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Background/aim Heat shock protein 105 (HSP105) is overexpressed in various cancers, but not in normal tissues. We investigated the expression levels of HSP105 in cervical cancer and the efficacy of immunotherapy targeting HSP105. Materials and methods Previously, we established human leukocyte antigen-A*02:01 (HLA-A2) restricted HSP105 peptide-specific cytotoxic T lymphocyte (CTL) clones from a colorectal cancer patient vaccinated with an HSP105 peptide. Herein, we evaluated the expression of HSP105 in cervical cancer and cervical intraepithelial neoplasia. Moreover, we tested the effectiveness of an HLA-A2-restricted HSP105 peptide-specific CTL clone against cervical cancer cell lines. Results HSP105 was expressed in 95% (19/20) of examined cervical cancer tissues. Moreover, the HSP105 peptide-specific CTL clone recognized HSP105- and HLA-A*02:01-positive cervical cancer cell lines and also showed that cytotoxicity against the cervical cancer cell lines depends on HSP105 peptide and HLA class I restricted manners. Conclusion HSP105 could be an effective target for immunotherapy in patients with cervical cancer.

Background Standard treatments for small cell carcinoma of the cervix (SCCC) have not been established. In this study, we aimed to estimate the optimal treatment strategy for SCCC. Methods This was a multicenter retrospective study. Medical records of patients with pathologically proven SCCC treated between 2003 and 2016 were retrospectively analyzed. Overall survival (OS) was plotted using the Kaplan-Meier method. Log-rank tests and Cox regression analysis were used to assess the differences in survival according to stage, treatment strategy, and chemotherapy regimen. Results Data of 78 patients were collected, and after excluding patients without immunohistopathological staining, 65 patients were evaluated. The median age of the included patients was 47 (range: 24–83) years. The numbers of patients with International Federation of Gynecology and Obstetrics (FIGO) 2018 stages I-IIA, IIB-IVA, IVB were 23 (35%), 34 (52%), and 8 (12%), respectively. Of 53 patients who had undergone chemotherapy, 35 and 18 received SCCC and non-SCCC regimens as their first-line chemotherapy regimen, respectively. The 5-year OS for all patients was 49%, while for patients with FIGO stages I-IIA, IIB-IVA, IVB, it was 60, 50, and 0%, respectively. The 5-year OS rates for patients who underwent treatment with SCCC versus non-SCCC regimens were 59 and 13% (p Conclusion Our results suggest that the application of an SCCC regimen such as EP or IP as first-line chemotherapy for patients with locally advanced SCCC may play a key role in OS. These findings need to be validated in future nationwide, prospective clinical studies.

Objective To clarify the decrease in response to controlled ovarian stimulation in patients who receive in vitro fertilization treatment after radical trachelectomy. Methods The outcomes of ovarian stimulation were retrospectively evaluated and compared between patients who have undergone radical trachelectomy and control patients who had male factor infertility or unexplained infertility. Results A total of 30 ovarian stimulation cycles in 14 radical trachelectomy patients and 54 cycles in 30 control patients were reviewed. The median age at ovarian stimulation was 34.8 years in the radical trachelectomy group and 36.5 years in the control group. Compared with the control group, the radical trachelectomy group had significantly lower mean estradiol concentration (1461.7 pg/ml, SD 775.0 vs. 1950.9 pg/ml, SD 1057.3, P = 0.029) during controlled ovarian stimulation cycle and smaller median number of retrieved oocytes (5, range 1-14 vs. 8, range 1-19, P = 0.007), despite the higher use of gonadotropin (3527.5 IU, SD 1313.4 vs. 2670.8 IU, SD 905.1, P = 0.001). Conclusion The response to controlled ovarian stimulation decreased after radical trachelectomy.

To evaluate the impact of maternal hypertensive disorders of pregnancy (HDP) on mortality and neurological outcomes in extremely and very preterm infants using a nationwide neonatal database in Japan. This population-based retrospective study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, between 22 and 31 weeks’ gestation. A total of 21,659 infants were randomly divided into two groups, HDP (n = 4,584) and non-HDP (n = 4,584), at a ratio of 1:1 after stratification by four factors including maternal age, parity, weeks of gestation, and year of delivery. Short-term (neonatal period) and medium-term (3 years of age) mortality and neurological outcomes were compared between the two groups by logistic regression analyses. In univariate analysis, HDP was associated with an increased risk for in-hospital death (crude odds ratio [OR], 1.31; 95% confidence interval, 1.04–1.63) and a decreased risk for severe intraventricular haemorrhage (0.68; 0.53–0.87) and periventricular leukomalacia (0.60; 0.48–0.77). In multivariate analysis, HDP was significantly associated with a lower risk for in-hospital death (adjusted OR, 0.61; 0.47–0.80), severe intraventricular haemorrhage (0.47; 0.35–0.63), periventricular leukomalacia (0.59; 0.45–0.78), neonatal seizures (0.40; 0.28–0.57) and cerebral palsy (0.70; 0.52–0.95) at 3 years after adjustment for covariates including birth weight. These results were consistent with those of additional analyses, which excluded cases with histological chorioamnionitis and which divided the infants into two subgroups (22–27 gestational weeks and 28–31 gestational weeks). Maternal HDP was associated with an increased risk for in-hospital death without adjusting for covariates, but it was also associated with a lower risk for mortality and adverse neurological outcomes in extremely and very preterm infants if all covariates except HDP were identical.

Immunoglobulin G4-related disease (IgG4-RD) is characterized by systemic lesions presenting as swellings, nodules and wall thickenings. The first-line therapy is glucocorticoids. This disease is common among middle-aged and elderly men, and its uterine mass formation is uncommon. We encountered a 39-year-old nulliparous woman with an IgG4-related uterine mass and enlarged pelvic lymph nodes. Complete remission was achieved by fertility-sparing resection of the uterine mass without glucocorticoids. This case showed that IgG4-RD can present as a uterine mass and we need to be careful of its diagnostic and therapeutic strategies because an IgG4-related uterine mass is difficult to distinguish from sarcoma or malignant lymphoma. Our case also demonstrated that IgG4-related lymphadenopathy could regress spontaneously without complete lymphadenectomy or glucocorticoids when IgG4-RD does not affect vital organs. A pelvic mass with hyperproteinemia may be a hint to remind us of IgG4-RD and may trigger a preoperative immunoglobulin test.

INTRODUCTION Shock index (SI), calculated by dividing heart rate by systolic blood pressure, is used to detect hemodynamic instability and hypovolemia. In obstetric practice, limited evidence is available regarding its usefulness in detecting postpartum hemorrhage (PPH). We aimed to evaluate the usefulness of SI in detecting PPH in vaginal deliveries using clinical data from 12 primary maternity care units in Japan. MATERIAL AND METHODS In this multicenter retrospective study, a total of 30,820 women who delivered vaginally at term at 12 primary maternity care units from January 2012 to December 2018 were included. Systolic and diastolic blood pressures and heart rate were measured at five different time points from admission to postpartum 2 h, and postpartum blood loss was measured. We evaluated the trend of average SI and the performance of each vital sign for detection of PPH. RESULTS The trend of average SI during labor and the immediate postpartum period was approximately 0.7 in women with blood loss of

Background: It remains unclear whether the end-of-life (EOL) treatment/environment impacts on survival after anticancer treatment in terminally ill women with ovarian carcinoma (OC). Objective: The...

Background Follicular dendritic cell sarcoma (FDCS) is a rare mesenchymal tumor that mostly occurs in systemic lymph nodes. FDCS in the uterine cervix has not yet been reported. Case presentation A 49-year-old woman was referred to our department with a cervical tumor, which was histologically suspected to be undifferentiated carcinoma. She underwent hysterectomy, salpingo-oophorectomy, and pelvic lymphadenectomy after neoadjuvant chemotherapy with paclitaxel and carboplatin. The resected specimen contained high numbers of spindle cells and was immunohistochemically confirmed to be FDCS. The tumor was completely resected and recurrence was not detected at a 16-month follow-up. Conclusion FDCS is an extremely rare malignant tumor in the uterine cervix, and an accurate diagnosis and complete resection are essential for a good prognosis.

Objective To investigate the clinical characteristics of women with Stage I primary mucinous epithelial ovarian carcinoma (mEOC) and evaluate the impact of uterus-preserving surgery (UPS) in terms of survival prognosis. Methods A regional multi-institutional retrospective study conducted between January 1986 and March 2017 by reviewing records of the Tokai Ovarian Tumor Study Group. Clinical and pathologic data and survival outcomes were assessed for women with Stage I primary mEOC. The baseline imbalance between women with and those without UPS was adjusted by an inverse probability of treatment weighting method using the propensity score (PS) of independent clinical variables. Results Among 4730 women with malignant ovarian tumors, 185 had Stage I primary mEOC and were included in the study. The mean age was 47.6 years (range 12-87 years), and 56 (30.3%) women underwent UPS. After PS-based adjustment, women in the UPS group did not have a poorer prognosis regarding overall survival (P=0.776) or recurrence-free survival (P=0.683). Even after age stratification, there was no statistical difference in survival outcomes between the UPS and non-UPS groups. Conclusion UPS was not associated with decreased survival and may be a treatment option for women with Stage I primary mEOC irrespective of age.

To estimate whether antenatal corticosteroids (ACS) improve short- and long-term preterm offspring outcomes in singleton pregnancies complicated by hypertensive disorders of pregnancy (HDP) similar to pregnancies without HDP. This population-based retrospective study was conducted based on an analysis of data collected by the Neonatal Research Network of Japan on 21,014 singleton neonates weighing ≤1,500 g between 24 and 31 weeks’ gestation during 2003–2016. Logistic regression analyses were performed to compare short- and long-term offspring outcomes between mothers receiving ACS treatment and those who did not among pregnancies with HDP and without HDP. Of 21,014 neonates, 4,806 (22.9%) were born to mothers with HDP. ACS treatment was associated with significant decreases in short-term adverse outcomes in the both HDP and non-HDP groups, with similar reduced odds of neonatal death, respiratory distress syndrome, and intraventricular haemorrhage (IVH). However, ACS treatment did not significantly decrease severe IVH (aOR 0.76; 95% CI 0.51–1.13) and periventricular leukomalacia (1.14; 0.78–1.66) in the HDP group. In addition, ACS treatment in mothers without HDP significantly decreased cerebral palsy (aOR 0.70; 95% CI 0.58–084), developmental quotient scores

Objective To estimate whether improvement in outcomes from antenatal corticosteroid treatment in extremely and very preterm twins is similar to that observed in singletons, and to investigate whether antenatal corticosteroid treatment has different effects according to chorionicity or birth order. Methods This population-based study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, from gestational ages of 24 0/7 to 31 6/7 weeks of gestation. After propensity score matching, univariate logistic and interaction analyses were performed to compare short-term (neonatal period) and medium-term (3 years of age) outcomes of the children of mothers who received antenatal corticosteroids with those of children of mothers who did not receive antenatal corticosteroids. We focused on differences between singletons and twins, between monochorionic and dichorionic twins and between the first and second twin. Results The study comprised 23,502 singletons and 6,546 twins. Antenatal corticosteroid treatment was associated with significant decreased short-term neurologic outcomes in both singletons and twins. However, antenatal corticosteroid treatment was associated with significantly decreased mortality (odds ratio [OR] 0.61; 95% CI 0.53-0.70), respiratory distress syndrome (OR 0.71, 95% CI 0.67-0.76), and cerebral palsy (OR 0.85, 95% CI 0.72-0.99) in singletons but not in twins (OR 0.89, 95% CI 0.68-1.17; OR 0.99, 95% CI 0.87-1.12; and OR 0.82, 95% CI 0.61-1.11, respectively). No association was found between chorionicity and the efficacy of antenatal corticosteroid treatment on outcomes. Further, no association was found between birth order and the efficacy of antenatal corticosteroid treatment on outcomes, except for periventricular leukomalacia and necrotizing enterocolitis (interaction: P=.02 and P=.04, respectively). Conclusion Antenatal corticosteroid treatment in twins was associated with a beneficial effect on short-term neurologic outcomes only, without improvement in other short-term and medium-term outcomes. There was no difference related to chorionicity.

Background. Lower-limb lymphedema (LLL) is a chronic and progressive complication of gynecologic cancer treatment, including pelvic lymphadenectomy. This study aims to investigate the therapeutic effect of goreisan, a traditional Japanese medicine, which has been used for hydrostatic modulation on patients with LLL. Methods. Patients diagnosed with LLL in our hospital in 2018 were included and principally treated with complex decongestive therapy (CDT), including elastic clothing and lymph drainage. The patients who received a combination therapy of CDT and goreisan (CDT-G group) were prescribed goreisan extract granules, with a dose of 7.5 g per os daily in three doses. Patients who were not prescribed goreisan received CDT alone (CDT group). The severity of lymphedema was evaluated by the estimated limb volume calculated by limb circumferences and the ratio of extracellular water (ECW) to total body water (TBW). Results. Nineteen women with LLL after pelvic lymphadenectomy were included in the study. The number of patients in the CDT and CDT-G groups was 8 and 11, respectively. There were no statistically significant differences between the CDT and CDT-G groups in terms of patient characteristics and severity of LLL before treatment. Reduction in ECW/TBW in the CDT-G group (in the whole body and the affected lower limb) after the intervention was significantly more remarkable than that in the CDT group. Conclusions. Goreisan-based Japanese herbal therapy may be effective in patients with LLL after retroperitoneal lymphadenectomy.

We report a case of recurrent small cell carcinoma of the uterine cervix that showed a complete response to paclitaxel, carboplatin, and bevacizumab (TC + Bev) combination therapy. Small cell carcinoma of the uterine cervix is extremely rare, with an incidence of only 1.3% in Japan, and a poor outcome. The patient was a 62-year-old woman with a chief complaint of irregular vaginal bleeding. Magnetic resonance imaging showed a 10-cm irregular mass from the uterine corpus’s posterior wall to the cervix. Abdominal total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node sampling were performed for suspected uterine sarcoma. Histopathological findings revealed small cell carcinoma with lymph node metastasis. Although 6 cycles of etoposide + cisplatin were performed, para-aortic lymph node recurrence was found 3 months after chemotherapy. Subsequently, the patient received 8 cycles of TC + Bev, which eliminated the metastases. The patient is currently alive at 24 months.

The prognostic nutritional index (PNI), which reflects preoperative malnutrition, is useful for predicting the incidence of postoperative complications and has been reported in recent years to predict the long-term prognosis of various malignancies. The purpose of this study was to clarify the significance of PNI as a prognostic factor for early-stage clear cell ovarian carcinoma. A total of 82 patients with stage I–II (FIGO 2014) ovarian clear cell carcinoma undergoing primary surgery at our hospital from January 2005 to December 2017 were enrolled. PNI was calculated using the formula: 10 × serum albumin (g/ dL) + 0.005 × peripheral blood lymphocyte count (/mm3). Preoperative PNI exhibited relatively high area under the curve value (0.709) for 5 year survival, and the optimal cutoff value was 46.5. The overall survival was significantly shorter in the PNI-low group than in the PNI-high group. Multivariate analysis showed that high PNI was a significant independent prognostic factor for favorable prognosis (hazard ratio = 0.102, p = 0.010). There was no significant difference in recurrence-free survival between the two groups (p = 0.220), but the postrecurrence survival was significantly longer in the PNI-high group than in the PNI-low group (p = 0.0383). The preoperative PNI was a useful predictor of prognosis, even in early-stage ovarian clear cell carcinoma.

Repeated tissue injury and repair and fibrosis play a pivotal role in endometriosis. Fibrotic tissue consists of extracellular matrix proteins, regulated by transcriptional factors promoting cell proliferation and survival. Periostin is one of the putative key extracellular matrix proteins. This study aimed to determine whether transcription factor 21 (TCF21) is involved in the development of endometriosis as an upstream regulatory gene of periostin. Formalin-fixed, paraffin-embedded tissue samples [normal endometrium of women without endometriosis; eutopic endometrium of women with endometriosis; ovarian endometriosis (OE); and deep infiltrating endometriosis (DIE)] and respective cells were analyzed. Basal, transiently stimulated, and knocked down periostin and TCF21 concentrations in stromal cells of women with or without endometriosis were examined. Periostin and TCF21 expressions were undetected in normal endometrium of women without endometriosis, weakly positive in eutopic endometrium of women with endometriosis, moderately positive in OE, and strongly positive in DIE. Type 2 helper T-cell cytokines (IL-4, IL-13, and transforming growth factor-β1) increased the mRNA expression of periostin and TCF21. These cytokines, periostin, and TCF21 colocalized in the stroma of OE and DIE. siRNA against human TCF21 gene suppressed periostin expression. Transfection of TCF21 plasmid vector into stromal cells of women without endometriosis, which originally expressed neither periostin nor TCF21, resulted in TCF21 and periostin expression. TCF21 and periostin are involved in the regulation of fibrosis in endometriosis. TCF21 may be a promising therapeutic target and biomarker in endometriosis.

Mental illnesses commonly occur in the reproductive age. This study aimed to identify the issues that exist within the perinatal mental health care system. A cross-sectional survey was conducted in Aichi Prefecture in central Japan. Questionnaires on the situation between 2016 and 2018 were mailed to the head physicians of 128 maternity care units, 21 neonatal intensive care units (NICUs), and 40 assisted reproductive technology (ART) units. A total of 82 (52.6 per 100,000 births) women were admitted to mental health care units during the perinatal period, and 158 (1.0 per 1000 births) neonates born to mothers with mental illness were admitted to NICUs. Approximately 40% of patients were hospitalized in psychiatric hospitals without maternity care units. Eighty-four (71.1%) and 76 (64.4%) maternity care units did not have psychiatrists or social workers, respectively. Moreover, 20–35% of the head physicians in private clinics, general hospitals, and ART units endorsed the discontinuation of psychotropic drug use during pregnancy. However, the corresponding figures were only 5% among those in maternal-fetal centers. Resources for perinatal mental illness might be limited. Perspectives on psychotropic drug use differed based on the type of facilities where the doctors were working.

Background Ubiquitin-associated protein 2-like (UBAP2L) has been demonstrated to be associated with the progression of multiple types of cancer. However, the function of UBAP2L in uterine cervical cancer remains unclear. Materials and methods Between 2005 and 2015, 84 patients who underwent surgery were included in this study. The patients were stratified into two groups on the basis of immunohistochemical staining for UBAP2L, and survival analysis was performed. Moreover, loss-of-function analysis was performed using the cervical cancer cell lines CaSki and SiHa. Results Based on immunohistochemistry, the overall survival in patients with low UBAP2L expression was significantly longer than that of those with high UBAP2L expression (p=0.045). The in vitro experiment revealed that knockdown of UBAP2L remarkably inhibited cell proliferation in both live cell imaging and the MTS assay. Conclusion Patients with high UBAP2L expression had unfavorable prognosis and UBAP2L appears to play an important role in proliferation.

Background The aim of this study was to investigate how much the risks of recurrence and death are increased as a consequence of selecting fertility-sparing surgery (FSS) in young women with epithelial ovarian cancer (EOC). Methods After a central pathological review and search of the medical records from 14 collaborating hospitals, a non-randomized, observational cohort study was conducted between 1987 and 2015, including 1183 women with stage I EOC. Finally, a total of 285 patients with stage I EOC at reproductive age were recruited. Oncologic outcomes were compared between the FSS (N = 101) and radical surgery (RS) group (N = 184) using a propensity score (PS)-matching technique to adjust for relevant risk factors: the age, substage, histological type, grade, CA125 values, ascites cytology, ascites volume, and chemotherapy. Results During 66.0 months (median) of follow-up, 42 patients (14.7%) developed recurrence, and 31 patients (10.9%) died. In the original cohort, there was no significant difference in overall survival (OS) or recurrence-free survival (RFS) between the FSS and RS groups {Log-rank: OS (P = 0.838), RFS (P = 0.377)}. In the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in RFS or OS between the FSS and RS groups {RFS (FSS vs. RS), HR: 1.262 (95% CI: 0.559–2.852), P = 0. 575; OS (FSS vs. RS), HR: 1.206 (95% CI: 0.460–3.163), P = 0.704}. Conclusions After adjustment for clinicopathologic factors, FSS in itself may not worsen the oncologic outcome in young women with early-stage EOC. A large-scale clinical study is necessary to validate the findings.

The standard treatment for cervical cancer is chemoradiation although some patients showed treatment resistance. The purpose of this study was to investigate the clinical efficacy of surgery after chemoradiation for cervical cancer. Patients with FIGO stage IB2 to IIB cervical cancer were included in the study between 2005 and 2015. A total of 50 patients who underwent surgery after neoadjuvant chemoradiation and 76 patients who received only chemoradiation were compared. Baseline differences between the two groups were adjusted with inverse probability of treatment weighting method using propensity scores composed of the following independent variables: age, stage, tumor size, lymph node metastasis, and histological subtypes. Median follow-up was 64.8 (range 4.8–143.9) months. After adjustment with inverse probability of treatment weighting, Kaplan–Meier curves showing adjusted progression-free survival and overall survival were significantly longer in the neoadjuvant chemoradiation compared with the chemoradiation-only group (p = 0.027 and p = 0.017, respectively). Moreover, in patients with squamous cell carcinoma, recurrence in previously irradiated field and recurrence both in and out of previously irradiated field were significantly decreased in the neoadjuvant chemoradiation compared with the chemoradiation-only group (3.1% and 18.4%, respectively; OR 0.142, p = 0.001]. Adverse events of surgery after chemoradiation were acceptable, although temporary hydronephrosis was frequently observed (23.1%). Surgery after chemoradiation reduced pelvic recurrence, and as a result, patients who underwent neoadjuvant chemoradiation showed more favorable survival outcomes compared with those who only underwent chemoradiation.

Background: Little is known about the effect of age on the prognosis of epithelial ovarian neoplasms. In the reproductive age, fertility-sparing surgery had been widely implemented. This study aimed to elucidate impact of age on the clinicopathologic characteristics and survival of epithelial ovarian neoplasms in the reproductive age. Methods: The clinical records of patients diagnosed as epithelial ovarian cancer or epithelial borderline ovarian tumor at the age of 40 years or younger at multiple institutions in the Tokai Ovarian Tumor Study Group were reviewed retrospectively. All patients were stratified into two age groups: group A (≤ 30 years) and group B (31–40 years). Univariate and multivariate analyses were performed to evaluate overall survival and disease-free survival. Results: A total of 583 patients (325 patients: cancer, 258 patients: borderline) were included. The median follow-up time was 62.0 months (range 1–270 months). Compared with group B, group A had a significantly higher rate of borderline tumor (66.7% vs. 32.7%, p, ファイル公開：2021/01/01

Aim Accumulation of ascites fluid is a major obstacle in the late phase of epithelial ovarian cancer. However, there is no consensus on a specific treatment for malignant ascites. The present study evaluated the clinical benefit of half-dose bevacizumab therapy (7.5 mg/kg every 3-4 weeks). Methods This was a single-arm interventional study performed at Aichi Cancer Center Hospital. Four patients with platinum-resistant epithelial ovarian cancer and symptomatic malignant ascites were no longer considered candidates for standard chemotherapy. As a palliative approach, half-dose bevacizumab therapy (7.5 mg/kg every 3-4 weeks) was used with informed consent. The clinical data of these patients were retrospectively reviewed. Results All patients had been heavily pretreated and showed progressive disease. Thus, standard chemotherapy was no longer feasible, and palliative paracentesis for malignant ascites was clinically needed. Among the four patients, three did not require additional paracentesis after bevacizumab therapy, and there were no adverse events. One patient needed paracentesis owing to lymphorrhea. Conclusion The use of bevacizumab therapy as a palliative approach for malignant ascites might be an option in patients with terminal-stage ovarian cancer. However, further evaluation is needed with regard to the possibility of severe side effects and medical expenses.

Aim Cancer treatment involves long-term therapy and follow-up, with mental disorders (MD) often affecting the treatment process. Hence, in this study, we retrospectively analyze cases involving gynecologic cancer with MD and clarify the relationship between psychosis and cancer prognosis. Methods Patients with both gynecologic cancer and MD from January 2003 to August 2016 were recruited in this study. Cases were limited to those whose MD had been diagnosed before their cancer. Control patients without MD were also analyzed. Both cases and controls were adjusted for age, cancer type, and cancer stage. Results A total of 54 patients with gynecologic cancer and MD, as well as 108 controls without MD, were included. The median age of the patients was 52 years. Details regarding cancer type were as follows: 11 ovarian cancers, 26 uterine corpus cancers and 17 cervical cancers. Among these, 25 schizophrenia cases, 15 depressive disorders, 4 bipolar disorders and 10 other MD were recorded. No significant differences in the 5-year survival rate were found between patients and controls. In advanced-stage cervical cancer, however, the prognosis was significantly poor given the low rate of initial treatment completion. Moreover, patients with advanced-stage cervical cancer had significantly lower chemotherapy completion rates compared to those with other gynecologic malignancies. Conclusion Mental disorders do not affect the prognosis of gynecologic cancers, except for advanced cervical cancer. Accordingly, improving the low rate of initial treatment completion seems to be a focal point for better prognosis in advanced cervical cancer.

Clear-cell carcinoma (CCC) in reproductive-age women is likely to become an increasingly critical issue regarding possibilities of infertility, hormonal dysfunction, and mortality. The aim of this study was to examine the long-term oncologic outcome and its prognostic indicators based on a multicentric cohort of young patients with CCC. During the period of 1990–2015, a total of 164 patients aged 45-year-old or younger were enrolled in the study. Clinicopathologic data of these young patients with CCC collected under a centralized pathological review system were subjected to uni- and multivariable analyses to evaluate overall survival (OS). The median follow-up was 73.8 months (range 5.2–244.2) in the surviving patients. Among these patients, 104 (63.4%) had FIGO I disease, and 22 (13.4%), 31 (18.9%), and 7 (4.3%) had II, III, and IV disease, respectively. The 5-year OS rate was 74.5%. On stratification by the FIGO stage, the 5-year OS rates were as follows: stage I (90.2%), stage II (57.9%), and stage III/IV (39.3%), respectively (P

OBJECTIVE: To examine the association between surgical volume and survival of women with early-stage cervical cancer who underwent radical hysterectomy. METHODS: This is a nationwide multicenter retrospective study examining consecutive women with clinical stage IB1-IIB cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy from 2004 to 2008 (N=5,964). The surgical volume per site over the 5-year period was defined as low-volume (fewer than 32 surgeries, 46 [39.7%] institutions, n=649 [10.9%]), mid-volume (32–104 surgeries, 60 [51.7%] institutions, n=3,662 [61.4%]), and high-volume (105 surgeries or more, 10 [8.6%] institutions, n=1,653 [27.7%]). Surgical volume-specific survival was examined with multivariable analysis and propensity score matching. RESULTS: The median number of surgeries per site was 44 (interquartile range, 17–65). The 5-year disease-free survival rates among stage IB1-IIB disease were 77.2%, 79.9%, and 84.5% for low-, mid-, and high-volume groups, respectively. On multivariable analysis, women in high-volume centers had a decreased risk of recurrence (adjusted hazard ratio [HR] 0.69, 95% CI 0.58–0.82, P

Postpartum haemorrhage (PPH) is a potentially life-threatening condition. Women undergoing caesarean section (CS) are at particular risk, and improvements in the management of PPH during CS are required. We investigated the use of a tissue hardness metre to quantify uterine contractions during CS with a view to its application for obstetric bleeding management. Fifty pregnant women at term who underwent elective CS were recruited. Using a tissue hardness metre, we measured uterine hardness twice during CS: after placental removal and before peritoneum closure. Each measurement was conducted at two standardised points: fundus and corpus uteri. Concurrently, obstetricians subjectively graded uterine contractions as weak, medium, or strong. The hardness metre accurately quantified the degree of uterine contraction assessed by the obstetricians, and could be an effective clinical tool for early recognition of intra-operative massive bleeding. IMPACT STATEMENT What is already known on this subject? Maintaining adequate uterine contraction leads to prevention of excessive blood loss, which decreases the incidence and severity of PPH. However, the assessment of uterine contraction is currently judged by obstetricians, who manually and subjectively evaluate uterine contraction according to uterine hardness. Therefore, uterine atony remains a clinical diagnosis without a universal definition. What do the results of this study add? The present study investigated the use of a tissue hardness metre to quantify uterine contractions during CS with a view to its application for obstetric bleeding management. The hardness metre was able to quantify the degree of uterine contraction perceived by obstetricians. Quantifying uterine hardness during CS correlates with the amount of intra-operative bleeding and is useful for early recognition of massive haemorrhage. What are the implications of these findings for clinical practice and/or further research? To improve the management of atonic PPH and avoid serious complications, the tissue hardness metre should be considered as a potential clinical tool during CS.

Fertility-sparing surgery (FSS) has mainly been chosen for young women with ovarian-confined/well-differentiated epithelial ovarian cancer (EOC). In general, FSS consists of at least conservation of contralateral ovary and the uterus with a staging surgery. However, information on the clinical outcome in women who underwent cystectomy as a fertility-preserving option is lacking. After a central pathological review and search of the medical records from multiple institutions between 1987 and 2015, a total of eight early-stage EOC patients treated with cystectomy as FSS were retrospectively evaluated. Diagnosis and staging were based on International Federation of Gynecology and Obstetrics criteria (2014). Surgery consisted of uni- or bilateral cystectomy. The oncologic and reproductive outcomes were assessed. The median age was 29 years (range 26–38 years). The median follow-up time was 103.6 months (range 42.2–218.3 months). The stage was IA in 3, IC1 in 4, and IC3 in one patient. Five patients received adjuvant chemotherapy. After cystectomy, two patients experienced recurrence in the pelvic cavity and bilateral ovaries, respectively. The former patient died of the disease 42 months after cystectomy, and conversely, the latter one was rescued by subsequent radical surgery. Four full-term childbirths were observed in three patients. Although oophorectomy is considered as an appropriate fertility-preserving operation, cystectomy may be an unavoidable option when it is the only surgical procedure available. It is desirable to verify the utility by accumulating larger numbers of patients through a future registry system.

The mesothelium, covered by a continuous monolayer of mesothelial cells, is the first protective barrier against metastatic ovarian cancer. However, mesothelial cells release tumor-promoting factors that accelerate the process of peritoneal metastasis. We identified cancer-associated mesothelial cells (CAMs) that had tumor-promoting potential. Here, we found that plasminogen activator inhibitor-1 (PAI-1) induced the formation of CAMs, after which CAMs increasingly secreted the oncogenic factors interleukin-8 (IL-8) and C-X-C motif chemokine ligand 5 (CXCL5), further promoting the metastasis of ovarian cancer cells in a feedback loop. After the formation of CAMs, PAI-1 activated the nuclear factor kappa B (NFκB) pathway in the CAMs, thus transcriptionally upregulating the expression of the downstream NFκB targets IL-8 and CXCL5. Moreover, PAI-1 correlated with peritoneal metastasis in ovarian cancer patients and indicated a poor prognosis. In both ex vivo and in vivo models, after PAI-1 expression was knocked down, the metastasis of ovarian cancer cells decreased significantly. Therefore, targeting PAI-1 may provide a potential target for future therapeutics to prevent the formation of CAMs and alleviate peritoneal metastasis in ovarian cancer patients., ファイル公開：2020-02-01

β-Lactam antibiotics are first-line agents for the treatment and prevention of group B Streptococcus (GBS) infections. We previously reported clinical GBS isolates with reduced β-lactam susceptibility (GBS-RBS) and characterized them as harbouring amino acid substitutions in penicillin-binding proteins (PBPs). However, to our knowledge, GBS-RBS clinical isolates have never previously been isolated from pregnant women worldwide. We obtained 477 clinical GBS isolates from vaginal/rectal swabs of 4530 pregnant women in Japan. We determined the MICs of seven β-lactams for all 477 clinical isolates. Five clinical isolates showed reduced ceftibuten susceptibility. For these isolates, we performed sequencing analysis of pbp genes. None of the 477 isolates were non-susceptible to penicillin G, ampicillin, and meropenem. For five isolates, the MICs of ceftibuten were relatively high (64–128 μg/ml). Each of these isolates possessed a single amino acid substitution in PBP2X, and some of the substitutions had been previously found in GBS with reduced penicillin susceptibility. This is the first report of the isolation of clinical GBS-RBS isolates harbouring amino acid substitutions in PBP2X that confer reduced ceftibuten susceptibility from pregnant women.

Gestational choriocarcinoma is a gestational trophoblastic neoplasia (GTN) originating from trophoblastic cells with abnormal proliferation. Although chemotherapy is effective for treating this cancer, when patients develop chemoresistance, personalized treatment, such as the use of drugs matching their genomes, is required. The present report describes a case of intractable gestational choriocarcinoma identified using a next-generation sequencing (NGS)-based tumor panel. A 51-year-old woman was diagnosed with gestational choriocarcinoma via pathological and short tandem repeat analyses. The patient did not achieve remission despite many regimens of chemotherapy, including high-dose therapy with autologous peripheral blood stem cell transplantation. To identify drugs tailored to this particular choriocarcinoma, NGS was performed on the tumor of the patient, and the tumor genome was compared with that of the patient's blood sample using the NCC Oncopanel System. Consequently, 245 single nucleotide variants (SNVs) with a mean SNV allele frequency of 63.1% were identified. This high frequency was because the genome of the gestational choriocarcinoma contained part of the genome of the partner. Therefore, our experience of the present intractable case of choriocarcinoma suggested that matched normal-tumor pair analysis is not appropriate for treatment decisions in GTN cases. When using an NGS-based tumor panel to assess choriocarcinoma, researchers must consider whether the genomic DNA of the patient and their partner are involved in the GTN.

Ovarian clear cell carcinoma (OCCC) has been treated with surgery and chemotherapy, however, the prognosis remains poor because of chemoresistance. Therefore, immunotherapies are attracting attention, including the GPC3 peptide vaccine, which improves overall survival. However, the response rate is limited and there are no sufficient predictive biomarkers that can identify responders before treatment. Our purpose was to identify circulating serum miRNAs as predictive biomarkers for response to GPC3 peptide vaccine. Eighty-four patients in a phase II trial of a GPC3 peptide vaccine were enrolled and miRNA sequencing was performed on their serum samples. Candidate miRNAs were selected from a group of 14 patients for whom treatment was responsive and validated in an independent group of 10 patients for whom treatment was responsive. Three markedly upregulated miRNAs, miR-375-3p, miR-193a-5p, and miR-1228-5p, were identified, and the combination of those miRNAs demonstrated high value in the prediction of the response. The origin of these miRNAs was assessed by referring to OCCC tissue miRNA profiles, and they were not identified as cancer tissue-related miRNAs. Functional annotation analysis suggested that they were associated with interferon-related pathways. The miRNAs identified herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine.

BackgroundOvert hyperthyroidism and hypothyroidism are associated with pregnancy complications; however, most women with these conditions are diagnosed before conception and are under treatment during pregnancy, especially in the developed countries. The purpose of this study was to investigate pregnancy complications among these women.MethodsA retrospective case-control study was conducted, and data on 3824 pregnant women who gave birth at Nagoya University Hospital located in Japan from 2005 to 2014 was collected. The pregnancy outcomes were divided and compared among three groups: the control group (n = 3709), the hyperthyroidism group (n = 52) and the hypothyroidism group (n = 63). Risk factors for placental abruption were also evaluated in singleton pregnancies (n = 3588) by multivariable logistic regression analysis. Moreover, in hyperthyroidism, thyroid function was also compared between successful and failed placentation group, and the latter group included placental abruption and preeclampsia. ResultsThe incidence of placental abruption was significantly higher in hyperthyroidism than in control and hypothyroidism groups (p < 0.01). Hyperthyroidism was independently associated with an increased risk of placental abruption (adjusted odds ratio = 12.52, 95% confidence interval = 2.91–53.88). Thyroid stimulating hormone (TSH) was significantly lower in failed placentation group than in successful placentation group (p < 0.05). ConclusionAccording to the results of our study, pregnancy outcomes in women with treated hypothyroidism were comparable with those in women without thyroid disease. Conversely, women with treated hyperthyroidism showed an independent risk of placental abruption, which might be related with lower TSH level at early gestation. However, further research is required to validate our findings.

A congenital diaphragmatic hernia (CDH) is an anomaly caused by defects in the diaphragm; the resulting limited thorax cavity in turn restricts lung growth (pulmonary hypoplasia). This condition is related to pulmonary hypertension. Despite advances in neonatal CDH therapy, the mortality for severe pulmonary hypoplasia remains high. Therefore, it is essential to establish prenatal therapeutic interventions. Vitamin D was reported to have beneficial effects on adult pulmonary hypertension. This study aims to evaluate the efficacy of prenatal vitamin D administration for CDH. First, serum 25-hydroxyvitamin D [25(OH)D] levels in umbilical cord blood were evaluated among CDH newborns. Second, Sprague Dawley rat CDH models were exposed to nitrofen on embryo day 9 (E9). Randomly selected rats in the nitrofen-treated group were infused with calcitriol from E9 to E21. Samples from CDH pups diagnosed after birth were used for lung weight measurements, blood gas analysis, and immunohistochemical analysis. Third, microarray analysis was performed to examine the effect of vitamin D on gene expression profiles in CDH pulmonary arterial tissues. Serum 25(OH)D levels in the umbilical cord blood of newborns who did not survive were significantly lower than those who were successfully discharged. Prenatal vitamin D showed no significant effect on CDH incidence or lung weight but attenuated alveolarization and pulmonary artery remodeling accompanied the improved blood gas parameters. Vitamin D inhibited several gene expression pathways in the pulmonary arteries of CDH rats. Our results suggest that prenatal vitamin D administration attenuates pulmonary vascular remodeling by influencing several gene pathways in CDH.

Aim Malignant transformation of mature cystic teratoma (MTMCT) of the ovary is a rare gynecological malignancy and commonly arises in women older than 50 years of age. The most common histological type of MTMCT is squamous cell carcinoma (SCC), and the prognosis is extremely poor. Patient-derived xenograft (PDX) models are promising animal models for preclinical drug screening. Here, we report the generation of a new PDX model of MTMCT, and a new cell line established from the tumors of PDX model animals. Methods Tumor tissue was obtained from a 32-year-old patient with MTMCT. To generate PDX, NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ) mice, a strain of super-immunodeficient mice, were used. Tumor-bearing mice were sacrificed, followed by the collection of these tumors and re-transplantation into new NSG mice (in vivo passage). Tumor samples were also cultured in vitro. Adherent cells were continuously cultured and passaged, a cell line was established. Results In the primary PDX mouse, tumor engraftment was confirmed 30 days after tumor implantation. After three times in vivo passage, we confirmed that the cryopreserved tumors could be engrafted even when transplanted into BALB/c nude mice. Using the tumor tissue at the time of the first in vivo passage, a new cell line NOSCC1 was established. PDX tumors and cell-line derived xenograft tumors exhibited similar morphology of SCC. Conclusion We established a new PDX model of MTMCT and a new cell line of it, which may be important tools for the development of new therapies and the elucidation of the carcinogenic mechanisms of MTMCT.

Background 5-Aminolaevulinic acid (5ALA) is a precursor of the strong sensitizer protoporphyrin IX (PpIX) in the heme synthesis pathway. We conducted aclinical trial designed to evaluate the efficacy and safety of 5ALA photodynamic therapy (PDT) using a light-emitting diode (LED) in patients with cervical intraepithelial neoplasia (CIN). Methods Data for 51 CIN patients who underwent 5ALA-PDT between 2012 and 2017 were prospectively analysed. After a 20 % 5ALA jelly formulation was topically applied to the cervix, the region was irradiated with red light at approximately 633 nm to excite PpIX for treatment. We estimated outcomes by cytology, pathology, and human papilloma virus (HPV) testing after PDT. Results Patients underwent two PDT sessions at one-week intervals during outpatient treatment and achieved favourable results without photosensitivity and severe adverse events. Over a long follow-up period, 96.1 % of all patients showed some positive effects, including approximately 70 % with a complete response (CR), 10 % with a partial response, and 15 % with downgrades. The HPV clearance rate in patients with CR was 79.4 %. Recurrence occurred in five patients who mostly remained HPV-positive after PDT. Conclusions Based on our study, topical 5ALA-PDT using an LED light source potentially represents a safe treatment for CIN on an outpatient basis.

Background This study was conducted to investigate the prognostic significance of sarcopenia in patients with organ metastatic cervical cancer. Methods Accordingly, the data of 40 patients with organ metastatic cervical cancer treated at our institute from December 2004 to December 2017 were retrospectively analyzed. The correlation between clinicopathological characteristics and survival was then evaluated using univariate and multivariate analyses. Psoas muscle index (PMI), calculated from the psoas muscle area at the L3 vertebral-body level using computed tomography images obtained for pretreatment evaluation, was adopted as an index of sarcopenia. Results The median follow-up period was 14 months (range, 1-91 months). Kaplan-Meier analysis showed a 3- and 5-year overall survival (OS) rate of 46.1% and 35.8% for all patients, respectively. Receiver operating characteristic curve maximizing the area under the curve showed that the optimal PMI for predicting 1-year survival was 3.72 cm2 /m2 . Patients with a PMI > 3.72 cm2 /m2 had significantly better OS than those with a PMI ≤ 3.72 cm2 /m2 (P = .046). Multivariate analysis revealed that only PMI was significantly associated with OS in patients with organ metastatic cervical cancer. Furthermore, patients with a PMI > 3.72 cm2 /m2 who underwent concurrent chemoradiotherapy (CCRT) had a longer OS than those receiving other therapies (P Conclusions High PMI was determined to be a favorable prognostic factor for patients with organ metastatic cervical cancer. Moreover, patients with organ metastatic cervical cancer who have a PMI > 3.72 cm2 /m2 may benefit from CCRT as an initial treatment.

Background: Patients with primary ovarian insufficiency (POI) occasionally present with follicle growth; however, it is difficult to predict exactly which cycles will show follicle growth. Serum anti-Müllerian hormone (AMH), a useful marker for ovarian reserve, is produced in early-stage follicles. Therefore, AMH levels should reflect the presence of small follicles, which are difficult to detect using ultrasonography, and may be useful as a marker for predicting follicle growth in patients with POI. Methods: Using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) kit, we found very low serum AMH levels in patients with POI. We assessed the follicle growth of each patient during each cycle to clarify the usefulness of measuring serum AMH levels for predicting follicle growth in patients with POI under hormone replacement therapy (HRT). Results: A total of 91 cycles of 19 patients with POI were analyzed in this study. Five patients presented with positive serum AMH levels during the observational periods, and all five experienced follicle growth. Only two of the 14 patients with negative serum AMH levels had follicle growth. Serum AMH and follicle-stimulating hormone (FSH) levels in cycles with follicle growth were significantly higher than in cycles without follicle growth. The median serum AMH level (2.77 pg/mL; 25th, 75th percentiles: 0.0, 9.64) in cycles with follicle growth was lower than the lower limit of detection of conventional AMH ELISA kits. The positive predictive value of positive serum AMH levels for follicle growth was higher than that of FSH (< 10 mIU/mL).Conclusions: Measurement of very low levels of serum AMH using picoAMH assays is useful for prediction of follicle growth in patients with POI under HRT conditions. Trial registration: UMIN-CTR UMIN000029464. Retrospectively registered on April 4, 2018. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000033550

Background: Patients with primary ovarian insufficiency (POI) present with follicle growth occasionally, however, it is difficult to predict the exact cycles with follicle growth. Serum anti-Müllerian hormone (AMH), a useful marker for ovarian reserve, is produced in early-stage follicles. Therefore, AMH levels should reflect the existence of small follicles which are difficult to detect using ultrasonography and may be useful for predicting follicle growth in patients with POI. Methods: Using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) kit, we found very low serum AMH levels of patients with POI; we further assessed the follicle growth of each patient and their cycles to clarify the usefulness of measuring serum AMH levels for predicting the follicle growth in patients with POI. Results: A total of 91 cycles of 19 patients with POI were analyzed in this study. Five patients presented with positive serum AMH levels during the observational periods and all five experienced follicle growth. Only two of the 14 patients with negative serum AMH levels had follicle growth. Serum AMH and follicle-stimulating hormone (FSH) levels in cycles with follicle growth were significantly higher than in cycles without follicle growth. The median serum AMH level (2.77 pg/mL; 25th, 75th percentiles: 0.0, 9.64) in cycles with follicle growth were lower than the lower limit of detection of conventional AMH ELISA kits. The positive predictive value of positive serum AMH levels for follicle growth was higher than that of FSH (

Objective: The impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked. Methods: Between 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB-IV CCC were collected (residual tumor of

Background Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age and a major cause of infertility; however, the pathophysiology of this syndrome is not fully understood. This can be addressed using appropriate animal models of PCOS. In this review, we describe rodent models of hormone‐induced PCOS that focus on the perturbation of the hypothalamic‐pituitary‐ovary (HPO) axis and abnormalities in neuropeptide levels. Methods Comparison of rodent models of hormone‐induced PCOS. Main findings The main method used to generate rodent models of PCOS was subcutaneous injection or implantation of androgens, estrogens, antiprogestin, or aromatase inhibitor. Androgens were administered to animals pre‐ or postnatally. Alterations in the levels of kisspeptin and related molecules have been reported in these models. Conclusion The most appropriate model for the research objective and hypothesis should be established. Dysregulation of the HPO axis followed by elevated serum luteinizing hormone levels, hyperandrogenism, and metabolic disturbance contribute to the complex etiology of PCOS. These phenotypes of the human disease are recapitulated in hormone‐induced PCOS models. Thus, evidence from animal models can help to clarify the pathophysiology of PCOS.

Background To elucidate the impact of fertility treatment on neonatal respiratory outcomes and amniotic lamellar body counts (LBCs) in twin pregnancies. Methods One hundred ninety twin pairs, including 99 dichorionic twin (DCT) and 91 monochorionic twin (MCT) pairs were registered at our institutions. All amniotic fluid samples were obtained from each sac at cesarean section. Samples were analyzed immediately after arrival at the laboratory without centrifugation. We divided the patients into 3 groups: the no therapy group (natural conception), the induced ovulation group (with or without intrauterine insemination), and the assisted reproductive technology (ART) group (in vitro fertilization or intracytoplasmic sperm injection). Results No statistically significant associations between the fertility treatment and the rates of neonatal RDS/TTN were observed in the whole study population (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.45–2.00), DCT (OR, 0.86; 95%CI, 0.30–2.47), and MCT (OR, 1.45; 95%CI, 0.41–5.11). In addition, there was no association between the fertility treatment and neonatal RDS/TTN in the propensity score analysis of the whole study population (OR, 1.25; 95%CI, 0.57–2.74). Conclusions None of the individual types of fertility treatment had a direct impact on respiratory disorders such as RDS and TTN in twin infants.

Non-thermal plasma represents a novel approach in cancer treatment. Both direct and indirect plasma treatments are available, with clinical trials of direct plasma treatment in progress. Indirect treatments involve chemotherapy (i.e., plasma-activated medium) and immunotherapy. Recent studies suggest that integrated plasma treatments could be an extremely effective approach to cancer therapy.

Patients with primary ovarian insufficiency (POI) have a high prevalence of thyroid autoimmune disorders. However, the extent of the contribution of thyroid autoantibodies or elevated thyroid-stimulating hormone (TSH) levels to decreased ovarian reserve is unclear. Therefore, we evaluated the serum levels of anti-Müllerian hormone (AMH) and thyroid autoantibodies [antithyroperoxidase antibody (TPOAb), and antithyroglobulin antibody (TgAb)] in euthyroid infertile women. One hundred and fifty-three women with normal menstrual cycles were recruited for this retrospective study. Serum levels of AMH were compared between patients with positive and negative thyroid autoantibodies. The correlation between serum levels of AMH and each thyroid autoantibody was also evaluated. Participants were observed to be either TPOAb or TgAb positive (n=27), only TPOAb positive (n=8), only TgAb positive (n=7), TPOAb and TgAb positive (double positive; n=12), and TPOAb and TgAb negative (double negative; n=126). No significant differences were found in serum AMH levels between the TPOAb- or TgAb-positive women and the antibody-double negative women. Serum AMH levels did not show a significant correlation with the concentration of TgAb or TPOAb. On the other hand, serum AMH levels negatively correlated with TSH levels in patients who were either positive for TPOAb or TgAb. Thyroid autoantibodies are not likely to influence ovarian reserve in euthyroid women whose TSH levels fall within the normal range although elevated TSH levels may be involved in the decline of serum AMH levels.

// Yuuki Ohara 1 , Shan Hwu Chew 1 , Nobuaki Misawa 1 , Shenqi Wang 1 , Daiki Somiya 1 , Kae Nakamura 2 , Hiroaki Kajiyama 2 , Fumitaka Kikkawa 2 , Yuta Tsuyuki 3 , Li Jiang 1 , Kyoko Yamashita 1 , Yoshitaka Sekido 4 , Kenneth E. Lipson 5 and Shinya Toyokuni 1, 6 1 Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan 2 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan 3 Department of Pathology and Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan 4 Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan 5 FibroGen, Inc., San Francisco, CA 94158, USA 6 Sydney Medical School, The University of Sydney, Sydney 2006, Australia Correspondence to: Shinya Toyokuni, email: toyokuni@med.nagoya-u.ac.jp Keywords: connective tissue growth factor (CTGF); malignant mesothelioma; molecular target therapy; FG-3019 (pamrevlumab); tumor microenvironment Received: October 31, 2017 Accepted: March 09, 2018 Published: April 06, 2018 ABSTRACT Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo . We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro , which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.

It has been more than 15 years since the measurement of serum anti-Mullerian hormone (AMH) first allowed the quantitative assessment of ovarian reserve. Meanwhile, the clinical implication of serum AMH has been expanding. The measurement of serum AMH has been applied in various clinical fields, including assisted reproduction, menopause, reproductive disorders and assessment of ovarian damage/toxicity. Well-known findings about the usefulness of serum AMH revealed by numerous studies executed in the early era include decline with aging, a good correlation with oocyte yield in assisted reproduction, upregulation in polycystic ovarian syndrome and a decrease on ovarian surgery and toxic treatment. More intensive research, including a meta-analysis, cutting-edge clinical trial and advances in AMH assays, has yielded newer findings and firmer clinical interpretations in serum AMH in the past few years. Variations in the AMH decline trajectory in the general population do not support the accurate prediction of menopause. The ability to predict pregnancy in infertility treatment and natural conception is poor, while a nomogram integrating serum AMH as a stimulation protocol is useful for avoiding poor and/or hyper-responses. On the other hand, improvements in measuring very low concentrations of serum AMH may be capable of distinguishing women with poor ovarian function. Age-independent standardization of AMH values may be helpful for comparing ovarian reserves among women at different ages.

The objective of this study is to identify any correlation between the maternal protein S (PS) activity, which decreases spontaneously during normal pregnancy, and the pregnancy outcome, especially the amount of bleeding during caesarean section (CS).We analyzed 129 pregnant women who received elective CS at our hospital which is a tertiary perinatal center. The relationship between the amount of intraoperative hemorrhage and PS activity was estimated by simple linear regression. Univariate and multivariate analyses were also performed to determine whether or not the maternal PS activity was associated with massive hemorrhage (1000 g).The maternal PS activity correlated with the amount of intraoperative hemorrhage (p = .048, r = 0.175) and could be an independent predictor of massive hemorrhage (odds ratio 1.06; 95% confidence interval 1.01-1.12; p = .013).Maternal PS activity was associated with the amount of hemorrhage during CS and the occurrence of massive hemorrhage. PS activity reduction naturally occurring during pregnancy could contribute to alleviation of massive hemorrhage.

The objective of this study was to estimate the frequency of possible occult metastasis through long-term survival analyses in patients with clear cell carcinoma (CCC) who had undergone complete resection. During the period of 1990-2015, 799 patients with stage I-IV CCC were identified in the TOTSG database. Of these, a total of 528 patients without a residual tumor were enrolled in the study and classified into four groups: Group 1: FIGO stage IA-IB (N=104), Group 2: FIGO stage IC1 (N=170), Group 3: FIGO stage IC2/IC3 (N=98), and Group 4: FIGO stage II-III (no residual tumor: N=156). Cumulative incidences of recurrence (CIR) and death (CID) were examined. The median age was 54, ranging from 29-87. The 5-year CIR / CID of each group were as follows: Group 1 (7.3% / 3.8%), Group 2 (14.3% / 10.2%), Group 3 (37.7% / 18.4%), and Group 4 (46.5% / 33.8%), respectively {P

We previously found that the serum level of fucosylated haptoglobin (Fuc-Hpt) was significantly increased in pancreatic cancer patients. To delineate the mechanism underlying this increase and develop a simple detection method, we set out to generate a monoclonal antibody (mAb) specific for Fuc-Hpt. After multiple screenings by enzyme-linked immunosorbent assay (ELISA), a 10-7G mAb was identified as being highly specific for Fuc-Hpt generated in a cell line as well as for Hpt derived from a pancreatic cancer patient. As a result from affinity chromatography with 10-7G mAb, followed by lectin blot and mass spectrometry analyses, it was found that 10-7G mAb predominantly recognized both Fuc-Hpt and prohaptoglobin (proHpt), which was also fucosylated. In immunohistochemical analyses, hepatocytes surrounding metastasized cancer cells were stained by the 10-7G mAb, but neither the original cancer cells themselves nor normal hepatocytes exhibited positive staining, suggesting that metastasized cancer cells promote Fuc-Hpt production in adjacent hepatocytes. Serum level of Fuc-Hpt determined with newly developed ELISA system using the 10-7G mAb, was increased in patients of pancreatic and colorectal cancer. Interestingly, dramatic increases in Fuc-Hpt levels were observed at the stage IV of colorectal cancer. These results indicate that the 10-7G mAb developed is a promising antibody which recognizes Fuc-Hpt and could be a useful diagnostic tool for detecting liver metastasis of cancer., This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan and was supported by JSPS KAKENHI Grant Number JP16H05226.

Spontaneous preterm birth is often caused by chorioamnionitis. Toll-like receptors (TLRs) have a role in the response of the innate immune system. The role of TLR5 in chorioamnionitis remains unclear: however, TLR5 was reported to have a significantly stronger effect on the induction of interleukin (IL)-6 when compared with other TLRs in amniotic epithelial cells. The aim of this study was to investigate TLR5 expression in placentas with preterm histologic chorioamnionitis (HCA). The expression levels of TLR5 were evaluated in the amnions, chorions, deciduae and villi with and without HCA using immunohistochemistry. The co-localization of IL-6 or IL-8 with TLR5 was examined by immunofluorescence. The production of IL-6 was examined in primary tissue cultured fetal membranes treated with and without the TLR5 agonist. The protein expression of TLR5 was significantly increased in amnions with HCA (p

Typical ultrasound findings of fetal abdominal lymphangioma include thick-walled, multiseptated anechoic masses. Although a majority of cases can be suspected promptly by ultrasound examination, the two cases presented herein did not meet the standard criteria and were misleading. Both cases involved unilocular cysts without clear septations, but in retrospect were atypical findings of fetal abdominal lymphangioma. A few reports of misleading cases have been described previously; however, the precise characteristics have not been reported in detail. Therefore, in this case report, we focused predominantly upon the difficulties encountered in the prenatal diagnosis of abdominal lymphangioma based on ultrasound morphology alone.

We examined the effect of simulation training for medical staff on the decision-to-delivery interval (DDI) in cases of emergent cesarean delivery and the effect of a shortened DDI on maternal and neonatal outcomes.Our hospital is a tertiary perinatal center. As the simulation training was performed in March 2014, the study population was divided into two groups: pretraining group (November 2011-March 2014, 29 months: n = 15) and post-training group (April 2014-August 2016, 29 months: n = 35).The DDI was significantly shorter in the post-training group than in the pretraining group (p = .009). In particular, the decision-to-entering the operating room interval was significantly shorter in the post-training group than in the pretraining group (p = .003). The umbilical artery pH was significantly better in post-training group than in the pretraining group (p = .019). Furthermore, the umbilical artery pH was significantly improved by simulation training only in "irreversible" cases (p = .012).The DDI was significantly shortened by introducing simulation training. We also demonstrated a beneficial effect of the simulation training on the umbilical artery pH, especially in "irreversible" cases, without increasing the rate of maternal adverse outcome.