Publications by authors named "Masaki Mandai"

187 Publications

Diagnostic Value of DCE-MRI for Differentiating Malignant Adnexal Masses Compared with Contrast-enhanced-T1WI.

Magn Reson Med Sci 2021 Sep 3. Epub 2021 Sep 3.

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine.

Purpose: To compare the diagnostic performance of dynamic contrast-enhanced-MR (DCE-MR) and delayed contrast-enhanced (CE)-MRI added to unenhanced MRI, including diffusion weighted image (DWI) for differentiating malignant adnexal tumors, conducting a retrospective blinded image interpretation study.

Methods: Data of 80 patients suspected of having adnexal tumors by ultrasonography between April 2008 and August 2018 were used for the study. All patients had undergone preoperative MRI and surgical resection at our institution. Four radiologists (two specialized in gynecological radiology and two non-specialized) were enrolled for blinded review of the MR images. A 3-point scale was used: 0 = benign, 1 = indeterminate, and 2 = malignant. Three imaging sets were reviewed: Set A, unenhanced MRI including DWI; Set B, Set A and delayed CE-T1WI; and Set C, Set A and DCE-MRI. Imaging criteria for benign and malignant tumors were given in earlier reports. The diagnostic performance of the three imaging sets of the four readers was calculated. Their areas under the curve (AUCs) were compared using the DeLong method.

Results: Accuracies of Set B were 81%-88%. Those of Set C were 81%-85%. The AUCs of Set B were 0.83 and 0.89. Those of Set C were 0.81-0.86. For two readers, Set A showed lower accuracy and AUC than Set B/Set C (less than 0.80), although those were equivalent in other readers. No significant difference in AUCs was found among the three sequence sets. Intrareader agreement was moderate to almost perfect in Sets A and B, and substantial to almost perfect in Set C.

Conclusion: DCE-MR showed no superiority for differentiating malignant adnexal tumors from benign tumors compared to delayed CE-T1WI with conventional MR and DWI.
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http://dx.doi.org/10.2463/mrms.mp.2021-0003DOI Listing
September 2021

A Case of Torsion in an Otherwise-Normal Ovary with a Giant Hematosalpinx Larger than Enlarged Ovary: Utilization of Diagnostic Laparoscopy for the Accurate Diagnosis.

Case Rep Obstet Gynecol 2021 23;2021:1371611. Epub 2021 Aug 23.

Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto City, Kyoto, Japan 606-8507.

We report a case of torsion in an otherwise-normal ovary with a giant hematosalpinx. A 23-year-old woman presented with complaints of abdominal pain and nausea. At initial visit, there was few abnormal findings of imaging tests, and we made a diagnosis of ovarian hemorrhage. Three days later, she came back with increased symptoms, and we detected the mass of a complex solid cystic structure with a unilocular cyst much larger than solid component. A diagnostic laparoscopy was performed immediately, and we could make a diagnosis of torsion in an otherwise-normal ovary with a giant hematosalpinx. We performed a salpingectomy and could preserve her ovary. This is the first case of torsion in an otherwise-normal ovary with a giant hematosalpinx which enlarged to a greater extent than the ovary.
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http://dx.doi.org/10.1155/2021/1371611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408003PMC
August 2021

PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma.

Cancer Sci 2021 Aug 31. Epub 2021 Aug 31.

Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, although the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.
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http://dx.doi.org/10.1111/cas.15125DOI Listing
August 2021

Surveillance of radical hysterectomy for early-stage cervical cancer in the early experienced period of minimally invasive surgery in Japan.

Int J Clin Oncol 2021 Aug 25. Epub 2021 Aug 25.

Department of Gynecology and Obstetrics, Tohoku University Graduate School of Medicine, Sendai, Japan.

Objective: The purpose of our study was to conduct a detailed survey of radical hysterectomy in Japanese patients with early-stage cervical cancer, and to compare oncologic outcomes between open and minimally invasive radical hysterectomy.

Methods: In Japan during 2015, the medical records of 929 patients with FIGO stage IB1 and IIA disease treated with radical hysterectomy were retrospectively reviewed. We assessed patients' characteristics, disease-free survival (DFS), overall survival (OS) and prognostic factors for survival.

Results: The median patient age was 44 (20-80) years. Most patients (94.4%) had stage IB1 disease. Of the patients who underwent radical hysterectomy, 91.2% underwent open surgery and 8.8% underwent minimally invasive surgery (MIS). The median follow-up period was 40.8 months (range, 0.49-51.1 months). The rate of DFS and OS at 4 years in all patients was 88.3% and 96.4%, respectively. Multivariate analysis identified age (≥ 47), adenocarcinoma histology, tumor size (≥ 2 cm), parametrial invasion, positive lymph node metastasis and institutional accreditation as independent predictors of recurrence, and adenocarcinoma, other cell types, and positive lymph node metastasis as independent predictors of death. Oncologic outcomes in all patients were similar between open and MIS, including DFS and OS.

Conclusion: The survival rate of the Japanese patients underwent radical hysterectomy for early-stage cervical cancer was favorable. No significant differences were observed for DFS and OS between open and MIS performed by a limited number of surgeons at a limited number of facilities in Japan. Further investigations are required to identify the appropriate patients might benefit from MIS.
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http://dx.doi.org/10.1007/s10147-021-02017-4DOI Listing
August 2021

A 36 kg Giant Ovarian Fibroma with Meigs Syndrome: A Case Report and Literature Review of Extremely Giant Ovarian Tumor.

Case Rep Obstet Gynecol 2021 15;2021:1076855. Epub 2021 Aug 15.

Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto city, Kyoto, Japan 606-8507.

Ovarian tumors can get extremely giant to occupy the whole abdominal cavity. We report a case of 36 kg solid ovarian tumor, which was the largest ovarian solid tumor that have been ever reported. A 54-year-old woman presented to our hospital with a chief complaint of markedly distended abdominal wall. Preoperative imaging examinations revealed that most of the tumor was uniform and its density was like that of subcutaneous fat. Pleural effusion was detected in the right thoracic region. We organized a multidisciplinary team and successfully resected the right adnexa. The patient had an uneventful postoperative course, and she was discharged on the 7 postoperative day and diagnosed with a fibroma of the ovary with Meigs syndrome. A comprehensive literature search revealed 48 cases of extremely giant ovarian tumor in these 20 years. Six out of 48 cases are solid. Twelve out of 48 cases are malignant or borderline malignant, and patients' age and tumor size/weight were not related to the frequency of malignancy/borderline malignancy. As many as 4 out of 48 patients died before their first hospital visit or early after surgery. Clinicians should consider a considerable high mortality and frequency of severe surgical complications when planning the treatment strategy for extremely giant ovarian tumors.
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http://dx.doi.org/10.1155/2021/1076855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382553PMC
August 2021

Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types.

JCO Precis Oncol 2021 Aug 11;5. Epub 2021 Aug 11.

Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan.

Homologous recombination DNA repair deficiency (HRD) is associated with sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors in certain cancer types, including breast, ovarian, pancreatic, and prostate. In these cancers, alterations and genomic scar signatures are useful indicators for assessing HRD. However, alterations in other homologous recombination repair (HRR)-related genes and their clinical significance in other cancer types have not been adequately and systematically investigated.

Methods: We obtained data sets of all solid tumors in The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and comprehensively analyzed HRR pathway gene alterations, their loss-of-heterozygosity status, and per-sample genomic scar scores, that is, the HRD score and mutational signature 3 ratio, DNA methylation profiles, gene expression profiles, somatic mutations, sex, and clinical or in vitro response to chemical exposure.

Results: Biallelic alterations in HRR genes other than were also associated with elevated genomic scar scores. The association between HRR-related gene alterations and genomic scar scores differed significantly by sex and the presence of somatic mutations. HRD tumors determined by a combination of indices also showed HRD features in gene expression analysis and exhibited significantly higher sensitivity to DNA-damaging agents than non-HRD cases in both clinical samples and cell lines.

Conclusion: This study provides evidence for the usefulness of HRD analysis in all cancer types, improves chemotherapy decision making and its efficacy in clinical settings, and represents a substantial advancement in precision oncology.A comprehensive pan-cancer analysis on the clinical significance of homologous recombination deficiency.
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http://dx.doi.org/10.1200/PO.21.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373547PMC
August 2021

Diagnostic Accuracy of Magnetic Resonance Imaging for International Federation of Gynecology and Obstetrics 2018 IB to IIB Cervical Cancer Staging: Comparison Among Magnetic Resonance Sequences and Pathologies.

J Comput Assist Tomogr 2021 Aug 16. Epub 2021 Aug 16.

From the Departments of Diagnostic Radiology and Nuclear Medicine Gynecology and Obstetrics, Kyoto University Hospital Department of Radiology, National Hospital Organization Kyoto Medical Center Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Objective: This study aimed to investigate the most accurate magnetic resonance (MR) sequence for tumor detection, maximal tumor diameter, and parametrial invasion compared with histopathologic diagnoses.

Methods: Fifty-one patients with International Federation of Gynecology and Obstetrics 2018 IB1 to IIB cervical cancer underwent preoperative MR imaging and surgical resection. Two radiologists independently evaluated the tumor detection, parametrial invasion, and tumor size in each of T2-weighted image, diffusion-weighted image, and contrast-enhanced T1-weighted image. Results obtained for squamous cell carcinoma (SCC) and adenocarcinoma were also compared.

Results: Neither the tumor detection rate nor parametrial invasion was found to be significantly different among sequences. Tumor size assessment using MR imaging with pathology showed good correlation: r = 0.63-0.72. The adenocarcinoma size tended to be more underestimated than SCC in comparison with the pathologic specimen.

Conclusions: Cervical cancer staging by MR images showed no significant difference among T2-weighted image, diffusion-weighted image, and contrast-enhanced T1-weighted image. Adenocarcinoma was prone to be measured as smaller than the pathologic specimen compared with SCC.
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http://dx.doi.org/10.1097/RCT.0000000000001210DOI Listing
August 2021

Maternal near-miss attributable to haemorrhagic stroke in patients with hypertensive disorders of pregnancy in Japan: A national cohort study.

Pregnancy Hypertens 2021 Aug 23;25:240-243. Epub 2021 Jul 23.

Department of Gynaecology and Obstetrics, Kyoto University, Kyoto, Japan. Electronic address:

Objectives: To investigate the epidemiologic and clinical characteristics of maternal near-misses attributable to haemorrhagic stroke (HS) occurring in patients with hypertensive disorders of pregnancy (HDP), with a focus on severe neurological morbidity.

Methods: A national retrospective cohort study was conducted using the national database of health insurance claims for the period 2010 to 2017. The subjects were all insured women with a diagnosis of both HDP and HS. Severe neurological morbidity requiring rehabilitation, types of HDP, types of HS, and magnesium sulphate use were tabulated.

Results: The number of women with HDP who were diagnosed with HS was 3.4 per 100,000 deliveries between 2010 and 2017. Forty percent of HDP-related HS cases had neurological morbidities requiring rehabilitation (1.4 per 100,000 deliveries), and 4.4% were in a persistent vegetative state after HS. Of the HDP cases who developed HS, 69.2% were severe HDP, of which 55.6% were without eclampsia. The most common type of HS was intracerebral haemorrhage (2.5 per 100,000 deliveries), followed by subarachnoid haemorrhage due to cerebral aneurysm (1.2 per 100,000 deliveries). The frequency of magnesium sulphate use increased in all patients with HDP-related HS in the second half of the study period (2014-2017) compared with the first half (2010-2013) (p < 0.0001). This was more evident in cases of HDP-related HS with eclampsia (31.9% to 83.8%) compared to those without eclampsia (25.0% to 42.9%).

Conclusion: Of the maternal near-miss cases due to HDP-related HS, 40.0% were rehabilitated and 69.2% were HDP without either eclampsia or severe hypertension.
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http://dx.doi.org/10.1016/j.preghy.2021.07.244DOI Listing
August 2021

Correction to: Diagnostic performance of preoperative MR imaging findings for differentiation of uterine leiomyoma with intraligamentous growth from subserosal leiomyoma.

Abdom Radiol (NY) 2021 Jul 16. Epub 2021 Jul 16.

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

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http://dx.doi.org/10.1007/s00261-021-03208-3DOI Listing
July 2021

Automatic segmentation of uterine endometrial cancer on multi-sequence MRI using a convolutional neural network.

Sci Rep 2021 Jul 14;11(1):14440. Epub 2021 Jul 14.

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyoku, Kyoto, 606-8507, Japan.

Endometrial cancer (EC) is the most common gynecological tumor in developed countries, and preoperative risk stratification is essential for personalized medicine. There have been several radiomics studies for noninvasive risk stratification of EC using MRI. Although tumor segmentation is usually necessary for these studies, manual segmentation is not only labor-intensive but may also be subjective. Therefore, our study aimed to perform the automatic segmentation of EC on MRI with a convolutional neural network. The effect of the input image sequence and batch size on the segmentation performance was also investigated. Of 200 patients with EC, 180 patients were used for training the modified U-net model; 20 patients for testing the segmentation performance and the robustness of automatically extracted radiomics features. Using multi-sequence images and larger batch size was effective for improving segmentation accuracy. The mean Dice similarity coefficient, sensitivity, and positive predictive value of our model for the test set were 0.806, 0.816, and 0.834, respectively. The robustness of automatically extracted first-order and shape-based features was high (median ICC = 0.86 and 0.96, respectively). Other high-order features presented moderate-high robustness (median ICC = 0.57-0.93). Our model could automatically segment EC on MRI and extract radiomics features with high reliability.
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http://dx.doi.org/10.1038/s41598-021-93792-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280152PMC
July 2021

Three-dimensional human placenta-like bud synthesized from induced pluripotent stem cells.

Sci Rep 2021 Jul 8;11(1):14167. Epub 2021 Jul 8.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo, Kyoto, 606-8507, Japan.

Placental dysfunction is related to the pathogenesis of preeclampsia and fetal growth restriction, but there is no effective treatment for it. Recently, various functional three-dimensional organs have been generated from human induced-pluripotent cells (iPSCs), and the transplantation of these iPSCs-derived organs has alleviated liver failure or diabetes mellitus in mouse models. Here we successfully generated a three-dimensional placental organ bud from human iPSCs. The iPSCs differentiated into various lineages of trophoblasts such as cytotrophoblast-like, syncytiotrophoblast-like, and extravillous trophoblast-like cells, forming organized layers in the bud. Placental buds were transplanted to the murine uterus, where 22% of the buds were successfully engrafted. These iPSC-derived placental organ buds could serve as a new model for the study of placental function and pathology.
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http://dx.doi.org/10.1038/s41598-021-93766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266876PMC
July 2021

Sebaceous carcinoma of the vulva treated with sentinel lymph node biopsy: a case report and literature review.

Int Cancer Conf J 2021 Jul 5;10(3):239-243. Epub 2021 May 5.

Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.

Sebaceous carcinoma (SC) is a rare and aggressive cutaneous malignancy. It often occurs on the eyelid, where it is called periocular SC, while extraocular SC mainly occurs on the head and heck. Extraocular vulvar SC is extremely rare; only nine cases have been described in the literature, and the optimal treatment strategy is unknown. We herein report a case of vulvar SC that was successfully treated with local excision in combination with sentinel lymph node biopsy (SNB). A 66-year-old female presented with vulvar discomfort. An 8 mm ulcerated mass was palpable in her left labia minora. Skin biopsy suggested SC. Imaging showed no swelling of the pelvic and inguinal lymph nodes and no metastasis. Sentinel lymph node scintigraphy using technetium-99 m showed three sentinel lymph nodes. The patient underwent local excision with SNB; intraoperative frozen-section examination revealed no nodal metastasis, and no further inguinal lymphadenectomy was performed. The final diagnosis was SC of the vulva, FIGO stage IB (pT1bN0M0). At the 14-month follow-up, she remained asymptomatic and had no signs of recurrence. The scientific rationale for SNB in extraocular SC has not yet been established, although SNB can be considered for periocular SC. However, considering the insufficient data on the management of vulvar SC and the aggressive nature of both periocular and extraocular SCs, SNB can be a reasonable and useful method for avoiding inadequate treatment and reducing the complications caused by unnecessary inguinal lymphadenectomy.
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http://dx.doi.org/10.1007/s13691-021-00488-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206379PMC
July 2021

Primary and recurrent serous borderline tumors during pregnancy: a case report and literature review.

Int Cancer Conf J 2021 Jul 26;10(3):160-169. Epub 2021 Feb 26.

Department of Obstetrics and Gynecology, Japanese Red Cross Wakayama Medical Center, 4-20 Komatsubara-dori, Wakayama, 640-8558 Japan.

The diagnosis and management of borderline ovarian tumors during pregnancy are still not standardized, because these tumors are rarely encountered. We report the case of a 27-year-old pregnant woman who presented with an ovarian mass in her first trimester. Magnetic resonance imaging revealed a multilocular cystic component with papillary lesions in the background of endometriosis, suggesting a seromucinous borderline tumor or ovarian cancer. A right salpingo-oophorectomy and partial omentectomy were performed at 7 weeks of gestation. Pathological examination demonstrated a serous borderline tumor. The subsequent pregnancy course was uneventful, and she gave birth to a healthy baby at 39 weeks of gestation. She wanted to retain fertility, and close follow-up was performed. Four years later, she became pregnant, and a lesion suggesting recurrence in the left ovary was detected. An abdominal left ovarian cystectomy was performed at 13 weeks of gestation, which demonstrated recurrence of the serous borderline tumor. She gave birth to a healthy baby at 39 weeks of gestation. Two months after delivery, she underwent total abdominal hysterectomy with left salpingo-oophorectomy, which revealed no malignant findings. We also reviewed 10 reports that included 58 cases of borderline ovarian tumors diagnosed during pregnancy. The borderline ovarian tumors diagnosed during pregnancy exhibited different characteristics according to each subtype, suggesting the importance of diagnosing borderline ovarian tumor subtypes preoperatively.
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http://dx.doi.org/10.1007/s13691-021-00471-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206299PMC
July 2021

Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer.

Sci Rep 2021 Jun 1;11(1):11427. Epub 2021 Jun 1.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8501, Japan.

Based on our previous phase II clinical trial of anti-programmed death-1 (PD-1) antibody nivolumab for platinum-resistant ovarian cancer (n = 19, UMIN000005714), we aimed to identify the biomarkers predictive of response. Tumor gene expression was evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas and a signature established prior for ovarian clear cell carcinoma. Resulting signature scores were statistically assessed with both univariate and multivariate approaches for correlation to clinical response. Analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) patient groups. The clear cell gene signature was scored significantly higher in the CR group, and the proliferative gene signature had significantly higher scores in the PD group where nivolumab was not effective (respective p values 0.005 and 0.026). Combinations of gene signatures improved correlation with response, where a visual projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. An applicable clinical response prediction formula was derived. Ovarian cancer-specific gene signatures and related pathway scores provide a robust preliminary indicator for ovarian cancer patients prior to anti-PD-1 therapy decisions.
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http://dx.doi.org/10.1038/s41598-021-91012-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169687PMC
June 2021

Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma.

Cancers (Basel) 2021 May 17;13(10). Epub 2021 May 17.

Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

Clear cell carcinoma (CCC) of the ovary exhibits a unique morphology and clinically malignant behavior. The eosinophilic cytoplasm includes abundant glycogen. Although the growth is slow, the prognosis is poor owing to resistance to conventional chemotherapies. CCC often arises in endometriotic cysts and is accompanied by endometriosis. Based on these characteristics, three clinical questions are considered: why does ovarian cancer, especially CCC and endometrioid carcinoma, frequently occur in endometriotic cysts, why do distinct histological subtypes (CCC and endometrioid carcinoma) arise in the endometriotic cyst, and why does ovarian CCC possess unique characteristics? Mutations in and genes may contribute to the carcinogenesis of ovarian CCC, whereas () plays crucial roles in sculpting the unique characteristics of ovarian CCC through metabolic alterations. HNF1B increases glutathione synthesis, activates anaerobic glycolysis called the Warburg effect, and suppresses mitochondria. These metabolic changes may be induced in stressful environments. Life has evolved to utilize and control energy; eukaryotes require mitochondria to transform oxygen reduction into useful energy. Because mitochondrial function is suppressed in ovarian CCC, these cancer cells probably acquired further metabolic evolution during the carcinogenic process in order to survive stressful environments.
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http://dx.doi.org/10.3390/cancers13102413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157013PMC
May 2021

Chronic abruption-oligohydramnios sequence (CAOS) revisited: possible implication of premature rupture of membranes.

J Matern Fetal Neonatal Med 2021 May 20:1-7. Epub 2021 May 20.

Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.

Aim: The pathogenic mechanism of chronic abruption-oligohydramnios sequence (CAOS) remains unknown, and there are no objective standards for diagnosis on imaging or using pathological evidence. We aimed to reconsider and clarify the true pathology of CAOS by integrating clinical, magnetic resonance imaging (MRI) and histopathological findings of the placenta.

Material And Methods: This is a case series of patients with CAOS managed at our hospital between 2010 and 2020. The clinical data of the patients, including MRI findings and placental pathology, were reviewed retrospectively.

Results: A total of 18 patients were eligible. Preterm birth occurred in 17 (94%) cases; the median gestational age at delivery was 25. Three neonates (17%) died within two years, and 10 neonates (56%) developed chronic lung disease. MRI was performed in 13 cases and clearly showed intrauterine hematoma and hemorrhagic amniotic fluid. Pathologically, in all cases, retroplacental hematoma was not detected, and fetal membranes were extremely fragile and ragged. Shedding and necrosis of the amniotic epithelium was a characteristic finding, which was confirmed in 17 cases (94%). Diffuse chorionic hemosiderosis (DCH) was detected in all cases.

Conclusions: The fundamental cause of CAOS is repeated intrauterine hemorrhage and subsequent subchorionic hematoma, which induces hemorrhagic amniotic fluid and DCH. Consequently, these factors result in the necrosis and weakening of the amnion. Therefore, the true pathology of CAOS is believed to be premature rupture of membranes rather than chronic abruption.
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http://dx.doi.org/10.1080/14767058.2021.1929159DOI Listing
May 2021

Figla promotes secondary follicle growth in mature mice.

Sci Rep 2021 05 10;11(1):9842. Epub 2021 May 10.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo, Kyoto, 606-8507, Japan.

The in vitro growth (IVG) of human follicles is a potential fertility option for women for whom cryopreserved ovarian tissues cannot be transplanted due to the risk of cancer cell reintroduction; however, there is currently no established method. Furthermore, optimal IVG conditions may differ between the follicles of adult and pre-pubertal females due to molecular differences suggested by basic research. To systematically identify differences between the secondary follicles of adult and pre-pubertal females, a comparative transcriptomic study using mice was conducted herein. Among differentially expressed genes (DEGs), Figla was up-regulated in mature mice. We successfully down-regulated Figla expression in secondary follicle oocytes by a Figla siRNA microinjection, and the subsequent IVG of follicles showed that the diameter of these follicles was smaller than those of controls in mature mice, whereas no significant difference was observed in premature mice. The canonical pathways of DEGs between control and Figla-reduced secondary follicles suggest that Figla up-regulates VDR/RXR activation and down-regulates stem cell pluripotency as well as estrogen signaling. We demonstrated for the first time that folliculogenesis of the secondary follicles of premature and mature mice may be regulated by different factors, such as Figla with its possible target genes, providing insights into optimal IVG conditions for adult and pre-pubertal females, respectively.
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http://dx.doi.org/10.1038/s41598-021-89052-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110814PMC
May 2021

Capturing human trophoblast development with naive pluripotent stem cells in vitro.

Cell Stem Cell 2021 06 7;28(6):1023-1039.e13. Epub 2021 Apr 7.

Department of Life Science Frontiers, CiRA, Kyoto University, Kyoto 606-8507, Japan. Electronic address:

Trophoblasts are extraembryonic cells that are essential for maintaining pregnancy. Human trophoblasts arise from the morula as trophectoderm (TE), which, after implantation, differentiates into cytotrophoblasts (CTs), syncytiotrophoblasts (STs), and extravillous trophoblasts (EVTs), composing the placenta. Here we show that naïve, but not primed, human pluripotent stem cells (PSCs) recapitulate trophoblast development. Naive PSC-derived TE and CTs (nCTs) recreated human and monkey TE-to-CT transition. nCTs self-renewed as CT stem cells and had the characteristics of proliferating villous CTs and CTs in the cell column of the first trimester. Notably, although primed PSCs differentiated into trophoblast-like cells (BMP4, A83-01, and PD173074 [BAP]-treated primed PSCs [pBAPs]), pBAPs were distinct from nCTs and human placenta-derived CT stem cells, exhibiting properties consistent with the amnion. Our findings establish an authentic paradigm for human trophoblast development, demonstrating the invaluable properties of naive human PSCs. Our system provides a platform to study the molecular mechanisms underlying trophoblast development and related diseases.
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http://dx.doi.org/10.1016/j.stem.2021.03.013DOI Listing
June 2021

Tumor Immune Microenvironment during Epithelial-Mesenchymal Transition.

Clin Cancer Res 2021 Sep 7;27(17):4669-4679. Epub 2021 Apr 7.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.

Epithelial-mesenchymal transition (EMT) has been shown to play a critical role in tumor development from initiation to metastasis. EMT could be regarded as a continuum, with intermediate hybrid epithelial and mesenchymal phenotypes having high plasticity. Classical EMT is characterized by the phenotype change of epithelial cells to cells with mesenchymal properties, but EMT is also associated with multiple other molecular processes, including tumor immune evasion. Some previous studies have shown that EMT is associated with the cell number of immunosuppressive cells, such as myeloid-derived suppressor cells, and the expression of immune checkpoints, such as programmed cell death-ligand 1, in several cancer types. At the molecular level, EMT transcriptional factors, including Snail, Zeb1, and Twist1, produce or attract immunosuppressive cells or promote the expression of immunosuppressive checkpoint molecules via chemokine production, leading to a tumor immunosuppressive microenvironment. In turn, immunosuppressive factors induce EMT in tumor cells. This feedback loop between EMT and immunosuppression promotes tumor progression. For therapy directly targeting EMT has been challenging, the elucidation of the interactive regulation of EMT and immunosuppression is desirable for developing new therapeutic approaches in cancer. The combination of immune checkpoint inhibitors and immunotherapy targeting immunosuppressive cells could be a promising therapy for EMT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4459DOI Listing
September 2021

Oncofertility care in young women and the outcomes of pregnancy over the last 5 years.

Future Sci OA 2021 Feb 2;7(4):FSO680. Epub 2021 Feb 2.

Department of Gynecology & Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 6068507, Japan.

Aim: To ascertain the actual outcomes of oncofertility care in young women to provide more appropriate care.

Materials & Methods: We analyzed the data of 67 female patients under 43 years of age who underwent oncofertility care between January 2015 and September 2019.

Results: There were 28 patients with breast cancer, 19 patients with hematologic cancer and 20 patients with other cancer diagnoses. Breast cancer patients tended to take longer than hematologic cancer patients to initiate oncofertility treatment. Despite undergoing oncofertility care, seven of nine pregnant patients did not choose assisted reproductive technology (ART).

Conclusion: As spontaneous pregnancies were more common than ART pregnancies in our study, pregnancy by not only ART but also non-ART method is a viable option for young cancer survivors.
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http://dx.doi.org/10.2144/fsoa-2020-0169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015666PMC
February 2021

Diagnostic performance of preoperative MR imaging findings for differentiation of uterine leiomyoma with intraligamentous growth from subserosal leiomyoma.

Abdom Radiol (NY) 2021 08 2;46(8):4036-4045. Epub 2021 Apr 2.

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Purpose: To evaluate the diagnostic performance of MRI findings for differentiating uterine leiomyoma with intraligamentous growth, or broad ligament fibroid, from subserosal leiomyoma.

Methods: This study included 37 patients with surgically confirmed uterine smooth muscle tumors (36 leiomyomas and one smooth muscle tumor of uncertain malignant potential) with intraligamentous growth (IL) and size-matched control of 37 patients with subserosal leiomyoma (SS). Two radiologists independently evaluated eight preoperative MRI findings: tumor shape, degeneration, attachment to uterus, ovary elevation, ureter displacement, bladder deformation, rectal displacement, and separation of round ligament (RL) and uterine artery (UA). The diagnostic values of these findings and interobserver agreement were assessed. Receiver-operating characteristic (ROC) analysis of the number of positive MRI findings for diagnosing IL was performed. Clinical outcomes including surgical method, operation time, intraoperative blood loss, perioperative complications, and postoperative hospital stay of the two groups were compared.

Results: Significant differences in tumor shape, attachment to uterus, ovary elevation, ureter displacement, and separation of RL and UA were found between IL and SS. Four of these findings, excluding ureter displacement, showed moderate to substantial interobserver agreement. When two or more of these four findings were positive, sensitivity, specificity, and area under the ROC curve were 91%, 77%, 0.90 in reader 1 and 82%, 89%, 0.91 in reader 2. The operation time was significantly longer for IL than for SS.

Conclusion: Tumor shape, attachment to uterus, ovary elevation, and separation of RL and UA are useful MRI findings for differentiating intraligamentous leiomyoma from subserosal leiomyoma.
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http://dx.doi.org/10.1007/s00261-021-03042-7DOI Listing
August 2021

The reliability and validity of the Japanese version of the Daily Record of Severity of Problems (J-DRSP) and Development of a Short-Form version (J-DRSP (SF)) to assess symptoms of premenstrual syndrome among Japanese women.

Biopsychosoc Med 2021 Mar 18;15(1). Epub 2021 Mar 18.

Department of Health Informatics, Kyoto University School of Public Health, Konoecho Yoshida, Sakyo-ku, Kyoto City, 606-8303, Japan.

Purpose: To assess the validity and reliability of the Japanese version of the Daily Record of Severity of Problems (J-DRSP, 24 items) for evaluating symptoms of premenstrual syndrome (PMS), and to develop a short form version of the J-DRSP.

Methods: Using the "DRSP-JAPAN" smartphone app, we collected daily J-DRSP records from cycle day - 6 (CD - 6) to CD 10, with CD 1 representing the menstruation onset date. Factorial validity (exploratory factor analysis: EFA, confirmatory factor analysis: CFA) and criterion validity were examined, and test-retest reliability (intraclass correlation: ICC) evaluated. The short-form version of the J-DRSP was developed using classical test theory.

Results: In total, 304 women participated and 243 recorded symptoms on at least 4 days spanning the week of the luteal phase (CD - 6 to CD 0) and 4 days spanning the week of the follicular phase (CD 4 to CD 10), with CD 0 set as the day before menstruation started. The EFA revealed a two-factor structure. Kaiser-Meyer-Olkin was 0.992, and Bartlett's test of sphericity chi-square was 3653.89 (P < 0.001). However, the model fitness of CFA was found to be suboptimal (comparative fit index (CFI): 0.83, root mean square error of approximation (RMSEA): 0.12). Total scores for J-DRSP and the sum scores for each subscale were higher on CD 0 than on CD 10 (p < 0.001), suggesting validity for some criteria. ICC values for the total J-DRSP score from CD 0 to CD - 1, and between CD 9 to CD 10, were 0.60 (95% CI: 0.48-0.72) and 0.76 (95% CI: 0.69-0.82), respectively. Having eliminated some original items after considering factor loading for each item, we developed an 8-item Short-Form J-DRSP (J-DRSP (SF)) comprising 2 factors (S-Psychological and S-Physical, 4 items for each). CFA showed a better model fit (CFI: 0.99, RMSEA: 0.048), and ICC values in the luteal and follicular phases were 0.61 (95%CI: 0.51-0.68) and 0.70 (95%CI: 0.62-0.77), respectively.

Conclusion: The J-DRSP has moderate to good reliability and a certain level of validity. The 8-item J-DRSP (SF) has a two-factor structure and can be used effectively among Japanese women to assess their PMS symptoms.
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http://dx.doi.org/10.1186/s13030-021-00208-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977312PMC
March 2021

Diffusion-weighted imaging of uterine adenomyosis: Correlation with clinical backgrounds and comparison with malignant uterine tumors.

J Obstet Gynaecol Res 2021 Mar 28;47(3):949-960. Epub 2021 Jan 28.

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Aim: To elucidate correlation between signal intensity on diffusion-weighted images (SI-DWI) and clinical backgrounds for uterine adenomyosis and to compare SI-DWI of adenomyosis and malignant uterine tumors.

Methods: This study examined 46 adenomyosis patients diagnosed using magnetic resonance imaging and 25 patients with surgically confirmed malignant uterine myometrial tumor. First, adenomyosis cases were classified visually into high-intensity and low-intensity groups based on the SI-DWI compared with that of normal uterine myometrium. Secondly, correlation was assessed between SI-DWI of adenomyosis and patient clinical background information such as age, menopausal status, menstrual cycle and dysmenorrhea severity. Third, quantitative comparison was made of low-intensity adenomyosis (LIA), high-intensity adenomyosis (HIA) and malignant tumor groups for the signal intensity ratio (SIR) on DWI and the apparent diffusion coefficient (ADC). Their diagnostic performance was evaluated using logistic regression analysis and receiver operating characteristic (ROC) analysis.

Results: The 46 adenomyosis cases were classified as 26 low-intensity and 20 high-intensity cases. Significant correlation was found only for menstrual cycle phases. HIA had significantly lower SIR and higher ADC than malignant tumor. The ADC of HIA was significantly higher than that of LIA. The combination of SIR and ADC showed excellent diagnostic performance (area under ROC curve, 0.99).

Conclusion: There is a variation in signal intensity on DWI of uterine adenomyosis and it is associated with menstrual cycle phase. Adenomyosis with high signal intensity on DWI can be differentiated from malignant lesions by its lower signal intensity on DWI and higher ADC than that found for malignant uterine tumors, however overlaps exist.
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http://dx.doi.org/10.1111/jog.14621DOI Listing
March 2021

Histological distribution pattern of hemosiderin deposition on the chorionic plate and fetal membrane of diffuse chorioamniotic hemosiderosis related to chronic abruption oligohydramnios sequence.

Placenta 2021 02 20;105:1-6. Epub 2021 Jan 20.

Department of Diagnostic Pathology, Kyoto University Hospital, Japan.

Introduction: Chronic abruption oligohydramnios sequence (CAOS) is histologically characterized by diffuse chorioamniotic hemosiderosis (DCH). However, the criteria for the histological evaluation of the extent of CAOS-related hemosiderin deposition (HD) of the membranes and the difference in HD between the chorionic plate (CP) and fetal membrane (FM) are not well studied. This case control study compared the degree and distribution pattern of HD on CP and FM to present the histological features of DCH and the criteria for histological evaluation.

Methods: From the medical records of Kyoto University Hospital (2010-2019), we selected 20 CAOS cases that were clinically diagnosed by Elliot's criteria. Twenty non-CAOS cases matched to the CAOS group by gestational age were selected as controls. We compared the clinical data and pathological features in the two groups. We performed iron staining in all the cases and analyzed HD in CP and FM according to the histological score (H-Score: 0-12), which was determined as the density (0-3) multiplied by the extent of staining (0-4).

Results: HD was found in 100% (20/20) of CAOS and 15% (3/20) of control cases. In both the FM and CP, CAOS cases showed a significantly higher HS than control cases (CAOS, HS = 4-12; Control, HS = 0-1, p < 0.0001). Three CAOS patients presented HD alone in the CP. The HS of the CP was significantly higher than that of the FM (p = 0.0003).

Discussion: CAOS presented DCH with HS ≥ 4. This study showed that the CP might be more suitable for evaluating DCH than the FM.
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http://dx.doi.org/10.1016/j.placenta.2021.01.013DOI Listing
February 2021

Epithelial expression of Gata4 and Sox2 regulates specification of the squamous-columnar junction via MAPK/ERK signaling in mice.

Nat Commun 2021 01 25;12(1):560. Epub 2021 Jan 25.

Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.

The squamous-columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal-distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.
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http://dx.doi.org/10.1038/s41467-021-20906-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835245PMC
January 2021

Three cases of seromucinous carcinoma of the ovary arising in endometriotic cysts.

Int Cancer Conf J 2021 Jan 21;10(1):46-53. Epub 2020 Sep 21.

Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.

Ovarian seromucinous carcinoma (SMC) is an uncommon neoplasia and is composed predominantly of serous and endocervical-type mucinous epithelium. Due to its low frequency and difficult diagnosis, the natural history, characteristic imaging findings, and pathological features of SMC have not been adequately described in the literature thus far. We herein report three cases of ovarian SMC along with magnetic resonance imaging (MRI) findings. The diagnosis of SMC was made after staging laparotomy in all cases, and systemic chemotherapy was performed in two cases. No recurrence was observed in any of the cases. The MRI findings in SMC were so varied that characteristic imaging features useful for diagnosis were not found. In two cases, MRI suggested endometriotic cysts, and endometriosis and seromucinous borderline tumors (SMBTs) were detected concurrently in all cases by histological examination. Thus, it was suggested that SMC develops in multiple stages via endometriosis and SMBT. The cooccurrence of endometriosis and SMBT could also make the diagnosis of SMC more convincing.
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http://dx.doi.org/10.1007/s13691-020-00447-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797404PMC
January 2021

Potential Novel Ovarian Cancer Treatment Targeting Myeloid-Derived Suppressor Cells.

Cancer Invest 2021 Apr 15;39(4):310-314. Epub 2021 Feb 15.

National Hospital Organization, Kyoto Medical Center, Kyoto, Japan.

Diagnosis by biopsy is difficult in the ovary since it is located deep in the abdomen. As a result, ovarian cancer is mostly found insidiously during exploratory laparotomy. Consequently, the early diagnosis of ovarian cancer is often difficult. The likelihood of peritoneal dissemination increases with the progress of ovarian cancer. With further progression, ovarian cancer metastasizes to the momentum, retroperitoneal lymph nodes, large intestine, small intestine, diaphragm, spleen, and other organs. Ovarian cancer has been considered a tumor that has a favorable response to chemotherapy, but more effective treatments are still being explored. Tumors use their own immune escape mechanism to evade host immunity. The immune checkpoint (IC) mechanism, one of the immune escape mechanisms, is established by programmed cell death-1 (PD-1)/PD-ligand-1 (PD-L1) communication. It has been shown that inhibiting PD-1/PD-L1 communication in various malignancies produces antitumor effects. However, the antitumor effect of ICI monotherapy on ovarian cancer is limited in actual clinical practice. In this review, we describe a novel cancer immunotherapeutic agent that targets myeloid-derived suppressor cells (MDSCs).
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http://dx.doi.org/10.1080/07357907.2020.1871487DOI Listing
April 2021

A Novel Direct Approach to the Deep Uterine Vein in Laparoscopic Radical Hysterectomy.

J Minim Invasive Gynecol 2021 Aug 23;28(8):1444-1445. Epub 2020 Dec 23.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine (Drs. Horie, Sunada, Kitamura, Yamanoi, Horikawa, Yamaguchi, Hamanishi, Kondoh, and Mandai).

Study Objective: To describe a direct approach to the deep uterine vein in laparoscopic radical hysterectomy.

Design: Demonstration of the laparoscopic technique with narrated video footage.

Setting: Securing sufficient radicality is extremely important when performing a radical hysterectomy for cervical cancer, either by laparotomy or by minimally invasive surgery. The nerve-sparing Okabayashi radical hysterectomy (NS-RH) was originally aimed at achieving both radical resection and function preservation [1-3]. A key procedure when performing NS-RH is intraoperative identification of the relationship between the deep uterine vein and pelvic splanchnic nerve fibers [4]. With this in mind, a safe and easy method for identifying the crossing point of the deep uterine vein and pelvic splanchnic nerve in the initial phase of the surgery may greatly improve the safety and efficacy of functional preservation in NS-RH. Herein, we describe a minimally invasive "direct approach" to the deep uterine vein.

Interventions: Before undergoing the pelvic lymphadenectomy, all steps of laparoscopic radical hysterectomy were performed. First, we identified the ureter on the posterior peritoneum, and the peritoneum was dissected just above the ureter. By continuously exploring the pelvic cavity along the ureter, especially through the opening of the space below the ureter in a cranial to caudal direction, we could easily identify the deep uterine vein. This procedure also exposed the fibers of the hypogastric nerve, clarifying the relationship of these structures.

Conclusion: Because the relationship between the deep uterine vein and nerve fibers is the most important guidepost of this surgery, their identification in the early phase of the surgery enables us to perform the subsequent procedure precisely and securely. This direct approach to the deep uterine vein can be easily and safely performed.
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http://dx.doi.org/10.1016/j.jmig.2020.12.018DOI Listing
August 2021
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