Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients.

DNA methylation contributes to tumor formation, development and metastasis. Epigenetic dysregulation of stem cells is thought to predispose to malignant development. The clinical significance of DNA methylation in ovarian tumor-initiating cells (OTICs) remains unexplored. We analyzed the methylomic profiles of OTICs (CP70sps) and their derived progeny using a human methylation array. qRT-PCR, quantitative methylation-specific PCR (qMSP) and pyrosequencing were used to verify gene expression and DNA methylation in cancer cell lines. The methylation status of genes was validated quantitatively in cancer tissues and correlated with clinicopathological factors. ATG4A and HIST1H2BN were hypomethylated in OTICs. Methylation analysis of ATG4A and HIST1H2BN by qMSP in 168 tissue samples from patients with ovarian cancer showed that HIST1H2BN methylation was a significant and independent predictor of progression-free survival (PFS) and overall survival (OS). Multivariate Cox regression analysis showed that patients with a low level of HIST1H2BN methylation had poor PFS (hazard ratio (HR), 4.5; 95% confidence interval (CI), 1.4-14.8) and OS (HR, 4.3; 95% CI, 1.3-14.0). Hypomethylation of both ATG4A and HIST1H2BN predicted a poor PFS (HR, 1.8; 95% CI, 1.0-3.6; median, 21 months) and OS (HR, 1.7; 95% CI, 1.0-3.0; median, 40 months). In an independent cohort of ovarian tumors, hypomethylation predicted early disease recurrence (HR, 1.7; 95% CI, 1.1-2.5) and death (HR, 1.4; 95% CI, 1.0-1.9). The demonstration that expression of ATG4A in cells increased their stem properties provided an indication of its biological function. Hypomethylation of ATG4A and HIST1H2BN in OTICs predicts a poor prognosis for ovarian cancer patients.

Gene Set-Based Functionome Analysis of Pathogenesis in Epithelial Ovarian Serous Carcinoma and the Molecular Features in Different FIGO Stages.

Serous carcinoma (SC) is the most common subtype of epithelial ovarian carcinoma and is divided into four stages by the Federation of Gynecologists and Obstetrics (FIGO) staging system. Currently, the molecular functions and biological processes of SC at different FIGO stages have not been quantified. Here, we conducted a whole-genome integrative analysis to investigate the functions of SC at different stages. The function, as defined by the GO term or canonical pathway gene set, was quantified by measuring the changes in the gene expressional order between cancerous and normal control states. The quantified function, i.e., the gene set regularity (GSR) index, was utilized to investigate the pathogenesis and functional regulation of SC at different FIGO stages. We showed that the informativeness of the GSR indices was sufficient for accurate pattern recognition and classification for machine learning. The function regularity presented by the GSR indices showed stepwise deterioration during SC progression from FIGO stage I to stage IV. The pathogenesis of SC was centered on cell cycle deregulation and accompanied with multiple functional aberrations as well as their interactions.

Gene Set-Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer.

Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis.

Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells.

Adenomyosis is an oestrogen-dependent disease characterized by the invasion of endometrial epithelial cells into the myometrium of uterus, and angiogenesis is thought to be required for the implantation of endometrial glandular tissues during the adenomyotic pathogenesis. In this study, we demonstrate that compared with eutopic endometria, adenomyotic lesions exhibited increased vascularity as detected by sonography. Microscopically, the lesions also exhibited an oestrogen-associated elevation of microvascular density and VEGF expression in endometrial epithelial cells. We previously reported that oestrogen-induced Slug expression was critical for endometrial epithelial-mesenchymal transition and development of adenomyosis. Our present studies demonstrated that estradiol (E2) elicited a Slug-VEGF axis in endometrial epithelial cells, and also induced pro-angiogenic activity in vascular endothelial cells. The antagonizing agents against E2 or VEGF suppressed endothelial cells migration and tubal formation. Animal experiments furthermore confirmed that blockage of E2 or VEGF was efficient to attenuate the implantation of adenomyotic lesions. These results highlight the importance of oestrogen-induced angiogenesis in adenomyosis development and provide a potential strategy for treating adenomyosis through intercepting the E2-Slug-VEGF pathway.

An increased risk of epithelial ovarian cancer in Taiwanese women with a new surgico-pathological diagnosis of endometriosis.

BACKGROUND: Epidemiological evidence of relationships between endometriosis and epithelial ovarian cancer (EOC) has been obtained mainly from Western countries. Our goal was to determine the risk of EOC due to endometriosis in Taiwanese women. METHODS: A retrospective cohort study was performed by linking to the National Health Insurance Research Database (NHIRD) of Taiwan. A total of 5,945 women with a new surgico-pathological diagnosis of endometriosis from 2000 to 2010 and 23,780 multivariable-matched controls (1:4) were selected. The Cox regression model adjusted for potential confounders was used to assess the risk of EOC due to endometriosis. RESULTS: The EOC incidence rate (IR) of the women with and without endometriosis was 11.64 and 2.66 per 10,000 person-years, contributing to a crude hazard ratio (HR) of 4.48 (95% confidence interval [CI] 2.84-7.06), and HR after adjustment for all confounders (adjusted HR) of 5.62 (95% CI 3.46-9.14); the risk was higher in clear-cell carcinoma subtypes (adjusted HR 7.36, 95% CI 1.91-28.33). The EOC IR of women with endometriosis consistently increased with increasing age, ranging from 4.99 (<30 years) to 35.81 (≥50 years) per 10,000 person-years, contributing to a progressively increased risk of EOC (crude HRs ranging from 2.80 to 6.74 and adjusted HRs ranging from 3.34 to 9.63) compared to age-matched women without endometriosis, whose EOC IR also increased with age. The older women (≥50 years) with endometriosis had a risk of EOC that was higher than both the age-matched women without endometriosis (adjusted HR 9.63, 95% CI 3.27-28.37) and the youngest women (<30 years) with endometriosis (adjusted HR 4.97, 95% CI 1.03-24.09). CONCLUSIONS: These significant findings corroborate the previously reported association between endometriosis and increased risk of EOC. Since the risk of EOC in women with a new surgico-pathological diagnosis of endometriosis constantly increased with age and this increased risk of EOC was more significant in women aged ≥50 years, active and intensive surgical intervention should be taken into consideration for older women with endometriosis.

Clinicopathological features and survival in young Taiwanese women with endometrial carcinoma.

OBJECTIVE: The aim of this study is to compare the clinicopathological features and survival of young women with endometrial cancer (aged <50 years) with those of older women with endometrial cancer (aged ≥50 years). METHODS: We conducted a retrospective cohort study of patients with histologically confirmed endometrial cancer treated at the Taipei Veterans General Hospital from 2001 to 2010. RESULTS: One hundred forty-six patients (28.5%) were aged younger than 50 years at diagnosis. The median follow-up was 36.5 months (range, 0.9-121.7 months). Low body mass index (P < 0.001), nulliparity (P < 0.001), less medical illness (P < 0.001), synchronous primary ovarian cancer (P = 0.001), endometrioid type (P = 0.005), low tumor grade (P < 0.001), no para-aortic lymph node involvement (P < 0.047), less myometrial invasion (P < 0.001), and no vascular space invasion (P = 0.001) were common among the younger women compared with the older women. There were significant differences in the disease-free survival (P = 0.006) and overall survival (P = 0.004) between the 2 groups. In the multivariate Cox model, advanced stage had an effect on both disease-free survival (P = 0.004) and overall survival (P = 0.050). CONCLUSIONS: Nulliparity, body mass index less than or equal to 23 kg/m, endometrioid type, low-grade tumor, synchronous primary ovarian cancer, and favorable survival were common among the younger women.

The role of secondary cytoreductive surgery in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers: a comparative effectiveness analysis.

Background. All published reports concerning secondary cytoreductive surgery for relapsed ovarian cancer have essentially been observational studies. However, the validity of observational studies is usually threatened from confounding by indication. We sought to address this issue by using comparative effectiveness methods to adjust for confounding. Methods. Using a prospectively collected administrative health care database in a single institution, we identified 1,124 patients diagnosed with recurrent epithelial, tubal, and peritoneal cancers between 1990 and 2009. Effectiveness of secondary cytoreductive surgery using the conventional Cox proportional hazard model, propensity score, and instrumental variable were compared. Sensitivity analyses for residual confounding were explored using an array approach. Results. Secondary cytoreductive surgery prolonged overall survival with a hazard ratio (95% confidence interval) of 0.76 (range 0.66-0.87), using the Cox proportional hazard model. Propensity score methods produced comparable results: 0.75 (range 0.64-0.86) by nearest matching, 0.73 (0.65-0.82) by quintile stratification, 0.71 (0.65-0.77) by weighting, and 0.72 (0.63-0.83) by covariate adjustment. The instrumental variable method also produced a comparable estimate: 0.75 (range 0.65-0.86). Sensitivity analyses revealed that the true treatment effects may approach the null hypothesis if the association between unmeasured confounders and disease outcome is high. Conclusions. This comparative effectiveness study provides supportive evidence for previous reports that secondary cytoreductive surgery may increase overall survival for patients with recurrent epithelial, tubal, and peritoneal cancers.

Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis.

Adenomyosis is an oestrogen-dependent disease caused by a downward extension of the endometrium into the uterine myometrium. Epithelial-mesenchymal transition (EMT) endows cells with migratory and invasive properties and can be induced by oestrogen. We hypothesized that oestrogen-induced EMT is critical in the pathogenesis of adenomyosis. We first investigated whether EMT occurred in adenomyotic lesions and whether it correlated with serum 17ß-oestradiol (E2) levels. Immunohistochemistry was performed on adenomyotic lesions and corresponding eutopic endometrium samples from women with adenomyosis. Endometria from women without endometrial disorders were used as a control. In the epithelial component of adenomyotic lesions, vimentin expression was up-regulated and E-cadherin expression was down-regulated compared to the eutopic endometrium, suggesting that EMT occurs in adenomyosis. In adenomyosis, the serum E2 level was negatively correlated with E-cadherin expression in the epithelial components of the eutopic endometrium and adenomyotic lesions, suggesting the involvement of oestrogen-induced EMT in endometrial cells. In oestrogen receptor-positive Ishikawa endometrial epithelial cells, oestrogen induced a morphological change to a fibroblast-like phenotype, a shift from epithelial marker expression to mesenchymal marker expression, increased migration and invasion, and up-regulation of the EMT regulator Slug. Raloxifene, a selective oestrogen receptor modulator, abrogated these effects. To determine the role of oestrogen-induced EMT in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium or adenomyotic lesions from adenomyosis patients into ovariectomized SCID mice. The implantation of endometrium was oestrogen-dependent and was suppressed by raloxifene. Collectively, these data highlight the crucial role of oestrogen-induced EMT in the development of adenomyosis and suggest that raloxifene may be a potential therapeutic agent for adenomyosis patients.

Development of a Multi-Institutional Prediction Model for Three-Year Survival Status in Patients with Uterine Leiomyosarcoma (AGOG11-022/QCGC1302 Study).

BACKGROUND: The existing staging systems of uterine leiomyosarcoma (uLMS) cannot classify the patients into four non-overlapping prognostic groups. This study aimed to develop a prediction model to predict the three-year survival status of uLMS. METHODS: In total, 201 patients with uLMS who had been treated between June 1993 and January 2014, were analyzed. Potential prognostic indicators were identified by univariate models followed by multivariate analyses. Prediction models were constructed by binomial regression with 3-year survival status as a binary outcome, and the final model was validated by internal cross-validation. RESULTS: Nine potential parameters, including age, log tumor diameter, log mitotic count, cervical involvement, parametrial involvement, lymph node metastasis, distant metastasis, tumor circumscription and lymphovascular space invasion were identified. 110 patients had complete data to build the prediction models. Age, log tumor diameter, log mitotic count, distant metastasis, and circumscription were significantly correlated with the 3-year survival status. The final model with the lowest Akaike's Information Criterion (117.56) was chosen and the cross validation estimated prediction accuracy was 0.745. CONCLUSION: We developed a prediction model for uLMS based on five readily available clinicopathologic parameters. This might provide a personalized prediction of the 3-year survival status and guide the use of adjuvant therapy, a cancer surveillance program, and future studies.

Human papillomavirus type and clinical manifestation in seven cases of large-cell neuroendocrine cervical carcinoma.

Large-cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a very rare malignancy. We aimed to investigate the role of human papillomavirus (HPV) on the survival of patients, and its correlation with clinical parameters of HPV status or survival outcomes. Only seven cases of LCNEC were retrospectively collected among 8018 (0.087%) invasive cervical carcinomas from the cancer registry systems at Mackay Memorial Hospital and Veterans General Hospital over a period of 17 years. The median survival time was 17.2 months, including only one long-term survivor (> 5 years). The 2 year and 5-year survival rates after diagnosis were 42% and 30%, respectively. The results indicated that the majority of LCNEC cases were dominated by high-risk HPV-18. No clinical parameters appeared to be associated with HPV-18 or survival outcomes of LCNEC patients. Pelvic lymph node metastasis positivity could also be considered as a prognostic factor for this disease.

Recurrent ovarian mixed germ cell tumor with unusual malignant transformation: a case report.

BACKGROUND: The value of this report is the identification of late recurrence with an extremely unusual combination of malignant transformation. In particular, the retroconversion of immature to mature teratoma as well as a somatic-type malignant transformation were both observed postchemotherapeutically in our case. CASE PRESENTATION: We report the case of a 20-year-old girl who completed fertility-sparing surgery and chemotherapy under the diagnosis of ovarian mixed germ cell tumor (immature teratoma and yolk sac tumor) and experienced subsequent recurrence 4 years after a second debulking surgery with a somatic type malignant transformation (teratoma with melanoma and leiomyosarcoma). Multiple metastases developed after a third debulking surgery, and the patient survived for 18 additional months. CONCLUSIONS: Recurrent disease after repeated cytoreduction and chemotherapy hints a poor outcome despite a generally excellent long-term survival rate among ovarian germ cell malignancies. It is important for clinicians to distinguish those at risk of poorer outcomes and establish individualized postoperative surveillance. Fertility-compromising surgery may be considered in selected patients.

Diffusion-weighted single-shot echo-planar imaging with parallel technique in assessment of endometrial cancer.

OBJECTIVE: The purposes of this study were to determine the feasibility of diffusion-weighted imaging (DWI) with a single-shot echo-planar sequence and parallel technique for depicting endometrial cancer and to examine the role of this technique in preoperative assessment. SUBJECTS AND METHODS: A total of 31 patients were recruited for MRI evaluation of suspicious endometrial lesions found on transvaginal sonography. Twenty-four of the patients were proved to have endometrial cancer (patient group), and seven to have benign diseases (control group). The MRI examinations included diffusion-weighted single-shot echoplanar sequences and contrast-enhanced T1-weighted 3D fat-suppressed spoiled gradient-echo sequences. The apparent diffusion coefficient of endometrial cancer in the patient group and of normal endometrium in the control group were measured on the apparent diffusion coefficient map of each diffusion-weighted image and compared for the two groups. In the patient group, myometrial invasion was evaluated with the two sequences. The diagnostic accuracy rates of each pulse sequence were compared. RESULTS: The mean apparent diffusion coefficient of endometrial cancer was 0.864 x 10(-3) mm2/s and that of benign endometrial lesions was 1.277 x 10(-3) mm2/s. The difference between the two groups was significant (p = 0.0058). The diagnostic accuracy for myometrial invasion was 61.9% for DWI and 71.4% for gadolinium-enhanced T1-weighted 3D fat-suppressed spoiled gradient-recalled echo images. In five cases, DWI provided information about tumor extent and depicted the tumor focus, findings that changed preoperative staging. CONCLUSION: DWI performed with parallel imaging technique has potential as a method for differentiating benign from malignant endometrial lesions. It also provides valuable information for preoperative evaluation and should be considered part of routine preoperative MRI evaluation for endometrial cancer.

Clinicopathologic Features and Treatment Outcomes in Patients with Stage I, High-Risk Histology or High-Grade Endometrial Cancer after Primary Staging Surgery: A Taiwanese Gynecologic Oncology Group Study.

To investigate the clinicopathological features and treatment outcomes in patients with stage I, high-risk endometrial cancer. Patients with International Federation of Gynecology and Obstetrics stage I, papillary serous, clear cell, or grade 3 endometrioid carcinoma treated between 2000 and 2012 were analyzed for the clinical and pathological factors in relation to prognosis. A total of 267 patients (stage IA; n = 175, stage IB; n = 92) were included. Among the clinicopathological features, stage and age were significant prognostic factors. The recurrence rate and overall survival for stage IB versus IA were 22.8% versus 9.1% (p = 0.003) and 149.7 months versus 201.8 months (p < 0.001), respectively. The patients >60 years of age also had a higher recurrence rate (21.7% versus 9.7%, p = 0.008) and poorer survival (102.0 months versus 196.8 months, p = 0.001) than those ≤60 years of age. Distant recurrence (64.9%) occurred more frequently than local recurrence (24.3%) and local combined with distant recurrence (10.8%) (p < 0.001). The postoperative treatment modality had no impact on tumor recurrence rate, recurrence site, or overall survival. Distant recurrence is a major cause of treatment failure in patients with stage I, high-risk endometrial cancer. However, current adjuvant treatment appeared to have little effect in preventing its occurrence.

Treatment outcomes of patients with stage II pure endometrioid-type endometrial cancer: a Taiwanese Gynecologic Oncology Group (TGOG-2006) retrospective cohort study.

OBJECTIVE: Choice of hysterectomy and adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) 2009 stage II endometrioid endometrial cancer (EEC) is still controversial. Aims of this study were to evaluate survival benefits and adverse effects of different hysterectomies with or without adjuvant radiotherapy (RT), and to identify prognostic factors. METHODS: The patients at 14 member hospitals of the Taiwanese Gynecologic Oncology Group from 1992 to 2013 were retrospectively investigated. Patients were divided into simple hysterectomy (SH) alone, SH with RT, radical hysterectomy (RH) alone, and RH with RT groups. Endpoints were recurrence-free survival (RFS), overall survival (OS), disease-specific survival (DSS), adverse effects and prognostic factors for survival. RESULTS: Total of 246 patients were enrolled. The 5-year RFS, OS, DSS and recurrence rates for the entire cohort were 89.5%, 94.3%, 96.2% and 10.2%, respectively. Patients receiving RH had more adverse effects including blood loss (p<0.001), recurrent urinary tract infections (p=0.013), and leg lymphedema (p=0.038). Age over 50-year (HR=9.2; 95% confidence interval [CI]=1.2-70.9) and grade 3 histology (HR=7.28; 95% CI=1.45-36.6) were independent predictors of OS. Grade 3 histology was an independent predictor of RFS (HR=5.13; 95% CI=1.38-19.1) and DSS (HR=5.97; 95% CI=1.06-58.7). Patients receiving adjuvant RT had lower locoregional recurrence (p=0.046), but no impact on survival. CONCLUSION: Different treatment modalities yield similar survival outcomes. Patients receiving SH with RT had lower locoregional recurrent with acceptable morbidity. Age and tumor grading remained significant predictors for survival among patients with FIGO 2009 stage II EEC.

Improved cervical cancer screening in premenopausal women by combination of Pap smear and speculoscopy.

OBJECTIVE: This study was done to evaluate the efficacy of the Pap smear, speculoscopy, and a combination of Pap smear and speculoscopy (PapSure examination) in pre- and postmenopausal women. STUDY DESIGN: All women were screened using the Pap smear and speculoscopy and combination of both (PapSure examination) in the multicenter trial. Final diagnosis of each patient was based on a histological evaluation of the colposcopic target biopsy. Results were analyzed using a proportional comparison test, sensitivity, specificity, and predictive value with significance determined at p<0.05. RESULTS: Of 1813 women screened, 1701 were eligible for analysis. Two hundred and fourteen women (12.6%) received at least one positive screening test result. Of the 1084 colposcopic biopsy specimens obtained, 24 showed low-grade squamous intraepithelial lesion (LSIL) and 19 high-grade SIL (HSIL). HSIL were considered test-positive. Rate of colposcopy was 21.5% (125/582) in the premenopausal group and 63.9% (321/502) in the postmenopausal group (p<0.001). For premenopausal women, speculoscopy (75.0%) or PapSure (91.7%) provided higher sensitivity than Pap smear (50%) (p<0.05). In postmenopausal women, no statistical significance in sensitivity existed between PapSure (85.7%) and Pap smear (57.1%). Speculoscopy (96.8%) or PapSure (96.5%) had lower specificity than Pap smear (99.6%) (p<0.001). CONCLUSION: PapSure was an accurate alternative screening method to Pap smear or speculoscopy for cervical intraepithelial lesions because of a significantly higher sensitivity along with adequate specificity for premenopausal women; however, PapSure was not a more effective cervical screening method for postmenopausal women.

Fertility preservation with treatment of immature teratoma of the ovary.

Fertility preservation for a patient with advanced immature teratoma of the ovary is reported. The patient, a 29-year-old woman, delivered a healthy baby after having had ovarian immature teratoma, grade 3, uncertain stage, at 13 years of age. She was initially treated with unilateral salpingo-oophorectomy and a contralateral wedge resection for tumor invasion, followed by a 6-course cisplatin+vinblastine+bleomycin regimen, a second operation, and an additional 6-course etoposide and cisplatin regimen with complete remission. The patient delivered a healthy baby 16 years after the initial treatment. Based on this successful case, intensive fertility-preserving surgery followed by chemotherapy, even in advanced-stage immature teratomas of the ovary, may be effective in preserving the reproductive function of women with malignant immature teratomas of the ovary.

Gene set-based integrative analysis of ovarian clear cell carcinoma.

OBJECTIVE: The pathogenesis of ovarian clear cell carcinoma is still poorly understood; therefore, we conducted a gene set-based analysis by integrating datasets downloaded from publicly available microarray gene expression databases to investigate the pathogenesis of clear cell carcinoma, which was based on the regularity of functions defined by gene ontology or canonical pathway databases. MATERIALS AND METHODS: The gene expression profiles of 80 clear cell carcinomas and 136 normal ovarian controls were downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. The gene expression profiles were converted to the gene set regularity (GSR) indexes computed using the modified differential rank conservation, an algorithm measuring the degree of gene expression ranking change in a gene set. Then the differences of GSR indexes between clear cell carcinomas and normal ovarian controls were analyzed. RESULTS: Machine learning can accurately recognize and classify the patterns of functional regularities containing the GSR indexes between the clear cell carcinomas and normal controls with an accuracy of 99.3%. The significant aberrations included oxidoreductase activity, binding, transport, channel activity, cell adhesion, immune response, chromosome assembly, and the deregulated signaling molecules, such as guanyl nucleotide exchange factors, phosphoinositide 3-kinase-activating kinase, receptor tyrosine kinase B, and protein tyrosine kinase. CONCLUSION: Our pioneering works using the functionome, which was converted from microarray gene expression profiles for integrative analysis, showed a clear distinction of functional changes between the clear cell carcinomas and normal ovarian controls. This approach might provide a comprehensive view of the deregulated functions of clear cell carcinomas for further investigation.

Uterine sarcoma part III-Targeted therapy: The Taiwan Association of Gynecology (TAG) systematic review.

Uterine sarcoma is a very aggressive and highly lethal disease. Even after a comprehensive staging surgery or en block cytoreduction surgery followed by multimodality therapy (often chemotherapy and/or radiation therapy), many patients relapse or present with distant metastases, and finally die of diseases. The worst outcome of uterine sarcomas is partly because of their rarity, unknown etiology, and highly divergent genetic aberration. Uterine sarcomas are often classified into four distinct subtypes, including uterine leiomyosarcoma, low-grade uterine endometrial stromal sarcoma, high-grade uterine endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Currently, evidence from tumor biology found that these tumors showed alternation and/or mutation of genomes and the intracellular signal pathway. In addition, some preclinical studies showed promising results for targeting receptor tyrosine kinase signaling, phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway, various kinds of growth factor pathways, Wnt/beta-catenin signaling pathway, transforming growth factor ß/bone morphogenetic protein signal pathway, aurora kinase A, MDM2 proto-oncogene, histone deacetylases, sex hormone receptors, certain types of oncoproteins, and/or loss of tumor suppressor genes. The current review is attempted to summarize the recurrent advance of targeted therapy for uterine sarcomas.

Low-dose add-back therapy during postoperative GnRH agonist treatment.

OBJECTIVE: Low-dose add-back therapy during postoperative GnRH agonist treatment could lower the risk of add-back-induced endometriosis recurrence and reduce treatment dropout compared with a regular dose. However, the effect of low-dose add-back therapy is still unknown. The aim of this study was to determine whether low-dose add-back therapy can also effectively relieve the hypoestrogenic side effects and simultaneously maintain a therapeutic response of GnRH agonist treatment. MATERIALS AND METHODS: This analysis was a prospective cohort study. During postoperative GnRH agonist treatment, a total of 107 women were prescribed add-back therapy [oral combination tablet; estradiol valerate (1 mg) and medroxyprogesterone acetate (2.5 mg)] (Indivina; Orion, Espoo, Finland) for 20 weeks. Patients in the low dose add-back therapy group were prescribed the tablet once a day, and patients in the regular dose group were given the tablet twice a day. Hypoestrogenic side effects, such as hot flashes and insomnia, were recorded. Patients were also questioned regarding their pelvic symptoms and pain to evaluate the possibility of endometriosis recurrence. Lumbar spine (L2-L4) bone mineral density was measured using dual X-ray absorptiometry. The dropout rates in both groups were also evaluated. RESULTS: The incidence of hypoestrogenic side effects was lower in the low dose group compared with the regular dose group, including hot flashes (19.2% vs. 21.8%, p = 0.741) and insomnia (15.4% vs. 18.2%, p = 0.699), although there were no significant difference between the groups. In addition, a higher number of patients in the regular dose group dropped out of treatment compared to the low dose group (14.5% and 9.6%, respectively, p = 0.435). The patients in both groups had a significant loss of mean bone mineral density during therapy (p < 0.001 and p = 0.018 for the low dose and regular dose groups, respectively). CONCLUSION: Low dose add-back therapy could effectively ameliorate hypoestrogenic side effects and simultaneously maintain the therapeutic response of GnRH agonist treatment. The treatment dropout was lower compared with a regular dose. Therefore, low dose add-back therapy can be considered a treatment choice during postoperative GnRH agonist treatment.

Uterine sarcoma Part I-Uterine leiomyosarcoma: The Topic Advisory Group systematic review.

Uterine sarcomas account for 3-7% of all uterine cancers. Because of their rarity, unknown etiology, and highly divergent genetic aberration, there is a lack of consensus on risk factors for occurrence and predictive poor outcomes as well as optimal therapeutic choices. Tumor types according to the World Health Organization classification include leiomyosarcoma, endometrial stroma sarcoma, and undifferentiated sarcoma. Staging is done using the 2014 Federation International Gynecology and Obstetrics and 2010 American Joint Committee on Cancer tumor, lymph node, and metastases systems. Tumor grade can be classified based on the French Federation of Cancer Centers Sarcoma Group system or the Broder's system that incorporates tumor differentiation, mitotic count, and tumor necrosis. This review is a series of articles discussing uterine sarcoma, and this is Part I, which focuses on one of the subtypes of uterine sarcomas-uterine leiomyosarcoma. The clinical characteristics, diagnosis, outcome, and recent advances are summarized in this article.