Allelic loss of HLA class I facilitates evasion from immune surveillance in cervical intraepithelial neoplasia.

Loss of heterozygosity (LOH) has been reported to occur in HLA regions in cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the details of how this is related to the progression of CIN have been unclear. In this study, we examined the human papillomavirus (HPV) antigen-presenting capacity of people with CIN and the significance of LOH of HLA class I in the progression of CIN. It was shown that differences in antigen-presenting capacity among each case depended on HLA types, not HPV genotypes. Focusing on the HLA type, there was a positive correlation between antigen-presenting capacity against HPV and the frequency of allelic loss. Furthermore, the lost HLA-B alleles had a higher HPV antigen-presenting capacity than intact alleles. In addition, frequency of LOH of HLA class I was significantly higher in advanced CIN (CIN2-3) than in cervicitis or early-stage CIN (CIN1): around half of CIN2-3 had LOH of any HLA class I. Moreover, the antigen-presenting capacity against E5, which is the HPV proteins that facilitate viral escape from this immune surveillance by suppressing HLA class I expression, had the most significant impact on the LOH in HLA-B. This study suggests that HPV evades immune surveillance mechanisms when host cells lose the capacity for antigen presentation by HLA class I molecules, resulting in long-term infection and progression to advanced lesions.

Carcinogenesis and epidemiology of cervical cancer: The hallmark of human papillomavirus-associated cancer.

Cervical cancer affects women worldwide and is the most common human papillomavirus (HPV)-associated cancer. Carcinogenesis caused by HPV results in specific cancer behavior because of the underlying viral infection. The mechanism and timing of the transformation from viral infection to cancer cells have been elucidated in detail. Treatments for this cancer are based on its characteristics and are being implemented. Moreover, HPV infection is widespread worldwide and is transmitted through sexual activity. Although the HPV vaccination is the most effective strategy of preventing cervical cancer, it is not feasible to vaccinate the entire human population especially in low- and middle-income countries. In order to consider the next step for HPV vaccination, we need to understand the characteristics of HPV carcinogenesis and cervical cancer. Additionally, treatment aimed at preservation of reproductive function in patients with cervical cancer is often required, as the cervix is a reproductive organ and because the disease is more prevalent in the adolescent and young adult generation. Thus, there are still many challenges in the diagnosis, treatment, and prevention of cervical cancer.

Quality of care measurement for patients with ovarian cancer in Japan.

AIM: Quality of care is important to reduce disease progression, and improve both survival and quality of life. The Japan Society of Gynecologic Oncology has published treatment guidelines to promote standardized high-quality care for ovarian cancer in Japan. We developed quality indicators based on the guideline recommendations and used them on large datasets of health service use to examine the quality of ovarian cancer care. METHODS: A panel of experts developed the indicators using a modified Delphi method. Adherence to each indicator was evaluated using data from a hospital-based cancer registry of patients diagnosed in 2018. All patients receiving first-line treatment at participating facilities were included. The adherence rates were returned to participating hospitals, and reasons for nonadherence were collected. A total of 580 hospitals participated, and the study examined the care received by 6611 patients with ovarian cancer and 1879 with borderline tumors using 11 measurable quality indicators. RESULTS: The adherence rate ranged from 22.6% for "Estrogen replacement within 6 months of operation" to 93.5% for "Bleomycin, etoposide, and cisplatin for germ cell tumor more than Stage II." Of 580 hospitals, 184 submitted the reasons for nonadherence. CONCLUSIONS: The quality of ovarian cancer care should be continuously assessed to encourage the use of best practices. These indicators may be a useful tool for this purpose.

Epstein-barr virus infections induce aberrant osteoclastogenesis in immune system-humanized NOD/Shi-scid/IL-2RγCnull mice.

Epstein-Barr virus (EBV) and other viral infections are possible triggers of autoimmune diseases, such as rheumatoid arthritis (RA). To analyze the causative relationship between EBV infections and RA development, we performed experiment on humanized NOD/Shi-scid/IL-2RγCnull (hu-NOG) mice reconstituted human immune system components and infected with EBV. In EBV-infected hu-NOG mice, breakdown of knee joint bones was found to be accompanied by the accumulation of receptor activator of nuclear factor-κB (NF-κB) (RANK) ligand (RANKL), a key factor in osteoclastogenesis, human CD19 and EBV-encoded small RNA (EBER)-bearing cells. Accumulation of these cells expanded in the bone marrow adjacent to the bone breakage, showing a histological feature like to that in bone marrow edema. On the other hand, human RANK/human matrix metalloprotease-9 (MMP-9) positive, osteoclast-like cells were found at broken bone portion of EBV-infected mouse knee joint. In addition, human macrophage-colony stimulating factor (M-CSF), an essential factor in development of osteoclasts, evidently expressed in spleen and bone marrow of EBV-infected humanized mice. Furthermore, RANKL and M-CSF were identified at certain period of EBV-transformed B lymphoblastoid cells (BLBCs) derived from umbilical cord blood lymphocytes. Co-culturing bone marrow cells of hu-NOG mice with EBV-transformed BLBCs resulted in the induction of a multinucleated cell population positive for tartrate-resistant acid phosphatase and human MMP-9 which indicating human osteoclast-like cells. These findings suggest that EBV-infected BLBCs induce human aberrant osteoclastogenesis, which cause erosive arthritis in the joints.

Intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer: association for pathological factors and oncologic outcomes.

OBJECTIVE: To examine the association between intrauterine manipulator use and pathological factors and oncologic outcomes in patients with endometrial cancer who had laparoscopic hysterectomy in Japan. METHODS: This was a nationwide retrospective cohort study of the tumor registry of the Japan Society of Obstetrics and Gynecology. Study population was 3846 patients who had laparoscopic hysterectomy for endometrial cancer from January 2015 to December 2017. An automated 1-to-1 propensity score matching with preoperative and intraoperative demographics was performed to assess postoperative pathological factors associated with the intrauterine manipulator. Survival outcomes were assessed by accounting for possible pathological mediators related to intrauterine manipulator use. RESULTS: Most patients had preoperative stage I disease (96.5%) and grade 1-2 endometrioid tumors (81.9%). During the study period, 1607 (41.8%) patients had intrauterine manipulator use and 2239 (58.2%) patients did not. In the matched cohort, the incidences of lymphovascular space invasion in the hysterectomy specimen were 17.8% in the intrauterine manipulator group and 13.3% in the non-manipulator group. Intrauterine manipulator use was associated with a 35% increased odds of lymphovascular space invasion (adjusted odds ratio 1.35, 95% confidence interval (CI) 1.08 to 1.69). The incidences of malignant cells identified in the pelvic peritoneal cytologic sample at hysterectomy were 10.8% for the intrauterine manipulator group and 6.4% for the non-manipulator group. Intrauterine manipulator use was associated with a 77% increased odds of malignant peritoneal cytology (adjusted odds ratio 1.77, 95% Cl 1.29 to 2.31). The 5 year overall survival rates were 94.2% for the intrauterine manipulator group and 96.6% for the non-manipulator group (hazard ratio (HR) 1.64, 95% Cl 1.12 to 2.39). Possible pathological mediators accounted HR was 1.36 (95%Cl 0.93 to 2.00). CONCLUSION: This nationwide analysis of predominantly early stage, low-grade endometrial cancer in Japan suggested that intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer may be associated with an increased risk of lymphovascular space invasion and malignant peritoneal cytology. Possible mediator effects of intrauterine manipulator use on survival warrant further investigation, especially with a prospective setting.

Immunotherapy that leverages HPV-specific immune responses for precancer lesions of cervical cancer.

Cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN), are caused by high-risk human papillomavirus (HPV) viral infection and are highly susceptible to host immunity targeting of HPV viral proteins, which include both foreign antigens and cancer antigens expressed by tumors. Immunotherapy that induces Th1 immunoreactivity against viral proteins is expected to take advantage of this immunological regression mechanism. However, although cancer immunotherapies for cervical cancer and CIN have been developed over the past several decades, none have been commercialized. Most of these immunotherapies target the viral cancer proteins E6 and E7, which are generally the same. The reasons for the underdevelopment of HPV-targeted immunotherapy differ depending on whether the target is invasive cancer or CIN. We here summarize the developmental history of cancer immunotherapy for CIN and discuss strategies for solving the problems that led to this underdevelopment. We note that CIN is a mucosal lesion and propose that inducing mucosal immunity may be the key.

Impact of COVID-19 on gynecological cancer incidence: a large cohort study in Japan.

BACKGROUND: The influence of the coronavirus disease 2019 (COVID-19) pandemic on the number of newly diagnosed gynecological cancers has not been extensively investigated in Japan. This study determined the impact of COVID-19 on the incidence of gynecological cancer. METHODS: Using the Japanese Society of Obstetricians and Gynecologic Oncology registry database, the distribution of the number of patients based on clinical staging or tumor-node-metastasis classifications before and during the COVID-19 pandemic was analyzed to compare the trends. The clinical staging classification of cervical cancer in Japan was based on the International Federation of Gynecology and Obstetrics (FIGO) 2008 from 2018 to 2020 and on the FIGO 2018 from 2021. Since FIGO-2018 classified N1 cases as stage IIIC, we focused on T classification without referencing the clinical staging (FIGO staging) of patients with cervical cancer in 2021. RESULTS: The number of patients with endometrial cancer and malignant ovarian tumors of all clinical stages increased uniformly yearly, while that of those with stage III cervical cancer rapidly increased in 2021 owing to the adoption of the revised classification. On comparing cases of cervical cancer in 2020 and 2021, we found that T1 cases decreased and T2 and T3 cases increased in 2021 compared to those in 2020 (p = 0.006). Cervical intraepithelial neoplasia/adenocarcinoma in situ incidence decreased in 2020 compared to that in 2019 but increased again in 2021. The number of patients with cervical cancer decreased in most prefectures in 2020. CONCLUSION: The incidence of locally advanced cervical cancer increased during the COVID-19 pandemic.

SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1-dependent reduction of esterified cholesterol.

We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8+ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8+ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8+ T cells. In vitro treatment of CD8+ T cells with SCD1 inhibitors enhanced IFN-γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8+ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8+ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN-γ production of tumor-infiltrating CD8+ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8+ T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models. Therefore, the SCD1-ACAT1 axis is regulating effector functions of CD8+ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.

Identification of target cells of human papillomavirus 18 using squamocolumnar junction organoids.

Human papillomavirus 18 (HPV18) is a highly malignant HPV genotype among high-risk HPVs, characterized by the difficulty of detecting it in precancerous lesions and its high prevalence in adenocarcinomas. The cellular targets and molecular mechanisms underlying its infection remain unclear. In this study, we aimed to identify the cells targeted by HPV18 and elucidate the molecular mechanisms underlying HPV18 replication. Initially, we established a lentiviral vector (HPV18LCR-GFP vector) containing the HPV18 long control region promoter located upstream of EGFP. Subsequently, HPV18LCR-GFP vectors were transduced into patient-derived squamocolumnar junction organoids, and the presence of GFP-positive cells was evaluated. Single-cell RNA sequencing of GFP-positive and GFP-negative cells was conducted. Differentially expressed gene analysis revealed that 169 and 484 genes were significantly upregulated in GFP-positive and GFP-negative cells, respectively. Pathway analysis showed that pathways associated with cell cycle and viral carcinogenesis were upregulated in GFP-positive cells, whereas keratinization and mitophagy/autophagy-related pathways were upregulated in GFP-negative cells. siRNA-mediated luciferase reporter assay and HPV18 genome replication assay validated that, among the upregulated genes, ADNP, FHL2, and NPM3 were significantly associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. Among them, NPM3 showed substantially higher expression in HPV-related cervical adenocarcinomas than in squamous cell carcinomas, and NPM3 knockdown of HPV18-infected cells downregulated stem cell-related genes. Our new experimental model allows us to identify novel genes involved in HPV18 early promoter activities. These molecules might serve as therapeutic targets in HPV18-infected cervical lesions.

Feasibility, accuracy and acceptability of self-sampled human papillomavirus testing using careHPV in Cambodia: a cross-sectional study.

OBJECTIVE: Self-sampled human papillomavirus (HPV) testing is a potential option for cervical cancer screening, but research is scarce in Cambodia. We evaluated the feasibility, accuracy, and acceptability of self-sampled HPV testing using careHPV. METHODS: A cross-sectional study including women aged 20-49 years attending 2 national hospitals in the capital city was conducted. Women underwent both self-sampling and clinician-sampling of specimens, and were then asked to complete an acceptability questionnaire. The paired samples were analyzed for high-risk HPV by careHPV and genotyped by polymerase chain reaction (PCR). RESULTS: A total of 375 women were eligible for inclusion. Based on PCR, 78.9% were negative for HPV in both self and clinician-samples, 9.9% had a complete HPV type match, and 6.1% had all HPV types in clinician-samples also detected in self-samples. In 5.1%, one or more HPV types identified in the clinician-samples were missed in self-samples. When using careHPV, the overall agreement between the 2 sampling methods was 95.7% (95% confidence interval [CI]=95.8-95.6) with good concordance (κ=0.66, 95% CI=0.56-0.76). Nearly 90% of the women preferred clinician-sampling over self-sampling, citing greater comfort, ease, and speed. CONCLUSION: Self-sampled HPV testing using careHPV could be an option for cervical cancer screening in Cambodia; however, it requires periodic quality control of handling procedures. In addition, women's health education regarding the accuracy of self-sampled HPV testing and the importance of follow-up in cases of positive results is needed.

Phase I and II randomized clinical trial of an oral therapeutic vaccine targeting human papillomavirus for treatment of cervical intraepithelial neoplasia 2 and 3.

BACKGROUND: Although many human papillomavirus (HPV)-targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine. METHODS: In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16-positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety. RESULTS: In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7-specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner. CONCLUSION: This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16-positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects. TRIAL REGISTRATION: jRCT2031190034.

Serum Free Fatty Acid Changes Caused by High Expression of Stearoyl-CoA Desaturase 1 in Tumor Tissues Are Early Diagnostic Markers for Ovarian Cancer.

Ovarian cancer has a poor prognosis and is difficult to detect in early stages. Therefore, developing new diagnostic markers for early-stage ovarian cancer is critical. Here, we developed a diagnostic marker for early-stage ovarian cancer on the basis of fatty acid metabolism characteristics of cancer cells. The expression of various fatty acid metabolizing enzymes such as stearoyl-CoA desaturase 1 (SCD1) was altered in early-stage ovarian cancer tissue compared with that in normal ovarian tissue. Changes in the expression of fatty acid metabolizing enzymes, particularly SCD1, in cancer tissues were found to alter concentrations of multiple free fatty acids (FFA) in serum. We were the first to show that fatty acid metabolic characteristics in tissues are related to the FFA composition of serum. Surprisingly, patients with stage I/II ovarian cancer also showed significant changes in serum levels of eight FFAs, which can be early diagnostic markers. Finally, using statistical analysis, an optimal early diagnostic model combining oleic and arachidic acid levels, fatty acids associated with SCD1, was established and confirmed to have higher diagnostic power than CA125, regardless of histology. Thus, our newly developed diagnostic model using serum FFAs may be a powerful tool for the noninvasive early detection of ovarian cancer. SIGNIFICANCE: Measurement of serum FFA levels by changes in the expression of fatty acid metabolizing enzymes in tumor tissue would allow early detection of ovarian cancer. In particular, the SCD1-associated FFAs, oleic and arachidic acid, would be powerful new screening tools for early-stage ovarian cancer.

Risk stratification of invasive cervical cancer diagnosed after cervical conization.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) diagnosis is based on colposcopy-aided histological examination. However, its accuracy in CIN diagnosis is limited. Some invasive cervical cancers (ICCs) are diagnosed after cervical conization. Therefore, risk stratification of undetected ICC is particularly important for the management of patients with CIN. This study aimed to identify the risk factors for undetected ICC. We especially focused on the association of human papillomavirus (HPV) genotypes. METHODS: We retrospectively reviewed the clinicopathological characteristics (including age, parity, and preoperative diagnosis) and HPV genotypes of 348 patients diagnosed with CIN or adenocarcinoma in situ (AIS) who underwent cervical conization at our hospital between 2008 and 2016. The relationship between preoperative factors, including HPV genotypes and post-conization ICC, was evaluated. RESULTS: Among the 348 patients, 322, 7, and 19 had preoperative CIN3, CIN2, and AIS, respectively; 181 were nulliparous. The median patient age was 41 (23-83) years. HPV genotyping was performed on 237 patients. Overall, post-conization ICC was detected in 16 patients (4.6%). Multivariate analysis showed that nulliparity and HPV16 positivity were the independent risk factors for post-conization ICC (OR: 6.01, P = 0.0302; OR: 5.26, P = 0.0347, respectively). The combination of HPV16 status and parity improved diagnostic accuracy. Seven of 53 HPV16-positive cases (13%) without childbirth history were diagnosed with post-conization ICC. In contrast, none of the HPV16-negative cases with childbirth history was diagnosed with post-conization ICC. CONCLUSION: HPV16 positivity and nulliparity were identified as risk factors for undetected ICC. Careful treatment selection and preoperative scrupulous examination are especially important in these cases.

Successful surgical treatment of postmyomectomy uterine diverticulum: a case report.

BACKGROUND: Uterine diverticulum is classified into congenital and acquired types. The acquired type is caused by caesarean scar syndrome, which occurs after caesarean section. There are no detailed reports on diverticulum after enucleation of uterine fibroids. Most cases are treated with hysteroscopy or laparoscopy, but a management consensus is lacking. We treated a patient with a uterine diverticulum that had formed after uterine fibroid enucleation by combining hysteroscopic and laparoscopic treatments. CASE PRESENTATION: The patient was a 37-year-old Japanese woman, G1P0. A previous doctor had performed abdominal uterine myomectomy for a pedunculated subserosal uterine fibroid on the right side of the posterior wall of the uterus near the internal cervical os. Menstruation resumed postoperatively, but a small amount of dark-red bleeding persisted. MRI two months after the myomectomy revealed a diverticulum-like structure 3 cm in diameter, communicating with the uterine lumen, on the right side of the posterior wall of the uterus. Under suspicion of uterine diverticulum after uterine fibroid enucleation, the patient sought treatment at our hospital approximately four months after the myomectomy. Through a flexible hysteroscope, a 5-mm-diameter fistula was observed in the posterior wall of the uterus, and a contrast-enhanced pocket, measuring approximately 3 cm, was located behind it. Uterine diverticulum following enucleation of a uterine fibroid was diagnosed, and surgery was thus deemed necessary. The portion entering the fistula on the internal cervical os side was resected employing a hysteroscope. Intra-abdominal findings included a 4-cm mass lesion on the posterior wall on the right side of the uterus. The mass was opened, and the cyst capsule was removed. A 5-mm fistula was detected and closed with sutures. Resuturing was not performed after dissection of the right round ligament due to tension. The postoperative course has been good to date, with no recurrence. CONCLUSION: Uterine diverticula after myomectomy may be treated with a combined laparoscopic and hysteroscopic approach, similar to caesarean scar syndrome.

The Factors Influencing Pregnant Women's Selection of Media Sources to Obtain Information on COVID-19 in Japan in 2021.

Pregnant women presumably gather information about the coronavirus disease 2019 (COVID-19) from various sources. However, it is difficult for pregnant women who are not medical professionals to source the appropriate information because of the infodemic related to the COVID-19 pandemic. Therefore, the objective of our study was to investigate how pregnant women gathered information about COVID-19 and COVID-19 vaccination. To address this issue, we conducted an online questionnaire survey between 5 October and 22 November 2021, which was approved by the Ethics Committee of Nihon University School of Medicine. We received 4962 responses after excluding 1179 insufficient answers. Our study found that age, occupation, and infection-risk anxiety influenced the selection of media for obtaining information. Pregnant women who were older, medical professionals, public servants, or educators tended to rely on specialized medical websites, whereas housewives tended to use mass media, social media, and sources with uncertain scientific evidence. Additionally, the number of weeks of gestation and the method of conception (natural or assisted reproductive conception) affected the selection of media. The accessibility of COVID-19 information for pregnant women was determined by their social background and pregnancy status. We need to continue making efforts to ensure that appropriate information is readily available to pregnant women and their families.

Trend and characteristics of minimally invasive surgery for patients with endometrial cancer in Japan.

OBJECTIVE: Owing to the potential benefits of minimally invasive hysterectomy for endometrial cancer, the practice pattern has recently shifted in Japan. This study examined the trends in minimally invasive surgery (MIS) in patients with endometrial cancer in Japan. METHODS: This retrospective observational study examined the Japan Society of Obstetrics and Gynecology Tumor Registry database between 2015-2019. This study examined the time-specific proportion change and predictors of MIS use in initial endometrial cancer treatment in Japan, and compared it with the use of abdominal surgery. Additionally, the association between hospital surgical treatment volume and MIS use was examined. RESULTS: A total of 14,059 patients (26.5%) underwent minimally invasive hysterectomy, and 39,070 patients (73.5%) underwent abdominal hysterectomy in the study period. Patients who underwent MIS were more likely to be treated at high-volume centers, younger, central, or western Japan residents, registered in recent years, and had a tumor with stage I disease, type 1 histology, and less myometrial invasion (all adjusted p<0.05). The proportion of MIS treatments increased from 19.1% in 2015 to 34.3% in 2019 (p<0.001). On multivariable analysis, treatment at high-volume centers was a contributing factor for MIS (adjusted odds ratio=3.85; 95% confidence interval=3.44-4.30). MIS at high-volume centers increased significantly from 24.8% to 41.0% (p<0.001) during the study period, whereas MIS at low-volume centers remained at median 8.8%. CONCLUSION: MIS has increased significantly in recent years, accounting for nearly 34% of surgical management of endometrial cancer in Japan. High-volume treatment centers take the lead in performing MIS.

Study of the effects of in-person attendance at academic conferences on the health of the attendees under COVID-19 pandemic.

OBJECTIVE: To analyze the effects of in-person attendance at an academic conference held during the Covid-19 pandemic on the health of the attendees, as assessed based on symptoms such as fever and cough attributed to infection with the Covid-19 virus. METHODS: A questionnaire was used to survey the members of the Japan Society of Obstetrics and Gynecology (JSOG) about their health during the period from August 7 to August 12, 2022, after the 74th Annual Congress of the JSOG, which was held August 5 to 7. RESULTS: Our survey yielded responses from 3054 members (1566 of whom had attended the congress in person and 1488 of whom had not attended in person); 102 (6.5%) of the in-person attendees and 93 (6.2%) of the people who did not attend in person reported problems with their health. No statistically significant difference was found between these two groups (p = 0.766). In a univariate analysis of factors affecting the presence of health problems, attendees with age ≥60 years had significantly fewer health problems than attendees who were in their 20s (odds ratio: 0.366 [0.167-0.802; p = 0.0120]). In a multivariate analysis, attendees who had received four vaccine shots had significantly fewer health problems than attendees who had received three shots (odds ratio: 0.397 [0.229-0.690, p = 0.0010]). CONCLUSION: Congress attendees who took precautions at the congress to avoid being infected and who had a high vaccination rate did not develop significantly more health problems associated with in-person attendance at the congress.

Pathological roles of antimicrobial peptides and pro-inflammatory factors secreted from the cervical epithelium in Gardnerella vaginalis-abundant vaginal flora in pregnancy.

Bacterial vaginosis due to Gardnerella vaginalis (GV) is one of the main causes of preterm birth. Antimicrobial function of the cervical glands prevents ascending pathogen infection. This study investigated the effect of GV on the cervical gland cells. We examined the correlation between GV and neutrophil elastase in the cervical mucous obtained from pregnant women's clinical samples. Culture supernatants (sup) of GV and Lactobacillus crispatus (LC) were added to human immortalized cervical gland cells (EndoCx). Quantitative reverse transcription PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to examine the effects on the production of antimicrobial peptides (AMPs), secretory leukocyte peptidase inhibitor (SLPI), and Elafin. mRNA microarray analysis revealed the expression profile of GV-exposed EndoCx. Moreover, the antimicrobial activity of Elafin against LC and GV was investigated. In the clinical samples, neutrophil elastase was increased in the GV-positive cervical mucous. In an in vitro assay, RT-qPCR and ELISA showed that GV-sup enhanced the secretion of Elafin, but not SLPI, from EndoCx, whereas LC-sup did not. mRNA microarray assay and ELISA results demonstrated that GV-sup enhanced the proinflammatory pathway and interleukin (IL)- 8 secretion from EndoCx as well as cell adhesion and tight junction pathways. Moreover, GV-sup directly enhanced Elafin and IL-8 secretion from the cervical gland cells. In the GV-abundant vaginal flora, IL-8 level increased the neutrophil elastase activity and Elafin inhibited the elastase activity to protect from tissue damage and infection. Thus, the balance of IL-8-induced neutrophil and Elafin-induced antiprotease activities may be crucial in preterm labor.

Application of organoid culture from HPV18-positive small cell carcinoma of the uterine cervix for precision medicine.

BACKGROUND: Small cell carcinoma of the uterine cervix (SCCC) is a rare and highly malignant human papillomavirus (HPV)-associated cancer in which human genes related to the integration site can serve as a target for precision medicine. The aim of our study was to establish a workflow for precision medicine of HPV-associated cancer using patient-derived organoid. METHODS: Organoid was established from the biopsy of a patient diagnosed with HPV18-positive SCCC. Therapeutic targets were identified by whole exome sequencing (WES) and RNA-seq analysis. Drug sensitivity testing was performed using organoids and organoid-derived mouse xenograft model. RESULTS: WES revealed that both the original tumor and organoid had 19 somatic variants in common, including the KRAS p.G12D pathogenic variant. Meanwhile, RNA-seq revealed that HPV18 was integrated into chromosome 8 at 8q24.21 with increased expression of the proto-oncogene MYC. Drug sensitivity testing revealed that a KRAS pathway inhibitor exerted strong anti-cancer effects on the SCCC organoid compared to a MYC inhibitor, which were also confirmed in the xenograft model. CONCLUSION: In this study, we confirmed two strategies for identifying therapeutic targets of HPV-derived SCCC, WES for identifying pathogenic variants and RNA sequencing for identifying HPV integration sites. Organoid culture is an effective tool for unveiling the oncogenic process of rare tumors and can be a breakthrough for the development of precision medicine for patients with HPV-positive SCCC.