Kentaro Nakayama

Letrozole as second-line hormonal treatment for recurrent low-grade endometrial stromal sarcoma: A case report and review of the literature

Low-grade endometrial stromal sarcoma (LGESS) is a rare malignancy. The tumor is reportedly responsive to hormonal therapy, most commonly with medroxyprogesterone acetate (MPA), but the effectiveness of aromatase inhibitors for recurrent LGESS remains unclear. The present study reports a case of stage IC LGESS presenting with abnormal uterine bleeding, and also provides a review of the literature. Following a total abdominal hysterectomy and bilateral salpingo-oophorectomy, MPA therapy was initiated; treatment was successful, but discontinued 19 months later due to disruptive side effects. A further 2 months later, the patient presented with recurrent disease and received chemotherapy. MPA treatment was restarted with a partial response. A second recurrence, 4 years later, presented with lung and para-aortic lymph node metastases. The patient responded to treatment with the aromatase inhibitor letrozole. The patient has since exhibited stable disease and remained free of symptoms for 7 years. This case suggests that aromatase-inhibitor treatment may be effective for recurrent LGESS as a second-line treatment.

Loss of autophagy-related protein Beclin 1 may define poor prognosis in ovarian clear cell carcinomas

The aim of the present study was to clarify the role of autophagy in cisplatin (CDDP) sensitivity in OCCCs and the role of Beclin 1 in OCCC progression. Autophagy was measured using: i) western blot analysis of LC3 and p62 and ii) microscopic observation of GFP-LC3 puncta. Autophagy was suppressed using chloroquine and Beclin 1 siRNA. Surgical specimens were examined for Beclin 1 protein expression by immunohistochemistry. The correlations between the loss of Beclin 1 expression and clinicopathological characteristics, prognosis and chemosensitivity were investigated. Inhibition of autophagy by chloroquine or Beclin 1 siRNA did not enhance the sensitivity of the ES2 and TOV-21G OCCC cell lines to CDDP. Loss of Beclin 1 expression was observed in 38.3% (23/60) of the analyzed tumors. There was no significant correlation between loss of Beclin 1 expression and FIGO stage, CA125 levels, patient age, status of endometriosis, Ki-67 labeling index, chemotherapy regimen or status of residual tumor. However, negative expression of Beclin 1 was associated with a shorter progression-free survival in comparison to positive Beclin 1 expression in OCCC who received cytoreductive surgery, followed by a standard platinum-based chemotherapy regimen (P=0.027, log-rank test). Beclin 1-negative tumors were no more resistant to primary adjuvant chemotherapy than were Beclin 1-positive tumors (50.0 vs. 66.7%, P=0.937). Beclin 1 knockdown using siRNA increased cell growth but not cell migration and invasion in ES2 and TOV-21G OCCC cell lines. Autophagy defects caused by loss of Beclin 1 are not related to chemoresistance and metastasis, but may be associated with malignant phenotype and poor prognosis of OCCC.

CCNE1 amplification is associated with aggressive potential in endometrioid endometrial carcinomas

The clinicopathological significance of amplification was investigated of the gene encoding cyclin E (CCNE1) and we assessed whether CCNE1 was a potential target in endometrioid endometrial carcinomas. CCNE1 amplification and CCNE1 or F-box and WD repeat domain-containing 7 (FBXW7) expression in endometrial endometrioid carcinoma was assessed by immunohistochemistry and fluorescence in situ hybridization. CCNE1 knockdown by small interfering RNA (siRNA) was used to assess the CCNE1 function. The results showed that CCNE1 amplification was present in 9 (8.3%) of 108 endometrial carcinomas. CCNE1 amplification was correlated with high histological grade (Grade 3; P=0.0087) and lymphovascular space invasion (P=0.0258). No significant association was observed between CCNE1 amplification and FIGO stage (P=0.851), lymph node metastasis (P=0.078), body mass index (P=0.265), deep myometrial invasion (P=0.256), menopausal status (P=0.289) or patient age (P=0.0817). CCNE1 amplification was significantly correlated with shorter progression-free and overall survival (P=0.0081 and 0.0073, respectively). CCNE1 protein expression or loss of FBXW7 expression in endometrial endometrioid carcinoma tended to be correlated with shorter progression-free and overall survival; however, this difference was not statistically significant. Multivariate analysis showed that CCNE1 amplification was an independent prognostic factor for overall survival but not for progression-free survival (P=0.0454 and 0.2175, respectively). Profound growth inhibition was observed in siRNA-transfected cancer cells with endogenous CCNE1 overexpression compared with that in cancer cells having low CCNE1 expression. CCNE1 amplification was independent of p53, HER2, MLH1 and ARID1A expression but dependent on PTEN expression in endometrial carcinomas. These findings indicated that CCNE1 amplification was critical for the survival of endometrial endometrioid carcinomas. Furthermore, the effects of CCNE1 knockdown were dependent on the CCNE1 expression status, suggesting that CCNE1-targeted therapy may be beneficial for patients with endometrial endometrioid carcinoma having CCNE1 amplification.

KRAS/BRAF Analysis in Ovarian Low-Grade Serous Carcinoma Having Synchronous All Pathological Precursor Regions

Ovarian low-grade serous carcinoma is thought to begin as a serous cystadenoma or adenofibroma that progresses in a slow stepwise fashion. Among the low-grade serous carcinomas, there is a high frequency of activating mutations in the KRAS or BRAF genes; however, it remains unclear as to how these mutations contribute to tumor progression. This is the first report to track the histopathological progression of serous adenofibroma to low-grade serous carcinoma. Each stage was individually analyzed by pathological and molecular genetic methods to determine what differences occur between the distinct stages of progression.

Efficacy of multiple microwave endometrial ablation technique for menorrhagia resulting from adenomyosis.

Conventional microwave endometrial ablation (MEA) can be insufficient to control menorrhagia resulting from adenomyosis. We compared the standard single ablation technique with multiple MEA – repeating ablation three times in the same region – in patients with adenomyosis and menorrhagia.

Nerve-sparing abdominal radical trachelectomy: a novel concept to preserve uterine branches of pelvic nerves

OBJECTIVES Nerve-sparing techniques to avoid bladder dysfunction in abdominal radical hysterectomy have been established during the past two decades, and they have been applied to radical trachelectomy. Although trachelectomy retains the uterine corpus, no report mentions the preservation of uterine branches of pelvic nerves. The aim of the present study was to introduce and discuss our unique concept for preserving them. STUDY DESIGN AND RESULTS Four cases with FIGO stage Ia2-Ib1 cervical cancer, in which preservation of uterine branches of the pelvic nerves was attempted, are presented. Operative procedures basically followed the previously reported standard approaches for nerve-sparing radical hysterectomy or trachelectomy, except for some points. Before resection of the sacrouterine ligament, the hypogastric nerve was first identified and translocated laterally. Subsequently, the uterine branches of the pelvic nerve were identified as a continuation of the hypogastric nerve and could be scooped with forceps by detachment of the surrounding connective tissues. Further detachment toward the uterine corpus enabled them to be completely separated from the cervix. This separation was extended up to the level of the junction of the upper and lower branches of the uterine artery. Thereafter, standard resection of the parametrium and paracolpium was performed, followed by cervical resection when it was confirmed that the isolated uterine branches of the pelvic nerves were safely translocated and preserved. There were no recurrences of cancer in these patients. CONCLUSIONS Uterine branches of autonomic nerves can be safely preserved, and the procedure may be considered one of the nerve-sparing techniques for radical abdominal trachelectomy, which may hopefully improve the reproductive outcomes of this operation, although it needs to be evaluated with more patients.

High-grade serous ovarian cancer 3 years after bilateral salpingectomy: A case report

Although epithelial ovarian cancer commonly originates from the ovarian surface epithelium and/or ovarian inclusion cysts, it was recently proposed that high-grade serous ovarian cancer (HGSC) develops from the Fallopian tubes. In our department, we encountered a case of HGSC that contradicts the hypothesis of a tubal origin for HGSC. A 51-year-old postmenopausal woman had undergone hysterectomy, left oophorectomy and bilateral salpingectomy for uterine myoma. Three years later, the patient was diagnosed with stage IV ovarian cancer and underwent primary debulking surgery. The pathological examination revealed HGSC, although there was no evidence of serous tubal intraepithelial carcinoma or any other type of cancer in the previously resected left ovary and bilateral Fallopian tubes. Moreover, p53 overexpression was not detected in the right ovarian cancer specimen, while paired box gene 8, a marker of Fallopian tube epithelium, was highly expressed. Therefore, HGSC may develop from an inclusion cyst with metaplasia of from the ovarian surface epithelium.

Efficacy of metformin for advanced-stage endometrial cancer: A case report

The paradigm of obesity, diabetes mellitus and insulin resistance possibly plays a critical role in the pathogenesis of endometrial cancer (EC). Impaired glucose tolerance and insulin resistance may play a direct or facilitating role in the neoplastic transformation of the endometrium, whereas antidiabetic therapy, particularly with metformin, has been suggested to inhibit EC progression. We herein present the case of a patient with EC who received metformin monotherapy due to complications after undergoing surgery. At 45 months after the introduction of metformin treatment, the patient had no complaints and continued receiving metformin without signs of tumor recurrence. As metformin is widely used among diabetic patients and in ongoing clinical trials in cancer patients, the aforementioned results deserve further clinical investigation.

Efficacy of microwave ablation for the treatment of endometrial carcinoma: A report of 3 cases

Microwave endometrial ablation (MEA) is effective for the emergency control of uterine hemorrhage. However, to the best of our knowledge, there has been only a single report of life-threatening hemorrhage induced by endometrial carcinoma that was treated with MEA. The present report evaluates the efficacy of MEA as an emergency therapeutic option for the control of bleeding due to advanced endometrial carcinoma and minimally-invasive, early-stage endometrial carcinoma in 3 patients. MEA was able to effectively control massive uterine bleeding due to endometrial carcinoma in 2 patients with advanced disease and was curative in a patient with minimally-invasive endometrial carcinoma. Given its safety, simplicity and effectiveness, MEA may be utilized for the emergency treatment of uterine bleeding in advanced endometrial carcinoma, and may be used as a curative treatment in early-stage endometrial carcinoma.

High pretreatment plasma D-dimer levels are related to shorter overall survival in endometrial carcinoma

OBJECTIVE The aim of the present study was to evaluate the prognostic value of pretreatment plasma dimerized plasmin fragment D (D-dimer) levels in endometrial carcinoma after adjusting for venous thromboembolism (VTE). STUDY DESIGN The relationships between the following clinical parameters from 110 patients were investigated: age, histological type, the International Federation of Gynecology and Obstetrics (FIGO) stage, tumor grade, pretreatment plasma D-dimer level, platelet count, fibrinogen, CA19-9, and CEA levels, progression-free survival (PFS), and overall survival (OS). A survival analysis was performed using the Kaplan-Meier method, and prognostic factors were assessed using Coxs proportional hazards regression model. RESULTS High pretreatment D-dimer levels were detected in 32% of cases. High D-dimer levels correlated with an advanced tumor stage, histological type, and tumor grade (P=0.001, P=0.021, P=0.044). A multivariate analysis identified high D-dimer levels as an independent prognostic factor for OS (P=0.013), whereas the histological type, but not D-dimer levels had independent prognostic value for PFS (P=0.225). CONCLUSION High pretreatment D-dimer levels have an impact on prognoses independently of VTE, and also have potential as markers to predict surgical outcomes in patients with endometrial carcinoma. Pretreatment D-dimer levels may contribute to the identification of high-risk populations for treatment decisions.