| 1. |
Kato K, The role of sex chromosomes in egg formation and the mechanism of age-related aging of the endometrium, The 63rd Annual Congress & The 10th International Symposium of TAOG, 2024, 2024.03. |
| 2. |
Murakami Y, Katsuchi D, Matsumoto T, Kawahara A, Akiba J, Kato K, Nishio S, Yanaihara N, Okamoto A, Kuwano M, Ono M, Cell Cycle and Checkpoints(P-1070); Y-box binding protein 1 YBX1 promotes cell growth in its close association with cyclin A 1 in ovarian cancer, 第82回日本癌学会学術総会, 2023.09. |
| 3. |
Kiyokoba R, Kamura S, Sugiura T, Hachisuga N, Sakai A, Ogawa M, Fujita Y, Kato K, Treatment outcome and fetal treatment indications for congenital diaphragmatic hernia managed at our hospital, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］The prognostic factors for congenital diaphragmatic hernia（CDH）include the severity of the disease, fetal complications, and the number of cases experienced by the facility. Severe cases are life threatened and fetoscopic endoluminal tracheal occlusion（FETO）is performed at the National Center for Child Health and Development in Japan. In this study, we examined the treatment outcome for CDH managed at our hospital and the percentage of patients eligible for FETO. ［Methods］From 2006 to 2020, 69 cases were diagnosed prenatally and treated in the neonatal period at our hospital. Treatment outcome were retrospectively examined using medical records. Multiple malformations and chromosomal disorders were excluded, and FETO subjects were based on the TOTAL trial criteria., ［Results］Sixty-three cases were included in this study（55 left-sided, 7 right-sided, 1 bilateral）. The median gestational age at diagnosis, at delivery, and median birthweight were 27.0 weeks, 37.6 weeks, and 2653 g, respectively. Overall survival to hospital discharge was 52/63（83％）and left- and right sided CDH was 47/55（86％）and 5/7（71％）, respectively. Survival to hospital discharge for left-sided CDH in severe and moderate was 5/8（63％）and 18/21（86％）, respectively. Cases eligible for FETO were 5/8（63％）with severe left-sided CDH（less than 30 weeks）and 20/21（95％）with moderate cases（less than 32 weeks）. ［Conclusion］The overall treatment outcome for moderate to severe cases at our hospital was comparable to previous reports, including those who underwent FETO. However, for extreme severe cases（O/E LHR＜15％）, FETO should be considered.. |
| 4. |
Hachisuga N, Takeuchi Y, Sugiura T, Kamura S, Kiyokoba R, Sakai A, Ogawa M, Fujita Y, Okugawa K, Yahata H, Kato K, The efficacy of our management policy of pregnancy after abdominal trachelectomy, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］We aimed to confirm the outcome of pregnancy after abdominal trachelectomy（AT）which was managed at a single institution, and to retrospectively examine the management policy for pregnancy after AT. ［Methods］The pregnant women after AT and delivered at our hospital were included in this study. In our hospital, the patients after AT were routinely hospitalized after 30 weeks for anticipated acute bleeding from vaginal varices, even if they did not have any symptoms. In this study, we retrospectively examined the incidence of adverse events according to gestational age and pregnancy outcomes from the medical records. Additionally, the efficacy of our management policy for pregnancy after AT was re-considered. ［Results］Between 2008 and 2021, 38 patients after AT delivered in our hospital. Of these, 22 patients were hospitalized with symptoms, such as genital bleeding, rupture of membrane and uterine contraction, while 16 patients were asymptomatic and routinely hospitalized after 30 weeks. The incidence of preterm delivery, preterm premature rupture of membranes and genital bleeding was 68.4％, 42.1％, 47.4％, respectively. There were no cases requiring emergency blood transfusion against sudden genital bleeding. ［Conclusion］Pregnancy after AT was associated with high incidence of premature birth, premature rupture of membranes, and genital bleeding. On the other hand, routine hospitalization after 30 weeks against sudden genital bleeding seems not needed as the management of pregnancy after AT.. |
| 5. |
Yagi H, Onoyama I, Asanoma K, Kawakami M, Hachisuga K, Maenohara S, Kodama K, Yasunaga M, Ohgami T, Yahata H, Kato K, Tumor-derived ARHGAP35 mutations enhance the Ga13-Rho signalling axis in human endometrial cancer, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］Dysregulated G-protein coupled receptor（GPCR）signaling is involved in the progression of human cancers. The heterotrimeric G protein Gα13 is highly expressed in various human cancers and regulates diverse cancer-related cellular functions by activating Rho. Here we evaluated the novel mechanisms by which Gα13-Rho signaling axis promotes cell proliferation of human endometrial cancer（EMCA）. ［Methods］Gα13 expression in human endometrial tissues were examined by immunohistochemistry. All patients involved in this study provided written informed consent. We used chimeric G-proteins and GPCRs activated solely by artificial ligands to selectively activate the signalling pathway downstream of Gα13. Signaling pathways and transcriptional activity regulated by Ga13 were examined by Western blot, qPCR and luciferase assay, using human EMCA cells, HOUA and HWCA. ［Results］Gα13 was highly expressed in human EMCA tissues compared with normal endometrial tissues. No histological subtype specificity was observed for Gα13 expression in EMCA. Gα13 activation promoted transcriptional activity of AP1 through Rho, leading to enhanced proliferation of EMCA cells. Of interest, The Cancer Genome Atlas revealed RhoGAP regulatory protein ARHGAP35 was mutated at high frequency as 24％ in EMCA. In Rho pull-down assay, the RhoGAP activity was impaired by 57 of 124 tumor-derived ARHGAP35 mutations. These loss-of-function mutations comprised 24 missense mutations, 19 nonsense mutations, 12 frame-shift mutations and two in-flame deletion. These data suggest that ARHGAP35 mutations found in human EMCA are involved in Gα13-mediated activation of Rho and AP1. ［Conclusion］Our findings suggest that Gα13-Rho signalling axis provide novel therapeutic opportunities for EMCA.. |
| 6. |
Maenohara S, Kawakami M, Hachisuga K, Kodama K, Yagi H, Yasunaga M, Ohgami T, Onoyama I, Okugawa K, Asanoma K, Yahata H, Kato K, Treatment outcome in cervical cancer patients with para-aortic lymph node metastases, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］In the FIGO 2018 classification, stage IIIC2 cervical cancer is indicated by para-aortic lymph node（PAN）metastasis. Therefore, this stage includes various statuses regarding local progression, and there are no clear criteria for treatment. In this study, we retrospectively examined the treatment methods and prognosis of patients with stage IIIC2 cervical cancer at our hospital. ［Methods］The outcomes of patients with cervical cancer diagnosed at our hospital between 2007 and 2020 who had PAN metastasis and who completed first-line treatment were selected. The diagnosis of metastasis was made pathologically or graphically using CT or PET/CT. ［Results］PAN metastasis was observed in 90 cases, 59 of which corresponded to stage IIIC2. The treatment modalities were radiation therapy（RT）in 39 cases（25 with concurrent chemoradiotherapy［CCRT］, 8 with RT plus chemotherapy, and 6 with RT alone）, surgery（OP）in 19 cases（adjuvant therapy：chemotherapy in 10 cases, CCRT in 5 cases, CCRT plus chemotherapy in 3 cases, no postoperative therapy in 1 case）, and chemotherapy in 1 case. The 3-year recurrence-free rate was 19.7％ in the OP group, versus 38.1％ in the RT group. Furthermore, in the RT group, patients who received CCRT had slightly superior 3-year survival rate（69.8％）and recurrence-free rates（43.2％）than those who received OP. ［Conclusion］In patients with cervical cancer and PAN metastasis, it was suggested that CCRT may provide better outcomes than OP. Further accumulation of cases with PAN metastasis is desirable in the future.. |
| 7. |
Hachisuga K, Kawakami M, Maenohara S, Kodama K, Yagi H, Ohgami T, Yasunaga M, Onoyama I, Okugawa K, Asanoma K, Yahata H, Kato K, Clinical significance of CD8 and PD-L1 expression in endometrial endometrioid carcinoma, G1 with DNA mismatch repair protein loss, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］Endometrial cancer with DNA mismatch repair protein loss（MMR loss）is classified as an intermediate prognostic group in the molecular classification of endometrial cancer. In previous studies, the clinical significance of MMR loss for the prognosis was a controversial issue in endometrial cancer, probably because high-grade endometrial adenocarcinomas were included in these studies and endometrial cancer with MMR loss is a heterogeneous population. The purpose of this study was to evaluate the expression of CD8 and PD-L1 in endometrial endometrioid carcinoma, G1 with MMR loss and relate it to clinicopathological features. ［Methods］We retrospectively analyzed tumor samples from 67 patients with endometrial endometrioid carcinoma, G1 with MMR loss（＜40 years：n=3, 40-59 years：n=42, ≥60 years：n=22）. ［Results］In our study, 40 cases of MLH1/PMS2 loss and 27 cases of MSH2/MSH6 loss were observed. Although 23（34.3％）PD-L1-positive cases were observed, there was no significant association between PD-L1 expression and clinicopathological features. The patients with low intraepithelial CD8 expression had significantly more frequent deep myometrial invasion, and the elderly group（≥60 years）significantly more frequently showed low stromal CD8 expression. In Kaplan-Meier analysis, the patients with low intraepithelial or stromal CD8 expression showed shorter PFS than those with high intraepithelial or stromal CD8 expression, but not statistically significant. ［Conclusion］In endometrial endometrioid carcinoma, G1 with MMR loss, low intraepithelial or stromal CD8 expression was associated with shorter PFS, but not statistically significant. Further studies are needed, including the patients administered with immune checkpoint inhibitors.. |
| 8. |
To G, Hachisuga N, Sugiura T, Kamura S, kamura S, Kiyokoba R, Sakai A, Ogawa M, Fujita Y, Kato K, A case of exacerbated lumbar-vulvar venous malformation during pregnancy, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Introduction］Vulvar venous malformation develops and exacerbates during pregnancy due to vasodilatory effects of estrogen and compression of the inferior vena cava by the pregnant uterus. We experienced a case of lumbar-vulvar venous malformation that worsened during pregnancy and improved after delivery. ［Case］41 years old, 2 gravida, 0 para. At the age of 25, the patient was diagnosed with vulvar venous malformation, complaining of perineal pain, and underwent sclerotherapy three times and resection of the vulvar venous malformation. Although the venous malformation lesion in the vulva remained, the perineal pain improved. At the age of 41, she became pregnant and at 28 weeks, perineal pain increased and walking difficulty was occurred. She felt a tenderness at the left side of her vulva where the 3 cm mass was palpable. To examine if her venous malformation in her pelvis were exacerbated with pregnancy, a pelvic MRI was performed, showing enlarged the vulvar and perirectal venous malformation. To prevent massive bleeding from the vulvar and perirectal venous malformation by injury concerning vaginal delivery, elective caesarean section was performed at 38 weeks. During laparotomy, no obvious venous malformations were observed around the uterus, bilateral adnexa, bladder-uterine fossa, and Douglas fossa, and intraoperative bleeding was 905 ml. The pain in the vulva improved immediately after delivery, and the vulvar mass disappeared. ［Conclusion］In a case of exacerbated lumbar-vulvar venous malformation with pregnancy, a pelvic MRI may be useful to decide the way of delivery.. |
| 9. |
Morishita H, Kiyokoba R, Kamura S, Sakai A, Hachisuga N, Sugiura T, Ogawa M, Fujita Y, Kato K, Mitochondrial dysfunction-induced high hCG associated with development of fetal growth restriction and pre-eclampsia with fetal growth restriction, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］We investigated how mitochondrial dysfunction and high hCG expression affected placenta in unexplained fetal growth restriction and preeclampsia with fetal growth restriction. ［Methods］We evaluated mitochondrial translation, hCGβ, antiangiogenetic factors, and inflammatory cytokine expression in 48 placenta samples（Control, n=15；fetal growth restriction, n=15；preeclampsia with fetal growth restriction, n=18）. We studied whether high hCGβ affected antiangiogenic factors and cytokine expression in vitro. Furthermore, we investigated how inhibition of mitochondrial translation increased hCGβ expression in cell lines. ［Results］We observed elevated expression of hCGβ and growth differentiation factor15 mRNA and protein levels in placenta of both disease states. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα were all elevated at the mRNA level. However, expression of the mitochondrial translational regulator p32 was predominantly reduced in both disease groups, which results in reduced levels of mtDNA-encoded COXI and COXII protein expression per mtDNA. In vitro, treatment of cell lines with high hCG levels increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via p38 and JNK kinase pathways. Treatment of JEG3 cells with mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α and increased IL8 and TNFα mRNA expression. ［Conclusion］This study revealed that mitochondrial translational dysfunction and high hCG expression play a critical role in the development of fetal growth restriction and preeclampsia with fetal growth restriction.. |
| 10. |
Onoyama I, Kato M, Kawakami M, Hachisuga K, Maenohara S, Kodama K, Yagi H, Yasunaga M, Ohgami T, Asanoma K, Yahata H, Kato K, Epigenetic characterization of ovarian high-grade serous carcinoma by genome-wide 5-hydroxymethylcytosine sequencing, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］Both DNA methylation in promoter regions of tumor-suppressor genes and genome-wide hypomethylation are epigenetic characteristics in cancer cells, however, the mechanisms and biological significance of DNA hypomethylation in cancer cells are still unclear. Here, we investigated 5-hydroxymethylcytosine（5hmC）levels and genome-wide distributions in ovarian cancers and tried to unveil the roles of an intermediate products of DNA demethylation processes. ［Methods］5hmC levels were examined by immunohistochemistry and ELISA. Genome-wide 5hmC distributions were investigated by NGS. Ovarian cancer specimens from 138 patients treated between 2002 and 2016 were included in these experiments. Informed consent was obtained from all patients prior to enrollment in the study. The ethics committee of our facility approved the study protocol. ［Results］Ovarian cancer cells showed higher levels of 5hmC compared with epithelial cells of normal ovary and fallopian tube. Notably, high-grade serous carcinomas（HGSCs）with lymph-node（LN）metastasis showed significantly higher levels of 5hmC compared with those without LN metastasis. Genome-wide 5hmC sequencing showed 5hmCs were adjacent to various oncogenes in HGSC cases regardless of LN metastasis, however, comparative gene ontology analysis revealed some characteristic pathways specific to HGSCs with LN metastasis. ［Conclusion］Epigenetic changes of 5hmC levels and their distributions could be implicated in LN metastasis in ovarian HGSCs.. |
| 11. |
Yasunaga M, Kawakami M, Hachisuga K, Maenohara S, Kodama K, Yagi H, Ohgami T, Onoyama I , Okugawa K，Asanoma K,Yahata H, Kato K, Decision making of subsequent therapy for recurrent or advanced endometrial cancer patients based on platinum-free interval, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］To evaluate the progression-free survival（PFS）and overall response rate（ORR）of patients with recurrent endometrial cancer（REC）or advanced endometrial cancer（AEC）retreated with platinum-containing chemotherapy based on the platinum-free interval（PFI）. We compared our results with those reported in the Keynote-775 study（which used pembrolizumab plus lenvatinib）. ［Methods］A retrospective analysis was conducted on 65 patients with REC or AEC retreated with platinum-containing regimens between 2005 and 2020 at our hospital. Various clinicopathological variables were analyzed：（1）age；（2）performance status；（3）histology；（4）history of pelvic irradiation in the adjuvant setting；（5）PFI；（6）chemotherapy regimen；（7）PFS and overall survival after retreatment with platinum-containing chemotherapy；（8）best ORR. Survival analyses were done using Kaplan-Meier curves with log-rank tests. ［Results］The best ORR and PFS was 43.3％ and 9.5 months, respectively, in REC AEC patients showing a PFI ≥ 6 months. These results were comparable with those of patients treated with pembrolizumab plus lenvatinib. The best ORR and PFS of patients showing a PFI＜6 months were inferior to those of patients treated with pembrolizumab plus lenvatinib. ［Conclusion］We should choose pembrolizumab plus lenvatinib for REC or AEC patients showing a PFI＜6 months. For a PFI ≥6 months, we can use pembrolizumab plus lenvatinib or platinum-containing chemotherapy depending on degree of residual side-effects associated with cytotoxic agents.. |
| 12. |
Kawakami M, Yahata H, Hachisuga K, Maenohara S, Kodama K, Yagi H, Yasunaga M, Ohgami T, Onoyama I, Asanoma K，Kato K, The predictive clinical course of positive peritoneal cytology alone in early stage endometrial cancer, 第75回日本産科婦人科学会学術講演会, 2023.05, ［Objective］Peritoneal cytology was excluded from the staging system from the 2008 FIGO classification in endometrial cancer, and our treatment strategy is no adjuvant therapy for the patients with early-stage endometrial cancer with only peritoneal positive cytology without any other risk factor. However, it is still now controversial whether positive peritoneal cytology is an independent prognostic factor or not. To evaluate the adequacy of our therapeutic strategy, we reviewed our cases. ［Methods］We performed 722 operations for endometrial cancer between 2005 and 2018. 400 patients were stage IA, and 34 of 400 had peritoneal positive cytology. 22 of 34 were high-grade histological subtype, who received adjuvant therapy. Remaining 12 patients with peritoneal positive cytology alone did not receive adjuvant therapy. We retrospectively evaluated the clinical outcome of these 12 patients. ［Results］The histological subtype was G1 in 11 patients and G2 in 1. Seven had no myometrial invasion and five had less than half myometrial invasion. Three patients had lympho-vascular space invasion. One of 12 patients（8％）experienced recurrence in the pelvic lymphnode after 38 months during a median follow-up period of 80 months（range, 11-143 months）. This patient had received paclitaxel plus carboplatin regimen, and is now alive without disease for more than ten years. ［Conclusion］Only peritoneal positive cytology doesn't seem to affect the prognosis without adjuvant therapy. Prospective randomized study is warranted to determine the standard of care for patients with only peritoneal positive cytology endometrial cancer.. |
| 13. |
Onoyama I, Kato M, Kawakami M, Maenohara S, Kodama K, Yagi H, Asanoma K, Kato K, Epigenetic characterization of ovarian serous carcinoma with lymphnode metastasis by 5-hydroxymethylcytosine sequencing, 第81回日本癌学会学術総会, 2022.09, ObjectiveTET family proteins-dependent conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) was recently found to be required for DNA demethylation. We investigated 5hmC levels and genome-wide distributions in ovarian cancers and tried to unveil the roles of an intermediate products of DNA demethylation processes.MethodsOvarian cancer specimens from 138 patients treated in Kyushu University Hospital between 2002 and 2016 were included. Informed consent was obtained from all patients prior to enrollment in the study. The ethics committee of Kyushu University Graduate School approved the study protocol.ResultsSerous carcinomas with lymph-node metastasis showed significantly higher 5hmC level compared with those without lymph-node metastasis. Genome-wide 5hmC sequencing showed 5hmCs were close to many oncogenes in cases of serous carcinomas with lymph-node metastasis. Also, GO analysis revealed some characteristic pathways specific to serous carcinomas with lymph-node metastasis.ConclusionEpigenetic changes of 5hmC levels and their distributions could be implicated in lymph-node metastasis in ovarian serous carcinomas.. |
| 14. |
Kido S, Kamura S, Nakahara K, Hachisuga N, Sakai A, Sugitani M, Hara E, Fujita Y, Kato K, Changes in unfractionated heparin requirements over time during pregnancy, 第74回日本産科婦人科学会学術講演会, 2022.08, ［Objective］Although pregnant women with a high risk of thrombosis sometimes need long-term continuous intravenous administration of unfractionated heparin, the change in heparin dose during pregnancy remains unknown. The aim of this study was to examine the changes in unfractionated heparin requirements during pregnancy.
［Methods］This retrospective observational study performed between April 2012 and September 2021 included pregnant women who received continuous intravenous unfractionated heparin for 4 weeks or longer. The dose of unfractionated heparin was adjusted according to the target activated partial thromboplastin time, and the daily dose（units/kg/day）was observed for each week. The gestational week at which the heparin requirement changed（inflection point）was mathematically calculated.
［Results］Nineteen pregnancies in 18 women were analyzed. Continuous heparin administration was indicated in 11 pregnancies with deep vein thrombosis（DVT）, 7 pregnancies after the Fontan procedure, and 1 pregnancy after mechanical valve replacement. Six pregnancies with DVT had a thrombophilia（Antithrombin III deficiency, protein S/C deficiency, or beta-thalassemia）. Heparin requirements increased in all pregnancies until the second trimester, and it tended to decrease in the third trimester. The inflection point was calculated to be 27 weeks of gestation. After 34 weeks of gestation, heparin requirements decreased in all pregnancies and at term, became equal to early pregnancy levels. ［Conclusion］The requirement for continuous intravenous administration of unfractionated heparin in pregnant women increases in the second trimester of pregnancy and tends to decrease in the third trimester.. |
| 15. |
Satomi Y, Hara E, Kamura S, Hachisuga N, Sakai A, Sugitani M, Kido S, Fujita Y, Kato K, A case of gestational diabetes mellitus diagnosed as type 1 diabetes after delivery, 第74回日本産科婦人科学会学術講演会, 2022.08, Gestational diabetes mellitus（GDM）is known as impaired glucose tolerance due to the effects of human placental lactogen and other factors. In some cases of GDM, abnormal glucose tolerance may become apparent during pregnancy,
leading to the diagnosis of type 1 diabetes. We report a case of GDM diagnosed with type 1 diabetes after delivery. The
patient was a 30-year-old primipara with a family history of type 2 diabetes. At 28 weeks of gestation, she underwent a 75g OGTT, and was diagnosed with GDM. HbA1c was 5.5 ％, the anti-glutamic acid decarboxylase（GAD）antibody was negative, and immunoreactive insulin was 20.7 µ U/mL. Insulin therapy was started at 34 weeks of gestation due to poor glycemic control. She was admitted to a hospital at 39 weeks of gestation. Her blood glucose was 180 mg/dl, which was considered difficult to control, and she was transferred to our hospital. On admission, continuous intravenous insulin was initiated, after which the baby was vaginally delivered. The insulin dose was increased to 3 U/min and the blood glucose was 175-200 mg/dl during delivery. The anti-GAD antibody was positive and C-peptide was 0.02 ng/dl, leading to the diagnosis of type 1 diabetes developed during pregnancy. Cases diagnosed and managed as poorly-controlled GDM may have a rapid onset of type 1 diabetes, and it can be difficult to distinguish each other. Type 1 diabetes should be diagnosed early by measuring islet-related antibodies and evaluating insulin secretion capacity in case of poor glycemic control.. |
| 16. |
Sakai A, Kamura S, Hachisuga N, Sugitani M, Hara E, Kido S, Fujita Y, Kato K, Comparison of two management for preeclampsia and superimposed preeclampsia：a single center analysis, 第74回日本産科婦人科学会学術講演会, 2022.08, ［Objective］Although advancement of maternal and neonatal care has improved their prognosis, hypertensive disorders of pregnancy is still a leading cause of maternal and neonatal morbidity and mortality. Therefore, evidence to establish a better management for the disorder is in need. We evaluated pregnancy outcome in patients with preeclampsia（PE）and superimposed preeclampsia（SPE）which were distinctly managed by two strategies.
［Methods］A retrospective analysis was performed on women with PE or SPE treated at Kyushu university hospital from January 2018 to March 2019（Period 1：P1）and from October 2019 to March 2021（Period 2：P2）. During P1, antihypertensive therapy was started when blood pressure was higher than 160/110mmHg, and pregnancies with severe PE/SPE beyond 34 weeks of gestation were terminated without exception. On the other hand, during P2, antihypertensive drugs were administered when blood pressure was higher than 140/90mmHg and attempted to extend gestation until 37 weeks of gestation. Maternal and neonatal outcomes were analyzed and compared between two periods.
［Results］Fourty five and 70 cases of PE or SPE were managed during P1 and P2, respectively. Background of the mothers was similar between two groups. Compared with P1, gestational week of delivery was significantly higher in P2. Birth weight of the newborns tended to be larger, and duration of neonatal intensive care unit admission was significantly
shorter in the newborns during P2.
［Conclusion］Aggressive antihypertensive therapy with cautious observation for PE/SPE can extend pregnancy duration, and may benefit the babies born from hypertensive mothers.. |
| 17. |
Tanaka H, Yasunaga M, Hachisuga K, Yasutake N, Maenohara S, Yagi H, Ohgami T, Onoyama I, Okugawa K, Asanoma K, Yahata H, Kato K, Clinical outcome of platinum sensitive ovarian cancer patients after PARP inhibitors maintenance therapy, 第74回日本産科婦人科学会学術講演会, 2022.08, ［Objective］Platinum responsiveness has been recognized as a surrogate marker for usefulness of PARP inhibitors for ovarian cancer. However, there has been a limited data about effectiveness of re-treatment by platinum doublet for platinum-sensitive relapse ovarian cancer patients under PARP inhibitors maintenance therapy. Herein, we report six platinum-sensitive relapse cases under PARP inhibitors maintenance therapy with a focus on platinum responsiveness. ［Methods］A retrospective analysis was conducted on six platinum-sensitive relapse ovarian cancer patients of 35
patients treated with PARP inhibitors maintenance therapy between 2018 and 2020 at our hospital. The data of best overall response based on RECIST criteria, accompanied by clinical information, were collected.
［Results］The patient’s age ranged 42 -77 years old. One of 6 patients performed by BRCA analysis had germline BRCA 1 mutation. Median platinum free interval was estimated 11.3 months on 6 patients. Three patients received paclitaxel
plus carboplatin as post progression therapy. The others were treated by other platinum-based regimens such as docetaxel plus cisplatin, docetaxel and carboplatin, and gemcitabine and carboplatin respectively. Overall response rate
was 16.6 ％.
［Conclusion］Response rate has been reported to be 30 - 60 ％ in treating conventional platinum sensitive relapse ovarian cancer patients with platinum doublet. The best overall response rate of re-treatment by platinum doublet for platinum-sensitive relapse ovarian cancer patients with PARP inhibitors failure were inferior to that of conventional platinum sensitive relapse patients by our small case series. Another treatment strategy may be urgently needed to treat platinum-sensitive relapse ovarian cancer after PARP inhibitors maintenance therapy.. |
| 18. |
Yoshida S, Asanoma K, Yagi H, Onoyama I, Okugawa K, Yahata H, Kato K, Fibronectin mediates activation of stromal fibroblasts by SPARC in endometrial cancer cells, 第74回日本産科婦人科学会学術講演会, 2022.08, ［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.. |
| 19. |
Asanoma K, Yagi H, Onoyama I, Kodama K, Kawakami M, Yasutake N, Maenohara S, Yasunaga M, Ohgami T, Okugawa K, Yahata H, Kato K, BHLHE40 regulates glycolysis and oxidative phosphorylation mediated by a phosphatase-AMPK axis in endometrial cancer cells, 第74回日本産科婦人科学会学術講演会, 2022.08, ［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 glycolysis and oxidative phosphorylation（OXPHOS）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 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. PPM1 family of phosphatase was examined to regulate AMPK activity. Transcriptional regulation of PPM1 family by BHLHE40 was also examined using a reporter assay.
［Results］Knockdown of BHLHE40 in the cancer cells resulted in upregulation of glycolysis accompanied with activaiton 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 discovered BHLHE40-regulated phosphatase suppressed AMPK activity.
［Conclusion］BHLHE40 is suggested to regulate the activity of AMPK to control the 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.. |
| 20. |
Onoyama I, Kato M, Kawakami M, Kodama K, Yagi H, Asanoma K, Kato K, Downregulation of 5-hydroxymethylcytosine is associated with the progression of cervical intraepithelial neoplasia, 第80回日本癌学会学術総会, 2021.10. |
| 21. |
Asanoma K, Yagi H, Onoyama I, Yoshida S, Kodama K, Tomonobe H, Yasutake N, Yasunaga M, Ohgami T, Okugawa K, Yahata H, Kato K, BHLHE40 regulates glycolysis and oxidative phosphorylation in endometrial cancer cells, 第73回日本産科婦人科学会学術講演会, 2021.04, ［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.. |
| 22. |
Onoyama I, Kato M, Kawakami M, Yoshida S, Kawamura K, Yagi H, Asanoma K, Yahata H, Kato K, Downregulation of 5-hydroxymethylcytosine is associated with the progression of cervical intraepithelial neoplasia, 第73回日本産科婦人科学会学術講演会, 2021.04, ［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.. |
| 23. |
Gα₁₃-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer. |
| 24. |
Kaoru Okugawa, Shusaku Inoue, Keisuke Kodama, Shinichiro Yamaguchi, Hironori Kenjo, Hiroshi Yagi, Tatsuhiro Ohgami, Masafumi Yasunaga, Ichirou Onoyama, Eisuke Kaneki, Hideaki Yahata, Kiyoko Kato, Safety evaluation of abdominal trachelectomy in patients with cervical cancer with tumors ≥2 cm：A single-institution, retrospective analysis, 第71回日本産科婦人科学会学術講演会, 2019.04, 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.. |
| 25. |
Hiroshi Yagi、Ichirou Onoyama、Kazuo Asanoma、Masafumi Yasunaga、Keisuke Kodama、Shusaku Inoue、Shinichiro Yamaguchi、Tatsuhiro Ohgami、Eisuke Kaneki、Kaoru Okugawa、Hideaki Yahata、Kiyoko Kato, GEP oncogene induces epithelial-mesenchymal transition in ovarian cancer through LATS1 proteolysis, 第71回日本産科婦人科学会学術講演会, 2019.04, 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.. |
| 26. |
Onoyama I, Sonoda K, Mechael,R Green, Kato K, Poster Exhibition; Oncogenic BRAF promotes global DNA hypomethylation via upregulation of DNA demethylase TET3 level
, The 5th Biennial Meeting of Asian Society of Gynecologic Oncology (ASGO), 2017.11, 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.
. |
| 27. |
Kodama K, Sonoda K, Kijima M, Yamaguchi S, Yagi H, Yasunaga M, Ogami T, Onoyama I, Kaneki E, Okugawa K, Kato K, Retrospective analysis of 14 leiomyosarcoma cases treated in our institution, The 5th Biennial Meeting of Asian Society of Gynecologic Oncology (ASGO), 2017.11, 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. . |
| 28. |
Kato K, Study of endometrial cell aging, The 22nd Seoul International Symposium, 2017.09. |
| 29. |
Kitade S, Onoyama I, Yagi H, Yoshida S, Kato M, Tsunematsu R, Asanoma K, Sonoda K, Kobayashi H, Hata K, Kiyoko Kato, FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors.
, 第69回日本産科婦人科学会学術講演会, 2017.04, 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 |
| 30. |
Yagi H, Kodama K, Yasunaga M, Ogami T, Onoyama I, Asanoma K, Sonoda K, Kato K, The pivotal role of LATS1 in ovarian cancer progression.
, 第69回日本産科婦人科学会学術講演会, 2017.04. |
| 31. |
Kiyoko Kato, Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms., 第54回日本癌治療学会学術総会, 2016.10. |
| 32. |
Kiyoko Kato, Identification and characterization of human trophoblast stem-like cells., The 102nd Annual Congress of Korean Society of Obstetrics and Gynecology, 2016.09. |
| 33. |
加藤 聖子, The current state of female doctors in Japanese Obstetrics and Gynecology.
, Ludwig Boltzmann Forum／Woman’s development and ledership, 2016.05. |
| 34. |
Kiyoko Kato, Identification and characterization of endometrial cancer stem-like cells.
, The 4th Biennial Meeting of Asian Society of Gynecologic Oncoligy, 2015.11. |
| 35. |
Hiroshi Yagi, Kenzo Sonoda, Kiyoko Kato, The Gα12/13-YAP signaling axis driving proliferation of ovarian cancer cells., 第67回日本産科婦人科学会学術講演会, 2015.04. |
| 36. |
Kiyoko Kato, Identification of endometrial cancer stem-like cells as a target for cancer therapy., The 54th Annual Congress & The 4th International Symposium of Taiwan Association of Obstetrics and Gynecology, 2015.03, Stem-like cell subpopularions,side-population(SP)cells,have been identified in several tumor types based on their ability to remove intracellular Hoechst 33342,a fluorescent dye,We have demonstrated that endometrial cancer SP cells possess cancer stem-like cell features including self-renewal capacity, enhanced migration,and bi-potential development(tumor cells and stroma-like cells).We showed that sodium butyrate,a histone deacetylase(HDAC)inhibitor,inhibited the self-renewal capacity of endometrial cancer SP cells by inducing a DNA damage response and salinomycin suppressed migration and proliferation of endometrial cancer SP cells by inducing apoptosis.Recently,we have demonstrated that the level of SPARC(secreted protein acidic and rich in cysteine),which is a target molecule of nab-paclitaxel,was enhanced in endmetrial cancer SP cells.SPARC was overexpressed in poorly differentiated endometrioid,clear and serous adenocarcinoma,but not in normal endometrial tissue.These results suggest that HDAC inhibitors,salinomycin and nab-paclitaxel would be promising drugs for endometrial cancer stem-like cells.. |
| 37. |
Hiroshi Yagi, Kenzo Sonoda, Hiroaki Kobayashi, Kiyoko Kato, IS Award Candiate：The role of GEP oncogenes, G12 and G13, in the progression of ovarian cancer．
, 第66回日本産科婦人科学会学術講演会, 2014.04. |
| 38. |
KAZUO ASANOMA, Hiroaki Kobayashi, Norio Wake, Kiyoko Kato, Transcriptional factors, DEC1 and DEC2 cooperatively regulate epithelial-to-mesenchymal transition of uterine endometrial cancer cells.
, 第66回日本産科婦人科学会学術講演会, 2014.04. |
| 39. |
加藤聖子, Development of new cancer therapy by targeting endometrial cancer stem cells, 第72回日本癌学会学術総会, 2013.10. |
