Proposal for individual treatment by tubal occlusion factor based on the results of salpingoscopic salpingoplasty.

AIM: As a treatment for tubal infertility, falloposcopic tuboplasty (FT) is one of the options for patients who wish to conceive naturally. Based on the results of FT, we propose an appropriate time of transitioning to assisted reproductive technology (ART) for tubal infertility. OBJECTS AND METHODS: We examined the outcomes of cases of tubal infertility during the period from June 1999 through March 2021 who were performed tuboplasty at our hospital using the FT catheter system under laparoscopy. RESULTS: The number of treated cases was 828. There were 243 cases of endometriosis and 119 cases of genital chlamydial infection. By FT, 712 cases (86.0%) were successfully recanalized. Of the 712 cases, 189 conceived naturally (26.5%) and miscarriages were 23 cases (12.2%), ectopic pregnancies were 8 cases (4.2%). The mean duration from FT to pregnancy was 6.5 months in natural pregnancy group, 90% of them were pregnant within 14 months. In endometriosis cases, the pregnancy rate after FT did not change significantly among clinical stage. CONCLUSIONS: Even when the fallopian tube was recanalized by FT, if the couple is unable to conceive naturally, they had better to consider switching to ART at about 14 months. When the couples with endometriosis consider switching to ART, we suggest deciding without considering the rASRM stage.

Tubo-ovarian abscess caused by Clostridioides difficile after eight months of surgery: Case report and review of extraintestinal abdominal abscess cases.

We present a case of tubo-ovarian abscess (TOA) caused by Clostridioides difficile (CD) in a 43-year-old female. Despite lacking a history of sexually transmitted diseases, the patient had undergone paraovarian cystectomy nine months before admission. Transvaginal ultrasonography performed eight months post-surgery revealed left ovarian enlargement, accompanied by subsequent lower abdominal pain and fever exceeding 38 °C. As oral antibiotic treatment was ineffective, the patient was admitted to our hospital. Computed tomography upon admission revealed a massive TOA. Surgical drainage of the abscess was performed, and CD was identified in the culture from the pus. The TOA was treated with a three-month course of metronidazole and oral amoxicillin/clavulanic acid. While CD is commonly associated with colitis, extraintestinal manifestations are exceptionally rare. This case represents the inaugural report of TOA resulting from CD. A literature review on abdominal and pelvic CD abscesses found that patients undergoing surgical drainage had a favorable prognosis. Therefore, surgical intervention plays an important role in the management of CD abscesses.

Validation of an on-chip p16ink4a/Ki-67 dual immunostaining cervical cytology system using microfluidic device technology.

More specific screening systems for cervical cancer may become necessary as the human papillomavirus (HPV) vaccine becomes more widespread. Although p16/Ki-67 dual-staining cytology has several advantages, it requires advanced diagnostic skills. Here, we developed an automated on-chip immunostaining method using a microfluidic device. An electroactive microwell array (EMA) microfluidic device with patterned thin-film electrodes at the bottom of each microwell was used for single-cell capture by dielectrophoresis. Immunostaining and dual staining for p16/Ki-67 were performed on diagnosed liquid cytology samples using the EMA device. The numbers of p16/Ki-67 dual-stained cells captured by the EMA device were determined and compared among the cervical intraepithelial neoplasia (CIN) lesion samples. Seven normal, fifteen CIN grade 3, and seven CIN grade 2 samples were examined. The percentage of dual-positive cells was 18.6% in the CIN grade 2 samples and 23.6% in the CIN grade 3 samples. The percentages of dual-positive staining increased significantly as the severity of the cervical lesions increased. p16/Ki67 dual immunostaining using the EMA device is as sensitive as the conventional method of confirming the histopathological diagnosis of cervical samples. This system enables a quantified parallel analysis at the individual cell level.

The TGF-ß/UCHL5/Smad2 Axis Contributes to the Pathogenesis of Placenta Accreta.

Placenta accreta is a high-risk condition causing obstetric crisis and hemorrhage; however, its pathogenesis remains unknown. We aimed to identify the factors contributing to trophoblast invasiveness and angiogenic potential, which in turn drive the pathogenesis of placenta accreta. We focused on the transforming growth factor (TGF)-ß1-Smad pathway and investigated the intrinsic relationship between the time- and dose-dependent inhibition of the ubiquitinating enzyme UCHL5 using bAP15, a deubiquitinase inhibitor, after TGF-ß1 stimulation and the invasive and angiogenic potential of two cell lines, gestational choriocarcinoma cell line JEG-3 and trophoblast cell line HTR-8/SVneo. UCHL5 inhibition negatively regulated TGF-ß1-induced Smad2 activation, decreasing extravillous trophoblast invasiveness. Smad1/5/9 and extracellular signal-regulated kinase (ERK) were simultaneously activated, and vascular endothelial growth factor was secreted into the trophoblast medium. However, extravillous trophoblast culture supernatant severely impaired the vasculogenic potential of human umbilical vein endothelial cells. These results suggest that the downstream ERK pathway and Smad1/5/9 potentially regulate the TGF-ß1-Smad pathway in extravillous trophoblasts, whereas Smad2 contributes to their invasiveness. The abnormal invasive and angiogenic capacities of extravillous cells, likely driven by the interaction between TGF-ß1-Smad and ERK pathways, underlie the pathogenesis of placenta accreta.

High-grade endometrial stromal sarcoma with YWHAE-NUTM2B fusion gene abnormality identified after 10 years of recurrent pulmonary metastases: A case report.

•Endometrial stromal sarcoma is the second most common type of uterine sarcoma.•Endometrial stromal sarcoma has undergone modifications since its proposal.•This case highlights the importance of accurately diagnosing endometrial stromal sarcoma.•Asymptomatic uterine fibroids may not be treated with therapeutic intervention or prompt regular check-ups.

Serum vascular endothelial growth factor associated with the progression of granulosa cell tumor: a report of two cases.

BACKGROUND: Granulosa cell tumors (GCTs) account for approximately 2% of ovarian malignancies and are considered a rare type of ovarian cancer. GCTs are characterized by irregular genital bleeding after menopause due to female hormone production as well as late recurrence around 5-10 years after initial treatment. In this study, we investigated two cases of GCTs to find a biomarker that can be used to evaluate the treatment and predict recurrence. CASE PRESENTATION: Case 1 was a 56-year-old woman who presented to our hospital with abdominal pain and distention. An abdominal tumor was found, and GCTs were diagnosed. Serum vascular endothelial growth factor (VEGF) levels decreased after surgery. Case 2 involved a 51-year-old woman with refractory GCTs. Carboplatin-paclitaxel combination therapy and bevacizumab were administered after the tumor resection. After chemotherapy, a decline in VEGF levels was observed, but serum VEGF levels increased again with disease progression. CONCLUSIONS: VEGF expression may be of clinical importance in GCTs as a clinical biomarker for disease progression, which may be used to determine the efficacy of bevacizumab against GCTs.

The role of transperineal ultrasonography for perinatal management: A review.

BACKGROUND: Transperineal ultrasound (TPUS) has become an increasingly popular tool in obstetrics due to its objective, non-invasive, and real-time imaging capabilities. AIM: This review aims to describe the basic approaches, current utilization, and potential future applications of TPUS. MATERIALS & METHOD: A comprehensive literature review on TPUS was conducted. In addition, discussions at academic meetings and congress focused on TPUS were also considered. RESULTS: TPUS was initially used in prostate biopsies and is currently applied to evaluating fetal head descent in labor, with the angle of progression being the most widely used parameter. It is more tolerated than conventional invasive or expensive methods, such as digital vaginal examinations or MRIs. Additionally, TPUS can assess the internal rotation of the fetal head in the birth canal. DISCUSSION: Compared to other imaging modalities like MRI and CT scans, TPUS is easier to perform and more cost-effective. It also provides real-time imaging, allowing for quick and accurate assessments. It also help clinicians make critical decisions regarding the mode of delivery and identify patients at high risk for fecal incontinence postpartum. With its many benefits, TPUS has the potential to become a standard tool in urogynecology and obstetrics. CONCLUSIONS: Transperineal ultrasound is a non-invasive imaging modality that is well-tolerated and easy to understand for patients and their family and help medical staff support the patients. Transperineal ultrasound can be applied in real-time monitoring of labor progress, helping predict the possibility of vaginal delivery during labor, and further research in this area is warranted.

Transcriptomic analysis of feeder-free culture system for maintaining naïve-state pluripotency in human pluripotent stem cells.

Background: Human pluripotent stem cells (hPSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (PSCs) have the capacity of self-renewal and multilineage differentiation in vitro. Conventional hPSCs, which are in a primed state, can produce various types of differentiated cells. However, the variability in their degree of pluripotency and differentiation propensities, which is influenced by the inductive methods and culture conditions, limit their availability. Therefore, PSCs in a naïve state are a promising source of PSCs. Methods: We recently developed a culture system for naïve hPSCs using an inhibitor of the NOTCH signaling pathway and a histone H3 methyltransferase disruptor. This culture system requires feeder cells for stably maintaining the naïve hPSCs. We aimed to develop a culture system for hPSCs that could maintain pluripotency under feeder-free conditions. Results: We used two inhibitors to develop an alternative feeder-free culture system to obtain naïve hPSCs. The naïve cells underwent stable cellular proliferation and were positive for naïve stem cell markers; in addition, they could differentiate into the three germ layers. These feeder-free dome-shaped induced pluripotent stem cells (FFDS-iPSCs) have characteristics similar to that of naïve-like PSCs. Conclusions: The naive hPSCs under feeder-free conditions could ensure supply of cells for various applications in regenerative medicine and disease modeling.

Chlamydia Peritonitis Mimicking Juvenile Carcinomatous Peritonitis Diagnosed by Exploratory Laparoscopy: A Case Report.

Chlamydia trachomatis infections may occur in multiple organs, including the lungs, lymph nodes, peritoneal cavity, and genitourinary systems. This disease results in significant ascites, the swelling of lymph nodes, and elevated tumor markers (CA125), sometimes mimicking an ovarian malignancy. At our hospital, we often perform examination laparoscopic surgery in cases of suspected gynecologic cancers before initial treatment. In this paper, we report the case of a 19-year-old woman who came to our hospital because of an ovarian tumor and ascites. There was no history of sexual intercourse (self-reported). We suspected ovarian cancer from image inspections, so we performed laparoscopic surgery for diagnosis. The final pathological diagnosis was acute-to-chronic inflammation of the bilateral fallopian tubes, and a cytologic examination of the ascites was negative for malignant cells. The C. trachomatis antigen was positive on vaginal examination after the operation. Based on this result, we diagnosed this patient with C. trachomatis infection. Chlamydia peritonitis should be a differential diagnosis for cancer peritonitis in juvenile patients with abnormal ascites. Exploratory laparoscopy should help confirm the pathological diagnosis.

Intrauterine adhesion after hysteroscopic myomectomy of submucous myomas.

PURPOSE: To evaluate the frequency of intrauterine adhesion (IUA) after hysteroscopic myomectomy, and to analyze the association of IUA and the location of submucous myomas and the use of postoperative barrier (POB). METHODS: Hysteroscopic myomectomy was performed in 217 patients with submucous myomas. The retrospective investigation was performed, and the cases were divided into three groups: cases with solitary submucous myoma (SSM; group 1), cases with apposing submucous myomas (ASMs; group 2) and cases with submucous myomas that were far from each other or not in apposition to one another (not apposing submucous myomas: NASMs; group 3). As POB, intrauterine device with oxidized regenerated cellulose and silicon sheet was inserted immediately after surgery. RESULTS: IUA formation after hysteroscopic myomectomy was more frequent in group 2 than groups 1 and 3 (p = 0.03 and 0.01, respectively), despite the higher rates of POB use (p = 0.02). There was no significant difference in IUA formation in cases with POB between each group (p = 0.06 and 0.21, respectively). But in cases without POB, group 2 showed higher rates of IUA formation than group 1 (p = 0.04) and group 3 (p = 0.03). Multivariable analysis for IUA formation demonstrated that ASMs were a risk factor of IUA (hazard ratio [HR] = 27.9, p < 0.01), and the use of POB was a prognostic factor for reduction of IUA formation (HR = 0.08, p < 0.01). CONCLUSION: ASMs appear to be a risk factor for IUA formation. The use of POB may be associated with preventing IUA formation after hysteroscopic myomectomy.

The Histone Methyltransferase SETD8 Regulates the Expression of Tumor Suppressor Genes via H4K20 Methylation and the p53 Signaling Pathway in Endometrial Cancer Cells.

The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.

Counting gross fetal movement using a fetal movement acceleration measurement recorder in two fetuses with gastroschisis.

We used the fetal movement acceleration measurement recorder to count gross fetal movement in two fetuses with gastroschisis. In conclusion, both fetuses moved as much as normal fetuses, which suggested that normal fetal movement could indicate reassuring status also in fetuses with malformation when they have normal neurological developments.

Effect of Different Educational Interventions on Knowledge of HPV Vaccination and Cervical Cancer among Young Women: A Preliminary Report.

The incidence and mortality rates of cervical cancer are rising among young women in Japan. In November 2021, the Japanese Ministry of Health, Labour, and Welfare reinstated the active recommendation for the human papillomavirus (HPV) vaccine, which was discontinued in June 2013 due to reports of adverse reactions, including chronic pain and motor dysfunction, following vaccination. However, vaccine hesitancy among the younger generation remains, and it is essential to identify the barriers in vaccination uptake. Therefore, we aimed to conduct a randomized study using different methods of providing educational contents to improve health literacy regarding cervical cancer and HPV vaccination among female students in Japan. Here, we present the results of our preliminary report and discuss current topics related to HPV vaccination in Japan. Data were collected from 27 female students-divided into three groups: no intervention, print-based intervention, and social networking service-based intervention-using the health literacy scale and communicative and critical health literacy scale. Our primary results indicate that participants' knowledge and health literacy improved post-intervention. Therefore, medical professionals must provide accurate scientific knowledge regarding routine HPV vaccination and the risk of cervical cancer to young women to improve their health literacy and subsequently increase the HPV vaccination rates.

Ulipristal acetate simultaneously provokes antiproliferative and proinflammatory responses in endometrial cancer cells.

Ulipristal acetate (UPA), a selective progesterone receptor modulator, is used for the treatment of uterine fibroids and selectively inhibits the proliferation and inflammation of leiomyoma cells. As few studies have focused on the molecular biological mechanism of UPA in Ishikawa endometrial cancer cells, we aimed to identify the effects of UPA on these cells. Ishikawa cells were treated with different concentrations of UPA. Cell viability and colony formation assays were performed to assess the growth of cancer cells, whereas invasion and migration assays were used to measure cell motility and invasiveness. Western blotting, caspase 3/7 assay, TUNEL assay, and flow cytometry were performed to analyze apoptosis. Moreover, expression levels of the proinflammatory cytokines oncostatin M, its receptor, interleukin 6, and interleukin 8 were examined using quantitative real-time PCR. UPA decreased cell viability and growth, thereby inhibiting cell migration and invasion via induction of apoptosis. Contrary to expectation, stand-alone application of UPA increased the expression of the proinflammatory cytokines but concomitant use of UPA and the estrogen receptor antagonist ICI 182,720 decreased it. These data revealed a novel dual role of UPA: It could attenuate cell growth via activation of apoptosis while simultaneously provoking the activation of proinflammatory cytokines in endometrial cancer cells. These indicate that the combination of UPA and an estrogen receptor antagonist may be useful in suppressing the secretion of proinflammatory cytokines by UPA alone.

Case report: Posterior reversible encephalopathy syndrome, an adverse effect of lenvatinib and pembrolizumab combination therapy, in a patient with advanced endometrial cancer.

Background: Lenvatinib-pembrolizumab combination (LEAP) is an approved therapy in Japan for advanced endometrial cancer, based on the data from the KEYNOTE-775 clinical trial. We report a case of posterior reversible encephalopathy syndrome (PRES) in a patient who received LEAP therapy for advanced endometrial cancer. Case presentation: A 53-year-old patient with stage IVB endometrial cancer having rectal metastases, after four cycles of paclitaxel-carboplatin therapy, was found to have increased rectal invasion, peritoneal dissemination, and multiple paraaortic lymph node metastases. She was treated with LEAP therapy and discharged on day 12 without adverse events, except for mild anemia on day 11 of treatment. She was carefully managed in the outpatient department, but on day 18, she was admitted to the emergency department with severely impaired consciousness and generalized seizures. Computed tomography of the head and lumbar tap showed no abnormal findings, and the seizures resolved with anticonvulsant medication alone. Based on a thorough physical examination and findings on magnetic resonance imaging (MRI), which showed high signal intensity in the left occipital lobe, encephalopathy, rather than encephalitis, was the likely diagnosis. Symptomatic improvement was observed, and pembrolizumab monotherapy was resumed. Conclusions: If consciousness is impaired during LEAP treatment, it is necessary to differentiate between immunogenic encephalitis caused by pembrolizumab or encephalopathy caused by lenvatinib. MRI and lumbar tap can help in distinguishing between the two and diagnosing the responsible drug.

A case of adenomyosis with leiomyoma that was effectively treated with relugolix and kamishoyosan add-on therapy.

BACKGROUND: Recently, relugolix, an oral gonadotropin-releasing hormone receptor antagonist, has been considered an effective therapy for leiomyoma based on a phase 3 study in Japanese women. Leiomyoma combined with severe adenomyosis occasionally occurs in perimenopausal women; however, little information on the effectiveness of relugolix against severe adenomyosis exists. CASE PRESENTATION: A 49-year-old woman was referred to our hospital with acute lower abdominal pain and abnormal uterine bleeding. Magnetic resonance imaging revealed multiple leiomyomas with diffuse adenomyosis. Left hydrosalpinx was also observed. The patient refused surgical treatment and preferred oral relugolix. Since she experienced a hot flush and headache induced by relugolix, a traditional Japanese Kampo, kamishoyosan, was added to improve the side effects of relugolix. The patient was asymptomatic at the time of this report and experienced a significant shrinkage in uterine volume. Ultimately, she avoided hysterectomy as desired. CONCLUSIONS: To our knowledge, this is the first report of co-occurring adenomyosis and leiomyoma, which was effectively treated with relugolix. Although the management of adverse side effects, including hot flush and headache by relugolix, has recently attracted attention and controversy, relugolix add-on therapy with kamishoyosan may help treat menopausal symptoms.

Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance.

Patient-derived cells and xenografts retain the biological characteristics of clinical cancers and are instrumental in gaining a better understanding of the chemoresistance of cancer cells. Here, we have established a panel of patient-derived spheroids from clinical materials of ovarian cancer. Systematic evaluation using therapeutic agents indicated that sensitivity to platinum-based compounds significantly varied among the spheroids. To understand the molecular basis of drug sensitivity, we performed integrative analyses combining chemoresistance data and gene expression profiling of the ovarian cancer patient-derived spheroids. Correlation analyses revealed that cisplatin resistance was significantly associated with elevated levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione-producing redox enzymes. Accordingly, cisplatin-resistant spheroids established in vitro showed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferation in vitro and largely eradicated peritoneal metastasis in mouse xenograft models. Furthermore, G6PD expression was elevated during carcinogenesis and associated with poor prognosis. Thus, the combination of gene expression data and chemosensitivity revealed the essential roles of G6PD-driven redox metabolism in cisplatin resistance, underscoring the significance of an integrative approach using patient-derived cells.

Automated system for diagnosing endometrial cancer by adopting deep-learning technology in hysteroscopy.

Endometrial cancer is a ubiquitous gynecological disease with increasing global incidence. Therefore, despite the lack of an established screening technique to date, early diagnosis of endometrial cancer assumes critical importance. This paper presents an artificial-intelligence-based system to detect the regions affected by endometrial cancer automatically from hysteroscopic images. In this study, 177 patients (60 with normal endometrium, 21 with uterine myoma, 60 with endometrial polyp, 15 with atypical endometrial hyperplasia, and 21 with endometrial cancer) with a history of hysteroscopy were recruited. Machine-learning techniques based on three popular deep neural network models were employed, and a continuity-analysis method was developed to enhance the accuracy of cancer diagnosis. Finally, we investigated if the accuracy could be improved by combining all the trained models. The results reveal that the diagnosis accuracy was approximately 80% (78.91-80.93%) when using the standard method, and it increased to 89% (83.94-89.13%) and exceeded 90% (i.e., 90.29%) when employing the proposed continuity analysis and combining the three neural networks, respectively. The corresponding sensitivity and specificity equaled 91.66% and 89.36%, respectively. These findings demonstrate the proposed method to be sufficient to facilitate timely diagnosis of endometrial cancer in the near future.

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

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

Use of Cap Analysis Gene Expression to detect human papillomavirus promoter activity patterns at different disease stages.

Transcription of human papillomavirus (HPV) genes proceeds unidirectionally from multiple promoters. Direct profiling of transcription start sites (TSSs) by Cap Analysis Gene Expression (CAGE) is a powerful strategy for examining individual HPV promoter activity. The objective of this study was to evaluate alterations of viral promoter activity during infection using CAGE technology. We used CAGE-based sequencing of 46 primary cervical samples, and quantitatively evaluated TSS patterns in the HPV transcriptome at a single-nucleotide resolution. TSS patterns were classified into two types: early promoter-dominant type (Type A) and late promoter-dominant type (Type B). The Type B pattern was more frequently found in CIN1 and CIN2 lesions than in CIN3 and cancer samples. We detected transcriptomes from multiple HPV types in five samples. Interestingly, in each sample, the TSS patterns of both HPV types were the same. The viral gene expression pattern was determined by the differentiation status of the epithelial cells, regardless of HPV type. We performed unbiased analyses of TSSs across the HPV genome in clinical samples. Visualising TSS pattern dynamics, including TSS shifts, provides new insights into how HPV infection status relates to disease state.