous medication., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Vaginal carcinoma is rare, accounting for only 2% of all gynecological malignancies. Due to a lack of prospective randomized studies, the role of concurrent chemoradiotherapy in the treatment of primary vaginal carcinoma remains unclear. We report the first two cases of primary vaginal carcinoma successfully treated with a regimen involving concurrent weekly carboplatin plus paclitaxel, external beam radiotherapy and high-dose-rate interstitial brachytherapy. These cases strongly indicate that definitive chemoradiation involving carboplatin plus paclitaxel may be a reasonable treatment for primary vaginal carcinoma., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

Purpose: To investigate the prognostic factors for survival in uterine cervical cancer patients who developed bone metastasis., Materials and Methods: Cervical cancer patients with bone metastasis who were treated at the present institute from April 1996 to September 2010 were identified from the authors' institutional tumor registries. Primary disease, follow-up, and recurrence data were collected and retrospectively reviewed. Univariate and multivariate analyses of prognostic factors for survival were performed., Results: A total of 37 patients that developed cervical cancer bone metastasis were included in the authors' database. The median survival time after recurrence was 12 months. Univariate analysis revealed that patients with a disease-free interval (DFI) of ten months or less achieved significantly shorter survival after bone metastasis detection than those with a DFI of 11 months or more (median: 8.5 months versus 17 months, p < 0.0001). Multivariate analysis also showed that DFI of ten months or less was a significant predictor of short survival (p = 0.0018)., Conclusions: The DFI was found to be independent prognostic factors for survival in cervical cancer patients who developed bone metastasis.

Clear cell carcinoma of the ovary (CCC) is a histologic subtype of epithelial ovarian cancer with a distinct clinical behavior. There are marked geographic differences in the prevalence of CCC. The CCC is more likely to be detected at an early stage than high-grade serous cancers, and when confined within the ovary, the prognosis is good. However, advanced disease is associated with a very poor prognosis and resistance to standard treatment. Cytoreductive surgery should be performed for patients with stage II, III, or IV disease. An international phase III study to compare irinotecan/cisplatin and paclitaxel/carboplatin as adjuvant chemotherapy for stage IIV CCC has completed enrollment (GCIG/JGOG3017). Considering the frequent PIK3CA mutation in CCC, dual inhibitors targeting PI3K, AKT in the mTOR pathway, are promising. Performing these trials and generating the evidence will require considerable international collaboration.

Objective: Although the healing response after carotid balloon injury and carotid patch angioplasty injury has been well-documented in animal models, there is limited information about this process after carotid endarterectomy (CEA) in human patients., Case Description: We describe the autopsy results of a 79-year-old man who died 18 days after CEA with patch angioplasty. The treated carotid artery had an adequate luminal diameter. Elastica-Masson staining revealed that the treated portion was covered with neointima but the patch graft was exposed to the arterial lumen at 18 days after CEA. Immunohistochemistry staining for alpha-smooth muscle actin (α-SMA), von-Willebrand factor, and vascular endothelial growth factor receptor-2 revealed that the neointima was mainly composed of α-SMA-positive cells. In addition, the α-SMA-rich neointima had many more Ki-67-positive cells than did the internal carotid artery intima in the area beyond the CEA-treated portion., Conclusions: This case report is the first to describe an entire carotid artery specimen in the acute stage after CEA with patch angioplasty. These findings suggest that an α-SMA-rich neointima with prominent proliferative activity covers the inner surface of the treated carotid artery, but patch grafts are left uncovered. The intrinsic arterial wall may have an important role in intimal regeneration after CEA, although the nature of the neointima and the mechanism by which it regulates proliferative activity remain unclarified., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism., Methods: Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided., Results: TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P = .006), advanced clinical stage (χ(2) test, P = .01), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P < .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (χ(2) test, P < .001), elevated serum G-CSF levels (Student t test, P = .03), larger spleens (Student t test, P = .045), and increased MDSC frequencies in the blood (Student t test, P < .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P = .008 and P = .02, respectively)., Conclusions: TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The objective of this study was to investigate the chemotherapeutic agents that produce the strongest synergistic effects when combined with trabectedin against ovarian clear cell carcinoma (CCC), which is regarded as an aggressive chemoresistant histological subtype., Methods: Using 4 human CCC cell lines (RMG1, RMG2, KOC7C, and HAC2), the cytotoxicities of trabectedin, SN-38, topotecan, doxorubicin, cisplatin, and paclitaxel as single agents were first assessed using the MTS assay. Then, the cytotoxicities of combination treatments involving trabectedin and 1 of the other 4 agents were evaluated by isobologram analysis to examine whether these combinations displayed synergistic, additive, or antagonistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines, which were derived from the parental CCC cells by continuously exposing them to cisplatin or paclitaxel. Finally, we determined the effect of everolimus on the antitumor efficacy of trabectedin-based combination chemotherapy., Results: Concurrent exposure to trabectedin and SN-38 or topotecan resulted in synergistic interactions in all 4 CCC cell lines. Among the tested combinations, trabectedin plus SN-38 was the most effective cytotoxic regimen. The combination of trabectedin plus SN-38 also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Treatment with everolimus significantly enhanced the antitumor activity of trabectedin plus SN-38 or topotecan., Conclusions: Combination treatment with trabectedin and SN-38 displays the greatest cytotoxic effect against ovarian CCC. Our in vitro study provides the rationale for future clinical trials of trabectedin plus irinotecan with or without everolimus in patients with ovarian CCC in both the front-line chemotherapy setting and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel.

Objective: Recent studies have demonstrated that lymphovascular space invasion (LVSI) is associated with increased risk of hematogenous and lymphatic metastasis and poor clinical outcome of women with epithelial ovarian cancer. Given the suspected role of estrogen in promoting ovarian cancer metastasis, we examined potential links between estrogen receptor and LVSI in high-grade serous ovarian carcinoma., Methods: Tumoral expression of ER, PR, p53, MDR1, EGFR, HER2, DNA ploidy, and S-phase fraction was examined for 121 cases of stage I-IV high-grade serous ovarian carcinoma samples obtained at primary cytoreductive surgery. Biomarker expression was correlated to LVSI and survival outcomes., Results: LVSI was observed in 101 (83.5%) of all cases. Immunohistochemistry of tested biomarkers showed ER (86.7%) to be the most commonly expressed followed by p53 (71.4%), HER2 (68.3%), EGFR (52.1%), MDR-1 (14.3%), and PR (8.9%). ER expression was positively correlated to PR expression (r=0.31, p=0.001). LVSI was only correlated with ER (odds ratio 6.27, 95%CI 1.93-20.4, p=0.002) but not with other biomarkers. In multivariate analysis, ER remained significantly associated with LVSI (p=0.039). LVSI remained a significant prognostic factor for decreased progression-free survival (HR 3.01, 95%CI 1.54-5.88, p=0.001) and overall survival (HR 2.69, 95%CI 1.18-6.23, p=0.021) while ER-expression did not remain as a significant variable in multivariate analysis., Conclusion: Our data demonstrated that estrogen receptor was positively correlated with LVSI that was an independent prognostic indicator of poor survival outcomes of high-grade serous ovarian carcinoma. This study emphasizes the importance of estrogen pathway in promoting lymphatic or vascular spread of high-grade serous ovarian carcinoma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of lymphovascular space invasion on survival of patients with early-stage epithelial ovarian cancer., Methods: A multicenter retrospective study was conducted for patients with stage IA-C epithelial ovarian cancer who underwent primary comprehensive surgery including lymphadenectomy. Histopathology slides for ovarian tumors were examined by gynecologic pathologists for the presence or absence of lymphovascular space invasion. Survival analysis was performed examining tumoral factors., Results: A total of 434 patients were included in the analysis. Lymphovascular space invasion was detected in 76 (17.5%) patients associated with histology (P=.042) and stage (P=.044). Lymphovascular space invasion was significantly associated with decreased survival outcomes (disease-free survival, 5-year rate 78.4% compared with 90.7%, P=.024 and overall survival, 84.9% compared with 93.2%, P=.031) in univariate analysis. In multivariate analysis, lymphovascular space invasion did not remain a significant variable for disease-free survival (hazard ratio [HR] 1.98, 95% confidence interval [CI] 0.97-3.97, P=.059) or overall survival (HR 2.41, 95% CI 0.99-5.85, P=.052). Lymphovascular space invasion was associated with increased risk of hematogenous and lymphatic metastasis (HR 4.79, 95% CI 1.75-13.2, P=.002) but not peritoneal metastasis (P=.33) in multivariate analysis. Among lymphovascular space invasion-expressing tumors, patients who received fewer than six cycles of postoperative chemotherapy had significantly poorer disease-free survival than those who received six or more cycles (HR 4.59, 95% CI 1.20-17.5, P=.015)., Conclusion: Lymphovascular space invasion is an important histologic feature to identify a subgroup of patients with increased risk of recurrence in stage I epithelial ovarian cancer., Level of Evidence: III.

Sex-cord stromal tumors (SCSTs) are rare ovarian cancers and their behavior during pregnancy is not well understood. To evaluate the maternal and fetal outcomes of pregnancy complicated by ovarian SCST, a systematic literature search was conducted in PubMed/MEDLINE using entry key words "pregnancy" and each type of ovarian SCST ("sex cord stromal tumor," "granulosa cell tumor," "thecoma," "Sertoli-Leydig cell tumor," or "gynandroblastoma") between 1955 and 2012 that identified 46 cases eligible for the analysis. Clinical characteristics, pregnancy outcome, tumor characteristics, and survival outcomes were evaluated. Serious adverse events were defined as complications related to the SCST that resulted in severe morbidity or mortality for mother, fetus, or both. The most common histology was granulosa cell tumor (22.0%), followed by thecoma (18.6%) and Sertoli-Leydig cell tumor (8.5%). Abdomino-pelvic pain (45.7%), palpable mass (30.4%), and virilization (26.1%) were the three most common symptoms. The majority were stage I (76.1%), tumor size <15cm (64.9%), and underwent unilateral adnexectomy (80.4%). Fetal conservation surgery was seen in 54.3%. Most cases had live births (78.3%) at full term (60.9%). Among cases proceeded expectant delay of delivery (45.7%), most cases resulted in live birth (95.2%) with median expectant interval of 20.7 weeks. Maternal and/or fetal serious adverse events (SAEs) were observed in 41.3% with maternal shock/hemoperitoneum being the most common complication (13.0%). Logistic regression test identified younger age (<30 versus ≥30, 73.3% versus 26.7%, odds ratio [OR] 11.7, 95%CI 1.35-101, p=0.026), large tumor (size ≥15cm versus <15cm, 64.9% versus 35.1%, OR 10.0, 95%CI 1.29-26.2, p=0.004), and advanced-stage (stages II-IV versus I, 76.1% versus 23.9%, OR 5.82, 95%CI 2.05-48.9, p=0.022) as risk factors of increased SAE. Overall survival of patients diagnosed with ovarian SCST during pregnancy was comparable to ovarian SCST not related to pregnancy (5-year rate, stages I and II-IV, 100% and 70.0%, respectively). In conclusion, although the majority of cases resulted in live birth, ovarian SCST-complicated pregnancy falls into the category of high-risk pregnancy. Risk factors for SAE identified in our study will help to guide strategic management of pregnancy complicated by ovarian SCST., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study aimed to evaluate the effectiveness and feasibility of reirradiation using high-dose-rate interstitial brachytherapy (HDR-ISBT) in patients with recurrent cervical cancer., Methods: The records of 52 consecutive women with central pelvic recurrence who were salvaged with HDR-ISBT-based reirradiation were retrospectively reviewed. Data regarding the primary disease, follow-up findings, recurrence, the treatment outcome, and toxicities were collected. Multivariate analysis was performed using the Cox proportional hazards regression model to identify predictors of the response to HDR-ISBT. Survival rate was calculated using the Kaplan-Meier method and compared using the log-rank test., Results: A total of 52 patients who had been treated with HDR-ISBT-based reirradiation were included in our database. The local control rate was 76.9% (40/52), and the median postrecurrence survival period was 32 months. Grade 3 or 4 late toxicities were observed in 13 patients (25%). Multivariate analysis revealed that tumor size and the treatment-free interval were significant poor prognostic factors of postrecurrence survival. In a comparison between the patients who were salvaged with HDR-ISBT-based reirradiation (ISBT group) and those who were treated with palliative therapy alone (palliative group), we found that among the patients who displayed 0 or 1 poor prognostic factors, the patients in the ISBT group survived significantly longer than those in the palliative group. In contrast, similar survival rates were seen in both groups among the patients with 2 or more poor prognostic factors., Conclusions: Reirradiation using HDR-ISBT is effective and feasible in patients with recurrent cervical cancer. Our 2-clinical variable prognostic model might enable physicians to identify patients who would not derive clinical benefit from HDR-ISBT and offer them the opportunity to receive other types of treatment.

Intrauterine infection is still a common trigger of preterm delivery (PTD) and also a determinant risk factor for the subsequent development of neurodevelopmental abnormalities in neonates. In this study, we examined the expressional pattern of various inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in placentae complicated with severe chorioamnionitis (CAM) and found that IL-6 is mainly expressed in macrophages in villous mesenchyme by immunohistochemical analysis with anti-CD-68 antibody. Using an experimental lipopolysaccharide (LPS)-induced PTD model, the therapeutic potential of targeting this cytokine was investigated. Anti-IL-6 receptor antibody (MR16-1) was delivered 6 h before LPS treatment. Mice in the MR16-1 group had a significantly lower rate of PTD (17%) than in the controls (53%, P = 0.026). As a result, MR16-1 treatment significantly prolonged the gestational period (control; 18.4 ± 1.7d, MR16-1; 19.8 ± 1.5d, P = 0.007) without any apparent adverse events on the mice and their pups. In primary human amniotic epithelial cells, pretreatment with a humanized anti-human IL-6 receptor antibody, tocilizumab, significantly inhibited the production of prostaglandin E2 induced by IL-6. In conclusion, IL-6 was strongly expressed mainly in macrophages in villous mesenchyme in placentae complicated with CAM. Anti-IL-6R antibody significantly decreased the rate of PTD in LPS-induced inflammatory model in mice, and inhibited PGE2 production from human primary amniotic epithelial cells. Targeting IL-6 signaling could be a promising option for the prevention of PTD and needs to be further explored for future clinical application.

Objective: To investigate the utility of serum squamous cell carcinoma antigen (SCC-Ag) levels upon the diagnosis of recurrent cervical cancer for decision making in patient management., Methods: Clinical records from 167 cervical cancer patients who developed recurrence between April 1996 and September 2010 were reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of serum SCC-Ag levels at the time of recurrence. The effects of various salvage treatments on survival outcomes of recurrent cervical cancer were examined with respect to serum SCC-Ag levels., Results: Serum SCC-Ag levels were elevated (>2.0 ng/mL) in 125 patients (75%) when recurrence was diagnosed. These patients exhibited significantly shorter postrecurrence survival than those with normal SCC-Ag levels (log-rank; p=0.033). Multivariate analyses revealed that an elevated serum SCC-Ag level was an independent prognostic factor for poor postrecurrence survival. In patients with SCC-Ag levels <14.0 ng/mL, radiotherapy or surgery resulted in improved survival compared with chemotherapy or supportive care. In contrast, in patients with SCC-Ag levels of ≥14.0 ng/mL, salvage treatment with radiotherapy had only a minimal impact on postrecurrence survival., Conclusion: The serum SCC-Ag level measured when cervical cancer recurrence is diagnosed can be useful for deciding upon the appropriate salvage treatment.

Objectives: This paper analyzes Avahan, an HIV prevention program in India, that achieved very rapid scale-up. The paper aims to (i) define the distinctive features of the management of Avahan, (ii) examine how the distinctive features relate to key constructs in management frameworks and (iii) investigate how the management approaches of Avahan contributed to the program's ability to scale-up rapidly while maintaining service quality., Design, Setting and Participants: The Delphi method was used to identify the distinctive features of Avahan. Through three rounds of questions, 38 participants closely associated with Avahan were asked to identify and develop consensus on its distinctive features. These features were then mapped against the Baldrige Health Care Criteria for Performance Excellence to investigate how they related to important dimensions of management., Results: A total of 17 distinctive features of Avahan were identified. These distinctive features emphasized the importance of data use and performance monitoring at all levels, especially combined with a flexible management style that facilitated local responsiveness to community, innovation and learning. The distinctive features comprehensively addressed the criteria for management excellence in the Baldridge framework., Conclusions: In the case of Avahan, the rigorous application of known management techniques to public health programs appears to have been an important factor in the successful scale-up of the program. Also, the Baldrige criteria seem applicable to health programs in low-income and middle-income countries; further applications would help test their robustness and utility in such contexts., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objectives: The objective of this study was to determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLTs) of intravenous carboplatin plus paclitaxel combined with intensity-modulated pelvic radiotherapy (pelvic IMRT) as an adjuvant treatment for early-stage cervical cancer patients with positive pelvic lymph nodes., Methods: Women with uterine cervical cancer who were treated with radical hysterectomy and pelvic lymphadenectomy and displayed positive pelvic lymph nodes were eligible for this study. The patients were postoperatively treated with pelvic IMRT (50.4 Gy). The concurrent weekly chemotherapy consisted of carboplatin (area under the curve [AUC], 2) and paclitaxel (starting at 35 mg/m² and escalating by 5 mg/m² in 3 patient cohorts). The primary end point of the escalation study was acute DLT that occurred within 30 days of the completion of radiation therapy., Results: Nine patients were enrolled and treated at 2 dose levels until DLT occurred. The median age of the patients was 47 years (range, 28-66 years). The median radiotherapy treatment time was 39.5 days (range, 38-64 days). At dose level I (35 mg/m² paclitaxel), 2 grade 3 leukopenia and a neutropenia were observed, but no DLT occurred. At dose level II (40 mg/m² paclitaxel), the first patient experienced a grade 2 hypersensitive reaction, which resulted in discontinuation of planned treatment. Thus, 2 more patients were evaluated at this dose level. Of these, 1 patient experienced febrile neutropenia, which was considered to be a DLT, and the other patient experienced long-lasting grade 3 leukopenia and grade 3 neutropenia, which resulted in the discontinuation of chemotherapy for 2 weeks (a DLT). We then evaluated 3 more patients at dose level 1, but no DLT occurred. The MTD of paclitaxel and carboplatin was thus defined as 35 mg/m² and an AUC of 2.0, respectively., Conclusions: Weekly paclitaxel/carboplatin and pelvic IMRT is a reasonable adjuvant treatment regimen for cervical cancer patients after radical hysterectomy. The MTD of paclitaxel and carboplatin for future phase II trials of this regimen is 35 mg/m² and an AUC of 2.0, respectively.

The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.

Granulocyte colony-stimulating factor (G-CSF)-producing nonhematopoietic malignancies have been reported in various organs, and most of them have been associated with poor clinical outcome. However, because of the rarity of reported cases, information regarding G-CSF-producing gynecological malignancies, especially uterine corpus cancer, is limited. We report a case of G-CSF-producing endometrial cancer, which exhibited a grave clinical outcome. Our case strongly indicates the aggressive nature of G-CSF-producing endometrial cancer., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Ovarian cancer is characterized by widespread peritoneal dissemination and ascites and has a cure rate of only 30%. As has been previously reported, integrin α5 plays a key role in the peritoneal dissemination of ovarian cancer. Our aim was to identify a new miRNA that regulates integrin α5 expression and analyze the therapeutic potential of targeting this miRNA. By using an IHC analysis, we proved that high integrin α5 expression correlates with a poor prognosis in Japanese patients with International Federation of Gynecology and Obstetrics stage III ovarian cancer. Based on an miRNA algorithm search, we identified hsa-mir-92a (miR-92a) as a candidate. The level of miR-92a expression was significantly inversely correlated with ITGA5 expression in various cancer cells. Transfection of precursor miR-92a reduced integrin α5 expression in ovarian cancer cells, which was accompanied by the inhibition of cancer cell adhesion, invasion, and proliferation. miR-92a overexpression reduced the luciferase activity of the ITGA5 3'-untranslated region, suggesting that ITGA5 mRNA is a direct target of miR-92a. In in vivo ovarian cancer xenografts, the enforced expression of miR-92a in HeyA-8 cells suppressed peritoneal dissemination. Although we still have a long way to go before an effective and nontoxic miRNA-based cancer therapy can be introduced into the clinic, the inhibition of integrin α5 expression by targeting miR-92a needs to be explored further for future applications in ovarian cancer treatment., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate dose-volume histogram (DVH) predictors for the development of chronic gastrointestinal (GI) complications in cervical cancer patients who underwent radical hysterectomy and postoperative concurrent nedaplatin-based chemoradiation therapy., Methods and Materials: This study analyzed 97 patients who underwent postoperative concurrent chemoradiation therapy. The organs at risk that were contoured were the small bowel loops, large bowel loop, and peritoneal cavity. DVH parameters subjected to analysis included the volumes of these organs receiving more than 15, 30, 40, and 45 Gy (V15-V45) and their mean dose. Associations between DVH parameters or clinical factors and the incidence of grade 2 or higher chronic GI complications were evaluated., Results: Of the clinical factors, smoking and low body mass index (BMI) (<22) were significantly associated with grade 2 or higher chronic GI complications. Also, patients with chronic GI complications had significantly greater V15-V45 volumes and higher mean dose of the small bowel loops compared with those without GI complications. In contrast, no parameters for the large bowel loop or peritoneal cavity were significantly associated with GI complications. Results of the receiver operating characteristics (ROC) curve analysis led to the conclusion that V15-V45 of the small bowel loops has high accuracy for prediction of GI complications. Among these parameters, V40 gave the highest area under the ROC curve. Finally, multivariate analysis was performed with V40 of the small bowel loops and 2 other clinical parameters that were judged to be potential risk factors for chronic GI complications: BMI and smoking. Of these 3 parameters, V40 of the small bowel loops and smoking emerged as independent predictors of chronic GI complications., Conclusions: DVH parameters of the small bowel loops may serve as predictors of grade 2 or higher chronic GI complications after postoperative concurrent nedaplatin-based chemoradiation therapy for early-stage cervical cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To identify groups of patients who derive clinical benefit from postoperative adjuvant concurrent chemoradiotherapy (CCRT), we retrospectively investigated the survival outcomes of surgically treated early-stage cervical cancer patients., Methods: We reviewed the medical records of 316 patients with FIGO stage IB1-IIB cervical cancer who had been treated with adjuvant radiotherapy (RT) (n = 124, RT group) or adjuvant CCRT (n = 192, CCRT group) after radical hysterectomy between January 1996 and December 2009. Of these, 187 patients displayed high-risk prognostic factors (high-risk group), and 129 displayed intermediate-risk prognostic factors (intermediate-risk group). Sixty patients with 1 intermediate-risk prognostic factor who received no adjuvant therapy were also identified and used as controls (NFT group). Survival was calculated using the Kaplan-Meier method and compared using the log-rank test., Results: In the high-risk group, adjuvant CCRT was significantly superior to RT alone with regard to recurrence rate, progression-free survival (PFS), and overall survival. In the intermediate-risk group, CCRT was superior to RT with regard to recurrence rate and PFS in patents with 2 or more risk factors. Among the patients with only 1 intermediate-risk factor, although no survival benefit of CCRT over RT was observed, addition of adjuvant treatment resulted in significantly improved PFS compared with the NFT group in patients with deep stromal invasion (log-rank, P = 0.012)., Conclusions: Postoperative CCRT improved the prognosis of FIGO stage IB1-IIB cervical cancer patients in the high-risk group and patients who displayed 2 or more intermediate-risk factors. Patients who displayed deep stromal invasion alone also derived clinical benefit from adjuvant treatment.

Objectives: The aim of this study was to investigate the prognostic significance of elevated white blood cell (WBC) count at the time of the diagnosis of cervical cancer recurrence., Methods: The baseline characteristics and outcome data of 219 patients who had a diagnosis of recurrent cervical cancer between April 1996 and September 2010 were collected and reviewed. Survival after recurrence was compared between the leukocytosis group (WBC ≥9000/μL) and the nonleukocytosis group (WBC <9000/μL). A Cox proportional hazards regression model was used to investigate the prognostic significance of elevated WBC count in patients with recurrent cervical cancer., Results: The patients in the leukocytosis group showed significantly shorter disease-free interval (P = 0.0005) and more frequently had multiple recurrences (P = 0.0101) than those in the nonleukocytosis group. The median survival after recurrence of the patients with elevated WBC count was 9 months, which was significantly shorter than the 21 months observed in the patients without normal WBC count (log rank; P < 0.0001). Multivariate analyses revealed that clinical stage, tumor diameter, histology, an elevated WBC count (≥9000/μL), and an elevated neutrophil count (≥6500/μL) were significant prognostic factors in survival after recurrence., Conclusion: The elevated WBC count at the time of the diagnosis of recurrence is an independent prognostic factor in patients with recurrent cervical cancer.

Objectives: To evaluate the significance of adenosquamous carcinoma (ASC) compared with adenocarcinoma (AC) in the survival of surgically treated early-stage cervical cancer., Methods: We retrospectively reviewed the medical records of 163 patients with International Federation of Gynecology and Obstetrics stage IA2 to stage IIB cervical cancer who had been treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to the following: (1) histological subtype (ASC group or AC group) and (2) pathological risk factors (low-risk or intermediate/high-risk group). Survival was evaluated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis of progression-free survival (PFS) was performed using the Cox proportional hazards regression model to investigate the prognostic significance of histological subtype., Results: Clinicopathological characteristics were similar between the ASC and AC histology groups. Patients with the ASC histology displayed a PFS rate similar to that of the patients with the AC histology in both the low-risk and intermediate/high-risk groups. Neither the recurrence rate nor the pattern of recurrence differed between the ASC group and the AC group. Univariate analysis revealed that patients with pelvic lymph node metastasis and parametrial invasion achieved significantly shorter PFS than those without these risk factors., Conclusions: Characteristics of the patients and the tumors as well as survival outcomes of ASC were comparable to adenocarcinoma of early-stage uterine cervix treated with radical hysterectomy. Our results in part support that the management of ASC could be the same as the one of AC of the uterine cervix.

Objectives: To evaluate the significance of adenocarcinoma (AC) compared with squamous cell carcinoma (SCC) with regard to the survival of surgically-treated early stage cervical cancer patients., Methods: We retrospectively reviewed the medical records of 520 patients with FIGO stage IA2-IIB cervical cancer who were treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to (i) pathological risk factors (low-, intermediate-, or high-risk group) and (ii) adjuvant radiotherapy (concurrent chemoradiotherapy [CCRT group] or radiotherapy alone [RT group]). Survival outcomes were examined by Kaplan-Meier method and compared with Log-rank test. Multivariate analysis for disease-specific survival (DSS) was performed using Cox proportional hazards regression model to investigate the prognostic significance of histological subtype., Results: AC histology was associated with significantly decreased DSS compared with SCC histology in the intermediate- and high-risk groups (hazard ratio: 3.06 and 2.88, respectively, both P<0.05) while there was no survival difference in the low-risk group (P=0.1). Among patients who received any types of adjuvant radiotherapy, DSS of AC histology patients were significantly poorer than SCC histology. Multivariate analysis demonstrated AC histology to be an independent predictor of decreased DSS in both CCRT and RT groups. Moreover, pelvic nodal metastasis significantly predicted the poor survival of patients with AC histology who received CCRT in multivariate analysis, Conclusions: Adenocarcinoma is an independent prognostic indicator of poor survival in early stage cervical cancer patients with intermediate- and high-risk factors, regardless of the type of adjuvant radiotherapy after radical hysterectomy., (Copyright © 2012. Published by Elsevier Inc.)

While the prognostic significance of lymphovascular space invasion (LVSI) is well established in endometrial and cervical cancer, its role in ovarian cancer is not fully understood. First, a training cohort was conducted to explore whether the presence and quantity of LVSI within the ovarian tumor correlated with nodal metastasis and survival (n = 127). Next, the results of the training cohort were applied to a different study population (validation cohort, n = 93). In both cohorts, histopathology slides of epithelial ovarian cancer cases that underwent primary cytoreductive surgery including pelvic and/or aortic lymphadenectomy were examined. In a post hoc analysis, the significance of LVSI was evaluated in apparent stage I cases (n = 53). In the training cohort, the majority of patients had advanced-stage disease (82.7%). LVSI was observed in 79.5% of cases, and nodal metastasis was the strongest variable associated with the presence of LVSI (odds ratio [OR]: 7.99, 95% confidence interval [CI]: 1.98-32.1, P = 0.003) in multivariate analysis. The presence of LVSI correlated with a worsened progression-free survival on multivariate analysis (hazard ratio [HR]: 2.06, 95% CI: 1.01-4.24, P = 0.048). The significance of the presence of LVSI was reproduced in the validation cohort (majority, early stage 61.3%). In apparent stage I cases, the presence of LVSI was associated with a high negative predictive value for nodal metastasis (100%, likelihood ratio, P = 0.034) and with worsened progression-free survival (HR: 5.16, 95% CI: 1.00-26.6, P = 0.028). The presence of LVSI is an independent predictive indicator of nodal metastasis and is associated with worse clinical outcome of patients with epithelial ovarian cancer.

Purpose: We investigated the role of physical examination, CT scan, chest X-ray, and Pap smear in the routine follow-up program for cervical cancer patients previously treated with radiotherapy., Methods: The records of women who had developed recurrent cervical cancer after radiotherapy were retrospectively reviewed. The optimal procedure for the detection of recurrence was evaluated according to the disease-free interval (DFI). Survival analysis was performed based on the Kaplan-Meier method and comparisons between groups were made using the log-rank test., Results: A total of 146 recurrent cervical cancer patients were included in our database. The majority of recurrences were diagnosed either by symptoms, physical examination, or CT scan. The patients whose recurrent disease was detected by Pap smear, physical examination, or CT scan had a significantly longer survival than those detected by symptoms. When analyzed according to DFI, physical examination, and CT scan led to the detection of recurrence in patients with a DFI of 1-5 years. In contrast, chest X-ray and Pap smear only had a clinical impact on the diagnosis of recurrence in patients with a DFI of 1-2 years., Conclusions: Chest X-ray and Pap smear can be routinely performed for the first 2 years after radiotherapy, but can be omitted or used sparingly thereafter.

Thermally assisted hydrolysis and methylation-gas chromatography (THM-GC) in the presence of trimethylsulfonium hydroxide, using a vertical microfurnace pyrolyzer, was validated for the compositional analysis of fatty acid components in microalgae. The chromatograms of a microalga, Pavlova lutheri , obtained under optimized THM conditions clearly showed a series of fatty acid methyl esters including thermally labile polyunsaturated fatty acid components. On the basis of these peak areas, their chemical compositions were rapidly determined without using any tedious sample pretreatment with a precision of <8% relative standard deviation. Moreover, the compositions thus obtained were in good agreement with those obtained by the conventional technique involving solvent extraction. Finally, the THM-GC technique was applied for the compositional analysis of fatty acid components in a newly found microalga, Coccomyxa gloeobotrydiformis . The obtained data showed a high abundance (24 mol %) of α-linolenic acid components, suggesting its potential usefulness as feed sources and/or functional foods.

Objective: The aim of this study was to identify predictors of the response to paclitaxel-carboplatin chemotherapy (TC) in recurrent or patients with advanced cervical cancer., Methods: The records of 61 consecutive women with recurrent or advanced cervical cancer who were treated with TC were retrospectively reviewed. Data regarding their primary disease, follow-up, recurrence, and the activity and toxicity of TC were collected. Multivariate analysis was performed using the Cox proportional hazards regression model to identify predictors of the response to TC. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test., Results: Overall, TC was well tolerated and displayed a response rate of 60.7% (19 complete response and 18 partial response). The median progression-free survival was 14 months for all patients and 20 months for the responders. Grade 3 to grade 4 toxicities were observed in 51 patients (83.6%). Multivariate analysis revealed that performance status, symptom status, and prior chemotherapy were independent prognostic predictors of a poor response. Patient survival was inversely correlated with the number of these prognostic factors. When the patients were divided into 2 prognostic groups (low risk: patients with no or one poor prognostic factor; and high-risk: patients with 2 or more poor prognostic factors), the patients in the high-risk group had a significantly shorter progression-free survival than those in the low-risk group (4 vs 16 months, log-rank; P < 0.0001)., Conclusions: The combination of paclitaxel and carboplatin is effective in patients with recurrent or advanced cervical cancer. Our prognostic model composed of 3 clinical variables might enable physicians to identify patients who would not derive clinical benefit from TC and offer them the opportunity to receive other types of treatment.

Objective: We investigated the prognostic significance of multiple pelvic node metastases in cervical cancer patients who were treated with radical hysterectomy plus adjuvant chemoradiotherapy., Methods: We retrospectively reviewed the medical records of 311 patients with International Federation of Gynecology and Obstetrics stage IB1-IIB cervical cancer who had been treated with radical hysterectomy plus adjuvant radiotherapy (RT) between January 1998 and December 2008. Of these, 119 received adjuvant RT and 192 received adjuvant concurrent chemoradiotherapy (CCRT) postoperatively. Multivariate analysis for progression-free survival (PFS) was performed using the Cox proportional hazards regression model to investigate the prognostic significance of pelvic node metastases in the 2 treatment groups. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test., Results: Multivariate analysis demonstrated pelvic node metastasis to be an independent prognostic factor for shorter PFS in both treatment groups. When the node-positive patients were analyzed according to the number of positive pelvic nodes, we found that the patients with multiple pelvic node metastases (≥3) displayed significantly shorter PFS than those with 1 or 2 pelvic node metastases in the RT group. In contrast, in the CCRT group, the PFS of the patients with multiple pelvic node metastases (≥3) was similar to that observed of the patients with 1 or 2 pelvic node metastases., Conclusions: The presence of multiple pelvic node metastases was not an independent predictor of shorter PFS in the CCRT group.

We report a case of longstanding asymptomatic direct carotid-cavernous fistula (CCF) which caused fatal subarachnoid hemorrhage (SAH). A 91-year-old female with no history of previous head trauma and optic symptoms presented acute subarachnoid hemorrhage. Angiography revealed a left direct carotid-cavernous fistula draining only into the contralateral cavernous sinus with leptomeningeal venous reflux and small varix on the pontine bridging vein. The affected cavernous sinus was markedly dilated and there was no septum between the left cavernous sinus and the internal carotid artery. The patient underwent transvenous coil embolization for intercavernous sinus and leptomeningeal venous reflux was successfully obliterated and opacification of the varix was diminished. The past history of this patient and angiographical findings strongly suggest long standing asymptomatic CCF caused SAH.

An 86-year-old female presented with rare bilateral chronic subdural hematomas (CSHs) of the posterior fossae which were successfully treated by surgical intervention. She had experienced mild head trauma one month before admission. She was transferred to our hospital because of consciousness disturbance and tetraparesis. Magnetic resonance (MR) imaging showed simultaneous occurrence of supratentorial and infratentorial CSHs. We tried to evacuate the CSHs of the bilateral posterior fossae because brainstem compression was markedly severe. Through bilateral burr-hole trepanations, chocolate-colored fluid, not containing clotted components, gushed out under great pressure. Postoperative course was uneventful. MR imaging revealed that the CSHs of the posterior fossae had completely disappeared and brainstem compression had also improved. The patient's neurological deficits were immediately improved after the operation. The patient was discharged one month after the operation for further rehabilitation. Trepanation and evacuation of the hematoma through the posterior fossa might be one of the therapeutic options for posterior fossa CSH, which is similar to supratentorial CSH. However, we considered that the emergency of this rare entity and the method of anesthesia were quite different from supratentorial CSH.

A 68-year-old man presented with severe conscious disturbance caused by pituitary apoplexy resulting in massive intracerebral hemorrhage (ICH). He had been periodically followed up for asymptomatic pituitary adenoma at another hospital for 8 years. Neuroimaging examination revealed pituitary apoplexy and massive ICH located in the left frontal lobe, and the ICH was directly connected to the intratumoral hemorrhage. The diagnosis was massive ICH from pituitary apoplexy. The patient underwent emergent evacuation of hematoma and removal of the pituitary adenoma via bi-frontal craniotomy. Postoperatively, he continued to exhibit deep consciousness disturbance and died 1 month after the operation. Pituitary apoplexy is usually characterized by intra-tumoral hemorrhage. The treatment strategy for asymptomatic pituitary adenoma is still controversial. This case shows that we should always consider the risk of pituitary apoplexy manifesting as ICH which may cause a fatal outcome.

Objectives: The aim of this study was to compare the treatment outcomes and adverse effects of radical hysterectomy followed by adjuvant radiotherapy with definitive radiotherapy alone in patients with FIGO stage IIB cervical cancer., Methods: We retrospectively reviewed the medical records of FIGO stage IIB cervical cancer patients who were treated between April 1996 and December 2009. During the study period, 95 patients were treated with radical hysterectomy, all of which received adjuvant radiotherapy (surgery-based group). In addition, 94 patients received definitive radiotherapy alone (RT-based group). The recurrence rate, progression-free survival (PFS), overall survival (OS), and treatment-related complications were compared between the two groups., Results: Radical hysterectomy followed by adjuvant radiotherapy resulted in comparable recurrence (44.2% versus 41.5%, p=0.77), PFS (log-rank, p=0.57), and OS rates (log-rank, p=0.41) to definitive radiotherapy alone. The frequencies of acute grade 3-4 toxicities were similar between the two groups (24.2% versus 24.5%, p=1.0), whereas the frequencies of grade 3-4 late toxicities were significantly higher in the surgery-based group than in the RT-based group (24.1% versus 10.6%, p=0.048). Cox multivariate analyses demonstrated that treatment with surgery followed by adjuvant radiotherapy was associated with an increased risk of grade 3-4 late toxicities, although the statistical significance of the difference was marginal (odds ratio 2.41, 95%CI 0.97-5.99, p=0.059)., Conclusions: Definitive radiotherapy was found to be a safer approach than radical hysterectomy followed by postoperative radiotherapy with less treatment-related complications and comparable survival outcomes in patients with FIGO stage IIB cervical cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype., Experimental Design: Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel-resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo., Results: Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin., Conclusion: Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC.

Objectives: The aim of this study was to investigate the prognostic value of pretreatment leukocytosis in patients with cervical cancer in relation to well-established conventional risk factors., Methods: The baseline characteristics and outcome data from 536 patients treated for cervical cancer between 1996 April to 2007 March were collected and reviewed. Cox proportional hazards regression model was used to identify independent prognostic factors for overall survival. Subsequently, the prognostic significance of pretreatment WBC count was prospectively investigated in 156 patients newly diagnosed cervical cancer from 2007 April to 2010 March., Results: In a retrospective analysis, patients with leukocytosis (WBC ≥ 10,000/μl) showed significantly higher treatment failure rate (P < 0.0001) and shorter OS (P < 0.0001) than the patients without leukocytosis. Tumors from patients with leukocytosis showed significantly stronger immunoreactivity for G-CSF than those obtained from patients without leukocytosis. Multivariate analyses revealed that clinical stage, tumor diameter, histology, and elevated WBC count (≥ 10,000/μl) were significant prognostic factors in terms of overall survival. In a prospective investigation, patients with leukocytosis showed significantly higher treatment failure rate (P < 0.0001), shorter PFS (P < 0.0001), and higher serum G-CSF concentrations (p = 0.001) than the patients without leukocytosis. Multivariate analyses revealed that clinical stage, tumor diameter, and elevated WBC count were significant prognostic factors in terms of PFS., Conclusion: Pretreatment leukocytosis is an independent prognostic factor in patients with cervical cancer. Our finding can be used to identify patients with poor prognosis and to design future tailored clinical trials., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to compare the efficacy of postoperative pelvic radiotherapy plus concurrent chemotherapy with that of extended-field irradiation (EFRT) in patients with FIGO Stage IA2-IIb cervical cancer with multiple pelvic lymph node metastases., Methods: We retrospectively reviewed the medical records of patients with FIGO Stage IA2-IIb cervical cancer who had undergone radical surgery between April 1997 and March 2008. Of these, 55 patients who demonstrated multiple pelvic lymph node metastases were treated postoperatively with pelvic radiotherapy plus concurrent chemotherapy (n=29) or EFRT (n=26). Thirty-six patients with single pelvic node metastasis were also treated postoperatively with pelvic radiotherapy plus concurrent chemotherapy. The recurrence rate, progression free survival (PFS), and overall survival (OS) were compared between the treatment groups., Results: Pelvic radiotherapy plus concurrent chemotherapy was significantly superior to EFRT with regard to recurrence rate (37.9% vs 69.2%, p=0.0306), PFS (log-rank, p=0.0236), and OS (log-rank, p=0.0279). When the patients were treated with pelvic radiotherapy plus concurrent chemotherapy, there was no significant difference in PFS or OS between the patients with multiple lymph node metastases and those with single node metastases. With regards to grade 3-4 acute or late toxicities, no statistically significant difference was observed between the two treatment groups., Conclusions: Postoperative pelvic radiotherapy plus concurrent chemotherapy is superior to EFRT for treating patients with FIGO Stage IA2-IIb cervical cancer displaying multiple pelvic lymph node metastases., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Despite the recent advances in the management of cervical cancer using cisplatin-based concurrent chemoradiotherapy, substantial treatment failure still occurs, especially in advanced-stage patients and early-stage cervical cancer patients with high-risk prognostic factors. Therefore, efforts to further improve the survival and quality of life of these patients are necessary. Nedaplatin (cis-diammine-glycoplatinum), a derivative of cisplatin, was developed with the aim of producing a treatment with a similar effectiveness to cisplatin but decreased renal and gastrointestinal toxicities. Based on the promising results of preclinical studies, the clinical efficacy of nedaplatin as a radiosensitizing agent was evaluated in patients with cervical cancer. Retrospective analysis of nedaplatin-based concurrent chemoradiotherapy (CCRT) against cervical cancer suggested that nedaplatin-based CCRT can be considered as an alternative to cisplatin-based CCRT in both early-stage and advanced-stage cervical cancer patients. However, due to the lack of a randomized controlled study, nedaplatin-based CCRT has not been convincingly proven to be clinically effective in patients with cervical cancer. Further investigations in randomized controlled trials are therefore needed.

Granulocyte colony-stimulating factor (G-CSF)-producing nonhematopoietic malignancies have been reported in various organs, and most of them have been associated with poor clinical outcome. However, because of the rarity of the reported cases, information regarding the G-CSF-producing gynecological malignancies is limited. We report the first 2 cases of G-CSF-producing cervical adenocarcinomas, which exhibited an aggressive clinical course. At initial diagnosis, both patients exhibited marked leukocytosis without an obvious sign of infections. Of these, one was initially treated with definitive radiotherapy and the other was treated with radical surgery. However, both of these patients experienced recurrences in a short period and died from disease progression in less than 6 months. According to the facts that the tumor cells were positive for G-CSF, the elevated serum level of G-CSF, and their clinical course correlated well with the white blood cell count, we concluded that these tumors were G-CSF-producing cancers. These cases strongly indicate the aggressive nature of the G-CSF-producing cervical adenocarcinomas.

This study examines the role of vascular endothelial growth factor (VEGF) as a therapeutic target in clear cell carcinoma (CCC) of the ovary, which has been regarded as a chemoresistant histologic subtype. Immunohistochemical analysis using tissue microarrays of 98 primary ovarian cancers revealed that VEGF was strongly expressed both in early-stage and advanced-stage CCC of the ovary. In early-stage CCCs, patients who had tumors with high levels of VEGF had significantly shorter survival than those with low levels of VEGF. In vitro experiments revealed that VEGF expression was significantly higher in cisplatin-refractory human CCC cells (RMG1-CR and KOC7C-CR), compared with the respective parental cells (RMG1 and KOC7C) in the presence of cisplatin. In vivo treatment with bevacizumab markedly inhibited the growth of both parental CCC cell-derived (RMG1 and KOC7C) and cisplatin-refractory CCC cell-derived (RMG1-CR and KOC7C-CR) tumors as a result of inhibition of tumor angiogenesis. The results of the current study indicate that VEGF is frequently expressed and can be a promising therapeutic target in the management of CCC. Bevacizumab may be efficacious not only as a first-line treatment but also as a second-line treatment of recurrent disease in patients previously treated with cisplatin., ((c) 2010 AACR.)

Introduction: The aim of this study was to identify the prognostic factors and to establish a model for the prediction of life expectancy in patients with recurrent cervical cancer that had previously been treated with radiotherapy., Methods: The records of consecutive women with recurrent cervical cancer after radiotherapy were retrospectively reviewed. Primary disease, follow-up, and recurrence data were collected. Univariate and multivariate analyses of prognostic factors of survival were performed., Results: A total of 162 patients were included in our database. The median survival after recurrence was 15 months. Multivariate analysis revealed that symptom status, the site of relapse, prior chemoradiotherapy, and treatment modality were significant prognostic factors in terms of survival after recurrence. Patient survival was inversely correlated with the number of these prognostic factors. When the patients were divided into 3 prognostic groups, (low risk: patients with no poor prognostic factors; intermediate: patients with one poor prognostic factor; and high-risk: patients with more than 2 poor prognostic factors), the patients in the high-risk group had a significantly shorter survival (median, 10 months) than those with one risk factor (median, 20 months) or no risk factors (median, 36 months)., Conclusions: Symptom status, the site of relapse, prior chemoradiotherapy, and treatment modality are significant prognostic factors in patients with recurrent cervical cancer that had previously been treated with radiotherapy. Our prognostic model, composed of 4 clinical variables, may enable physicians to predict survival more accurately.