記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes(1-5). Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down's syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.

DOI： 10.1038/s41586-023-05834-x

リポジトリ公開URL： https://hdl.handle.net/2324/6788765

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

哺乳類の生殖細胞は、雌では卵子、雄では精子へと分化する。卵子と精子は融合して受精卵となり新しい個体が誕生し、その遺伝情報およびエピジェネティック情報を次世代に伝える。近年、多能性幹細胞であるiPS細胞／ES細胞を用いて、対外培養で生殖細胞の発生を再現する研究が進んでいる。これらの研究は、生殖細胞発生のメカニズムをさらに解明するための基盤となる。今後、対外培養によるiPS細胞からの卵子形成過程の観察をヒトに応用して不妊症への病態解明に寄与することなど、生殖医療への応用が期待される。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα13 is highly expressed in various cancers and regulates diverse cancer-related transcriptional networks and cellular functions by activating Rho. Herein, we demonstrate that increased expression of Gα13 promotes cell proliferation through activation of Rho and the transcription factor AP-1 in human endometrial cancer. Of interest, the RhoGTPase activating protein (RhoGAP), ARHGAP35 is frequently mutated in human endometrial cancers. Among the 509 endometrial cancer samples in The Cancer Genome Atlas database, 108 harbor 152 mutations at 126 different positions within ARHGAP35, representing a somatic mutation frequency of 20.2%. We evaluated the effect of 124 tumor-derived ARHGAP35 mutations on Gα13-mediated Rho and AP-1 activation. The RhoGAP activity of ARHGAP35 was impaired by 55 of 124 tumor-derived mutations, comprised of 23 nonsense, 15 frame-shift, 15 missense mutations, and two in-frame deletions. Considering that ARHGAP35 is mutated in >2% of all tumors, it ranks among the top 30 most significantly mutated genes in human cancer. Our data suggest potential roles of ARHGAP35 as an oncogenic driver gene, providing novel therapeutic opportunities for endometrial cancer.

DOI： 10.1038/s41417-022-00547-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: To analyze the effects of in-person attendance at an academic conference held during the Covid-19 pandemic on the health of the attendees, as assessed based on symptoms such as fever and cough attributed to infection with the Covid-19 virus.
Methods: A questionnaire was used to survey the members of the Japan Society of Obstetrics and Gynecology (JSOG) about their health during the period from August 7 to August 12, 2022, after the 74th Annual Congress of the JSOG, which was held August 5 to 7.
Results: Our survey yielded responses from 3054 members (1566 of whom had attended the congress in person and 1488 of whom had not attended in person); 102 (6.5%) of the in-person attendees and 93 (6.2%) of the people who did not attend in person reported problems with their health. No statistically significant difference was found between these two groups (p = 0.766). In a univariate analysis of factors affecting the presence of health problems, attendees with age ≥60 years had significantly fewer health problems than attendees who were in their 20s (odds ratio: 0.366 [0.167-0.802; p = 0.0120]). In a multivariate analysis, attendees who had received four vaccine shots had significantly fewer health problems than attendees who had received three shots (odds ratio: 0.397 [0.229-0.690, p = 0.0010]).
Conclusion: Congress attendees who took precautions at the congress to avoid being infected and who had a high vaccination rate did not develop significantly more health problems associated with in-person attendance at the congress.
Keywords: Covid-19 virus; academic conference; health of the attendees.

DOI： 10.1111/jog.15626

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Predictive genetic testing (PT) for hereditary diseases that do not have effective treatment or prevention strategies places a psychological burden on parties and their families. There has been little research on the psychosocial aspects of PT in Japan, nor are there any guidelines. To address this gap, we conducted a questionnaire survey of parties at genetic risk for untreatable hereditary neuromuscular diseases, and the National Liaison Conference of Genetic Medicine Departments (GMDs). Of the 63 parties who responded to the survey, 10 (15.9%) had undergone PT. Of the 67 GMDs, only 18 facilities (26.9%) were conducting PT with written procedures. At least two of the six parties with such results felt that some follow-up would be helpful. One party had taken PT for preimplantation genetic testing for monogenic (PGT-M); four, who had no experience, provided free text responses indicating that PGT-M or prenatal genetic testing was chosen as a motivation. Eight were unaware of PT, and six were unaware of their blood relatives' diseases being "hereditary." The results highlighted the need to: 1) develop guidelines for PT in untreatable hereditary diseases; 2) provide access to PT information; and 3) share the "heritability" of diseases with family and relatives.

DOI： 10.1016/j.ejmg.2022.104667

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim Westernization of lifestyle has increased the numbers of patients with endometrial cancer and obesity. This study aimed to compare the clinical outcomes of robotic-assisted surgery according to whether patients are obese, morbidly obese, or nonobese. Methods Sixty-three patients with endometrial cancer who underwent robotic-assisted surgery between March 2014 and June 2022 were categorized according to whether they had a body mass index (BMI) <30 (group A, nonobese, n = 40), >= 30 and <35 (group B, obese, n = 13), or >= 35 (group C, morbidly obese, n = 10). Operation time, blood loss, perioperative complications, and recurrence rate were investigated. Results Conversion to laparotomy was required in one case in group A and one in group C. There was no difference in total operation time, time for setting (including trocar installation and docking of the da Vinci robot), console time, or time for wound closure between the groups; however, there was a significant between-group difference in the total time for setting and wound closure. There was no significant difference in blood loss or complications between the groups. Three patients in group A and two in group B received adjuvant treatment; none have shown evidence of recurrent disease during a mean observation time of 21 months (range, 2-29). Two cases in group A and one in group B had recurrence during a mean observation time of 38 months (range, 19-46). Conclusion Patients with endometrial cancer who are obese can be treated safely by robotic-assisted surgery with a low risk of complications and few relapses.

DOI： 10.1111/jog.15434

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: Recent randomized phase III trial has shown significant benefit in overall survival (OS) for patients with advanced cervical cancer by adding bevacizumab to conventional chemotherapy. The aim of this study was to evaluate the prognostic impact for Japanese recurrent, persistent, or metastatic cervical cancer patients where bevacizumab was added to paclitaxel plus carboplatin.
Materials and methods: A retrospective analysis was performed on 90 patients with recurrent, persistent, or metastatic cervical cancer mainly treated by paclitaxel plus carboplatin between 2005 and 2019 at our hospital. Data for the following clinicopathological variables were analyzed: (1) bevacizumab use; (2) histology; (3) disease presentation; (4) performance status; (5) prior chemotherapy containing platinum agent; (6) pelvic disease; (7) prior pelvic radiotherapy; (8) location of target lesions. Survival analysis was performed using Kaplan-Meier curves, log-rank tests, Wilcoxon tests, and Cox proportional hazards models combined with propensity score matching.
Results: Adding bevacizumab to paclitaxel plus carboplatin showed significantly increased complete response to compared with that of non-users. In a Cox regression hazard model, bevacizumab use tended to show better OS though without statistically significance. After propensity score matching, adding bevacizumab to paclitaxel plus carboplatin showed a significant better OS by univariate analysis using Wilcoxon test, not by log-rank test.
Conclusion: Adding bevacizumab to paclitaxel plus carboplatin showed a limited prognostic impact for recurrent, persistent or advanced cervical cancer patients in the real world. Further effective second-line treatments are needed to prolong OS of patients with recurrent, persistent or advanced cervical cancer.
Keywords: Bevacizumab; Carboplatin; Drug therapy; Prognosis; Uterine cervical neoplasms.

DOI： 10.1016/j.tjog.2022.06.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cyclin-dependent kinase 8 (CDK8) is associated with the transcriptional mediator complex and regulates several transcription factors implicated in cancer. CDK8 expression is a poor prognostic marker in colon and breast cancer by immunohistochemistry. However, somatic mutations in exon 2 of the RNA polymerase II transcriptional mediator subunit MED12 occur in 7-30% of cases of uterine leiomyosarcoma (ULMS), suggesting that these alterations contribute to tumorigenesis. Public genomic mutation data of 80 patients with ULMS were used for MED12 and CDK8 mutation analysis. The expression of MED12, CDK8 and β-catenin was evaluated by immunohistochemistry in our cohort of 60 patients with ULMS, in addition with MED12 mutation status and survival stage. Univariate analysis was performed using the log-rank test, and Cox regression was used to identify independent prognostic factors. Multivariate Cox regression analysis revealed that advanced stage (p < 0.0001) and high CDK8 expression (p = 0.0014) were independent predictors of poor prognosis. MED12 mutation status was not significantly associated with CDK8 expression (p = 0.6873) and DSS (p = 0.8075). In conclusion, our data suggest that CDK8 expression may identify a subset of ULMS patients with a poor prognosis.
Keywords: CDK8; Leiomyosarcoma; MED12; Prognosis; Uterus.

DOI： 10.1016/j.prp.2022.153920

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: Sentinel node biopsy alone (SNB) reduces the postoperative complications of pelvic lymphadenectomy, such as lymphedema and lymphangitis; however, the long-term prognosis after SNB is unclear. The objective of this study was to evaluate the long-term outcome and complications of patients with early-stage cervical cancer who underwent SNB for hysterectomy or trachelectomy.
Methods: We performed SNB for cervical cancer using a radioisotope method in 181 patients between 2009 and 2017. If the intraoperative sentinel lymph node evaluation was negative for metastasis, no further lymph nodes were removed.
Results: The median age of the patients was 34 years (range, 21-73 years). The International Federation of Gynecology and Obstetrics 2008 stage was IA1 in 6 patients, IA2 in 18, IB1 in 154, and IIA1 in 3. Of the 181 patients (44 with hysterectomy, 137 with trachelectomy), 8 did not undergo pelvic lymphadenectomy because of a false-negative intraoperative diagnosis, 20 received adjuvant therapy after surgery, and 4 (2.2%) experienced recurrence over a median follow-up period of 83.5 months (range, 25-145 months). In the four recurrent cases, recurrence occurred in the pelvis, lung, and bone in one patient each, while the remaining patient developed pelvic and para-aortic lymph node metastases. Of these four patients, one died, and the remaining three are alive without disease after multidisciplinary therapy. The 5-year progression-free and overall survival rates were 98.8% and 99.4%, respectively. Postoperative complications, such as lymphedema, were very low rate.
Conclusions: SNB for early-stage cervical cancer might be safe and effective, with no increase in the recurrence and postoperative complications rate.
Keywords: Cervical cancer; Long-term follow up; Sentinel node biopsy.

DOI： 10.1016/j.ygyno.2022.01.031

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: The prognostic significance of lymphovascular space invasion (LVSI) in stage IA endometrial cancer remains unclear. The aim of this study was to evaluate the clinical significance of LVSI in stage IA endometrial cancer.
Methods: Clinical data of patients with stage IA endometrial cancer who underwent initial surgery at our institution between January 2008 and December 2018 were reviewed retrospectively. Information of patients, surgery, and characteristics of cancer were obtained from medical records and pathological reports.
Results: Two hundred ninety-seven patients were enrolled in this study. With a median follow-up of 60 months, 15 patients experienced recurrence (5.1%) and 4 patients died of endometrial cancer (1.3%). The recurrence and mortality rates did not differ significantly between the LVSI-positive and -negative groups (p = 0.07 and p = 0.41, respectively). Recurrence-free survival and endometrial cancer-specific survival also did not differ significantly between these groups (p = 0.11 and p = 0.49, respectively). The 5-year endometrial cancer-specific survival rates for tumors with and without LVSI were 97.0% and 98.9%, respectively. Among patients with low-grade tumors, recurrence-free survival and endometrial cancer-specific survival did not differ significantly between patients with tumors with and without LVSI (p = 0.92 and p = 0.72, respectively). The 5-year endometrial cancer-specific survival rates for low-grade tumors with and without LVSI were 100% and 99.3%, respectively.
Conclusion: LVSI was not a prognostic factor of not only stage IA endometrial cancer but also stage IA low-grade cancer.
Keywords: Endometrial cancer; Lymphovascular space invasion; Prognostic factors; Treatment outcome.

DOI： 10.1159/000521382

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.

DOI： 10.1038/s41598-022-07893-y

リポジトリ公開URL： http://hdl.handle.net/2324/4793640

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Nature  

Eye movement density (EMD) is an evaluation index of rapid eye movements observed during sleep. This study aimed to investigate the association of fetal EMD with sleeping and developmental problems in infancy. We observed 60 normal singleton pregnancies (gestational age 28-37 weeks) using ultrasonography for 1 h. Fetal eye movements were counted, and EMD was calculated. Participants answered questionnaires regarding their child's sleep and development 1.5 years after their delivery. The outcomes of an infant's sleep were night awakening (yes or no), bedtime (before or after 22:00), and nighttime sleep duration (< 9 or ≥ 9 h). An infant's development was evaluated using the Child Behavior Checklist (CBCL) T-score. We found that decreased fetal EMD was associated with increased night awakening at the age of 1.5 years (odds ratio 0.84, 95% confidence interval 0.69-1.00 per unit decrease in EMD). However, fetal EMD was not associated with bedtime or nighttime sleep duration. In addition, fetal EMD was independently associated with the total problems T-score of the CBCL at the age of 1.5 years in the multivariate model (p = 0.047). In conclusion, fetal EMD may be associated with sleep and developmental problems in infants.

DOI： 10.1038/s41598-022-12330-1

Web of Science

Scopus

PubMed

CiNii Research

リポジトリ公開URL： http://hdl.handle.net/2324/4793622

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Obstetrics and Gynaecology Research  

Our committee was founded in 2010 with the goal of improving women's health. This academic year we focused on the following five activities for the second consecutive year: cooperation between the department of pediatric surgery and the department of obstetrics and gynecology for the treatment of persistent cloaca and Mayer-Rokitansky-Küster-Hauser syndrome in Japan; assessment of the educational training of women's healthcare advisers; increasing screening for breast and cervical cancer; conducting the Nationwide Survey of Prescribing Practices for the Treatment of Menopausal Symptoms; and preventing osteoporosis in survivors of gynecologic cancer. The activities of each subcommittee are detailed below. This report is based on the Japanese version of the annual report (Acta Obst Gynaec Jpn 2021;73(6):684-699).
Keywords: Mayer-Rokitansky-Küster-Hauser syndrome; cancer screening; healthcare adviser; menopausal symptoms; osteoporosis; persistent cloaca.

DOI： 10.1111/jog.14986

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The International Federation of Gynecology and Obstetrics (FIGO) staging system for Müllerian cancer was changed in 2014. Our objective was to evaluate the prognostic impact of stage IV subclassification in this new staging system, especially focusing on extra-abdominal lymph node metastasis.
Methods: Eighty-two patients with stage IV Müllerian cancer treated between 2005 and 2016 at our hospital were retrospectively analyzed. Data for the following clinicopathological variables were analyzed: (1) FIGO stage; (2) tumor stage; (3) lymph node status; (4) histologic type; (5) neoadjuvant chemotherapy; (6) optimal surgery; and (7) bevacizumab use. Survival analysis was performed using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models.
Results: In accordance with the new classification, 28 and 54 patients were classified as FIGO IVA and IVB, respectively. In the Cox proportional hazards model, early-stage tumors (T1b-3b) and optimal surgery were statistically significant favorable prognostic factors. However, the new FIGO system did not discriminate prognostically between stage IVA and IVB. Median overall survival of stage IVB patients diagnosed with extra-abdominal lymph node metastasis only was better than that of stage IVA and stage IVB patients diagnosed with solid organ metastasis.
Conclusions: In this analysis of the revised FIGO system of patients reclassified as FIGO stage IVA or IVB, no new prognostic information was obtained. There is a possibility that stage IVB patients diagnosed with extra-abdominal lymph node metastasis only can be classified as an earlier stage. Further modification of the FIGO staging system may be needed to improve the prediction of patient prognosis.
Keywords: Extra-abdominal lymph nodes; Müllerian cancer; Prognosis; Stage IV subclassification.

DOI： 10.1007/s10147-021-01908-w

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Cervical intraepithelial neoplasia (CIN) is a precancerous lesion that may progress to invasive cervical cancer without intervention. We aim to examine the prognostic outcomes and risk factors for recurrence after laser vaporization for CIN 3, CIN 2 with high-risk human papillomavirus (HPV) infection, and CIN 1 persisting for more than 2 years.
Methods: Between 2008 and 2016, a total of 1070 patients underwent cervical laser vaporization using a carbon dioxide laser. We performed a retrospective review of their medical records to assess their clinical characteristics, pathologic factors, and prognostic outcomes.
Results: The mean patient age was 34 years (range 18-64 years). The preoperative diagnosis was CIN 1 in 27 patients, CIN 2 in 485 patients, and CIN 3 in 558 patients. Over a median follow-up period of 15 months, the 2-year recurrence rate was 18.9%, and the 5-year recurrence rate was 46.5%. The 2-year retreatment rate was 12.6%, and the 5-year retreatment rate was 30.5%. We diagnosed 9 patients with invasive cancer after treatment; all patients underwent combined multidisciplinary treatment, and there were no deaths during follow-up. The recurrence-free interval was correlated with patient age (hazard ratio [HR], 1.028; 95% CI 1.005-1.051; P = 0.0167), body mass index (HR, 1.052; 95% CI 1.008-1.098; P = 0.0191), and glandular involvement (HR, 1.962; 95% CI 1.353-2.846; P = 0.0004).
Conclusions: Cervical laser vaporization is effective and useful for patients with CIN who wish to preserve fertility. However, patients with glandular involvement, older age, and higher body weight require close follow-up for recurrence.
Keywords: Cervical intraepithelial neoplasia; Laser vaporization; Recurrence-free interval.

DOI： 10.1007/s10147-020-01848-x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: To determine whether vaginal progesterone (VP) reduces the rate of preterm birth in pregnant women after abdominal trachelectomy (AT) for early-stage cervical cancer STUDY DESIGN: This is an interventional study with a historical cohort. For the interventional study participants who had singleton pregnancies after AT between October 2016 and September 2020, the administration of vaginal progesterone was started between 16+ and 19+6 weeks of gestation and discontinued at 34 weeks of gestation or at the time of delivery, rupture of membranes, or massive uterine bleeding. We investigated obstetric and neonatal outcomes among the study participants and compared them with outcomes of the historical control group participants, included women with singleton pregnancies after AT who were managed without VP at our institution between January 2007 and September 2016, using Fisher's exact test and the Mann-Whitney U test The main outcomes were the gestational age at delivery and incidence of preterm birth before 37 weeks and 34 weeks of gestation.
Result: Twelve pregnancies in ten women were included in the VP group. In contrast, 19 pregnancies in 17 women were included in the historical control group. The incidence of preterm birth at <37 weeks was 10/12 (83 %) in the VP group and 11/19 (58 %) in the control group. The incidence of preterm birth at <34 weeks was 6/12 (50 %) in the VP group and 9/19 (48 %) in the control group. The incidence of preterm birth in the two groups was similar, and the difference between the two groups was not statistically significant.
Conclusion: The administration of vaginal progesterone did not reduce the rate of preterm birth among pregnant women after AT.
Keywords: Abdominal trachelectomy; Preterm birth; Preterm premature membranes rupture; Vaginal progesterone.

DOI： 10.1016/j.ejogrb.2021.02.009

リポジトリ公開URL： https://hdl.handle.net/2324/4479604

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Matricellular glycoprotein, SPARC is a secreted molecule, that mediates the interaction between cells and extracellular matrix. SPARC functions as a regulator of matrix organization and modulates cell behavior. In various kinds of cancer, strong SPARC expression was observed in stromal tissues as well as in cancer epithelial cells. The function of SPARC in cancer cells is somewhat controversial and its impact on peritumoral stromal cells remains to be resolved.
Methods: We investigated the effects of SPARC expression in endometrial cancer cells on the surrounding stromal fibroblasts using in vitro co-culture system. Changes in characteristics of fibroblasts were examined by analysis of fibroblast-specific markers and in vitro contraction assay.
Results: SPARC induced AKT phosphorylation and epithelial-to-mesenchymal transition, consistent with previous reports. Cancer-associated fibroblasts of endometrial cancer expressed higher levels of mesenchymal- and fibroblast-associated factors and had a stronger contraction ability. Unexpectedly, cancer-associated fibroblasts expressed comparable levels of SPARC compared with fibroblasts from normal endometrium. However, co-culture of normal fibroblasts with SPARC-expressing Ishikawa cells resulted in activation of the fibroblasts. Immunodepletion of SPARC did not affect the activation of fibroblasts.
Conclusions: Our data indicated that SPARC activated fibroblasts only in the presence of fibronectin, which was abundantly secreted from SPARC-expressing endometrial cancer cells. These results suggested that a SPARC-fibronectin-mediated activation of fibroblasts might be involved in enhanced mobility and invasion of cancer cells.

DOI： 10.1186/s12885-021-07875-9

リポジトリ公開URL： http://hdl.handle.net/2324/4479046

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Y-box binding protein 2 (YBX2) has been associated with the properties of both germ cells and cancer cells. We hypothesized that YBX2 might contribute to the characteristics of cancer stem cells (CSCs). In this study, we clarified the function of YBX2 in endometrial cancer stem cells. We established a human YBX2-expressing Ishikawa (IK) cell line (IK-YBX2 cells). We analyzed gene expression associated with stemness and isolated SP cells from IK-YBX2 cells. The SP population of IK-YBX2 cells, the expression of ALDH1 and serial sphere-forming capacity were associated with levels of YBX2 expression. IK-YBX2 cells were resistant to anti-cancer drugs. In gene expression analysis, a gene for cancer testis antigen, CT45, was generally overexpressed in IK-YBX2 cells. YBX2-mediated CT45 expression was associated with increased levels of self-renewal capacity and paclitaxel resistance. The level of CT45 expression was enhanced in high-grade and/or advanced stages of human endometrial cancer tissues. We conclude that expression of YBX2 is essential for the stem cell-like phenotype. CT45 contributes to stemness associated with YBX2 and might be related to the progression of endometrial cancer.

DOI： 10.1038/s41598-021-83200-5

リポジトリ公開URL： http://hdl.handle.net/2324/4476151

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ageing of the uterine endometrium is a critical factor that affects reproductive success, but the mechanisms associated with uterine ageing are unclear. In this study, we conducted a qualitative examination of age-related changes in endometrial tissues and identified candidate genes as markers for uterine ageing. Gene expression patterns were assessed by two RNA-sequencing experiments using uterine tissues from wild type (WT) C57BL/6 mice. Gene expression data obtained by RNA-sequencing were validated by real-time PCR. Genes expressing the pro-inflammatory cytokines Il17rb and chemokines Cxcl12 and Cxcl14 showed differential expression between aged WT mice and a group of mice composed of 5- and 8-week-old WT (young) animals. Protein expression levels of the above-mentioned genes and of IL8, which functions downstream of IL17RB, were analysed by quantitative immunohistochemistry of unaffected human endometrium tissue samples from patients in their 20s and 40s (10 cases each). In the secretory phase samples, 3,3'- diaminobenzidine staining intensities of IL17RB, CXCL12 and CXCL14 for patients in their 40s were significantly higher than that for patients in their 20s, as detected by a Mann-hitney U test. These results suggest that these genes are candidate markers for endometrial ageing and for prediction of age-related infertility, although confirmation of these findings is needed in larger studies involving fertile and infertile women.
Keywords: CXCL12; CXCL14; IL17RB; endometrial cell ageing; infertility; quantitative immunohistochemistry.

DOI： 10.1093/molehr/gaaa078

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Our committee was founded in 2010 with the goal of improving women's health. This academic year, we focused on five activities: cooperation between the departments of pediatric surgery and obstetrics and gynecology for the treatment of persistent cloaca and Mayer-Rokitansky-Küster-Hauser syndrome in Japan; assessment of the educational training of women's health-care advisers; increasing screening for breast and cervical cancer; conducting the Nationwide Survey of Prescribing Practices for the Treatment of Menopausal Symptoms; and preventing osteoporosis in survivors of gynecologic cancer. The activities of each subcommittee are detailed below. This report is based on the Japanese version of the annual report (Acta Obst Gynaec Jpn 2020;72(6):697-707).

DOI： 10.1111/jog.14417

リポジトリ公開URL： https://hdl.handle.net/2324/6777140

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Adjuvant therapy is usually recommended for patients with intermediate-risk cervical cancer (deep stromal invasion [DSI], lymphovascular space invasion [LVSI], and bulky tumor) after radical hysterectomy. However, we previously reported that DSI, LVSI, and bulky squamous cell carcinoma (SCC) were not correlated with prognosis in multivariate analysis; therefore, the indications we use for adjuvant therapy include complete stromal invasion, not DSI or LVSI or bulky SCC. The objective of this study was to evaluate the adequacy of our therapeutic strategy for cervical cancer after radical hysterectomy.
Methods: We performed 321 type III open radical hysterectomies for cervical cancer between 2001 and 2013. Eighty-two patients with DSI, LVSI, or bulky SCC did not receive adjuvant therapy after radical hysterectomy under informed consent. We retrospectively evaluated the prognosis of these 82 patients.
Results: Forty-two patients had >2/3 DSI and 35 patients had 1/3-2/3 DSI. Five patients had LVSI alone. The mean patient age was 43 years (range, 27-72). Six patients (7%) experienced recurrence during a median follow-up period of 84 months (range, 1-206). Two of the 6 patients with recurrence suffered cervical cancer-related deaths, but the remaining 4 cases are alive without evidence of disease after treatment during a follow-up period of 87-165 months. The 5-year disease-free survival rate was 92.6%, and the 5-year overall survival rate was 96.3%.
Conclusions: Adjuvant therapy for DSI, LVSI, or bulky SCC after open radical hysterectomy might not be necessary. Further data collection is warranted to determine the standard of care for patients with intermediate-risk cervical -cancer.

DOI： 10.1159/000508569

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The prognosis of patients with high-grade or advanced-stage endometrial cancer remains poor. As cancer stem-like cells (CSCs) are thought to be associated with endometrial cancers, it is essential to investigate the molecular mechanisms that regulate endometrial CSCs. Dual-specificity phosphatase 6 (DUSP6) functions as a negative-feedback regulator of MAPK-ERK1/2 signaling, but its role in endometrial cancer remains unknown. We investigated whether DUSP6 is involved in cancer cell stemness using endometrial cancer cell lines and specimens from endometrial cancer patients. DUSP6 induced the expression of CSC-related genes including ALDH1, Nanog, SOX2 and Oct4A, increased the population of cells in the G0/G1 phase, and promoted sphere formation ability. DUSP6 knockdown resulted in reduced cell invasion and metastasis, whereas DUSP6 overexpression inhibited apoptosis under serum-free conditions. Moreover, DUSP6 decreased phosphorylated ERK1/2 and increased phosphorylated Akt levels, which potentially induces CSC features. In patients with endometrial cancers, DUSP6 expression was determined using immunohistochemistry, and based on the results, the patients were dichotomized into high- and low-DUSP6-expression groups. Progression-free survival and overall survival were significantly shorter in the high-DUSP6-expression group. These results suggest that DUSP6 has potential value as a biomarker of CSCs and as a target of therapies designed to eliminate CSCs in endometrial cancer.

DOI： 10.1002/ijc.32965

リポジトリ公開URL： http://hdl.handle.net/2324/4476146

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Around the world, cervical cancer is one of the most common neoplastic diseases among women, and the prognosis of patients in an advanced stage remains poor. To reduce the mortality rate of cervical cancer, early diagnosis and treatment are essential. DNA methylation is an important aspect of gene regulation, and aberrant DNA methylation contributes to carcinogenesis and cancer progression in various cancers. Although 5-methylcytosine (5mC) has been analyzed intensively, the function of 5-hydroxymethylcytosine (5hmC) has not been clarified. The purpose of our study was to identify the molecular biomarkers for early diagnosis of cervical tumors due to epigenetic alterations. To assess the clinical relevance of DNA methylation, we used immunohistochemistry (IHC) to characterize the level of 5hmC in 102 archived human cervical intraepithelial neoplasia (CIN) samples and cervical cancer specimens. The level of 5hmC was significantly decreased between CIN2 and CIN3. The progression of cervical tumors is caused by a reduction of TP53 and RB1 because of HPV infection. We observed that Tp53 and Rb1 were knocked down in mouse embryonic fibroblasts (MEF), a model of normal cells. The level of 5hmC was reduced in Tp53-knockdown cells, and the expression levels of DNA methyltransferase 1 (DNMT1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) were induced. In contrast, there was no significant change in Rb1-knockdown cells. Mechanistically, we focused on apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) 3B (A3B) as a cause of 5hmC reduction after TP53 knockdown. In the human cell line HHUA with a wild-type TP53 gene, A3B was induced in TP53-knockdown cells, and A3B knockdown recovered 5hmC levels in TP53-knockdown cells. These data indicate that TP53 suppression leads to 5hmC reduction in part through A3B induction. Moreover, IHC showed that expression levels of A3B in CIN3 were significantly higher than those in both normal epithelium and in CIN2. In conclusion, 5hmC levels are decreased between CIN2 and CIN3 through the TP53-A3B pathway. Since A3B could impair genome stability, 5hmC loss might increase the chances of accumulating mutations and of progressing from CIN3 to cervical cancer. Thus, these epigenetic changes could predict whether CINs are progressing to cancer or disappearing.

DOI： 10.1371/journal.pone.0241482

リポジトリ公開URL： http://hdl.handle.net/2324/4479070

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Histopathologic analysis through biopsy has been one of the most useful methods for the assessment of malignant neoplasms. However, some aspects of the analysis such as invasiveness, evaluation range, and turnaround time from biopsy to report could be improved. Here, we report a novel method for visualizing human cervical tissue three-dimensionally, without biopsy, fixation, or staining, and with sufficient quality for histologic diagnosis. Near-infrared excitation and nonlinear optics were employed to visualize unstained human epithelial tissues of the cervix uteri by constructing images with third-harmonic generation (THG) and second-harmonic generation (SHG). THG images enabled evaluation of nuclear morphology in a quantitative manner with six parameters after image analysis using deep learning. It was also possible to quantitatively assess intraepithelial fibrotic changes based on SHG images and another deep learning analysis. Using each analytical procedure alone, normal and cancerous tissue were classified quantitatively with an AUC ≥0.92. Moreover, a combinatory analysis of THG and SHG images with a machine learning algorithm allowed accurate classification of three-dimensional image files of normal tissue, intraepithelial neoplasia, and invasive carcinoma with a weighted kappa coefficient of 0.86. Our method enables real-time noninvasive diagnosis of cervical lesions, thus constituting a potential tool to dramatically change early detection. SIGNIFICANCE: This study proposes a novel method for diagnosing cancer using nonlinear optics, which enables visualization of histologic features of living tissues without the need for any biopsy or staining dye.

DOI： 10.1158/0008-5472.CAN-20-0348

リポジトリ公開URL： https://hdl.handle.net/2324/6777143

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: For oncologic safety, vaginal radical trachelectomy is generally performed only in patients with cervical cancers smaller than 2 cm. However, because inclusion criteria for abdominal trachelectomy are controversial, we evaluated the safety of abdominal trachelectomy for cervical cancers ≥2 cm.
Methods: We began performing abdominal trachelectomies at our institution in 2005, primarily for squamous cell carcinoma ≤3 cm or adenocarcinoma/adenosquamous carcinoma ≤2 cm. If a positive sentinel lymph node or cervical margin was diagnosed intraoperatively by frozen section, the trachelectomy was converted to a hysterectomy. Medical records of these patients were reviewed retrospectively. Patients who had undergone simple abdominal trachelectomy were excluded from this study.
Results: We attempted trachelectomy in 212 patients. Among the 135 patients with tumors <2 cm, trachelectomy was successful in 120, one of whom developed recurrence and none of whom died of their disease. Among 77 patients with tumors ≥2 cm, trachelectomy was successful in 62, 2 of whom developed recurrence and 1 of whom died of her disease. The overall relapse rate after trachelectomy was 1.6% (0.8% in <2 cm group and 3.2% in ≥2 cm group), and the mortality rate was 0.5% (0% in <2 cm group and 1.6% in ≥2 cm group). Recurrence-free survival (p=0.303) and overall survival (p=0.193) did not differ significantly between the <2 cm and ≥2 cm groups.
Conclusions: Abdominal trachelectomy with intraoperative frozen sections of sentinel lymph nodes and cervical margins is oncologically safe, even in patients with tumors ≥2 cm.

DOI： 10.3802/jgo.2020.31.e41

リポジトリ公開URL： http://hdl.handle.net/2324/4479071

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Successful assisted reproductive technology pregnancy depends on the viability of embryos and endometrial receptivity. However, the literature has neglected effects of the endometrial environment during the proliferative phase on implantation success or failure. Human endometrial stromal cells (hESCs) were isolated from endometrial tissues sampled at oocyte retrieval during the proliferative phase from women undergoing infertility treatment. Primary hESC cultures were used to investigate the relationship between stemness and senescence induction in this population and embryo receptivity. Patients were classified as receptive or non-receptive based on their pregnancy diagnosis after embryo transfer. Biomarkers of cellular senescence and somatic stem cells were compared between each sample. hESCs from non-receptive patients exhibited significantly higher (p < 0.01) proportions of senescent cells, mRNA expressions of CDKN2A and CDKN1A transcripts (p < 0.01), and expressions of genes encoding the senescence-associated secretory phenotype (p < 0.05). hESCs from receptive patients had significantly higher (p < 0.01) mRNA expressions of ABCG2 and ALDH1A1 transcripts. Our findings suggest that stemness is inversely associated with senescence induction in hESCs, and by extension, that implantation failure in infertility treatment may be attributable to a combination of senescence promotion and disruption of this maintenance function in this population during the proliferative phase of the menstrual cycle. This is a promising step towards potentially improving the embryo receptivity of endometrium. The specific mechanism by which implantation failure is prefigured by a loss of stemness among endometrial stem cells, and cellular senescence induction among hESCs, should be elucidated in detail in the future.

DOI： 10.1093/biolre/ioaa044

リポジトリ公開URL： http://hdl.handle.net/2324/4476153

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gα13, a heterotrimeric G-protein of the Gα12/13 subfamily, is associated with aggressive phenotypes in various human cancers. However, the mechanisms by which Gα13 promotes cancer progression have not been fully elucidated. Here, we demonstrate that the activation of Gα13 induces epithelial-mesenchymal transition in ovarian cancer (OvCa) cells through down-regulation of large tumor suppressor kinase (LATS) 1, a critical component of the Hippo signaling pathway. A synthetic biology approach using a mutant GPCR and chimeric G-protein revealed that Gα13-regulated phosphorylation of LATS1 at serine 909 within its activation loop induced recruitment of the itchy E3 ubiquitin protein ligase to trigger LATS1 degradation. Our findings uncover novel mechanisms through which Gα13 activation induces dysregulation of the Hippo signaling pathway, which leads to aggressive cancer phenotypes, and thereby identify a potential target for preventing the metastatic spread of OvCa.-Yagi, H., Onoyama, I., Asanoma, K., Hori, E., Yasunaga, M., Kodama, K., Kijima, M., Ohgami, T., Kaneki, E., Okugawa, K., Yahata, H., Kato, K. Gα13-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer.

DOI： doi: 10.1096/fj.201901278R

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To evaluate how the desire to have children and engage in sexual activity change after trachelectomy in Japanese women with early-stage cervical cancer who strongly desired to have children before surgery.
METHODS: Desire to have children, coital pain, fear of sexual intercourse, sexual activity frequency and libido were assessed in cervical cancer patients who received follow-up after trachelectomy. An anonymous questionnaire survey was conducted via informed consent.
RESULTS: Of the 151 patients who underwent trachelectomy at Kyushu University Hospital between 2005 and 2015, 46 patients were evaluated; the response rate was 30%. The desire to have children disappeared in 13 of 46 (28%) patients, and 14 (30%) patients experienced increased coital pain. Moreover, 19 (41%) patients experienced fear of sexual intercourse, and sexual frequency decreased in 24 (52%) patients.
CONCLUSION: Trachelectomy is an important fertility-sparing surgical method; however, this study revealed loss of the desire to have children and/or to engage in sexual activity in some patients after surgery. Counseling about these issues is important and should be addressed.

DOI： 10.1111/jog.14099

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: To evaluate the prognostic outcome and surgical complications in patients with early-stage cervical cancer who underwent sentinel node navigation surgery (SNNS) for hysterectomy or trachelectomy.
METHODS: A total of 139 patients who underwent SNNS using 99mTc phytate between 2009 and 2015 were evaluated. No further lymph node dissection was performed when intraoperative analysis of the sentinel lymph nodes (SLNs) was negative for metastasis. We compared the surgical complications between the SNNS group and 67 matched patients who underwent pelvic lymph node dissection (PLND) after SLN mapping between 2003 and 2008. We also examined the clinical outcomes in the SNNS group.
RESULTS: The mean number of detected SLNs was 2.5 per patient. Fourteen of the 139 patients in the SNNS group underwent PLND based on the intraoperative SLN results. The amount of blood loss, the operative time, and the number of perioperative complications were significantly less in the SNNS group than in the matched PLND group. There was no recurrence during a follow-up period ranging from 2 to 88 months (median 40 months) in the SNNS group.
CONCLUSIONS: Using SNNS for early-stage cervical cancer is safe and effective and does not increase the recurrence rate. A future multicenter trial is warranted.

DOI： 10.1007/s10147-018-1327-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To investigate the surgical outcome of FIGO stage IA1 cervical adenocarcinoma.
METHODS: Between 2005 and 2011, 12 patients from Kyushu University Hospital had cervical adenocarcinoma, with a tumor depth of less than 3 mm and a horizontal width of less than 7 mm (FIGO stage IA1), diagnosed by cervical conization. All patients underwent simple hysterectomy or simple trachelectomy with pelvic lymphadenectomy.
RESULTS: The mean patient age was 34 years (range, 26-70 years). The median follow-up period was 70.5 months (range, 26-99 months). No pelvic lymph-node metastasis was seen, and no patient experienced disease recurrence.
CONCLUSION:Early invasive cervical adenocarcinoma with a depth of invasion of 3 mm or less and a horizontal spread of 7 mm or less has little potential for nodal metastasis or recurrence. Therefore, simple hysterectomy or trachelectomy, without lymphadenectomy, might be an alternative treatment option for stage IA1 cervical adenocarcinoma.

DOI： 10.1111/ajco.12691

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: The aim of this study was to identify the prognostic factors of uterine leiomyosarcoma (ULMS).
METHODS AND RESULTS: We reviewed 60 cases of surgically resected ULMSs and investigated conventional clinicopathological factors, together with the expression of insulin-like growth factor II messenger RNA-binding protein-3 (IMP3), hormone receptors and cell cycle regulatory markers by immunohistochemistry. Mediator complex subunit 12 (MED12) mutation analysis was also performed. Univariate analyses revealed that advanced stage (P < 0.0001), older age (P = 0.0244) and IMP3 expression (P = 0.0011) were significant predictors of a poor outcome. Multivariate analysis revealed advanced stage (P < 0.0001) and IMP3 (P = 0.0373) as independent predictors of a poor prognosis. Expressions of cell cycle markers and hormone receptors, and MED12 mutations (12% in ULMSs) were not identified as prognostic markers in this study.
CONCLUSIONS: IMP3 expression in ULMS could be a marker of a poor prognosis.

DOI： 10.1111/his.13422

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although fibrosis is one of the most prominent pathologic features of preeclamptic (PE) placentas, its mechanism remains largely unknown. Consistent with previous reports, we observed overexpression of collagen; actin, α2, smooth muscle, aorta; connective tissue growth factor; and fibronectin in PE placentas compared with control ones. To investigate the mechanism of fibrosis in PE placentas, placental fibroblasts were isolated from PE placentas or normal pregnancies at delivery. The expression of fibrosis-related factors in fibroblasts was evaluated by real-time RT-PCR, Western blotting, enzyme-linked immunosorbent assay, and gene microarrays. An in vitro collagen gel contraction assay was also performed. Fibroblasts isolated from PE placentas showed higher expression levels of fibrosis-related factors compared with those from control ones. Global gene expression profiling of PE fibroblasts was contrasted with that of control ones and indicated an intimate association with transforming growth factor-β1 (TGF-β1) signaling. Furthermore, the PE fibroblasts expressed abundant phosphorylated SMAD family member 2 and showed higher expression levels of target genes of TGF-β1 signaling compared with the control ones. The PE fibroblasts also had a greater ability to contract compared with the control ones. Contractility also depended on TGF-β1 signaling. Our results suggest that TGF-β1 signaling is activated in the fibroblasts in PE placentas and that these active fibroblasts contribute to fibrosis.

DOI： 10.1016/j.ajpath.2017.11.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND OBJECTIVES: Trachelectomy, a fertility-sparing surgery for early-stage cervical cancer, can be performed only when there is no extrauterine extension present. Therefore, identifying the sentinel lymph nodes (SLNs) and using them to obtain an intraoperative pathologic diagnosis can provide information on the feasibility and safety of trachelectomy. Our aim was to assess the value of an intraoperative SLN diagnosis.
METHODS: We retrospectively analyzed the accuracy of intraoperative imprint cytology and frozen-section examination in 201 patients at our institution in whom trachelectomy was planned.
RESULTS: All patients could be evaluated for SLNs; a total of 610 SLNs were analyzed. Although the specificity of both imprint cytology and frozen-section examination was 100.0%, the sensitivity was only 58.6 and 65.5%, respectively. The diagnostic sensitivity was higher in 2-mm slices along the short axis than on bisection along the longitudinal axis. Imprint cytology correctly diagnosed 2 patients who had false-negative results on frozen section. The nature of the metastatic foci that caused an intraoperative false-negative diagnosis was either micrometastasis or isolated tumor cells.
CONCLUSIONS: The accuracy of intraoperative SLN diagnosis requires improvement, especially when small metastatic foci are present.

DOI： 10.1159/000484049

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Although the efficacy of thoracoamniotic shunting (TAS) for fetal hydrothorax is well-recognized, the coexistence of hydrops fetalis is still a clinical challenge. The preoperative determinants of shunting efficacy are not fully understood. In this study, we aimed to investigate the perinatal and postnatal outcomes of hydrops fetalis with pleural effusion treated by TAS using a double-basket catheter, and to discuss the preoperative factors predictive of patients who will benefit from TAS.

STUDY DESIGN: We conducted a retrospective study in hydropic fetuses with pleural effusion treated by TAS between 2007 and 2015. We extracted information regarding postnatal survival and pretherapeutic sonographic findings, including skin-edema thickness, pleural-effusion pocket size, and Doppler readings.

RESULTS: Twelve subjects underwent TAS at a median gestational age of 29+5 weeks (range, 25+5-33+2 weeks). Skin edema disappeared or regressed in 7. Three experienced early neonatal death and the other 9 ultimately survived after a live birth at a median gestational age of 33+4 weeks (range, 29+1-38+2 weeks). All surviving children, except for 1, had a pretherapeutic pleural-effusion pocket greater than the precordial-edema thickness. All 3 children that died had precordial-edema thickness equal to or greater than the size of the pleural-effusion pocket.

CONCLUSIONS: We achieved a high survival rate (75%) using the double-basket technique. A greater pretherapeutic width of skin edema compared with the pleural-effusion pocket is possibly suggestive of a treatment-resistant condition and subsequent poor postnatal outcome.

DOI： 10.1016/j.ejogrb.2017.12.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Fetal heart rate (FHR) monitoring is essential for fetal management during pregnancy and delivery but results in many false-positive diagnoses. Air pollution affects the uterine environment; thus, air pollution may change FHR reactivity. This study assessed the association between exposure to air pollution during pregnancy and FHR monitoring abnormalities using 2005-2010 data from the Japan Perinatal Registry Network database. Participants were 23,782 singleton pregnant women with FHR monitoring, without acidemia or fetal asphyxia. We assessed exposure to air pollutants, including particulate matter (PM), ozone, nitrogen dioxide (NO2), and sulfur dioxide (SO2). In a multi-trimester model, first-trimester PM exposure was associated with false positives in FHR monitoring (odds ratio [OR] per interquartile range (10.7 μg/m3) increase = 1.20; 95% CI: 1.05-1.37), but not second-trimester exposure (OR = 1.05; 95% CI: 0.91-1.21) and third-trimester exposure (OR = 1.06; 95% CI: 0.96-1.17). The association with first-trimester PM exposure persisted after adjustment for exposure to ozone, NO2, and SO2; however, ozone, NO2, and SO2 exposure was not associated with false positives in FHR monitoring. First-trimester PM exposure may alter fetal cardiac response and lead to false positives in FHR monitoring.

DOI： 10.1038/s41598-017-12663-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We aimed to investigate whether the lung-to-thorax transverse area ratio (LTR) immediately before birth is of diagnostic value for the prediction of postnatal short-term outcomes in cases of isolated left-sided congenital diaphragmatic hernia (CDH). We retrospectively reviewed the cases of fetal isolated left-sided CDH managed at our institution between April 2008 and July 2016. We divided the patients into two groups based on LTR immediately before birth, using a cut-off value of 0.08. We compared the proportions of subjects within the two groups who survived until discharge using Fisher's exact test. Further, using Spearman's rank correlation, we assessed whether LTR was correlated with length of stay, duration of mechanical ventilation, and supplemental oxygen. Twenty-nine subjects were included (five with LTR < 0.08, and 24 with LTR ≥ 0.08). The proportion of subjects surviving until discharge was 40% (2/5) for patients with LTR < 0.08, as compared with 96% (23/24) for those with LTR ≥ 0.08. LTR measured immediately before birth was negatively correlated with the postnatal length of stay (Spearman's rank correlation coefficient, rs = -0.486), and the duration of supplemental oxygen (rs = -0.537). Further, the duration of mechanical ventilation was longer in patients with a lower LTR value. LTR immediately before birth is useful for the prediction of postnatal short-term outcomes in fetuses with isolated left-sided CDH. In particular, patients with prenatal LTR value less than 0.08 are at increased risk of postnatal death.

DOI： 10.1111/cga.12243

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Rapid eye movement (REM) sleep occurs throughout a relatively large proportion of early development, and normal REM activity appears to be required for healthy brain development. The eye movements (EMs) observed during REM sleep are the most distinctive characteristics of this state. EMs are used as an index of neurological function postnatally, but no specific indices of EM activity exist for fetuses. We aimed to identify and characterize EM activity, particularly EM bursts suggestive of REM periods, in fetuses with a gestational age between 24 and 39 weeks. This cross-sectional study included 84 normal singleton pregnancies. Fetal EMs were monitored using real-time ultrasonography for 60 min and recorded as videos. The videos were manually converted into a time series of EM events, which were then analyzed by piecewise linear regression for various EM characteristics, including EM density, EM burst density, density of EMs in EM bursts, and continuous EM burst time. Two critical points for EM density, EM burst density, and density of EMs in EM bursts were evident at gestation weeks 28-29 and 36-37. Overall EM activity in human fetuses increased until 28-29 weeks of gestation, then again from 36-37 to 38-39 weeks of gestation. These findings may be useful for creating indices of fetal neurological function for prognostic purposes.

DOI： 10.1371/journal.pone.0178722

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dioxins are highly toxic to foetuses and prenatal exposure leads to adverse health effects; however, the metabolic pathways involved in dioxin excretion are poorly understood. We determined the dynamics of maternal-to-foetal dioxin transfer during normal pregnancy and how foetuses eliminate polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and non-ortho polychlorinated biphenyls. Dioxin levels in maternal blood, cord blood, placenta, vernix caseosa, meconium, and amniotic fluid were analysed by high-resolution gas chromatography/mass spectrometry. The average levels of total dioxins, expressed as picograms of toxic equivalency quantity per gram of lipid and in parentheses, dioxin fraction, with maternal blood levels arbitrarily set as 100%, were as follows: maternal blood, 15.8 (100%); placenta, 12.9 (81.5%); cord blood, 5.9 (37.2%); vernix caseosa, 8.4 (53.2%); meconium, 2.9 (18.2%); and amniotic fluid, 1.5 (9.2%). Similar proportions were observed for each dioxin congener. Thus, the highest content of foetal dioxins was observed in the vernix caseosa, indicating that this is the major site of dioxin excretion in human foetuses.

DOI： 10.1038/s41598-017-00863-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Trachelectomy was developed as a fertility-sparing surgery for early-stage cervical cancer in patients of childbearing age. The purpose of this study is to evaluate oncologic and obstetric outcomes and complications after abdominal trachelectomy.

METHODS: We began to perform abdominal trachelectomy in 2005. Our institutional review board approved this clinical study, and fully informed consent was obtained from each patient. The medical records of patients who underwent trachelectomy were retrospectively reviewed.

RESULTS: We performed 151 abdominal trachelectomies (89 radical trachelectomies, 48 modified radical trachelectomies, and 14 simple trachelectomies). The median age of the patients was 33 years, and the median postoperative follow-up period was 61 months. Although one patient experienced recurrence at the preserved cervix, none died after treatment. A total of 61 patients attempted to conceive after trachelectomy, and 21 pregnancies were achieved in 15 women. Hence, the pregnancy rate among patients who attempted to conceive was 25%. Fifteen babies were delivered by cesarean section between gestational weeks 23 and 37. Six babies were delivered at term. Six cases of preterm premature rupture of the membranes occurred. Varices appeared around the uterovaginal anastomotic site in five patients.

CONCLUSIONS: Our data indicate that the oncologic outcome was excellent but infertility treatment was necessary to achieve the majority of conceptions. Additionally, preterm premature rupture of the membranes and premature delivery were frequently observed. An improved pregnancy rate and prevention of complications during pregnancy are issues that should be addressed in future studies.

DOI： 10.1007/s10147-016-1059-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch and
c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various
human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian
cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes.
We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was
negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression
levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors
(P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major
histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels
of FBXW7 expression compared with p53 wild-type cancer samples (P < 0.001). DNA methylation arrays
and bisulfite PCR sequencing experiments revealed that 5'-upstream regions of FBXW7 gene in p53-mutated
samples were significantly higher methylated compared with those in p53 wild-type samples (P < 0.01).
This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation
of FBXW7 5'-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was
associated with p53 mutations and the DNA methylation status of the 5'-upstream regions of FBXW7.

DOI： 10.1111/cas.13026.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Substance P contributes to the hypersensitivity reaction (HSR) to paclitaxel in a rat model.
Aprepitant acts as an inhibitor of the binding of substance P to the neurokinin-1 receptor and, consequently,
may reduce the frequency of paclitaxel-induced HSR. While aprepitant has a prophylactic effect against
vomiting caused by high-dose cisplatin, the benefits of aprepitant have not been clearly demonstrated in
patients receiving paclitaxel and carboplatin (TC) combination chemotherapy.

METHODS: We conducted a multicenter, placebo-controlled, double-blind, randomized study in Japanese
patients with gynecologic cancer who received TC combination chemotherapy. Patients received aprepitant
or placebo together with both a 5-HT3 receptor antagonist and dexamethasone prior to chemotherapy.
The primary endpoint was the proportion of patients with HSR, and the secondary endpoints were the
proportion of patients with "no vomiting", "no significant nausea", and complete response, respectively.

RESULTS: Of the 324 randomized patients, 297 (151 in the aprepitant group; 146 in the placebo group)
were evaluated. The percentage of patients with HSR (9.2 vs. 7.5 %, respectively; P = 0.339) was not
significantly different between the groups. The percentage of "no vomiting" patients (78.2 vs. 54.8 %;
P < 0.0001), "no significant nausea" patients (85.4 vs. 74.7 %; P = 0.014), and patients showing complete
response (61.6 vs. 47.3 %, P = 0.0073) was significantly higher in the aprepitant group than in the placebo
group.

CONCLUSION: The administration of aprepitant did not have a prophylactic effect on the HSR but was
effective in reducing nausea and vomiting in gynecologic cancer patients receiving TC combination
chemotherapy.

DOI： 10.1007/s10147-015-0928-y.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

妊娠中のサイトメガロウイルス（CMV）感染は児に不良な予後をもたらしうる重大な感染症であり，診断には母体の血清CMV-IgMが
用いられることが多い．症例は29歳の初産婦．妊娠24週の超音波検査で胎児の発育不全，腹水，腸管高輝度像を認めた．
胎児中大脳動脈最高血流速度が2.5 MoMと高値であり臍帯穿刺を行ったが，臍帯血の血色素量は9.2 g/dlと貧血は軽度で，一方で
血小板数が2.8万/μlと著明低値であった．母体血清よりTORCHスクリーニングを行ったが，CMV-IgMをはじめ全て陰性であった．
しかし諸所見からCMV感染を強く疑い，羊水でのCMV-PCR検査を行ったところ，陽性であり先天感染の診断に至った．
妊娠26週に胎児機能不全と診断したが急速墜娩を選択されず，子宮内胎児死亡となった．死産後の胎盤病理検査で巨細胞封入体を認め，免疫染色で抗CMV抗体が陽性であった．先天性CMV感染は母体のCMV-IgMが陰性であることをもって必ずしも否定されず，
諸所見で感染を強く疑えば羊水PCR検査を考慮すべきである．

DOI： 10.3179/jjmu. JJMU.A.59

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

2006年1月から2015年2月までに当科で胎児発育不全と診断し妊娠22週以降に500g未満で出生となった単胎症例を対象とし, 診療録から後方視的に検討した. 形態異常児は除外した. 対象は17例で, 児出生体重の中央値は404g(267-496g), 分娩週数の中央値は妊娠26週2日(妊娠24週0日-妊娠29週2日)で, すべて帝王切開分娩となっていた. 7例(41%)が高血圧または妊娠高血圧症候群を合併し, 11例(64%)に羊水過少, 全例に血流再分配像, 14例(82%)に臍帯動脈の拡張期途絶逆流現象を認めていた. 児は11例(65%)が生存退院し, 1例が精神発達遅滞, 1例が脳性麻痺と診断されていた. 生存退院率は低くなく, 重篤な発達障害をきたしたものも少数であった. 24週, 300gというラインは相応の予後が見込める水準と考えられ, 早期発症の胎児発育不全を管理するにあたって, 児救命を目指した産科管理を適用することが原則になって良いと考えられた.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We aimed to improve the efficiency of isolating endometrial epithelial and stromal cells (EMECs and EMSCs) from the human endometrium. We revealed by immunohistochemical staining that the large tissue fragments remaining after collagenase treatment, which are usually discarded after the first filtration in the conventional protocol, consisted of glandular epithelial and stromal cells. Therefore, we established protease treatment and cell suspension conditions to dissociate single cells from the tissue fragments and isolated epithelial (EPCAM-positive) and stromal (CD13-positive) cells by fluorescence-activated cell sorting. Four independent experiments showed that, on average, 1.2 × 10(6) of EMECs and 2.8 × 10(6) EMSCs were isolated from one hysterectomy specimen. We confirmed that the isolated cells presented transcriptomic features highly similar to those of epithelial and stromal cells obtained by the conventional method. Our improved protocol facilitates future studies to better understand the molecular mechanisms underlying the dynamic changes of the endometrium during the menstrual cycle.

DOI： 10.1262/jrd.2015-137

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The continual proliferation and differentiation of trophoblasts are critical for the maintenance of pregnancy. It is well known that the tissue stem cells are associated with the development of tissues and pathologies. It has been demonstrated that side-population (SP) cells identified by fluorescence-activated cell sorting (FACS) are enriched with stem cells. The SP cells in HTR-8/SVneo cells derived from human primary trophoblast cells were isolated by FACS. HTR-8/SVneo-SP cell cultures generated both SP and non-SP (NSP) subpopulations. In contrast, NSP cell cultures produced NSP cells and failed to produce SP cells. These SP cells showed self-renewal capability by serial colony-forming assay. Microarray expression analysis using a set of HTR-8/SVneo-SP and -NSP cells revealed that SP cells overexpressed several stemness genes including caudal type homeobox2 (CDX2) and bone morphogenic proteins (BMPs), and lymphocyte antigen 6 complex locus D (LY6D) gene was the most highly up-regulated in HTR-8/SVneo-SP cells. LY6D gene reduced its expression in the course of a 7-day cultivation in differentiation medium. SP cells tended to reduce its fraction by treatment of LY6D siRNA indicating that LY6D had potential to maintain cell proliferation of HTR-8/SVneo-SP cells. On ontology analysis, epithelial-mesenchymal transition (EMT) pathway was involved in the up-regulated genes on microarray analysis. HTR-SVneo-SP cells showed enhanced migration. This is the first report that LY6D was important for the maintenance of HTR-8/SVneo-SP cells. EMT was associated with the phenotype of these SP cells.

DOI： 10.1007/s13577-015-0121-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

G-protein-coupled receptors (GPCRs) and their ligands function in the progression of human malignancies. Gα12 and Gα13, encoded by GNA12 and GNA13, respectively, are referred to as the GEP oncogene and are implicated in tumor progression. However, the molecular mechanisms by which Gα12/13 activation promotes cancer progression are not fully elucidated. Here, we demonstrate elevated expression of Gα12/13 in human ovarian cancer tissues. Gα12/13 activation did not promote cellular migration in the ovarian cancer cell lines examined. Rather, Gα12/13 activation promoted cell growth. We used a synthetic biology approach using chimeric G proteins and GPCRs activated solely by artificial ligands to selectively trigger signaling pathways downstream of specific G proteins. We found that Gα12/13 promotes proliferation of ovarian cancer cells by activating the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway. Furthermore, we reveal that inhibition of YAP by short hairpin RNA or a specific inhibitor prevented the growth of ovarian cancer cells. Therefore, YAP may be a suitable therapeutic target in ovarian cancer.Oncogene advance online publication, 25 January 2016; doi:10.1038/onc.2015.505.

DOI： 10.1038/onc.2015.505.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adult stem cells have recently been identified in several types of mature tissue and it has been also suggested that stem-like cells exist in cancerous tissues. It is believed that many cancer stem cells (CSCs) upregulate the expression of drug transporters, allowing them to efficiently pump antitumor agents out of the cells. CSCs reside in a quiescent state, making them resistant to chemotherapeutic agents that target rapidly cycling cells. They are also endowed with a more invasive and metastatic phenotype. These results indicate the requirement to develop a new target treatment for CSCs. There are several methods for the identification of CSCs; for example, detection by CSC markers, such as CD133, CD44, CD117(c-kit), aldehyde dehydrogenase 1 (ALDH1), and isolation of side population (SP), which are identified based on their ability to remove intracellular Hoechst 33342, a fluorescent dye. Here, we review recent articles that show the presence of stem cells in endometrial cancer and introduce the results of our own recent studies using CD133 or CD117 positive cells and SP cells.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND:
The functional single nucleotide polymorphism (SNP) in the MDM2 promoter region, SNP309, is known to be associated with various diseases, particularly cancer. Although many studies have been performed to demonstrate the mechanism of allele-specific expression (ASE) on SNP309, they have only utilized in vitro techniques. It is unknown whether ASE of MDM2 is ascribed solely to SNP309, in vivo.

METHODS:
We attempted to evaluate ASE of MDM2 in vivo using post-labeling followed by automated capillary electrophoresis under single-strand conformation polymorphism conditions. For measuring a quantitative difference, we utilized the SNPs on the exons of MDM2 as markers, the status of which was heterozygous in a large population. To address the cause of ASE beyond 20 %, we confirmed sequences of both MDM2-3'UTR and promoter regions. We assessed the SNP which might be the cause of ASE using biomolecular interaction analysis and luciferase assay.

RESULTS:
ASE beyond 20 % was detected in endometrial cancers, but not in cancer-free endometria samples only when an SNP rs1690916 was used as a marker. We suspected that this ASE in endometrial cancer was caused by the sequence heterogeneity in the MDM2-P2 promoter, and found a new functional polymorphism, which we labelled SNP55. There was no difference between cancer-free endometria and endometrial cancer samples neither for SNP55 genotype frequencies nor allele frequencies, and so, SNP55 alone does not affect endometrial cancer risk. The SNP55 status affected the DNA binding affinity of transcription factor Sp1 and nuclear factor kappa-B (NFκB). Transcriptional activity of the P2 promoter containing SNP55C was suppressed by NFκB p50 homodimers, but that of SNP55T was not. Only ASE-positive endometrial cancer samples displayed nuclear localization of NFκB p50.

CONCLUSIONS:
Our findings suggest that both the SNP55 status and the NFκB p50 activity are important in the transcriptional regulation of MDM2 in endometrial cancers.

DOI： 10.1186/s12881-015-0216-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The decidua is known to be a major source of intrauterine PGF2α during late gestation and labor, and inflammatory cytokines, including IL-1β, IL-6, and IL-8, are elevated in spontaneous preterm deliveries. In the present study, to elucidate how progesterone blocks the pathways associated with preterm birth, we determined the effects of P4 on the expression of PTGS-2 and PTGFR mRNA in human decidua fibroblast cells, as well as the genes, using microarray analysis. Senescence was induced in primary cultured human decidual cells treated with IL-1β. The IL-1β treatment implicated by microarray analysis increased gene expression levels of PTGS-2, PTGFR, NFκ-B p65, IL-17, and IL-8. In contrast, P4+IL-1β decreased the expression levels of all of these genes in comparison to treatment with IL-1β alone (p<0.05). IL-1β also increased the proportion of SA-β-gal-positive cells. Treatment with IL-1β also increased the p21 protein level in comparison to cells treated either with the vehicle or P4. Neither the p21 protein level nor the number of SA-β-gal-positive cells was increased in normal endometrial glandular cells by IL-1β (p<0.05). Our studies demonstrated that P4 changes the level of gene expression in a manner that favors an anti-inflammatory milieu. Because IL-8 appears to be the cytokine whose expression is most significantly modulated by P4, further studies evaluating IL-8 as a therapeutic target are needed.

DOI： 10.1016/j.jri.2014.03.008

記述言語：英語  

Objectives
We previously demonstrated that side-population (SP) cells found in human endometrial cancer tissue have features of cancer stem cells (CSCs). Endometrial cancer SP cells show enhanced migration, the potential to differentiate into the mesenchymal cell lineage, and they are associated with the epithelial–mesenchymal transition (EMT). In this study, we analyzed the expression and function of a specific protein, SPARC (secreted protein acidic and rich in cysteine) which we found to be up-regulated in endometrial cancer.

Methods
We performed microarray expression analysis to screen for up-regulated genes in CSCs using a set of RK12V-SP cells and -non-SP (NSP) cells. We used the MetaCore package to identify the Gene GO pathway MAPs associated with the up-regulated genes. Here, we investigated the expression and functions of SPARC, one of the genes up-regulated in endometrial CSCs.

We established SPARC-overexpressing cells by transfecting endometrial cancer cells (Ishikawa cells [IK-SPARC cells]). We characterized these cells' growth rate, tumorigenicity, migration and invasion activity. The levels and locations of SPARC protein expression in Hec1SP cells-derived tumors and endometrial cancer tissues were examined by immunohistochemistry.

Results
SPARC was detected by microarray expression analysis during screens for up-regulated genes in SP and NSP CSC. The level of SPARC expression was enhanced in Hec1 SP cells compared with that in Hec1 non-SP cells. SPARC enhanced fibronectin expression and promoted migration activity in IK cells. SPARC expression suppressed tumor growth but promoted formation of tumor stroma.

SPARC was expressed in endometrial cancer tissues, in particular, poorly differentiated endometrioid adenocarcinoma, clear and serous adenocarcinoma,but not in normal endometrial tissue.

Conclusion
This is the first report of overexpression of SPARC in endometrial cancer stem-like cells. SPARC expression is associated with cell migration and stroma formation.

Keywords
SPARC; Endometrial cancer; EMT; CSCs; Cell migration

記述言語：英語  

DOI： 10.3892/or.2013.2433

記述言語：英語  

Goals: We previously demonstrated that side-population (SP) cells in human endometrial cancer cells (Hec1 cells) and in rat endometrial cells expressing oncogenic human K-Ras protein (RK12V cells) have features of cancer stem cells (CSCs). Hec1-SP cells showed enhanced migration and
the potential to differentiate into the mesenchymal cell lineage. In this study, we analyzed the association of the epithelial-mesenchymal transition (EMT) with the properties of these endometrial CSCs. We also assessed and the effects of salinomycin (a compound with EMT-specific toxicity) on the proliferative capacity, migration and invasiveness of these endometrial CSCs using Hec1-SP cells.
Method: We performed microarray expression analysis to screen for up-regulated genes in CSCs using a set of RK12V-SP cells and –non-SP(NSP) cells and used the Metacore package to identify the Gene GO pathway MAPs involved in the up-regulated genes. To analyze their association with EMT, the expression of several EMT associated genes in Hec1-SP cells was investigated by real time PCR and compared with that in Hec1-NSP cells. We assessed the expression of BAX, BCL2, LEF1, cyclinD and fibronectin by real time PCR. We also evaluated the viabilities, migration and invasive activities, and tumorigenicities of these SP cells and NSP cells in the presence or absence of salinomycin.
Results: We demonstrated that i) EMT processes were observed in both RK12V-SP cells and Hec1-SP cells, ii) the level of fibronectin was enhanced in Hec1-SP cells and salinomycin reduced the level of fibronectin expression, iii) salinomycin induced apoptosis and inhibited Wnt signaling, and iv) salinomycin inhibited the proliferation, migration, invasiveness and tumorigenicity of these SP cells.
Conclusion: This is the first report of an inhibitory effect of salinomycin on the properties of endometrial CSCs.

DOI： 10.1016/j.ygyno.2013.03.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語  

掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/0008-5472.CAN-3487-2

出版者・発行元：JCO Precision Oncology  

PURPOSE Human epidermal growth factor receptor 2 (HER2)–targeted therapies have shown promise in treating HER2-amplified metastatic colorectal cancer (mCRC). Identifying optimal biomarkers for treatment decisions remains challenging. This study explores the potential of artificial intelligence (AI) in predicting treatment responses to trastuzumab plus pertuzumab (TP) in patients with HER2-amplified mCRC from the phase II TRIUMPH trial. MATERIALS AI-powered HER2 quantification continuous score (QCS) and tumor micro-AND METHODS environment (TME) analysis were applied to the prescreening cohort (n 5 143) and the TRIUMPH cohort (n 5 30). AI analyzers determined the proportions of tumor cells (TCs) with HER2 staining intensity and the densities of various cells in TME, examining their associations with clinical outcomes of TP. RESULTS The AI-powered HER2 QCS for HER2 immunohistochemistry (IHC) achieved an accuracy of 86.7% against pathologist evaluations, with a 100% accuracy for HER2 IHC 31 patients. Patients with ≥50% of TCs showing HER2 31 staining intensity (AI-H3-high) exhibited significantly prolonged progression-free survival (PFS; median PFS, 4.4 v 1.4 months; hazard ratio [HR], 0.12 [95% CI, 0.04 to 0.38]) and overall survival (OS; median OS, 16.5 v 4.1 months; HR, 0.13 [95% CI, 0.05 to 0.38]) compared with the AI-H3-low (<50% group). Stratification among patients with AI-H3-high included TME-high (all lymphocyte, fibroblast, and macrophage densities in the cancer stroma above the median) and TME-low (anything below the median), showing a median PFS of 1.3 and 5.6 months for TME-high and TME-low respectively, with an HR of 0.04 (95% CI, 0.01 to 0.19) for AI-H3-high with TME-low compared with AI-H3-low. CONCLUSION AI-powered HER2 QCS and TME analysis demonstrated potential in enhancing treatment response predictions in patients with HER2-amplified mCRC undergoing TP therapy.

DOI： 10.1200/PO-24-00385

Scopus

出版者・発行元：Materials Today Catalysis  

Understanding the behavior of noble-metal catalysts is a key point of catalysis research aimed at reducing the environmental and economic costs associated with the increased use of automobiles. In this study, the atomic-behaviors of Ru and Pd atoms in PdRu solid-solution nanoparticles (NPs) supported on CeO2-ZrO2 (CZ) as a Rh-free three-way catalyst in a modeled three-way catalytic reaction (TWCR) were elucidated using a gas conversion analysis, transmission electron microscopy, and in-situ X-ray absorption fine structure spectroscopy. We found that the PdRu NPs enlarged by the annealing effect separated a smaller grain size with the Pd-rich and Ru-rich phase under TWCR. Most of the oxidation and reduction reactions under the modeled TWCR occurred on the Ru. However, the Pd metals acted as a major role of the reduction of NO gas and oxidation of CO and C3H6 gas. Ru atoms just is a minor role during the modeled TWCR. This study demonstrates the potential of PdRu NPs as a three-way catalyst and reveals the atomic-behavior and catalytic role under the modeled TWCR.

DOI： 10.1016/j.mtcata.2024.100078

Scopus

記述言語：英語   出版者・発行元：Hematological Oncology  

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides durable remission for patients with adult T-cell leukemia/lymphoma (ATL); however, few studies have focused on post-transplant outcomes in ATL patients ≤49 years. To clarify prognostic factors in ATL among patients <40 years (adolescents and young adult [AYA]; n = 73) and 40–49 years (Young; n = 330), we conducted a nationwide retrospective study. Estimated 3-year overall survival (OS) rates were 61.8% and 43.1% in AYA and Young patients, respectively (p = 0.005). In the multivariate analysis, Young patients showed worse OS (Hazard ratio (HR) [95% confidential interval] 1.62 [1.10–2.39], p = 0.015), chronic graft-versus-host disease (GVHD)-free and relapse-free survival (CRFS) (HR 1.54 [1.10–2.14], p = 0.011), and GVHD-free and relapse-free survival (GRFS) (HR 1.40 [1.04–1.88], p = 0.026) than AYA patients. No significant differences were observed in OS, CRFS, or GRFS between the myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens; however, non-relapse mortality was significantly lower in patients with the RIC regimen than those with the MAC regimen (HR 0.46 [0.24–0.86], p = 0.015). In summary, OS was worse in Young patients than in AYA patients in the allo-HSCT setting for ATL. Furthermore, the RIC regimen has potential as an alternative treatment option for ATL patients ≤49 years.

DOI： 10.1002/hon.3315

Scopus

PubMed

記述言語：英語   出版者・発行元：Pediatric Blood and Cancer  

Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.

DOI： 10.1002/pbc.31244

Scopus

PubMed

記述言語：英語   出版者・発行元：American Journal of Hematology  

Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7–97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan–Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46–90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90–8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0–51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.

DOI： 10.1002/ajh.27424

Scopus

PubMed

出版者・発行元：Nature Chemistry  

Providing affordable, safe drinking water and universal sanitation poses a grand societal challenge. Here we developed atomically dispersed Au on potassium-incorporated polymeric carbon nitride material that could simultaneously boost photocatalytic generation of ·OH and H2O2 with an apparent quantum efficiency over 85% at 420 nm. Potassium introduction into the poly(heptazine imide) matrix formed strong K–N bonds and rendered Au with an oxidation number close to 0. Extensive experimental characterization and computational simulations revealed that the low-valent Au altered the materials’ band structure to trap highly localized holes produced under photoexcitation. These highly localized holes could boost the 1e− water oxidation reaction to form highly oxidative ·OH and simultaneously dissociate the hydrogen atom in H2O, which greatly promoted the reduction of oxygen to H2O2. The photogenerated ·OH led to an efficiency enhancement for visible-light-response superhydrophilicity. Furthermore, photo-illumination in an onsite fixed-bed reactor could disinfect water at a rate of 66 L H2O m−2 per day. (Figure presented.)

DOI： 10.1038/s41557-024-01553-6

Scopus

出版者・発行元：Journal of Gastroenterology  

Background: This study aimed to clarify the morphological changes in esophageal varices after achieving sustained virological response (SVR) with direct-acting antivirals (DAAs) in patients with cirrhosis. Methods: A total of 243 patients underwent esophagogastroduodenoscopy before DAA treatment and after achieving SVR. Morphological changes in esophageal varices were investigated using esophagogastroduodenoscopy. Results: This study comprised 125 males and 118 females with a median age of 68 years. Esophageal varices at baseline were classified into no varix in 155 (63.8%), F1 in 59 (24.3%), F2 in 25 (10.3%) and F3 in 4 (1.6%) patients. The improvement, unchanged, and aggravation rates of esophageal varices after SVR were 11.9%, 73.3%, and 14.8%, respectively. High ALBI score at SVR12 was an independent factor associated with post-SVR esophageal varices aggravation (p = 0.045). Time-dependent receiver operating characteristic (ROC) curve analysis revealed a cut-off value of − 2.33 for ALBI score at SVR12 in predicting post-SVR esophageal varices aggravation. Of the 155 patients without esophageal varices at baseline, 17 developed de novo post-SVR esophageal varices. High ALBI score at SVR12 was a significant independent factor associated with de novo post-SVR esophageal varices (p = 0.046). ROC curve analysis revealed a cut-off value of − 2.65 for ALBI score at SVR12 in predicting de novo post-SVR esophageal varices. Conclusions: Patients with cirrhosis can experience esophageal varices aggravation or de novo esophageal varices, despite achieving SVR. In particular, patients with high ALBI score at SVR12 have a high likelihood of developing post-SVR esophageal varices aggravation or de novo post-SVR esophageal varices.

DOI： 10.1007/s00535-024-02109-8

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aims: p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in endocervical adenocarcinoma (ECA); however, its specificity is not perfect.

Methods and results: We examined p16 and Rb expressions by immunohistochemistry (IHC) and the transcriptionally active HR-HPV infection by mRNA in-situ hybridisation (ISH) with histological review in 108 ECA cases. Thirteen adenocarcinomas of endometrial or equivocal origin (six endometrioid and seven serous carcinomas) were compared as the control group. HR-HPV was detected in 83 of 108 ECA cases (77%), including five HPV-associated adenocarcinomas in situ and 78 invasive HPV-associated adenocarcinomas. All 83 HPV-positive cases showed consistent morphology, p16 positivity and partial loss pattern of Rb. Among the 25 cases of HPV-independent adenocarcinoma, four (16%) were positive for p16, and of these four cases, three of 14 (21%) were gastric type adenocarcinomas and one of 10 (10%) was a clear cell type adenocarcinoma. All 25 HPV-independent adenocarcinomas showed preserved expression of Rb irrespective of the p16 status. Similarly, all 13 cases of the control group were negative for HR-HPV with preserved expression of Rb, even though six of 13 (46%) cases were positive for p16. Compared with p16 alone, the combination of p16 overexpression and Rb partial loss pattern showed equally excellent sensitivity (each 100%) and improved specificity (100 versus 73.6%) and positive predictive values (100 versus 89.2%) in the ECA and control groups. Furthermore, HR-HPV infection correlated with better prognosis among invasive ECAs.

Conclusions: The results suggest that the combined use of p16 and Rb IHC could be a reliable method to predict HR-HPV infection in primary ECAs and mimics. This finding may contribute to prognostic prediction and therapeutic strategy.

Keywords: Rb; endocervical adenocarcinoma; human papillomavirus; p16; uterus.

DOI： 10.1111/his.15169

記述言語：英語   出版者・発行元：Journal of Alzheimer's Disease  

Background: An association between poor oral health and cognitive decline has been reported. Most of these studies have considered the number of teeth as a criterion, only a few studies have analyzed the relationship between occlusal status and Alzheimer’s disease (AD). Objective: To elucidate whether posterior occlusal contact is associated with AD, focusing on the Eichner classification, among an older population aged 65 years or older in Japan. Methods: This study used monthly claims data of National Health Insurance in Japan from April 2017 to March 2020. The outcome was newly diagnosed AD defined according to ICD-10 code G30. The number of teeth was estimated by dental code data, and occlusal contact was divided into three categories, namely A, B, and C, according to the Eichner classification. Multivariate Cox proportional hazards models were used to analyze the association between a new diagnosis of AD and the Eichner classification. Results: A total of 22,687 participants were included, 560 of whom had newly diagnosed AD during a mean follow-up period of 12.2 months. The AD participants had a lower proportion of Eichner A and a higher proportion of Eichner C. After adjusting for covariates, hazard ratios (95% confidence intervals) with Eichner B and C were 1.34 (1.01–1.77) and 1.54 (1.03–2.30), respectively. Conclusions: In older people aged ≥ 65 years old, reduced posterior occlusal contact as well as tooth loss have an impact on AD. This study emphasizes the importance of paying attention to occlusal contacts to reduce the risk of AD.

DOI： 10.3233/JAD-230449

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia and the failure of meiotic double-strand break (DSB) formation, leading to meiotic prophase I arrest and cell death. Transcriptional analyses demonstrate that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia, necessary for spermatogonial proliferation and meiosis. CHD8 directly binds and regulates genes crucial for meiosis, including H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain-containing genes, synaptonemal complex genes, and DNA damage response genes. We infer that CHD8 contributes to meiotic DSB formation and subsequent meiotic progression through combined regulation of these meiosis-related genes. Our study uncovers an essential role of CHD8 in the proliferation of undifferentiated spermatogonia and the successful progression of meiotic prophase I.

DOI： 10.1093/nar/gkad1256

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Although many human papillomavirus (HPV)-targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine.

Methods: In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16-positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety.

Results: In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7-specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner.

Conclusion: This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16-positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects.

Trial registration: jRCT2031190034.

DOI： 10.1093/jncics/pkad101.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tubo-ovarian high-grade serous carcinoma (HG-SC) and ovarian endometrioid carcinoma (EC) can show overlapping morphologic features, such as glandular and solid patterns. The differential diagnosis of these subtypes is thus sometimes difficult. The existence of "squamous differentiation" tends to lead to a diagnosis of EC rather than HG-SC. We noticed that HG-SC can contain a "squamoid component," but its nature has been poorly investigated. This study was thus established to clarify the nature of this "squamoid component" in HG-SC by investigating its frequency and immunohistochemical features. We reviewed hematoxylin and eosin-stained slides of 237 primary untreated cases of tubo-ovarian HG-SC and identified 16 cases (6.7%) of HG-SC with "squamoid component." An immunohistochemical staining panel (CK5/6, CK14, CK903, p40, p63, WT1, ER, and PgR) was used to analyze all of these 16 cases. We also selected 14 cases of ovarian EC with "squamous differentiation" as a control. The "squamoid component" in HG-SC was completely p40-negative and showed significantly lower expression of CK5/6, CK14, CK903, and p63 than the "squamous differentiation" in EC. The immunophenotype of the "squamoid component" in HG-SC was concordant with the conventional HG-SC component (WT1-positive/ER-positive). Furthermore, all 16 tumors were confirmed to be truly "HG-SC" by the findings of aberrant p53 staining pattern and/or WT1/p16 positivity, and the lack of mismatch repair deficiency and POLE mutation. In conclusion, HG-SC can on rare occasions show a "squamoid component" mimicking "squamous differentiation." However, the "squamoid component" in HG-SC does not represent true "squamous differentiation." The "squamoid component" is one part of the morphologic spectrum of HG-SC, which should be interpreted carefully for the differential diagnosis of HG-SC and EC. An immunohistochemical panel including p40, p53, p16, and WT1 is a useful adjunct to achieve a correct diagnosis.

DOI： 10.1097/PAS.0000000000002089

リポジトリ公開URL： https://hdl.handle.net/2324/7183383

記述言語：英語   掲載種別：研究論文（学術雑誌）  

As 2 years have passed since the outbreak of coronavirus disease 2019 (COVID-19), we had an examination of the measures taken at the perinatal medical and child centers during this period at 42 National University Hospital. The first questionnaire survey was conducted during March 17-25, 2022 and the second questionnaire survey was conducted during April 4-30, 2022. For the treatment of pregnant women with COVID-19, a public health center-coordinated triage system had been created and implemented in each region and prefecture. The issues related to the hospital management of pregnant women with COVID-19 include the hindrances to the normal functioning of the center, the limited number of hospital beds and medical care systems as the beds were dedicated to patients with COVID-19, and the problems associated with the mode of delivery. There were no set rules regarding the management of mothers and babies at delivery and thereafter. Initially, cesarean delivery was allowed in almost all cases to reduce the risk of exposure to medical staff. Furthermore, many institutions did not permit expressed breast milk feeding and direct breastfeeding during the quarantine period. The COVID-19 pandemic has been created a shortage of healthcare delivery systems. It is expected that the emergence of new infectious diseases and pandemics will cause the same pressure on systems providing healthcare in the future.

DOI： 10.1111/jog.15650

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Sleep problems and irritable temperaments are common among infants with autism spectrum disorder (ASD). The prospective association between such sleep problems and irritable temperaments and ASDs needs to be determined for elucidating the mechanism and exploring the future intervention study. Thus, in this study, we investigated whether sleep quality and temperament in 1-month-old infants are associated with the onset of ASD in 3-year-old children. We also assessed its sex-stratified associations.
Methods: We conducted a longitudinal study using data from 69,751 mothers and infants from a large-cohort study, the Japan Environment and Children's Study. We examined the prospective association between infant sleep quality and temperament at 1 month of age and ASD diagnosis by 3 years of age.
Results: Here we show infants with longer daytime sleep have a higher risk of later ASD than those with shorter daytime sleep (risk ratio [RR]: 1.33, 95% confidence interval [CI]: 1.01-1.75). Infants who experienced intense crying have a higher risk of ASD than those who did not (RR: 1.31, 95% CI: 1.00-1.72). There is a difference in sex in the association between a bad mood and later ASD. In particular, female infants experiencing bad moods have a higher risk of ASD than others (RR: 3.59, 95% CI: 1.91-6.75).
Conclusions: The study findings provide important information for future intervention to reduce the risk of future ASD.

DOI： 10.1038/s43856-023-00314-9

リポジトリ公開URL： https://hdl.handle.net/2324/7183385

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although fungi can have a large impact on host health through the stimulation of the immune system and toxin production, few studies have investigated the gut mycobiota during infancy, a period during which sensitivity to internal and external stimuli is high. To capture the trend in fungal colonization during infancy, we evaluated the gut mycobiota of ten Japanese infants during the first 3 years of life. Infants had two major phyla, Ascomycota (68.9%) and Basidiomycota (29.6%), and the most abundant genus was Saccharomyces (26.8%), followed by Malassezia (18.5%), Candida (12.3%), Meyerozyma (8.5%), and Penicillium (8.3%). Alpha diversity analysis revealed a significant decrease in fungal richness and evenness with age, suggesting adaptive selection of the colonizing species in the gut environment. Beta diversity analysis divided infant mycobiota into age-related clusters and showed discrete separation before and after weaning, suggesting shift in microenvironment via weaning. In the initial stage, a variety of fungal species that likely originated from an environment, such as Malassezia spp., was highly colonized and were replaced by yeasts, such as Saccharomyces, after weaning. Further studies are needed to shed light on how the passage of the series of fungal colonizations in infancy affects the development of the host immune system and the other homeostasis involved in health later in life.

DOI： 10.1016/j.jbiosc.2023.01.007

記述言語：英語   出版者・発行元：International Journal of Hematology  

Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T‑cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open‑label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment. Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914.

DOI： 10.1007/s12185-022-03494-7

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出版者・発行元：Chem-Bio Informatics Journal  

The fragment molecular orbital (FMO) method enables quantum mechanical calculations for macromolecules by dividing the target into fragments. However, most calculations, even for metalloproteins, have been performed by removing metal ions from the structures registered in the Protein Data Bank (PDB). For more realistic and useful calculations, FMO calculations must be performed without removing the metal ions. In this study, we discuss the results obtained from FMO calculations performed using 6-31G* and model core potentials (MCPs) for metal proteins containing Zn and Mg ions. Subsequently, we analyze the differences in atomic charges and interactions.

DOI： 10.1273/cbij.23.14

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出版者・発行元：International Conference on Infrared, Millimeter, and Terahertz Waves, IRMMW-THz  

We developed a fiber-coupled uni-traveling-carrier photodiode (UTC-PD) array chip for the purpose of combining the generated THz waves, and the feasibility of 300 GHz beam steering with the aid of a genetic algorithm is demonstrated in this work. Not only is this algorithm capable of automatically compensating for the optical path difference arising from the inconsistent lengths of coupled fibers, but it can also calculate the optimal phase shift in each channel for deflecting the THz beam to a predetermined angle. The implementation of this optimization algorithm in THz beam steering provides an attractive solution for efficient THz wireless communication or imaging applications in a large-scale UTC-PD array.

DOI： 10.1109/IRMMW-THz57677.2023.10299236

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The pathogenesis of hypertensive disorder of pregnancy (HDP), which affects about 10% of pregnant women, is still incompletely understood. Our previous study showed that endoplasmic reticulum (ER) stress influences high-temperature requirement A serine peptidase 1 (HTRA1) expression and trophoblast invasion. However, the involvement of ER stress in the regulation of HTRA subtype expression and pathophysiology of HDP has not been characterized in extravillous trophoblasts (EVTs). To investigate this, HTR8/SVneo EVTs cell line was treated with the ER stress inducers Thapsigargin (Thap) or Tunicamycin (Tuni). Treatment with either Thap or Tuni inhibited trophoblast invasion, reduced HTRA1 and HTRA3 expression, but did not alter HTRA2 or HTRA4 expression. Knockdown of HTRA1 or HTRA3 also inhibited trophoblast invasion. Furthermore, treatment with either ER stress inducer or HTRA1 silencing increased the ratio of soluble fms-like tyrosine kinase-1/placental growth factor (sFLT1/PlGF), which is a marker of HDP. Immunohistochemical analysis revealed that HTRA1 is localized to EVTs and the endometrial decidua in the placenta of patients with HDP. These results suggest that factors that cause ER stress could result in the inhibition of EVTs invasion via HTRA1.

DOI： 10.1016/j.jphs.2022.10.003.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Ensuring an appropriate continuum of care in maternal, newborn, and child health, as well as providing nutrition care, is challenging in remote areas. To make care accessible for mothers and infants, we developed a telehealth care system called Portable Health Clinic for Maternal, Newborn, and Child Health.
Objective: Our study will examine the telehealth care system's effectiveness in improving women's and infants' care uptake and detecting their health problems.
Methods: A quasi-experimental study will be conducted in rural Bangladesh. Villages will be allocated to the intervention and control areas. Pregnant women (≥16 gestational weeks) will participate together with their infants and will be followed up 1 year after delivery or birth. The intervention will include regular health checkups via the Portable Health Clinic telehealth care system, which is equipped with a series of sensors and an information system that can triage participants' health levels based on the results of their checkups. Women and infants will receive care 4 times during the antenatal period, thrice during the postnatal period, and twice during the motherhood and childhood periods. The outcomes will be participants' health checkup coverage, gestational and neonatal complication rates, complementary feeding rates, and health-seeking behaviors. We will use a multilevel logistic regression and a generalized estimating equation to evaluate the intervention's effectiveness.
Results: Recruitment began in June 2020. As of June 2022, we have consented 295 mothers in the study. Data collection is expected to conclude in June 2024.
Conclusions: Our new trial will show the effectiveness and extent of using a telehealth care system to ensure an appropriate continuum of care in maternal, newborn, and child health (from the antenatal period to the motherhood and childhood periods) and improve women's and infants' health status.

DOI： 10.2196/41586

リポジトリ公開URL： https://hdl.handle.net/2324/7161923

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: PM2.5 exposure is a suspected risk factor for diabetes. It is hypothesized that maternal PM2.5 exposure contributes to the development of gestational diabetes mellitus (GDM). The association between PM2.5 exposure and GDM is controversial and limited evidence is available for the exposure to PM2.5 chemical components. We investigated the association between maternal exposure to total PM2.5 mass and its components, particularly over the first trimester (early placentation period), and GDM.
Methods: Data were obtained from the Japan Perinatal Registry Network database, which includes all live births and stillbirths after 22 weeks of gestation at 39 cooperating hospitals in 23 Tokyo wards (2013-2015). At one fixed monitoring site, we performed daily filter sampling of fine particles and measured daily concentrations of carbon and ion components. The average concentrations of total PM2.5 and its components over the 3 months before pregnancy and the first (0-13 gestational weeks) and second (14-27 gestational weeks) trimesters were calculated and assigned to each woman. We estimated the odds ratios (ORs) of GDM in a multilevel logistic regression model.
Results: Among 82,773 women (mean age at delivery = 33.7 years) who delivered singleton births, 3,953 (4.8%) had GDM. In the multiexposure period model, an association between total PM2.5 exposure and GDM was observed for exposure over the first trimester (OR per interquartile range (IQR = 3.63 μg/m3) increase = 1.09; 95% confidence interval (CI) = 1.02-1.16), but not for the 3 months before pregnancy or the second trimester. For PM2.5 components, only organic carbon exposure over the first trimester was positively associated with GDM (OR per IQR (0.51 μg/m3) increase = 1.10; 1.00-1.21).
Conclusions: This is the first evidence that exposure to total PM2.5 and one of its components, organic carbon, over the first trimester increases GDM occurrence in Japan.

DOI： 10.31662/jmaj.2022-0141

リポジトリ公開URL： https://hdl.handle.net/2324/7183397

記述言語：英語   出版者・発行元：Nature  

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

DOI： 10.1038/s41586-022-05163-5

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記述言語：英語   出版者・発行元：PLoS ONE  

This study aimed to examine the association between infant sleep quality and temperament in one-month-old infants using a large cohort study data. We used data from the Japan Environment and Children’s Study, a cohort study which follows around 100,000 women from pregnancy until their children’s development. The mothers were asked about their infants’ sleep and temperament using a structured questionnaire. Frequent crying (adjusted odds ratio [AOR]: 1.05, 95% confidence interval [CI]: 1.00–1.10) and intense crying (AOR: 1.19, 95% CI: 1.13–1.25) were positively associated with longer sleep periods during the day than at night. Female infants with longer daytime sleep periods than that at nighttime were more likely to cry frequently (AOR: 1.11, 95% CI: 1.04–1.20). Parous women with infants who had frequent night awakening believed their infants cried more intensely (AOR: 1.17, 95% CI: 1.03–1.31). The study demonstrated a specific association between sleep quality and temperament in one-month-old infants. Based on the results of this study, further sleep intervention studies are required to improve infant temperament.

DOI： 10.1371/journal.pone.0274610

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/aim: Immature teratomas (IMT) are malignant germ cell tumours composed of immature embryonal tissue, mostly neuroectodermal tubules and rosettes. Meanwhile, embryonal tumours with multilayered rosettes (ETMR) are aggressive central nervous system tumours composed of neurocyte proliferation with rosette formation. The histopathological appearance of rosette formation in ETMR is the same as that in IMT. Recently, 19q13.42 amplification was reported as a specific genetic marker of ETMR. The aim of this study was to compare ETMR with IMT from histological, immunohistochemical and genetic perspectives.
Materials and methods: We retrospectively analysed tumour samples from 48 patients with IMT and 1 patient with ETMR. We performed fluorescence in situ hybridization (FISH) analysis, which revealed amplification of the 19q13.42 locus in the ETMR case. In addition, immunohistochemical analyses of LIN28A, β-catenin and p53 were performed.
Results: In FISH analysis all 48 cases of IMT showed diploidy. By immunohistochemical analysis, LIN28A expression was observed in 54% of IMT cases (25/48 cases) and in the ETMR case. Nuclear staining of β-catenin was observed in 33% of IMT cases (16/48 cases). Meanwhile, aberrant expression of p53 was not identified in IMT nor ETMR cases.
Conclusion: Genetic changes associated with IMT differ from those in ETMR, but LIN28A protein immunohistochemical expression, which is specific for ETMR, can be a biomarker for the immature neuroepithelial component in IMT.

DOI： 10.21873/anticanres.15934

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Infants with congenital diaphragmatic hernia (CDH) are at risk of neurodevelopmental disabilities. This study aimed to investigate the association between lung to thorax transverse area ratio (LTR) and neurodevelopmental outcomes at 3 years of age in fetuses with CDH.
Methods: We performed a retrospective study of infants with prenatally diagnosed isolated left-sided CDH born in Kyushu University Hospital between 2008 and 2016. We examined the association between prenatal ultrasound findings including LTR and development quotient (DQ) at 36 to 42 months of chronological age.
Results: We identified 34 live-born fetuses with isolated left-sided CDH, of which 30 survived and four died before discharge. The median LTR in the survivors was higher than in the non-survivors (p < 0.01). Among the survivors, 26 had available data on LTR (median 0.12, range 0.08-0.18) and overall DQ at 3 years of age (93, 61-112). Their median gestational age and birth weight were 37.6 (range 34.4-39.1) weeks and 2716 (2.256-3494) grams, respectively. There was no significant difference in overall DQ scores between the two groups divided according to the median LTR values (p = 0.62). LTR values were not associated with overall DQ scores after adjusting for gestational age (p = 0.39). In addition, no association was observed between LTR values and any subscale DQ scores.
Conclusion: In fetuses with isolated left-sided CDH, prenatal LTR predicts the mortality but not neurodevelopmental outcomes at 3 years of age.
Keywords: Congenital diaphragmatic hernia; Neurodevelopmental outcome; Predictive parameter; Prenatal diagnosis.

DOI： 10.1016/j.earlhumdev.2022.105598

記述言語：英語   出版者・発行元：Progress in Neuro-Psychopharmacology and Biological Psychiatry  

Background It is gradually becoming clear that obsessive-compulsive disorder (OCD) patients have aberrant resting-state large-scale intrinsic networks of cingulo-opercular salience (SN), default mode (DMN), and front-parietal network (FPN). However, it remains unknown whether unaffected first-degree relatives of OCD patients have these alterations as a vulnerability marker to the disorder. Methods We performed resting-state functional magnetic resonance imaging (rsfMRI) scans of 47 medication-free OCD patients, 21 unaffected healthy first-degree relatives of OCD patients, and 62 healthy control (HC) participants. We explored differences between the three groups in the functional connectivity from SN (seeds: anterior-insula (AI) and dorsal anterior cingulate cortex (dACC)), DMN (seeds: medial prefrontal cortex (MPFC) and posterior parietal cortex (PCC)), and FPN (seeds: dorsolateral prefrontal cortex (DLPFC)). Results Compared to HC, both OCD patients and first-degree relatives showed significantly greater functional connectivity between AI and PCC and between DLPFC and the thalamus. Compared to first-degree relatives and HC, OCD patients showed reduced functional connectivity between PCC and DLPFC, and this altered functional connectivity was negatively correlated with anxiety and depressive symptom within OCD group. Conclusions OCD patients and unaffected first-degree relatives of OCD patients showed overlapping alterations in resting state functional connectivity between the regions of SN and DMN and between DLPFC and the thalamus. Our results suggested that alterations between large-scale intrinsic networks and within the dorsal cognitive cortico-striato-thalamo-cortical (CSTC) circuit could represent endophenotype markers of OCD.

DOI： 10.1016/j.pnpbp.2022.110516

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出版者・発行元：International Journal of Surgical Pathology  

Phyllodes tumors of the breast are uncommon, and 6.2% of phyllodes tumors behave in a malignant fashion. The metastatic spread of malignant phyllodes tumor is mainly hematogenous to lung and bone, and malignant phyllodes tumor metastasizing to the ovary is rare, with only 2 cases reported. We report the third case of metastatic malignant phyllodes tumor to the ovary with a focus on the differential diagnosis of ovarian cancer.

DOI： 10.1177/10668969211056912

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記述言語：英語   出版者・発行元：Leukemia  

Fit patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) in relapsed or refractory (R/R) disease status often receive salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHCT) or allogeneic HCT (alloHCT). However, there is no consensus on the type of HCT that should be applied for such patients. Herein, we retrospectively evaluated the survival outcome of 760 adult R/R PTCL-NOS or AITL patients who underwent the first HCT. Among them, 318 relapsed after first remission (REL) and 442 were refractory to the primary therapy (PIF). The 4-year overall survival (OS) of autoHCT and alloHCT was 50 and 50% for REL patients, and 52 and 49% for PIF patients, respectively. In the multivariable analysis, alloHCT tended to be associated with better progression-free survival (PFS) in REL (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.53–1.03), and significantly better PFS in PIF (HR 0.64; 95% CI: 0.46–0.88) compared with autoHCT. The subgroup analysis with propensity-score matching showed that alloHCT was associated with better OS for REL-sensitive and PIF-nonremission disease. This study suggested that the advantage of alloHCT for R/R PTCL-NOS or AITL is different, depending on the disease status at HCT.

DOI： 10.1038/s41375-022-01545-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Nature  

Background: We hypothesized that maternal lifestyle factors, such as physical activity and sleep habits, may be associated with autism spectrum disorder (ASD) in infants. This study aimed to investigate the association between maternal physical activity and sleep before and during pregnancy with infant ASD diagnosed by the age of 3 years.
Methods: We used the data from the Japan Environment and Children's Study between 2011 and 2014. The study included 103,060 pregnant women, among which, 69,969 women were analyzed. Participants were asked about their physical activity and sleep before and during pregnancy using questionnaires during pregnancy. Maternal physical activity was estimated using the international physical activity questionnaire. Based on the levels of physical activity before or during pregnancy, the participants were divided into five groups. Maternal sleep was analyzed based on sleep duration and bedtime. The outcome was diagnosis of ASD in 3-year-old infants.
Results: In mothers with higher physical activity levels during pregnancy, the risk ratios (RR) for ASD in their 3-year-old infants were lower (RR = 0.61, 95% confidence interval (CI) = 0.42-0.90). In contrast, too short (<6 h) and too long (>10 h) sleep durations during pregnancy were associated with higher risk ratios for ASD than 7-8 h sleep duration (too short: RR = 1.87, 95% CI = 1.21-2.90; too long: RR = 1.56, 95% CI = 1.00-2.48). These associations were not observed before pregnancy.
Conclusion: Maternal physical activity and sleep duration during pregnancy may be associated with ASD in infants.
Keywords: Autism spectrum disorders; Epidemiology; Paediatric research.

DOI： 10.1038/s43856-022-00101-y

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CiNii Research

リポジトリ公開URL： http://hdl.handle.net/2324/4798528

記述言語：英語  

DOI： 10.4103/JMU.JMU_28_21

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Health Science Reports  

Background and aims: Maternal hemoglobin concentration during pregnancy is reported to be associated with various perinatal outcomes and may also be associated with infant development. This study aims to investigate the association between maternal hemoglobin levels during early or mid-pregnancy and sleep and developmental problems in 1-year-old infants.
Methods: We used the data of 66,935 pregnant women who were participants of the Japan Environment and Children's Study, a nationwide cohort study in Japan, between 2011 and 2014. Maternal hemoglobin level was examined at recruitment (mean gestational age, 15.3 weeks; SD, 2.85 weeks; range, 6-22 weeks). Information on infant sleep and development at the age of 1 year was acquired using a questionnaire. Infant development was evaluated using the Ages and Stages Questionnaire (ASQ).
Results: The mean (SD) maternal hemoglobin level was 12.0 (1.0) g/dl. Maternal hemoglobin levels were not associated with the majority of infant sleep and developmental outcomes. In the group with maternal hemoglobin <10.0 g/dl, the risk ratio (RR) for sleep at 22:00 or later was higher than that in the reference group with 11.0 g/dl ≤ hemoglobin < 14.0 g/dl (RR 1.12, 95% confidence interval = 1.00-1.25). In the analysis with maternal hemoglobin level as a continuous variable, both high and low hemoglobin levels were associated with a higher RR of a late bedtime. In addition, a low maternal hemoglobin level was associated with a higher RR for abnormal fine motor skills in the ASQ.
Conclusion: Our results suggest that a low level of maternal hemoglobin during pregnancy is associated with late bedtime and abnormal fine motor skills in 1-year-old infants. Conversely, a high level of maternal hemoglobin may also be associated with the infant's late bedtime.
Keywords: development; hemoglobin; infant; pregnancy; sleep.

DOI： 10.1002/hsr2.552

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Women with nausea and vomiting of pregnancy (NVP) have higher birth weight infants, while those with hyperemesis gravidarum, a severe manifestation of NVP, have lower birth weight infants. We aimed to investigate the associations between maternal weight loss (a consequence of hyperemesis gravidarum), NVP, and infant birth weight.
Methods: This study was a secondary analysis of a nationwide birth cohort in Japan. Singleton pregnancies delivered at 28-41 weeks of gestation were included in the analysis. Women were categorized based on their weight change in the 1st trimester (as a proportion to their pre-pregnancy weight: > + 3%, > 0 to + 3%, > -3 to 0%, > -5 to -3%, ≤ -5%) and severity of NVP (no nausea, only nausea, vomiting but able to eat, vomiting and unable to eat). The effects of weight change and severity of NVP on infant birth weight and small for gestational age (SGA) were assessed using regression models. We further examined how these effects could be modified by maternal weight gain up to the 2nd trimester.
Results: Among 91,313 women, 5,196 (5.7%) lost ≥ 5% of their pre-pregnancy weight and 9,983 (10.9%) experienced vomiting and were unable to eat in the 1st trimester. Women with weight loss ≥ 5% in the 1st trimester had infants 66 (95% CI: 53, 78) g lighter and higher odds of SGA (aOR: 1.29; 95% CI: 1.14, 1.47) than women who gained > 3% during the same period. However, when adjusting for weight gain up to the 2nd trimester, women with weight loss ≥ 5% in the 1st trimester had infants 150 (95% CI: 135, 165) g heavier and lower odds of SGA (aOR: 0.39; 95% CI: 0.33, 0.46) than those who gained > 3% during the same period. In contrast, women with more severe NVP tended to have infants with larger birth weight and lower odds of SGA compared to women without NVP. These trends were strengthened when adjusting for weight gain up to the 2nd trimester.
Conclusions: Our study suggests the possibility that reduced fetal growth in pregnancies with hyperemesis gravidarum may be caused by the lack of catch-up in gestational weight gain up to the 2nd trimester.
Keywords: Birth weight; Fetal growth; Gestational weight gain; Hyperemesis gravidarum; Morning sickness; Nausea and vomiting of pregnancy; Small for gestational age.

DOI： 10.1186/s12884-022-04542-0

リポジトリ公開URL： http://hdl.handle.net/2324/4793642

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

妊娠第2三半期の頸管開大例に対する治療的頸管縫縮術は妊娠延長効果が期待でき、分娩までの期間（中央値）は待機群で3-20日に対し、縫縮群で41-117日までに延長すると報告されている。しかし胎盤突出例では術中破水や、数日内に流早産に至る症例も少なからず存在し、手術に際し、週数や母体侵襲のバランスに苦慮することもある。また細胞可視例でも一部は術後早期の分娩に至る例があり、経過予測に基づいた個別管理が必要になる。手術時点でどういった臨床・検査所見に着目すると十分な妊娠延長を期待できる症例と判断できるのか、また術後はどの所見に留意すればより慎重な管理が必要な症例をピックアップできるのか、これらを知ることは臨床診療の上で有用である。そこで本研究では胎胞視認例における治療的頸管縫縮術の成否に関わる因子について検討した。

リポジトリ公開URL： http://hdl.handle.net/2324/4793655

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Our hypothesis was that exposure to fine particulate matter (PM2.5) is related to abnormal cord insertion, which is categorized as a form of placental implantation abnormality. We investigated the association between exposure to total PM2.5 and its chemical components over the first trimester and abnormal cord insertion, which contributes to the occurrence of adverse birth outcomes.
Methods: From the Japan Perinatal Registry Network database, we used data on 83 708 women who delivered singleton births at 39 cooperating hospitals in 23 Tokyo wards (2013-2015). We collected PM2.5 on a filter and measured daily concentrations of carbon and ion components. Then, we calculated the average concentrations over the first trimester (0-13 weeks of gestation) for each woman. A multilevel logistic-regression model with the hospital as a random effect was used to estimate the odds ratios (ORs) of abnormal cord insertion.
Results: Among the 83 708 women (mean age at delivery = 33.7 years), the frequency of abnormal cord insertion was 4.5%, the median concentration [interquartile range (IQR)] of total PM2.5 was 16.1 (3.61) μg/m3 and the OR per IQR for total PM2.5 was 1.14 (95% confidence interval = 1.06-1.23). In the total PM2.5-adjusted models, total carbon, organic carbon, nitrate, ammonium and chloride were positively associated with abnormal insertion. Organic carbon was consistently, and nitrate tended to be, associated with specific types of abnormal insertion (marginal or velamentous cord insertion).
Conclusions: Exposure to total PM2.5 and some of its components over the first trimester increased the likelihood of abnormal cord insertion.
Keywords: Abnormal cord insertion; fine particle; implantation; nitrate; organic carbon; pregnancy.

DOI： 10.1093/ije/dyab192

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Maternal exposure to fine particulate matter (PM2.5) was associated with pregnancy complications. However, we still lack comprehensive evidence regarding which specific chemical components of PM2.5 are more harmful for maternal and foetal health.
Objective: We focused on exposure over the first trimester (0-13 weeks of gestation), which includes the early placentation period, and investigated whether PM2.5 and its components were associated with placenta-mediated pregnancy complications (combined outcome of small for gestational age, preeclampsia, placental abruption, and stillbirth).
Methods: From 2013 to 2015, we obtained information, from the Japan Perinatal Registry Network database, on 83,454 women who delivered singleton infants within 23 Tokyo wards (≈627 km2). Using daily filter sampling of PM2.5 at one monitoring location, we analysed carbon and ion components, and assigned the first trimester average of the respective pollutant concentrations to each woman.
Results: The ORs of placenta-mediated pregnancy complications were 1.14 (95% CI = 1.08-1.22) per 0.51 μg/m3 (interquartile range) increase of organic carbon and 1.11 (1.03-1.18) per 0.06 μg/m3 increase of sodium. Organic carbon was also associated with four individual complications. There was no association between ozone and outcome.
Significance: There were specific components of PM2.5 that have adverse effects on maternal and foetal health.
Keywords: Chemical component; Particulate matter; Placenta-mediated pregnancy complications; Placentation.

DOI： 10.1038/s41370-021-00299-4

リポジトリ公開URL： http://hdl.handle.net/2324/4793657

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated folic acid (FA) intake and disturbing factors in pregnant women who visited our center in 2017. Among 1531 pregnant women, 45.1% of women initiated FA supplementation before pregnancy. The risk of failure of supplementation was significantly lower among women of ≥35 (adjusted odds ratio [aOR] 0.43) and 30-34 years of age (aOR: 0.59) in comparison to women of <30 years of age, and among those conceived with timing/artificial insemination of husband (aOR 0.47) and in vitro fertilization/intracytoplasmic sperm injection (aOR 0.32) in comparison to those conceived naturally. The risk among those with 1 (aOR 1.44) or ≥2 previous deliveries (aOR 2.75) was significantly higher in comparison to nulliparous women. Young, multiparous women, and those with natural conception should be targeted to promote preconceptional FA intake.
Keywords: folic acid; neural tube defect (NTD); preconceptional care; risk factors; supplementation.

DOI： 10.1111/cga.12449

出版者・発行元：OECC/PSC 2022 - 27th OptoElectronics and Communications Conference/International Conference on Photonics in Switching and Computing 2022  

We proposed a physical layer secure wireless communication system using AND operation. In this paper, we demonstrate data transmission based on AND operation between two 300-GHz-band signals from two transmitters.

DOI： 10.23919/OECC/PSC53152.2022.9850185

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and objective: Regular health checkups are important for mothers and newborns to detect health problems at an early stage; however, this is often difficult in resource-limited settings. Therefore, the portable health clinic (PHC) for maternal and child health (MCH), a telemedicine health checkup system, was introduced as an intervention study in a rural area in Bangladesh. The aim of this research project was to report findings that we had observed at a mid-point of the intervention period.
Methods: This was an intervention study conducted in Shariatpur, Bangladesh. The study population included pregnant/parturient women aged 15-49 years and their newborns. With the help of the newly created PHC for MCH, health workers, with a set of sensor devices in an attaché case, visited mothers and newborns at home to examine their health status. Their health status was triaged into four categories using a data management application, and in cases of affected or emergent health status, they were placed on remote video consultation with a doctor.
Results: In total, 94 women were included in the PHC for MCH intervention. The rate of participants who received antenatal care at least four times or postnatal care at least once increased (from 29% to 51%, and from 27% to 78%, respectively) compared with before introducing PHC for MCH. Using the PHC for MCH, we detected health problems in pregnant/parturient women; a relatively high percentage had anemia (45-54%) and/or abnormal pulse rate (20-40%). Moreover, after introducing the PHC for MCH, more than 40% of women who received multiple antenatal care or postnatal care checkups improved their health status.
Conclusions: The PHC for MCH could be an effective system to improve the health of mothers and newborns by increasing the availability of care. In the future, this system is expected to be used as a primary resource for maternity healthcare, not only in rural areas but also in other social environments.
Keywords: Bangladesh; Global Health; Maternal–Child Health Services; Telemedicine.

DOI： 10.1016/j.cmpb.2021.106156

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), are three reportedly predictive biomarkers that reflect subclinical chronic inflammatory burden. However, how these biomarkers change during pregnancy and its clinical utility among pregnant women have been rarely studied. Among 76,853 singleton pregnancies delivered at 28-41 weeks of gestation that were enrolled in the Japan Environment and Children's Study, we observed the distribution of maternal NLR, PLR, and LMR values from week 0 to week 36 using spline curves, as well as their predictive values for preterm delivery with and without hypertensive disorders in pregnancy, placental abruption and intrauterine growth restriction (collectively termed ischemic placental disease due to their shared pathological and pathophysiological features) for measurements at 8-11 weeks, 12-17 weeks, and 18-21 weeks. NLR and PLR increased, whereas LMR decreased, with increasing gestation. High LMR and low NLR observed at 18-21 weeks, but not at earlier gestations, were associated with higher risk of preterm delivery with IPD (odds ratio 1.80 [95% CI 1.02, 3.19] per log[LMR]; odds ratio 0.49 [95% CI 0.29, 0.82] per log[NLR]). All parameters were not predictive of preterm delivery without IPD. We provide a robust reference curve for maternal blood count parameters NLR, PLR, and LMR by gestational week.

DOI： 10.1038/s41598-021-93101-2

リポジトリ公開URL： http://hdl.handle.net/2324/4705288

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

目的：異型腺細胞(atypical glandular cell:AGC)の数量的解析を行い組織型推定困難症例における上皮内腺癌(AIS)細胞の特徴を調べる。
方法：細胞診検査が実施され、病理組織的診断が確定している61症例の細胞診標本を、細胞診の細胞像から組織型推定困難群(A群19症例)と、組織型推定可能群(B群42症例)に分け、細胞所見と集塊所見をImage Jを用いて比較検討を行った。
成績：A群におけるAISに関して、①AISの核面積は子宮頸部上皮内腫瘍(CIN)1より小さく良性腫瘍(Benign)との間に有意差がない。②AISの核間距離はCIN1およびBenignより有意に小さく分業状頸管腺過形成(LEDH)との間に有意差がない。③A群の全ての組織型において核クロマチンは主に核偏在し判別困難、④AISとLEGHの”核面積と核間距離の相関”は低い、という結果がが得られた。
結論：組織型推定困難症例であったAISの細胞診像では核の大きさやクロマチンの分布が良性と差がなく、核所見が乏しいため組織型の推定が困難であったと思われた。よって、腺細胞の集塊において、核間距離に有意差がある不規則重積性の認識は、AIS鑑別の一助になる可能性が示唆された。
Key words：cervical cytology, morphometry atypical glandular cell, adenocarcinoma in situ, irregular nuclear intussusception

リポジトリ公開URL： http://hdl.handle.net/2324/4793653

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study investigated the association of maternal sleep before and during pregnancy with sleeping and developmental problems in 1-year-old infants. We used data from the Japan Environment and Children's Study, which registered 103,062 pregnancies between 2011 and 2014. Participants were asked about their sleep habits prior to and during pregnancy. Follow-up assessments were conducted to evaluate the sleep habits and developmental progress of their children at the age of 1 year. Development during infancy was evaluated using the Ages and Stages Questionnaire (ASQ). Maternal short sleep and late bedtime before and during pregnancy increased occurrence of offspring's sleeping disturbances. For example, infants whose mothers slept for less than 6 h prior to pregnancy tended to be awake for more than 1 h (risk ratio [RR] = 1.49, 95% confidence interval [CI] 1.34-1.66), sleep less than 8 h during the night (RR = 1.60, 95% CI 1.44-1.79), and fall asleep at 22:00 or later (RR = 1.33, 95% CI 1.26-1.40). Only subjective assessments of maternal sleep quality during pregnancy, such as very deep sleep and feeling very good when waking up, were inversely associated with abnormal ASQ scores in 1-year-old infants.

DOI： 10.1038/s41598-021-91271-7

リポジトリ公開URL： http://hdl.handle.net/2324/4482783

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aims: The aim of this study was to characterise grade 1 (G1) endometrioid carcinoma in the elderly, by using clinicopathological features and immunohistochemical features of surrogate markers of molecular subtypes.
Methods and results: We retrospectively analysed tumour samples from 268 patients with G1 endometrioid carcinoma (<40 years, n = 24; 40-59 years, n = 169; ≥60 years, n = 75) for whom long-term clinical follow-up data were available. G1 endometrioid carcinoma in the elderly (≥60 years) was characterised by frequent deep myometrial invasion, less frequent endometrioid intraepithelial neoplasia (EIN), lack of benign hyperplasia (BH), less frequent squamous differentiation, and occasional aberrant p53 expression. In contrast, this condition in the young (<40 years) was characterised by frequent EIN, BH, and squamous differentiation. Univariate analysis revealed that elderly status (≥60 years), International Federation of Obstetrics and Gynecology (FIGO) 2009 stage and aberrant p53 expression were significantly associated with shorter progression-free survival, and multivariate analysis revealed that elderly status and FIGO 2009 stage were independently associated with a poor prognosis.
Conclusions: G1 endometrioid carcinoma in the elderly is more aggressive than that in the young, and elderly status is an independent predictor of shorter progression-free survival in this condition. We propose that type 1 tumours can be subdivided into type 1a (young age at onset and indolent) and type 1b (old age at onset and relatively aggressive).
Keywords: G1 endometrioid carcinoma; elderly; p53 expression; shorter progression-free survival.

DOI： 10.1111/his.14400

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: PEGylated liposomal doxorubicin (PLD) is a therapeutic agent for gynecological malignancy. Hypersensitivity reaction (HSR) is a major adverse effect that usually disappears after halting administration of PLD. Premedication is usually not necessary before administration of PLD to prevent HSR. Here, we evaluated the frequency of HSR during administration of PLD following premedication in Japanese women.
Methods: We performed PLD administration in 78 patients (386 cycles) between 2013 and 2018. Granisetron hydrochloride and dexamethasone sodium phosphate were administered 30 min before PLD administration. Then, PLD (40 or 30 mg/m2 combined usage with carboplatin) was administered. We retrospectively reviewed the medical records of 78 patients and examined the frequency of HSR.
Results: Seven of 78 (9%) patients showed HSR by PLD administration following premedication. One patient showed cardiopulmonary arrest in 13 min after PLD administration (grade 4). The other six patients showed grade 2 HSR. All patients developed HSR in the first course. The incidence of HSR was significantly higher in patients with allergic history than in patients without allergic history (p = 0.0151).
Conclusions: Clinicians should be aware of the potential for HSR in patients administered PLD, particularly those with allergic history and those receiving the first cycle of PLD, even following premedication.

DOI： 10.1111/jog.14680

リポジトリ公開URL： https://hdl.handle.net/2324/6777142

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alpha-1 antitrypsin (A1AT) is a glycoprotein that has been shown to protect tissues from proteolytic damage under various inflammatory conditions. Several studies show that A1AT may be associated with pre-eclampsia. However, the role of A1AT expression in placental physiology is not fully understood. In the present study, we aim to characterize the expression and function of placental A1AT. A1AT knockdown is found to reduce the expression of the serine protease HTRA1 in a trophoblast cell line. In addition, A1AT overexpression (A1AT-OE) increases the expression of HTRA1, IL6, CXCL8, and several markers of endoplasmic reticulum (ER) stress. Treatment with tunicamycin or thapsigargin, which induces ER stress, increases HTRA1 expression. Furthermore, immunohistochemistry reveals that HTRA1 is expressed in trophoblasts and the endometrial decidual cells of human placentas. An invasion assay shows that A1AT and HTRA1 stimulate cell invasion, but treatment with the ER stress inhibitors reduces the expression of HTRA1 and ER stress markers and prevents cell invasion in A1AT-OE trophoblasts. These results suggest that endogenous A1AT regulates inflammatory cytokine expression and HTRA1-induced trophoblast invasion via the induction of ER stress. It is concluded that an imbalance in the functional link between A1AT and ER stress at the maternal-fetal interface might cause abnormal placental development.
Keywords: alpha-1 antitrypsin; cell invasion; endoplasmic reticulum stress; extravillous trophoblast; high-temperature requirement A serine peptidase 1.

DOI： 10.3390/ijms22073683

リポジトリ公開URL： http://hdl.handle.net/2324/4705309

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aim of this study was to investigate the association between maternal physical activity (PA) before and during pregnancy and sleep and developmental problems in 1-year-old infants. We used data from a nationwide cohort study in Japan that registered 103,062 pregnancies between 2011 and 2014. Participants were asked about their PA before and during pregnancy, and the sleep and development of their children at the age of 1 year. Maternal PA was estimated using the International Physical Activity Questionnaire and was expressed in METs per week. We defined scores below the cut-off points of the Ages and Stages Questionnaire (ASQ) as abnormal for infant development. Based on the levels of PA before or during pregnancy, the participants were divided into five groups. In mothers with higher PA levels, the risk ratio for bedtime after 22:00 or abnormal ASQ scores in their 1-years-old infants were lower. These associations were observed for PA before and during pregnancy. Higher levels of maternal PA, both before and during pregnancy, may reduce sleep and developmental problems in infants.

DOI： 10.1038/s41598-021-87612-1

リポジトリ公開URL： http://hdl.handle.net/2324/4476152

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Due to the recent trend of women having children at an older age, the number of pregnancies complicated by cervical cancer has increased. In the present study, the clinical characteristics of patients with cervical cancer complicated by pregnancy were analyzed. The clinicopathological characteristics and prognosis of patients with cervical cancer during pregnancy who underwent treatment at Kyushu University Hospital from January 2008 to December 2017 were assessed retrospectively from their medical records. The medical information of patients diagnosed within 6 months after parturition was also evaluated as these patients were considered to be affected by cervical cancer during pregnancy. A total of 19 women were diagnosed with cervical cancer during pregnancy (median age, 33 years), three of whom were diagnosed as negative for intraepithelial lesion or malignancy at the initial visit to a previous clinic after pregnancy. The tumor stage was IA1 in one patient, IB1 in 16 patients, IB2 in one patient and IVB in one patient. The median gestational age at the time of cervical cancer diagnosis was 13 weeks. One patient died of cervical cancer during the follow-up period. An additional 12 patients were diagnosed within 6 months after parturition. The median age of these patients was 35.5 years. Cancer screening was performed in 10 patients during pregnancy, none of whom were diagnosed with cervical cancer, including three patients who were negative for intraepithelial lesion or malignancy. Of the 12 patients, one had tumor stage IA1, eight had IB1, two had IB2 and one had IIB. Three patients experienced recurrence, of whom one died of cervical cancer. Advanced cervical cancer was diagnosed both during pregnancy and within 6 months after parturition. Diagnosis of cervical cancer during pregnancy is difficult even at an advanced stage; however, rapid diagnosis and prompt multidisciplinary treatment are critical. Therefore, it is necessary to improve the accuracy of cervical cancer diagnosis, and to characterize tumor cells and their microenvironment, during pregnancy.
Keywords: diagnosis; parturition; pregnancy; prognosis; uterine cervical neoplasms.

DOI： 10.3892/mco.2021.2229

リポジトリ公開URL： http://hdl.handle.net/2324/4479072

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

【はじめに】婦人科疾患開腹手術後のイレウス予防として、術後から大建中湯(以下TJ-100)を処方されていたが、本試験前までは、ほとんどの患者は顆粒のまま水で内服し、内服する際に飲み込みにくいという声が聞かれた。TJ-100は「腹中寒」が主要な使用目的であり、白湯で溶解し温服することがより理にかなっているとされる。そこで、TJ-100を白湯で溶解し内服する群と顆粒の状態で内服する群とで比較し内服状況と術後経過の調査を行った。
【方法】婦人科疾患の良性腫瘍を除く開腹手術を施行した患者に対し、術後1日目より、毎食前にTJ-100 2包を白湯100mLに溶解し内服する群(A:溶解群)と顆粒の状態で内服する群(B:顆粒群)の計30症例のランダム化比較試験を行った。術式や麻酔時間、出血量(輸血の有無)、排便状況、食事量、TJ-100以外の薬剤使用頻度、イレウスの有無、内服状況のデータ収集とともに、腹痛・悪心・不眠をvisual analogue scale(VAS)スケールでデータを数値化し、患者へ内服後の変化(腹部症状の変化)ついてアンケート調査を行った。【結果と考察】溶解群に侵襲の大きな手術が偏ったが、術後の初回排便が有意に早く、効果的であった。両群ともに、VASスケールに有意差は認めなかった。その他の副次的な項目に関しては、内服による効果が認められた。その他、アンケート調査結果などについて述べ、それらについて考察する。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: The KOSMOS study, a multicenter, randomized, double-blind, placebo-controlled trial, investigated the effects and safety of kamishoyosan (TJ-24), a traditional Japanese medicine, in the treatment of climacteric disorder.
Methods: Japanese women with climacteric disorder were administered a placebo during a 4-week run-in period, after which they were classified as placebo responders (R group) if their score on the modified Questionnaire for the Assessment of Climacteric Symptoms in Japanese Women (m-QACS) with excitability and irritability as the primary outcome improved by ≥ 3 points and as placebo nonresponders (NR group) otherwise. Members of the NR group were randomly allocated to receive either TJ-24 or placebo. After 12 weeks, their m-QACS scores, anxiety and depression, sleep, and overall quality of life (QOL) were compared.
Results: The TJ-24 and placebo arms in the NR group included 20 patients each. The change in the m-QACS scores of members of the NR group for excitability and irritability at 12 weeks versus baseline was -3.1 ± 1.7 in the TJ-24 arm, a significant decrease, but compared with -2.7 ± 2.2 in the placebo arm, no significant difference was between two arms. However, the proportion of participants whose score improved by ≥3 points was significantly higher in the TJ-24 arm. In the subgroup analysis of premenopausal women, the changes in the score for excitability and irritability were significantly larger in the TJ-24 arm. The incidence of adverse drug reactions or adverse events did not differ between the two arms, and no serious events were reported.
Conclusion: Although no significant difference was identified for the primary outcome, a significantly higher proportion of patients who received TJ-24 displayed improvement. Its high level of safety and effects on excitability and irritability in premenopausal women suggest that TJ-24 may be a useful treatment.

DOI： 10.1155/2021/8856149

リポジトリ公開URL： http://hdl.handle.net/2324/4479045

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: To avoid the loss of fertility, chemotherapy should be chosen as an adjuvant treatment after trachelectomy. Our study evaluated the effectiveness and safety of adjuvant chemotherapy after abdominal trachelectomy for cervical cancer.

Methods: Our institutional review board approved this clinical study, and informed consent was obtained from each patient. We began performing abdominal trachelectomy at our institution in 2005. Deep stromal invasion (more than two-thirds) with lymphovascular space invasion, diffuse cervical invasion, skip lesions in the vagina, and lymphovascular space invasion in the cardinal ligament and vagina were defined as intermediate-risk factors, and parametrial invasion and pelvic lymph node metastasis were defined as high-risk factors. Patients who had intermediate- or high-risk factors received post-trachelectomy adjuvant treatment. The medical records and information of the patients were reviewed retrospectively.

Results: Through January 2020, we performed 212 trachelectomies. Among the included patients, 16 and 7 patients with intermediate- and high-risk cancer, respectively, received adjuvant chemotherapy after trachelectomy (2 and 21 patients underwent abdominal modified radical trachelectomy and radical trachelectomy, respectively). Among these patients, only one (4.3%) experienced relapse and subsequent death of the disease after a median postoperative follow-up of 80 months (range 12-146 months). The 5-year survival rate was 95.5%. Chemotherapy-related life-threatening acute adverse events were not observed. Persistent ovarian dysfunction and late adverse events did not occur. One woman achieved three pregnancies, and two infants were delivered.

Conclusion: Adjuvant chemotherapy after abdominal trachelectomy could be an alternative treatment option from the aspects of effectiveness, safety, and fertility preservation.

DOI： 10.1007/s10147-020-01778-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study aimed to investigate the association of maternal sleep before and during pregnancy with preterm birth, infant sleep and temperament at 1 month of age. We used the data of the Japan Environment and Children's Study, a cohort study in Japan, which registered 103,099 pregnancies between 2011 and 2014. Participants were asked about their sleep before and during pregnancy, and the sleep and temperament of their newborns at 1 month of age. Preterm birth data were collected from medical records. Maternal sleep was not associated with preterm birth, but subjective sleep quality during pregnancy was associated with late preterm birth (birth at 34-36 weeks of gestation). For example, participants with extremely light subjective depth of sleep were more likely to experience preterm birth (RR = 1.19; 95% confidence interval [CI] = 1.04-1.35). Maternal sleep both before and during pregnancy seemed to be associated with infant sleep and temperament at 1 month of age. Infants, whose mothers slept for less than 6 hours before pregnancy, tended to cry intensely (RR = 1.15; 95% CI = 1.09-1.20). Maternal sleep problems before and during pregnancy were associated with preterm birth and child sleep problems and temperament.

DOI： 10.1038/s41598-020-67852-3

リポジトリ公開URL： http://hdl.handle.net/2324/4476149

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abnormal autonomic function may cause false-positive non-reassuring foetal status (fpNRFS) and may also cause sleeping problems after birth. However, an association between fpNRFS and sleeping problems in infants has not been reported. We previously showed an association of NRFS with temperament, including bad mood and frequent crying for long durations in 1-month-old infants. In the present study, we aimed to assess this association in 1-year-old infants. A total of 62,612 single pregnant women were included in the analysis. fpNRFS was identified from medical records. Sleep problems, such as short sleep duration or crying at night, were investigated in 1-year-old infants using a questionnaire for mothers. We used a log-binominal regression model to explore the association of fpNRFS with each sleep problem and to estimate risk ratios (RRs). The number of fpNRFS cases was 2,071, with a frequency of 3.3%. We observed an association of fpNRFS with shorter sleep duration of less than 8 h a night (RR 1.30, 95% confidence intervals [CI] 1.10-1.54), crying at night (RR 1.19, 95% CI 1.03-1.39), and bedtime after 22:00 (RR 1.09, 95% CI 1.00-1.18). fpNRFS may be associated with sleep problems in 1-year-old infants.

DOI： 10.1038/s41598-020-67856-z

リポジトリ公開URL： http://hdl.handle.net/2324/4476150

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Mother-infant bonding is an emerging perinatal issue. While emergency cesarean deliveries are associated with a risk of bonding disorders, the mode of anesthesia used for emergency cesarean deliveries has never been studied in this context. We aimed to investigate the impact of administering general anesthesia and neuraxial anesthesia to women undergoing cesarean deliveries on mother-infant bonding. Methods This was a retrospective, propensity score-matched multivariable analysis of 457 patients who underwent emergency cesarean deliveries between February 2016 and January 2019 at a single teaching hospital in Japan. The Mother-Infant Bonding Scale (MIBS) scores at hospital discharge and the 1-month postpartum outpatient visit were evaluated in the general anesthesia and the neuraxial anesthesia groups. A high score on the MIBS indicates impaired mother-infant bonding. Results The primary outcome was the MIBS score at hospital discharge in propensity score-matched women. After propensity score matching, the median [interquartile range (IQR)] MIBS scores were significantly higher in the general anesthesia group than those in the neuraxial anesthesia group at hospital discharge [2 (1-4) vs. 2 (0-2); P = 0.015] and at the 1-month postpartum outpatient visit [1 (1-3) vs. 1 (0-2); P = 0.046]. In linear regression analysis of matched populations, general anesthesia showed a significant and positive association with the MIBS scores at hospital discharge [beta coefficient 0.867 (95% confidence interval [CI] 0.147-1.59); P = 0.019] but not at the 1-month postpartum outpatient visit [0.455 (-0.134 to 1.044); P = 0.129]. Conclusion General anesthesia for emergency cesarean delivery is an independent risk factor associated with impaired mother-infant bonding.

DOI： 10.1515/jpm-2019-0412

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Regular Mouthing Movements (RMMs) are movements in which lips and lower jaw movements occur regularly and can be observed in the fetus using transabdominal ultrasonic tomography. In near term infants, it is known that RMMs form clusters during the quiet sleep period. The notation of RMMs is not uniform, and is described as spontaneous sucking movement or non-nutritive sucking in newborns. Non-nutritive sucking is used to evaluate neurological function after birth, but there are no fetal indicators. The purpose of this study was to clarify the changes in the RMM clusters in fetuses at 24-39 weeks of gestation, and to investigate the relationship with the non-eye movement (NEM) period, which corresponds to the quiet sleep period after birth. Subjects included 83 normal single pregnancy cases. Fetal RMMs and eye movement (EM) were observed for 60 minutes using ultrasonic tomography and recorded as moving image files. We created time series data of eye movements and mouth movements from video recordings, and calculated RMM clusters per minute within effective observation time, RMM clusters per minute in EM period, RMM clusters per minute in NEM period, mouthing movements per cluster and ratio of number of RMM clusters per minute between NEM and EM periods and analyzed using linear regression analysis. As a result, critical points were detected in at two time points, at 32-33 weeks and 36-37 weeks of gestation, in RMM clusters per minute within the effective observation time and RMM clusters per minute in NEM period, respectively. RMM clusters in human fetuses increased from 32-33 to 36-37 weeks. This change is thought to represent fetal sleep development and central nervous system development.

DOI： 10.1371/journal.pone.0233909

リポジトリ公開URL： http://hdl.handle.net/2324/4479067

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Uterine leiomyosarcoma (ULMS) is a highly aggressive and lethal disease. This malignancy remains the most common type of uterine sarcoma, affecting approximately 0.4/100 000 women each year. Our aim was to assess the treatment and prognosis of ULMS patients.

METHODS: A total of 14 patients were treated at our institution between January 2008 and July 2017. We retrospectively analyzed their clinicopathological variables, treatment and prognosis.

RESULTS: The median patient age was 63 years (range, 35-83 years). The largest group of patients had stage IB disease (stage IB, n = 8; IIB, n = 2; IIIB, n = 1; IVB, n = 3) and the largest group by histological subtype was ordinary (ordinary, n = 11; myxoid, n = 2; epithelioid, n = 1). Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed for all patients, with additional surgical procedures (e.g., tumor resection, lymphadenectomy) performed if necessary. Twelve patients received adjuvant chemotherapy (ACT) consisting of gemcitabine and docetaxel. Ten patients experienced recurrence and received multidisciplinary therapies, including tumor resection, chemotherapy, radiation and targeted therapies. The median observation period was 17 months (range, 5-75 months), and 11 patients were alive (without disease, n = 5; with disease, n = 6). Intriguingly, five of eight stage IB patients who received postoperative ACT were alive without disease.

CONCLUSION: ULMS is rare but is associated with a poor prognosis, even if multidisciplinary therapies are administered. However, ACT appears to be effective in improving the prognosis of patients with stage IB disease.

DOI： 10.1111/ajco.13286

リポジトリ公開URL： https://hdl.handle.net/2324/4479606

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Uterine leiomyosarcoma (ULS) is a highly aggressive and lethal tumor. The absence of specific symptoms and diagnostic imaging findings makes the diagnosis of ULS challenging. Endometrial sampling reportedly has a significantly lower predictive value in diagnosing ULS compared with epithelial uterine malignancies. Materials and Methods: The authors retrospectively reviewed the preoperative endometrial cytology findings in seven of the 12 patients with ULS who were treated in this institution between 2008 and 2017. The other five patients did not have preoperative samples obtained for cytology. Results: Only one of the seven patients was originally diagnosed with a malignant tumor, with preoperative cytology showing rounded tumor cells with enlarged, irregular, hyperchromatic, and sometimes multiple nuclei, with conspicuous nucleoli in a necrotic background. After re-evaluation of the preoperative specimens, atypical cells were detected in four of the six patients who were initially deemed to have negative findings. A monomorphic population of spindle cells with slightly hyperchromatic, elongated nuclei was detected in two patients. Another two patients had rounded tumor cells with a moderate amount of basophilic cytoplasm and round or oval nuclei with minimal atypia. Conclusion: Novel diagnostic techniques are needed to accurately identify ULS in the preoperative period. Careful microscopic observation of the entire cytological specimen, together with detailed patient medical information, are essential to making a correct preoperative diagnosis of ULS.

DOI： 10.31083/j.ejgo.2020.02.4950 Original Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A set of sex chromosomes is required for gametogenesis in both males and females, as represented by sex chromosome disorders causing agametic phenotypes. Although studies using model animals have investigated the functional requirement of sex chromosomes, involvement of these chromosomes in gametogenesis remains elusive. Here, we elicit a germ cell-intrinsic effect of sex chromosomes on oogenesis, using a novel culture system in which oocytes were induced from embryonic stem cells (ESCs) harboring XX, XO or XY. In the culture system, oogenesis using XO and XY ESCs was severely disturbed, with XY ESCs being more strongly affected. The culture system revealed multiple defects in the oogenesis of XO and XY ESCs, such as delayed meiotic entry and progression, and mispairing of the homologous chromosomes. Interestingly, Eif2s3y, a Y-linked gene that promotes proliferation of spermatogonia, had an inhibitory effect on oogenesis. This led us to the concept that male and female gametogenesis appear to be in mutual conflict at an early stage. This study provides a deeper understanding of oogenesis under a sex-reversal condition.

DOI： 10.1371/journal.pgen

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Objective: We compared the clinical outcomes of total laparoscopic radical hysterectomy (LRH) with abdominal radical hysterectomy (ARH) performed in women with cervical cancer.
Methods: Between November 2015 and February 2018, 19 women with cervical cancer (Stage IB1 or IIA1) underwent LRH, and 40 women with cervical cancer (Stage IB1 or IIA1) underwent ARH in our department. Patients' background, surgical outcomes, perioperative complications, and postoperative course were retrospectively compared between the groups. Statistical analysis was performed using the Student's t-test, Wilcoxon test, and the Fisher exact test.
Results: The operative time was significantly longer (587 vs. 422 min, p<0.0001) and estimated blood loss was significantly lesser (417 vs. 1077 mL, p<0.0001) in the LRH group. No statistically significant intergroup difference was observed in the number of lymph nodes removed, surgical margin, and perioperative complications. Median follow-up was 16 and 23 months, respectively, and recurrence occurred in 1 patient in each group.
Conclusion: Although this study included a limited number of patients and was a short-term study, LRH was safely performed in women with cervical cancer. Notably, no intergroup difference was observed in short-term outcomes. We will continue observation to determine the long-term prognosis in these women.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

目的：鏡視下手術におけるRadioisotope法でのセンチネルリンパ節（Sentinel Lymph Node:SLN）同定法の有用性について検討する。
方法：2014年1月から2018年12月までに子宮頸癌の診断で腹腔鏡下あるいはロボット支援下に広汎子宮全摘出術およびSLN検査を行った16例を対象とした。
結果：腹腔鏡下手術12例、ロボット支援下手術4例で進行期はIA1期1例、IB1期14例、IIA1期1例であった。16例中15例で両側にSLNを同定でき、1例は片側のみ同定できた。同定できたSLNは計47個であり、1症例あたり2.9個であった。部位別では外腸骨節が30個で最も多く、次いで閉鎖節14個であった。16例中7症例ではSLN生検後に骨盤リンパ節のバックアップ郭清まで行った。3症例でリンパ節転移を認めたが、全てのSLNに転移を認めたため、感度は100％であった。
結語：子宮頸癌鏡視下手術におけるRI法を用いたSLN同定は同定率、感度、陰性的中率も高く、有用な方法であると考えられた。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: H19 and IGF2 genes are imprinted and involved in regulating fetal and placental growth. The H19 differentially methylated region (DMR) is paternally methylated and maternally unmethylated and regulates the imprinted expression of H19 and IGF2. Epimutation at the H19-DMR in humans results in congenital growth disorders, Beckwith-Wiedemann and Silver-Russell syndromes, when erroneously its maternal allele becomes methylated and its paternal allele becomes unmethylated, respectively. Although H19 and IGF2 have been assessed for their involvement in pregnancy complications including fetal growth restriction (FGR) and pregnancy-induced hypertension (PIH)/hypertensive disorder of pregnancy (HDP) intensively in the last decade, it is still not established whether epimutation at the H19-DMR in the placenta results in pathogenic conditions in pregnancy. We aimed to assess the frequency of H19-DMR epimutation and its effects on the allelic expression patterns of H19 and IGF2 genes among normal and abnormal pregnancy cases.
RESULTS: We enrolled two independently collected sets of placenta samples from normal pregnancies as controls and common pregnancy complications, FGR and PIH (HDP). The first set consisted of 39 controls and 140 FGR and/or PIH cases, and the second set consisted of 29 controls and 62 cases. For these samples, we initially screened for DNA methylation changes at H19-DMR and IGF2-DMRs by combined bisulfite restriction analysis, and further analyzed cases with methylation changes for their allelic methylation and expression patterns. We identified one case each of FGR and PIH showing hypomethylation of H19-DMR and IGF2-DMRs only in the placenta, but not in cord blood, from the first case/control set. For the PIH case, we were able to determine the allelic expression pattern of H19 to be biallelically expressed and the H19/IGF2 expression ratio to be highly elevated compared to controls. We also identified a PIH case with hypomethylation at H19-DMR and IGF2-DMRs in the placenta from the second case/control set.
CONCLUSIONS: Placental epimutation at H19-DMR was observed among common pregnancy complication cases at the frequency of 1.5% (3 out of 202 cases examined), but not in 68 normal pregnancy cases examined. Alteration of H19/IGF2 expression patterns due to hypomethylation of H19-DMR may have been involved in the pathogenesis of pregnancy complications in these cases.

DOI： 10.1186/s13148-019-0712-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BHLHE40 and BHLHE41 (BHLHE40/41) are basic helix-loop-helix type transcription factors involved in multiple cell activities including epithelial-to-mesenchymal transition (EMT). However, the expression mechanism of BHLHE40/41 in EMT remains unclear. In the present study, we showed that the expression levels of BHLHE40/41 were negatively correlated with those of the microRNA (MIR) 130 family in endometrial cancer (EC) specimens. Our in vitro assays indicated that the expression of BHLHE40/41 was suppressed directly by the MIR130 family in a 3'-untranslated region-mediated manner. In EC cells, the MIR130 family promoted EMT and tumor cell invasion by suppressing the expression of BHLHE40/41. We identified the critical promoter region of the MIR301B-MIR130B cluster for its basal transcription by the transcription factor, SP1. We also found that BHLHE40/41 suppressed the expression of MIR301B and MIR130B, and we identified a binding site in the promoter region for BHLHE40/41. This study is the first to report that BHLHE40/41 and the MIR301B-MIR130B cluster suppressed each other to regulate EMT and invasion of EC cells. We propose that BHLHE40/41 and the MIR130 family are excellent markers to predict the progression of EC cases, and that molecular therapy targeting the MIR130 family-BHLHE40/41 axis may effectively control EC extension.

DOI： 10.18632/oncotarget.27061

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We developed an HPV16 E7-expressing Lactobacillus-based therapeutic vaccine, IGMKK16E7, to elicit mucosal E7-specific TH1 cellular immune responses. This study aims to examine the safety and clinical efficacy of IGMKK16E7 on HPV16-positive high-grade squamous intraepithelial lesion (HSIL). This is a multicenter, placebo-controlled, double-blind randomized phase I/II trial to test the safety and efficacy of IGMKK16E7 against HPV16-positive HSIL. The groups will include placebo, low-dose (0.5 g/day), middle-dose (1 g/day), and high-dose (1.5 g/day) IGMKK16E7. The target sample size will be 41 patients per group, and our data on our former agent, GLBL101c, were used to calculate sample size for 70% power and an α level = 0.05. The primary endpoint is IGMKK16E7 safety and pathological regression at week 16, and the secondary endpoints are cytological regression and HPV16 E7 immunological response. This study protocol has been approved by the Japanese Pharmaceuticals and Medical Devices Agency. Patient enrollment will begin in May 2019.

DOI： 10.1093/jico/hyz095

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

全身性エリテマトーデス(SLE)を有する女性において, 妊娠中の原疾患増悪および妊娠高血圧腎症(PE)に関連する妊娠時所見を抽出することを目的とした. 2008年から2017年に当院で管理したSLE合併妊娠を対象とし診療録より後方視的に検討した. 妊娠中に症状や検査所見の増悪により加療が強化された症例あるいはPE合併例を増悪群とし, 妊娠成立時の諸所見を非増悪群と比較した. 対象は48女性計59妊娠で, 19妊娠が増悪群に, 40妊娠が非増悪群に分類された. SLE関連臓器障害既往(p<0.01), 妊娠前1年以内の病勢増悪(p<0.01), 症状残存(p=0.01), ステロイドや免疫抑制剤の使用(p<0.01), ステロイド内服量(p<0.01)が有意に増悪群で多かった. 検査所見は両群間で有意差がなかった. SLE増悪やPE合併と関連する妊娠時所見として臓器障害の既往, 1年内の病勢, 薬物療法の強度が抽出された.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Cesarean hysterectomy(CH)時の出血量低減目的に総腸骨動脈バルーン閉塞術(CIABO)が行われるが, 有効性や合併症の頻度に関しては十分に明らかではない. CIABOの有効性と合併症を検討した. 対象は2011年4月から2018年3月の間に当科でCHを施行した症例で, CIABOを併使したCIABO群(7例)としなかった非CIABO群(7例)に分類した. 術中出血量, 輸血量, 合併症を主要評価項目とした. 術中出血量はCIABO群が2,200-6,758g(中央値3,300g), 非CIABO群が1,908-23,319g(4,650g)で, 前者で少ない傾向がみられたが有意差は認めず, 輸血量も同様であった. CIABO群の1例で右総腸骨動脈血栓症を発症し, ヘパリンで加療した. CIABOがCH時の出血量を減らす可能性がある一方, 動脈血栓症を来した症例はリスク対効果に疑問を呈した.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The number of elderly patients with gynecological cancer in Japan is increasing in line with the aging of society. However, little has been reported on the survival of elderly patients aged 75 or older with gynecological cancer in Japan.
METHODS: To clarify survival in women aged 75 years or older with gynecological cancer, we analyzed data of 4,089 gynecological cancer cases (cervical cancer, 1,309 cases; endometrial cancer, 1,319 cases; and ovarian cancer, 1,461 cases) in patients aged 75 or older from 21 population-based cancer registries in Japan, diagnosed in 2006-2008. We calculated the net survival (NS) of younger (75-79 years old), older (80-84 years old) and the oldest age group (85-99 years old). We also calculated NS stratified by extent of disease and histological type.
RESULTS:Five-year NS of cervical cancer patients was 54.5% in the younger age group, 40.8% in the older age group and 28.2% in the oldest age group. Five-year NS of endometrial cancer patients was 64.5%, 51.6% and 39.0% in the younger, older and oldest age groups, respectively. Five-year NS of ovarian cancer was 34.7%, 18.8% and 8.3%, respectively.
CONCLUSION:We estimated NS in elderly patients aged 75 years or older with gynecological cancers in Japan using data from population-based cancer registries.

DOI： 10.31557/APJCP.2019.20.2.437

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Point shear wave elastography is an ultrasonography technique used to evaluate tissue elasticity. We examined whether placental elasticity is useful for predicting the onset of pre-eclampsia. Two hundred twenty-one participants were divided into two groups: one group at low risk (n = 185) and the other at high risk (n = 36) for pre-eclampsia. The two groups were compared with respect to shear wave velocity (SWV) of the placenta. Use of SWV as a predictor of pre-eclampsia was also investigated by creating a receiver operating characteristic (ROC) curve. The ROC curve was used to set a cutoff SWV value for predicting pre-eclampsia. The SWV of the high-risk group was significantly higher than that of the low-risk group (p < 0.001). Thirteen participants developed pre-eclampsia after SWV measurements, and the SWVs of these participants were significantly higher than those of participants in who pre-eclampsia did not develop. The cutoff value and area under the ROC curve were 1.188 m/s and 0.9118, respectively. Placental elasticity was significantly increased even before the onset of pre-eclampsia onset and, thus, may be a parameter used to predict the onset of pre-eclampsia.

DOI： 10.1016/j.ultrasmedbio.2018.09.007

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Clinical trials show that protein supplement increases infant size in malnourished populations; however, epidemiological studies in high-income countries have reported mixed results. Although these findings suggest a non-linear relationship between maternal macronutrient intake and fetal growth, this relationship has not been closely examined. We assessed the association between maternal protein intake and fetal growth among 91 637 Japanese women with singletons in a nation-wide cohort study using validated FFQ. The respondents answered the FFQ twice, once during early pregnancy (FFQ1; 16·3 (sd 6·0) weeks), and second during mid-pregnancy (FFQ2, 28·1 (sd 4·1) weeks). Daily energy intake and percentage energy from protein, fats and carbohydrates were 7477 (sd 2577) kJ and 13·5 (sd 2·0), 29·5 (sd 6·5) and 55·3 (sd 7·8) %, respectively, for FFQ1, and 7184 (sd 2506) kJ and 13·6 (sd 2·1), 29·8 (sd 6·6) and 55·3 (sd 7·9) %, respectively, for FFQ2. The average birth weight was 3028 (sd 406) g, and 6350 infants (6·9 %) were small for gestational age (SGA). In both phases of the survey, birth weight was highest and the risk of SGA was lowest when the percentage energy from protein was 12 %, regardless of whether isoenergetic replacement was with fat or carbohydrates. Furthermore, when protein density in the maternal diet was held constant, birth weight was highest when 25 % of energy intake came from fat and 61 % came from carbohydrates during early pregnancy. We found maternal protein intake to have an inverse U-curve relationship with fetal growth. Our results strongly suggest that the effect of protein on birth weight is non-linear, and that a balanced diet fulfilling the minimum requirement for all macronutrients was ideal for avoiding fetal growth restriction.

DOI： 10.1017/S000711451800291X

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Despite numerous reports on pregnancy outcomes after trachelectomy, there are few descriptions of fertility treatment after trachelectomy. Moreover, little is known about the differences in fertility outcomes between various radical trachelectomy procedures. The purpose of this report was to clarify the infertility problems that occur in patients who have previously undergone an abdominal trachelectomy.
MATERIAL AND METHODS: We retrospectively investigated the medical records of 37 patients who received fertility treatments or were evaluated for menstrual disorders after trachelectomies in our institution between 2012 and 2016.
RESULTS: Twenty-two of 37 patients had complications which affected fecundity. Six patients had cervical stenosis requiring surgical dilation, 4 had ovarian insufficiency, and 14 had Asherman's syndrome.
CONCLUSIONS: In spite of efforts to preserve fertility, some patients have severe complications after trachelectomy, such as Asherman's syndrome, resulting in infertility. Clinicians should pay careful attention to the status of the endometrial cavity after trachelectomy.

DOI： doi: 10.1111/aogs.13429

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Although nonabsorbable woven tape has been widely used for cervical cerclage, technical difficulties that can occur with an effaced cervix because of the thickness of the tape, and the risks of local infection are two major concerns. This study investigated perinatal outcomes of pregnancies involving an emergency cervical cerclage using absorbable monofilament polydioxanone sutures, which is a narrow thread and protects against bacterial infection.
Materials and Methods: We performed a chart review of patients who underwent emergency McDonald cerclage with polydioxanone sutures at our institution between 2007 and 2015. Gestational age at delivery, duration between cerclage and delivery, and neonatal prognosis were evaluated as primary outcomes.
Results:Among the 23 patients (18 singleton and five twin pregnancies) evaluated, ultrasound-indicated (progressive cervical length shortening) were eight (35%) and physical examination-indicated (fetal membranes that prolapsed into the vagina or dilated cervix) were 15 patients (65%). The median gestational age at cerclage was 22+3 weeks (range, 17+5 to 25+3 weeks). Postoperative spontaneous abortion occurred in only one patient. The median gestational age at delivery was 32+5 weeks (range, 20+5 to 40+6 weeks). Extremely preterm delivery before 28 weeks of gestation occurred in four (17%) cases. Full-term delivery was achieved in 10 (42%) cases. The duration between cerclage and delivery ranged from 5 to 136 days (median, 77 days). Except for one case of spontaneous abortion, all newborns survived till hospital discharge.
Conclusions:Although our series included some patients at high risk for spontaneous abortion and preterm delivery, satisfactory prolongation and favorable neonatal outcomes were achieved for most patients by using absorbable monofilament sutures, thus suggesting the efficacy of this type of suture for emergency cervical cerclage.

DOI： 10.1155/2018/4049792

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aim of this study was to investigate whether non-reassuring foetal status (NRFS) affected an infant's temperament, or if the temperament formed prenatally resulted in an excessive heart rate reaction that was diagnosed as NRFS. We examined the correlation between NRFS and difficulty in holding a baby, and the amount of crying in the one month after birth, which was considered an indicator of the newborn's temperament. We divided the cases with NRFS into positive NRFS and false positive NRFS. NRFS was associated with bad mood, frequent crying for a long duration, and intense crying. After adjustment for other covariates, NRFS was associated with bad mood (odds ratio, OR = 1.15, 95% confidence interval, CI = 1.00-1.33), and intense crying (1.12, 1.02-1.24). In the multi-variable model, positive and false positive NRFS were not clearly associated with neonatal irritability. When stratified by parity, NRFS and false positive NRFS were likely to be positively associated with neonatal irritability in parous women. The clear association between NRFS and intense crying was observed in parous women (multi-variable adjusted OR = 1.46, 95% CI = 1.16-1.83), but not in nulliparae (1.01, 0.91-1.12) (p for effect modification <0.01). Similarly, increased odds of intense crying associated with false positive NRFS were only found in parous women (multi-variable adjusted OR = 1.40, 95% CI = 1.09-1.81) (p for effect modification = 0.03). There was no association observed between positive NRFS and irritability; therefore, NRFS has no effect on an infant's temperament.

DOI： 10.1038/s41598-018-34231-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Since 2010, the Women's Health Care Committee has addressed important issues linked to women's quality of life. The five agendas this committee has engaged this academic year are: (i) clinical study of urinary complications in perinatal and postpartum women's health care; (ii) education on infectious diseases prophylaxis in obstetrics and gynecology in Japan; (iii) educational activities regarding management guidelines for a female athlete's health care; (iv) training program for women's healthcare advisers; and (v) pregnancy- and lactation-associated osteoporosis (PLOP). The detailed activities of the five subcommittees are described herein. This report is based on the Japanese version of our annual report (Acta Obst Gynaec Jpn 2018; 70: 1538-1546), which publicizes the activities of our committee.

DOI： 10.1111/jog.13803

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM:Only a few reports of pelvic abscess as a late complication of trachelectomy have been published to date. To evaluate the cases of pelvic abscess as a late complication of abdominal trachelectomy for cervical cancer.
METHODS: In June 2005, we began a clinical trial of abdominal trachelectomy at our institution. Written informed consent was obtained from all patients. We retrospectively reviewed the medical records of patients who underwent trachelectomy and extracted the data of patients who experienced pelvic abscess as a late complication.
RESULTS: From June 2005 to September 2017, we performed 181 trachelectomies at our institution. In total, 15 pelvic abscesses occurred in 12 of these patients more than 1 month after trachelectomy. The median postoperative period before the onset of pelvic abscess was 51 months (range, 1-104 months). Among the 15 cases, abscess formed in the uterine adnexa in 12, in a pelvic lymphocyst in two, and in the uterus in one. Abscess drainage was performed in six cases. Three patients underwent laparotomy with salpingo-oophorectomy.
CONCLUSION: It is possible that not only surgical removal of the uterine cervix but also the use of nonabsorbable suture in cervical cerclage and placement of an intrauterine device triggered post-trachelectomy infection. Pelvic abscess can occur as a late complication of abdominal trachelectomy.

DOI： 10.1111/jog.13814

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aortic pulse waveforms are composed of a forward wave from the heart and a reflection wave from the periphery. We focused on this forward wave and suggested a new parameter, the maximum slope of aortic pulse waveforms (max dD/dt), for fetal cardiac contractility. Max dD/dt was calculated from fetal aortic pulse waveforms recorded with an echo-tracking system. A normal range of max dD/dt was constructed in 105 healthy fetuses using linear regression analysis. Twenty-two fetuses with suspected fetal cardiac dysfunction were divided into normal and decreased max dD/dt groups, and their clinical parameters were compared. Max dD/dt of aortic pulse waveforms increased linearly with advancing gestational age (r = 0.93). The decreased max dD/dt was associated with abnormal cardiotocography findings and short- and long-term prognosis. In conclusion, max dD/dt calculated from the aortic pulse waveforms in fetuses can substitute for max dP/dt, an index of cardiac contractility in adults.

DOI： 10.1016/j.ultrasmedbio.2018.02.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We developed a simplified three-dimensional ultrasonic device that can scan a wide area and performed measurements in the scanned area. The system is more compact than magnetic resonance imaging (MRI) systems and can measure random cross sections by acquiring volume data over a wide range through freehand scanning with a magnetic sensor unit that detects the transducer position. The system was applied successfully to a case with a huge myoma. Our system, in ways similar to computed tomography or MRI systems, can support both the objective understanding of the pathology of huge tumors and follow-up determinations of tumor diameters at arbitrary cross sections in the volume data.

DOI： 10.4103/JMU.JMU_17_18

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epilepsy is a neurological disorder often associated with seizure that affects ∼0.7% of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA-disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA-exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero.

DOI： 10.1073/pnas.1716479115

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Right aortic arch with aberrant left subclavian artery (RAA/aLSCA) is a rare aortic arch anomaly. The clinical association of aLSCA stenosis with RAA/aLSCA has not yet been fully elucidated. The aim of this study was to investigate the diagnosis, incidence, management and outcome of aLSCA stenosis in infants with prenatally diagnosed RAA/aLSCA. Ten fetuses who were diagnosed as having RAA/aLSCA in Kyushu University Hospital between January 2011 and December 2014 were enrolled. The maternal and child medical records were reviewed to investigate sex, gestational age at the fetal diagnosis, gestational age and body weight at birth, the findings of computed tomography (CT), Doppler ultrasonography of the vertebral artery and angiography, and the complications and outcomes of aLSCA stenosis. In 8 of 10 patients, aLSCA stenosis was identified on the first CT examination after birth. No patients had dysphagia or respiratory distress. The stenosis spontaneously resolved in 3 patients. In 4 of the 5 remaining patients, aLSCA stenosis progressed, including one case in which complete occlusion occurred-the case was associated with retrograde flow from the left vertebral artery supplying the distal LSCA. Balloon angioplasty was successfully used to treat stenosis in two cases. The subclavian steal phenomenon and developmental problems were not observed in any patients. aLSCA stenosis was identified in 80% of patients with RAA/aLSCA after birth. The early detection and elective treatment of stenotic lesions may be required to prevent complete occlusion during the development of the cardiovascular and cerebrovascular systems.

DOI： 10.1007/s00380-017-1056-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Medical circumstances in Japanese patients with cancer of the corpus uteri have greatly changed since the late 1990s, including the introduction of concomitant therapy with taxane and platinum. We evaluated changes in survival rates for this cancer following these advances by analyzing data from population-based cancer registries in Japan.
METHODS:Data were available for 8562 cases of cancer of the corpus uteri from six prefectural cancer registries. We defined the two periods of 1993-2000 (1st period) and 2001-2006 (2nd period). Relative survival (RS) in each period was calculated to assess changes using an excess mortality model, with adjustment for age group (15-54, 55-69, and 70-99 years), extent of disease (localized, regional, and distant), and histological subtype.
RESULTS: Overall 5-year RS improved from 77.7% in the 1st period to 80.2% in the 2nd period, with an excess hazard ratio (EHR) of 0.785 (95% confidence interval [CI], 0.705-0.873). Five-year RS significantly improved in the group aged 55-69 years, in all groups by extent of disease, and in the endometrioid adenocarcinoma group. In particular, 5-year RS significantly improved in patients with endometrioid adenocarcinoma, from 84.5% to 89.7%, with an EHR of 0.698 (95% CI, 0.560-0.870).
CONCLUSION:Overall 5-year RS for cancer of the corpus uteri in Japan improved from the 1990s to early 2000s. These improvements might have been aided by the comprehensive medical development of management for this cancer, including the spread of concomitant therapy with taxane and platinum as a standard adjuvant chemotherapy in the early 2000s.

DOI： 10.2188/jea.JE20170008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The ontogeny associated with the arm-hanging posture, which is considered ape-specific, remains unknown. To examine its ontogeny, we measured foetal movements of 62 human foetuses aged 10-20 gestation weeks using four-dimensional sonography. We observed that the first-trimester foetuses show this particular species-specific posture. After 11 weeks of gestation, all foetuses showed the arm-hanging posture, and the posture was most frequently observed at 14-16 weeks of gestation. Moreover, this posture often involved extension of both arms and both legs, indicating that it is not myogenic but neurogenic. Furthermore, early ontogeny suggests that it originates because of subcortical activity. Such posture extension bias and persistence indicates that vestibulospinal tract maturation involves the ontogeny of arm-hanging posture during 14-16 weeks of gestation.

DOI： 10.1038/s41598-017-18384-w

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

子宮頸部細胞診による子宮頚がん検診は、老人保健法により1983年より全国で開始され、2002年より現在の健康増進法に引き継がれている。2012年に策定されたがん対策推進基本計画では、「5年以内に受診率50％以上」の目標値が掲げられているが、子宮頚がんの受診率は、2013年が32.7％で、欧米諸国の受診率80％以上と比較すると極端に低いのが問題である。健診受診率50％以上の目標達成を考えると、今後子宮頸部細胞診検体数が増加することは確実で、細胞診断に携わる細胞検査士や細胞診専門医の大幅な負担増加が予想される。その結果、偽陰性すなわち、見落とし例の増加が懸念される。
日本臨床細胞学会では、偽陰性を少なくするため、細胞診断に関する精度管理の内容を定め、細胞検査士により陰性と判定された標本の10％以上について、細胞診専門医もしくは細胞検査士によちダブルチェックによる再検査を推奨している。したがって現状では、細胞検査士により陰性と判定された標本の約90％が再検査されることなく、陰性と報告されている。わが国で用いているこの10％ランダム再検査に比較して自動スクリーニング支援システムを使用したほうがより効率的に偽陰性を発見できるという事実から、米国では自動スクリーニング支援システムを精度管理目的に使用することが1996年FDAで承認され、広く用いられている。
すでにわれわれは、多施設共同研究として、「子宮頸部細胞診精度管理における自動スクリーニング支援システムの有用性に関する検討」を施行し、細胞検査士により陰性と判断された標本を本システムで再検査した。その結果、偽陰性すなわち、見落とし例が117例（1.19％）検出でき、その内高度扁平上皮内病変以上と判定されたものが、40例（34.2％）も検出でき、精度管理上本システムが有用であることを報告した。
今後子宮頸部細胞診検体数が増加する現状を考えた場合、偽陰性を減少させる効率的なシステム作りが精度管理上喫緊の課題である。本報告では、児童スクリーニング支援システムの子宮頸部細胞診精度管理における有用性について概説し、多施設共同研究の追加研究結果と合わせて報告する。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Y-box binding protein-1 (YB-1), involved in cancer progression and chemoradiation resistance, is overexpressed in not only cancer cells but also tumor blood vessels. In this study, we investigated the potential value of amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting YB-1 (YB-1 ASOA) as an antiangiogenic cancer therapy. YB-1 ASOA was superior to natural DNA-based ASO or locked nucleic acid (LNA)-modified YB-1 ASO in both knockdown efficiency and safety, the latter assessed by liver function. YB-1 ASOA administered i.v. significantly inhibited YB-1 expression in CD31-positive angiogenic endothelial cells, but not in cancer cells, in the tumors. With regard to the mechanism of its antiangiogenic effects, YB-1 ASOA downregulated both Bcl-xL/VEGFR2 and Bcl-xL/Tie signal axes, which are key regulators of angiogenesis, and induced apoptosis in vascular endothelial cells. In the xenograft tumor model that had low sensitivity to anti-VEGF antibody, YB-1 ASOA significantly suppressed tumor growth; not only VEGFR2 but also Tie2 expression was decreased in tumor vessels. In conclusion, YB-1/Bcl-xL/VEGFR2 and YB-1/Bcl-xL/Tie signal axes play pivotal roles in tumor angiogenesis, and YB-1 ASOA may be feasible as an antiangiogenic therapy for solid tumors.

DOI： 10.1016/j.omtn

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: We aimed to evaluate the outcomes of growth-restricted fetuses with absent end-diastolic velocity in the umbilical arteries (UA-AEDV), and investigate the relationship between Doppler flow velocity waveforms in the ductus venosus (DV) and the clinical features.

MATERIALS AND METHODS: This was a retrospective study of growth-restricted fetuses diagnosed with UA-AEDV delivered at our institution between 2013 and 2015. The time from diagnosis of UA-AEDV to delivery, postnatal survival, and developmental prognoses were the primary outcomes. The time lag between the occurrence of UA-AEDV and an abnormal increase in the DV pulsatility index (DV-PI) were investigated. We also examined the correlation between the DV-PI values immediately before birth and umbilical cord arterial pH at birth.

RESULTS: The median gestational age at birth among the 18 subjects was 28+2 (24+0-34+6) weeks, and the observation period between the first detection of UA-AEDV and delivery ranged from 0 to 35 days with a median of 8 days. Among the 18 infants, 15 (83%) survived, among whom 2 were diagnosed with a developmental disability. Gestational age at delivery was significantly lower in the poor outcome group. A positive correlation (correlation coefficient, 0.68) was observed between the umbilical artery pH and the last measured DV-PI.

CONCLUSION: The time interval from initial detection of UA-AEDV to delivery is highly variable, and it is reasonable to manage these growth-restricted fetuses with UA-AEDV expectantly with careful surveillance for fetal well-being. Specifically, Doppler DV analysis is clinically valuable for their evaluation.

DOI： 10.1016/j.tjog.2017.08.012

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To assess the feasibility and practicality of expectant management for pregnancies with fetal growth restriction (FGR) at term without evidence of placental dysfunction.
METHODS: We reviewed the records of pregnancies with an estimated fetal weight ≤ 1.5 SD below the mean at 37 weeks of gestation. We excluded elective cesarean deliveries and pregnancies that, at 37 weeks, were complicated by oligohydramnios, decreased fetal cerebroplacental ratio, or pregnancy-related hypertensive disorders. Prior to May 2013, we performed routine labor induction for FGR at term; after that time, we used routine expectant management. The rate of delivery by cesarean or instrumental assist and the rate of neonatal morbidity were compared between the groups.
RESULTS: The gestational age at delivery and the neonatal birthweight were higher in the expectant management policy group (39+4 vs 38+1 weeks; 2405 vs 2205 g). The cesarean rate (7/77 vs 7/73) and the instrumental delivery rate (5/77 vs 6/73) did not differ. Neonatal hypoglycemia and hyperbilirubinemia were significantly less frequent (10/77 vs 21/73; 7/77 vs 20/73) in the expectant management policy group. Seven patients in the expectant management policy group underwent emergency cesarean delivery; five of these (71%) had required labor induction because of progression to oligohydramnios.
CONCLUSIONS: Expectant management policy for FGR at term can reduce neonatal morbidity without increasing maternal risk or the cesarean rate. Caution should be used, however, during labor if oligohydramnios develops during expectant management.

DOI： 10.1111/jog.13461

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

双胎妊娠における試験経腟分娩の不成功に関わる因子を明らかにすることを目的とした. 対象は2005年から2014年の10年間に, 当院で妊娠34週以降に試験経腟分娩を行った双胎妊娠である. 両児経腟分娩となった症例を成功例, それ以外を不成功例と定義し, 不成功例の頻度を評価項目, 様々な母体背景を検討因子として調整オッズ比(aOR)をロジスティック回帰分析により求めた. 解析対象は129例であり, 試験経腟分娩の不成功例が22例(18%)であった. ロジスティック回帰分析の結果, 双胎経腟分娩の不成功に対する独立した予測因子は初産婦(aOR: 5.11, 95%信頼区間: 1.65-19.88)と分娩週数(aOR: 1.86, 95%信頼区間: 1.04-3.55)であり, 初産婦であることと分娩週数が遅いことは双胎経腟分娩の不成功に関わる因子であると考えられた.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Small for gestational age infants have an increased risk of immediate complications, short-term morbidity and mortality, and long-term neurologic and metabolic disorders in adulthood. Previous research has shown that reduced sleep duration is a risk factor for SGA birth. However, only a few studies have evaluated maternal sleep as a risk factor for SGA birth. In the present study, we investigated the relationship between the amount and quality of mothers' sleep and infants' birth weight.

RESULTS: This cohort study (n = 8631) used data from the Japan Environment and Children's Study, an ongoing cohort study that began in January 2011. Data on sleep status (sleep duration and one indicator of sleep quality) and potential confounding factors were recorded. A log-binomial regression model was used to estimate the risk of small for gestational age birth, and the results were expressed as risk ratios and their respective 95% confidence interval. No significant results were observed for sleep duration or tiredness upon waking. Neither the amount nor the quality of mothers' sleep was associated with the risk of small for gestational age birth.

DOI： 10.1186/s13104-017-2675-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background：Numerous earlier studies examining the association of air pollution with maternal and foetal health estimated maternal exposure to air pollutants based on the women’s residential addresses. However, residential addresses, which are personally identifiable information, are not always obtainable. Since a majority of pregnant women reside near their delivery hospitals, the concentrations of air pollutants at the respective delivery hospitals may be surrogate markers of pollutant exposure at home. We compared air pollutant concentrations measured at the nearest monitoring station to Kyushu University Hospital with those measured at the closest monitoring stations to the respective residential postal code regions of pregnant women in Fukuoka.

Methods：Aggregated postal code data for the home addresses of pregnant women who delivered at Kyushu University Hospital in 2014 was obtained from Kyushu University Hospital. For each of the study’s 695 women who resided in Fukuoka Prefecture, we assigned pollutant concentrations measured at the nearest monitoring station to Kyushu University Hospital and pollutant concentrations measured at the nearest monitoring station to their respective residential postal code regions.

Results：Among the 695 women, 584 (84.0%) resided in the proximity of the nearest monitoring station to hospital or one of the four other stations (as the nearest stations to their respective residential postal code region) in Fukuoka city. Pearson’s correlation for daily mean concentrations among the monitoring stations in Fukuoka city was strong for fine particulate matter (PM2.5), suspended particulate matter (SPM), and photochemical oxidants (Ox) (coefficients ≥0.9), but moderate for coarse particulate matter (the result of subtracting the PM2.5 from the SPM concentrations), nitrogen dioxide, and sulphur dioxide. Hospital-based and residence-based concentrations of PM2.5, SPM, and Ox were comparable.

Conclusions：For PM2.5, SPM, and Ox, exposure estimation based on the delivery hospital is likely to approximate that based on the home of pregnant women.

DOI： 10.1186/s12199-017-0663-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cyt.12379

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Evidence supporting an inverse association between maternal exposure to air pollutants and foetal growth has been accumulating. However, the findings from Asian populations are limited, and the question of critical windows of exposure remains unanswered. We examined whether maternal exposure to air pollutants, in particular exposure during the first trimester (an important period of placental development), was associated with foetal growth in Japanese term infants. From the Japan Perinatal Registry Network database, we received birth data for 29,177 term singleton births in western Japan (Kyushu-Okinawa Districts) between 2005 and 2010. Exposure was expressed in terms of average concentrations of air pollutants (ozone, suspended particulate matter, nitrogen dioxide, and sulphur dioxide), as measured at the nearest monitoring stations to the respective delivery hospitals of the pregnant women, during the entire pregnancy and each trimester. As proxy markers of foetal growth restriction, we used small for gestational age (SGA), and adverse birth weight (low birth weight in addition to SGA). For pollutant exposure during the entire pregnancy, we did not observe the association with SGA and adverse birth weight. In the single-trimester model for the first trimester, however, we found a positive association between ozone exposure, and SGA (odds ratio [OR] per 10 ppb increase = 1.07, 95% confidence interval [CI] = 1.01-1.12) and adverse birth weight (OR = 1.07; 95% CI = 1.01-1.14). This association persisted in the multi-trimester model, and no association for exposure during the second or third trimester was observed. Exposure to other pollutants during each trimester was not associated with these outcomes. In conclusion, maternal exposure to ozone during the first trimester was independently associated with an elevated risk of poor foetal growth.

DOI： 10.1016/j.envpol.2017.06.069

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To determine the characteristics, outcomes, and prognostic factors of fetal hydrothorax (FHT) with trisomy 21.
METHODS: A nationwide survey was conducted on FHT fetuses with trisomy 21 delivered after 22 weeks' gestation between January 2007 and December 2011 at perinatal centers.
RESULTS: The 91 cases of FHT with trisomy 21 included 28 (30.8%) diagnosed in utero and 63 (69.2%) diagnosed after birth. The natural remission rate was 6.6% (6/91). Thoracoamniotic shunting was performed in 14.3% (13/91) of cases. The survival rates of the hydropic, nonhydropic, and total cases were 47.0% (31/66), 84.0% (21/25), and 57.1% (52/91), respectively. The crude odds ratio for death was 8.2 (p = 0.003) for fetuses diagnosed at 26-30 weeks of gestational age (vs ≥30 weeks), 5.9 (p = 0.003) for hydrops, 4.0 (p = 0.04) for bilateral pleural effusion, 0.68 (p = 0.42) for associated cardiovascular anomalies, and 2.1 (p = 0.26) for thoracoamniotic shunting (vs no fetal therapy).
CONCLUSIONS: The prognosis of FHT with trisomy 21 was not very poor, but it was still worse than that of primary FHT. Hydrops, an early gestational age at the diagnosis and bilateral effusion, but not associated anomalies, were risk factors for death. Fetal therapy showed no survival benefit for FHT with trisomy 21.

DOI： 10.1002/pd.5066

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The fourth edition of the World Health Organization classification set up new entities of endocervical adenocarcinoma (ECA), namely the "usual type" and "gastric type." These 2 types are considered to be distinct histogenetically because of their differing immunophenotypes, human papillomavirus (HPV) status, and prognoses. Usual-type ECAs (U-ECAs) are virtually always associated with high-risk human papillomavirus (HR-HPV) infection. Gastric-type ECAs (G-ECAs) are believed not to be associated with HR-HPV infection. Morphologically, U-ECA cells are characterized by mucin-poor and eosinophilic cytoplasm, resembling endometrioid carcinoma (a pseudoendometrioid feature). G-ECA cells are characterized by abundant clear or pale, mucinous cytoplasm and distinct cell borders. However, in routine practice we noticed that some ECAs contain morphologically usual type-like components and gastric type-like components in a single tumor; we have named these "G+U" ECAs. The histogenesis of such tumors has not been investigated. We conducted the present study to clarify the clinicopathologic and immunohistochemical features and HPV status of G+U ECAs, and to determine whether G+U ECAs are genuine G-ECAs mimicking U-ECAs or genuine U-ECAs with gastric type-like morphology. We retrospectively analyzed a series of 70 consecutive cases of ECA diagnosed as mucinous ECA, endocervical type, and we reclassified them on the basis of the latest World Health Organization classification. We identified 48 (69%) pure U-ECAs, 9 pure G-ECAs, and 13 G+U ECAs. Ten of the 13 G+U ECAs (77%) showed no HR-HPV infection by in situ hybridization (HPV-unrelated G+U ECAs) and showed frequent HIK1083 expression and aberrant p53 expression in both usual type-like and gastric type-like components. The other 3 G+U ECAs showed HR-HPV infection (HPV-related G+U EACs) and frequent p16+/p53-/HIK1083- immunophenotype in both usual type-like and gastric type-like components. The U-ECAs were characterized by HR-HPV infection detected by in situ hybridization and frequent p16+/p53-/HIK1083- immunophenotype, similar to that of the HPV-related G+U ECAs. In contrast, the pure G-ECAs were characterized by the absence of HPV infection and frequent HIK1083 expression and aberrant p53 expression, similar to that of HPV-unrelated G+U ECAs. G+U ECAs thus represent a heterogenous group composed of genuine G-ECAs and genuine U-ECAs. Most of the G+U ECAs we examined were genuine HPV-unrelated G-ECAs with usual type-like components showing mucin-poor, eosinophilic cytoplasm (pseudoendometrioid morphology). A small population of G+U ECAs was genuine HPV-related U-ECAs with gastric type-like components showing mucin-rich, voluminous cytoplasm. Thus, both types of ECAs can occasionally display patterns of differentiation suggesting a component of the other type but true mixed tumors do not appear to exist. Ancillary techniques (immunohistochemical analysis of p16, p53, and HPV DNA detection assays) should be used to assure proper classification of tumors with mixed morphologic features.

DOI： 10.1097/PAS.0000000000000833

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

2013年から2015年までの鉗子分娩61例を対象として、その成功率や母体・申請時合併症につき、診療録から後方視的に検討した。また、同時期の吸引分娩137例とMann-Whitne U 検定及びFisher直接確率検定を用いて比較した。61例の内訳は高位鉗子17例、低位鉗子32例、出口部鉗子8例であった。後方後頭位の牽引が5例含まれ、60例で遂娩が成功し、1例で帝王切開に移行した。57例が1回のみの牽引で娩出に至り、膣壁裂傷。3度以上の会陰裂傷、外陰膣血腫が各々39例、7例、4例で生じた。骨折や帽状腱膜下血腫などの重篤な児外傷はなかった。吸引分娩と比較して、最終的な遂娩成功率には差がなかったが、1回の牽引での遂娩成功率は有意に高く（57/61 vs 88/137. p<0.01）。産道裂傷や新生児合併症の頻度に差を認めなかった。鉗子分娩は少ない牽引回数で児娩出が可能な効果的な急速遂娩法であり、新生児合併症の頻度も高くないが、産道裂傷や血腫形成には留意を要する。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent studies demonstrated that Protease-activated receptor-2 (PAR-2) correlates with tumor progression in various tissues. On the other hand, oxidative stress arising from endometriosis has been considered a cause of carcinogenesis in ovarian clear cell carcinoma (OCCC). We previously demonstrated that oxidative stress upregulates PAR-2 expression, and we conducted the present study to investigate the PAR-2 expression and its relation to clinicopathological factors and oxidative stress in OCCC. We performed an immunohistochemical evaluation in 95 cases of OCCC. For the evaluation of oxidative stress markers, 31 cases of ovarian endometrioid carcinoma (OEC) were also examined. No significant differences in the expression of COX2 and iNOS were observed between OCCC and OEC. Sixty-two percent of the OCCC cases showed high 8-OHdG expression, whereas all of the OEC cases showed almost negative immunoreactivities. The presence of endometriosis did not affect the expression of these oxidative stress markers or prognosis. High PAR-2 expression was observed in 20% (14/71) of the early FIGO stage cases but 58% (14/24) of the advanced FIGO stage cases. High PAR-2 expression was significantly correlated with advanced FIGO stage and shorter overall survival. We found no correlations between PAR-2 expression and oxidative stress in OCCC. Our results suggest that PAR-2 plays an important role in the progression of OCCC. The expression of 8-OHdG is a characteristic finding of OCCC, indicating that the injury of DNA by oxidative stress may be involved in the carcinogenesis of OCCC.

DOI： 10.1016/j.humpath.2017.04.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Placental abruption is an emergency obstetric complication. Although the etiology of abruption is not fully understood, acute stimuli, such as ischemia and/or inflammation, are associated with rupture of the decidual artery, resulting in placental separation. Ischemia and inflammation are acute biologic effects of air pollution. Using a case-crossover design, we tested the hypothesis that a short-term increase in exposure to air pollutants is a potential trigger of placental abruption.

METHODS: We received data for western Japan (Kyushu-Okinawa Districts) from the Japan Perinatal Registry Network database. From 2005 to 2010, 821 singleton pregnant women with placental abruption were identified. We assigned daily concentrations of air pollutants, including nitrogen dioxide (NO2), suspended particulate matter, ozone, and sulfur dioxide (SO2), from the nearest monitoring station to the respective delivery hospital of each woman. Because information on the onset day of abruption was not obtained, we assumed the case day to be 1 day before the day of delivery.

RESULTS: Exposure to NO2 at 2 days' lag was associated with placental abruption (temperature adjusted odds ratio per 10 ppb increase = 1.4; 95% confidence interval = 1.1, 1.8). The association patterns were similar, when we restricted to participants who delivered by emergency cesarean (1.4, 1.1, 1.9), or who delivered after 35 weeks of gestation (1.4, 1.0, 2.0). There was no association with suspended particulate matter, ozone, or SO2.

CONCLUSIONS: We observed an association between NO2 exposure at 2 days before the day of delivery and placental abruption in pregnant Japanese women.

DOI： 10.1097/EDE.0000000000000605

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

【緒言】羊水除去の至適除去速度に関するコンセンサスはない。急激な羊水内圧の減少が胎盤早期剥離を誘発するかもしれないという懸念から緩徐な除去が慣習化されてきたが、その証拠は実際にはほとんどなく、長時間の仰臥位姿勢に伴う患者の苦痛は軽くない。当科で行った急速羊水除去の安全性を検証した。
【方法】2013年5月から2016年2月の間に羊水過多症に対して羊水除去を行った20症例（計31回）を対象とし、術中術直後の合併症、分娩転帰などについて診療録より後方視的に検討した。羊水除去の穿刺には18G PTC針を用い、延長チューブで穿刺針とATOM吸引娩出器VP-400を接続し、除去速度がおよそ100ml/分になるよう吸引圧を調節した。
【成績】母体年齢の中央値は32歳（25～43歳）で、初産婦、経産婦の10例ずつであった。羊水過多の原因として母体妊娠糖尿病が1例、胎児疾患が18例、特発性が1例あった。2回の羊水除去を要したものが9例、3回要したものが1例あった。羊水除去施行週数の中央値は33⁺⁵週（28⁺⁵－37⁺²週）で、1回除去量、除去所要時間、除去速度の中央値はそれぞれ2,000ml、20分、90ml/分であった。1週間以内の前期破水となったものが3例のみあったが、いずれもlate pretermの症例であった。1例に羊膜分離を認めたが早産には至らず、胎盤早期剥離や用紙肝塞栓をきたした症例はなかった。
【考案】吸引器を用いた急速羊水除去は胎盤早期剥離などの重篤な合併症を発生させることなく、母児に対して安全に施行されていた。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Small-for-gestational-age in infancy is a known risk factor not only for short-term prognosis
but also for several long-term outcomes, such as neurological and metabolic disorders in adulthood.
Previous research has shown that severe nausea and vomiting in early pregnancy (NVP) and hyperemesis
gravidarum, which is an extreme form of NVP, represent risk factors for small-for-gestational-age birth.
However, there is no clear consensus on this association. Thus, in the present study, we investigated the
correlation between hyperemesis gravidarum and NVP on the one hand, and infant birth weight on the other,
using data from the Japan Environment and Children's Study (JECS).

METHODS: The data utilized in the present study were obtained from the JECS, an ongoing cohort study
that began in January 2011. Our sample size was 8635 parent-child pairs. The presence or absence of severe
NVP, hyperemesis gravidarum, and potential confounding factors were noted. A multivariable regression
analysis was used to estimate risks for small-for-gestational-age birth, and the results were expressed as risk
ratios and 95 % confidence intervals.

RESULTS: The risk ratios of small-for-gestational-age birth (95 % confidence interval) for mothers with
severe NVP and those with hyperemesis gravidarum were 0.86 (0.62-1.19) and 0.81 (0.39-1.66),
respectively, which represents a non-significant result.

CONCLUSIONS: In our analysis of JECS data, neither severe NVP nor hyperemesis gravidarum was associated with increased risk for small-for-gestational-age birth.

DOI： 10.1186/s12884-016-1041-6.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

【目的】当院では器械分娩の方法として長らく吸引分娩単独で行ってきたが、2013年に牽引力のより強いとされる鉗子分娩を導入し、必要状況に合わせて選択しとしてきた。鉗子分娩の成功率や母体・新生児合併症を検討した。
【方法】2013年から2015年までに鉗子分娩を施行した単胎妊娠例を対象とし、鉗子分娩の種類、牽引時の回旋、牽引回数、墜娩の成否、外傷や黄疸などの新生児合併症、母体産道裂傷や血腫形成の有無などにつき、診療録から後方視的に検討した。また、同時期の吸引分娩137例とMann-Whitney U検定及びFisher直接確率検定を用いて比較した。
【結果】鉗子分娩61例の内訳は高位鉗子4例、中位鉗子17例、低位鉗子32例、出口部鉗子8例であった。後方後頭位の牽引が5例含まれ、全61例中60例で墜娩が成功し、1例で帝王切開に移行した。墜娩成功60例のうち57例が1回の牽引で娩出に至り、膣壁裂傷、3度以上の会陰裂傷、外陰膣血腫がそれぞれ39例、7例、4例で生じた。骨折や頭蓋内出欠、帽状腱膜下血腫などの児合併症はなく、9例で黄疸に対して光線治療が行われた。吸引分娩と比較して、最終的な墜娩成功率には差がなかったが、1回の牽引での墜娩成功率は有意に高く(57/61vs90/137,p<0.01)、産道裂傷や新生児合併症の頻度に差を認めなかった。
【結論】鉗子分娩は少ない牽引回数で児娩出が可能な効果的な急速墜娩法であり、新生児合併症の頻度も高くないが、産道裂傷や血腫形成には留意を要する。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Placenta praevia is an obstetric complication involving placental implantation in the lower uterine segment. Given the suggested aetiology of placenta praevia, adverse biological effects of air pollutants, such as plasma viscosity increment, endothelial dysfunction, and systemic inflammation, have the potential to induce low implantation. We explored the association between exposure to air pollutants during the pregnancy period up to implantation, and placenta praevia, in pregnant Japanese women. The outcome also included placenta accreta, which often exists in combination with placenta praevia.

METHODS: From the Japan Perinatal Registry Network database, we obtained data on 40,573 singleton pregnant women in western Japan (Kyushu-Okinawa Districts) between 2005 and 2010. We assigned pollutant concentrations (suspended particulate matter [SPM], ozone, nitrogen dioxide [NO2], and sulphur dioxide [SO2]), measured at the nearest monitoring station to the respective delivery hospital of each woman. A logistic regression model was used to adjust for several covariates.

RESULTS: The odds ratios (ORs) of placenta praevia per 10 units increase were 1.12 (95% confidence interval (CI)=1.01-1.23) for SPM over 0-4weeks of gestation, and 1.08 (1.00-1.16) for ozone. The association between exposure to NO2 and SO2, and praevia, was in the direction of increased risk. SPM exposure during 0-4weeks was associated with placenta accreta without praevia (OR=1.33, 95% CI=1.07-1.66). We found no association with exposure to air pollutants during 5-12weeks and the second trimester.

CONCLUSIONS: Exposure to air pollutants through to implantation was positively associated with placenta praevia and accreta.

DOI： 10.1016/j.envint.2016.04.037

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: To determine the frequency of squamous cell change associated with endometrial carcinoma, to evaluate the relationship between squamous cell change and clinicopathological features, and to assess cytological findings for squamous cells with and without nuclear atypia in endometrial smears.

METHODS: In 103 cases of endometrioid adenocarcinoma of the endometrium having both histological and cytological specimens, the frequencies and relationships between the presence and absence of squamous cell changes were evaluated, as were the clinicopathological features of such changes. In endometrial smears, squamous cells with and without nuclear atypia were clinicopathologically assessed.

RESULTS: Squamous cell changes were found in 58.3% of cases that had both histological and cytological preparations. There were no significant differences between the group with squamous cell changes and the group without in any of the clinicopathological features. In the cytological smears, 70.0% of the 60 cases that showed squamous cell changes in both preparations did not have nuclear atypia of squamous cells, while 30.0% of those cases had atypia. The group of cases with squamous cells without atypia tended to be better differentiated than the group with atypia. Vessels were permeated significantly more often in the group with atypia than in the group without.

CONCLUSIONS: Our data suggest the importance of observing squamous cells in endometrial cytology, especially concerning findings on nuclei with vs without atypia, when endometrial carcinoma is suspected.

DOI： 10.1002/dc.23418

記述言語：英語   掲載種別：研究論文（学術雑誌）  

"Invasive micropapillary serous carcinoma" has been proposed as a synonym for low-grade serous carcinoma by some expert pathologists. In contrast, Singer and colleagues reported that some serous carcinomas with conspicuous invasive micropapillary pattern (SC-IMPs) can show high-grade nuclear atypia. However, the molecular features of such tumors have not been well documented. The aim of this study was to demonstrate and emphasize the fact that high-grade serous carcinoma confirmed by immunohistochemistry and molecular analysis can show conspicuous invasive micropapillary pattern. We selected 24 "SC-IMPs" and investigated: (1) their morphologic features; (2) the immunostaining pattern of p53 protein; and (3) KRAS/BRAF/TP53 gene mutations. The 24 SC-IMPs were subdivided into low-grade and high-grade tumors based primarily on the nuclear atypia, with the mitotic rate used as a secondary feature: low grade (n=5) and high grade (n=19). Low-grade SC-IMPs were characterized by low-mitotic activity, absence of abnormal mitosis, presence of serous borderline tumor, occasional BRAF mutation, and infrequent TP53 mutation. High-grade SC-IMPs were characterized by high-mitotic activity, presence of abnormal mitosis, conventional high-grade serous carcinoma, frequent TP53 mutation, and lack of KRAS/BRAF mutation. We demonstrated that high-grade serous carcinoma confirmed by aberrant p53 immunostaining and molecular analysis can show conspicuous invasive micropapillary pattern, validating Singer and colleague's report. Serous carcinoma with conspicuous invasive micropapillary pattern should not be readily regarded as low-grade serous carcinoma. Nuclear grade is the most important diagnostic feature in the SC-IMPs.

DOI： 10.1097/PGP.0000000000000211.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Uterine leiomyosarcoma (LMS) is the worst malignancy among the gynecologic cancers. Uterine leiomyoma (LM),
a benign tumor of myometrial origin, is the most common among women of childbearing age. Because of their similar symptoms, it is difficult to preoperatively distinguish the two conditions only by ultrasound and pelvic MRI. While histopathological diagnosis is currently the main approach used to distinguish them postoperatively, unusual histologic variants of LM tend to be misdiagnosed as LMS. Therefore, development of molecular diagnosis as an alternative or confirmatory means will help to diagnose LMS more accurately. We adopted omics-based technologies to identify genome-wide features to distinguish LMS from LM and revealed that copy number, gene expression, and DNA methylation profiles successfully distinguished these tumors. LMS was found to possess features typically observed in malignant solid tumors, such as extensive chromosomal abnormalities, overexpression of cell cycle-related genes, hypomethylation spreading through large genomic regions, and frequent hypermethylation at the polycomb group target genes and protocadherin genes. We also identified candidate expression and DNA methylation markers, which will facilitate establishing postoperative molecular diagnostic tests based on conventional quantitative assays. Our results demonstrate the feasibility of establishing such tests and the possibility of developing preoperative and noninvasive methods.

DOI： 10.1155/2015/412068

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although several studies have demonstrated the tumor suppressive function of CNN1 (calponin 1), no studies have performed a site-specific analysis of CNN1 on tumor cell activities.

MATERIALS AND METHODS: We herein studied the site-specific effects of CNN1 in ovarian cancer cells using full-length CNN1 (fCNN1), three CNN1 repeats (3CNRs), or the first CNN1 repeat (CNR1) expression vectors. Ovarian cancer cells stably expressing each construct were analyzed for in vitro proliferation, cell motility, invasion, and soft agar assays. An in vitro model of pleural dissemination was also established.

RESULTS: Cell proliferation, anchorage-independent colony formation, cell motility, and cell invasion were all suppressed in fCNN1, 3CNRs, and CNR1-stably-expressing cells. CNN1 expression in mesothelial cells suppressed cancer cell invasion into a monolayer of mesothelial cells.

CONCLUSION: CNR1 showed similar suppressive effects as fCNN1. Results suggest CNR1 as a potential small synthetic peptide candidate for therapeutic strategies against ovarian cancer.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The aim of this study was to clarify the diagnostic significance of the presence of intranuclear inclusions in clear cell carcinoma (CCC).

MATERIALS AND METHODS: We analyzed 98 imprint specimens and 53 ascites specimens from 98 ovarian carcinoma cases [28 CCCs, 37 serous carcinomas (SCs), 22 endometrioid carcinomas (ECs), and 11 mucinous carcinomas (MCs)]. We examined (1) frequency of intranuclear inclusion-positive cases of each ovarian carcinoma subtype, using imprint specimens, (2) frequency of intranuclear inclusion-positive cells of each ovarian carcinoma subtype, using imprint specimens, (3) frequency of intranuclear inclusion-positive cases of each ovarian carcinoma subtype, using ascites specimens, and (4) sensitivity and specificity of the presence of intranuclear inclusions for the cytological diagnosis of CCC.

RESULTS: (1) The frequency of intranuclear inclusion-positive cases in CCC (96.4%) was significantly higher than in SC (13.5%), EC (13.6%), and MC (18.2%) (P < 0.001). Two or more intranuclear inclusions in a single nucleus were observed only in CCC. (2) The frequency of intranuclear inclusion-positive cells in CCC (median, 0.41%) was significantly higher than in non-CCC subtypes (0.010%) (P < 0.001). (3) Using ascites specimens, the frequency of intranuclear inclusion-positive cases in CCC (78.6%) was significantly higher than in SC (10.3%), EC (0%), and MC (0%) (P < 0.001). (4) The sensitivity of intranuclear inclusions was 96.4%, and the specificity was 85.7%.

CONCLUSIONS: The identification of intranuclear inclusions, in particular a high frequency and multiple intranuclear inclusions in a single nucleus, is useful for the cytological diagnosis of CCC. Furthermore, these results may be applicable to ascites cytology. Diagn. Cytopathol. 2015;43:879-884. © 2015 Wiley Periodicals, Inc.

DOI： 10.1002/dc.23322

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the role of interventional radiology in the field of obstetrical hemorrhage has been widely reported upon recently, the rate of procedure-related complications has not been fully determined. We present the case of a patient who developed an external iliac artery thrombosis, a rarely reported complication associated with prophylactic common iliac artery balloon occlusion (CIABO). After CIABO, we found that the dorsalis pedis artery of the right foot was weak and the foot was cold, despite the fact that the patient had no complaints. Computed tomography demonstrated a linear thrombus in the right external iliac artery. We managed the patient conservatively using a heparin drip without the need for thromboembolectomy. Our experience suggests that it is important to consider the risk of thrombosis formation after CIABO. Physical examination post-procedure is key to identifying this complication early.

DOI： 10.1111/jog.12777

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND:
Ambient air pollution is hypothesized to be a risk factor for hypertensive disorders in pregnancy, one of the major pregnancy complications. Past studies have reported the supporting evidence, however this mainly referred to the Western population, and results from trimester-specific analysis have been varied. In this study, we focused on exposure during the first trimester of pregnancy (placental development stage), and tested the hypothesis among the Japanese population.

METHODS:
We drew on data from the Japan Perinatal Registry Network database, and studied 36,620 singleton pregnant women without medical complications, in western Japan (Kyushu and Okinawa districts) between 2005 and 2010. In addition, data on ozone, suspended particulate matter (SPM), nitrogen dioxide (NO2), and sulfur dioxide (SO2) concentrations were obtained. The nearest monitoring station to the respective birthing hospital was used as a reference point for assigning average concentrations of each pollutant during the first trimester of pregnancy for each woman. The logistic regression model was applied to assess the association between quintiles of each pollutant and hypertensive disorders in pregnancy.

RESULTS:
Mean concentrations during the first trimester were 41.3ppb for ozone, 27.4μg/m(3) for SPM, 11.8ppb for NO2, and 3.2ppb for SO2. High exposure to ozone was associated with an increased risk of hypertensive disorders in pregnancy (for highest quintile vs. lowest: odds ratio=1.20, 95% confidence interval=1.01-1.42). With regard to SPM, NO2 and SO2, we did not obtain the results with constant directionality.

CONCLUSIONS:
Ozone exposure during early pregnancy may be a risk factor for hypertensive disorders in pregnancy.

DOI： 10.1016/j.envres.2015.08.024.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ovarian serous borderline tumors (SBTs) being a precursor of low-grade serous carcinomas are morphologically characterized by noninvasive growth and low-grade cytology. On the other hand, many pathologists regard cytologically high-grade, noninvasive (HG-noninv) ovarian serous tumors resembling SBTs in low magnification as conventional high-grade serous carcinomas (HGSCs) by personal experiences. Nonetheless, there are no established molecular characteristic of such tumors. In this study, therefore, we attempted to provide the molecular evidence. We selected 37 ovarian serous tumors that exhibited a cytologically HG-noninv growth pattern, including 36 tumors that coexisted with conventional invasive HGSC components (HG-inv) and a single tumor exclusively composed of pure HG-noninv. Histologically, all HG-noninv showed many mitotic figures, and serous tubal intraepithelial carcinomas were identified in 3 tumors with HG-noninv. Immunohistochemically, most HG-noninv showed aberrant p53 expression, frequent IMP3 positivity, p16 overexpression, a high MIB-1 labeling index, and infrequent PAX2. By molecular analysis, the pure HG-noninv and 13 HGSCs with HG-noninv showed TP53 mutations, but KRAS/BRAF mutations were not detected in any of them. In 1 tumor, we detected an identical TP53 mutation in both HG-noninv and HG-inv components by using laser capture microdissection. These immunohistochemical and molecular features of HG-noninv were similar to those of conventional invasive HGSCs but different from those of SBTs. In conclusion, our results showed that a cytologically HG-noninv growth pattern simulating an SBT is a morphological spectrum of HGSC, but not a true SBT.

DOI： 10.1016/j.humpath.2015.06.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BHLHE40 and BHLHE41 are basic helix-loop-helix type transcription factors that play key roles in multiple cell behaviors. BHLHE40 and BHLHE41 (BHLHE40/41) were recently shown to be involved in epithelial-to-mesenchymal transition (EMT). However, the precise mechanism of EMT control by BHLHE40/41 remains unclear. In the present study, we demonstrated that BHLHE40/41 expression was controlled in a pathological stage-dependent manner in human endometrial cancer (HEC). Our in vitro assays showed that BHLHE40/41 suppressed tumor cell invasion. BHLHE40/41 also suppressed the transcription of the EMT effectors, SNAI1, SNAI2, and TWIST1. We identified the critical promoter regions of TWIST1 for its basal transcriptional activity. We elucidated that the transcription factor, SP1, was involved in the basal transcriptional activity of TWIST1 and that BHLHE40/41 competed with SP1 for DNA binding to regulate gene transcription. This study is the first to report the detailed functions of BHLHE40 and BHLHE41 in the suppression of EMT effectors in vitro. Our results suggest that BHLHE40/41 suppress tumor cell invasion by inhibiting EMT in tumor cells. We propose that BHLHE40/41 are promising markers to predict the aggressiveness of each HEC case, and that molecular targeting strategies involving BHLHE40/41 and SP1 may effectively regulate HEC progression.

記述言語：日本語  

「概要」可及的迅速な児娩出を要する場合に全身麻酔下の超緊急帝王切開が行われるが, 児娩出までの時間をいかに短縮するかは周産期医療施設の重要な課題である. また, 下腹部横切開は美容上の優位性に加えて, 創痛やヘルニア形成が少ない利点をもつ. 2013年より導入した Joel-Cohen 変法による超緊急帝王切開術を後方視的に検討した. 全12例の手術週数の範囲は28+5-41+1週で, 4例が早産期の手術であった. 手術開始から児娩出までの時間は1.7±0.9分で, 最長3分であった. 総手術時間は62.8±16.2分, 術中出血量は947±468mlであった. 輸血例はなく, 他臓器損傷などの術中合併症もなかった. Tukey-Kramer 検定を用いて2012年以降の Pfannenstiel 法による超緊急帝王切開18例, 下腹部縦切開法による17例と多重比較すると, 手術開始から児娩出までの時間が Joel-Cohen 変法で他法より有意に短く, 総手術時間や出血量には差がなかった. Joel-Cohen 変法は超緊急帝王切開において短時間に児を娩出できる有効かつ安全な開腹法である.

記述言語：日本語  

「概要」急性虫垂炎合併妊娠の臨床像と周産期経過を後方視的に検討した. 診断週数の中央値は27週5日(14週0日-32週6日)であった. 全例が腹痛を主訴とし, 3例が右下腹部, 1例が心窩部を最強点とした. 1例に反跳痛を認め, 筋性防御を示した例はなかった. 1例で超音波検査で, 他の3例はCT検査で診断し, 手術を施行した. 妊娠14週の症例1例で全身麻酔下に腹腔鏡手術を行い, その他の3例では開腹手術が行われた. 自然穿孔例はなかった. 3例で術後に子宮収縮抑制剤を要し, 平均投与期間は6日間であった. 4例中3例はその後の妊娠経過で産科合併症を認めないまま正期産経腟分娩に至った. 低出生体重児や asphyxia 例はなかった. 今回の検討で, 虫垂切除術後の分娩転帰, 母児の予後は良好であった. これは来院後速やかに画像診断と手術を行ったことによると考えられた. また, 妊娠週数によっては腹腔鏡手術が第一選択となりうると考えた.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus. To provide insight into the mechanisms underlying such diabetes-related heart defects, we examined the effects of high-glucose concentrations on formation of the left-right axis in mouse embryos. Expression of Pitx2, which plays a key role in left-right asymmetric morphogenesis and cardiac development, was lost in the left lateral plate mesoderm of embryos of diabetic dams. Embryos exposed to high-glucose concentrations in culture also failed to express Nodal and Pitx2 in the left lateral plate mesoderm. The distribution of phosphorylated Smad2 revealed that Nodal activity in the node was attenuated, accounting for the failure of left-right axis formation. Consistent with this notion, Notch signal-dependent expression of Nodal-related genes in the node was also down-regulated in association with a reduced level of Notch signaling, suggesting that high-glucose concentrations impede Notch signaling and thereby hinder establishment of the left-right axis required for heart morphogenesis.

DOI： 10.1073/pnas.1504529112

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Virtual touch tissue quantification (VTTQ) has been developed to evaluate tissue elasticity. Our previous study using delivered placentas showed increased elasticity in fetal growth restriction (FGR). Therefore, we investigated changes in placental elasticity during pregnancy, including complicated pregnancies.

METHODS: Based on complications, 199 women were divided into 5 groups (normal, FGR, pregnancy induced hypertension (PIH), diabetes mellitus and collagen disease), and shear wave velocity (SWV) of the placenta, measured using VTTQ, was compared. A cross-sectional study was performed with the 143 normal cases to construct the reference range. The association between placental SWV and the expression ratio of collagen fibers in the placenta stained with Masson's trichrome was determined.

RESULTS:The SWV was safely measured for all participants. The correlation between SWV and gestational weeks was not significant. The mean ± SD SWVs in the normal, FGR, and PIH groups were 0.98 ± 0.21, 1.28 ± 0.39, and 1.60 ± 0.45 m/sec, respectively. The FGR and PIH groups had significantly higher SWVs than that of the normal group. SWV and the expression ratio of collagen fibers were significantly correlated.

DISCUSSION: Based on the present findings, changes in SWV during pregnancy were associated with placental fibrosis, and increased SWV in PIH and/or FGR cases might be influenced by infarction, ischemic changes, and inflammation, as well as fibrosis. In conclusion, the measurement of placental SWV is potentially useful to evaluate the condition of the placenta during pregnancy.

DOI： 10.1016/j.placenta.2015.06.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Correlations among Chiari type II malformation (CMII) morphological findings, the proportion of fetal heart rate patterns corresponding to the quiet phase (QP), and neurological outcomes have yet to be investigated.

FINDINGS: The correlations among the morphological findings (i.e., the degree of ventriculomegaly, myelomeningocele levels, and degree of cerebellar herniation), proportion of time spent in QP, and developmental quotients (DQs) were analyzed in 22 children. The proportion of time spent in QP was compared between children with poor neurological outcomes (n = 9) and those with good outcomes (n = 13). Pearson's correlations and the Mann-Whitney U-test were used to assess for statistical significance; P < 0.05 was considered statistically significant. No significant differences were observed between the DQs and morphological findings, but the DQs and the proportion of time spent in QP were significantly correlated (r = 0.287, P = 0.01). The proportion of time spent in QP was significantly different between children with poor outcomes and those with good outcomes (median, 11% [range, 0-32%] vs. 28% [range, 2-55%]; P = 0.006).

CONCLUSIONS: The proportion of fetal heart rate patterns corresponding to the QP might be a useful predictor of neurological outcomes in 2-year-old children with CMII.

DOI： 10.1186/s13104-015-1014-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although DNA methylation is considered to play an important role during myogenic differentiation, chronological alterations in DNA methylation and gene expression patterns in this process have been poorly understood. Using the Infinium HumanMethylation450 BeadChip array, we obtained a chronological profile of the genome-wide DNA methylation status in a human myoblast differentiation model, where myoblasts were cultured in low-serum medium to stimulate myogenic differentiation. As the differentiation of the myoblasts proceeded, their global DNA methylation level increased and their methylation patterns became more distinct from those of mesenchymal stem cells. Gene ontology analysis revealed that genes whose promoter region was hypermethylated upon myoblast differentiation were highly significantly enriched with muscle-related terms such as 'muscle contraction' and 'muscle system process'. Sequence motif analysis identified 8-bp motifs somewhat similar to the binding motifs of ID4 and ZNF238 to be most significantly enriched in hypermethylated promoter regions. ID4 and ZNF238 have been shown to be critical transcriptional regulators of muscle-related genes during myogenic differentiation. An integrated analysis of DNA methylation and gene expression profiles revealed that de novo DNA methylation of non-CpG island (CGI) promoters was more often associated with transcriptional down-regulation than that of CGI promoters. These results strongly suggest the existence of an epigenetic mechanism in which DNA methylation modulates the functions of key transcriptional factors to coordinately regulate muscle-related genes during myogenic differentiation.

DOI： 10.1093/hmg/ddu457

記述言語：英語  

Dioxins are persistent environmental pollutants that cause multiple adverse health effects in humans, mainly through binding to the ligand-activated transcription factor, aryl hydrocarbon receptor (AhR). Genetic variation in AhR may modulate the susceptibility to dioxins. In this study, we aimed to evaluate the effects of the single nucleotide polymorphism (SNP) -130 C/T in the AhR promoter on dioxin-inducible gene transcription, and to investigate interleukin-24 (IL-24) and interleukin-1β (IL-1β) as proxies for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Using primary human chorionic stromal cells, we found that cells with the TT genotype showed higher AhR mRNA and protein levels than did those of the CC genotype. Microarray was carried out to analyze the gene expression profiles of cells (CC and TT genotype) after exposing the cells to TCDD. Several genes associated with human disorders were more highly up-regulated in cells of the TT genotype. Higher up-regulation of IL-24 and IL-1β mRNA in cells with the TT genotype was observed. Furthermore, blood samples from 64 Yusho patients who were accidentally exposed to high concentrations of dioxins were analyzed for the genotype, dioxins concentrations and serum levels of IL-24 and IL-1β. We observed higher serum IL-24 levels and lower serum IL-1β levels in Yusho patients with the TT genotype than in those with the CC genotype. AhR SNP -130 C/T affects serum IL-24 and IL-1β levels, independently of serum dioxins concentrations in Yusho patients. Our observations demonstrate that SNP -130 C/T modulates AhR expression and expression levels of IL-24 and IL-1β, and suggest an association of AhR SNP -130 C/T with the susceptibility to dioxins.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

乳癌合併妊娠の臨床経過と周産期予後を明らかにすることを目的とし, 2007年から2013年までの7例につき, 後方視的に検討を行った. 6例が妊娠中初発例, 1例が再発例であった. 初発6例の診断週数の中央値は20週(11-29週)であった. 進行期はstage Iが3例, IIAが2例, IIIBが1例, IV期が1例であった. 1例で胎児の18トリソミーを理由とした人工妊娠中絶が選択され, それ以外の6例で妊娠を継続し生児を得た. 中絶1例を除いた6例の治療開始週数の中央値は29週(19-32週)で, 全例で外科手術が行われた. また1例で妊娠中に化学療法が行われた. 中絶例以外の分娩週数の中央値は36週(35-37週)であった. 乳癌治療中や分娩中のNRFS診断例はなかった. 出生体重と臍帯動脈血pHの中央値は2,540g(2,125-2,970g), 7.29(7.19-7.38)であった. 重篤な新生児合併症はなかった. 今回の結果により乳癌合併妊娠の良好な周産期予後が示され, これは妊娠中に化学療法を行った症例でも同様であり, 乳癌治療に人工早産を先行させる必要はないと考えられた.

記述言語：英語  

BACKGROUND/AIM: Concurrent chemoradiation (CCRT) is the standard treatment for locally advanced cervical cancer. The purpose of the study was to compare the outcomes of triweekly cisplatin plus 5-fluorouracil and weekly cisplatin regimens.

PATIENTS AND METHODS: We retrospectively reviewed data from 91 patients with stage IB1-IVA cervical cancer.

RESULTS: Out of 91 patients, 48 received triweekly CCRT and 43 received weekly CCRT. For triweekly CCRT, patients received a median of two chemotherapy cycles and median total doses of cisplatin and 5-fluorouracil were 210 mg/body and 8,525 mg/body, respectively. For weekly CCRT, patients received a median of five chemotherapy cycles and the median total dose of cisplatin was 252 mg/body. No statistically significant differences in overall survival or progression-free survival were noted between the two groups.

CONCLUSION: Both triweekly CCRT and weekly CCRT appear to have similar efficacy for cervical cancer patients, but the toxicities were better tolerable in weekly CCRT.

記述言語：英語  

BACKGROUND: We aimed to investigate which factors in the clinical profile of mothers with idiopathic thrombocytopenic purpura (ITP) can predict neonatal risk of thrombocytopenia.
METHODS: Data was retrospectively collected from all pregnant women with ITP who presented to our institution between 2001 and 2013. Neonatal offspring of these women were classified into 2 groups based on the presence or absence of neonatal thrombocytopenia (platelet count <100×10(9)/L). Several parameters were compared between the 2 groups, including maternal age, maternal platelet count, maternal treatment history, and thrombocytopenia in siblings. We further examined the correlation between maternal platelet count at the time of delivery and neonatal platelet count at birth; we also examined the correlation between the minimum platelet counts of other children born to multiparous women.
RESULTS: Sixty-six neonates from 49 mothers were enrolled in the study. Thrombocytopenia was observed in 13 (19.7%) neonates. Maternal treatment for ITP such as splenectomy did not correlate with a risk of neonatal thrombocytopenia. Sibling thrombocytopenia was more frequently observed in neonates with thrombocytopenia than in those without (7/13 vs. 4/53, P<0.01). No association was observed between maternal and neonatal platelet counts. However, the nadir neonatal platelet counts of first- and second-born siblings were highly correlated (r=0.87).
CONCLUSION: Thrombocytopenia in neonates of women with ITP cannot be predicted by maternal treatment history or platelet count. However, the presence of an older sibling with neonatal thrombocytopenia is a reliable risk factor for neonatal thrombocytopenia in subsequent pregnancies.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In several human malignancies, the expression of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is associated with aggressive characteristics and poor overall survival. RCAS1 alters the tumor microenvironment by inducing peripheral lymphocyte apoptosis and angiogenesis, while reducing the vimentin-positive cell population. Although proteolytic processing, referred to as "ectodomain shedding," is pivotal for induction of apoptosis by RCAS1, the proteases involved in RCAS1-dependent shedding remain unclear. Here we investigated proteases involved in RCAS1 shedding and the association between tumor protease expression and serum RCAS1 concentration in uterine cancer patients. A disintegrin and metalloproteinase (ADAM) 9 was shown to be involved in the ectodomain shedding of RCAS1. Given the significant correlation between tumor ADAM9 expression and serum RCAS1 concentration in both cervical and endometrial cancer as well as the role for ADAM9 in RCAS1 shedding, further exploration of the regulatory mechanisms by which ADAM9 converts membrane-anchored RCAS1 into its soluble form should aid the development of novel RCAS1-targeting therapeutic strategies to treat human malignancies.

DOI： 10.1155/2014/482396

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abstract Aim: To determine the factors affecting neonatal prognosis in preterm premature rupture of membranes (PPROM). Method: We conducted a case-control study involving 92 women between the years 2000 and 2010 diagnosed with PPROM between 25 and 31 weeks' gestation, who received antenatal steroids, and delivered between 26 and 31 weeks' gestation; a retrospective cohort study was conducted based on the results. We used data from four tertiary centers and compared the frequencies of neonatal neurologic deficits and neonatal deaths. Results: There was a difference between the two groups; specifically, the ND group (n=18) consisted of patients whose infants had neurologic deficits and/or neonatal deaths and the neurologically normal (NN) group (n=74) included NN neonates amongst the patients who had expectant management (94% vs. 73%, respectively). Multivariable analysis revealed that expectant management was independently associated with an increased risk for neonatal neurologic deficits and neonatal deaths (odds ratio, 16.14). All neonates with poor prognosis in the expectant-management group delivered within 14 days after PPROM. Conclusions: Expectant management within 14 days after PPROM is associated with poor neonatal outcomes. Decisions regarding an expectant strategy should be made carefully. An immediate, planned delivery after steroid administration should be considered to improve neonatal prognosis in patients who have PPROM after 26 weeks' gestation.

記述言語：英語  

DOI： 10.1016/j.earlhumdev.2013.08.020

記述言語：英語  

記述言語：英語  

DOI： 10.1159/000355818

記述言語：英語  

記述言語：英語  

DOI： 10.1016/j.earlhumdev.2012.12.007

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.yexcr.2005.01.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ijc.20971

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/nar/gki555

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ygyno.2004.07.050

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   著書種別：学術書

思春期・妊娠期・生殖期・更年期・老年期を対象とする産科婦人科領域で，女性ヘルスケアは4つ目のサブスペシャリティとして重要性が増している。月経回数の増加による生殖期の弊害と閉経後40～50年に及ぶ老年期はこれまでの常識を覆し，生殖内分泌学・婦人科腫瘍学に加え，運動器・泌尿器・皮膚・循環器など幅広い分野の研究成果が欠かせなくなっている。 全身を診る知識と的確な診断技術を紹介。

担当ページ：60：1315-1316   記述言語：日本語   著書種別：一般書・啓蒙書

悪性軟部腫瘍治療薬としてバゾバニブ（ヴォトリエント）に加えてトラベクテジン（ヨンデリス）、エリブリン（ハラヴェン）が承認を受け、子宮肉腫への治療効果が期待される。

担当ページ：207-218   記述言語：英語   著書種別：学術書

担当ページ：看護のための最新医学講座　31　医学と分子生物学 372-378   記述言語：日本語   著書種別：学術書

担当ページ：41,19-42   記述言語：日本語   著書種別：学術書

担当ページ：231-4   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：117-32   記述言語：日本語   著書種別：学術書

子宮体癌は先進諸国において最も頻度の高い婦人科悪性腫瘍であり、日本人女性における罹患率も増加している。1975年に10万人あたり1.6人だった粗罹患率は2017年には22.8人まで著増し、その生涯罹患率は1.8％と計算される。増加の背景には、女性の社会進出に伴う非婚化・晩婚化に加えて結婚している女性の出生率低下、食生活の欧米化による肥満や糖尿病の有病率増加などがあり、多くが持続的かつ過剰なエストロゲン刺激に起因するリスクの増加と考えられる。 大部分の子宮体癌は散発性であるが、およそ5％は遺伝性と考えられている。代表的な遺伝性腫瘍症候群のLynch症候群は子宮体癌の2～5％を占め、Lynch症候群の女性における子宮体癌の生涯罹患率は最大で70％に及ぶ。Lynch症候群は常染色体優性遺伝形式を示し、DNAミスマッチ修復（mismatch repair:MMR）遺伝子であるMLH1,MSH2,MSH6,PMS2の1つに生殖細胞系列変異を認める。MMRタンパクはDNA複製エラーから起こる塩基の誤対合や挿入・欠矢を修復することで、ゲノムの完全性の維持を担っている。そのため、MMR遺伝子に変異があると、さまざまな遺伝子の異常が蓄積して発がんが誘導されると考えられる。MMR遺伝子の変異はマイクロサテライト領域の反復配列の繰り返し回数にも影響を及ぼし、マイクロサテライト不安定性（microsatellite instability:MSI）として検出されるようになる。 このように、近年は遺伝性・散発性に関わらず子宮体癌の発がん・進展機構の包括的な解明が進んでおり、分子標的治療の標的となりうる分子やシグナル経路も数多く同定されている。また、分子プロファイルによる新たな分子サブタイプ分類も提唱され、組織型による分類よりも予後をよく反映するとともに、層別化治療への足掛かりとして注目されている。本稿では、分子サブタイプ分類と分子標的治療、そして子宮体癌でもその存在が推測されるがん幹細胞について解説する。

担当ページ：119-121   記述言語：日本語   著書種別：学術書

産褥期は精神疾患の好発時期であり、これは、分娩に伴う心理的および生理的因子の変更により精神疾患が誘発されるためと考えられている。産後発症の精神障害は「マタニティブルーズ」「産後うつ病」「産後精神病」に大別される。 ・治療のための診断と検査 ・治療 ・処方例 ・ピットフォール・患者説明のポイント

担当ページ：183-186   記述言語：日本語   著書種別：学術書

がん治療は時代とともに進歩を遂げているが、治療開始時から治療が奏功しない症例や、手術療法や化学療法、放射線療法がいったん奏功したように見えてもその後治療抵抗性となり、再発や転移をきたす症例が存在する。がんの根治に向けては、治療に難渋する症例に対しての治療法の開発が課題となっているが、がん幹細胞はその開発において重要な役割を担っていると考えられている。 本稿ではがん幹細胞について概説し、がん幹細胞に対する治療開発の現状について、婦人科がんを中心に述べる。

担当ページ：1464-66   記述言語：日本語   著書種別：学術書

担当ページ：167-170   記述言語：日本語   著書種別：学術書

婦人科がんにおけるリンパ節郭清は正確な進行期の決定や再発リスク分類としての意義は確立されているため、子宮頸癌、子宮体癌、卵巣癌、外陰癌の根治手術においてそれぞれの所属リンパ節である骨盤リンパ節、傍大動脈リンパ節、鼠径リンパ節に対して系統的郭清が行われることが多い。一方で、リンパ節郭清が行われた結果生じるリンパ浮腫やリンパ管炎は術後のQOLを著しく損ね、非可逆的なリンパ浮腫を生じた場合は根治的な治療は望めない。そのため、リンパ節転移が陰性と考えられる症例に対しては系統的リンパ節郭清を省略する縮小手術が望まれる。センチネルリンパ節（SLN）とは腫瘍から最初にリンパ流が到達するリンパ節であるが、乳癌や悪性黒色腫ではその理論的妥当性が証明され、既に保険収載されている。婦人科がんにおいてもSLNの転移陰性が術中に証明されれば、不必要なリンパ節郭清を施行しないことにより先述した術後合併症は回避可能である。そこで、本稿では婦人科がんにおけるセンチネルリンパ節ナビゲーション手術（sentinel node navigation surgery;SNNS）について概説する。

担当ページ：298頁   記述言語：日本語   著書種別：学術書

担当ページ：1319頁   記述言語：日本語   著書種別：学術書

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担当ページ：1221-1222   記述言語：日本語   著書種別：一般書・啓蒙書

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開催年月日： 2023年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2023年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2023年10月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：大分県別府市   国名：日本国  

開催年月日： 2023年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：松江市   国名：日本国  

子宮頸部明細胞癌は子宮頸部腺癌の4％ と稀な組織型である．Diethylstilbestro（l DES）への子宮内暴露により若年で発症した 症例が報告されており，また子宮頸部腺癌は化学療法や放射線療法に抵抗性であることが知られている．今回，14 歳で診断さ れた子宮頸部明細胞癌4B 期の一例を経験したので報告する．症例は14 歳，性交歴はなく，HPV ワクチン接種後であり，在 胎期間中に母体のDES 使用歴はなかった．不正性器出血を主訴に受診し，腟鏡診で腟内に7cm 大の易出血性腫瘤を認めた． 子宮頸部細胞診および組織診でHigh-grade adenocarcinomaの診断となり，明細胞癌が疑われた．また画像精査で骨盤リン パ節，傍大動脈リンパ節，右鼠径リンパ節に転移を認めた．以上から子宮頸部明細胞癌4B 期（cT2a2N1M1）と診断した．若 年であり，組織型が明細胞癌であることから化学療法および放射線療法に抵抗性である可能性が考えられ，手術療法を選択し た．準広汎子宮全摘出術，両側付属器摘出術，骨盤リンパ節生検，傍大動脈リンパ節生検，右鼠径リンパ節生検を施行した． 病理組織学的検査の結果，子宮頸部明細胞癌4B 期（pT2bN1M1）と診断した．PD-L1 のCPS が1 以上であったため，術後療法としてPem+TC+Bev 療法を行っている．若年でも不正性器出血を認める症例では，子宮頸部細胞診・組織診を含めた精密検査を考慮する必要がある．

開催年月日： 2023年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

産婦人科は、卵の発生から始まり、胎児期・新生児期・思春期・生殖期・更年期・老年期を経て死を迎えるまで、「女性の一生を診る」診療科である。これらの全てを産婦人科医だけではカバーすることは不可能で多職種連携が必須となる。本講演ではまず、胎児期や新生児期に診断され、成人期までのフォローが必要な「ターナー症候群」「総排泄腔遺残症」を例に、管理における産婦人科医の関与や小児科・小児外科からの移行期医療について考える。また、子宮頸がん予防のためのHPVワクチンや望まない妊娠への対応は小児期からの性教育・がん教育が必要であり、小児科や教育現場との連携の必要性も考えていきたい。

開催年月日： 2023年6月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋国際会議場   国名：日本国  

子宮体癌の罹患率は最近15年間で3倍と増加している。子宮体癌は、エストロゲン依存性のtupeIとエストロゲン非依存性のtypeⅡに分類されてきたが、最近はThe Cancer Genome Atlas(TCGA)プロジェクトによる子宮体がんの統合的ゲノム解析によりPOLE ultramuted, microsatellite instability hypermuted, copy-number low, copy-number highの4つに分類され予後とも相関することが示されている。子宮体癌のリスク因子に肥満症がある。内臓脂肪蓄積による脂肪細胞からはアディポサイトカインが産生され、子宮体癌のリスク因子である月経異常・糖尿病・高血圧・脂質異常症などの疾患を引き起こす。肥満症ががんのリスクを上昇させるメカニズムとしては、インスリン抵抗性・ホルモン分泌異常・慢性炎症などが考えられており、これらの病態を改善させるメトホルミン・スタチンの役割が注目され臨床研究もおこなわれている。子宮体癌はエストロゲンが低下する周閉経期に罹患率が増えるが、マウスやヒトの子宮内膜においてIL-17RBが若年に比べて高齢の子宮内膜に発現が亢進していた。IL-17RBの下流で発現するサイトカインの中には老化に関係するものと増殖に関係する者があり、この違いが子宮体癌の発癌に関与していることが示唆された。また、エストロゲンはエストロゲンレセプター(ER)が転写因子として作用するgenomicや細胞膜に結合するnon-genomicの機序により下流の増殖シグナル経路を亢進する。我々は以前、typeIに多くみられる変異型RAS変異がERの転写活性を亢進することを報告した。その後この機序は特に幹細胞でのみ見られることや、KRAS変異を持つ子宮体癌細胞の幹細胞形質に重要な遺伝子を同定した。 本講演ではエストロゲン、肥満、炎症、KRAS変異、幹細胞の視点から子宮体癌の生物学的特性について考察する。

開催年月日： 2023年5月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：大分県別府市   国名：日本国  

近年、その導入が促進されている医師の働き方改革は、勤務時間が制限されるようになり、継続性のある働き方になるという点で望ましい変革である。一方で、実質ほぼ無制限に勤務が可能であり、時間外受診した患者の診療を多数経験していた頃と比較して、若手産婦人科医の経験値は減少しているものと思われる。そのため、これからの時代の医師は、これまで以上に経験した症例からより多くのことを効率よく学ぶことが重要である。また、新型コロナウイルス感染症の蔓延によって人的交流を伴う教育も制限されている。その一方で、ネットワークサービスの普及により、学術講演会への参加が容易となるなど学習機会は増加している。 周産期医療においては妊娠高血圧症候群や胎児発育不全をはじめとするcommon diseaseや常位胎盤早期剥離、産科出血といった、どの施設でも発生しうる救急疾患が存在する。また、胎児心拍数陣痛図を用いた胎児健常性評価や超音波検査、分娩誘発などの日常的に実施する検査や治療介入が存在する。これらの疾患や検査、手技について深く理解した上で経験を積むことが、効率よい学びを促進するという点で重要である。 当施設では、これまでに主に後期研修医を対象として日常的に診断・治療している疾患や実施している検査、手技について、その理解が深まることを目的に周産期専門医による講義を行ってきた。新型コロナウイルス感染症が蔓延してからはネットワークサービスを活用し、当施設外の後期研修医に対しても受講ができるようにしている。今回、我々の取り組みを紹介するとともに今後の課題について考察する。

開催年月日： 2023年5月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：札幌市   国名：日本国  

今後の産婦人科医療を考える上で重要な点は、「少子化」「晩婚化・晩産化」であり、我々産婦人科医はこの社会状況の変化への対応が求められている。昨年４月から不妊治療が保険適応となっているが、生殖補助医療を行っても年齢とともに妊娠率・生産率は減少してくる。加齢に伴う卵の老化による胚の異数性などが原因と考えられているが、着床には子宮内膜の状態も関与している。我々は以前より子宮内膜の機能やその異常に着目し研究を行ってきた。現在は加齢とともに発現が上昇してくる炎症性サイトカインとの関連を検討している。また、最近増加している子宮体癌に対して臨床の現場では、高用量黄体ホルモンによる妊孕性温存療法、進行・再発例に対しては分子標的治療が行われている。しかし、難治性の症例もあり、その原因の一つにがん幹細胞の存在が考えられている。我々は幹細胞の同定と生物学的特性の解析を行い、子宮体癌幹細胞は自己複製能と間質への分化能を持つことを明らかに しこの特性が再発・転移に重要であることを報告した。がん幹細胞を標的にした治療はがん幹細胞だけではなくその微小環境も標的とした多角的な治療戦略が必要であり、現在、腫瘍間質を標的とした治療法の開発を試みている。臨床面では、AYA世代のがんに対する対応も必要である。20 ～ 30代で増加している子宮頸癌はこの代表である。我々は高度扁平上皮内病変（CIN2/3）に対してレーザー治療、妊孕性温存希望の初期子宮頸癌に対して子宮頸部摘出術、低侵襲手術としてセンチネルリンパ節生検を行っており、その予後や問題点を紹介する。また、今後は他分野との連携もより一層重要になってくる。子宮頸癌は、HPV ワクチンの予防効果が証明されており、2023年４月から９価HPVワクチンの定期接種化や９～ 15歳未満には２回接種も始まり、この普及には小児科医との連携が必須である。近年、プレコンセプションケアの重要性が注目されており、小児科・内科・外科と連携が必要である。女性ヘルスケアの面からの乳癌、子宮頸癌、子宮体癌の予防における産婦人科医が果たすべき役割についても考えていきたい。

開催年月日： 2023年5月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：鳥取県米子市   国名：日本国  

開催年月日： 2023年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京都千代田区   国名：日本国  

セクシュアル・リプロダクティブヘルス/ライツ（Sexual Reproductive Health and Rights；SRHR）は，性と⽣殖に関する健康と権利である．⾃分のセクシュアリティや望む時に望むだけの⼦どもを持つことをすべての⼈が⾃分で決められる．セックスを安心して生殖（妊娠すること）と分離できる．そのために，避妊の⽅法や不妊治療について知ること．⽣殖器のがんや感染症の予防や治療ができること．⺟⼦保健や育児⽀援．SRHRは，これらすべてを⼤切にする理念である．2022年6月本学会からSRHR普及推進宣言を発出し，わが国及び世界におけるSRHRに関する課題に対して積極的に関わること，わが国の社会のジェンダー平等の達成に貢献すること，SRHRの侵害を含む，ジェンダー平等を阻害する課題が提起された場合には，専門学会として正面から対応することを宣言した． しかしながらSRHRに関して我が国が抱える問題点は多数存在する．⺟体保護法には配偶者同意の問題がある．我が国の性教育では（包括的性教育）どのように妊娠するかなど人間の生理学や，幸福な人間関係の一環としての性的関係などは全く教育されていない．社会全体の性⾃認，性的指向の認識や理解が不⾜している．LGBTへの差別はいまだに存在する．避妊法では，⼥性が主体的に選択できる低⽤量ピルや⼦宮内避妊などの医学的避妊法の情報や種類が少ない．⼥性の約15⼈に1⼈が無理やり性交された経験を持つという性暴力の問題．産後うつなどの問題に対して社会全体の認識不足，将来の妊娠を考えて女性やカップルが⾃⾝の⽣活習慣や健康状態に向き合いセルフケアをするプレコンセプションケアの認知度の低さ．さまざまな問題点を抱える我が国の現状であるが，SRHRの問題のテーマを絞り4名のディスカッサントが解決の糸口を述べていく．

開催年月日： 2023年3月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：北海道旭川市   国名：日本国  

開催年月日： 2023年2月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京都千代田区   国名：日本国  

【背景】近年、がん治療の進歩により、若年がん患者の予後は大幅に改善されつつある。一方で、化学療法や放射線療法などによる性腺機能障害は深刻な問題であり、現在、国レベルでの妊孕性温存療法の研究促進事業が行われている。当院では2018年より倫理委員会の承認を得て、若年がん患者等への妊孕性温存療法を行っており、そのうち乳がん患者における治療の現況について報告する。 【方法】2018年4月から2022年11月に、乳癌の診断で当院にて妊孕性温存療法を行った18例を対象とし、年齢、AMH値、調節卵巣刺激法、アロマターゼ阻害薬併用の有無、採卵前E₂値、採卵数、卵子／胚凍結数、合併症、妊孕性温存療法後の不妊治療症例等について診療録より後方視的に調査した。 【結果】年齢は25-39歳(中央値34歳)、AMH値は0.24-6.40(中央値1.27)、調節卵巣刺激法はランダムスタート法が15例であった。採卵前E₂値はアロマターゼ阻害薬を併用した症例で中央値1071.5pg/ml、併用しなかった症例で1413.0pg/mlであった。採卵数は1-40個(中央値11)、凍結卵子/胚数は0-27個(中央値9)で、凍結保存できなかった症例が2例、凍結したが原病死により凍結中止した症例が1例あった。合併症は、重症OHSSが1例、ゴナドトロピン製剤による嘔気が1例であった。妊孕性温存療法後の不妊治療を行った症例は1例であった。 【結論】乳がん治療が最優先であることは大原則だが、妊孕性温存療法は患者のQOL維持や治療意欲を高めるために意義深く、より安全、より効果的に行えるよう、今後も情報発信や症例の蓄積が必要である。

開催年月日： 2022年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：金沢市   国名：日本国  

【背景】胎児発育不全(FGR;fetal growth restriction)およびFGRを伴う妊娠高血圧症腎症(PE/FGR;preeclampsia with FGR)は、高レベルのヒト絨毛性ゴナドトロピン(hCG;human chorionic gonadotropin)およびミトコンドリア機能障害と関連している可能性のあるハイリスクな周産期疾患である。しかし、これらの要因が胎盤にどのような影響を与えているかに関してはほとんど解明されていない。 【目的】ミトコンドリア機能障害と高hCGが原因不明のFGRとPEFGRの胎盤にどのような影響を与えているかを検討した。 【研究デザイン】ミトコンドリアの翻訳、hCG β、抗血管新生因子、炎症性サイトカインの発現を48の胎盤サンプルで評価した(control:n=15、FGR;n=15、PE/FGR;n=18)。また、高hCGがin vitroで血管新生抑制因子と炎症性サイトカインの発現に影響を与えるかどうかを検討した。さらに、ミトコンドリアの翻訳障害が細胞株におけるhCGの発現にどのような影響を与えるかを検討した。 【結果】FGR、PE/FGRの胎盤では、hCG β、GDF15のmRNAおよびタンパク質レベルが上昇していた。また、Ang2、IP10、sFit1、IL8、IL1B、TNFαなどの血管新生抑制因子、炎症性サイトカインはすべてmRNAレベルで上昇していた。また、ミトコンドリアDNAあたりのミトコンドリア由来のCOXI、COXIIタンパク質が低下しており、この結果はミトコンドリアの翻訳が低下していることを示唆している。hCGを細胞株に添加すると、Ang2、IP10、IL8、TNFαのmRNAレベルが増加した。さらに、ミトコンドリアの翻訳阻害剤をJEG3細胞に添加すると、HIF1αの安定化を介してhCGβを発現を増加させ、IL8およびTNFαｍＲＮＡの発現を増加させた。 【結論】この研究は、ミトコンドリアの翻訳障害と高hCGが、FGRとPE/FGRの発症に重要な役割を果たす可能性があることを示している。

開催年月日： 2022年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：横浜市   国名：日本国  

【目的】子宮内膜パターンと妊娠分娩転帰の関連性については，これまで様々な検討がなされているが，一定の見解を得ていない．今回，凍結融解胚移植における子宮内膜パターンと妊娠分娩転帰を検討した．【方法】2012年2月から2019年12月までにホルモン補充周期下に単一胚盤胞を凍結融解胚移植した35歳以下の症例を対象とした．経腟超音波断層法で子宮内膜厚7mm以上を目安として胚移植日を決定し，その時点の子宮内膜像を記録した．子宮内膜のLeaf pattern中央の線状エコーに注目し，3つのパターンに分類した（Lf：線状エコーが連続，Partial Lf（P-Lf）：線状エコーが一部断裂，Non-Lf（N-Lf）：線状エコーが不明瞭）．子宮内膜の抽出が不良であった症例を除外した1383周期を対象として，胚Grade毎の子宮内膜パターンと妊娠率，出生率，流産率の関連を後方視的に解析，検討した．【成績】子宮内膜パターンの内訳はLf 483周期，P-Lf 840周期，N-Lf 60周期であった．全周期において，Lf，P-Lf，N-Lfの妊娠率はそれぞれ70.4％，58.1％，28.3％（p＜0.01），出生率は56.3％，45.5％，15.0％（p＜0.01），流産率はそれぞれ20.0％，21.7％，47.1％（Lf，P-Lf間は有意差なし）であった．胚grade毎の検討では，全ての胚gradeにおいてN-LfはLfよりも妊娠率が低く（p＜0.05），出生率は良好胚盤胞で低かったが（p＜0.05），流産率は有意差がなかった．胚Grade，着床，流産に関わる因子を共変量としたロジスティック回帰分析では，N-Lfに対するLfのオッズ比は，妊娠が6.04（95％CI：3.23-11.31，p＜0.01），出生が7.39（95％CI：3.45-15.83，p＜0.01），流産が0.20（95％CI：0.07-0.57，p＜0.01）であった．【結論】今回の検討では，胚移植決定日の超音波断層法で子宮内膜パターンがNon-Lfを呈する症例では妊娠率，出生率が低いことから移植に適していない可能性が示唆される．今後それらを向上させるために，子宮内膜パターンに寄与する因子の検討が必要と考える．

開催年月日： 2022年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：茨城県つくば市   国名：日本国  

産婦人科学は、「女性の一生を診る」学問である。本講演では胎児期や新生児期に診断され、成人期までのフォローが必要な「性分化疾患」を月経異常と月経随伴症状の観点から取り上げる。性は、遺伝（性染色体）、性線、性器、心理的、社会的の各段階で決定される。生殖細胞の分化における性染色体の役割について基礎的実験をもとに紹介する。性染色体異常症の代表的な疾患であるターナー症候群は、X染色体の1本の全欠失や短腕の欠失が起こる。低身長に加え心疾患などを併発し、小児科で成長ホルモン投与や合併症のフォローを受けている。卵巣機能不全のため原発性無月経となる。産婦人科ではエストロゲン少量療法を開始し、Kaufmann 療法へ移行する。骨粗鬆症の予防を行うことも重要である。性器の異常としては、Mayer-Rokitansky-Küster-Hauser（MRKH）症候群、副腎性器症候群、子宮頸部・腟無形成、総排泄腔遺残症などがあり、外科的治療を行う。機能性子宮のある子宮頸部や腟形成症例は月経血逆流による子宮内膜症の治療も行う。総排泄腔遺残症は膀胱・尿道と直腸・肛門の分離過程が障害され尿道・腟・直腸が共通の総排泄腔に開き、会陰には総排泄腔のみが開口している。治療は新生児期に人工肛門造設が行われた後、幼児期に一期的に腟・肛門形成を行う。共通菅が3cm以上の場合は術後腟狭窄による月経血流出障害を起こすことが多く、腟拡張術を行う。しかし、多くの症例において腟形成後も腟狭窄による月経血流出路障害に関連する症状が認められる。成人症例にて結婚後は不妊治療が必要になる場合が多い。性交渉及び妊娠成立・維持の問題が継続している。性分化疾患は遺伝カウンセリングを含む多職種で行う必要がある。最後に社会的性の観点から女性ヘルスケアや女性活躍社会における月経や更年期の諸問題について考察する。

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：鹿児島市（ハイブリッド開催）   国名：日本国  

開催年月日： 2022年8月

記述言語：英語  

開催地：福岡市   国名：日本国  

［Objective］Matricellular glycoprotein, SPARC is a secreted molecule, that mediates the interaction between cells and extracellular matrix. SPARC functions as a regulator of matrix organization and modulates cell behavior. In various kinds of cancer, strong SPARC expression was observed in stromal tissues as well as in cancer epithelial cells. The function of SPARC in cancer cells is somewhat controversial and its impact on peritumoral stromal cells remains to be resolved. ［Methods］We investigated the effects of SPARC expression in endometrial cancer cells on the surrounding stromal fibroblasts using in vitro co-culture system. Changes in characteristics of fibroblasts were examined by analysis of fibroblast-specific markers and in vitro contraction assay. ［Results］SPARC induced AKT phosphorylation and epithelial-to-mesenchymal transition, consistent with previous reports. Cancer-associated fibroblasts of endometrial cancer expressed higher levels of mesenchymaland fibroblast-associated factors and had a stronger contraction ability. Unexpectedly, cancer-associated fibroblasts expressed comparable levels of SPARC compared with fibroblasts from normal endometrium. However, co-culture of normal fibroblasts with SPARC-expressing Ishikawa cells resulted in activation of the fibroblasts. Immunodepletion of SPARC did not affect the activation of fibroblasts. ［Conclusion］Our data indicated that SPARC activated fibroblasts only in the presence of fibronectin, which was abundantly secreted from SPARC-expressing endometrial cancer cells. These results suggested that a SPARC-fibronectin-mediated activation of fibroblasts might be involved in enhanced mobility and invasion of cancer cells.

開催年月日： 2022年8月

記述言語：日本語  

開催地：福岡市   国名：日本国  

はじめに 産婦人科学はヒトの発生から老年期までを対象とした学問である。専門分野として周産期・生殖内分泌・婦人科腫瘍・女性ヘルスケアがあり、それぞれに様々な疾患があり、病態がある。生命倫理やリプロダクティブヘルス・ライツなどの社会医学も重要である。各分野の専門家が力を合わせて創り上げ躍進する「共創と飛翔」の学問であると考える。 時代の流れとともに概念、治療法も変化してきている。これらの変化に対応するためには継続的な研鑽と研究が必要である。私は医師になりたての頃、患者さんを診ていく中で、治療により救われる命とともに、失う命に伴う悲しみを知った。その経験から専門分野として婦人科腫瘍を選び、がん発生機構の解明の研究を始めた。 1)RAS研究との出会い 私が医師になった1980年代、がんは遺伝子の病気であるという概念が定着し、がん遺伝子・がん抑制遺伝子の研究が盛んになってきていた。幸運なことに主人に帯同して渡米し働き始めたのは、サンディエゴにあるラ・ホヤ癌研究所のがん遺伝子RASをテーマとした研究室であった。RASは低分子G蛋白の一つでGTP結合の活性化型とGDP結合の不活性化型があり、細胞内情報伝達系の重要なシグナルスイッチャーである。RASの下流にはRAFやPI3Kをはじめとする複数のシグナル経路があり、増殖・分化・アポトーシス・細胞老化などを制御している（図1）。私はそこでKRAS蛋白のC末端のCAAXモチーフ(CはCys、Aはaliphaticなアミノ酸、Xは任意のアミノ酸）に起こる翻訳後修飾の研究を行った。このC-末端では Cysのプレニル化、AAXペプチドの切断、カルボキシメチル化という一連 のCAAXプロセシングを受け細胞膜に結合し機能を発現することがわかっていたが、Cysのファルネシル化が腫瘍形成能獲得に必須であることを明らかにし、ファルネシル化阻害剤が新しい癌治療薬の候補になる可能性を報告した（図2）。この論文で論文博士の学位が取得できた(1)(Kato K et al. Proc Natl Proc Sci 1992)。自分の研究が将来、癌治療に役立つかもしれないという期待を感じ、研究の楽しさを知った。しかし、その後、ファルネシル化を阻害してもRASの尾部がファルネシル化（脂質修飾）されていない場合には、別の酵素が異なる種類の脂質尾部を付加することができることが報告され、残念ながらファルネシル化阻害剤は治療薬とはならなった。 ２）RAS経路とエストロゲンレセプター（ER）経路のクロストーク 帰国後も癌の基礎研究を続けたいと思い、別府市の九州大学生体防御医学研究所に赴任した。何を研究テーマにするかを考える中で着目したのは子宮体癌である。生活様式の欧米化とともに子宮体癌の増加が報告されていた。子宮体癌は約８割がエストロゲン依存性であり、２〜３割にKRAS遺伝子の変異が同定されている。まず、この２つの関連に着目しKRASシグナル経路とエストロゲン経路のクロストークの研究を行った。NIH3T3細胞にKRAS遺伝子を形質導入し過剰発現させた細胞を樹立したところ（K12V細胞）、エストロゲンレセプター（ER）の発現と機能が亢進した。このK12V細胞は内因性プロゲステロンレセプターB(PR-B)の発現が低下しており、PR-Bを形質導入したところ、ER機能と腫瘍形成能が抑制された（図3）。また、ドミナントネガティブERをK12V細胞に形質導入すると細胞老化が誘導され腫瘍形成能が抑制された(図4)。その経路にAP-1を介したMDM2の発現亢進・p53機能抑制が関与していることを明らかにした（図5）(2,3)(Kato K et al. Oncogene1997, J Bio Chem 2002)。本経路の阻害剤はERが発現するタイプの子宮体癌の分子標的薬の候補になると考えられる（図6）。 ３）がん幹細胞研究 （１）Side-population細胞の解析 子宮体癌において高分化型早期の症例の予後は良いが、悪性度の高い組織型、進行期の症例は難治性となる。治療抵抗性のがんの克服ががん治療研究の課題である。治療抵抗性の要因として、がん組織に存在するがん幹細胞の存在が考えられている。幹細胞は自己複製能と多分化能を持つ細胞と定義されるが、最近、がん幹細胞には可塑性や多様性があること、周囲のがん微小環境と相互作用を持つことが報告され、多角的な治療戦略が必要である。私はこの癌幹細胞に着目し、Side-population(SP)細胞を分離する方法を用いて子宮体がん幹細胞の解析を始めた。まず、発生母地の子宮内膜のSP細胞を分離し、長期増殖能を持つことや腺上皮や間質細胞への分化能を持つことを報告した（図7）(4)（Kato K et al. Hum Reprod 2007）。次に子宮体癌のSP細胞を分離し、自己複製能・長期増殖能の他に、間質細胞への分化や運動能の亢進を示すことを報告した(図8)(5)（Kato K et al. Am J Pathol 2010）。この性質が癌の再発や転移に関与すると示唆される。 （２）EMT関連因子の解析 さらにマイクロアレイによる網羅的解析を行いSP細胞は非SP細胞に比べ、炎症性サイトカインや増殖因子、間質形成に関与する遺伝子群の発現が増加し、TGFβを介した上皮間葉移行（EMT）の経路や間質リモデリングの経路が亢進していることを明らかにした（図9）。これまでの結果より、がん幹細胞の重要な特徴は自己複製能と上皮間葉移行（EMT）であり、EMTに関与する分子の中でもfibronectin、SPARCの発現の亢進が、がん幹細胞の運動能や浸潤能、周囲のがん関連線維芽細胞に関与していると考えている。そこで、EMT阻害剤として報告されていたsalinomycinを用いて解析し、salinomycinがfibronectinの発現を抑制し子宮体癌SP細胞の遊走能や運動能を抑制すること（図10）、アポトーシスを誘導し、増殖能、腫瘍形成能を抑制することを報告した（図11）(6)（Kusunoki S et al. Gynecol Oncol 2013）。また、間質リモデリングの経路の中で、線維芽細胞との関連が報告されている分泌蛋白であるSPARCに着目した。臨床検体では、SPARCは低分化型類内膜癌・明細胞癌・漿液性癌など予後不良の組織型の間質に発現が多く（図12）、子宮体癌細胞株IshikawaにSPARCを過剰発現させた細胞（IK-SPARC）を用いた解析で、IK-SPARC細胞はmock細胞に比べてfibronectinの発現が亢進し、運動能が亢進することやマウスに間質に富んだ腫瘍を形成することを報告した（図13）(7)（Yusuf N et al. Gynecol Oncol 2014）。さらに、SPARCの発現は癌細胞のAKTのリン酸化を亢進させ、fibronectin以外にもVimentin,CDH2などのEMT関連蛋白の発現を増加させ、遊走能を亢進させることを明らかにした(図14)。また、SPARC蛋白を正常線維芽細胞に添加するとACTA2やCDH2蛋白の発現、細胞増殖能、ゲル収縮能がそれぞれ亢進され、SPARCのこれらの機能発現にはfibronectinの存在が必須であることを明らかにした（図15）(8)（（Yoshida S et al. BMC Cancer2021）。 （３）幹細胞形質発現因子の検索と解析 SP細胞は幹細胞研究の有効なツールではあるが、その割合は1%以下と少数であり継代培養や解析が難しい。この分画を増やすためいくつかの遺伝子導入を試みてきた。その中でがんや胚細胞のみに発現が報告されているYBX2を子宮体癌細胞株に導入したところ(IK-YBX2細胞株)、SP細胞の分画が約10倍に増加すること、幹細胞マーカーALDH1の発現が亢進すること、スフェア形成能の評価による自己複製能が増加することを明らかにした（図16）。このIK-YBX2細胞株を用いてマイクロアレイ解析を行いYBX2強制発現細胞に発現が亢進している遺伝子としてcancer testis antigenの一つであるCT45A5を同定した（図17）。CT45A5は子宮体癌細胞株IKにCT45A5を過剰発現させると(IK-CT45A5)、自己複製能を増加させ、siRNAによる発現抑制は、この効果を打ち消した（図18）。YBX2発現細胞はPclita臨床検体の解析ではCT45A5の発現は予後不良因子であった（図20）(9)（Suzuki I et al. Sci Rep 2021）。 ES細胞ではstemnessに関与する遺伝子は脱メチル化され発現が亢進していることが報告されている。また、我々は網羅的なメチル化解析を行い、脱メチル化により発現が増加している遺伝子を網羅的に解析し、ERKの脱リン酸化酵素であるDUSP6を同定した。子宮体癌細胞Hec1を用いた解析ではDUSP6の発現は、幹細胞マーカーやALDH1の発現（図21）・、自己複製能（図22）・遊走能・浸潤能（図23）・転移能（図24）に正に相関していた。また、DUSP6の発現は、低血清状態でアポトーシスを抑制することにより低血清飢餓抵抗性を上昇させていた（図25）。その経路として活性化型RASの下流のシグナルバランスを増殖優位のMAPKから細胞生存優位のAKTへ変化させることを明らかにした（図26）。また臨床検体の解析ではDUSP6は類内膜癌では低分化型に発現が多く、予後不良因子であった（図27）(10)（Kato M et al. Int J Cancer 2020）。これらの結果より、がん幹細胞の自己複製能は再発、EMT誘導による運動能・浸潤能の亢進は転移に関与し予後不良の原因になることが考えられる。 ４）難治性がんに対する新規治療法開発の展望 癌細胞の周囲微小環境は多様性を持ち、がんの浸潤や治療抵抗性に関与することが報告されている。我々は、子宮体癌のSP細胞はSPARCを高発現していること、SPARC過剰発現子宮体癌細胞は、遊走能亢進やfibronectinの発現増加、マウスに間質に富んだ腫瘍を形成すること、臨床検体の解析では予後不良の組織型（漿液性癌、明細胞癌）に発現が亢進していることを報告した。（Yusuf N et al 2014）。更にSPARC は細胞外に分泌されること、癌細胞だけではなく周囲の正常線維芽細胞をCAF様に変化させることを明らかにした（Yoshida S et al. BMC Cancer 2021）。SPARCはアルブミンと結合する性質を持つことを利用し、通常の抗がん剤はSPARC高発現子宮体癌細胞の増殖を抑制しないが、アルブミン結合抗がん剤は細胞増殖を抑制し、マウスの腫瘍形成能も抑制することを明らかにした。予後不良の組織型（漿液性癌、明細胞癌）の治療法に応用できると考えられる（図28）。また、CT45の発現は、卵巣癌では抗がん剤感受性に関与することが報告されている。我々は子宮体癌細胞においてCT45A5は抗がん剤抵抗性に関与し、その発現は予後不良因子であった。子宮体癌におけるDuoらの報告では、cancer testis antigenは漿液性癌に多いことが報告されている。おそらくCT45のようなcancer testis antigenは癌抗原としての機能を持ち、癌腫により抗腫瘍効果を持つものと持たないものがあると推測される。幹細胞マーカーとしての機能だけではなく、癌ワクチンの標的にもなると期待されるが、誘導される免疫細胞の解析やPDL-1の発現との関連などの解析が重要になってくる。 これまでの研究結果より子宮体癌がん幹細胞の特徴は自己複製能と間質への分化能を持つことであり、著明な遊走能を獲得していた。自己複製能に必須な因子として、DUSP6・YBX2・CT45A5を同定した。間質への分化にはEMT経路が重要であり、そこに作用する因子としてSPARC・fibronectinを同定し、これらは癌の微小環境に関与すると考えられた。DUSP6・SPARC・fibronectinは遊走能・浸潤能を亢進させ、DUSP6は転移能獲得に関与していた。これらの分子の下流ではいずれもPI3K-AKT経路が活性化していた。YBX2やCT45A5は癌精巣抗原として癌免疫に関与していると考えられる(図29)。今後はこれらの分子をがん幹細胞マーカーとして、これらやこれらに関与するシグナル経路を標的治療の開発を進めていく予定である。 ５）産婦人科の未来に向けて 長年、がん研究に取り組んできたが、私の子宮体癌発生機構の解明への挑戦はまだ道半ばである。がん細胞の持つ多様性・可塑性が大きな壁である。これまでは自施設の限られた臨床検体を使って遺伝子変異をシークエンスにより同定し、遺伝子を細胞に導入し、その性質を解析するという実験を繰り返してきたが、今は次世代シークエンス、３次元培養、単一細胞解析など新しい技術が次々に登場し多くの知見が得られる時代になった。また、TCGAなどの容易にアクセスできる大規模データを用いて遺伝子変異を検索することも可能になった。例えば、上記のDUSP6やCT45A5がどのような組織型に発現が多いかや他の遺伝子変異との関連に加え、予後との相関も検討できている。また、当教室の八木はTCGAのデータから子宮体癌症例の約20%において、Rhoの活性化を負に制御するRho GTPase activating proteinのひとつであるARHGAP35遺伝子変異が認められ、その多くが機能欠失型の変異であること、これらの遺伝子変異がGα13-Rhoシグナルの増強に関与していることが明らかにしている。今後も次々と研究手法は進歩していくであろう。最初は私一人で始めた子宮体癌の研究であったが、その後は九州大学や順天堂大学の大学院生が取り組んでくれた。これまでご指導いただいた先生、一緒に研究してくれた仲間達に感謝する。今後、新しい発見により少しでもがん発生機構の解明に近づき、患者さんの予後を改善する治療法の開発が進むことを願う。

開催年月日： 2022年8月

記述言語：日本語  

開催地：福岡市   国名：日本国  

【目的】生殖補助医療では，子宮内膜の老化が着床不全の原因として疑われる症例を認める．先行研究で我々は子宮内膜老化マー カー遺伝子として IL17RB を同定した．IL17RB は上皮細胞や免疫細胞に発現する受容体で，様々なシグナル経路を介してサ イトカイン分泌や炎症に関与する．今回，我々は IL17RB 発現により子宮内膜に生じる変化および老化との関連を明らかにす ることを目的とした． 【方法】（1）ヒト子宮内膜不死化細胞株（hEM）の IL17RB 強制発現株を作成し，リガンドを添加した際の phenotype を解析した．（2）ヒト宮内膜オルガノイドを作成し，IL17RB 発現の有無による違いを観察した．（3）IL17RB シグナル経路の下流で発現するサイトカインが子宮内膜に及ぼす影響についてヒト子宮内膜オルガノイドを用いて解析した．（4）血液から分離した単球由来のマクロファージを LPS で刺激し，マクロファージが分泌するサイトカインについて分析した． 【成績】（1）IL17RB 強制発現株では SAPK/JNK や NF-κ B のシグナル経路を介して IL-6，IL-8，IL1 βの mRNA 発現が上昇してい た．（2）IL17RB 発現細胞は非発現細胞と比し細胞増殖能が低下していた．（3）IL1 β存在下では子宮内膜オルガノイドの増殖能 は低下し，p21 および senescence-associated β-galactosidase（SA-β-gal）の発現が上昇した．（4）マクロファージへの LPS 刺激で IL17RB のリガンドである IL17B の mRNA 発現が上昇していた．【結論】子宮内膜は IL17B/IL17RB pathway を介し たシグナルにより炎症を惹起し，下流に発現する IL1 βにより自己の老化を誘導する可能性が示唆された．

開催年月日： 2022年8月

記述言語：日本語  

開催地：福岡市   国名：日本国  

【目的】 OC・LEP は女性の QOL 向上に限らず，女性アスリートのパフォーマンス向上にも有用であるが，現在 OC・LEP 服用時 に血栓症を予測できる有用なコンパニオン診断はない．プロテイン S（PS）は OC 内服中に低下し，活性化プロテイン C 抵抗性を きたす．海外では OC・LEP の含有する黄体ホルモンにより PS低下の程度が異なるとの報告がある．世代別 OC・LEP が PS に与える影響を調べる． 【方法】 13 歳以上の女性で OC・LEP 治療予定患者及び治療中の患者の血液検体を用いて PS 活性を測 定した． 【成績】ノルエチステロン（NET）/エチニルエストラジオール（EE）7 例，レボノルゲストレル（LNG）/EE 10 例，デ ゾゲストレル（DSG）/EE6 例，ドロスピレノン（DRSP）/EE11 例であった．治療中の PS 活性平均値は NET/EE 群 81.7 ± 10.6 ％，LNG/EE 群 90.7 ± 16.7 ％，DSG/EE 群 77.8 ±18.0 ％，DRSP/EE 63.3 ± 15.8 ％で，DRSP/EE 群の PS 活 性は NET/EE 群及び LNG/EE 群の PS 活性と比較して有意に低値であった．治療前と治療中を観察できたのは LNG/EE 7 例及び DRSP/EE 5 例であった．PS 活性平均値は LNG/EE群で治療前 99 ％，治療中 90 ％，DRSP/EE 群で治療前 88.2 ％，治療中 65 ％であり，DRSP/EE 群は治療により PS 活性が有意に低下した．【結論】 PS 活性は OC・LEP 服用で低下する が，DRSP/EE 服用で著明に低下し，他世代 OC・LEP 治療中の値より低値であった．LNG/EE は PS に与える影響が最も少 なかった．含有黄体ホルモンの違いが血栓症の起こしやすさに影響する可能性があり，さらなる検討が必要である．

開催年月日： 2022年2月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：Web開催   国名：日本国  

開催年月日： 2022年1月

記述言語：日本語  

開催地：大阪市   国名：日本国  

開催年月日： 2022年1月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：ハイブリッド   国名：日本国  

産婦人科学の中でも、女性医学は女性の一生の健康を見守る学問であり、患者の年代は思春期、性成熟期、更年期、老年期にわたり、その分野も予防医学、社会医学など多岐にわたる。全てのライフステージにわたり重要な疾患の一つに高血圧がある。エストロゲンに末梢血管抵抗を低下させる作用があることより、エストロゲンが減少する閉経後の女性に多くなる疾患であるが、学童検診などで、高血圧が見つかることもあり、小児期・思春期からの管理も必要である。とくに早産や低出生体重児は腎臓のネフロン数は少なく腎臓への血流を保持するためにレニシーアンギオテンシン経路が活性化されるといわれている。このように妊娠中も胎児の状態・出生時の情報も重要である。 思春期や35歳以下の若年の高血圧には二次性高血圧の鑑別が必要であり、腎性が最も多いが内分泌性や先天性副腎過形成など婦人科の診療で気付く場合もあり注意が必要である。これらの若年の高血圧の管理は妊娠前から行うことが重要であり、プレコンセプションケアの一つとして注目されている。高血圧と関連した病態として動脈硬化があるが、最近の疫学研究で子宮内膜症は動脈硬化性心疾患のリスク因子であることが報告された。そのメカニズムとして子宮内膜症の慢性炎症が血管内皮障害を引き起こすことが考えられている。 動脈硬化の病理像に血管内膜線維性肥厚や中膜平滑筋の線維化があり、血管平滑筋から分泌される線維化を誘導する因子と細胞外基質のリモデリングが関与している。我々は剪断弾性波伝搬速度を用いて胎盤の弾性を評価し、妊娠高血圧症候群の胎盤は正常妊娠の胎盤に比べ弾性が高く、病理学的に膠原線維、線維化関連因子(ACTA2,CTGF,FN1)が過剰発現していることを明らかにした。胎盤の線維化の機序を明らかにするため、胎盤より線維芽細胞を分離しマイクロアレイで網羅的解析し、妊娠高血圧症候群の胎盤由来線維芽細胞はTGF-βSMAD経路に関連する線維化関連遺伝子群の発現が亢進していた。妊娠高血圧症候群発症胎盤における線維化にTGFβ1 signalingが関与しており、活性化した線維芽細胞により線維化が進行することが示唆された。 Japan Nurses'Health Studyの疫学研究から、妊娠高血圧症候群の既往は、その後の高血圧発症リスクは2.85倍であり、リスク因子になっていることが示唆されている。高血圧は我が国の脳心血管病による死亡の一番のリスク因子であり、高血圧治療ガイドライン2019では正常高値血圧(120-129/80ｍｍHg)から生活習慣の修正が必要とされている。我々は高血圧予備軍として妊娠高血圧症候群の既往患者のフォローアップは、更年期から老年期の健康管理のためにも重要と考え、女性ヘルスケア外来での管理を行っている。以上、本講演では女性の一生のヘルスケアの観点から高血圧の管理を考えてみたい。

開催年月日： 2021年10月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：横浜市   国名：日本国  

開催年月日： 2021年8月

記述言語：日本語  

開催地：京都市   国名：日本国  

開催年月日： 2021年7月

記述言語：日本語  

開催地：大阪市   国名：日本国  

【緒言】DNAのメチル化は様々な癌腫で、癌細胞形質の獲得に寄与している。メチル化の指標である5-メチルシトシン(5ｍC)に関する研究は多いが、脱メチル化の過程でみられる5-ヒドロキシメチルシトシン(5hmC)の役割は明らかではない。今回我々は5hmCと子宮頚部上皮肉腫瘍(CIN)の関係に注目し研究を行った。 【方法】CINと子宮頸癌、計103例の臨床検体と、mouse embryonic fibroblast(MEF)やヒト子宮内膜癌細胞株HHUAを用いて5hmC量を免疫組織染色、ELISA法で調べた。 【結果】CINと子宮頸癌、計103例の臨床検体で5hmC量を測定すると、CIN2以下の症例に比べCIN3以上の症例では5hmC量が有意に低下していた。次にMEFでp53とRb1の発現を抑制すると、p53を抑制した細胞で5hmC量が低下した。HHUAでは、TP53を抑制すると5hmC量の低下に加えAPOBEC3B(A3B)の発現上昇を認め、反対にA3Bの抑制で5hmC量が回復した。また、前出の臨床検体で確認すると、CIN2以下の症例と比べ、CIN3の症例でA3Bの発現が高かった。 【結論】5hmC量はCIN2以下に比べCIN3以上の症例で低下していた。TP53機能低下によるA3Bの発現上昇でゲノム不安定性が増すため、ゲノム安定性のマーカーである5hmC量が低下し、遺伝子変異の蓄積とそれに伴う病変の進行が想定された。5hmC量の変化が、子宮頚部上皮肉腫瘍の進退を予測する指標となり得ると考えられた。

開催年月日： 2021年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンデマンド配信（ハイブリッド開催・宮崎市）   国名：日本国  

【目的】子宮頚部摘出術（abdominal trachelectomy:AT）後妊娠は早産ハイリスクと認識されているが、有効な予防法は示されていない。一方、欧米において、流早産既往や頸管長短縮に伴う早産ハイリスク妊婦に対してはプロゲステロン製剤（vaginal progesterone:VP）による早産予防効果が実証されている。今回、AT後妊娠に対するVPの早産予防効果について検討した。 【方法】本研究はヒストリカルコントロールと比較した前方視介入試験で、所属機関の倫理委員会の了承を得たのちに2016年10月より開始した。介入群は、当科でATを施行した妊婦で本研究に対するインフォームド・コンセントを得たものとした。妊婦16+0～19+6週よりVP200ｍｇを連日膣挿入し、33+6週に到達、分娩、前期破水もしくは子宮からの大量出血のいずれかで終了とした。対象群は2007年6月から2016年9月に当科で管理したＡＴ後妊娠とし、後方視的に調査した。早期割合及び分娩週数を主要評価項目とした。 【結果】介入群は12例、対象群は19例であり、母体背景及び手術背景に差はなかった。早産割合は介入群で10/12例（83％）、対象群で11/19例（58％）、分娩週数の中央値（範囲）は介入群で33+6週（26+0-37+4週）、対象群で34+6週（23+5-37+5週）であり、ともに統計学的有意差はなかった。また、早産期前期破水は介入群で6/12例（50％）、対象群で8/19例（42％）であり、両群に差はなかった。 【結語】ＡＴ後妊娠においてプロゲステロン製剤による早産予防効果は示されなかった。

開催年月日： 2021年6月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：Web開催   国名：日本国  

最近、がん診療の世界では、診断・治療の各分野においてめざましい変化が起きている。診断では様々な癌腫で従来の病理・画像検査だけではなく、The Cancer Genome Atlas(TCGA)を代表とする網羅的ゲノム解析による分類が予後に相関することが報告され、診断・治療法の選択にも影響を与えている。これにより平均的な患者のためにデザインされた従来型医療から、ヒトゲノム情報などから得られた、疾患への罹患性や薬物感受性等に関わる情報を基に個人に適した治療を提供する「個別化医療」や患者を”特定の疾患にかかりやすい集団(subpopulation)"に分類し、その集団ごとの治療法のみならず疾病予防を確立し、提供していく「精密医療」への移行がはじまっている。精密医療の検査として重要なのががん遺伝子パネル検査であり、2019年より「OncoGuide NCCオンコパネル」および「FoundationOne CDxがんゲノムプロファイル」が保険適用となり臨床の現場でもゲノム医療が現実化してきた。このがんゲノム医療を行うために現在、全国に12の中核拠点病院、33の拠点病院、180の連携病院を選定され体制が整いつつある。 婦人科腫瘍領域においては子宮体癌のTCGAの4つのサブタイプが報告され、このサブタイプ別に治療法を選択する臨床研究が欧米では開始されている。肺がんや消化器癌などに比べ婦人科腫瘍では保険適用のある薬剤はまだ少ないが、2018年に承認されたMSI検査は臓器横断的な免疫チェックポイント阻害剤の適応を決める初めてのコンパニオン診断薬となり子宮体癌においても使用可能となった。卵巣癌はここ数年で遺伝子検査や分子標的治療が最も取り入れられた婦人科腫瘍である。BRCA1・2遺伝子検査がPARP阻害剤のコンパニオン診断となり、最近ではHRD検査も行われるようになり、初回治療の選択肢にも用いられている。このような検査の拡がりにおり血液を使った検査では生殖細胞系列の遺伝子変異もわかるようになった。2020年4月から遺伝性乳がん卵巣がん症候群(HBOC)の既発症者に対するリスク低減乳房切除術(RRM)・乳房再建術ならびにリスク低減卵管卵巣摘出術(RRSO)が保険収載となり、今まで以上にHBOCやLynch症候群など遺伝性がんのカウンセリング体制も重要になってきている。今後、我々はがん患者さん本人だけではなく未発症の家族への対応も求められる。 PARP阻害剤の登場は劇的に無増悪生存期間を延長させたが、最終的な目標である生存率の改善に対しては、早期発見・残存病変なしの手術の遂行の他に、治療抵抗性・再発や転移に関与する遺伝子を同定してそれを標的とした新規治療法の開発などの基礎研究が必要である。以上の動きを踏まえて、本講演では、がんゲノム医療中核病院診療科としての当科の取り組み、臨床遺伝医療部との連携、PARP阻害剤や免疫チェックポイント阻害剤の使用経験に加えて、最近我々が同定した再発・転移・化学療法抵抗性に関与する遺伝子やその機能、新規治療法の開発を紹介する。

開催年月日： 2021年4月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：新潟市（ハイブリッド開催）   国名：日本国  

［Objective］Oogenesis is a highly sex-dependent differentiation process that commences at the mid-gestation stage. A set of sex chromosomes is required for gametogenesis in both males and females, as represented by sex chromosome disorders causing agametic phenotypes. Although studies using model animals have investigated the functional requirement of sex chromosomes, involvement of these chromosomes in gametogenesis remains elusive. Therefore, in this study, we used a novel culture system as a tool to gain insight into the germ cell-intrinsic role of sex chromosomes on oogenesis. ［Methods］Recently, we reported that oogenesis can be reconstituted in culture using mouse embryonic stem cells（mESCs）. Here, we elicit a germ cell-intrinsic effect of sex chromosomes on oogenesis, using this novel culture system in which oocytes were induced from mESCs harboring XX, XO or XY. ［Results］Our results showed that oogenesis from XO and XY mESCs was severely disturbed due to defective processes such as delayed meiotic initiation/progression, aberrant gene expression and mispairing of homologous chromosomes. In addition, our results demonstrate that a Y-linked gene, Eif2s3y that promotes spermatogenesis, has conversely a negative impact on oogenesis. Interestingly, Eif2s3y, a Y-linked gene that promotes proliferation of spermatogonia, had an inhibitory effect on oogenesis. ［Conclusion］This study provides a culture system that serves as a useful model of sex reversal and contributes the concept of a substantial germ cell-intrinsic conflict between male and female gametogenesis. Further study using the culture system will reveal molecular insights into infertility with sex chromosome disorder（s）.

開催年月日： 2021年4月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：新潟市（ハイブリッド開催）   国名：日本国  

［Objective］Aberrant DNA methylation contributes to carcinogenesis in various cancers. Although 5-methylcytosine（5mC）has been analyzed intensively, the function of 5-hydroxymethylcytosine（5hmC）has not been clarified. We investigated the significance of 5hmC as a molecular biomarker for early diagnosis of cervical tumors. ［Methods］We performed immunohistochemistry（IHC）to characterize the level of 5hmC in 103 archived human cervical intraepithelial neoplasia（CIN）samples and cervical cancer specimens. Mouse embryonic fibroblasts（MEF）and the human cell line HHUA were also used to assess molecular basis of 5hmC level aberration. ［Results］The level of 5hmC was significantly decreased between CIN2 and CIN3. Next, we examined the effects of TP53 or RB1 knockdown in mouse embryonic fibroblasts（MEF）, a model of normal cells with HPV infection, and observed 5hmC levels were reduced in Tp53-knockdown cells. In HHUA cells with a wild-type TP53 gene, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B（A3B）was induced after TP53-knockdown, and A3B knockdown recovered 5hmC levels. Moreover, IHC showed that expression levels of A3B in CIN3 were significantly higher than those in both normal epithelium and in CIN2. ［Conclusion］5hmC levels are decreased between CIN2 and CIN3 through the TP53-A3B pathway. Since A3B could impair genome stability, 5hmC loss might increase the chances of accumulating mutations and of progressing from CIN3 to cervical cancer. Thus, these epigenetic changes could predict whether CINs are progressing to cancer or disappearing.

開催年月日： 2021年4月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：新潟市（ハイブリッド開催）   国名：日本国  

［Objective］Cancer cells are known to depend on glycolysis for energy production. However, regulatory mechanism of metabolism in cancer cells remains largely unknown. In this study, we examined regulation of glycolysis and oxidative phosphorylation（OXPHOS）by a tumor suppressive transcription factor, BHLHE40 in endometrial cancer cells. ［Methods］We used HHUA and KLE cells to knockdown BHLHE40；and HEC-1 and Ishikawa cells to overexpress BHLHE40 to examine their cellular glycolysis and OXPHOS using a flux analyzer. The expression and activity of AMP-activated protein kinase, AMPK；lactate dehydrogenase A subunit, LDHA；and pyruvate dehydrogenase E1 subunit alpha 1, PDHA1 were examined by antibodies to detect total and phosphorylated forms of each protein. ［Results］Knockdown of BHLHE40 in the cancer cells resulted in upregulation of glycolysis accompanied with phosphorylation of LDHA Tyr10（activative phosphorylation）, and downregulation of OXPHOS accompanied with phosphorylation of PDHA1 Ser293（inactivative phosphorylation）. Remarkable suppression of phosphorylation of AMPKA Thr172（activative phosphorylation）, but no change in AMPKB Ser182（activative phosphorylation）was observed. On the contrary, forced expression of BHLHE40 in the cancer cells exert the reverse effects. ［Conclusion］BHLHE40 is suggested to regulate the expression and activity of AMPK to control metabolic balance between glycolysis and OXPHOS in endometrial cancer cells. Understanding mechanism of energy production in cancer cells might lead to a new strategy to control development of endometrial cancer.

開催年月日： 2021年4月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：ハイブリッド開催・大阪市（Web参加）   国名：日本国  

開催年月日： 2021年4月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：Web開催   国名：日本国  

総排泄腔遺残症は膀胱・尿道と直腸・肛門の分離過程が障害され尿道・膣・直腸が共通の総排泄腔に開き、会陰には総排泄腔のみが開口している。この遺残した総排泄腔は共通管とも呼ばれる。本邦での厚生労働科学研究費による難治性疾患政策研究事業における2014年の全国集計では、6万人から10万人の出生に1人の割合で発生しており、年間発生数は平均14.8人と報告される先天性難治性希少泌尿生殖器疾患の一つである。治療は新生児期に人工肛門造設が行われた後、共通管が3cm未満の場合、幼児期に一時的に膣・肛門形成を行う。二次性徴発来前後に置いて産婦人科を受信してもらい、FSH、エストラジールを測定する。共通管が3cm以上の場合は術後膣狭窄による月経血流出路障害を起こすことが多く、膣拡張を行う。また、外陰形成不全を合併することも多く、形成外科と一緒に外陰形成を行うこともある。しかし、多くの症例において膣形成後も膣狭窄による月経血流出路障害に関連する症状が認められる。成人症例にて結婚・妊娠・出産に至った症例はあるが、性交渉及び妊娠成立・維持の問題が継続している。また、当科ではこれまで2例の妊娠・分娩症例を経験している。総排泄腔遺残症術後の妊娠中の管理では、子宮奇形による早産傾向、腎機能障害に注意が必要である。また、小児期の間に複数回の手術を繰り返していることが多く、高度癒着に対し帝王切開時には他科との連携が必要になってくる。 総排泄腔遺残症の治療及び管理は、出生直後から小児期・思春期を経て成人期まで生涯にわたり続く。小児科・小児外科・産婦人科・泌尿器科・内科・形成外科の他、心理的なケア・サポートが必要な場合も多く、看護師や遺伝子異常を伴う場合は遺伝カウンセリングを含む多職種で行う必要があり、女性の一生のヘルスケアを扱う分野である産婦人科の重要な疾患の一つである。本発表では、これまでの当科の経験を提示し、この疾患の管理における外科をはじめとする他診療科や多職種との連携体制を考察したい。

開催年月日： 2021年3月

記述言語：日本語  

開催地：Web開催   国名：日本国  

生殖医療の現場では、卵の質は悪くないのに妊娠に至らない原因不明の不妊症のケースに遭遇し、子宮内膜の機能不全による着床環境の障害が疑われる。加齢とともに不妊症の数が増加してくるが若い世代でも原因不明の不妊患者は一定の割合で存在する。我々は子宮内膜幹細胞維持機構と周囲微小環境（ニッチ）の破綻による幹細胞の劣化が細胞老化を誘導し、誘導された細胞老化には加齢による生物学的老化と年齢には依存しない機能的老化があると考え、着床における子宮内膜の果たす役割をマウスモデルとヒト子宮内膜を用いて解析した。 まず、加齢による老化の影響を明らかにするため、若年マウスと老齢マウスの子宮を比較し、網羅的解析により老化のマーカーと成り得る遺伝子を抽出し、ヒト子宮内膜を用いて加齢により発現が変化する遺伝子の同定を試みた。5週齢、8週齢、60週齢を超える野生型マウスから子宮を摘出し、total RNAを抽出しRNA-seqで網羅的に解析した。抽出した発現変動遺伝子について、検証実験として20歳代10例、40歳代10例のヒト子宮のサンプルを用いて、抽出した発現変動遺伝子の蛋白発現について組織免疫化学染色を用いて定量的に解析した。マウス子宮から抽出したtotal RNAのRNA-seq解析により、加齢により発現が増加する炎症に関連する遺伝子を3つ同定した。同時にパスウェイ解析を施行したところ、細胞分裂に関連する経路に関する遺伝子群の発現が加齢マウスにおいて減少していた。前述した3つの遺伝子がコードする蛋白は全て20歳代に比べて40歳代で子宮内膜腺上皮における発現が増加していた。次に機能的な原因を明らかにするため、不妊治療における採卵時（増殖期）に採取したヒト子宮内膜組織から分離した子宮内膜間質細胞を用いて、胚移植後に妊娠反応が陽性であった症例（妊娠群）と陰性であった症例（非妊娠群）において複数の細胞老化誘導のマーカー（SA-β-Gal染色,細胞周期解析,遺伝子発現,SASP因子）を解析した。妊娠群と非妊娠群の年齢を含めた患者背景は同等であった。非妊娠群の子宮内膜間質細胞では妊娠群と比較して細胞老化が顕著に誘導され、細胞老化関連遺伝子CDKN2A,CDKN1A and TP53mRNA発現が亢進していた。また、老化細胞から分泌されることが報告されているIL6,CXCL8,IL17A, and CCI.2の発現も亢進し、細胞周期ではG0/G1期の割合が増加した。さらに、組織幹細胞マーカーの遺伝子発現解析により非妊娠群の子宮内膜間質細胞では妊娠群と比較してABCG2およびALDH1の発現が低く、子宮内膜幹細胞の減少が示唆された。以上より、着床障害には、加齢による子宮内膜の細胞分裂経路の障害、機能的には子宮内膜間質の細胞老化やそれに伴う炎症性サイトカイン分泌が関与していることが示唆された。

開催年月日： 2020年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：Web収録・オンデマンド配信   国名：日本国  

開催年月日： 2020年10月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：Web開催   国名：日本国  

生殖医療の現場では、卵の質は悪くないのに妊娠に至らない原因不明の不妊症のケースに遭遇し、子宮内膜の機能不全による着床環境の生涯が疑われる。加齢とともに不妊症の数が増加してくるが若い世代でも原因不明の不妊患者は一定の割合で存在する。我々は子宮内膜幹細胞維持機構と周囲微小環境（ニッチ）の破綻による幹細胞の劣化が細胞老化を誘導し、誘導された細胞老化には加齢による生物学的老化と年齢には依存しない機能的老化があると考え、着床における子宮内膜の果たす役割をマウスモデルとヒト子宮内膜を用いて解析した。 まず、加齢による老化の影響を明らかにするため、若年マウスと老齢マウスの子宮を比較し、網羅的解析により老化のマーカーと成り得る遺伝子を抽出し、ヒト子宮内膜を用いて加齢により発現が変化する遺伝子の同定を試みた。5週齢、8週齢、60週齢を超える野生型マウスから子宮を摘出し、total RNAを抽出しRNA-seqで網羅的に解析した。抽出した発現変動遺伝子について、確証実験として20歳代10例、40歳代10例のヒト子宮のサンプルを用いて、抽出した発現変動遺伝子の蛋白発現について組織免疫化学染色を用いて定量的に解析した。マウス子宮から抽出したtotal RNAのRNA-seq解析により、加齢により発現が増加する炎症に関連する遺伝子を3つ同定した。同時にパスウェイ解析を施行したところ、細胞分裂に関連する経路に関する遺伝子群の発現が加齢マウスにおいて減少していた。前述した3つの遺伝子がコードする蛋白は全て20歳代に比べて40歳代で子宮内膜腺上皮における発現が増加していた。次に機能的な原因を明らかにするため、不妊治療における採卵時（増殖期）に採取したヒト子宮内膜組織から分離した子宮内膜間質細胞を用いて、胚移植後に妊娠反応が陽性であった症例（妊娠群）と陰性であった症例（非妊娠群）において複数の細胞老化誘導のマーカー（SA-β-Gal染色、細胞周期解析、遺伝子発現、SASP因子）を解析した。妊娠群と非妊娠群の年齢を含めた患者背景は同等であった。非妊娠群の子宮内膜間質細胞では妊娠群と比較して細胞老化が顕著に誘導され、細胞老化関連遺伝子CDKN2A,CDKN1A and TP53 mRNA発現が亢進していた。また、老化細胞から分泌されることが報告されているIL6,CXCL8,IL17A, and CCL2の発現も亢進し、細胞周期ではG0/G1期の割合が増加した。さらに、組織幹細胞マーカーの遺伝子発現解析により非妊娠群の子宮内膜間質細胞では妊娠群と比較して、ABCG2およびALDH1の発現が低く、子宮内膜幹細胞の減少が示唆された。以上より、着床障害には、加齢による子宮内膜の細胞分裂経路の障害、機能的には子宮内膜間質の細胞老化やそれに伴う炎症性カイトサイン分裂が関与していることが示唆された。

開催年月日： 2020年10月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：Web開催（オンデマンド配信）   国名：日本国  

生殖医療の現場では、卵の質は悪くないのに妊娠に至らない原因不明の不妊症のケースに遭遇し、子宮内膜の機能不全による着床環境の障害が疑われる。加齢とともに不妊症の数が増加してくるが若い年代でも原因不明の不妊患者は一定の割合で存在する。我々は子宮内膜幹細胞維持機構と周囲微小環境（ニッチ）の破綻による幹細胞の劣化が細胞老化を誘導し、誘導された細胞老化には加齢による生物学的老化と年齢には依存しない機能的老化があると考え、着床における子宮内膜の果たす役割をマウスモデルとヒト子宮内膜を用いて解析した。 まず、加齢による老化の影響を明らかにするため、若年マウスと老齢マウスの子宮を比較し、網羅的解析により老化のマーカーと成り得る遺伝子を抽出し、ヒト子宮内膜を用いて加齢により発現が変化する遺伝子の同定を試みた。5週齢、8週齢、60週齢を超える野生型マウスから子宮を摘出し、total RNAを抽出しRNA-seqで網羅的に解析した。抽出した発現変動遺伝子について、検証実験として20歳代10例、40歳代10例のヒト子宮のサンプルを用いて、抽出した発現変動遺伝子の蛋白発現について組織免疫化学染色を用いて定量的に解析した。マウス子宮から抽出したtotal RNAのRNA-seq解析により、加齢により発現が増加する炎症に関連する遺伝子を3つ同定した。同時にパスウエイ解析を施行したところ、細胞分裂に関連する経路に関する遺伝子群の発現が加齢マウスにおいて減少していた。前述した３つの遺伝子がコードする蛋白は全て20歳代に比べて40歳代で子宮内膜腺上皮における発現が増加していた。次に機能的な原因を明らかにするため、不妊治療における採卵時（増殖期）に採取したヒト子宮内膜組織から分離した子宮内膜間質細胞を用いて、胚移植後に妊娠反応が陽性であった症例（妊娠群）と陰性であった症例（非妊娠群）において複数の細胞老化誘導のマーカー（SA-β-Gal染色，細胞周期解析，遺伝子発現，SASP因子）を解析した。妊娠群と非妊娠群の年齢を含めた患者背景は同等であった。非妊娠群の子宮内膜間質細胞では妊娠群と比較して細胞老化が顕著に誘導され、細胞老化関連遺伝子CDKN2A, CDKN1A and TP53 mRNA発現が亢進していた。また、老化細胞から分泌されることが報告されているIL6 , CXCL8 , IL17A , and CCL2の発現も亢進し、細胞周期ではG0/G1期の割合が増加した。さらに、組織幹細胞マーカーの遺伝子発現解析により非妊娠群の子宮内膜間質細胞では妊娠群と比較してABCG2およびALDH1の発現が低く、子宮内膜幹細胞の減少が示唆された。以上より、着床障害には、加齢による子宮内膜の細胞分裂経路の障害、機能的には子宮内膜間質の細胞老化やそれに伴う炎症性サイトカイン分泌が関与していることが示唆された。

開催年月日： 2020年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：Web開催   国名：日本国  

年代毎の女性のヘルスケアを考える上で体重は重要なファクターである。体重の評価法にはBody Mass Index(BMI)が用いられる。日本肥満学会の定義ではBMI18.5未満が低体重（やせ）、25以上が肥満とされる。平成30年国民健康・栄養調査報告によるとやせの割合は男性3.7％、女性11.2％で女性の方が多く、特に20歳代女性のやせの割合は20.3％になっている。肥満の割合は男性32.2％、女性21.9％と男性の方が多いが、男性は30歳以降30％代であまり変化がないのに対し、女性は年代毎に増加し、20歳代では10.7％と低いが60歳代では27.5％となる。 各年代により体重と関連する疾患がある。若年者のやせは体重減少性続発性無月経の原因となる。そのメカニズムには代謝栄養やストレスに反応するCRH、キスペプチン、レプチンをはじめとする脳内神経ネットワークが作用しGnRHバルス分泌の低下により性線機能抑制が関与すると考えられている。また、Peak Bone Massも低下し、骨量減少、骨粗鬆症の原因となる。体重減少の理由は様々だが、神経性やせ症による摂食障害を伴う場合は、精神科や心理カウンセラーを交えたチーム医療が必要となってくる。このやせが妊娠期にも続く場合、低出生体重児の原因となり出征後の生活習慣病の増加をもたらすなど次世代への影響も知られている。中高年移行は肥満が影響する疾患が増えてくる。その代表的なものがメタボリックシンドロームや生活習慣病である。この病態には肥満により内臓脂肪蓄積が起こり、脂肪細胞から分泌されるアディポサイトカインプロファイルの異常、ホルモン分泌異常、遊離脂肪酸産生増加はインスリン抵抗性・耐糖能異常・脂質代謝異常・循環系異常を誘導する。 肥満により様々ながんの発生リスクが上昇することが報告されているが、その中には子宮体癌が含まれる。その病態には、脂肪細胞のアロマターゼ活性によりテストステロンから産生されるエストロゲンが関与している。また、エストロゲンレセプター(ER)はエストロゲンだけではなく癌遺伝子のRASシグナル刺激でも転写活性が起こることが知られており、エストロゲン依存性の子宮体癌の発癌機構にRASを介した経路は重要である。RASタンパクの作用発現にはコレステロールの中間代謝産物であるイソプレノイドの付加による翻訳語修飾が必要である(プレニル化)。コレステロール産生の代謝経路にあるHMG-CoA還元酵素の阻害剤(スタチン)はコレステロールを低下させる脂質異常症の治療薬であるが、イソプレノイド産生も阻害するため、RASのプレニル化も阻害する。最近スタチンのがん細胞増殖抑制作用が注目されている。スタチンは乳癌や子宮体癌の予後を改善することが報告されており、興味深い。 本講演では、女性の各ライフステージ疾患に肥満ややせが及ぼす影響をそのメカニズムとともに解説する。

開催年月日： 2019年11月

記述言語：日本語  

開催地：福岡市   国名：日本国  

産婦人科学は、卵の発生から始まり、胎児期・新生児期・思春期・生殖期・更年期・老年期を経て死を迎えるまで、「女性の一生を診る」学問である。産婦人科医専門医を取得するまでは、これら全ての年代にわたる疾患の知識・医療技術を学んでいるが、サブスペシャリティーと言われる専門医を取得後は、多くの産婦人科医が自分の専門領域以外の診療を受け持たなくなる傾向がある。しかし、患者の女性としての人生を考えると目の前の「病気」を診るだけでは十分ではなく、過去・未来を含めた時間軸で「人」を診ることが必要となってくる。こういう視点で、女性ヘルスケアを扱う専門領域が「女性医学」である。女性医学は診断・治療だけではなく予防医学・社会医学の側面も持つ。全てを産婦人科医だけではカバーすることは不可能で、他の領域の医師や看護師・助産師・薬剤師・保健師など多職種連携が必須となる。本講演では胎児期や新生児期に診断され、成人期までのフォローが必要な「ターナー症候群」「総排泄腔遺残症」を例に、多診療科連携による移行期医療について考える。 ターナー症候群は、性染色体異常症の一つでX染色体の1本の全欠失や短腕の欠失が起こる。染色体核型がXOとなった生殖細胞の機能異常のメカニズムは、本学会の教育講演を担当している林克彦教授らにより明らかにされつつある。胎児期には後頚部の皮膚のたるみ（胎児嚢胞性ヒグローマ）で見つかり、羊水検査で診断されることもある。 出生後は小児科で成長ホルモン投与や合併症のフォローを受けている。産婦人科では12～15 歳の間にエストロゲン少量療法を開始し、成人量0.72 mgにまで増量する。 Kaufmann 療法への移行は，上記の最大量，すなわち成人量で6 か月を経過するか，あるいは途中で消退出血が起こるか，いずれかの早い時点で行う。また、骨粗鬆症の予防を行うことも重要である。 総排泄腔遺残症は膀胱・尿道と直腸・肛門の分離過程が障害され尿道・腟・直腸が共通の総排泄腔に開き、会陰には総排泄腔のみが開口している。この遺残した総排泄腔は共通菅とも呼ばれる。治療は新生児期に人工肛門造設が行われた後、共通菅が３cm未満の場合、幼児期に一期的に腟・肛門形成を行う。二次性徴発来前後において産婦人科を受診してもらい、FSH、エストラジールを測定する。共通菅が3cm以上の場合は術後腟狭窄による月経血流出障害を起こすことが多く、腟拡張術を行う。また、外陰形成不全を合併することも多く、形成外科と一緒に外陰形成を行うこともある。 しかし、多くの症例において腟形成後も腟狭窄による月経血流出路障害に関連する症状が認められる。成人症例にて結婚に至った症例はあるが、性交渉及び妊娠成立・維持の問題が継続している。小児外科から産婦人科への移行期医療が重要である。

開催年月日： 2019年9月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：京都市   国名：日本国  

Gα₁₃-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer

開催年月日： 2019年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：京都市   国名：日本国  

【目的】当科では2015年11月より腹腔鏡下広汎子宮全摘術(LRH)を臨床試験として開始し、2016年8月からは先端医療として、2018年4月からは保険診療として施行してきた。2018年10月に早期子宮頸癌患者を対象に低侵襲広汎子宮全摘術と閉腹広汎子宮全摘術(ARH)を行った症例を比較した海外での前向き試験(LACC trial)の結果が発表され、低侵襲手術群で閉腹手術群よりも局所再発が多く、無病生存率および全生存率が低かった。今回、当科で施行したLRH症例の治療成績について後方視的にARH症例と比較検討した。 【方法】2015年11月から2018年12月に当科でLRHを施行した子宮頸癌IB1期(組織型：扁平上皮癌、腺癌、腺扁平上皮癌)26例を対象とし、同時期に当院でARHを施行した子宮頸癌IB1期およびⅡA1期(組織型：扁平上皮癌、腺癌、腺扁平上皮癌)46症例と比較検討し、治療成績(再発の有無)について後方視的に検討した。LRH群は全例で腟カフを作成し、子宮マニュピュレーターは使用しなかった。統計学的手法としてKaplan-Meier法を用いた。 【成績】観察期間の中央値はそれぞれLRH群で19ヶ月(5-41ヶ月)、ARH群で26ヶ月(5-40ヶ月)で、LRH群には再発例はなく、ARH群の1例で術後10ヶ月目に腟断端再発を認めた。LRH群とARH群の間に再発率に差を認めなかった(P=0.46)。 【考察】短い期間の比較ではあるが、LRH群とARH群の再発率に差を認めず、ともに良好な治療成績であった。当科においては主要散布の防止の工夫をLRH群の全例に行っていることが、良好な治療成績に結びついた可能性が示唆された。

開催年月日： 2019年6月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：山口市   国名：日本国  

近年、産婦人科医療をめぐっては、生殖内分泌・周産期・婦人科腫瘍のいずれの分野でも様々な課題がでてきている。まずは晩婚化・晩産化に伴う妊孕性低下があげられる。多くは卵の老化が原因と考えられているが、生殖補助医療の現場では受精卵の質は問題なくても、35歳を過ぎると妊娠率が低下することはよく知られた事実である。我々は着床の場である子宮内膜に着目した。子宮内膜の老化に焦点をあて、マウスを用いた加齢により変化する遺伝子同定の試みや、ヒト臨床検体を用いた着床不全の病態への子宮内膜の関与の研究を紹介する。晩産化に伴うもう一つの問題は合併症妊娠の増加である。この中でも妊娠高血圧症候群は全妊娠の５％をしめ、重篤になると母児共に生命を危うくする合併症を併発する。胎盤の形成不全が原因と考えられているが不明な点も多くその病態の解明は重要である。我々は妊娠高血圧症候群と正常妊娠の胎盤を用いて網羅的発現遺伝子解析や免疫染色を行い、妊娠高血圧症の胎盤は硬度が高く病理学的には線維化が起こっていることを明らかにした。本講演ではそのメカニズムを解析した研究を紹介する。また、婦人科腫瘍の分野では、若年子宮頸癌の増加が社会的問題である。妊孕性を温存する手術として現在多くの施設で子宮頸部摘出術（トラケレクトミー）が行われている。当教室ではこれまでに約200例のトラケレクトミーを経験している。我々は、予後、不妊治療の実際、妊娠管理の問題点、術後合併症などを解析し報告してきたので紹介する。以上、産婦人科医療をめぐる問題を、晩婚化・晩産化・若年子宮頸癌の増加を例に基礎研究・臨床研究の視点より考えていく。

開催年月日： 2019年4月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：名古屋市   国名：日本国  

Purpose：For oncologic safety, vaginal radical trachelectomy is generally limited to patients with cervical cancer ＜ 2 cm. However, inclusion criteria for abdominal trachelectomy are unclear. Our aim was to evaluate the safety of abdominal trachelectomy for cervical cancer 2 cm. Methods：Our institutional review board approved this clinical study, and informed consent was obtained from each patient. We began performing abdominal trachelectomy at our institution in 2005. The preoperative criteria consisted primarily of（1）stage IB1 or less advanced squamous cell cancer 3 cm（including stage IIA1 with slight vaginal involvement）；or（2）adenocarcinoma/adenosquamous carcinoma 2 cm. If a positive sentinel lymph node or cervical margin was diagnosed intraoperatively by frozen section, trachelectomy was converted to hysterectomy. The medical records of these patients were reviewed retrospectively. Results：We attempted trachelectomy in 217 patients. Among 142 patients with tumors ＜ 2 cm, trachelectomy was successful in 127, none of whom developed recurrence. Altogether, 29 pregnancies were achieved in 22 women with 15 infants delivered. For 75 patients with tumors 2 cm, trachelectomy was successful in 61. Among them, two developed recurrence, eight pregnancies were achieved in five women with five infants delivered. For 29 patients who could not undergo trachelectomy, 14 had tumors 2 cm, and 22 had vascular permeation. Considerations ＆ Conclusions：Intraoperative frozen sections of sentinel lymph nodes and cervical margins allowed us to perform trachelectomy safely even in patients with tumors 2 cm.

開催年月日： 2019年4月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋市   国名：日本国  

性分化疾患の治療は、出生直後から小児期・思春期を経て成人期まで生涯にわたり続く。本講演では本疾患の内科的・外科的治療法を解説する。ターナー症候群は約2000人に１人の割合で発症し、低身長に加え心疾患などを併発し、小児科で成長ホルモン投与や合併症のフォローを受けている。産婦人科では身長が140cmに達した後、段階的にエストロゲンを投与し子宮の成熟を促し、骨粗鬆症の予防をする。完全型の表現型は女性型で、無月経で来院することが多い。精巣の腫瘍化、悪性化のリスクがあり、青年期に摘出術を行い、その後はエストロゲン補充療法や必要に応じて造腟術を行う。先天性副腎皮質過形成は常染色体劣性遺伝を示し、90％が21-水酸化酵素欠損症である。外性器の以上（陰核肥大・腟開口部狭窄）がみられ、陰核形成や腟形成が施行される。適切なグルココルチコイドが投与されていれば妊娠・分娩も可能であり、内分泌専門医との連携が必要である。総排泄腔遺残症は出生５万人に１人という稀な疾患である。尿道・腟・直腸が共通管に開き、会陰には総排泄口のみが開口している。幼児期に肛門形成・腟形成をされるが、腟狭窄のため思春期以降、子宮・腟留血症、月経困難症などが問題となり産婦人科の関与が必要になる。生命予後が改善され、結婚し挙児希望症例には排便・排尿機能だけでなく生殖機能の管理が重要で、月経血流出路や性交障害改善のため、腟拡張術や外陰形成術を行う。以上のように、小児科・小児外科・産婦人科・泌尿器科・内科・形成外科の他、心理的なケア・サポートが必要な場合も多く、遺伝子異常を伴う場合は遺伝カウンセリングを含む多職種で行う必要がある。

開催年月日： 2019年4月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：名古屋市   国名：日本国  

Purpose：Cancer cells can co-opt the activity of G protein-coupled receptors（GPCRs）for their progression. Recent studies have revealed that overexpression of, or activating mutations in, GPCR-linked heterotrimeric G proteins, including GNAS, GNAQ, GNA12 and GNA13, play critical roles in the progression of human cancers. Among them, G α 13, encoded by the GEP oncogene, GNA13, has been implicated in the progression of various human cancers. However, our understanding of the function of G α 13 in cancer progression remains limited because of the lack of experimental systems that enable the exclusive examination of G α 13 signaling. Here, we evaluated downstream targets of GEP oncogene that are implicated in ovarian cancer progression. Methods：To examine the effect of G α 13 activation on ovarian cancer cells, we employed constitutively active mutant of G α 13（G α 13QL）or synthetic biology approach using a mutant GPCR and chimeric G protein. Morphological change, protein expression profiles and intracellular signaling pathways were analyzed. Results：Regarding both in cell morphology and protein expression profile, sustained activation of G α 13 induced epithelial-mesenchymal transition in ovarian cancer cells through down regulation of LATS1, a critical component of the Hippo signaling pathway. A synthetic biology approach revealed that G α 13-regulated phosphorylation of LATS1 at Serine 909 within its activation loop induced recruitment of the E3 ubiquitin ligase, ITCH, to trigger LATS1 degradation. Considerations ＆ Conclusions：Our findings uncover novel mechanisms through which G α 13 activation induces dysregulation of the Hippo signaling pathway, leading to aggressive cancer phenotypes, thereby identifying a potential target for preventing metastatic spread of ovarian cancer.

開催年月日： 2018年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京都   国名：日本国  

近年、産婦人科医療をめぐっては、生殖内分泌・周産期・婦人科腫瘍のいずれの分野でも様々な課題がでてきている。まずは晩婚化・晩産化に伴う妊孕性低下があげられる。多くは卵の老化が原因と考えられているが、生殖補助医療の現場では受精卵の質は問題なくても、35歳を過ぎると妊娠率が低下することはよく知られた事実である。我々は着床の場である子宮内膜に着目した。子宮内膜の老化に焦点をあて、マウスを用いた加齢により変化する遺伝子同定の試みや、ヒト臨床検体を用いた着床不全の病態への子宮内膜の関与の研究を紹介する。晩産化に伴うもう一つの問題は合併症妊娠の増加である。この中でも妊娠高血圧症候群は全妊娠の５％をしめ、重篤になると母児共に生命を危うくする合併症を併発する。胎盤の形成不全が原因と考えられているが不明な点も多くその病態の解明は重要である。我々は妊娠高血圧症候群と正常妊娠の胎盤を用いて網羅的発現遺伝子解析や免疫染色を行い、妊娠高血圧症の胎盤は硬度が高く病理学的には線維化が起こっていることを明らかにした。本講演ではそのメカニズムを解析した研究を紹介する。また、婦人科腫瘍の分野では、若年子宮頸癌の増加が社会的問題である。妊孕性を温存する手術として現在多くの施設で子宮頸部摘出術（トラケレクトミー）が行われている。当教室ではこれまでに200例以上のトラケレクトミーを経験している。我々は、予後、不妊治療の実際、妊娠管理の問題点、術後合併症などを解析し報告してきたので紹介する。以上、産婦人科医療をめぐる問題を、晩婚化・晩産化・若年子宮頸癌の増加を例に基礎研究・臨床研究の視点より考えていく。

開催年月日： 2018年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：横浜市   国名：日本国  

background:To evaluate the prognostic outcome and surgical complications in patients with early-stage cervical cancer who underwent sentinel node navigation surgery(SNNS) for hysterectomy or trachelectomy. Methods:A total of 139 patients who underwent SNNS using 99m Tc phytate between 2009 and 2015 were evaluated. No further lymph node dissection was performed when intraoperative analysis of the sentinental lymph nodes (SLNs) was negative for metastasis. We compared the surgical complications between the SNNS group and 67 matched patients who underwent pelvic lymph node dissection (PLND) after SLN mapping between 2003 and 2008. We also examined the clinical outcomes in the SNNS group. Results: The mean number of detected SLNs was 2.5 per patient. Fourteen of the 139 patients in the SNNS group underwent PLND based on the intraoperative SLN results. The amount of blood loss, the operative time, and the number of perioperative complications were significantly less in the SNNS group than in the matched PLND group. There was no recurrence during a follow-up period ranging from 2 to 88 months(median, 40 months) in the SNNS group. Conclusions: Using SNNS for early-stage cervical cancer is safe and effective and does not increase the recurrence rate. A future multicenter trial is warranted.

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：島根県出雲市   国名：日本国  

開催年月日： 2018年6月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：弘前市   国名：日本国  

開催年月日： 2018年4月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：宮崎市   国名：日本国  

開催年月日： 2018年1月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京都中央区   国名：日本国  

近年、様々な成体組織や癌組織に自己複製能と多分化能を持つ幹細胞の存在が報告されている。組織および癌組織の幹細胞を同定する手段として、DNA結合色素Hoechst33342で細胞を染色し、UVで励起させた際、450/600nmの波長を暗く発現している細胞集団side population(以下SP細胞）を分離する方法が用いられている。 　子宮体癌は近年増加しており約8割はestrogenエストロゲン依存性である。我々は、正常子宮内膜にSP細胞が存在することを明らかにした。このSP細胞は、長期増殖能をもち、３次元培養にて腺管上皮様構造に分化するなど幹細胞様の性質を示した。ラット子宮内膜より分離したSP細胞とnon-SP細胞に変異性KRAS遺伝子を導入したところ、SP細胞に導入した時のみ継代的な腫瘍形成能を獲得し、Estrogen Receptor機能の亢進もみとめられた。この結果は子宮体癌発生機構への正常子宮内膜幹細胞の関与を示唆している。 　次に子宮体癌細胞株Hec1細胞からSP細胞を分離し、その生物学的特性を解析し、分化マーカー発現低下、長期増殖能、自己複製能、運動能亢進、造腫瘍能亢進に加え、腫瘍細胞だけではなく間質細胞への分化能を示すなどがん幹細胞様の性質を持つことを明らかにした。平滑筋への分化条件下で３次元培養を行ったところ、SP細胞はα-Smooth muscle actinを発現する細胞に分化した。SP細胞はnon-SP細胞に比べて、マイクロアレイのパスウェイ解析にて上皮間葉移行（EMT）に関与するシグナル伝達経路を構成する遺伝子群の発現が亢進していた。EMT関連遺伝子であるSPARC,fibtonectinの発現と運動能の亢進は正の相関を示した。現在、EMT関連遺伝子発現の細胞生物学的影響を解析中である。

開催年月日： 2017年11月 - 2017年12月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Tokyo   国名：日本国  

Although a hallmark of human cancer genomes is global DNA hypomethylation accompanied by focal DNA hypermethylation, the basis of DNA hypomethylation remains to be determined. We investigated the mechanisms and the biological significance of DNA hypomethylation in the process of carcinogenesis. With the use of embryonic fibroblasts from oncogenic BrafV600E knock-in mice, we found that the expression of BrafV600E is sufficient to promote global DNA hypomethylation. DNA demethylase Tet3 is maintained at low level resulting from ubiquitination and degradation by SCF-type ubiquitin ligase SCF Fbxw7 in wild type mice. BrafV600E increased Tet3 protein levels via inhibition of Gsk3β、an inhibitor of Tet3 phosphorylation that is required for SCF Fbxw7-mediated ubiquitination. Consistent with these results, we found that the levels of TET3 and 5-hydroxymethylcytosine, an intermediate product of 5-methylcytosine demethylation, increased in human colorectal adenomas containing BRAFV600E. Conversely, we showed that knockdown of Tet3 decreased BrafV600E-induced lung tumorigenesis in mice. Our results elucidate a mechanism of global DNA hypomethylation promoted by oncogenic BRAF and establish an essential role for TET3 at an early stage of oncogenesis.

開催年月日： 2017年11月 - 2017年12月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Tokyo   国名：日本国  

Background and Objectives: Uterine leiomyosarcoma is a highly aggresive and lethal disease. This malignancy remains the most common type of uterine sarcoma, affecting approximately 0.4/100,000 women per year. Our aim is to assess the treatment and prognosis of leiomysarcoma patients Methods: We retrospectively analyzed the clinicopathological variables and prognosis in 14 patients who were treated at our institution. Results: A total of 14 patients were trated at our institution between January 2008 and July 2017. The median patients age and observation period were 63 years(range, 35-83 years) and 17months(range, 5-75 months), respectively. The largest group of patients by tumor stage was IB(IB, n=8; IIB, n=1; IVB, n=3); the largest group by historogical subtype was conventional leiomyosarcoma(conventional, n=11; myxoid, n=2; epithelioid, n=1). We performed total abdominal hysterectomy and bilateral salpingo-oophorectomy for all patients with additional operative procedure(e.g. tumor resection, lymphadenectomy) if necessary. Twelve patients received adjuvant chemotherapy consisting of docetaxel and gemcitabine. Ten patients experienced recurrence and multidisciplinary therapy was performed including tumor resection, chemotherapy, radiation and molecular-targetted agents. In observation period so far, 11 patients are alive (without disease, n=5; with disease, n=6). Conclusions: Although uterine leiomyosarcoma is a lethal tumor, multidisciplinary therapy might be useful to control disease after recurrence.

開催年月日： 2017年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：長崎県雲仙市   国名：日本国  

本邦では胞状奇胎除去術後の再搔爬が多くの施設で行われてきた。絨毛性疾患取り扱い規約ー第3版ーでも、「画像検査で胞状奇胎の遺残が疑われる場合は1週間後に再度子宮内容搔爬を施行し、胞状奇胎の遺残がないことを組織学的に確認することが望ましい」と記載されている。一方で、海外では胞状奇胎に対して通常1回の搔爬のみ行われている。奇胎除去後に続発性症を発症した場合に再搔爬は不要とする報告は存在するが、本邦で行われている胞状奇胎除去術より1週間目での再搔爬の有用性について検討した報告はない。当科で胞状奇胎除去術を施行した症例の後方視的解析をもとに再搔爬の必要性を検討した。

開催年月日： 2017年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2017年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：横浜市   国名：日本国  

開催年月日： 2017年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：横浜市   国名：日本国  

開催年月日： 2017年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Seoul   国名：大韓民国  

開催年月日： 2017年9月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：新潟市   国名：日本国  

開催年月日： 2017年5月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：松山市   国名：日本国  

開催年月日： 2017年4月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Hiroshima   国名：日本国  

FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch and c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild-type cancer samples (P < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5'-upstream regions of FBXW7 gene in p53-mutated samples were significantly higher methylated compared with those in p53 wild-type samples (P < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5'-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5'-upstream regions of FBXW7.

開催年月日： 2017年4月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Hiroshima   国名：日本国  

開催年月日： 2016年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：横浜市   国名：日本国  

開催年月日： 2015年4月

記述言語：日本語  

開催地：横浜市   国名：日本国  

開催年月日： 2014年9月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：横浜市   国名：日本国  

開催年月日： 2014年8月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京都   国名：日本国  

開催年月日： 2014年4月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Tokyo   国名：日本国  

開催年月日： 2014年4月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Tokyo   国名：日本国  

開催年月日： 2013年10月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：横浜市   国名：日本国  

開催年月日： 2008年10月

会議種別：口頭発表（一般）  

開催地：nagoya   国名：日本国  

開催年月日： 2008年10月

会議種別：口頭発表（一般）  

開催地：kobe   国名：日本国  

開催年月日： 2008年6月

会議種別：口頭発表（一般）  

開催地：tokyo   国名：日本国  

記述言語：日本語  

開催地：宮崎市   国名：日本国  

会議種別：口頭発表（一般）  

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：富山   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：京都   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜市   国名：日本国  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：福岡県北九州市   国名：日本国  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：札幌市   国名：日本国  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：札幌市   国名：日本国  

記述言語：日本語  

開催地：東京都   国名：日本国  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：那覇市   国名：日本国  

開催年月日： 2024年1月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2024年1月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2023年12月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：宮崎県延岡市   国名：日本国  

開催年月日： 2023年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋市   国名：日本国  

開催年月日： 2023年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2023年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2023年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2023年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京都千代田区   国名：日本国  

【目的】鏡視下根治手術にセンチネルリンパ節(SN)生検を併用することは低侵襲手術としての特性からも臨床的意義が大きい。我々の施設は2019年より再発低リスクと推定される子宮体癌に対する鏡視下根治手術にSN生検を併用しているが、SNが同定できない症例にもしばしば遭遇する。そこでSN非同定症例の特徴について解析した。 【方法】2019年6月より2023年3月まで術前診断が子宮体癌推定ⅠＡ期類内膜癌グレード1,2の症例に対し当科でSN生検併用の腹腔鏡下またはロボット支援下根治術を計画した98例を後方視的に検討した。SNの同定には手術前日にテクネシウムフチン酸を子宮膣部に4か所局注し手術中にガンマプローブを用いた。同定したSNは短軸方向2㎜間隔で術中迅速組織診断を行い、転移陰性であれば郭清を省略し転移陽性であれば開腹術に移行した。SN非同定例には非同定側の骨盤リンパ節郭清を行った。 【成績】98例中27例(28％)において片側または両側のSNを同定できなかった。非同定群の平均年齢は61.1歳で両側とも同定できた群の53.0歳より有意に高かった。(p＝0.0004)。また、非同定群の平均BMIは29.25で両側とも同定できた群の24.65より有意に高かった。(p=0.0021)。術前のCA125値、MRIによる腫瘍径、筋層浸潤の程度、脈絡侵襲、手術進行期、再発率には関連していなかった。非同定例の中に術後リンパ節転移陽性と判明した症例は無かった。 【結論】当科での検討ではSN非同定群は同定群に比して有意に年齢が高く、BMIが高かった。この2つの要素はこれまでの報告に一致するものであった。

開催年月日： 2023年10月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：津市（ハイブリッド開催）   国名：日本国  

開催年月日： 2023年10月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：佐賀市（ハイブリッド開催）   国名：日本国  

開催年月日： 2023年10月

記述言語：日本語  

開催地：横浜市   国名：日本国  

Objective: Fertility preservation (FP) is an assisted reproductive technology that enables pregnancy and childbirth after cancer treatment. At our hospital, we perform oocyte and embryo cryopreservation as FP. We investigated the implementation status of FP for HBOC at our hospital. Methods: We investigated the patient’s backgrounds and fertility preservation status of patients diagnosed with HBOC among breast cancer patients under 43 years of age, who were referred to the Department of Clinical Genetics and Medicine for BRCA1/2 genetic testing between July 2018 and April 2023. Results: During the study period, 63 patients under 43 years of age presented for BRCA1/2 genetic testing. 53 of 63 patients (84.1%) underwent testing. 10 of 53 patients (18.9%) were diagnosed with HBOC. The Breast Surgery Department confirmed the fertility preservation intention of 9 patients (excluding 1 recurrent case), and the Department of Clinical Genetics and Medicine provided genetic counseling regarding HBOC. FP was considered in three cases and was abandoned in two cases in favor of treatment. None of the patients abandoned FP because of heredity. One patient who underwent FP was 31 years old, married, had no live births, and had stage II hormone-sensitive breast cancer. About 2 months after the breast cancer surgery, a random start oocyte retrieval was performed, and embryos were cryopreserved. Discussion: FP requires patients to make decisions about future pregnancy and childbirth within a limited time from diagnosis to treatment. At the same time, patients are burdened by the information about heredity in HBOC. It was considered necessary to respond promptly and flexiblyResponding promptly and flexibly was necessary, considering the patient's backgrounds and disease progression.

開催年月日： 2023年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：Web開催   国名：日本国  

産婦人科の４つのサブスペシャリティの中で女性医学はQOLの維持・向上のために、女性に特有な心身にまつわる疾患を主として予防医学の観点から取り扱うことを目的とする分野である。本講演では、女性ヘルスケアの立場から更年期医療について考えてみたい。女性は閉経によるエストロゲンの低下により様々な症状が出現する。その中でも最初に出現するのが、ほてりを代表とする血管運動神経障害である。視床下部のGnRHニューロンの上位に存在する弓状核のキスペプチンニューロンはニューロキニンB(MKB)やオピオイドペプチドであるダイノルフィンも発現しており、KNDyニューロンとよばれ、エストロゲンのネガティブフィードバックを受けることが知られている。最近の研究で、更年期にはこの調整が乱れ、KNDyニューロンの肥大化が起こり、NKBが視床下部に作用し温度中枢を刺激することが、ほてりの原因ではないかと考えられている。また、血中に分泌されるホルモンとして血管拡張・汗腺刺激作用を有することが知られているカルシトニン遺伝子関連ペプチド（CGRP）が、ほてりの原因物質として着目されている。これらの阻害剤が将来、ほてりの治療薬の候補になる可能性もある。また、更年期には生活習慣病も増えてくる。この原因として肥満症があり、これを防ぐためには体を動かし、適正体重を維持することが重要である。更年期障害の治療としてホルモン補充療法があるが、乳癌のリスクをあげることが知られている。このリスクは使用される黄体ホルモンの種類と施行期間に関連しており、微粒子化した経口の天然型プロゲステロン製剤はリスクの上昇はみられなかったと報告されている。日本産科婦人科学会女性ヘルスケア委員会の更年期障害治療を専門とする医師を対象に行ったアンケート調査では、ホルモン療法や漢方薬と並んでエクオール等のサプリメントが多く用いられていることが明らかになった。エクオールは閉経後の更年期症状の軽減、骨代謝の改善、シワの進展抑制作用などの効果は報告されている。我々が行った検討では乳癌細胞や子宮体癌細胞の増殖促進作用はないものの、抑制作用もないため、これらのがん患者さんの治療後の卵巣欠落症状にエクオールを用いる際は、定期検診をしながら使用することが重要である。

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

開催年月日： 2023年9月

記述言語：英語  

開催地：横浜市   国名：日本国  

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：和歌山市   国名：日本国  

開催年月日： 2023年9月

記述言語：日本語  

開催地：大津市   国名：日本国  

【症例】56歳、3妊2産、閉経52歳。X年10月の検診で右付属器領域の嚢胞性腫瘤を指摘され、精査加療目的で11月に当科を紹介受診した。初診時、内診および腟鏡診で明らかな異常所見を認めず、経腟超音波断層法で右付属器領域に径4cm大で内部不均一な腫瘤像を認めた。骨盤造影MRI検査で右付属器領域に径7x3cm大の嚢胞性腫瘤を認め、T1WIで低信号、T2WIで高信号を呈し、増強効果を認めず右卵巣漿液性嚢胞腺腫を示唆する所見であった。腫瘍マーカーのCEAは16.9ng/ml、CA19-9は38.5U/ml、CA125は基準値未満であった。上部・下部消化管内視鏡検査で2mm大のS状結腸ポリープを認めた。胸腹部骨盤造影CT検査およびPET-CT検査では既知の嚢胞性腫瘤のみ指摘され、その他の異常所見を認めなかった。以上より右卵巣腫瘍（漿液性嚢胞腺腫疑い）の診断でX+1年4月に腹腔鏡下手術を施行した。術中所見で少量の淡黄色腹水を認め、右付属器領域の腫瘤は虫垂由来で両側付属器は正常外観であった。外科へコンサルトし、虫垂腫瘍の診断で腹腔鏡下虫垂切除術を施行した。手術時間は120分、出血量は少量であった。摘出標本の肉眼所見で虫垂内容物は黄色の粘液状物質であった。術後病理組織診はLow-grade Appendiceal Mucinous Neoplasm, compatibleで悪性所見を認めず、術後経過良好で術後5日目に退院した。【考察】低異型度虫垂粘液性腫瘍（Low-grade Appendiceal Mucinous Neoplasm, LAMN）は虫垂切除例の0.08%～4.1%と報告され、比較的稀な疾患とされる。本症例は術前のCEA値が高値で消化管腫瘍を疑ったものの、消化管内視鏡検査やその他の画像検査で鑑別できず右卵巣腫瘍の術前診断となった。虫垂腫瘍の可能性が否定できず鑑別困難な場合は、術前から外科と綿密な連携の上、手術に臨むことが必要であると考えられた。

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：大津市   国名：日本国  

【目的】再発低リスクと推定される子宮体癌に対する鏡視下根治手術にセンチネルリンパ節(SN)生検を併用することは低侵襲手術としての特性からも臨床的意義が大きい。我々の施設は2014年より上記該当手術にSN生検を併用しておりその妥当性について検討した。【方法】2014年3月より2023年3月まで術前診断が子宮体癌推定IA期類内膜癌grade1,2の症例に対し当科でSN生検併用の腹膜鏡下またはロボット支援下根治術を計画した98例を後方視的に検討した。SNの同定にはテクネシウムフチン酸を用いた。同定したSNは短軸方向2mm間隔で術中迅速組織診断を行い、転移陰性であれば郭清を省略し陽性であれば開腹術に移行した。SN非同定例には非同定側の骨盤リンパ郭清を行った。【成績】98例中71例において両側のSNを同定できた。非同定群の平均年齢は61歳で両側とも同定できた群の53歳より有意に高かった。術中にSN転移陽性と判明した4例を含む12例が術後再発中リスク以上であったため術後補助療法を奨めた。追跡期間の中央値は22ヶ月(1～104ヶ月)で、初回治療終了後4例に中央値30ヶ月(19ヶ月-46ヶ月)でリンパ節転移を含む再発を認めた。【結論】再発低リスクと推定される子宮体癌に対する鏡視下根治手術にセンチネルリンパ節(SN)生検を併用し術式の選択を行った。今後、術前画像診断・術中病理組織診断の精度を高めていくひつようがある。【考察】術後再発低リスクと推定され鏡視下根治手術を行った症例の7例(7％)にリンパ節転移を認めた。この中にはIB期や明細胞癌が4例含まれており術前診断の蓋然性が問われる。これらを除いた3例が筋層没潤や組織型から術後再発低リスクと推定される症例でSN生検が真に有効と考えられた。SN生検術の有用性と安全性はさらなる検討を要するが本研究での再発率4％はLAP2試験でのIA期の5.9％と比較して妥当な成績であった。

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：Web配信   国名：日本国  

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡市   国名：日本国  

【緒言】異所性平滑筋腫は子宮との連続性を持たず発育する平滑筋腫である。子宮筋腫核出術に伴う医原性のものが多いが、自然発生するものは稀である。今回、卵巣皮様嚢腫の腹腔鏡下手術の際腹膜上に発見された自然発生の異所性平滑筋腫の1例を報告する。【症例】49歳、1妊0産。更年期症状を主訴に近医婦人科を受診した際に左卵巣嚢腫を指摘され当科紹介受診となった。10～15年前より左下腹部に腹壁の腫瘤を自覚していたが、経時的な増大傾向もなく画像精査を受けなかった。当科での術前骨盤MRI検査にて子宮には2～3ｃｍの禁酒結節を2つ認め左卵巣腫瘍は皮様嚢腫に矛盾しない所見であったが左下腹部腹壁の腫瘤は撮像範囲外で評価不能であった。左卵巣嚢腫に対して腹腔鏡下卵巣嚢腫摘出術を行い、術中迅速組織診はmature cystic teratoma であった。子宮から離れた左下腹部の壁側腹膜上に各径2ｃｍの結節が4つ数珠状に繋がり一塊となった腫瘤を認め、これも摘出の上、術中迅速組織診に提出しltomyomaであった。【結論】手術歴のない腹膜上の異所性平滑筋腫の1例を経験した。医原性以外の異所性平滑筋腫は稀であり、エストロゲン刺激が誘因の1つと考えられている。腹膜上などに遊離・生着した間葉系幹細胞から発生するとの考察もある。本症例は腹腔内を十分観察したが異所性平滑筋腫は1か所のみでホルモン治療の既往もなかった。

開催年月日： 2023年8月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸市   国名：日本国  

開催年月日： 2023年7月

記述言語：日本語  

開催地：松江市   国名：日本国  

【緒言】成人型顆粒膜細胞腫（GCT）は卵巣悪性腫瘍全体の2.7％を占める比較的稀な疾患である．約20％ の症例で再発し，晩期再発も認める．今回我々は初回治療から19 年後に再発し，術前化学療法後に手術を施行しえた一例を経験したので報告する． 【症例】72 歳，2 妊2 産．52 歳時にGCTIA 期に対して手術を施行し以後経過観察した．71 歳時に転倒を契機に施行された造影CT検査で再発を疑われ当科を再診した．MRI 検査で右腎門部から大静脈下面にかけて長径110mm の内部に壊死と変性を伴う腫瘤を認めた．CT ガイド下生検の結果，GCT 再発と診断した．腫瘍が下大静脈に近接しており，外科と協議の上，一期的な手術は困難であると判断し，術前化学療法により腫瘍の縮小を図った上で摘出術を行う方針とした．パクリタキセル・カルボプラチン療法を6 コース施行し，腫瘍長径は66mm と40％ の縮小を得たため開腹手術を行った．腫瘍は右腎静脈合流部背側に存在し癒着が高度であったが，下大静脈を剥離，離断した上で，右腎合併切除により再発腫瘤摘出術を施行しえた．残存病変はなく術後14 日目に全身状態良好のため退院し，以後外来で経過観察中である． 【結語】GCT の再発例は手術が第一選択であるが，手術困難な症例に対しては化学療法による腫瘍縮小後の手術が選択肢となる と考えられた．

開催年月日： 2023年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：松江市   国名：日本国  

【目的】がんゲノム医療中核拠点病院である当院では，がんゲノム外来を介してがん遺伝子パネル検査の提供を行っている．これまでの当外来での実績をまとめ，現在の課題について検討を行った． 【方法】2019年8 月から2022 年12 月までに当科がんゲノム外来を受診した80 例についてIRB の承認を得た上で，後方視的に調査を行った． 【成績】受診者は80 例（院内65 例，院外からの紹介15 例），そのうち70 例ががん遺伝子パネル検査を希望した．症例の内訳は，卵巣癌23 例，腹膜癌5 例，子宮頸癌21 例，子宮体がん20例，腟癌1 例であった．検査方法は，FoundationOne CDx が52 例，FoundationOne Liquid CDx が2 例，NCC オンコパネルシステムが16 例であった．検体不良などのため3 例が検査中止となった．エキスパートパネルを実施した67 例のうち，18 例（26.9％）に対して遺伝子異常に基づいた治療が推奨，26 例（37.1％）に対して臨床試験が提示され，そのうち2 例（3.0％，患者申出療養制度を用いた受け皿試験1 例，臨床試験1 例）が治療に到達した． 【結論】当院ではがんゲノム外来を通した一元管理によって，がん遺伝子パネル検査のスムーズな提供が可能となっている．しかしながら，他のがんゲノム中核拠点病院と比較して検査後の治療到達率は低く，その理由の一つとして治験実施施設への通院にともなう時間的，経済的負担が大きいことが考えられた．

開催年月日： 2023年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：松江市   国名：日本国  

【Objective】Bevacizumab is a molecular target drug used for various types of cancer including ovarian cancer and cervical cancer in gynecologic field. Gastrointestinal（GI）perforation is well known as a serious adverse event of bevacizumab. A history of abdominal radiotherapy and certain types of cancer（colorectal cancer, and renal cell carcinoma）are reported as the risk factors of GI perforation. The aim of this study is to investigate the incidence of GI perforations in cervical cancer patients who received radiotherapy and chemotherapy containing evacizumab. 【Methods】We retrospectively reviewed medical records of patients with cervical cancer who received chemotherapy containing bevacizumab between 2017 to 2022 in our hospital. Informed consent was obtained from all patients prior to enrollment in the study. The ethics committee approved the study protocol. 【Results】92 patients received bevacizumab-containing chemotherapy（median 6 cycles, 1-18）for cervical cancer. 71（77.1％）cases of them had radiotherapy including external beam pelvis radiotherapy, concurrent chemoradiotherapy (CCRT）, and heavy ion radiotherapy. No GI perforation was observed in patients without radiotherapy. Of 71 patients who received radiotherapy, GI perforation occurred in 2（2.8％）cases. One case had CCRT, and the other case had heavy ion radiotherapy before bevacizumabcontaining chemotherapy. 【Conclusion】This study indicates that use of bevacizumab before or after radiotherapy for cervical cancer would be tolerable considering GI perforation.

開催年月日： 2023年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：松江市   国名：日本国  

【Objective】Cancer cells are known to depend on glycolysis for energy production. However, regulatory mechanism of metabolism in cancer cells remains largely unknown. In this study, we studied a regulation of energy metabolism by a tumor suppressive transcription factor, BHLHE40 in endometrial cancer cells. 【Methods】We used endometrial cancer cells to knockdown or overexpress BHLHE40 to examine their cellular glycolysis and OXPHOS（oxidative phosphorylation）using a flux analyzer. The expression of AMP-activated protein kinase alpha, AMPKA ； lactate dehydrogenase A subunit, LDHA；and pyruvate dehydrogenase E1 subunit alpha 1, PDHA1 were examined by antibodies to detect total and phosphorylated forms of each protein. The activity of PDH and LDH was also examined. A PPM family of phosphatase was examined to regulate AMPK activity. Transcriptional regulation of PPM family by BHLHE40 was also examined using a reporter assay, gel-shift assay and ChIP assay. 【Results】Knockdown of BHLHE40 in the cancer cells resulted in upregulation of glycolysis accompanied with activation of LDH, and downregulation of OXPHOS accompanied with suppression of PDH. Remarkable suppression of AMPK activity was observed. On the contrary, forced expression of BHLHE40 in the cancer cells exert the reverse effects. We also found that PPM phosphatases mediated BHLHE40-regulated AMPK activity. 【Conclusion】BHLHE40 is suggested to regulate the activity of AMPK mediated by PPM phosphatases to control the energy metabolic balance between glycolysis and OXPHOS in endometrial cancer cells. Understanding the mechanism of energy production in cancer cells might lead to a new strategy to control the development of endometrial cancer.

開催年月日： 2023年7月

記述言語：日本語  

開催地：名古屋市   国名：日本国  

発作性夜間ヘモグロビン尿症(PNH)は、補体活性化により毛管内溶血を呈する稀な溶血性貧血で、PNH合併妊娠ではHDP、FGR,血栓症の発症リスクが上昇する。今回、妊娠前より原因不明の溶血性貧血を認め、妊娠21週にHELLP症候群を発症し、人工妊娠中絶後にPNHと判明した一例を経験した。症例は25歳、1妊0産、23歳時の健康診断で溶血性貧血を認めたが、原因不明であった。自然妊娠成立後の初期検査で貧血と血小板減少を認め、血液内科を受診したが、診断に至らず経過観察されていた。妊娠21週2日に重傷高血圧、蛋白尿を認め、当院へ母体搬送された。初診時、血圧は184/118mmHg、尿蛋白/Cr比5.26、血液検査で溶血性貧血、血小板減少を認めた。肝酵素は軽度上昇に留まり、妊娠週数を考慮し、降圧治療を行いつつ慎重に経過観察し、溶血性貧血、血小板減少に対して骨髄穿刺を含めた精査を行ったが、原因の特定には至らなかった。妊娠21週6日に血圧の再上昇、上腹部痛、血小板数の急激な低下、溶血性貧血の増悪、腎機能障害を認め、HELLP症候群の増悪と判断し、妊娠帰結の方針とした。妊娠帰結後にフローサイトメトリーでPNHと判明し、予防的に抗凝固療法を開始し、現在も継続中である。溶血性貧血、肝酵素上昇、血小板減少といった症状を有する疾患は妊娠後に診断を確定することが重要であり、また、本症例のようにPNH合併妊娠でHDPを発症した際にはHELLP症候群の発症か否かの鑑別が困難なことがあことを留意すべきである。

開催年月日： 2023年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋市   国名：日本国  

開催年月日： 2023年7月

記述言語：日本語  

開催地：名古屋市   国名：日本国  

肝海綿状血管腫は最も一般的な肝臓良性腫瘍で、エストロゲンで増大の可能性があり、血小板数減少や凝固機能障害を伴う腫れ辻の死亡率は60-70％と非常に高い。妊娠中の肝海綿状血管腫に対する管理指針はなく、管理法を模索した症例を経験した。症例は34歳、1妊0産、19歳時に超音波検査で偶発的に多発の肝海綿状血管腫を指摘された。その後は無症状であったが、腫瘍径は援徐に増大し、妊娠前の最大腫瘍径は9ｃｍであった。今回、自然妊娠が成立し、妊娠17週の当科初診時、超音波検査で肝臓右後区域に既知の最大9ｃｍがあり、他に2ｃｍ大の血管腫が多発していた。破裂時の死亡率が高いことから、妊娠中の治療に関して肝臓内科と相談したが、無症状であるため適応がないと判断された。妊娠・分娩中の腫瘍破裂時には緊急のＩＶＲが行えるよう放射線科と相談、準備をした。その後の妊娠経過中に腫瘍径の増大や血小板数の低下はなかった。妊娠に伴うエストロゲン刺激による腫瘍増大や経腟分娩に伴う腫瘍破裂の可能性などを文献的に検索した上で、分娩時期、分娩様式を患者・家族に提示しインフォームドチョイスの結果、妊娠37週1日に帝王切開分娩で児を娩出した。周術期は特に合併症なく経過した。巨大な肝海綿状血管腫の合併妊娠の報告例は少なく、今後、本疾患合併妊娠の妊娠・分娩管理方針を検討する上で、症例の蓄積が重要である。

開催年月日： 2023年6月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：兵庫県姫路市 (ハイブリッド形式)   国名：日本国  

開催年月日： 2023年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：大分県別府市   国名：日本国  

【目的】化学療法歴のある子宮体癌再発症例には、これまでAP療法やTC療法が用いられてきた。一方、近年ペンブロリズマブ療法(Pem療法)やペンブロリズマブ・レンバチニブ療法(Pem/Len療法)が登場し、その効果が期待されている。これら新しい治療法の有効性について検討するため、当科における治療成績を解析した。 【方法】当科において2019年8月から2023年2月の間に施行したPem/Len療法およびPem療法の症例17例を後方視的に解析した。本研究は当院倫理審査委員会に承認され、全例文書によるインフォームドコンセントを取得している。 【成績】化学療法歴を有する子宮体癌再発症例17例(28-84歳、中央値66歳)に免疫チェックポイント阻害薬による治療を行った(Pem/Len療法12例、Pem療法5例)。Pem/Len療法12例中、MSI院生は8例、未検が4例であった。Platinum-free interval(PFI)<6ヶ月でPem/Len朗報を開始した8例(観察期間4-9ヶ月)における奏効率は50％であり、Progression-free survival(PFS)中央値は未到達、4ヶ月におけるPFS率は87.5％であった。うち5例は2レジメン以上の化学療法歴があり、奏効率60％、4ヶ月におけるPFS率は80％であった。Pem療法5例(観察期間4-26ヶ月)は全例PFI＜6ヶ月で治療を開始し、奏効率は60％、PFS中央値は19ヶ月であった。Grade3以上の有害事象をPem/Len療法で6例、Pem療法で2例に認めた。またPem/Len療法12例中、10例でLenの休薬、減量を要した。 【結論】免疫チェックポイント阻害薬は化学療法既治療の子宮体癌再発症例に対する有効な治療法であると考えられる。今後は従来の化学療法を含め、より効率的な治療法の選択が可能となるパラメータについて検討したい。