Efficacy and safety of a novel pain management device, AT-04, for endometriosis-related pain: study protocol for a phase III randomized controlled trial.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

Endometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-related pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endometriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first randomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, that incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a multicenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone standard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains effective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 on reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects the strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole efficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual cycles may influence the assessment of pain and quality of life. However, the study findings regarding the effectiveness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain that is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproductive health within society.

Impact of adenomyosis on perinatal outcomes: a large cohort study (JSOG database).

BACKGROUND: A previous study investigated the effect of adenomyosis on perinatal outcomes. Some studies have reported varying effect of adenomyosis on pregnancy outcomes in some patients and dependence on the degree and subtype of uterine lesions. To elucidate the impact of adenomyosis on perinatal outcomes. METHODS: This large-scale cohort study used the perinatal registry database of the Japan Society of Obstetrics and Gynecology. A dataset of 203,745 mothers who gave birth between January 2020 and December 2020 in Japan was included in the study. The participants were divided into two groups based on the presence or absence of adenomyosis. Information regarding the use of fertility treatment, delivery, obstetric complications, maternal treatments, infant, fetal appendages, obstetric history, underlying diseases, infectious diseases, use of drugs, and maternal and infant death were compared between the groups. RESULTS: In total, 1,204 participants had a history of adenomyosis and 151,105 did not. The adenomyosis group had higher rates of uterine rupture (0.2% vs. 0.01%, P = 0.02) and placenta accreta (2.0% vs. 0.5%, P < 0.001) than the non-adenomyosis group. A history of adenomyosis (odds ratio: 2.26; 95% confidence interval: 1.43-3.27; P < 0.001), uterine rupture (odds ratio: 3.45; 95% confidence interval: 0.89-19.65; P = 0.02), placental abruption (odds ratio: 2.11; 95% confidence interval: 1.27-3.31; P < 0.01), and fetal growth restriction (odds ratio: 2.66; 95% confidence interval: 2.00-3.48; P < 0.01) were independent risk factors for placenta accreta. CONCLUSION: Adenomyosis in pregnancies is associated with an increased risk of placenta accreta, uterine rupture, placental abruption, and fetal growth restriction. TRIAL REGISTRATION: Institutional Review Board of Tottori University Hospital (IRB no. 21A244).

Evaluation of the Characteristics of Ovarian Endometriomas in Patients with Endometriosis: Efficacy of a Low-Dose Estrogen/Progestogen Combination.

OBJECTIVES: Approximately 17-44% of women diagnosed with endometriosis have ovarian endometriomas (cysts). Although ovarian endometriomas may adversely affect quality of life and work performance, the associations among patient characteristics, cyst size, and pain in women with endometriosis have not yet been reported. Thus, the objective of this study was to assess the association among age, cyst size, and pain in women with ovarian endometriomas. DESIGN: This was a retrospective secondary analysis of pooled data from six randomized clinical trials on the use of low-dose estrogen/progestogen drugs for endometriosis. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Data on 491 patients enrolled in four randomized and two nonrandomized trials between 2003 and 2017 were pooled. None of the participants had undergone surgical treatment before trial participation. We examined differences in dysmenorrhea score, menstrual pain score, analgesic score, and pelvic pain, as measured using a visual analog scale (VAS), by age and endometrioma size. RESULTS: The mean dysmenorrhea, menstrual pain, and analgesic scores were 4.2, 2.2, and 2.0, respectively. The mean VAS for pelvic pain was 55, which decreased significantly with an increase in age. Age was not associated with endometrioma size, including volume and maximum diameter, or dysmenorrhea score. Additionally, endometrioma volume and maximum diameter were not associated with menstrual pain, analgesic score, or pelvic pain. LIMITATIONS: The details of past treatment history were not available; therefore, these could not be considered in the analysis. Additionally, the assessment of pain is heavily influenced by psychological factors, making it difficult to assess the true extent of pain. CONCLUSIONS: Endometrioma size was not associated with dysmenorrhea or pelvic pain measured using the VAS.

The learning curve of introduced robotic-assisted hysterectomy versus skilled laparoscopic hysterectomy for benign gynecologic diseases.

AIM: This study aimed to compare introduced robotic-assisted hysterectomy (RAH) and skilled total laparoscopic hysterectomy (TLH) for the treatment of benign gynecological diseases. METHODS: Patients who underwent RAH or TLH by two surgeons at the Tottori University Hospital between January 2018 and May 2022 were included in this retrospective study. Inclusion criteria were patients with 100-300 g of uterine weight. The exclusion criteria were patients with stage IV endometriosis. Mean operative time and learning curve were compared among the first-half RAH, second-half RAH, and TLH groups. RESULTS: There were 40 eligible cases (first-half RAH: 20 cases, second-half RAH: 20 cases) in the RAH group and 44 cases in the TLH group. The total operative time (TOT) of the second half of RAH was significantly shorter than that of the first half of RAH (p = 0.021) and was comparable to that of the TLH group. The operative time (OT) of the second half of RAH was shorter than that of TLH (p = 0.023). The preparation time of TLH was shorter than that of the RAH group (p < 0.01). The learning curve of the TOT in RAH crossed that of TLH on the 31st case of RAH. In contrast, both curves of the OT crossed on the 11th case of RAH. CONCLUSION: The TOT of the introduced RAH was equivalent to that of skilled TLH in approximately 30 cases since the first RAH. Furthermore, the OT of RAH was comparable to that of TLH in approximately 10 cases of surgery since the first RAH.

A nationwide survey of the use of the laparoscopic power morcellator.

AIM: Laparoscopic power morcellator (LPM) can be used for tissue retrieval through laparoscopic port site, but the dissemination of uterine and/or myoma tissues is a serious complication. To study the use of LPM for uterine fibroid treatment in Japan, we aimed to perform two national cross-sectional surveys comprising multiple questionnaires. METHODS: The first survey (2011-2013) was conducted in November 2014, and 203 medical institutions responded. The second survey (2017-2019) was conducted in December 2020, and 302 medical institutions were investigated. RESULTS: Overall, 72 104 and 120 425 surgeries and 0.04% and 0.05% cases of postoperative malignancy diagnosis were reported in the first and second surveys, respectively. Magnetic resonance imaging was performed in >90% of the cases in the first and second surveys as preoperative examinations. The frequency of LPM at hysterectomy was 8.9% and 4.6% and the frequency of LPM at laparoscopic myomectomy was 80.4% and 54.8% in the first and second surveys, respectively; both the parameters decreased in the second survey. CONCLUSIONS: It is impossible to completely exclude malignant diseases even if extensive preoperative diagnosis has been done before surgery. Therefore, the use of LPM in patients requires careful attention and informed consent in Japan.

The Asian Society of Endometriosis and Adenomyosis guidelines for managing adenomyosis.

This is the first guidelines for adenomyosis from the Asian Society of Endometriosis and Adenomyosis.

D-dimer level significance for deep vein thrombosis screening in the third trimester: a retrospective study.

BACKGROUND: Venous thromboembolism often develops after surgery and childbirth, resulting in death in some cases. Although early deep vein thrombosis (DVT) detection can predict pulmonary thromboembolism, there is no early screening method for DVT in pregnant women. Lack of consensus regarding significance or setting and cut-off value interpretation of D-dimer levels further impedes venous thromboembolism screening in pregnant women. This study aimed to examine the utility of third-trimester serum D-dimer levels as a screening test for DVT during pregnancy and to determine the frequency of asymptomatic DVT using lower-limb compression ultrasonography. METHODS: This single-center retrospective study included 497 pregnant women who underwent elective cesarean section at term in our hospital between January 2013 and December 2019. Serum D-dimer levels were preoperatively measured at 32-37 weeks' gestation. The presence or absence of DVT in patients with serum D-dimer levels ≥ 3.0 µg/ml, the cut-off value, was examined using compression ultrasonography. In all patients, the presence or absence of clinical venous thrombosis (symptoms such as lower-limb pain, swelling, and heat sensation) was examined within 4 postoperative weeks. The Royal College of Obstetricians and Gynecologists Guideline 2015 was referred to determine risk factors for the onset of venous thrombosis during pregnancy. Among those, we examined the risk factors for DVT that result in high D-dimer levels during pregnancy. RESULTS: The median age and body mass index were 35 (20-47) years and 21.2 (16.4-41.1) kg/m2, respectively. Further, the median gestational age and D-dimer levels were 37 weeks and 2.1 (0.2-16.0) µg/ml, respectively. Compression ultrasonography was performed on 135 (26.5%) patients with a D-dimer level ≥ 3.0 µg/ml, with none of the patients showing DVT. All patients were followed up for 4 postoperative weeks, with none presenting with venous thromboembolism. Multivariate analysis showed that hypertensive disorders of pregnancy are an independent risk factor for venous thromboembolism that causes high D-dimer levels (odds ratio: 2.48, 95% confidence interval: 1.05-6.50, P = 0.04). CONCLUSION: There may be low utility in screening for DVT using D-dimer levels in the third trimester. Further, prepartum asymptomatic DVT has a low frequency, indicating the low utility of compression ultrasonography. TRIAL REGISTRATION: Institutional Review Board of Tottori University Hospital (IRB no. 20A149 ).

A simplified procedure of nerve-sparing radical hysterectomy.

AIM: We devised a simplified nerve-sparing radical hysterectomy that is simpler than commonly used procedures. METHODS: We retrospectively examined 16 cases of classical non-nerve-sparing radical hysterectomy (non-nerve-sparing group) and 16 cases of simplified nerve-sparing radical hysterectomy (nerve-sparing group) performed between 2019 and 2020. We examined and compared the duration of surgery, blood loss, perioperative complications, postoperative urinary function (presence or absence of urinary sensation, number of days with residual urine measurement, and frequency and duration of oral sustained release urapidil capsules and self-catheterization), and short-term prognosis between the two groups. RESULTS: Compared to conventional non-nerve-sparing radical hysterectomy, the duration of surgery for nerve-sparing radical hysterectomy was significantly shorter (407 [339-555] min vs. 212 [180-356] min; p < 0.001), and blood loss was significantly less. Compared to the nerve-sparing group, the non-nerve-sparing group had more cases of oral urapidil use and a higher frequency of clean intermittent catheterization. Clean intermittent catheterization was required in two cases in the nerve-sparing group; however, it was withdrawn at 180 and 240 days. Conversely, clean intermittent catheterization was still required in three cases in the non-nerve-sparing group. There were no statistically significant differences in progression-free survival and overall survival between the two groups. CONCLUSION: The simple nerve-sparing radical hysterectomy resulted in shorter duration of surgery and less blood loss as well as in a clear improvement in the postoperative urinary status and short-term prognosis. This technique simplifies nerve-sparing radical hysterectomy, which is commonly thought to be complicated, making it easier to understand.

Bleeding patterns of women with heavy menstrual bleeding or dysmenorrhoea using the levonorgestrel-releasing intrauterine system: results from a real-world observational study in Japan (J-MIRAI).

PURPOSE: To collect real-world safety and clinical outcome data on the levonorgestrel-releasing intrauterine system (LNG-IUS) for functional/organic heavy menstrual bleeding (HMB) and dysmenorrhoea in Japanese women (J-MIRAI). MATERIALS AND METHODS: In this prospective, multicentre, single-cohort, open-label, post-authorisation study, we assessed menstrual blood loss after LNG-IUS insertion by changes from baseline in pictorial blood loss assessment chart (PBAC) scores. Scores for the menorrhagia multi-attribute scale (MMAS) were collected for 12 months to assess quality of life. RESULTS: We included 47 patients with complete PBAC score and patient diary data. The median PBAC score before LNG-IUS insertion was 159.0, which decreased significantly to 6.0 at 12 months post-insertion; for patients with adenomyosis (n = 20), PBAC score decreased from 174.5 pre-insertion to 19.5 at 12 months. The number of patient-reported bleeding days was correlated with PBAC score ≥5. The proportion of women with prolonged bleeding decreased from 85.7% to 34.6% by the study's end. Some women reported no bleeding after the first 90-day reference period. The mean MMAS overall score significantly increased from 50.50 before insertion to 88.67 at 12 months. CONCLUSIONS: Japanese women with functional/organic HMB experienced substantial reductions in bleeding symptoms and improvements in quality of life after 12-month use of the LNG-IUS.

Increased risk of obstetric complications in patients with adenomyosis: A narrative literature review.

Background: Reproductive-age women occasionally face the pathological condition of adenomyosis, which is often concurrent with endometriosis. It is believed that endometriosis and adenomyosis increases the risk of obstetric complications. Although new insights into the mechanism of obstetric complications due to endometriosis are emerging, there is little information on the etiology of adverse pregnancy outcomes in pregnant women with adenomyosis. Methods: We performed a literature review focusing on the pathophysiological pathways of obstetric complications in women with adenomyosis using currently available basic and clinical studies. We used the internet search engines PubMed and Google Scholar to search for studies published between January 2000 and June 2021. We carefully read pertinent sections within each document to ensure relevancy. Main findings: The prevalence of adverse pregnancy outcomes in women with adenomyosis is increased after adjusting for conceiving by assisted reproductive technology. Thus, adenomyosis emerges as a relevant factor associated with several obstetric complications such as preterm birth, preterm premature rupture of membranes, placental abruption, small for gestational age/fetal growth restriction, and preeclampsia. Conclusion: It is plausible that the impact of adenomyosis on pregnancy outcomes is not always the same; rather it is dependent on the degree of uterine involvement and subtypes.

Effects of pretreatment radiological and pathological lymph node statuses on prognosis in patients with ovarian cancer who underwent interval debulking surgery with lymphadenectomy following neoadjuvant chemotherapy.

AIM: To analyze whether radiological and pathological lymph node statuses affected prognosis in patients with epithelial ovarian cancer who underwent neoadjuvant chemotherapy followed by interval debulking surgery. METHODS: In total, 82 patients undergoing interval debulking surgery, including systematic retroperitoneal lymphadenectomy, were eligible for this study. We retrospectively analyzed the association among radiological diagnosed retroperitoneal lymphadenopathy by computed tomographic scan before (rLN) and after (yrLN) neoadjuvant chemotherapy, pathological lymph node metastasis (pLN) and prognosis. Patient survival distribution was calculated using the Kaplan-Meier method. RESULTS: There were 36 rLN+ cases (44%); there were no significant differences between rLN+ and rLN- with respect to progression-free survival and overall survival. Progression-free survival and overall survival did not differ between yrLN+ cases and yrLN- cases. Thirty-nine cases (47.5%) were pLN+, and both progression-free survival and overall survival were significantly shorter in pLN+ cases than in pLN- cases (P < 0.001 and P = 0.004, respectively). In univariate analysis, FIGO stage, pLN and surgical completion were prognostic factors for overall survival. Moreover, in multivariate analysis, pLN+ was the independent prognostic factor for progression-free survival (P = 0.001, 95% confidence interval: 1.911-15.69), and pLN and surgical completion were the only independent prognostic factors for overall survival (P = 0.046, P = 0.012). CONCLUSION: Radiological lymph node status may not be a prognostic factor in patients with ovarian cancer who underwent neoadjuvant chemotherapy followed by interval debulking surgery. Pathological lymph node metastasis affects progression-free survival and overall survival.

Evaluating the efficacy and safety of ureteral stent placement as a preoperative procedure for gynecological cancer surgeries: A retrospective cohort study.

AIM: To evaluate the efficacy and safety of ureteral stent placement (USP) as a preoperative procedure for gynecological cancer surgeries. METHODS: This was a single-institution retrospective cohort study of 259 patients with gynecological cancer who underwent laparotomy. In 126 patients (USP+ group), a ureteral stent was inserted into the bilateral ureters after the induction of general anesthesia. The remaining 133 patients (USP- group) did not undergo USP. We compared operation time, blood loss, and frequency of laparotomy-related perioperative urinary complications between the groups. The stent was removed 5-7 days postoperatively. Patients were evaluated for signs of hydronephrosis at discharge. The Fisher's exact test was used to investigate the significance of differences in patient characteristics, and multivariate analysis was performed using a Cox proportional hazards model. A p-value of <0.05 was considered statistically significant. RESULTS: There were no significant differences in age and body mass index between the groups. Two patients in the USP- group experienced intraoperative ureteral injury. Total operation time and blood loss were significantly increased in the USP+ group. The risk of bladder tamponade and postoperative hydronephrosis was influenced by USP. USP was unaffected by a history of abdominal surgery, stage of tumor progression, lymphadenectomy type, or hysterectomy type. CONCLUSIONS: The incidence of bladder tamponade and hydronephrosis postoperatively was significantly higher in patients with USP than in those without USP.

National survey of bladder endometriosis cases in Japan.

AIM: We aimed to describe the clinical presentation, operative or medical management, and postoperative recurrence of bladder endometriosis (BE). METHODS: We conducted a national survey to investigate BE cases from 2006 to 2016 in Japan. Histologically diagnosed cases were extracted and then investigated for the following factors: age at diagnosis, body mass index, symptoms, imaging modalities, surgical therapy, hormonal therapy, follow-up period, and postoperative recurrence. RESULTS: Eighty-nine patients with pathologically benign BE were identified. Eighty patients underwent surgery, whereas nine did not. Moreover, 34 and 44 patients underwent transurethral resection (TUR) and partial cystectomy (PC), respectively. Cumulative recurrence rates were significantly higher with TUR than with PC (p < 0.05). The recurrence rate tended to be higher after laparoscopic PC (n = 24) than after open PC (n = 20), but the difference was not statistically significant (p = 0.0879). Of the nine nonsurgical patients, eight received hormonal therapy and one did not. Efficacy rates of dienogest, GnRH agonist, and OC were 85.7%, 66.7%, and 66.7%, respectively. Of five patients with BE extending to the ureter or ureteral orifices, two underwent PC and ureteroneocystostomy and one underwent total nephroureterectomy due to renal function loss. CONCLUSION: To our knowledge, this is the first study to compare the postoperative recurrence of BE after TUR and PC. We found that cumulative recurrence rate is significantly lower after PC than after TUR. BE extending to the ureter or ureteral orifices is a very challenging condition. Further studies are required for the optimal management of BE.

Efficacy of cyclic and extended regimens of ethinylestradiol 0.02 mg -levonorgestrel 0.09 mg for dysmenorrhea: A placebo-controlled, double-blind, randomized trial.

PURPOSE: We aimed to evaluate the efficacy and safety of 28-day Cyclic and 84-day Extended regimens of NPC-16 (ethinylestradiol 0.02 mg plus levonorgestrel 0.09 mg) in patients with dysmenorrhea. METHODS: This was a placebo-controlled, double-blind, randomized trial conducted in Japan. A total of 251 primary and secondary dysmenorrhea patients were randomly assigned to the NPC-16-Cyclic group, NPC-16-Extended group, or the Placebo group. The primary end point was a comparison of the efficacy and safety of the Cyclic and Extended NPC-16 regimen for the treatment of dysmenorrhea relative to the Placebo. MAIN FINDINGS: Significantly greater reductions in total dysmenorrhea score and visual analog scale score were observed in the Cyclic and Extended groups compared with the Placebo group. Compared with the Cyclic regimen as a secondary end point, the Extended regimen exhibited greater efficacy in the treatment of dysmenorrhea over the course of the study period, particularly in patients with severe dysmenorrhea. The incidence of adverse drug reactions (ADRs) was significantly higher in the Cyclic and Extended groups than in the Placebo group. CONCLUSION: The Cyclic and Extended regimens of NPC-16 significantly reduced dysmenorrhea severity compared to placebo. The Extended regimen was superior to cyclic regimen in reducing the dysmenorrhea.

A controlled clinical trial comparing potent progestins, LNG-IUS and dienogest, for the treatment of women with adenomyosis.

PURPOSE: To evaluate the efficacy of two progestins, levonorgestrel intrauterine system (LNG-IUS) and dienogest (DNG), for adenomyosis. METHODS: This study enrolled 157 women with adenomyosis, randomized to either LNG-IUS (n = 76) or DNG (n = 81) groups as a controlled clinical trial for 72 months. Participants were classified by three different localizations of adenomyosis: diffuse, focal, and extrinsic. VAS (Visual analog scale) score, days, and amount of uterine bleeding were assessed. Uterine volume or bone mineral density (BMD) were measured by three-dimensional ultrasonography or dual-energy X-ray absorptiometry. RESULTS: LNG-IUS and DNG comparably reduced pain scores in patients with adenomyosis. With regard to pain control, DNG offered greater efficacy than LNG-IUS in 3 months of treatment. In all types of adenomyosis, the days of bleeding after 12 months with DNG were significantly decreased compared to those with LNG-IUS. The decrease of whole uterine body was transient in any subtypes. A comparable decrease in BMD due to age-related changes in both groups was observed. CONCLUSIONS: LNG-IUS and DNG could be useful for long-term management of adenomyosis. In terms of durations of uterine bleeding, DNG was superior to LNG-IUS for 6 years.

Differential expression of estrogen receptor subtypes in ovarian high-grade serous carcinoma and clear cell carcinoma.

PURPOSE: To investigate the role of estrogen receptors (ERs) in high-grade serous carcinoma (HGSC) and clear cell carcinoma (CCC) of the ovary and evaluate ERs as prognostic biomarkers for ovarian cancer. METHODS: This study included 79 patients with HGSC (n = 38) or CCC (n = 41) treated at our institution between 2005 and 2014. Immunohistochemistry examined protein expression of ERα, ERß, and G protein-coupled estrogen receptor-1 (GPER-1); relationships between ERα, ERß, and GPER-1 with patient survival were evaluated. Additionally, cell proliferation assay and phosphokinase proteome profiling were performed. RESULTS: In HGSC patients, expression of ERα, cytoplasmic GPER-1, or nuclear GPER-1 was associated with poor progression-free survival (PFS) (P = .041, P = .010, or P = .013, respectively). Cytoplasmic GPER-1 was an independent prognostic factor for PFS in HGSC patients (HR = 2.83, 95% CI = 1.03-9.16, P = .007). ER expressions were not associated with prognosis in CCC patients. GPER-1 knockdown by siRNA reduced the cells number to 60% of siRNA-control-treated cells (P < .05), and GPER-1 antagonist, G-15 inhibited two HGSC cell lines proliferation (KF and UWB1.289) in a dose-dependent manner. Phosphoprotein array revealed that GPER-1 silencing decreased relative phosphorylation of glycogen synthase kinase-3. CONCLUSIONS: High GPER-1 expression is an independent prognostic factor for PFS in HGSC patients, and GPER-1 may play a role in HGSC cell proliferation.

Deep vein thrombosis and serum D-dimer after pelvic lymphadenectomy in gynecological cancer.

INTRODUCTION: Venous thromboembolism prevention during the perioperative period requires comprehensive risk-level assessment. The aim of this study was to evaluate the incidence of deep vein thrombosis and to assess the cut-off levels of serum D-dimer as a screening strategy for deep vein thrombosis during the perioperative period. METHODS: A total of 205 patients (ovarian cancer: 68, endometrial cancer: 76, cervical cancer: 61) who underwent gynecological surgery, including retroperitoneal lymph node dissection, were enrolled. We retrospectively analyzed the data on the cut-off value of D-dimer assessed using area under the receiver operating characteristic curve preoperatively, and 2 or 3 months, postoperatively. All patients underwent leg vein ultrasonography regardless of the serum D-dimer level. Furthermore, CT scans were performed to evaluate both disease status and venous thromboembolism, including pulmonary thromboembolism. Statistical analyzes were performed using the Mann-Whitney U-test (D-dimer values of each cancer), Chi-square test, Fisher's exact test (incidence of deep vein thrombosis), and one-way analysis of variance (patient characteristics). RESULTS: A total of 205 patients (ovarian cancer: 68, endometrial cancer: 76, cervical cancer: 61) who underwent gynecological surgery, including retroperitoneal lymph node dissection, were included in the analysis. Deep vein thrombosis rates were significantly higher in patients with ovarian cancer (P<0.001). The postoperative D-dimer value was significantly higher than the preoperative value. Postoperative D-dimer values were also significantly higher in patients who received adjuvant chemotherapy (P=0.001). The cut-off value of D-dimer was 1.55 µg/mL preoperatively (sensitivity, 48.0%; specificity, 94.1%), and this value was higher postoperatively, at 1.95 µg/mL (sensitivity, 37.0%; specificity, 90.9%). CONCLUSION: Postoperative D-dimer values are higher not only after surgery but also in patients who received adjuvant chemotherapy. The cut-off value of D-dimer at 2 or 3 months postoperatively was higher than preoperative value.

A National Survey of Umbilical Endometriosis in Japan.

STUDY OBJECTIVE: To identify the clinical presentation, diagnostic evaluation, operative or medical management, and postoperative recurrence of umbilical endometriosis. DESIGN: A retrospective national survey. SETTING: Obstetrics and Gynecology and Plastic Surgery Departments at a teaching hospital in Japan. PATIENTS: Patients with umbilical endometriosis or malignant transformation. INTERVENTIONS: A national survey was conducted to identify and evaluate cases of umbilical endometriosis or malignant transformation documented between 2006 and 2016. MEASUREMENTS AND MAIN RESULTS: The following were evaluated for each patient: age at diagnosis, body mass index, medical history, presence of extragenital endometriosis, surgical history, symptoms, imaging modalities, surgical therapy, hormonal therapy, follow-up period, postoperative recurrence, and time to recurrence. Ninety-six patients were identified with pathologically diagnosed benign umbilical endometriosis. The patients frequently had swelling (86.5%), pain (81.3%), or bleeding (44.8%) in the umbilicus. Sensitivity was 87.1% for physical examination, 76.5% for transabdominal ultrasonography, 75.6% for computed tomography, and 81.8% for magnetic resonance imaging. The cumulative recurrence rate was 1.34% at 6 months, 6.35% at 12 months, and 6.35% at 60 months after surgery. Importantly, there was no recurrence after wide resection including of the peritoneum (0 of 37 cases). The efficacy of dienogest (an oral progestin), gonadotropin-releasing hormone agonists, and oral contraceptives was 91.7%, 81.8%, and 57.1%, respectively. Finally, 2 cases of malignant transformation were identified. CONCLUSION: There was a low recurrence rate following surgery, and hormonal treatment is an option, although the current findings suggest surgical therapy as the first choice of treatment for umbilical endometriosis.

Long-term evaluation of renal function and neurogenic bladder following radical hysterectomy in patients with uterine cervical cancer.

OBJECTIVE: This study aimed to determine whether radical hysterectomy (RH) affects renal function. METHODS: Renal function was followed up in 83 patients with stage IB1-IIB cervical cancer who underwent RH during 2006-2015. Serum creatinine (sCre) levels were measured preoperatively and every year postoperatively. Estimated glomerular filtration rate (eGFR) was calculated using sCre levels. Patients who were unable to urinate by themselves or whose residual urine was ≥100 mL were referred to a urologist with the diagnosis of neurogenic bladder (NB). The relationship between NB occurrence and changes in sCre level or eGFR was evaluated respectively. RESULTS: Urological intervention was required in 45 patients (54.2%), and self-urethral catheterization was performed in 41 (49.3%) patients. The NB and clean intermittent catheterization (CIC) groups exhibited significant increases in sCre levels, which were not observed in the non-NB or non-CIC groups. In the non-NB group, eGFR did not change following surgery. However, in the NB group, significant decreases in eGFRs were observed at postoperative 2 and 3 years and at final follow-up. There was no difference in the incidence of cardiovascular events between patients with and without NB. CONCLUSION: In patients with NB following RH, a significant decrease in renal function was observed after postoperative 2 years.

Efficacy of Tokishakuyakusan add-on therapy with low-dose oral contraceptive pills on endometriosis patients with dysmenorrhea.

AIM: Tokishakuyakusan (TSS) is representative of popular Kampo medicines for Japanese women to treat dysmenorrhea, irregular menstruation and menopause. Current hormonal treatments and low-dose oral contraceptives (OCs) used as a first-choice drug for primary symptoms, however, have a high incidence of adverse events without improving patients' satisfaction. We evaluated the efficacy of TSS as additional treatment on the quality of life (QOL) of patients taking OCs with reduced therapeutic satisfaction. METHODS: Twelve patients treated with OCs for endometriosis were enrolled. TSS (7.5 g/day) in combination with OCs were given for three menstrual cycles. The main outcome was the degree of QOL assessed using the Endometriosis Health Profile-30 (EHP-30). Secondary outcomes were the Menstrual Distress Questionnaire (MDQ), patient's satisfaction using a Likert scale and cold feeling-visual analogue scale (VAS). RESULTS: In EHP-30, significant changes by TSS with OCs in each menstrual cycle were not found, although the scores for pain and emotional well-being tended to decrease. In MDQ, water retention in the premenstrual phase was improved. With regard to cold feeling-VAS, 61.6 mm at pretreatment decreased to 31.3 mm at the endpoint. Average Likert scale values after TSS treatment declined from 4.3 to 2.6. Cold feeling and patient's satisfaction have improved. CONCLUSION: Although the influence of TSS add-on therapy on QOL was moderate, possible improvement of cold feeling and menstruation-related symptoms was suggested.