A case of a blind-ending right ureter first identified intraoperatively during total laparoscopic hysterectomy for uterine adenomyosis and fibroids in a woman with severe ipsilateral kidney hypoplasia.

Detecting ureteral injury-a serious intraoperative and postoperative complication of hysterectomy-is a high level of difficulty if ureteral malformations are not identified preoperatively. A 39-year-old Japanese woman underwent total laparoscopic hysterectomy for uterine adenomyosis. During surgery, ureteral peristalsis was absent on the right side, whereas the left ureter was visible under the peritoneum. Transabdominal ultrasonography failed to locate the right kidney, with cystoscopy showing no flow from the right ureteral orifice. The ureteral tunnel was identified by tracing the vascular path of the internal iliac and uterine arteries, confirming that the corded tissue was the right ureter. Postoperative contrast-enhanced CT revealed severe right kidney atrophy with no contrast effect or connected ureter. Based on intraoperative laparoscopy and postoperative examination, a diagnosis of a unilateral ureteral scar with a proximal blind end and ipsilateral renal dysgenesis was established, marking the first reported instance of endoscopic visualization of this anomaly. In addition to normal pelvic anatomy, surgeons must consider embryological abnormalities to prevent intraoperative complications.

Even though active recommendation for HPV vaccination has restarted, Japan's rates have not recovered.

Japan has a particularly critical situation surrounding its collapsed HPV vaccination program for preventing HPV-caused cervical cancers, a problem exacerbated by the lack of a national immunization database. We have determined the year-to-year HPV vaccination uptake by Japanese females and analyzed by birth fiscal year (FY) the monthly number of people receiving initial HPV vaccination. Our analysis covers the period from the start of public subsidies in 2010 to September 2023, using data provided by local governments. We calculated the cumulative number of monthly immunizations for those unimmunized as of April (the beginning of each vaccination year). The monthly number of initial HPV vaccinations was highest in August for every FY from FY 2010 to FY 2023; a second vaccination peak tended to occur in March when the vaccination year ended. The highest number of August vaccinations occurred in FY 2011, followed (in order) by 2012, 2021, 2022, 2023, and 2013. In Japan's ongoing catch-up vaccination program for young women, the monthly number of vaccinations increased in August 2022 but then slowed the following year. After FY 2021, the cumulative vaccination coverage of subjects unvaccinated at the beginning of the vaccination year but subsequently covered by routine immunizations was slightly improved. FY 2021 was when the governmental recommendations for HPV vaccination were resumed. More recent vaccination rates are considerably lower than those in FY 2011-2012 when vaccinations were first fully endorsed. Paralyzing HPV vaccination hesitancy, which began in FY 2013, will linger in Japan in FY 2024.

Protease-Activated Receptor 1 (PAR1) Expression Contributes to HPV-Associated Oropharyngeal Cancer Prognosis.

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer occasionally has a poor prognosis, making prognostic risk stratification crucial. Protease-activated receptor-1 (PAR1) is involved in carcinogenesis, and its expression is regulated by alpha-arrestin domain-containing protein 3 (ARRDC3). It is also involved in the tumor microenvironment. We sought to evaluate the predictive ability of PAR1, ARRDC3, and tumor-infiltrating lymphocyte (TIL) scores in patients with oropharyngeal, hypopharyngeal, and uterine cervical cancers, serving as comparators for HPV-associated oropharyngeal cancer. METHODS: Immunohistochemical analysis of p16, ARRDC3, and PAR1 expression was performed on 79 oropharyngeal, 44 hypopharyngeal, and 42 uterine cervical cancer samples. The TIL scores were assessed and classified into the following groups based on invasion: low: 0-10%, medium: 20-40%, and high: > 50%. For prognostic analysis, the three groups were evaluated by dividing them into low, medium, and high categories, or alternatively into two groups using the median value as the cutoff. RESULTS: p16 was expressed in 44 (56%) oropharyngeal, 8 (18%) hypopharyngeal, and all uterine cervical cancer samples. ARRDC3 was detected in 39 (49%) oropharyngeal, 25 (57%) hypopharyngeal, and 23 (55%) uterine cervical cancer samples. PAR1 was expressed in 45 (57%) oropharyngeal, 22 (50%) hypopharyngeal, and 22 (50%) uterine cervical cancer samples. Patients diagnosed with p16-positive oropharyngeal cancer had a substantially improved prognosis compared to those diagnosed with p16-negative cancer. The PAR1-negative cases had a considerably improved prognosis compared to the positive cases (disease-specific survival [DSS] and -negative cases (disease-free survival [DFS]). Multivariate analysis revealed that ARRDC3-positive cases had an appreciably better DSS prognosis than patients with p16-negative oropharyngeal cancers. PAR1-positive patients among patients with p16-positive oropharyngeal cancer had a poor prognosis. With respect to DFS, patients with PAR1-positive and p16-negative oropharyngeal cancer had a 35-fold higher recurrence rate than those with PAR1-negative and p16-negative oropharyngeal cancer. CONCLUSION: Our results suggest that PAR1 expression affects the prognosis and recurrence rate of HPV-associated oropharyngeal cancer.

A nationwide study of obstetric management and outcomes in premature rupture of membrane at term: Report from the Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2017-2018.

AIM: This nationwide study aimed to investigate the practical management of term premature rupture of membrane (PROM) and its relationship with maternal and neonatal outcomes. METHODS: We conducted a questionnaire survey of 415 facilities participating in the Japan Perinatal Registry Network of the Japan Society of Obstetrics and Gynecology in 2016. The patients were women expecting vaginal birth after PROM at term without clinical chorioamnionitis. We classified the facilities into three groups based on duration of the expectant management after PROM (within 24, 24, and 48 h). Furthermore, we analyzed the association between perinatal outcomes and management protocol using the Japan Perinatal Registry Network Database 2016. RESULTS: Of 415 facilities, 346 (83.4%) completed and returned the survey. Among 231 facilities with management protocols, an interval of 3 days from PROM to delivery was acceptable in 167 facilities (72.3%). One hundred forty-nine facilities (64.5%) responded that they did not perform mechanical cervical dilation, and 90 (39.0%) used oxytocin as a uterotonic irrespective of cervical maturation. The number of hospitals that had a policy to administer antibiotics to Group B streptococcus-positive patients was 211 (91.3%). Neonatal outcomes at birth and the frequency of cesarean section and postpartum fever did not differ among the three groups. CONCLUSIONS: Most facilities in the Japan Perinatal Registry Network managed women at term to delivery within 3 days after PROM with attention to bacterial infection. Expectant management up to 48 h after PROM did not increase the risk of postpartum fever, compared to labor induction immediately after PROM.

Histone deacetylase inhibitor, panobinostat, exerts anti-proliferative effect with partial normalization from aberrant epigenetic states on granulosa cell tumor cell lines.

The prognosis of the patients with inoperable or advanced granulosa cell tumors (GCTs) is still poor, and therefore it is important to establish a novel treatment strategy. Here we investigated the in vitro effects of a histone deacetylase inhibitor, panobinostat (PS) on two GCT cell lines (KGN and COV434). GCT cell lines were found to be susceptible to PS treatment and it inhibited cell growth mainly by apoptosis. In cell cycle analysis, PS reduced only the ratio of S phase in GCT cell lines. Combined treatment of PS with a deubiquitinase inhibitor, VLX1570 enhanced the expression of p21, cleaved PARP, cleaved caspase-9, heme oxygenase-1, and the acetylation of histone H4 and α-tubulin, leading to an additive anti-proliferative effect on KGN and COV434. The gene set enrichment analysis revealed that PS treatment suppressed DNA replication- or cell cycle-related gene expression which led to chemotherapeutic cell death and in addition, this treatment induced activation of the gene set of adherens junction towards a normalized direction as well as activation of neuron-related gene sets that might imply unexpected differentiation potential due to epigenetic modification by a HDAC inhibitor in KGN cells. Exposure of KGN and COV434 cells to PS increased the expression of E-cadherin, one of the principal regulators associated with adherens junction in quantitative RT-PCR and immunoblotting analysis. In the present study, we indicate a basis of a novel therapeutic availability of a HDAC inhibitor for the treatment of GCTs and further investigations will be warranted.

Diagnostic Laparoscopy for Ovarian Tumor Due to Salmonella Infection.

Ovarian abscess is thought to be caused by ascending infection. We experienced a case with ovarian abscess caused by Salmonella. The patient had been monitored for endometrial cysts at an outpatient clinic. She visited our hospital emergently with chief complaints of persistent fever and diarrhea. Although sexually transmitted disease was not suspected, she was diagnosed with pelvic inflammatory disease due to her high C-reactive protein (CRP) level and started antibacterial treatment. Two days later, diagnostic laparoscopy was performed for persisting CRP elevation, and she was diagnosed with ovarian abscesses due to Salmonella infection. As the patient had regularly eaten soft-boiled eggs and chicken, an association with her eating habits was strongly suspected as a cause. When a patient has symptoms of enteritis, preceding tubo-ovarian abscess should be considered the possibility of Salmonella infection. Early diagnosis and treatment are necessary for fertility preservation, and minimally invasive diagnostic laparoscopy is useful.

Examination of fetal well-being evaluation metrics for fetal growth restriction as seen from Japan Obstetric Compensation Cause Analysis Report data.

Advances in perinatal care have improved the prognoses of both mothers and neonates; however, cerebral palsy continues to occur. In this study, we examined methods for the intragestational evaluation of the health of infants who later developed cerebral palsy. A retrospective review was conducted on light-for-dates cases among the 2113 cause analysis reports issued by the Japan Obstetric Compensation System between January 2009 and September 2018. In our examination, we determined that non-stress tests and ultrasonic Doppler tests were used to evaluate fetal well-being. Moreover, we observed cases in which additional testing was not performed even when fetal growth restriction (FGR) was identified. Appropriate management of FGR may help reduce the incidence of cerebral palsy.

Clinical guide for women with mental health problems during the perinatal period.

Pregnancy and childbirth have various effects on the physical as well as mental aspects of women. Therefore, appropriate considerations must be given to the mental health of pregnant women. The Guideline Review Committee of the Japanese Society of Psychiatry and Neurology launched a liaison meeting for the Japanese Society of Psychiatry and Neurology and the Japan Society of Obstetrics and Gynecology, with a view to creating a "Clinical guide for women with mental health problems during the perinatal period" by cooperation of these two fields. After repeated discussions with input from both academic societies, they jointly formulated the "Clinical guide for women with mental health problems during the perinatal period: Overview" in May 2020, and reported its "Detailed Contents" in April 2021. We hope that this guide, which is the English overview of the detailed guide, will contribute to the mental health of pregnant women, facilitating healthy pregnancies and childbirth.

A New Technique for Seprafilm® That Can Be Practiced with a 5-mm Trocar.

Seprafilm® is an adhesion barrier sheet. However, it is difficult to handle it through a 5-mm trocar. We have devised a method of applying Seprafilm® safely and reliably through a 5-mm trocar by using a holder that comes with the film. We practiced this method in three cases of total laparoscopic hysterectomy for uterine leiomyoma. The quarter-pack is cut into three pieces. The film placed on the holder sheet was rolled up with forceps (or wrapped around forceps) and inserted into a 5 mm trocar. After application, the center of the short axis of the holder was pinched with a grasping forceps, and the holder was drawn out of the body through the trocar. Of the 36 pieces placed, Seprafilm® broke only in once. Insertion was successful in 100%, and the holder was successfully retrieved through the trocar in 92% (33/36) of the cases. The holder may be easily retrieved after application. This technique represents an extremely simple versatile application method in operations in which only 5-mm trocars can be used.

A case of total hysterectomy due to massive maternal bleeding immediately after fetoscopic laser surgery for twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) complicates approximately 10% of monochorionic twin pregnancies and is associated with almost 90% mortality if left untreated. Fetoscopic laser photocoagulation (FLP) is the first-line therapy for TTTS, and an overall twin survival rate of 75% and at least one survival rate of 90% have been established. We report a case of TTTS complicated with bleeding from the uterine wall by inserting the procedure after FLP. The patient consequently underwent emergency caesarean section. The bleeding was uncontrollable due to atonic bleeding and emergency hysterectomy was performed. To detect the possibility of amniotic fluid embolism (AFE), biochemical blood samples demonstrated that there was no inflow of fetal ingredients in blood vessels of uterine tissue. There was no evidence of damage to any specific vessels by histopathological staining. These findings indicated that the cause of massive bleeding was unlikely to have been AFE. It was concluded that atonic bleeding was likely caused by uncontrollable hemorrhage from an injury lesion where an endoscope had been inserted.

Co-implantation of Tumor and Extensive Surrounding Tissue Improved the Establishment Rate of Surgical Specimens of Human-Patient Cancer in Nude Mice: Toward the Goal of Universal Individualized Cancer Therapy.

BACKGROUND/AIM: The discovery of the nude mouse model enabled the experimental growth of human-patient tumors. However, the low establishment rate of tumors in nude and other immunodeficient strains of mice has limited wide-spread clinical use. MATERIALS AND METHODS: In order to increase the establishment rate of surgical specimens of patient tumors, we transplanted tumors to nude mice subcutaneously along with large amounts of surrounding tissue of the tumor. RESULTS: The new transplantation method increased the establishment rate in nude mice to 66% compared to the old method of implanting the surgical tumor specimen with surrounding tissue removed (14%). High stage and presence of metastasis in the patient donor are positively correlated to tumor engraftment in nude mice. CONCLUSION: The new method can potentially allow most cancer patients who undergo surgery or biopsy to have their own mouse model for drug-sensitivity testing.

Eribulin Regresses a Cisplatinum-resistant Rare-type Triple-negative Matrix-producing Breast Carcinoma Patient-derived Orthotopic Xenograft Mouse Model.

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. RESULTS: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). CONCLUSION: Eribulin has clinical potential for triple-negative MPBC patients.

Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model.

PURPOSE: Cervical cancer is a recalcitrant disease. To help overcome this problem, we previously established a patient-derived orthotopic xenograft (PDOX) model of cervical cancer. In the previous study, we found the tumor to be resistant to nab-paclitaxal (nab-PTX). We also previously developed the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R). The aim of the present study was to investigate the efficacy of S. typhimurium A1-R to overcome nab-PTX resistance in the cervical cancer PDOX model. METHODS: Cervical-cancer tumor fragments were implanted orthotopically into the neck of the uterus of nude mice. The cervical-cancer PDOX models were randomized into the following four groups after the tumor volume reached 60 mm3: G1: untreated group; G2: nab-PTX (i.v., 10 mg/kg, biweekly, 3 weeks); G3: Salmonella typhimurium A1-R (i.v., 5 × 107 CFU/body, weekly, 3 weeks); G4: nab-PTX combined with Salmonella typhimurium A1-R (nab-PTX, 10 mg/kg, i.v., biweekly, 3 weeks; S. typhimurium A1-R, 5 × 107 CFU/body, i.v., weekly, 3 weeks). Each group comprised eight mice. All mice were sacrificed on day 22. Tumor volume was measured on day 0 and day 22. Body weight was measured twice a week. RESULTS: Nab-PTX and Salmonella typhimurium A1-R did not show significant efficacy as monotherapy compared to the control group (P = 0.564 and P = 0.120, respectively). In contrast, nab-PTX combined with Salmonella typhimurium A1-R significantly suppressed tumor growth compared to the untreated control group and nab-PTX group (P < 0.001 and P = 0.026, respectively). CONCLUSIONS: Salmonella typhimurium A1-R has potential future clinical application to overcome drug resistance in cervical cancer.

Primary non-gestational uterine choriocarcinoma mimicking leiomyoma.

Uterine choriocarcinoma is a trophoblastic neoplasm that is most commonly gestational but can also be non-gestational in origin. However, primary non-gestational uterine choriocarcinoma is very rare, with only few cases having been reported. We report a case of a premenopausal woman who had initially been diagnosed with myoma delivery but who was discovered to have primary non-gestational uterine choriocarcinoma. This 46-year-old woman had no history of pregnancy. She was referred to our hospital for treatment of the myoma delivery. After tumor removal, histological examination led to the diagnosis of choriocarcinoma. The serum human chorionic gonadotropin level (207,300 mIU/mL) prior to surgery was abnormally high, and because the computed tomography scans additionally revealed lung metastasis, the patient was diagnosed with FIGO stage III choriocarcinoma. Due to the lack of pregnancy history and abstinence from sexual intercourse for >1 year, we performed short tandem repeat analysis, and diagnosed the patient with non-gestational choriocarcinoma. Despite treatments using multiple anticancer agents after the surgery, the patient died 1 year after starting the treatments. On this occasion, we report a very rare case of a premenopausal woman who was diagnosed with primary non-gestational uterine choriocarcinoma mimicking leiomayoma.

Does local infiltration anesthesia on laparoscopic surgical wounds reduce postoperative pain? Randomized control study.

PURPOSE: Recently, endoscopic surgeries are widely performed in the gynecological field. Several studies on the use of local anesthesia for pain control after laparoscopic surgery have been conducted; however, its effects remain controversial. Herein, a randomized control study on gynecological laparoscopic surgeries was conducted to analyze the effectiveness of local anesthesia on postoperative pain. METHODS: Patients who underwent laparoscopic surgeries due to gynecologic benign diseases or endometrial cancer in the early stage were enrolled, and randomly divided into intervention (injected with levobupivacaine), and control (injected with saline) groups. The primary outcome was the dosage of analgesic consumption within 12 hours postoperatively. RESULTS: A total of 147 patients were enrolled in the intervention group and 147 in the control group. The outcome of local anesthesia was not significantly different between the two groups during the whole analysis. We analyzed the effects of local anesthesia in the laparoscopic surgery subgroup. The dosage of analgesic consumption within 12 h after a laparoscopic hysterectomy (TLH) or TLH with pelvic lymph node dissection (TLH+PLD) in the intervention group was significantly smaller than that in the control group. CONCLUSION: Local infiltration anesthesia can effectively reduce postoperative pain in patients who underwent TLH or TLH +PLD.

[A Case Report of Surgery and Chemotherapy for a Patient with Rapidly Progressing Breast Cancer during Pregnancy].

A 33-year-old woman became aware of a right breast mass at her 28th week of pregnancy. From the biopsy results, we diagnosed her with right breast cancer. At her 33rd week of pregnancy, she underwent modified radical mastectomy (pT2N3aM0, Stage III C, ER-negative, PR-negative, HER2-positive), and she elected to receive adjuvant therapy after the surgery during her pregnancy. She received the first course of EC (epirubicin plus cyclophosphamide) therapy on the 13th postoperative day (35 weeks of gestation) and gave a natural, vaginal delivery at 36 weeks and 5 days of gestation. On the 4th day after birth, the patient noticed a contralateral left breast mass and was diagnosed with left breast cancer, after core needle biopsy. She received 4 courses of EC therapy and is currently undergoing PTX plus HER (paclitaxel plus trastuzumab) therapy. Regarding chemotherapy during pregnancy, we recommend that there is no need to perform artificial preterm birth, because chemotherapy has little influence on children after their second-trimester. After the second-trimester, chemotherapy can be safely performed.

The Analysis of Cell Cycle-related Proteins in Ovarian Clear Cell Carcinoma Versus High-grade Serous Carcinoma.

In Japan, the frequency of ovarian clear cell carcinoma (CCC) is twice as high as that in the United States and Europe. Often, patient prognosis with CCC is poor because of chemoresistance. Here, we focus on the cell cycle, which is one of the mechanisms of chemoresistance. To detect the informative markers and improve the strategy of chemotherapy for CCC, we performed immunohistochemical staining of cell cycle-related proteins in ovarian malignant tumors. We detected that each of the 29 samples of CCC and high-grade serous carcinoma (HGSC) were necessary to reveal the significant differences in immunostaining and prognosis. We performed the immunostaining analysis using the antibodies of cell cycle-related proteins such as Ki-67, Cdt1, MCM7, and geminin. The positive rate of Cdt1 in the CCC group was significantly higher than that in the HGSC group (P<0.0001). However, the positive rate of geminin in the HGSC group was significantly higher than that in the CCC group (P<0.0001). The overall survival of CCC patients with high labeling index of Cdt1 was significantly worse than that of CCC patients with low labeling index of Cdt1 (P=0.004). The study results suggested that the cancer cells of CCC and HGSC exist in the G1 phase and S, G2, and M phases, respectively. The differences in cell cycle of CCC might be one of the reasons for chemotherapy resistance. Further investigations are necessary to reveal the usefulness of Cdt1 as a biomarker in CCC.

Vasohibin-1 Is a Poor Prognostic Factor of Ovarian Carcinoma.

Vasohibin-1 (VASH1) is an identified negative feedback inhibitor of angiogenesis induced by vascular endothelial growth factor (VEGF) in vascular endothelial cells (ECs). Expression of VASH1 has been reported not only in ECs of normal tissue, but also in ECs surrounding malignant tumors. In malignant tumors, VASH1 is also gaining attention as a prognosis prediction marker. The aim of this study is to investigate the correlation between VASH1 expression and vascular-related factors and various clinicopathological outcomes in clinical cases of ovarian carcinoma. We retrospectively analyzed clinical records of 58 patients with ovarian carcinoma. The expression patterns of VASH1 and other vascular-related factors (CD31 as markers of microvessel density (MVD), VEGF receptor type 2 (VEGFR2), D2-40 as markers of lymphovessel density), and Ki67 (as proliferation markers of cancer cells) were examined immunohistochemically. We studied the correlation between immunohistochemical expression and overall survival. VASH1 expression pattern significantly differed between Federation of Obstetrics and Gynecology (FIGO) Stages. Numbers of VASH1-positive vessels had a significant positive correlation with MVD (Speaman's correlation coefficient (ρ) was 0.51, p < 0.001), VEGFR2-positive vessels (ρ = 0.61, p < 0.001), and percentage of Ki67 (ρ = 0.28, p = 0.034). The Cox univariable analyses revealed that the group of high VASH1 expression (> 14.6 vessels per mm2) at Stages I-III is a prognostic factor (HR = 3.3, 95%CI = 0.4-8.4; p = 0.013). Our results indicate that VASH1 expression in ovarian carcinoma is significantly associated with vascular-related factors and Ki67 expression. We propose that VASH1 is a prognostic marker in ovarian carcinoma.