Publications by authors named "Takayuki Enomoto"

258 Publications

Genetic Test and Risk-Reducing Salpingo-Oophorectomy for Hereditary Breast and Ovarian Cancer: State-of-the-Art.

Cancers (Basel) 2021 May 23;13(11). Epub 2021 May 23.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.

In the field of gynecology, the approval of the PARP inhibitors (PARPi) has been changing the treatment of ovarian cancer patients. The genetic test and the HRD test are being used as a companion diagnosis before starting PARPi treatment. BRACAnalysis CDx and Myriad myChoice HRD test are widely used as a BRCA genetic test and HRD test, respectively. In addition, FoundationOneCDx is sometimes used as a tumor BRCA test and HRD test. In clinical practice, gynecologists treating ovarian cancer are faced with making decisions such as whether to recommend the g test to all ovarian cancer patients, whether to perform the g test first or HRD test first, and so on. Regarding the judgment result of the HRD test, the cutoff value differs depending on the clinical trial, and the prevalence of g pathogenic variant rate is different in each histological type and country. A prospective cohort study showed that RRSO reduced all-cause mortality in both pre- and postmenopausal women; however, RRSO significantly reduced the risk of breast cancer for 2 pathogenic variant carriers, but not for 1 pathogenic variant carriers. Moreover, salpingectomy alone is said to not decrease the risk of developing ovarian or breast cancer, so further discussion is evidently required. We discuss the current situation and problems in doing genetic test and RRSO in this review article.
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http://dx.doi.org/10.3390/cancers13112562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197088PMC
May 2021

Precision medicine for hereditary tumors in gynecologic malignancies.

J Obstet Gynaecol Res 2021 May 25. Epub 2021 May 25.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Genomic medicine for gynecologic tumors is characterized by hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Poly ADP-ribose polymerase (PARP) inhibitor, olaparib, and the immune checkpoint inhibitor, pembrolizumab, which are drugs that show sensitivity to each hereditary tumor, have begun to spread in clinical practice for gynecologic malignancies. In clinical use, platinum sensitivity is used as a clinical surrogate marker for olaparib sensitivity, and microsatellite instability is used as a biological surrogate marker for pembrolizumab sensitivity. BRCA genetic testing and microsatellite instability test have been used as companion diagnostics before starting olaparib and pembrolizumab treatment, respectively. Homologous recombination deficiency test could be used for companion diagnostic of olaparib combination with bevacizumab in first-line maintenance treatment and niraparib without re-administration of platinum agents in the treatment of recurrence. The approval of the three drugs has been changing the treatment of gynecologic malignancies. Furthermore, preventive medical care has been covered by insurance since April 2020 for breast and/or ovarian cancer patients with germline BRCA1/2 mutation in Japan. This review article outlines the current status and future prospects of precision medicine for gynecologic hereditary tumors focusing on HBOC and LS.
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http://dx.doi.org/10.1111/jog.14861DOI Listing
May 2021

Uterine serous carcinoma.

Gynecol Oncol 2021 Apr 29. Epub 2021 Apr 29.

Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy.

Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.029DOI Listing
April 2021

Exclusive Breastfeeding Is Not Associated with Maternal-Infant Bonding in Early Postpartum, Considering Depression, Anxiety, and Parity.

Nutrients 2021 Apr 2;13(4). Epub 2021 Apr 2.

Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.

It is important to clarify how the breastfeeding method affects women's mental health, and how women's mental health affects the breastfeeding method in the early postpartum period when major depression and other psychiatric problems are most likely to occur. This study aimed to examine this bidirectional relationship in the early postpartum period. Participants were 2020 postpartum women who completed the Hospital Anxiety and Depression Scale (HADS) and Mother-to-Infant Bonding Scale (MIBS). We obtained data for participants' breastfeeding method for four weeks after childbirth. We performed a path analysis with factors including breastfeeding method (exclusive breastfeeding or non-exclusive breastfeeding), parity (primipara or multipara), the two HADS subscales (anxiety and depression), and the two MIBS subscales (lack of affection and anger and rejection). The path analysis showed that breastfeeding method did not significantly affect depression, anxiety, and maternal-infant bonding in the early postpartum period. Women with higher anxiety tended to use both formula-feeding and breastfeeding. Our study suggests that exclusive breastfeeding is not associated with maternal-fetal bonding in early postpartum, considering depression, anxiety, and parity.
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http://dx.doi.org/10.3390/nu13041184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066877PMC
April 2021

A retrospective study for investigating the outcomes of endometrial cancer treated with radiotherapy.

Int J Gynaecol Obstet 2021 Apr 29. Epub 2021 Apr 29.

Department of Obstetrics and Gynecology, Tokai University School of Medicine, Kanagawa, Japan.

Objective: To clarify the role of radiotherapy for endometrial cancer.

Methods: Data were analyzed for 39 247 patients with endometrial cancer registered with the Gynecologic Cancer Registry of the Japan Society of Obstetrics and Gynecology from 2004 to 2011.

Results: The rates of 5-year overall survival (5y-OS) in the radiotherapy and surgery groups were 53.6% and 94.5% in stage I or II, and 15.5% and 67.5% in stage III or IV, respectively. The prognosis in the radiotherapy group was significantly poorer than that in the surgery group. In multivariate analysis, age, advanced stage, histological type, risk of recurrence, and initial radiotherapy were independent prognostic factors. The rates of 5y-OS with no adjuvant therapy, adjuvant chemotherapy, and adjuvant radiotherapy were 95.3%, 92.9%, and 87.1% for stage I or II, respectively, with significant differences among all groups (P < 0.001), and 60.0%, 70.4%, and 55.5% for stage III or IV, respectively, with significant differences of adjuvant chemotherapy with no adjuvant therapy (P < 0.001) and with adjuvant radiotherapy (P < 0.001). In multivariate analysis, age, advanced stage, histological type, lymphadenectomy, and adjuvant radiotherapy were independent prognostic factors.

Conclusion: Patients treated with radiotherapy had a significantly poorer prognosis and the appropriate indication of radiotherapy for endometrial cancer requires further study.
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http://dx.doi.org/10.1002/ijgo.13725DOI Listing
April 2021

PET/MR imaging for the evaluation of cervical cancer during pregnancy.

BMC Pregnancy Childbirth 2021 Apr 10;21(1):288. Epub 2021 Apr 10.

Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

Background: Malignancy during pregnancy is increasing, and the most common type of malignancy is uterine cervical cancer. When planning the treatment of cervical cancer, it is important to look for signs of metastasis before surgery, especially metastasis to the lymph nodes. In this report, we assessed the diagnostic value of positron emission tomography/magnetic resonance imaging (PET/MRI) for evaluating cervical cancer propagation before surgery, with a focus on pregnant women.

Case Presentation: F Fluorodeoxyglucose (FDG)-PET/MRI was performed in seven pregnant cervical cancer patients (28-34 years old) at 9-18 gestational weeks. In case #5, a second PET/MRI was performed at 24 gestational weeks. Of seven FDG-PET/MRI examination series in six cases (cases #1-6), FDG-PET/MR imaging could detect cervical tumors with abnormal FDG accumulation; these tumors were confirmed with a standardized uptake value max (SUV max) titer of 4.5-16. A second PET/MRI examination in case #5 revealed the same SUV max titer as the first examination. In these six imaging series (cases #1-5), there were no signs of cancer metastasis to the parametrium and lymph nodes. However, in case #6, abnormal FDG accumulation in the left parametrial lymph nodes was also detectable. Pathological examination showed lymph node metastasis in case #6. In case #7, PET/MRI could not detect any abnormal FDG accumulation in the cervix and other sites. Cone biopsy demonstrated only micro-invasive squamous cell carcinoma. After treatment for cervical cancer, all seven patients have had no recurrence of disease within the follow-up period (2.8-5.6 years), and their children have developed appropriately.

Conclusion: PET/MRI is an effective imaging tool to evaluate cervical cancer progression in pregnancy.
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http://dx.doi.org/10.1186/s12884-021-03766-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037915PMC
April 2021

Clinical Significance of Mesenteric Lymph Node Involvement in the Pattern of Liver Metastasis in Patients with Ovarian Cancer.

Ann Surg Oncol 2021 Apr 5. Epub 2021 Apr 5.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Mesenteric lymph node (MLN) involvement is often observed in ovarian cancer (OC) with rectosigmoid invasion. This study aimed to investigate the clinical significance of MLN involvement in the pattern of liver metastasis in patients with OC.

Methods: We included 85 stage II-IV OC patients who underwent primary or interval debulking surgery. Twenty-seven patients underwent rectosigmoid resection, whose status of MLN involvement was judged from hematoxylin and eosin (H&E) staining of resected specimens. The prognostic significance of clinicopathological characteristics, including MLN involvement, was evaluated using univariate and multivariate analyses.

Results: MLN involvement was detected in 14/85 patients with stage II-IV OC. Residual tumor status, cytology of ascites, and MLN involvement were independent prognostic factors for progression-free survival (PFS; p = 0.033, p = 0.014, and p = 0.008, respectively). When patients were classified into three groups (no MLN, one MLN, two or more MLNs), the number of MLNs involved corresponded to three distinct groups in PFS (p = 0.001). The 3-year cumulative incidence of liver metastasis of patients with MLN involvement was significantly higher than that of patients without MLN involvement (61.1% vs. 8.9%, p < 0.001). MLN involvement was significantly associated with liver metastasis of hematogenous origin (p < 0.001) compared with peritoneal disseminated origin.

Conclusion: MLN involvement is an important prognostic factor in OC, predicting poor prognosis and liver metastasis of hematogenous origin.
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http://dx.doi.org/10.1245/s10434-021-09899-8DOI Listing
April 2021

How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development.

Cancers (Basel) 2021 Mar 22;13(6). Epub 2021 Mar 22.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.

Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as "endometriosis-associated ovarian cancer" (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.
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http://dx.doi.org/10.3390/cancers13061439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004227PMC
March 2021

Three-dimensional understanding of the morphological complexity of the human uterine endometrium.

iScience 2021 Apr 2;24(4):102258. Epub 2021 Mar 2.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.

The fundamental morphology of the endometrial glands is not sufficiently understood by 2D observation because these glands have complicated winding and branching patterns. To construct a large picture of the endometrial gland structure, we performed tissue-clearing-based 3D imaging of human uterine endometrial tissue. Our 3D immunohistochemistry and layer analyses revealed that the endometrial glands form a plexus network in the stratum basalis and expand horizontally along the muscular layer, similar to the rhizome of grass. We then extended our method to assess the 3D morphology of tissue affected by adenomyosis, a representative "endometrium-related disease," and observed its 3D morphological features, including the direct invasion of endometrial glands into the myometrium and an ant colony-like network of ectopic endometrial glands within the myometrium. Thus, further understanding of the morphology of the human endometrium based on 3D analysis will lead to the identification of the pathogenesis of endometrium-related diseases.
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http://dx.doi.org/10.1016/j.isci.2021.102258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995615PMC
April 2021

ASO Author Reflections: Clinical Significance of Mesenteric Lymph Node Involvement in Patients with Ovarian Cancer.

Ann Surg Oncol 2021 Mar 31. Epub 2021 Mar 31.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan.

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http://dx.doi.org/10.1245/s10434-021-09919-7DOI Listing
March 2021

Bcl11b is required for proper odorant receptor expression in the mouse septal organ.

Cell Tissue Res 2021 Jun 30;384(3):643-653. Epub 2021 Mar 30.

Department of Life Science and Technology, Graduate School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.

Individual olfactory sensory neurons (OSNs) in the mouse main olfactory epithelium express a single odorant receptor (OR) gene from the repertoire of either class I or class II ORs. The transcription factor Bcl11b determines the OR class to be expressed in OSNs. The septal organ (SO), a small neuroepithelium located at the ventral base of the nasal septum, is considered as an olfactory subsystem because it expresses a specific subset of ORs. However, the mechanisms underlying the generation and differentiation of SO-OSN remain unknown. In the present study, we show that the generation and differentiation of SO-OSN employ the same genetic pathway as in the OSN lineage, which is initiated by the neuronal fate determinant factor Ascl1. Additionally, the key role of Bcl11b in the SO is demonstrated by the abnormal phenotypes of Bcl11b-deficient mice: significant reduction in the expression of OR genes and in the number of mature SO-OSNs. Although SO-OSNs are specified to express a subset of class II OR genes in wild-type mice, the Bcl11b deletion led to the expression of class I OR genes, while the expression of class II OR genes was significantly decreased, with one exception of Olfr15. These results indicate that Bcl11b is necessary for proper OR expression in SO-OSNs.
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http://dx.doi.org/10.1007/s00441-021-03444-5DOI Listing
June 2021

A successfully treated case of an acute presentation of congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) with decreased ADAMTS13 during late stage of pregnancy.

J Obstet Gynaecol Res 2021 May 9;47(5):1892-1897. Epub 2021 Mar 9.

Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata City, Japan.

We herein report the case of a 28-year-old pregnant woman with an acute presentation of remarkable petechiae on her lower extremities and severe thrombocytopenia (16 000/mm ) at the 35th week of gestation. Although idiopathic thrombocytopenic purpura was initially suspected, subsequent examinations revealed that her ADAMTS13 (a Disintegrin And Metalloprotease, with ThromboSpondin type 1 repeats, member 13) titer was extremely decreased, while she was negative for antibodies against ADAMTS13. Infusion of fresh frozen plasma was immediately performed, and the platelet count was observed to increase. However, severe pregnancy-induced hypertension and proteinuria emerged at 36 weeks and 2 days of gestation, and a male infant was delivered by emergency cesarean section on the 37th week of gestation. The postnatal development was uncomplicated. After delivery, although the mother's platelet count and ADAMTS13 activity decreased temporarily, both values increased following fresh frozen plasma transfusion. This case showed interesting aspects of congenital thrombocytopenic purpura (Upshaw-Schulman syndrome) in pregnancy. Moreover, the rapid measurement of the patient's ADAMTS13 activity and the subsequent accurate diagnosis of congenital thrombocytopenic purpura made it possible to treat the patient with fresh frozen plasma infusion and avoid contraindicated platelet infusion. Close cooperation between obstetricians, hematologists and pediatricians is necessary to achieve successful outcomes in cases of thrombocytopenic purpura during pregnancy.
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http://dx.doi.org/10.1111/jog.14737DOI Listing
May 2021

Noninvasive positive-pressure ventilation in pregnancy to treat acute pulmonary edema induced by tocolytic agents: a case report.

J Med Case Rep 2021 Mar 21;15(1):126. Epub 2021 Mar 21.

Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

Background: We report a case of pulmonary edema induced by tocolytic agents that was successfully managed with noninvasive positive-pressure ventilation (NPPV) and resulted in extended gestation.

Case Presentation: A 36-year-old Japanese pregnant woman received tocolytic therapy with ritodrine hydrochloride, magnesium sulfate, nifedipine, and betamethasone from 28 weeks of gestation. She developed respiratory failure. and her chest X-ray showed enlarged pulmonary vascular shadows. At 29 weeks and 1 day of gestation, she was diagnosed with pulmonary edema induced by tocolytic agents. Because respiratory failure worsened 2 days after ritodrine hydrochloride and magnesium sulfate were stopped, NPPV was initiated. Her respiratory status improved and she was weaned off of NPPV after 3 days. She underwent cesarean section because of breech presentation at 30 weeks and 0 days of gestation due to initiation of labor pains.

Conclusions: NPPV can be safely administered in cases of tocolytic agent-induced pulmonary edema during pregnancy.
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http://dx.doi.org/10.1186/s13256-021-02704-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981838PMC
March 2021

Attitudes toward overtime work and self-training: A survey on obstetricians and gynecologists in Japan.

J Obstet Gynaecol Res 2021 May 10;47(5):1666-1674. Epub 2021 Mar 10.

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

Aim: The Ministry of Health, Labour, and Welfare of Japan proposed a regulation of overtime work as a reform in work style. However, the regulation may deteriorate the quality of medical services due to the reduction in training time. Thus, the study aimed to reveal perceptions in terms of generation gaps in views on self-training and overtime work, among members of the Japan Society of Obstetrics and Gynecology (JSOG).

Methods: A web-based, self-administered questionnaire survey was conducted among members of the JSOG. In total, 1256 respondents were included in the analysis. Data were collected on age, sex, experience as a medical doctor, location of workplace, work style, the type of main workplace, and number of full-time doctors in the main workplace. The study examined the attitudes of the respondents toward overtime work and self-training. The respondents were categorized based on experience as a medical doctor.

Results: According to years of experience, 112 (8.9%), 226 (18.0%), 383 (30.5%), 535 (42.6%) doctors have been working for ≤5, 6-10, 11-19, and ≥ 20 years, respectively. Although 54.5% of doctors with ≤5 years of experience expected the regulation on working hours to improve the quality of medical services, those with ≥20 years of experience expressed potential deterioration. After adjusting for covariates, more years of experience were significantly related with the expectation of deterioration in the quality of medical services.

Conclusions: The study revealed a generation gap in the views about self-training and overtime work among obstetricians and gynecologists in Japan.
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http://dx.doi.org/10.1111/jog.14735DOI Listing
May 2021

Biological significance of KRAS mutant allele expression in ovarian endometriosis.

Cancer Sci 2021 May 30;112(5):2020-2032. Epub 2021 Mar 30.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

KRAS is the most frequently mutated in ovarian endometriosis. However, it is unclear whether the KRAS mutant allele's mRNA is expressed and plays a biological role in ovarian endometriosis. Here, we performed mutation-specific RNA in situ hybridization to evaluate mutant allele expression of KRAS p.G12V, the most frequently detected mutation in ovarian endometriosis in our previous study, in formalin-fixed paraffin-embedded tissue (FFPE) samples of ovarian endometriosis, cancer cell lines, and ovarian cancers. First, we verified that mutant or wild-type allele of KRAS were expressed in all 5 cancer cell lines and 9 ovarian cancer cases corresponding to the mutation status. Next, we applied this assay to 26 ovarian endometriosis cases, and observed mutant allele expression of KRAS p.G12V in 10 cases. Mutant or wild-type allele of KRAS were expressed in line with mutation status in 12 available endometriosis cases for which KRAS gene sequence was determined. Comparison of clinical features between ovarian endometriosis with KRAS p.G12V mutant allele expression and with KRAS wild-type showed that KRAS p.G12V mutant allele expression was significantly associated with inflammation in ovarian endometriosis. Finally, we assessed the spatial distribution of KRAS mutant allele expression in 5 endometriosis cases by performing multiregional sampling. Intratumor heterogeneity of KRAS mutant allele expression was observed in two endometriosis cases, whereas the spatial distribution of KRAS p.G12V mutation signals were diffuse and homogenous in ovarian cancer. In conclusion, evaluation of oncogene mutant expression will be useful for clarifying the biological significance of oncogene mutations in benign tumors.
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http://dx.doi.org/10.1111/cas.14871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088964PMC
May 2021

Establishment of 3D spheroid cell cultivation from human gynecologic cancer tissues.

STAR Protoc 2021 Mar 18;2(1):100354. Epub 2021 Feb 18.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, Niigata 951-8510, Japan.

Advanced-stage gynecologic cancer remains a life-threatening disease. Here, we present a protocol for establishment of stable 3D spheroid cells derived from human uterine endometrial and ovarian cancer tissues. The tumor-derived spheroid cells have cancer stem cell-related characteristics, including tumorigenesis, and can be used for biological and biochemical analyses and drug efficacy assays. Because these cells possess the biological characteristics of original human tumors, spheroid cells and spheroid-derived xenografts will have applications in personalized medicine in the future. For complete details on the use and execution of this protocol, please refer to Ishiguro et al. (2016) and Mori et al. (2019).
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http://dx.doi.org/10.1016/j.xpro.2021.100354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905465PMC
March 2021

A randomized phase III trial of adjuvant chemotherapy versus concurrent chemoradiotherapy for postoperative cervical cancer: Japanese Gynecologic Oncology Group study (JGOG1082).

Int J Gynecol Cancer 2021 Apr 4;31(4):623-626. Epub 2021 Mar 4.

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

Background: The standard treatment for stage IB-IIB cervical cancer is radiotherapy or radical hysterectomy; after radical hysterectomy, adjuvant concurrent chemoradiotherapy is recommended for patients with high risk factors. However, adjuvant concurrent chemoradiotherapy can cause severe gastrointestinal and urinary toxicity.

Primary Objective: To assess whether postoperative adjuvant chemotherapy is not inferior to adjuvant concurrent chemoradiotherapy for overall survival in patients with high risk cervical cancer.

Study Hypothesis: Adjuvant chemotherapy is not inferior to adjuvant concurrent chemoradiotherapy for overall survival and will reduce severe toxicities.

Trial Design: Patients with high risk factors after radical hysterectomy will be randomized 1:1 to receive adjuvant concurrent chemoradiotherapy or adjuvant chemotherapy. Treatment will be started within 6 weeks of surgery. The concurrent chemoradiotherapy group will receive whole pelvis irradiation (50.4 Gy) and cisplatin (40 mg/m/week). The chemotherapy group will receive paclitaxel (175 mg/m) plus cisplatin (50 mg/m) or carboplatin (AUC=6) every 3 weeks for six cycles.

Major Inclusion/exclusion Criteria: Patients with high risk stage IB-IIB cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma) who underwent radical hysterectomy are eligible for the study. High risk is defined as the presence of pelvic lymph node metastasis and/or parametrial invasion.

Primary Endpoint: The primary endpoint is overall survival.

Sample Size: 250 patients in total are required.

Estimated Dates For Completing Accrual: This study began in November 2019, and 250 patients will be accrued within 5 years.

Trial Registration Number: The study has been registered with the Japan Registry of Clinical Trials (jRCTs041190042).
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http://dx.doi.org/10.1136/ijgc-2020-002344DOI Listing
April 2021

The validity of the subsequent pregnancy index score for fertility-sparing trachelectomy in early-stage cervical cancer.

Fertil Steril 2021 May 13;115(5):1250-1258. Epub 2021 Feb 13.

Department of Obstetrics and Gynecology, Tokai University School of Medicine, Kanagawa, Japan. Electronic address:

Objective: To evaluate timing and a prediction model for pregnancy in early-stage cervical cancer patients who underwent fertility-sparing trachelectomy.

Design: Retrospective cohort.

Setting: Academic multicenter.

Patient(s): Women ages <45 years with clinical stage I-II cervical cancer were enrolled between 2009 and 2013 (n = 393).

Intervention(s): Planned fertility-sparing trachelectomy.

Main Outcome Measure(s): Cumulative incidences and clinicopathological characteristics of those who developed subsequent pregnancy were examined.

Result(s): There were 77 (21.6%) women who had subsequent pregnancies after fertility-sparing trachelectomy with 1-, 2-, and 5-year cumulative pregnancy rates of 2.8%, 6.2%, and 17.4%, respectively. The median time to develop subsequent pregnancy was 3.2 years. In a competing risk analysis, women had a higher risk of recurrent cancer than conception during the first 11 months postsurgery. On multivariable analysis, younger age, being married, and postoperative reproductive treatment were independently associated with an increased chance of developing a subsequent pregnancy. The subsequent pregnancy index (SPI) score to predict the likelihood of having pregnancy was proposed, and it was calculated based on age, marital status, and reproductive treatment (2, 2, and 4 points, respectively). Women with a higher SPI score had significantly higher subsequent pregnancy rates (5-year pregnancy rate; the score was 3 in 4.7% of cases; 4 to 5 in 11.3%; 6 to 7 in 27.4%; and 8 in 50.8%), but they had similar recurrence rates (5.0%).

Conclusion(s): The SPI score proposed in our study is useful in predicting subsequent pregnancy in women with early-stage cervical cancer undergoing fertility-sparing trachelectomy.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.162DOI Listing
May 2021

Risk factors for HPV infection and high-grade cervical disease in sexually active Japanese women.

Sci Rep 2021 Feb 3;11(1):2898. Epub 2021 Feb 3.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan.

In Japan, recommendations for HPV vaccines were suspended in 2013 due to unfounded safety fears. Although vaccine opponents claim modifying sexual behavior can prevent cervical cancer, no comprehensive data exist on sexual behavior and the risk of high-grade cervical disease in a Japanese population. This study investigates sexual behavior and the risk of HPV infection and cervical disease in 3968 women aged 20-41 yrs undergoing cervical screening between April 2014 and March 2016. Mean age at first intercourse was 18.4 yrs ± 2.8 and 32% of women reported ≥ 6 lifetime sexual partners. In regression analyses, number of partners was a significant risk factor for HPV infection. However, for high-grade disease (CIN2+), when HPV genotype was adjusted for, number of partners was not statistically significant. The greatest risk factor was an HPV16/18 infection (adjusted odds ratio 113.7, 95% CI: 40.8-316.9). In conclusion, we found that having an HPV16/18 infection and not sexual behavior was the most significant risk factor for high grade cervical disease in young Japanese women. These infections can be prevented by a highly effective vaccine and we recommend that the Japanese government resume proactive recommendations for the HPV vaccine immediately.
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http://dx.doi.org/10.1038/s41598-021-82354-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858628PMC
February 2021

Factor Structure and Measurement Invariance of the Hospital Anxiety and Depression Scale Across the Peripartum Period Among Pregnant Japanese Women.

Neuropsychiatr Dis Treat 2021 26;17:221-227. Epub 2021 Jan 26.

Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Purpose: The Hospital Anxiety and Depression Scale (HADS) is a self-report questionnaire widely used to assess anxiety and depression. To the best of our knowledge, only four studies have examined the factor structure of the HADS for assessing pregnant women, with conflicting results. This study aimed to assess the factor structure and measurement invariance of the HADS for use with pregnant Japanese women.

Participants And Methods: A total of 936 pregnant Japanese women completed the HADS questionnaire at three time points: the first and third trimester of pregnancy, and postpartum. We examined the factor structure of the HADS in Group 1 (n = 466) using exploratory factor analysis (EFA). We then compared the models identified in Group 1 with those from previous studies using confirmatory factor analysis (CFA) in Group 2 (n = 470). We performed multiple-group CFA for Group 2 to test the measurement invariance of the best-fit model across the three time points.

Results: The EFA for the Group 1 data at the three time points revealed a two-factor model. In the CFA, the two-factor model from Group 1 showed the best fit with the data at the three time points. In the multiple-group CFA for Group 2, we confirmed the configural and metric invariance of the two-factor model across the three time points.

Conclusion: Our findings provide evidence for a two-factor structure and weak measurement invariance of the HADS in pregnant Japanese women during the peripartum period.
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http://dx.doi.org/10.2147/NDT.S294918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847374PMC
January 2021

The disease sites of female genital cancers of BRCA1/2-associated hereditary breast and ovarian cancer: a retrospective study.

World J Surg Oncol 2021 Feb 2;19(1):36. Epub 2021 Feb 2.

Division of Breast Surgical Oncology, Department of Surgery, Showa University School of Medicine, Tokyo, Japan.

Disease sites of female genital tract cancers of BRCA1/2-associated hereditary breast and ovarian cancer (HBOC) are less understood than non-hereditary cancers. We aimed to elucidate the disease site distribution of genital cancers in women with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+) of HBOC. For the primary disease site, the proportion of fallopian tube and peritoneal cancer was significantly higher in BRCA2+ (40.5%) compared with BRCA1+ (15.4%) and BRCA- (no pathogenic variant, 12.8%). For the metastatic site, the proportion of peritoneal dissemination was significantly higher in BRCA1+ (71.9%) than BRCA- (55.1%) and not different from BRCA2+ (71.4%). With one of the most extensive patients, this study supported the previous reports showing that the pathogenic variants of BRCA1/2 were involved in the female genitalia's disease sites.
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http://dx.doi.org/10.1186/s12957-021-02151-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856749PMC
February 2021

Internet Survey of Awareness and Behavior Related to HPV Vaccination in Japan.

Vaccines (Basel) 2021 Jan 25;9(2). Epub 2021 Jan 25.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.

Recommendations for HPV vaccines were suspended in 2013 due to unfounded safety fears in Japan. We aimed to clarify the differences between vaccinated and unvaccinated females in their awareness, knowledge, and behaviors toward cervical cancer, HPV vaccination and sex. Questionnaires were administered online to women aged 16 to 20. We conducted investigations for the following: awareness, knowledge, and actions for cervical cancer, HPV vaccination, and sexual activity, as well as items related to participants' social background. The survey in 828 girls revealed three points. The first is that more than half of the surveyed Japanese girls had poor knowledge about cervical cancer screening, HPV, or HPV vaccines. The second is that those in the unvaccinated group had a particularly poor knowledge of the subject and tended to have higher sexual activity. The final is that only 0.5% of the girls experienced changes in awareness about sexual activity after vaccination. In conclusion, this is the first large-scale survey analyzing the association between HPV vaccination and sexual activity in Japanese girls. Not only do unvaccinated girls not benefit from vaccines, but they also tend to engage in high-risk sexual behavior, and thus it is even more important to provide information on the effectiveness of vaccines and the usefulness of cancer screening.
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http://dx.doi.org/10.3390/vaccines9020087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910902PMC
January 2021

Enlarged uterine fibroid forming uterine diverticulum during pregnancy: a case report.

BMC Pregnancy Childbirth 2021 Jan 7;21(1):34. Epub 2021 Jan 7.

Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

Background: Although uterine fibroids are a common gynecologic neoplasm, uterine diverticulum accompanied by a uterine fibroid is unique. In addition, pregnancy complicated with uterine diverticulum is extremely rare. We experienced a case of a uterine fibroid that was associated with a uterine diverticulum that enlarged during pregnancy and puerperium.

Case Presentation: A 25-year-old nulligravida woman had an abnormal uterine cavity surrounded by myomatous mass. After natural conception, the mass and pouch had enlarged during pregnancy. Six months after elective cesarean delivery, she underwent laparotomy because of abdominal pain caused by the myomatous mass and the fluid inside. The tumor was connected to the midline of the posterior wall of the normal uterus. The resected tumor was pathologically diagnosed as leiomyoma and diverticulum.

Conclusions: Pregnancy can stimulate uterine fibroids to form uterine diverticula. Resection of the diverticulum and fibroid is a useful option for symptomatic patients with desired future fertility.
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http://dx.doi.org/10.1186/s12884-020-03505-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792331PMC
January 2021

Surgical margin status and recurrence pattern in invasive vulvar Paget's disease: A Japanese Gynecologic Oncology Group study.

Gynecol Oncol 2021 Mar 29;160(3):748-754. Epub 2020 Dec 29.

Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata, Niigata, Japan.

Objective: To examine the association between surgical margin status and recurrence pattern in invasive vulvar Paget's disease.

Methods: This is a preplanned secondary analysis of a previously organized nationwide retrospective study in Japan (JGOG-1075S). Women with stage I-IV invasive vulvar Paget's disease who received surgical treatment from 2001-2010 were examined (n=139). Multivariable analysis was performed to assess local-recurrence, distant-recurrence, and all-cause mortality based on surgical margin status.

Results: The median age was 70 years. The majority had stage I disease (61.2%), and the median tumor size was 5.0cm. Nodal metastasis was observed in 15.1%. Simple vulvectomy (46.0%) was the most common surgery type followed by radical vulvectomy (28.1%). More than half received vulvar reconstructive surgery (59.0%). Positive surgical margin was observed in 35.3%, and close margin <1cm was observed in 29.5%. Vulvectomy type was not associated with surgical margin status (P=0.424). The median follow-up was 5.8 years. Positive surgical margin was associated with increased local-recurrence (5-year cumulative rates for positive versus negative margin: 35.8% versus 15.0%, P=0.010) but not distant-recurrence (18.3% versus 16.0%, P=0.567). Positive surgical margin was also associated with increased all-cause mortality (5-year overall survival rates for positive versus negative margin: 72.6% versus 88.2%, P=0.032). In multivariable analysis, positive surgical margin remained an independent factor associated with increased risk of local-recurrence (hazard ratio 2.80, 95% confidence interval 1.18-6.63) and all-cause mortality (hazard ratio 2.87, 95% confidence interval 1.20-6.83).

Conclusion: Positive surgical margin appears to be common in invasive vulvar Paget's disease that is associated with increased local-recurrence and all-cause mortality risks. Role of alternative surgical technique or adjuvant therapy merits further investigation to improve local disease control.
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http://dx.doi.org/10.1016/j.ygyno.2020.12.023DOI Listing
March 2021

Depression, Anxiety and Primiparity are Negatively Associated with Mother-Infant Bonding in Japanese Mothers.

Neuropsychiatr Dis Treat 2020 14;16:3117-3122. Epub 2020 Dec 14.

Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Purpose: Postpartum depression is a well-known risk factor, and postpartum anxiety and parity are potential risk factors, for mother-infant bonding disorder. However, few studies have focused on the relationships among these factors and mother-infant bonding. This cross-sectional study explored the associations between depression, anxiety and parity, and mother-infant bonding.

Materials And Methods: Japanese mothers, both primiparas and multiparas, completed the Mother-to-Infant Bonding Scale (MIBS) and the Hospital Anxiety and Depression Scale (HADS) one month after childbirth. We performed a stepwise multiple regression analysis with the forward selection method to assess the effects of HADS anxiety and depression scores and parity as independent variables on mother-infant bonding as the dependent variable.

Results: A total of 2379 Japanese mothers (1116 primiparas and 1263 multiparas) took part in the study. MIBS score (2.89 ± 2.68 vs 1.60 ± 2.11; < 0.0001) was significantly higher in primiparas than in multiparas. HADS anxiety (6.55 ± 4.06 vs 4.63 ± 3.41; < 0.0001) and depression (6.56 ± 3.43 vs 5.98 ± 3.20; < 0.0001) scores were also significantly higher in primiparas than in multiparas. A stepwise multiple regression analysis with the forward selection method revealed that HADS depression and anxiety scores and parity were significantly associated with MIBS score ( = 0.003, 0.015 and 0.023).

Conclusion: Depression, anxiety and primiparity were negatively associated with mother-infant bonding one month after childbirth.
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http://dx.doi.org/10.2147/NDT.S287036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751780PMC
December 2020

Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-like Cells using the Three-dimensional Co-culture System, NICO-1.

J Vis Exp 2020 12 5(166). Epub 2020 Dec 5.

Department of Obstetrics and Gynecology, Teikyo University School of Medicine.

Cancer stem cells (CSCs) reside in a supportive niche, constituting a microenvironment comprised of adjacent stromal cells, vessels, and extracellular matrix. The ability of CSCs to participate in the development of endothelium constitutes an important characteristic that directly contributes to the general understanding of the mechanisms of tumorigenesis and tumor metastasis. The purpose of this work is to establish a reproducible methodology to investigate the tumor-initiation capability of ovarian cancer stem cells (OCSCs). Herein, we examined the neovascularization mechanism between endothelial cells and OCSCs along with the morphological changes of endothelial cells using the in vitro co-culture model NICO-1. This protocol allows visualization of the neovascularization step surrounding the OCSCs in a time course manner. The technique can provide insight regarding the angiogenetic properties of OCSCs in tumor metastasis.
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http://dx.doi.org/10.3791/61751DOI Listing
December 2020

MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells.

Cancer Sci 2021 Mar 22;112(3):1209-1224. Epub 2021 Jan 22.

Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan.

Cancer stem-like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c-Myc. c-Myc-dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient-derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S-phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c-Myc-MCM10 axis for preventing drug resistance and recurrence of tumors.
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http://dx.doi.org/10.1111/cas.14776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935783PMC
March 2021

Health consciousness and cervical cancer screening rates in HPV-unvaccinated girls: comparison from HPV-recommended and HPV-recommendation-suspended program periods.

Hum Vaccin Immunother 2021 Apr 3;17(4):1068-1072. Epub 2020 Dec 3.

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

In Japan, the vast majority of females between 13 and 24 are now unvaccinated for HPV and thus unprotected from HPV-caused cervical cancer. We analyzed the differences among these unvaccinated females regarding their understanding of the HPV vaccine, its role in cervical cancer prevention, and their need for cervical cancer screening - based on whether they refused vaccination when their government's recommendation for HPV vaccination was still in effect () - or during the last 7 years, while the government suspension was in effect (). The understood more about the HPV vaccine and the best timing for HPV vaccination than the ( < .0001 and = .002, respectively). We found that girls in the had more chances to talk with the family about cervical cancer and they were more afraid of acquiring the disease ( < .0001 and < .0001, respectively). The girls in the tended to feel more inhibited from talking about cervical cancer with friends and acquaintances ( = .0262). The cervical cancer screening rate of the was significantly higher ( = .014).
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http://dx.doi.org/10.1080/21645515.2020.1830684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018379PMC
April 2021

Impact of lymphadenectomy on the treatment of endometrial cancer using data from the JSOG cancer registry.

Obstet Gynecol Sci 2021 Jan 27;64(1):80-89. Epub 2020 Nov 27.

Department of Obstetrics and Gynecology, Tokai University School of Medicine, Kanagawa, Japan.

Objective: Regional lymph node (LN) dissection is a standard surgical procedure for endometrial cancer, but there is currently no clear consensus on its therapeutic significance. We aimed to determine the impact of regional LN dissection on the outcome of endometrial cancer.

Methods: Study subjects comprised 36,813 patients who were registered in the gynecological tumor registry of the Japan Society of Obstetrics and Gynecology, had undergone initial surgery for endometrial cancer between 2004 and 2011, and whose clinicopathological factors and prognosis were appropriate for our investigation. The following clinicopathological factors were obtained from the registry: age, surgical stage classification, Union for International Cancer Control tumor, node, metastasis classification, histological type, histological differentiation, presence or absence of LN dissection, and postoperative treatment. We retrospectively analyzed the clinicopathological factors and therapeutic outcomes for patients with endometrial cancer.

Results: Analysis of all subjects showed that the group that underwent LN dissection had a significantly better overall survival than the group that did not undergo dissection. Analysis based on stage showed similar results across groups, except for stage Ia. Analysis based on stage and histological type showed similar results across groups, except for stage Ia endometrial carcinoma G1 or Ia G2. Multivariate analysis of prognostic factors indicated that LN dissection is an independent prognostic factor and that it has a greater impact on prognosis than adjuvant chemotherapy.

Conclusion: Despite the limitations of a retrospective study with some biases, the results suggest that LN dissection in endometrial cancer has a prognostic effect.
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http://dx.doi.org/10.5468/ogs.20186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834758PMC
January 2021