良性の子宮内膜症性嚢胞と悪性転化を鑑別するのに腫瘍内容液中の鉄関連物質が有用なマーカーとなる

OBJECTIVE: The purpose of this study was to investigate cyst fluid levels of total iron, heme iron and free iron in benign endometriotic cysts and endometriosis-associated ovarian cancer (EAOC) and to demonstrate the significance of these biomarkers in differential diagnosis between EAOC and endometriotic cysts. METHODS: Cyst fluid samples were obtained from eleven patients with EAOC and thirty-six women with benign endometriotic cysts at the time of surgery. RESULTS: The median (± SD) total iron levels for endometriotic cysts and EAOC cysts were 244.4 ± 204.9 mg/L and 14.2 ± 36.6 mg/L, respectively. EAOC patients had much lower levels of iron-related compounds compared with endometriotic cyst samples (p< 0.001). When the total iron results were analyzed using the receiver operating characteristics (ROC) curve method, the optimum diagnostic cut-off point was 64.8 mg/L, sensitivity was 90.9%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 97.3%. Patient demographic characteristics such as tumor size, age at operation, parity and menopause were not correlated with cyst fluid iron levels. CONCLUSIONS: We conclude for the first time that iron-related compounds are important biomarkers that can predict malignant transformation with high sensitivity and specificity for women with endometriosis.博士（医学）・乙第1367号・平成27年11月27日Copyright ©2015 IOS Press All rights reserved.The definitive version is available at " http://dx.doi.org/10.3233/CBM-150484

卵巣明細胞癌と類内膜癌の鑑別に関するMRIについての知見

BACKGROUND: Common cancerous histological types associated with endometriosis are clear cell carcinoma (CCC) and endometrioid carcinoma (EC). CCC is regarded as an aggressive, chemoresistant histological subtype. Magnetic resonance imaging (MRI) offers some potential advantages to diagnose ovarian tumors compared with ultrasonography or computed tomography. This study aimed to identify MRI features that can be used to differentiate between CCC and EC. METHODS: We searched medical records of patients with ovarian cancers who underwent surgical treatment at Nara Medical University Hospital between January 2008 and September 2018; we identified 98 patients with CCC or EC who had undergone preoperative MRI. Contrasted MRI scans were performed less than 2 months before surgery. Patients were excluded from the study if they had no pathology, other pathological subtype of epithelial ovarian cancer, and/or salvage treatment for recurrence and metastatic ovarian cancer at the time of study initiation. Clinically relevant variables that were statistically significant by univariate analysis were selected for subsequent multivariate regression analysis to identify independent factors to distinguish CCC from EC. RESULTS: MRI of CCC and EC showed a large cystic heterogeneous mixed mass with mural nodules protruding into the cystic space. Univariate logistic regression analysis revealed that the growth pattern (broad-based nodular structures [multifocal/concentric sign] or polypoid structures [focal/eccentric sign]), surface irregularity (a smooth/regular surface or a rough/irregular/lobulated surface), "Width" of mural nodule, "Height-to-Width" ratio (HWR), and presence of preoperative ascites were factors that significantly differed between CCC and EC. In the multivariate logistic regression analysis, the growth pattern of the mural nodule (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.013-0.273, p = 0.0004) and the HWR (OR = 3.71, 95% CI: 1.128-13.438, p = 0.036) were independent predictors to distinguish CCC from EC. CONCLUSIONS: In conclusion, MRI data showed that the growth pattern of mural nodules and the HWR were independent factors that could allow differentiation between CCC and EC. This finding may be helpful to predict patient prognosis before operation.博士（医学）・乙第1433号・令和元年9月27日© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Oxidative Stress and Antioxidant Defense in Endometriosis and Its Malignant Transformation

The aim of this study was to investigate the role of redox status in endometriosis and its malignant transformation. A search was conducted between 1990 and 2014 through the English language literature (online MEDLINE PubMed database) using the keywords endometriosis combined with malignant transformation, oxidative stress, and antioxidant defense. In benign endometriosis, autoxidation and Fenton reaction of hemoglobin from the ferrous Fe2+ (oxyhemoglobin) state to the ferric Fe3+ (methemoglobin) state lead to production of excess reactive oxygen species (ROS) such as O2- and OH∙. Hemoglobin, heme, and iron derivatives in endometriotic cysts cause distortion in the homeostatic redox balance. Excess oxidative stress could trigger DNA damage and cell death. In contrast, endometriosis-associated ovarian cancer (EAOC) might be associated with an effective antioxidant defense, including heme oxygenases, cytochrome P450 family, and glutathione transferase family. The pattern of redox balance supports that enhanced antioxidants may be involved in the pathogenesis of malignant transformation. In conclusion, oxidant/antioxidant balance function is a double-edged sword, promoting cell death or carcinogenesis. Upregulation of antioxidant functions in endometriotic cyst may result in restoration of cell survival and subsequent malignant transformation

Involvement of Visceral Adipose Tissue in Immunological Modulation of Inflammatory Cascade in Preeclampsia

Objectives. The pathophysiology of preeclampsia is characterized by abnormal placentation, an exaggerated inflammatory response, and generalized dysfunction of the maternal endothelium. We investigated the effects of preeclampsia serum on the expression of inflammation-related genes by adipose tissue. Materials and Methods. Visceral adipose tissue was obtained from the omentum of patients with early ovarian cancer without metastasis. Adipose tissue was incubated with sera obtained from either five women affected with severe preeclampsia or five women from control pregnant women at 37°C in a humidified incubator at 5% CO2 for 24 hours. 370 genes in total mRNA were analyzed with quantitative RT-PCR (Inflammatory Response & Autoimmunity gene set). Results. Gene expression analysis revealed changes in the expression levels of 30 genes in adipose tissue treated with preeclampsia sera. Some genes are related to immune response, oxidative stress, insulin resistance, and adipogenesis, which plays a central role in excessive systemic inflammatory response of preeclampsia. In contrast, other genes have shown beneficial effects in the regulation of Th2 predominance, antioxidative stress, and insulin sensitivity. Conclusion. In conclusion, visceral adipose tissue offers protection against inflammation, oxidative insults, and other forms of cellular stress that are central to the pathogenesis of preeclampsia

卵巣チョコレート嚢胞とその悪性転化における酸化抗酸化パラメーターの比較

The present study aimed to evaluate the levels of oxidative stress and antioxidant markers in benign endometrioma (OE) and its malignant transformation [endometriosis-associated ovarian cancer (EAOC)] by measuring 8-hydroxy-2-deoxyguanosine (8-OHdG), heme oxygenase-1 (HO-1) and total antioxidant capacity (TAC/Heme-iron) alterations associated with disease progression. Cyst fluid samples from 44 patients with OE and 14 patients with EAOC were studied using an enzyme-linked immunosorbent assay. A χ2 test, t-test and Pearson correlation test were performed using SPSS version 22.0. The cut-off point, sensitivity and specificity of each marker for EAOC diagnosis were evaluated by receiver operating characteristic curve analysis. Cyst fluid 8-OHdG and HO-1 levels in the EAOC group were significantly decreased compared with the OE subjects (P=0.013 and P<0.001, respectively). The levels of TAC/Heme-iron in patients with EAOC were significantly higher compared with those in the OE subjects (P<0.001). The present study demonstrated a positive correlation between 8-OHdG and HO-1 levels (P=0.012). HO-1 exhibited the highest discriminant value for EAOC (Area Under the Curve=0.901). The optimal cut-off point of HO-1 for the diagnosis of EAOC was 2.314 ng/ml, with a sensitivity and specifity of 95.2 and 85.7%, respectively. The present study revealed a clear separation between the overall redox state in OE and EAOC. It was concluded that characteristic alterations in important factors in redox may be helpful for understanding the pathogenesis of the malignant transformation of endometriosis.博士（医学）・乙第1472号・令和2年9月30日Copyright © 2018, Spandidos PublicationsArticles from Oncology Letters are provided here courtesy of Spandidos Publications.The publication is available at Spandidos Publications via https://doi.org/10.3892/ol.2018.924

NM-IIB, TGF-β1, TGF-β type I receptor (phosphorylated S-165) immunostainings for control, Subtype I and II adenomyotic cases.

<p>A strong cytoplasmic staining of NM-IIB is seen only for Subtype II cases. A clear membrane/cytoplasmic staining of TGF-β and TGF-β type I receptors is seen only for Subtype II cases. Original magnification: X400. Scale bar = 50μm.</p

Smad3/Smad2 ratios of control uteri, Subtype I and II adenomyotic foci.

<p>IM: inner myometrium of control uteri. OM: outer myometrium of control uteri. The <i>P</i> value was obtained from the Mann-Whitney U test.</p

α-SMA, Desmin, Smoothelin, and MHC immunostainings for control, Subtype I, and II adenomyotic cases.

<p>(Control IM, MM, OM: inner, middle, and outer myometrium of control uteri.) The whole myometrium for control and adenomyotic uteri were uniformly stained by α-SMA. Desmin, Smoothelin, and MHC staining was depleted or decreased at the inner myometrium of the control uteri. The vascular walls are stained by Smoothelin and MHC as an internal positive control (arrows). In adenomyotic cases, Desmin, Smoothelin and MHC negative SMCs are mainly observed at the proximal of the glands. EM: endometrium. Arrowheads indicate the uterine serosal surface, while arrows indicate vascular walls. Original magnification: X100. Scale bar = 50μm.</p

Smad2 and Smad3 immunohistological scorings of control uteri, Subtype I and II adenomyotic foci.

<p>IM: inner myometrium of control uteri. OM: outer myometrium of control uteri.</p