Publications by authors named "Nobuo Yaegashi"

473 Publications

The trend and outcome of postsurgical therapy for high-risk early-stage cervical cancer with lymph node metastasis in Japan: a report from the Japan Society of Gynecologic Oncology (JSGO) guidelines evaluation committee.

J Gynecol Oncol 2021 May;32(3):e44

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

Objective: The Japan Society of Gynecologic Oncology published the first guidelines for the treatment of cervical cancer in 2007. The aim of this research was to evaluate the influence of the introduction of the first guideline on clinical trends and outcomes of patients with early-stage cervical cancer who underwent surgery.

Methods: This analysis included 9,756 patients who were diagnosed based on the pathological Tumor-Node-Metastasis (pTNM) classification (i.e., pT1b1, pT1b2, pT2b and pN0, pN1, pNX) and received surgery as a primary treatment between 2004 and 2009. Data of these patients were retrospectively reviewed, and clinicopathological trends were assessed. The influence of the introduction of the guideline on survival was determined by using a competing risk model.

Results: For surgery cases, the estimated subdistribution hazard ratio (HR) by the competing risk model for the influence of the guideline adjusted for age, year of registration, pT classification, pN classification, histological type, and treatment methods was 1.024 (p=0.864). Following the introduction of the first guideline in 2007, for patients with lymph node metastasis, the use of chemotherapy (CT) as a postsurgical therapy increased, whereas that of concurrent chemoradiotherapy (CCRT)/radiotherapy (RT) decreased (p<0.010). For pN1 cases, the estimated subdistribution HR by the competing risk model for the influence of the guideline was 1.094 (p=0.634). There was no significance in the postsurgical therapy between CT and CCRT/RT (p=0.078).

Conclusions: Survival of surgical cases was not improved by the introduction of the guidelines. It is necessary to consider more effective postsurgical therapy for high-risk early-stage cervical cancer.
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http://dx.doi.org/10.3802/jgo.2021.32.e44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039172PMC
May 2021

Abnormal early folliculogenesis due to impeded pyruvate metabolism in mouse oocytes.

Biol Reprod 2021 Apr 6. Epub 2021 Apr 6.

Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Miyagi, Japan.

Fetal ovarian germ cells show characteristic energy metabolism status, such as enhanced mitochondrial metabolism as well as glycolysis, but their roles in early folliculogenesis are unclear. We show here that inhibition of pyruvate uptake to mitochondria by UK5099 in organ cultures of fetal mouse ovaries resulted in repressed early folliculogenesis without affecting energy production, survival of oocytes, or meiosis. In addition, the abnormal folliculogenesis by UK5099 was partially rescued by α-ketoglutarate and succinate, intermediate metabolites in the TCA cycle, suggesting the importance of those metabolites. The expression of TGFβ-related genes Gdf9 and Bmp15 in ovarian germ cells, which are crucial for folliculogenesis, was downregulated by UK5099, and the addition of recombinant GDF9 partially rescued the abnormal folliculogenesis induced by UK5099. We also found that early folliculogenesis was similarly repressed, as in the culture, in the ovaries of a germ cell-specific knockout of Mpc2, which encodes a mitochondria pyruvate carrier that is targeted by UK5099. These results suggest that insufficient Gdf9 expression induced by abnormal pyruvate metabolism in oocytes results in early follicular dysgenesis, which is a possible cause of defective folliculogenesis in humans.
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http://dx.doi.org/10.1093/biolre/ioab064DOI Listing
April 2021

Involvement of small extracellular vesicle-derived TIE-1 in the chemoresistance of ovarian cancer cells.

Cancer Treat Res Commun 2021 Mar 28;27:100364. Epub 2021 Mar 28.

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

Background: Ovarian cancer is the most lethal gynecologic malignancy due to the tumor's acquisition of chemoresistance to platinum-based chemotherapy. To solve this problem, we conducted RNAi-based large-scale screening and determined that tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) is a key molecule involved in the platinum resistance of ovarian cancer cells. Recently, a variety of studies have investigated that small extracellular vesicles (sEVs) contribute to the communication between cancer cells, including the development of chemoresistance in ovarian cancer. The purpose of our study is to determine if sEVs-derived TIE-1 is involved in the chemoresistance of ovarian cancer cells.

Materials And Methods: TIE-1-overexpressed TOV112D cells, termed TOV112D cells, were established, and sEVs were isolated from TOV112D cells supernatants by ultracentrifugation. We assessed cisplatin sensitivity in recipient cells with TOV112D-derived sEVs by cell-Titer Glo kit. We also asked whether sEV-derived TIE-1 suppressed the DNA damage response in recipient cells and evaluated the DNA damage response by counting cells positive for DNA damage foci.

Results: TIE-1 was contained within sEV derived from the cellular supernatant of TOV112D. We showed that sEV-derived TIE-1 decreased chemosensitivity to cisplatin by suppressing the DNA damage response in recipient cells.

Conclusion: Our findings suggest that sEV-derived TIE-1 could be a new therapeutic target for refractory ovarian cancer.
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http://dx.doi.org/10.1016/j.ctarc.2021.100364DOI Listing
March 2021

Survey of the clinical practice pattern of using sentinel lymph node biopsy in patients with gynecological cancers in Japan: the Japan Society of Gynecologic Oncology study.

Int J Clin Oncol 2021 May 25;26(5):971-979. Epub 2021 Mar 25.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

Background: Sentinel lymph node (SN) biopsy is essential for evaluating survival and minimal treatment-related morbidity associated with cervical, endometrial, and vulvar cancer in Japan. As such, our aim in this study was to evaluate the current practice pattern of using SN biopsy for cervical, endometrial, and vulvar cancer in Japan.

Methods: We deployed a 47-question survey on the use of SN biopsy for gynecological cancers to 216 gynecological oncology training facilities. The survey included information on the use of SN biopsy for uterine (cervical and endometrial) and vulvar cancers; details on the type, timing, and concentration of tracers used; surgical approach used for SN biopsy; method of biopsy and pathological examination; and facilities' experience with clinical research on SN biopsy.

Results: The response rate was 84% (181/216), with 40 facilities (22%) having experience in SN biopsy for gynecological cancers, 34 (85%) for uterine cancers, and 15 (37%) for vulvar cancers. Radioisotope, indocyanine green (ICG), and blue dyes were available for the detection of uterine cancers in 21 (52%), 25 (62%), and 19 (48%) facilities and for vulvar cancers in 9 (22%), 3 (7%), and 11 (27%) facilities, respectively. Thirty-four facilities (85%) used intraoperative frozen section procedure for diagnosis when possible, with 24 (71%) of these facilities using 2-mm specimen cuts. Diagnosis included pathological examination (85%), immunostaining (57%), and one-step nucleic acid amplification (5%).

Conclusion: Increasing research evidence, providing insurance coverage for radioisotope tracers, and increasing the availability of training are expected to increase the use of SN biopsy in Japan.
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http://dx.doi.org/10.1007/s10147-021-01862-7DOI Listing
May 2021

Prospective Association between Maternal Bonding Disorders and Child Toothbrushing Frequency: a cross-sectional study of the Japan Environment and Children's Study.

Int J Paediatr Dent 2021 Mar 25. Epub 2021 Mar 25.

Department of Orthodontics and Speech Therapy for Craniofacial Anomalies, Tohoku University Hospital, Sendai, Miyagi, Japan, 980-8574.

Background: Daily toothbrushing effectively prevents early childhood caries, but it depends on facilitative parenting behaviours. Mother-to-infant bonding, the maternal affection toward the infant, is an environmental factor that strongly influences parenting.

Aim: This study examined the association between maternal bonding and children's daily toothbrushing frequency.

Design: The sample consisted of 83,954 mother-infant pairs at two years postpartum, derived from the initial sample of JECS (cohort study), that included 104,062 foetuses. Maternal bonding disorders were assessed using the Mother-to-Infant Bonding Scale (MIBS). After multiple imputations for missing data, a multinomial logistic regression analysis was conducted with adjustments for several maternal (e.g., age at delivery) and child-related (e.g., self-performed toothbrushing) variables.

Results: The odds ratio (95% confidence interval) for the association of maternal bonding disorders with the low (once per day) and the very low child toothbrushing frequency (<1 per day) was 1.12 (1.07-1.17) and 1.23 (0.91-1.66), respectively after covariate adjustments. Furthermore, the univariate general linear model showed that the mean MIBS scores significantly decreased as the daily child toothbrushing frequency increased.

Conclusions: The prevalence of maternal bonding disorders at one year postpartum was prospectively associated with a lower frequency of child toothbrushing at two years of age.
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http://dx.doi.org/10.1111/ipd.12791DOI Listing
March 2021

The prevalence of psychological distress during pregnancy in Miyagi Prefecture for 3 years after the Great Eas t Japan Earthquake.

Environ Health Prev Med 2021 Feb 26;26(1):27. Epub 2021 Feb 26.

Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8573, Japan.

Background: To examine changes in psychological distress prevalence among pregnant women in Miyagi Prefecture, which was directly affected by the Great East Japan Earthquake and tsunami, and compare it with the other, less damaged areas of Japan.

Methods: This study was conducted in conjunction with the Japan Environment and Children`s Study. We examined 76,152 pregnant women including 8270 in Miyagi Regional Center and 67,882 in 13 other regional centers from the all-birth fixed data of the Japan Environment and Children's Study. We then compared the prevalence and risk of distress in women in Miyagi Regional Center and women in the 13 regional centers for 3 years after the disaster.

Results: Women in the Miyagi Regional Center suffered more psychological distress than those in the 13 regional centers: OR 1.38 (95% CI, 1.03-1.87) to 1.92 (95% CI, 1.42-2.60). Additionally, women in the inland area had a consistently higher prevalence of psychological distress compared to those from the 13 regional centers: OR 1.67 (95% CI, 1.18-2.38) to 2.19 (95% CI, 1.60-2.99).

Conclusions: The lack of pre-disaster data in the Japan Environment and Children's Study made it impossible to compare the incidence of psychological distress before and after the March 2011 Great East Japan Earthquake. However, 3 years after the Great East Japan Earthquake, the prevalence of pregnant women with psychological distress did not improve in Miyagi Regional Center. Further, the prevalence of mental illness in inland areas was consistently higher than that in the 13 regional centers after the disaster.
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http://dx.doi.org/10.1186/s12199-021-00944-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913250PMC
February 2021

Annual report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology: Annual patient report for 2017 and annual treatment report for 2012.

J Obstet Gynaecol Res 2021 May 25;47(5):1631-1642. Epub 2021 Feb 25.

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

Aim: To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2017 and the Annual Treatment Report for 2012, on the outcomes of patients who started treatment in 2012.

Methods: The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry, where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment with gynecologic malignancies was initiated in 2017 were analyzed retrospectively. Survival of the patients who started treatment with cervical, endometrial and ovarian cancer in 2012 was analyzed by using the Kaplan-Meier, log-rank and Wilcoxon tests.

Results: Treatment was initiated in 2017 for 7710 patients with cervical cancer; 11 120 with endometrial cancer; 7029 with ovarian, tubal and peritoneal cancer; 2164 with ovarian borderline tumors; and with the others (213 vulvar cancer, 139 vaginal cancer, 366 uterine sarcoma, 41 uterine adenosarcoma and 131 trophoblastic diseases). This clinicopathological information was summarized as the patient annual report. The 5-year survival rates of the patients with cervical cancer were 92.9, 75.5, 58.2 and 26.7% for stages I, II, III and IV, respectively. The 5-year survival rates for the patients with endometrial cancer were 93.6, 85.6, 72.6 and 27.3% for stages I, II, III and IV, respectively. The 5-year survival rates for the patients with ovarian cancer (surface epithelial-stromal tumors) were 92.5, 83.5, 49.5 and 30.8% for stages I, II, III and IV, respectively.

Conclusion: The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan.
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http://dx.doi.org/10.1111/jog.14724DOI Listing
May 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

Lymphadenectomy issues in endometrial cancer.

J Gynecol Oncol 2021 Mar 7;32(2):e25. Epub 2021 Jan 7.

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

Objectives: This review aims to introduce preoperative scoring systems to predict lymph node metastasis (LNM) and ongoing clinical trials to investigate the therapeutic role of lymphadenectomy for endometrial cancer.

Methods: We summarized previous reports on the preoperative prediction models for LNM and evaluated their validity to omit lymphadenectomy in our recent cohorts. Next, we compared characteristics of two ongoing lymphadenectomy trials (JCOG1412, ECLAT) to examine the survival benefit of lymphadenectomy in endometrial cancer, and described the details of JCOG1412.

Results: Lymphadenectomy has been omitted for 64 endometrial cancer patients who met low-risk criteria to omit lymphadenectomy using our scoring system (LNM score) and no lymphatic failure has been observed. Other two models also produced comparable results. Two randomized phase III trials to evaluate survival benefit of lymphadenectomy are ongoing for endometrial cancer. JCOG1412 compares pelvic lymphadenectomy alone with pelvic and para-aortic lymphadenectomy to evaluate the therapeutic role of para-aortic lymphadenectomy for patients at risk of LNM. For quality assurance of lymphadenectomy, we defined several regulations, including lower limit of the number of resected nodes, and submission of photos of dissected area to evaluate thoroughness of lymphadenectomy in the protocol. The latest monitoring report showed that the quality of lymphadenectomy has been well-controlled in JCOG1412.

Conclusion: Our strategy seems reasonable to omit lymphadenectomy and could be generalized in clinical practice. JCOG1412 is a high-quality lymphadenectomy trial in terms of the quality of surgical procedures, which would draw the bona-fide conclusions regarding the therapeutic role of lymphadenectomy for endometrial cancer.
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http://dx.doi.org/10.3802/jgo.2021.32.e25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930450PMC
March 2021

Estimation of the carrier frequencies and proportions of potential patients by detecting causative gene variants associated with autosomal recessive bone dysplasia using a whole-genome reference panel of Japanese individuals.

Hum Genome Var 2021 Jan 15;8(1). Epub 2021 Jan 15.

Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.

Bone dysplasias are a group of rare hereditary diseases, with up to 436 disease types. Perinatal diagnosis is clinically important for adequate personalized management and counseling. There are no reports focused on pathogenic variants of bone dysplasias in the general population. In this study, we focused on autosomal recessive bone dysplasias. We identified pathogenic variants using whole-genome reference panel data from 3552 Japanese individuals. For the first time, we were able to estimate the carrier frequencies and the proportions of potential patients. For autosomal recessive bone dysplasias, we detected 198 pathogenic variants of 54 causative genes. We estimated the variant carrier frequencies and the proportions of potential patients with variants associated with four clinically important bone dysplasias: osteogenesis imperfecta (OI), hypophosphatasia (HPP), asphyxiating thoracic dysplasia (ATD), and Ellis-van Creveld syndrome (EvC). The proportions of potential patients with OI, ATD, and EvC based on pathogenic variants classified as "pathogenic" and "likely pathogenic" by InterVar were closer to the reported incidence rates in Japanese subjects. Furthermore, the proportions of potential patients with HPP variants classified as "pathogenic" and "likely pathogenic" in InterVar and "pathogenic" in ClinVar were closer to the reported incidence rates. For bone dysplasia, the findings of this study will provide a better understanding of the variant types and frequencies in the Japanese general population, and should be useful for clinical diagnosis, genetic counseling, and personalized medicine.
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http://dx.doi.org/10.1038/s41439-020-00133-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810679PMC
January 2021

Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2).

PLoS One 2021 11;16(1):e0236907. Epub 2021 Jan 11.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236907PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799847PMC
April 2021

Ceramide synthase 2-C -ceramide axis limits the metastatic potential of ovarian cancer cells.

FASEB J 2021 Feb;35(2):e21287

Laboratory of Immunopharmacology, Setsunan University, Osaka, Japan.

Regulation of sphingolipid metabolism plays a role in cellular homeostasis, and dysregulation of these pathways is involved in cancer progression. Previously, our reports identified ceramide as an anti-metastatic lipid. In the present study, we investigated the biochemical alterations in ceramide-centered metabolism of sphingolipids that were associated with metastatic potential. We established metastasis-prone sublines of SKOV3 ovarian cancer cells using an in vivo selection method. These cells showed decreases in ceramide levels and ceramide synthase (CerS) 2 expression. Moreover, CerS2 downregulation in ovarian cancer cells promoted metastasis in vivo and potentiated cell motility and invasiveness. Moreover, CerS2 knock-in suppressed the formation of lamellipodia required for cell motility in this cell line. In order to define specific roles of ceramide species in cell motility controlled by CerS2, the effect of exogenous long- and very long-chain ceramide species on the formation of lamellipodia was evaluated. Treatment with distinct ceramides increased cellular ceramides and had inhibitory effects on the formation of lamellipodia. Interestingly, blocking the recycling pathway of ceramides by a CerS inhibitor was ineffective in the suppression of exogenous C -ceramide for the formation of lamellipodia. These results suggested that C -ceramide, a CerS2 metabolite, predominantly suppresses the formation of lamellipodia without the requirement for deacylation/reacylation. Moreover, knockdown of neutral ceramidase suppressed the formation of lamellipodia concomitant with upregulation of C -ceramide. Collectively, the CerS2-C -ceramide axis, which may be countered by neutral ceramidase, is suggested to limit cell motility and metastatic potential. These findings may provide insights that lead to further development of ceramide-based therapy and biomarkers for metastatic ovarian cancer.
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http://dx.doi.org/10.1096/fj.202001504RRDOI Listing
February 2021

The delivery of a placenta/fetus with high gonadal steroid production contributes to postpartum depressive symptoms.

Depress Anxiety 2021 04 4;38(4):422-430. Epub 2021 Jan 4.

Department of Psychiatry, Tohoku University Hospital, Sendai, Japan.

Background: A correlation between gonadal steroids and depressive symptoms during the perinatal period has long been suggested; however, the underlying mechanism for this relationship remains unclear.

Methods: This study was designed to examine the correlation between gonadal steroid concentrations of umbilical cord blood and postpartum depressive symptoms as well as longitudinal alterations in maternal plasma gonadal steroid concentrations among 204 perinatal women. The levels of postpartum depressive state at 1 month postpartum were evaluated using the Edinburgh Postnatal Depression Scale.

Results: Umbilical progesterone, estradiol, and testosterone levels were significantly higher in infants delivered by depressed mothers (870.7 ± 281.7 ng/ml, 8607.7 ± 4354.6 pg/ml, and 2.5 ± 0.9 ng/ml, respectively) than those delivered by nondepressed mothers (741.3 ± 324.0 ng/ml, 5221.9 ± 3416.3 pg/ml, and 2.1 ± 0.6 ng/ml, p < .01, p < .05, and p < .05, respectively). Postpartum plasma progesterone levels of depressed mothers (3.5 ± 3.1 ng/ml) measured in the early postpartum period were significantly lower than those of nondepressed mothers (9.1 ± 9.7 ng/ml, p < .01). The decrease in progesterone from mid-pregnancy to the early postpartum period was significantly higher in depressed mothers than in nondepressed mothers. Subgroup analyses specific to primiparas or multiparas indicated that a significant drop of progesterone was seen only in primiparas.

Conclusion: The current study suggests that the delivery of a placenta/fetus with high gonadal steroid production may cause a wider range of fluctuations in maternal plasma gonadal steroid concentrations, which may be concurrent with postpartum depressive symptoms.
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http://dx.doi.org/10.1002/da.23134DOI Listing
April 2021

Prospective evaluation of sentinel node navigation surgery in Japanese patients with low-risk endometrial cancer-safety and occurrence of lymphedema.

Jpn J Clin Oncol 2021 Apr;51(4):584-589

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

Objective: The present study aimed to clarify the occurrence rate of lymphedema and prognosis in patients with endometrial cancer according to sentinel lymph node biopsy alone with intraoperative histopathological examination.

Methods: The study included 45 consecutive patients with endometrial cancer treated at Tohoku University Hospital between October 2014 and August 2017. All patients had endometrial carcinoma with endometrioid histology Grade 1 or Grade 2 confirmed by biopsy and stage I on magnetic resonance imaging and/or computed tomography at their preoperative evaluation. Sentinel lymph node detection was performed by radioisotope and dye. Patients who were diagnosed intraoperatively as negative for sentinel lymph node metastasis did not undergo further systematic pelvic lymphadenectomy. The occurrence rate of lymphedema and prognosis was evaluated.

Results: Bilateral sentinel lymph nodes were detected in 44 of 45 patients (97%). Forty-three patients underwent sentinel lymph node biopsy alone, and only two patients underwent systematic lymphadenectomy. Sentinel lymph node metastases were detected in one patient intraoperatively and two patients postoperatively as ITCs. No patients experienced recurrence. New symptomatic lower-extremity lymphedema was identified in one of 43 patients (2.3%) who underwent sentinel lymph node biopsy alone.

Conclusion: Sentinel lymph node biopsy alone with intraoperative histopathological diagnosis appears to be a safe and effective strategy to detect lymph node metastasis and to reduce the number of patients with lower-extremity lymphedema among patients with endometrial cancer.
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http://dx.doi.org/10.1093/jjco/hyaa252DOI Listing
April 2021

Associations of umbilical cord fatty acid profiles and desaturase enzyme indices with birth weight for gestational age in Japanese infants.

Prostaglandins Leukot Essent Fatty Acids 2021 Feb 30;165:102233. Epub 2020 Dec 30.

Department of Development and Environmental Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

Long-chain polyunsaturated fatty acids (LCPUFAs) required for infant development are produced by Δ6 desaturase (D6D) and Δ5 desaturase (D5D). The D6D index and D5D index are calculated based on their respective precursor/product ratios. The D5D and D6D indices are related to obesity and lifestyle-related diseases. The aim of the present study was to examine the associations of umbilical cord fatty acid profiles, D6D index, and D5D index in appropriate for gestational age (AGA), small for gestational age (SGA), and large for gestational age (LGA) infants. This was a nested case-control study, and the relationship between case and control maternal blood and umbilical cord blood fatty acid compositions was examined. Cases were small for gestational age (SGA; n = 55) and large for gestational age (LGA; n = 149) infants, whereas controls were appropriate for gestational age (AGA; n = 204) infants. Fatty acid profiles in maternal blood and umbilical cord plasma were analyzed by gas-liquid chromatography. The D6D index was calculated as dihomo-γ-linolenic acid (DGLA 20: 3 n-6) / linoleic acid (18: 2 n - 6), and the D5D index was calculated as arachidonic acid (20: 4 n - 6) / DGLA (20: 3 n - 6). Statistical analysis of umbilical cord blood fatty acids was performed with multiple comparisons. SGA infants showed high umbilical cord values for α-linolenic acid and DHA and lower values for DGLA compared to AGA infants. SGA infants showed a higher D5D index but a lower D6D index than AGA infants. LGA infants showed high values for α-linolenic acid and DGLA and lower values for arachidonic acid than AGA infants. LGA infants showed a high D6D index and a low D5D index relative to AGA infants. No significant differences in maternal blood fatty acid profiles, the D6D index, and D5D index desaturase activities were found among the three groups. There were differences in umbilical cord fatty acid profiles and D6D and D5D indices among AGA, SGA, and LGA infants, but further study is needed.
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http://dx.doi.org/10.1016/j.plefa.2020.102233DOI Listing
February 2021

Impact of Histopathological Risk Factors on the Treatment of Stage IB-IIB Uterine Cervical Cancer.

Tohoku J Exp Med 2020 12;252(4):339-351

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

In the past decade, the incidence of adenocarcinoma of the uterine cervix gradually increased. Recent literature revealed that the molecular pathogenesis differs by histological subtype, and the histological subtype should be considered in deciding treatments for patients with uterine cervical cancer. However, no treatment based on histological type or genomic signature has been recommended in various treatment guidelines. The Japanese treatment guidelines recommend either radical hysterectomy or definitive radiotherapy as primary treatment for patients with stage IB-IIB squamous cell carcinoma and a radical hysterectomy-based approach for those with non-squamous cell carcinoma because of its lower radiosensitivity. The impact of histological type on survival outcome of uterine cervical cancer is controversial. Our retrospective studies suggested that the difference in survival outcome by histological subtype might be remarkable with disease progression. Recent literature suggested that usual-type endocervical adenocarcinoma, which is the most common histological type of cervical adenocarcinoma, showed a similar survival outcome to squamous cell carcinoma. In contrast, gastric-type mucinous carcinoma of the uterine cervix, which has aggressive clinical behavior and is not associated with high-risk human papillomavirus infection, showed resistance to chemotherapy and radiotherapy. Importantly, gastric-type mucinous carcinoma is rather common in Japan, compared with Western countries. It is therefore conceivable that the survival outcome of non-squamous cell carcinoma may be affected by regional difference in the frequency of gastric-type mucinous carcinoma. A molecular target to refractory uterine cervical cancer, such as gastric-type mucinous carcinoma of uterine cervix, still remains to be identified.
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http://dx.doi.org/10.1620/tjem.252.339DOI Listing
December 2020

Propensity score-matched analysis of systemic chemotherapy versus salvage hysterectomy for persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy.

BMC Cancer 2020 Nov 30;20(1):1169. Epub 2020 Nov 30.

Department of Obstetrics and Gynecology, Tohoku University Hospital, Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.

Background: The aim of the current study was to evaluate oncologic outcomes of patients who were treated with salvage hysterectomy (HT), compared to systemic chemotherapy (CT) for persistent cervical cancer after definitive radiotherapy (RT)/ concurrent chemoradiotherapy (CCRT).

Methods: Patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions from 2005 to 2014 were reviewed retrospectively (n = 317). Those who underwent a HT for persistent cervical cancer after definitive RT/CCRT were matched with propensity scores for patients who underwent systemic CT. Oncologic outcomes between the two groups using a propensity score matched-cohort analysis were compared.

Results: A total of 142 patients with persistent cervical cancer after definitive RT/CCRT were included after matching (HT: 71, systemic CT: 71). All background factors between HT and CT groups were well balanced. Median overall survival was 3.8 and 1.5 years in the HT and CT groups, respectively (p = 0.00193, hazards ratio [HR] 0.41, 95% confidence interval [CI] 0.23-0.73), Increasing residual tumor size was significantly associated with a high incomplete resection rate (p = 0.016, Odds Ratio 1.11, 95%CI 1.02-1.22). Severe late adverse events occurred in 7 patients (9.9%) in the HT cohort.

Conclusion: The current study demonstrated that, when compared to systemic CT, the adoption of salvage HT for patients with persistent cervical cancer after definitive RT/CCRT reduced mortality rate by about 60%. This indicates that salvage HT could be curative treatment for those patients. Further prospective clinical trials with regard to salvage HT after RT/CCRT are warranted.
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http://dx.doi.org/10.1186/s12885-020-07672-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708164PMC
November 2020

The post-progression survival of patients with recurrent or persistent ovarian clear cell carcinoma: results from a randomized phase III study in JGOG3017/GCIG.

J Gynecol Oncol 2020 Nov;31(6):e94

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Morioka, Japan.

Objective: In this study we sought to investigate the clinical factors that affect post-progression survival (PPS) in patients with recurrent or persistent clear cell carcinoma (CCC). We utilized the JGOG3017/Gynecological Cancer InterGroup data to compare paclitaxel plus carboplatin (TC) and irinotecan plus cisplatin (CPT-P) in the treatment of stages I to IV CCC.

Methods: We enrolled 166 patients with recurrent or persistent CCC and assessed the impact of variables, including platinum sensitivity, treatment arm, crossover chemotherapy, primary stage, residual tumor at primary surgery, performance status, ethnicity, and tumor reduction surgery at recurrence on the median of PPS in patients with recurrent or persistent CCC.

Results: A total of 77 patients received TC, and 89 patients received CPT-P. The median PPS for patients with platinum-resistant disease was 10.9 months, compared with 18.8 months for patients with platinum-sensitive disease (hazard ratio [HR]=1.88; 95% confidence interval [CI]=1.30-2.72; log-rank p<0.001). In the multivariate analysis, the platinum sensitivity (resistant vs. sensitivity; HR=1.60; p=0.027) and primary stage (p=0.009) were identified as independent predictors of prognosis factors for PPS in recurrent or persistent CCC.

Conclusions: Our findings revealed that platinum sensitivity and primary stage are clinical factors that significantly affect PPS in patients with recurrent or persistent CCC as well as other histologic subtypes of ovarian cancer. PPS in patients with recurrent CCC should establish the basis for future clinical trials in this population.
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http://dx.doi.org/10.3802/jgo.2020.31.e94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593225PMC
November 2020

Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

J Epidemiol 2020 Oct 10. Epub 2020 Oct 10.

Tohoku Medical Megabank Organization, Tohoku University.

Background: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants.

Methods: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group.

Results: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy.

Conclusions: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.
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http://dx.doi.org/10.2188/jea.JE20200338DOI Listing
October 2020

Highly conserved binding region of ACE2 as a receptor for SARS-CoV-2 between humans and mammals.

Vet Q 2020 Dec;40(1):243-249

National Hospital Organization Kyoto Medical Center, Kyoto, Japan.

Several cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection transmitted from human owners to their dogs have recently been reported. The first ever case of SARS-CoV-2 transmission from a human owner to a domestic cat was confirmed on March 27, 2020. A tiger from a zoo in New York, USA, was also reportedly infected with SARS-CoV-2. It is believed that SARS-CoV-2 was transmitted to tigers from their caretakers, who were previously infected with this virus. On May 25, 2020, the Dutch Minister of Agriculture, Nature and Food Quality reported that two employees were infected with SARS-CoV-2 transmitted from minks. These reports have influenced us to perform a comparative analysis among angiotensin-converting enzyme 2 (ACE2) homologous proteins for verifying the conservation of specific protein regions. One of the most conserved peptides is represented by the peptide "353-KGDFR-357 ( ACE2 residue numbering), which is located on the surface of the ACE2 molecule and participates in the binding of SARS-CoV-2 spike receptor binding domain (RBD). Multiple sequence alignments of the ACE2 proteins by ClustalW, whereas the three-dimensional structure of its binding region for the spike glycoprotein of SARS-CoV-2 was assessed by means of Spanner, a structural homology modeling pipeline method. In addition, evolutionary phylogenetic tree analysis by ETE3 was used. ACE2 works as a receptor for the SARS-CoV-2 spike glycoprotein between humans, dogs, cats, tigers, minks, and other animals, except for snakes. The three-dimensional structure of the KGDFR hosting protein region involved in direct interactions with SARS-CoV-2 spike RBD of the mink ACE2 appears to form a loop structurally related to the human ACE2 corresponding protein loop, despite of the reduced available protein length (401 residues of the mink ACE2 available sequence vs 805 residues of the human ACE2). The multiple sequence alignments of the ACE2 proteins shows high homology and complete conservation of the five amino acid residues: 353-KGDFR-357 with humans, dogs, cats, tigers, minks, and other animals, except for snakes. Where the information revealed from our examinations can support precision vaccine design and the discovery of antiviral therapeutics, which will accelerate the development of medical countermeasures, the World Health Organization recently reported on the possible risks of reciprocal infections regarding SARS-CoV-2 transmission from animals to humans.
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http://dx.doi.org/10.1080/01652176.2020.1823522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580767PMC
December 2020

Associations between glycosylated hemoglobin level at less than 24 weeks of gestation and adverse pregnancy outcomes in Japan: The Japan Environment and Children's Study (JECS).

Diabetes Res Clin Pract 2020 Nov 21;169:108377. Epub 2020 Aug 21.

Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryomachi, Sendai 980-8573, Miyagi, Japan; Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1, Seiryomachi, Sendai 980-8574, Miyagi, Japan; Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryomachi, Sendai 980-8572, Miyagi, Japan. Electronic address:

Aims: To investigate the associations between glycosylated hemoglobin (HbA1c) levels at less than 24 weeks of gestation and adverse pregnancy outcomes in Japan.

Methods: This was a prospective nationwide birth cohort study of 77,526 subjects with an HbA1c level of <6.5% (<48 mmol/mol) at less than 24 weeks of gestation. Associations of HbA1c level with adverse pregnancy outcomes were evaluated using multivariate analyses.

Results: The adjusted odds ratios per 1% (11 mmol/mol) increase in HbA1c level were 1.77 (95% confidence interval [CI]: 1.48-2.12) for hypertensive disorders of pregnancy; 1.78 (95% CI: 1.12-2.83) for placental abruption; 1.30 (95% CI: 1.12-1.50) for preterm birth; 2.11 (95% CI: 1.41-3.16) for very preterm birth; 1.49 (95% CI: 1.33-1.68) for low birth weight infants; 1.95 (95% CI: 1.42-2.70) for macrosomia; 1.23 (95% CI: 1.09-1.39) for small for gestational age; 1.15 (95% CI: 1.04-1.28) for large for gestational age; and 1.29 (95% CI: 1.20-1.39) for the composite adverse pregnancy outcome.

Conclusions: The higher the HbA1c level, the higher the risk of adverse pregnancy outcomes in Japan. Further studies will be needed to determine prenatal management based on the HbA1c level in pregnant women with HbA1c <6.5% (<48 mmol/mol) at less than 24 weeks of gestation.
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http://dx.doi.org/10.1016/j.diabres.2020.108377DOI Listing
November 2020

Two Cases of Multiple Chemical Sensitivity Successfully Treated With Kampo Medicine.

Altern Ther Health Med 2021 May;27(3):54-58

Context: Multiple chemical sensitivity (MCS) is a chronic disorder in which minimal but sustained exposure to particular chemicals causes headaches, vertigo, and multiple other symptoms. Up to 10% of cases are clinically unresponsive to treatment. Kampo medicines include multiple crude components with many applications for organ disorders.

Objective: The research team aimed to assess the efficacy of goreisan, a Japanese Kampo medicine, for 2 patients diagnosed with intractable cases of MCS.

Design: The research team conducted case studies with 2 female patients.

Setting: The study took place at the Kampo clinic in the Department of Gynecology and Obstetrics at the Japanese Red Cross Maebashi Hospital in Maebashi, Gunma, Japan.

Participants: The participants were patients at the clinic.

Intervention: The first participant received the Kampo formula goreisan for her headaches and keigairengyoto for her mucosal discomfort; the second received goreisan for her headaches and kakkonto to reduce her shoulder-muscle stiffness. The participants received Kampo treatments for one month.

Outcome Measures: The first participant's MCS symptoms were evaluated with the Quick Environment Exposure Sensitivity Inventory questionnaire (QEESI); the second using a numeric rating scale (NRS).

Results: After the Kampo treatments, the first participant's QEESI scores for chemical intolerance, symptom severity, and life impact were reduced from 47, 92, and 76 to 37, 39, and 55 points, respectively. The second participant's NRS scores were likewise reduced from 6, 8, and 8 out of 10 to 1, 2, and 1 out of 10. Symptoms were relieved in both patients, and didn't recur.

Conclusions: These results highlight the potential benefits of Kampo medicine for the treatment of intractable MCS. Further investigations will be needed to confirm the mechanism of action, thereby improving the understanding of the effectiveness of Kampo medicine for MCS therapy.
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May 2021

Low birth weight and abnormal pre-pregnancy body mass index were at higher risk for hypertensive disorders of pregnancy.

Pregnancy Hypertens 2020 Oct 5;22:119-125. Epub 2020 Aug 5.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address:

Low birth weight is known to be associated with hypertension, cardiovascular disease and hypertensive disorders of pregnancy (HDP); however, this association might vary by race/ethnicity. This study aimed to clarify the association between women's own birth weight and their subsequent risk for HDP in a Japanese population, in combination with pre-pregnancy body mass index (BMI). We conducted a cohort study as part of the Tohoku Medical Megabank Birth and Three-Generation Cohort Study in Miyagi, Japan. Our study's population included 4810 women. A multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (aOR) and the 95% confidence interval (CI) of the women's own birth weight for HDP, in the combination categories of birth weight and pre-pregnancy BMI. As a result, the group with a low birth weight of <2500 g had a significant association with HDP (the aOR, 1.50; 95% CI, 1.02-2.21). In the subtype analysis, the odds ratio for only preeclampsia was significantly increased in the low birth weight group (aOR, 3.37; 95% CI, 1.84-6.16). In the group with a low birth weight, the prevalence of HDP was higher in both the underweight and overweight groups. In conclusion, there was a significant association between low birth weight and subsequent HDP in Japanese women. Furthermore, a significant association with HDP was found for women born with a low birth weight who were underweight or overweight as adults. Maintaining a normal weight may be effective for preventing HDP even if a woman was born small.
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http://dx.doi.org/10.1016/j.preghy.2020.08.001DOI Listing
October 2020

Human Papillomavirus (HPV) Genotyping Assay Suitable for Monitoring the Impact of the 9-Valent HPV Vaccine.

Tohoku J Exp Med 2020 08;251(4):287-294

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

In Japan, a bivalent human papillomavirus (HPV) vaccine against carcinogenic HPV16/18 was licensed in 2009, and a quadrivalent vaccines against HPV16/18 and non-carcinogenic HPV6/11 was licensed in 2011. Recently, the next-generation 9-valent vaccine targeting HPV6/11/16/18/31/33/45/52/58 has been approved. Accurate HPV genotyping is essential for HPV vaccine research and surveillance. The Roche Linear Array (LA) has long been a standard assay for HPV genotyping, but its recent product discontinuation notice has urged us to introduce an alternative assay with comparable performance. In the present study, an in-house HPV genotyping assay that employs PCR with PGMY09/11 primers and reverse blotting hybridization (PGMY-CHUV) was compared with LA to assess genotype-specific agreement. A total of 100 cervical precancer specimens were subjected to both PGMY-CHUV and LA. For detection of genotypes included in the 9-valent vaccine, PGMY-CHUV completely agreed with LA for detection of HPV6, HPV11, HPV16, HPV18, HPV33 and HPV45, and showed near-complete agreement for HPV31 and HPV58 (98% and 99%, respectively). Moreover, PGMY-CHUV detected a significantly higher prevalence of HPV52 than LA (22% vs. 14%, P = 0.008 by McNemar's exact test), with 92.0% overall agreement, 63.6% positive agreement and a kappa value of 0.73. Most (87.5%) of HPV52 discordant cases involved mixed infections with HPV35 or HPV58. In conclusion, while the two assays present equivalent data for assessing the effectiveness of the bivalent and quadrivalent vaccines, PGMY-CHUV is more suitable for evaluating the impact of the current 9-valent vaccine because of its superior detection of HPV52 in co-infection cases.
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http://dx.doi.org/10.1620/tjem.251.287DOI Listing
August 2020

Ultrasound measurement of fetal arterial pulse pressure using phased-tracking methods: A phantom study and clinical experience with antenatal corticosteroid therapy.

J Obstet Gynaecol Res 2020 Oct 3;46(10):1994-2001. Epub 2020 Aug 3.

Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan.

Aim: This study aimed to compare the accuracy of fetal pulse pressure estimated with a vascular simulator with that obtained by a manometer (reference) and evaluate the pulse pressure in normal human fetuses and fetuses whose mothers received corticosteroids.

Methods: Fetal pulse pressure was estimated as the product of blood flow velocity and pulse wave velocity, based on the water hammer equation. Ultrasonic raw radiofrequency signals for blood flow velocity were captured from the fetal descending aortas at the diaphragm level, and pulse wave velocity was simultaneously measured from different directions using the phased-tracking method. First, the precision and accuracy of pulse pressure in the estimated method were verified by a circulatory phantom simulator, which reproduced fetal blood flow using a pulsating pump. Then, the pulse pressure of 98 normal human fetuses after 17 weeks of gestation and the fetal pulse pressure in 21 mothers who received antenatal corticosteroids for fetal maturation were measured.

Results: A significant correlation between the estimated pulse pressure values and the actual values was found in the phantom simulation (r = 0.99, P < 0.01). The estimated pulse pressure was significantly correlated with gestational age in normal fetuses (r = 0.74, P < 0.01). In steroid-treated pregnant women, fetal pulse pressure was observed to increase significantly on the second day of administration (P < 0.01).

Conclusion: A noninvasive and accurate estimation model of fetal pulse pressure could be established using phased-tracking method, and this method has the potential to improve the assessment of human fetal hemodynamics.
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http://dx.doi.org/10.1111/jog.14402DOI Listing
October 2020

Feasibility of Non-invasive Pulse Pressure Measurement Using the Phased-Tracking Method.

Ultrasound Med Biol 2020 Oct 28;46(10):2711-2716. Epub 2020 Jul 28.

Department of Obstetrics and Gynecology, Tohoku University, Sendai, Miyagi, Japan. Electronic address:

Phased tracking (PT) is a high-precision ultrasonic technology that enables measurements of pulse pressure (PP). The aim of this study was to verify the accuracy of estimated PP using PT. Estimated PPs were compared with measured PPs in three sheep fetuses that were connected to an artificial placenta system. Similarly, estimated and measured PPs of 30 human neonates were compared. PP was calculated using the Water-Hammer equation (PP = ρ × PWV (pulse wave velocity) × ΔU). PWV was estimated by measuring the transit times of pulse waves at two sites along the aorta using the PT method, and ΔU was obtained by subtracting end-diastolic velocity from peak systolic velocity. The correlation between the estimated and measured PPs of the sheep fetuses was strong (r = 0.95, p ˂ 0.01), as was the case with the human neonates (r = 0.88, p ˂ 0.05). It can be concluded from the results of this study that PT may be a non-invasive alternative method used to predict PP.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.06.019DOI Listing
October 2020

MicroRNA Let-7c Contributes to Paclitaxel Resistance via Aurora-B in Endometrial Serous Carcinoma.

Tohoku J Exp Med 2020 08;251(4):263-272

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

The incidence of endometrial cancer has rapidly risen over recent years. Paclitaxel, a key drug for endometrial cancer treatment, inhibits microtubule depolymerization and induces apoptosis in cancer cells. Endometrial serous carcinoma (ESC) accounts for < 10% of all endometrial carcinomas, but its aggressive nature makes it responsible for close to 40% of cancer deaths. Thus, novel therapeutic targets are required for ESC. To identify microRNAs that promote paclitaxel resistance, we established two paclitaxel-resistant cell lines from USPC1 human ESC cells by exposing paclitaxel to parental cells for 12 weeks. Paclitaxel concentrations were increased every 2 weeks, and after 12 weeks of paclitaxel exposure, two replicate paclitaxel-resistant cell lines were established (USPC1-PTSR1 and USPC1-PTXR2). The microarray analysis was performed using USPC1 cells and USPC1-PTXR1 cells, and eight candidate microRNAs were thus selected as potential mediators of paclitaxel sensitivity. Among these candidate microRNAs, let-7c precursor treatment of paclitaxel-resistant USPC1-PTXR1 cells caused the greatest increase in paclitaxel-mediated cytotoxicity. Let-7c inhibition conversely decreased paclitaxel-induced apoptosis. It is known that let-7a microRNA, a member of the let-7 family, inhibits growth of endometrial carcinoma cells targeting Aurora-B that controls progression through each phase of mitosis. We thus studied whether let-7c mediates Aurora-B expression in ESC cells. The expression levels of Aurora-B mRNA and protein were higher in USPC-PTXR1 cells compared with USPC1 cells. Let-7c inhibition increased Aurora-B expression in USPC1 cells but decreased Aurora-B expression in USPC1-PTXR1 cells. These results indicate that let-7c mediates paclitaxel resistance via inhibition of Aurora-B expression in ESC cells.
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http://dx.doi.org/10.1620/tjem.251.263DOI Listing
August 2020

Epidemiological guideline influence on the therapeutic trend and patient outcome of uterine cervical cancer in Japan: Japan society of gynecologic oncology guideline evaluation committee project.

Gynecol Oncol 2020 10 25;159(1):248-255. Epub 2020 Jul 25.

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

Objective: The Japan Society of Gynecologic Oncology published its first clinical guidelines for uterine cervical cancer in 2007 which has been revised twice in 2011 and 2017. The aim of this study was to investigate the influence of the first guideline publication on the therapeutic trend and patient outcome by analyzing uterine cervical cancer cases registered to the cancer registry organized by the Japan Society of Obstetrics and Gynecology.

Methods: Data of uterine cervical cancer cases registered to the cancer registry from 2000 to 2012 were provided. Epidemiological and clinical trend were analyzed by the Chi-squared test with subsequent standardized residual analysis. Overall survival among the patients registered between 2004 and 2009 was analyzed using the Fine and Gray competing risk model.

Results: 68,707 cases were registered during the study period. A trend analysis revealed that the guideline publication may have led to a decrease in neoadjuvant chemotherapy in parallel with an increase in radiation therapy mainly in stage II and III patients undergoing primary treatment. A survival analysis indicated that the introduction of the guideline may have improved overall survival among stage III uterine cervical cancer patients, even though a significant difference was not observed in all of the cases.

Conclusions: This study demonstrated the potential influence of the guideline publication on the clinical trend and patient outcome. As this is the first assessment of the guideline for uterine cervical cancer in Japan, continuous evaluation is necessary to further comprehend the significance of this guideline.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.023DOI Listing
October 2020

Scoping Review of Hospital Business Continuity Plans to Validate the Improvement after the 2011 Great East Japan Earthquake and Tsunami.

Tohoku J Exp Med 2020 07;251(3):147-159

Division of International Cooperation for Disaster Medicine, International Research Institute of Disaster Science (IRIDeS), Tohoku University.

During a disaster, all hospitals are expected to function as "social critical institutions" that protect the lives and health of people. In recent disasters, numerous hospitals were damaged, and this hampered the recovery of the affected communities. Had these hospitals business continuity plans (BCPs) to recover quickly after the disaster, most of the damage could have been avoided. This study conducted a scoping review of the historical trend and regional differences in hospital BCPs to validate the improvement of the BCP concept based on our own experience at Tohoku University Hospital, which was affected by the 2011 Great East Japan Earthquake and Tsunami (GEJET). We searched PubMed by using keywords related to BCP and adapted 97 articles for our analysis. The number of articles on hospital BCPs has increased in the 2000s, especially after Hurricane Katrina in 2005. While there are regional specificity of hazards, there were many common topics and visions for BCP implementation, education, and drills. From our 2011 GEJET experience, we found that BCPs assuming region-specific disasters are applicable in various types of disasters. Thus, we suggest the following integral and universal components for hospital BCPs: (1) alternative methods and resources, (2) priority of operation, and (3) resource management. Even if the type and extent of disasters vary, the development of BCPs and business continuity management strategies that utilize the abovementioned integral components can help a hospital survive disasters in the future.
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http://dx.doi.org/10.1620/tjem.251.147DOI Listing
July 2020

Proteomic and metabolomic analyses uncover sex-specific regulatory pathways in mouse fetal germline differentiation†.

Biol Reprod 2020 10;103(4):717-735

Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Miyagi, Japan.

Regulatory mechanisms of germline differentiation have generally been explained via the function of signaling pathways, transcription factors, and epigenetic regulation; however, little is known regarding proteomic and metabolomic regulation and their contribution to germ cell development. Here, we conducted integrated proteomic and metabolomic analyses of fetal germ cells in mice on embryonic day (E)13.5 and E18.5 and demonstrate sex- and developmental stage-dependent changes in these processes. In male germ cells, RNA processing, translation, oxidative phosphorylation, and nucleotide synthesis are dominant in E13.5 and then decline until E18.5, which corresponds to the prolonged cell division and more enhanced hyper-transcription/translation in male primordial germ cells and their subsequent repression. Tricarboxylic acid cycle and one-carbon pathway are consistently upregulated in fetal male germ cells, suggesting their involvement in epigenetic changes preceding in males. Increased protein stability and oxidative phosphorylation during female germ cell differentiation suggests an upregulation of aerobic energy metabolism, which likely contributes to the proteostasis required for oocyte maturation in subsequent stages. The features elucidated in this study shed light on the unrevealed mechanisms of germ cell development.
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http://dx.doi.org/10.1093/biolre/ioaa115DOI Listing
October 2020