The Development of a New Uterine Manipulation Method during Minimally Invasive Radical Hysterectomy.

STUDY OBJECTIVE: The use of a vaginal uterine manipulator may compromise the oncological outcomes of patients with cervical cancer undergoing minimally invasive radical hysterectomy (MIS-RH). We aimed to describe the safety and efficacy of a novel uterine manipulation device during MIS-RH. DESIGN: Retrospective study. SETTING: A university hospital and a tertiary care hospital. PATIENTS: Patients with early-stage cervical cancer who were treated with MIS-RH. INTERVENTIONS: We developed the U-traction, a new device that consists of a 65-mm half-curved cutting needle with a 2.5-mm polyester tape (45-cm long), and investigated its utility to manipulate the uterus during MIS-RH. MEASUREMENTS AND MAIN RESULTS: This study describes the utility and safety of the U-traction for uterine manipulation during laparoscopic or robotic RH in 8 patients with cervical cancer. Uterine manipulation was successfully and safely performed using the U-traction during laparoscopic or robotic RH in patients with cervical cancer without any complications. The application time was less than 5 minutes. In all cases, the use of a vaginal manipulator, an additional incision for an extra port, or the need for assistant surgeons for uterine manipulation was avoided. CONCLUSION: The novel U-traction device allows for easy and reproducible uterine manipulation during MIS-RH. With this device, the use of a vaginal uterine manipulator can be avoided, and MIS-RH can be safely performed without the need for an assistant surgeon for uterine manipulation.

Preoperative plasma D-dimer level is a useful prognostic marker in ovarian cancer.

A high pre-treatment plasma D-dimer level was recently identified as a poor prognostic factor in several malignancies. The aim of this study was to evaluate the prognostic significance of plasma D-dimer levels in epithelial ovarian cancer (EOC). Data of 199 patients were retrospectively analysed. The relationships between pre-treatment D-dimer levels and other clinical parameters and prognosis were evaluated. Univariate analysis identified age, pre-treatment plasma D-dimer level, massive ascites, residual tumours, pre-treatment CA125 level, histological type, and FIGO stage as predictors of overall survival. The multivariate analysis showed that a high pre-treatment plasma D-dimer level (p=.017), residual tumours (p < .001), and FIGO stage (p = .036) were independent risk factors of overall survival. Venous thromboembolism (VTE) did not influence overall survival (p=.091). High pre-treatment D-dimer levels are associated with a poor prognosis independent of VTE status in EOC patients, and might be a useful prognostic biomarker.Impact statementWhat is already known on this subject? In recent years, a high pre-treatment plasma D-dimer level has been identified as a prognostic factor in several malignancies, but only a handful of studies have assessed the role of pre-treatment plasma D-dimer levels in patients with EOC patients. Thus, the clinical significance and prognostic value of the plasma D-dimer level in EOC remain controversial, and there is also debate related to the association of the higher mortality rate among cancer patients with elevated D-dimer levels with VTE.What do the results of this study add? In our study, high pre-treatment D-dimer levels are associated with a poor prognosis independently of VTE in EOC patients.What are the implications of these findings for clinical practice and/or further research? The D-dimer level might emerge as a valuable prognostic biomarker, which will help doctors in the choice of initiating a more aggressive therapy, the combination of chemotherapy with anticoagulation therapy.

Subtype I (intrinsic) adenomyosis is an independent risk factor for dienogest-related serious unpredictable bleeding in patients with symptomatic adenomyosis.

We aimed to retrospectively analyze the risk factors of a continuous dienogest (DNG) therapy for serious unpredictable bleeding in patients with symptomatic adenomyosis. This is a retrospective study based on data extracted from medical records of 84 women treated with 2 mg of DNG orally each day between 2008 and 2017. 47 subjects were excluded from the original analyses due to an inadequate subcategorization into subtype I and subtype II and a lack of hemoglobin levels. The influence of various independent variables on serious unpredictable bleeding was assessed. Of the 37 eligible patients who received the continuous DNG therapy, 14 patients experienced serious unpredictable bleeding. Univariate analysis revealed that the serious bleeding group had subtype I adenomyosis (P = 0.027). There was no correlation between age, parity, minimum hemoglobin level before treatment, previous endometrial curettage, and duration of DNG administration, or uterine or adenomyosis size and the serious bleeding. A DNG-related serious unpredictable bleeding is associated with the structural type of adenomyosis (subtype I) in patients with symptomatic adenomyosis.

Immunohistochemical expression of CD44v9 and 8-OHdG in ovarian endometrioma and the benign endometriotic lesions adjacent to clear cell carcinoma.

AIM: Expression of CD44 variant isoforms (CD44v) promotes the synthesis of reduced glutathione and contributes to reactive oxygen species defense through up-regulation of the intracellular antioxidant. The aim of the study was to investigate the expression of CD44v9 and oxidative DNA damage marker, 8-OHdG, in benign ovarian endometrioma (OE) and OE harboring clear cell carcinomas (CCC). METHODS: A retrospective study was performed at the Department of Gynecology, Nara Medical University hospital from January 2006 to December 2012. Patients with histologically confirmed benign OE (n = 27) and OE harboring areas of CCC (n = 8) were selected. Tissue samples were immunohistochemically analyzed for the presence of CD44v9 and 8-OHdG using avidin-biotin complex method. RESULTS: CD44v9 was located on the cell membrane of endometriotic epithelial cells and expressed in 88.9% (24/27) of benign OE tissues. Only 25.0% (2/8) of benign endometriotic lesions adjacent to CCC was found to stain weakly for CD44v9. Percentage of CD44v9 positive cells was 68.5 ± 20.2% (mean ± standard deviation) of benign OE, 16.7 ± 16.5% of CCC endometriotic tissue (P < 0.001). Compared to benign OE, CCC endometriotic tissue showed a significant increase in the proportion of 8-OHdG expression (77.3 ± 22.5% vs 94.9 ± 3.0%, P = 0.049). A significant negative correlation was observed between CD44v9 status and 8-OHdG nuclear expression (r = -0.458, P  =  0.006). CONCLUSION: Alterations in CD44v9 and 8-OHdG may be associated with malignant transformation of benign OE.

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary.

Targeting non-oncogenes may result in the selective death of cancer cells. Clear cell carcinoma of the ovary (CCC) may exhibit resistance against conventional chemotherapy and is associated with poor prognosis. The aim of the present report was to review synthetic lethality-based therapies for CCC. Previous English-language studies were reviewed to accumulate preclinical and clinical data on targeting synthetic lethal partners. Synthetic lethal interactions have a variety of types, involving components of a backup or parallel pathway with overlapping functions, components encoded by paralogous pairs, subunit components that form heteromeric complexes and components that are arranged in a single linear pathway. A set of candidate gene targets potentially resulting in synthetic lethality have been previously identified. HNF class homeobox, AT-rich interaction domain 1A, ATR serine/threonine kinase, ATM serine/threonine kinase, checkpoint kinase 1 and phosphatase and tensin homolog may be the key partner genes. A variety of loss of function genes in CCC are driver or passenger events and may function as synthetic lethal pairs under replication stress conditions. Further clinical studies will be required to investigate the safety and therapeutic effect of synthetic lethality pairs in CCC tumor types with replication stress.

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3ß and ß-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

Sequential molecular changes and dynamic oxidative stress in high-grade serous ovarian carcinogenesis.

The mechanism of high-grade serous ovarian cancer (HGSC) development remains elusive. This review outlines recent advances in the understanding of sequential molecular changes associated with the development of HGSC, as well as describes oxidative stress-induced genomic instability and carcinogenesis. This article reviews the English language literature between 2005 and 2017. Clinicopathological features analysis provides a sequential progression of fallopian tubal epithelium to precursor lesions to type 2 HGSC. HGSC may develop over a long time after incessant ovulation and repeated retrograde menstruation via stepwise accumulation of genetic alterations, including PAX2, ALDH1A1, STMN1, EZH2 and CCNE1, which confer positive selection of cells with growth advantages through acquiring driver mutations such as BRCA1/2, p53 or PTEN/PIK3CA. Haemoglobin and iron-induced oxidative stress leads to the emergence of genetic alterations in fallopian tubal epithelium via increased DNA damage and impaired DNA repair. Serous tubal intraepithelial carcinoma (STIC), the likely precursor of HGSC, may be susceptible to DNA double-strand breaks, exhibit DNA replication stress and increase genomic instability. The induction of genomic instability is considered to be a driving mechanism of reactive oxygen species (ROS)-induced carcinogenesis. HGSC exemplifies the view of stepwise cancer development. We describe how genetic alterations emerge during HGSC carcinogenesis related to oxidative stress.

Comparison of the Different Definition Criteria for the Diagnosis of Amniotic Fluid Embolism.

INTRODUCTION: There are several sets of criteria for the diagnosis of Amniotic Fluid Embolism (AFE), but little is known about their degree of agreement. AIM: To evaluate the concordance of the Japan criteria for AFE in comparison with two definitions: the US AFE registration entry criteria (the US criteria) and UK Obstetric Surveillance System criteria for defining cases of amniotic fluid embolism (the UK criteria). MATERIALS AND METHODS: A retrospective observational study was conducted in which the AFE cases registered in the Obstetrical Gynaecological Society of Kinki District in Japan for the period of April 2005 to December 2012 have been analysed by the expert steering obstetric committee, organized by the members of the Obstetric Research group. Cohen's kappa coefficient was used to calculate the agreement among three clinical diagnoses. For inter-group comparison, the Pearson Chi-square test was used (for categorical) and Mann-Whitney test was used (for continuous variables). RESULTS: Among the 26 cases registered for this period, a total of 18 women were selected as having AFE according to the Japan criteria. Five women died (case fatality rate 27.8%). Agreement between the Japan criteria and the US and UK criteria was k = 0.453 and k = 0.538, respectively, reflecting moderate agreement. However, only 38.9% were given a diagnosis of AFE according to all three criteria. The factor that most often caused disagreement in diagnosis between the Japan criteria and the US criteria was "onset within 30 minutes postpartum". The UK criteria excluded "women with postpartum haemorrhage as the first presenting feature in whom there was no evidence of cardiorespiratory compromise". The case fatality rates in US and UK are higher than in Japan (50.0% and 38.5% vs 27.8%), but this did not result in a significant difference (p=0.497). CONCLUSION: The groups of subjects identified as having AFE by the Japan criteria had a medium agreement with the US (k=0.453) or UK criteria (k=0.538). These three definition criteria identified different subgroups of patients. Such disagreement has serious implications for research and treatment.

The conceptual advances of carcinogenic sequence model in high-grade serous ovarian cancer.

The present review focuses on the current status of molecular pathology in high-grade serous cancer (HGSC) and preneoplastic conditions. This article reviews the English-language literature on HGSC, precursor, fallopian tubal epithelium, secretory cells, ciliated cells, secretory cell expansion, secretory cell outgrowth (SCOUT), p53 signature, serous tubal intraepithelial carcinoma (STIC), DNA damage and immunohistochemistry in an effort to identify the precursor-carcinoma sequence in HGSC. The majority of HGSC originates from the fimbriated end of the fallopian tube secretory epithelial cells, while the small part of this disease may develop from ovarian cortical inclusion cyst (CIC). A series of morphological changes from normal fallopian epithelium to preneoplastic to neoplastic lesions were concomitant with the multistep accumulation of molecular and genetic alterations. Recent studies provide a stepwise progression of fallopian tubal epithelium to precursor lesions to carcinoma, with the aid of a 'secretory cell-SCE-SCOUT-p53 signature-STIC-HGSC sequence' model. Immunohistochemical markers, including p53, STMN1, EZH2, CCNE1, Ki67 and γ-H2AX, were gradually increased during the SCOUT-p53 signature-STIC-HGSC sequence. Conversely, PAX2 expression was decreased during the early phase of SCOUT development. Potential genes and proteins are involved in the evolutionary trajectory of the precursor-cancer lineage model. In the present review we examined detailed aspects of the molecular changes involved in malignant transformation from fallopian tube epithelium to HGSC. A precursor condition originating in 'field cancerization' may gain a growth advantage, leading to HGSC.

Skin-mucous membrane disorder and therapeutic effect of pegylated liposomal doxorubicin in recurrent ovarian cancer.

AIM: Hand-foot syndrome (HFS) induced by chemotherapy and molecule-targeting drugs is correlated with treatment efficacy. We conducted a retrospective analysis to evaluate the relationship between HFS and efficacy of pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer. METHODS: Patients were treated with PLD between July 2009 and May 2014. We evaluated patient characteristics, incidence of adverse events, clinical benefit (rate of complete response, partial response, and stable disease), progression-free survival, and overall survival. RESULTS: Twenty-seven patients were included in the study. Median age was 63 years (range, 41-77 years). The median number of cycles of PLD was 3 (range, 1-6). The clinical benefit rate was 33.3%, and progressive disease was noted in 18 patients (66.7%). Median overall survival was 6.7 months (range, 1.1-41 months). Compared with patients with grade 0/1 HFS and oral mucositis, patients with grade 2-4 toxicity (n = 9, 33.3%) had a significantly higher rate of clinical benefit (11.1% vs 77.7%; P < 0.001) and a longer median overall survival (3.7 months vs 20.8 months; P < 0.001). CONCLUSIONS: Severity of HFS and mucositis may be a predictive marker of PLD efficacy. The prevention and management of HFS and mucositis are important for continued treatment.

Genes Downregulated in Endometriosis Are Located Near the Known Imprinting Genes.

There is now accumulating evidence that endometriosis is a disease associated with an epigenetic disorder. Genomic imprinting is an epigenetic phenomenon known to regulate DNA methylation of either maternal or paternal alleles. We hypothesize that hypermethylated endometriosis-associated genes may be enriched at imprinted gene loci. We sought to determine whether downregulated genes associated with endometriosis susceptibility are associated with chromosomal location of the known paternally and maternally expressed imprinting genes. Gene information has been gathered from National Center for Biotechnology Information database geneimprint.com. Several researchers have identified specific loci with strong DNA methylation in eutopic endometrium and ectopic lesion with endometriosis. Of the 29 hypermethylated genes in endometriosis, 19 genes were located near 45 known imprinted foci. There may be an association of the genomic location between genes specifically downregulated in endometriosis and epigenetically imprinted genes.

Mechanism of pain generation for endometriosis-associated pelvic pain.

PURPOSE: Endometriosis-associated pelvic pain appears due to persistent nociceptive stimulation, but the precise mechanisms remain poorly understood. METHODS: A search was conducted to screen and select articles from PubMed. MAIN RESULTS: Neurotrophins (NTs), a family of neuronal growth factors, are overexpressed in endometriosis and encompass NGF, BDNF and NT-3 and NT-4/5. NT receptors, TrkA and p75NTR, and NT receptor-interacting proteins, MAGE and NDN, were also expressed. NTs and their receptors play a role in the development and maintenance of neural tissues in non-neuronal cell types such as endometriosis. Nerve fibers contain unmyelinated sensory C, myelinated sensory Adelta and adrenergic nerve fibers that innervate abnormal cell growths. An increased release of proinflammatory cytokines from endometriotic lesions is responsible for the excessive sensory innervation and development of chronic pelvic pain. CONCLUSIONS: The preponderance of the inflammatory milieu and subsequent hyperinnervation might be involved in the pathophysiology of pain generation in women with endometriosis.

Fetal programming theory: implication for the understanding of endometriosis.

Comparison of the transcriptomes and proteomes of the decidualization-specific genes that express high vs low levels of the eutopic and ectopic endometrium of women with endometriosis compared with controls, could be useful in understanding the pathogenesis of endometriosis. Genome-wide comparison between decidual tissue and non-decidual tissue identified many genes significantly modulated in the process of decidualization. Comparison of eutopic endometrium and endometriotic sites also revealed up- and down-regulated genes. A combined analysis of the experimental data showed specific genes up-regulated both at the endometriotic site and in the decidualization process, representing a broad diversity of molecular functions, including cell cycle regulation, angiogenesis and adhesion molecules. In contrast, down-regulated genes identified in endometriosis among genes overexpressed in decidualization encode Müllerian embryogenesis, which includes transcription factors, hormonal regulation and cytokine expression. The mechanism responsible for insufficient decidualization in endometriosis may be mediated through down-regulation of the Müllerian embryogenesis-related genes. In conclusion, a range of decidualization resistance has been associated with endometriosis. Future study will identify the putative mechanisms relating epigenetic changes of decidualization susceptibility genes in early life to the risk of developing endometriosis in adulthood.