The Effects of Low Concentrations of Pravastatin on Placental Cells.

Pravastatin is a promising medication to treat preeclampsia. However, the appropriate dose of pravastatin for managing preeclampsia has not been established. In this in vitro study, we examined the effects of low concentrations of pravastatin (0.01 to 10 µM) under hypoxic conditions on two types of placental cells and found that pravastatin decreased sFlt-1 levels up to 34% in cytotrophoblast cells isolated from human term placentas. Furthermore, we showed that sFlt-1 levels in HTR-8/SVneo cells, a cell line derived from first trimester trophoblast cells, decreased after exposure to very low concentrations of pravastatin (0.01, 0.1 µM). We also examined the effects of pravastatin on uterine spiral artery remodeling-related events and showed in wound healing and tube formation assays that low concentrations of pravastatin upregulated cell migration and invasion in HTR-8/SVneo cells. These results demonstrated that a low dose of pravastatin has in vitro effects that suggest a potential for anti-preeclamptic effects in vivo.

Local vaginal bioelectrical impedance can predict preterm delivery in mice.

Preterm birth is a serious pregnancy complication that affects neonatal mortality, morbidity and long-term neurological prognosis. Predicting spontaneous preterm delivery (PTD) is important for its management. While excluding the risk of PTD is important, identifying women at high risk of PTD is imperative for medical intervention. Currently used PTD prediction parameters in clinical practice have shown high negative predictive values, but low positive predictive values. We focused on sulfated and sialylated glycocalyx changes in the uterus and vagina prior to the onset of parturition and explored the potential of electrophysiological detection of these changes as a PTD prediction parameter with a high positive predictive value. In vivo local vaginal bioelectrical impedance (VZ) was measured using two different mouse PTD models. PTD was induced in ICR mice through the subcutaneous injection of mifepristone or local intrauterine injection of lipopolysaccharide (LPS). The PTD rates were 100% and 60% post-administration of mifepristone (16-20 hours, n = 4) and LPS (12-24 hours, n = 20), respectively. The local VZ values (15 and 10 hours after mifepristone or LPS treatment, respectively) were significantly lower in the PTD group than in the non-PTD group. Receiver operator characteristic (ROC) curve analysis of VZ at 125 kHz as a predictor of PTD showed an area under the ROC curve of 1.00 and 0.77 and positive predictive values of 1.00 and 0.86, for the mifepristone and LPS models respectively, suggesting that local VZ value can predict PTD. Histological examination of the LPS-treated model 6 hours post-treatment revealed increased expression of sulfomucins and/or sulfated proteoglycans and sialomucins in the cervical endometrium, cervical stroma and vaginal stroma. In conclusion, local VZ values can determine sulfated and sialylated glycocalyx alterations within the uterus and vagina and might be a useful PTD prediction parameter.

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.

First ray mobility in hallux rigidus, hallux valgus, and normal feet based on weightbearing computed tomography and three-dimensional analysis: A case-control study.

BACKGROUND: Hallux valgus and hallux rigidus are disorders affecting the first ray and are associated with hypermobility of this structure. This study aimed to investigate the three-dimensional mobility of each joint of the first ray between feet with hallux valgus or hallux rigidus and healthy feet using weightbearing and nonweightbearing computed tomography (CT). METHODS: This case-control study analyzed 17 feet of 11 healthy volunteers (control group), 16 feet of 16 patients with hallux valgus (HV group), and 16 feet of 11 patients with hallux rigidus (HR group). First, nonweightbearing foot CT imaging was performed in the supine position on a loading device with no load applied, with the legs extended and the ankle in the neutral position. Next, a load equivalent to body weight was applied for weightbearing CT imaging. Distal bone displacement relative to the proximal bone was quantified three-dimensionally under both conditions. RESULTS: In the HV group, the talonavicular joint showed significantly greater eversion (P = 00.011) compared with the control group and significantly greater dorsiflexion (P = 00.027) and eversion (P < 00.01) compared with the HR group. In the medial cuneiform joint, the HV group showed significantly greater eversion (P < 00.01) and abduction (P = 00.011) than the control group. For the first tarsometatarsal joint, the HV group showed significantly greater dorsiflexion (P = 00.014), inversion (P = 00.028), and adduction (P < 00.01) than the control group, and greater inversion (P < 00.01) and adduction (P < 00.01) than the HR group. Dorsiflexion of the first tarsometatarsal joint was significantly greater in the HR group compared with the control group (P = 00.026). CONCLUSION: Hypermobility of the first ray appears to be three-dimensional: in hallux valgus, it is centered at the first tarsometatarsal joint, while in hallux rigidus it is mainly in the sagittal plane at the first tarsometatarsal joint only. This difference may explain the different deformities ultimately observed in each condition.

Patient-Derived Exosomes as siRNA Carriers in Ovarian Cancer Treatment.

RNA interference is a powerful gene-silencing tool with potential clinical applications. However, its therapeutic use is challenging because suitable carriers are unavailable. Exosomes are stable small endogenous vesicles that can transport functional molecules to target cells, making them ideal small interfering RNA (siRNA) carriers. Herein, we elucidated the therapeutic potential of patient-derived exosomes as an siRNA carrier for ovarian cancer (OC) treatment. The exosomes were extracted from the culture medium of primary fibroblasts collected from the omentum of patients with OC during surgery. MET proto-oncogene, receptor tyrosine kinase (MET) was selected for gene silencing, c-Met siRNAs were synthesized and loaded into the exosomes (Met-siExosomes) via electroporation, and the treatment effect of the Met-siExosomes was assessed in vitro and in vivo. The Met-siExosomes downregulated the c-Met protein levels and inhibited OC cell proliferation, migration, and invasion. In xenograft experiments using SKOV3-13 and ES-2 cells, Met-siExosomes were selectively extracted from peritoneally disseminated tumors. Intraperitoneal treatment suppressed the c-Met downstream targets in cancer cells and prolonged mouse survival. The synthesized siRNAs were successfully and selectively delivered via the exosomes to intraperitoneally disseminated tumors. As patients with OC routinely undergo omentectomy and abundant fibroblasts can be easily collected from the omentum, patient-derived exosomes may represent a promising therapeutic siRNA carrier to treat OC.

Correction of Equinus Deformity by Ilizarov Frame Using the Matsushita Method and Achilles Tendon Lengthening: A Case Report.

CASE: The patient was an 18-year-old man who had sustained diaphyseal fractures of the left femur and tibia in a traffic accident and underwent surgery at another hospital. A severe left foot equinovarus deformity developed in the early after surgery. The patient's left foot deformity was addressed using unconstrained gradual external fixator correction (the Matsushita method) in combination with soft-tissue contracture through Achilles tendon lengthening and was maintained after removing the external fixation. CONCLUSION: The Matsushita method can be effective in the correction of post-traumatic equinovarus foot deformities.

HPV Vaccine Issues in Japan: A review of our attempts to promote the HPV vaccine and to provide effective evaluation of the problem through social-medical and behavioral-economic perspectives.

In Japan, subsidies from local and national government programs for HPV vaccination of girls aged 13-16 began in 2010. By 2013, HPV vaccines were being used routinely for vaccinating girls aged 12-16 as part of its national immunization program. However, in June of 2013, in response to reports of possible adverse reactions to the vaccine, Japan's Ministry of Health, Labor, and Welfare (MHLW) announced a 'temporary suspension' of its governmental recommendation for HPV vaccination. The vaccination rate quickly dropped from 70 % of age-eligible girls to almost zero. It was not until 2021 that the government's recommendation suspension finally ended. The efficacy and safety of the HPV vaccine is now well documented, yet Japan has failed to reestablish any credible level of HPV vaccination. The World Health Organization (WHO) warned that Japan's HPV vaccination debacle was likely to result in real harm to the girls who lacked its protection; something we have already demonstrated with real-world data. To reinvigorate the HPV vaccination program in Japan to its prior levels, in the face of the current high level of HPV vaccine hesitancy, we will have to address the irrationality of human decision-making pointed out by behavioral economics. The Japanese government must act expeditiously to promote stronger cervical cancer control measures.

Severe hemolysis, elevated liver enzymes, and low platelet syndrome requiring differentiation of thrombotic microangiopathy: Four cases from a nationwide survey in Japan.

Severe cases of hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome requiring plasma exchange or dialysis should be differentiated from other thrombotic microangiopathy (TMA) and treated appropriately. To evaluate the prevalence and clinical characteristics of such cases in Japan, a questionnaire-based survey was conducted among obstetricians who are members of the Perinatal Research Network Group in Japan. There were a total of 335 cases of HELLP syndrome over a 3-year period in the 48 facilities that responded to the survey. Four patients required plasma exchange or dialysis, of which two were diagnosed with atypical hemolytic uremic syndrome and two with TMA secondary to systemic lupus erythematosus. Although such severe HELLP syndrome is rare, identifying the clinical features and making accurate differential diagnosis are critical for optimal clinical outcomes for mothers and neonates.

Ganglion Cysts in the Hallux: A Report of Two Cases.

We experienced two cases of intractable hallux ganglion. Case 1 was a 70-year-old woman with a recurrent ganglion and severe pain on the plantar aspect of the hallux. The continuity between the mass and the distal flexor hallucis longus (FHL) tendon sheath was confirmed. The ganglion was resected along with part of the tendon sheath, and the tendon sheath was incised as proximally as possible. Case 2 was a 69-year-old woman with a ganglion on the dorsal aspect of the interphalangeal joint that repeatedly ruptured due to thinning of the skin. The ganglion was contiguous with the joint capsule but not with the FHL tendon sheath, and the entire capsule was resected. There was no recurrence one year after surgery in either case. The risk of recurrence of an intractable hallux ganglion can be reduced by blocking the synovial supply route and lowering the pressure inside the joint or tendon sheath.

Complicated pancreatic fistula after gynecologic surgery for left fallopian tube carcinosarcoma: A case report.

Pancreatic fistulas are rare after gynecologic surgeries but are sometimes difficult to manage. A 62-year-old woman was admitted to a local hospital with acute abdominal pain. Computed tomography (CT) images showed subileus and an obstruction site in the transverse/descending colon, with invasion of peritoneal metastasis. A metal stent was placed in the bowel through colonoscopy. Suspecting advanced-stage ovarian cancer, the patient was referred to a tertiary hospital. Diagnostic laparoscopy was performed prior to neoadjuvant chemotherapy. Due to concerns raised by gastrointestinal surgeons regarding the high risk of stent perforation during chemotherapy, an abdominal colectomy of the transverse/descending colon was performed along with the removal of the disseminated tumor and the stent. Post-surgery, the patient was histologically diagnosed with stage IVB left fallopian tube carcinosarcoma. On postoperative day 3, the patient developed a fever, and CT images showed an abscess around the pancreas/spleen, prompting the placement of a drainage tube. The amylase level in the drained fluid was 258,111 U/L, leading to a diagnosis of a pancreatic fistula. Conservative management was undertaken, with drainage, fasting, and octreotide administration. After two months, the drainage tube was removed as the volume of drained fluid had decreased. After four cycles of carboplatin/paclitaxel chemotherapy, CT images showed partial response to chemotherapy, and interval debulking surgery was performed. The necessity of metallic stent placement should be carefully considered as the subileus caused by peritoneal metastasis might be alleviated by the induction of chemotherapy for gynecologic cancer.

Explainable Machine Learning Classification to Identify Vulnerable Groups Among Parenting Mothers: Web-Based Cross-Sectional Questionnaire Study.

BACKGROUND: One life event that requires extensive resilience and adaptation is parenting. However, resilience and perceived support in child-rearing vary, making the real-world situation unclear, even with postpartum checkups. OBJECTIVE: This study aimed to explore the psychosocial status of mothers during the child-rearing period from newborn to toddler, with a classifier based on data on the resilience and adaptation characteristics of mothers with newborns. METHODS: A web-based cross-sectional survey was conducted. Mothers with newborns aged approximately 1 month (newborn cohort) were analyzed to construct an explainable machine learning classifier to stratify parenting-related resilience and adaptation characteristics and identify vulnerable populations. Explainable k-means clustering was used because of its high explanatory power and applicability. The classifier was applied to mothers with infants aged 2 months to 1 year (infant cohort) and mothers with toddlers aged >1 year to 2 years (toddler cohort). Psychosocial status, including depressed mood assessed by the Edinburgh Postnatal Depression Scale (EPDS), bonding assessed by the Postpartum Bonding Questionnaire (PBQ), and sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI) between the classified groups, was compared. RESULTS: A total of 1559 participants completed the survey. They were split into 3 cohorts, comprising populations of various characteristics, including parenting difficulties and psychosocial measures. The classifier, which stratified participants into 5 groups, was generated from the self-reported scores of resilience and adaptation in the newborn cohort (n=310). The classifier identified that the group with the greatest difficulties in resilience and adaptation to a child's temperament and perceived support had higher incidences of problems with depressed mood (relative prevalence [RP] 5.87, 95% CI 2.77-12.45), bonding (RP 5.38, 95% CI 2.53-11.45), and sleep quality (RP 1.70, 95% CI 1.20-2.40) compared to the group with no difficulties in perceived support. In the infant cohort (n=619) and toddler cohort (n=461), the stratified group with the greatest difficulties had higher incidences of problems with depressed mood (RP 9.05, 95% CI 4.36-18.80 and RP 4.63, 95% CI 2.38-9.02, respectively), bonding (RP 1.63, 95% CI 1.29-2.06 and RP 3.19, 95% CI 2.03-5.01, respectively), and sleep quality (RP 8.09, 95% CI 4.62-16.37 and RP 1.72, 95% CI 1.23-2.42, respectively) compared to the group with no difficulties. CONCLUSIONS: The classifier, based on a combination of resilience and adaptation to the child's temperament and perceived support, was able identify psychosocial vulnerable groups in the newborn cohort, the start-up stage of childcare. Psychosocially vulnerable groups were also identified in qualitatively different infant and toddler cohorts, depending on their classifier. The vulnerable group identified in the infant cohort showed particularly high RP for depressed mood and poor sleep quality.

Residual Medial Ankle Pain After the Delayed Union of a Lateral Malleolus Fracture: A Case Report.

A 17-year-old girl sprained her left ankle and was diagnosed with a lateral malleolar fracture. She was treated conservatively for six months but had medial ankle pain with activity. Imaging revealed an oblique lateral malleolar fracture, with posterolateral displacement and partial fusion of the bone fragments, and bone marrow edema on the medial articular surface of the talus and medial malleolus. We diagnosed ankle instability due to delayed union with a displacement of the lateral malleolus, which caused an osteochondral lesion. We performed arthroscopic and open surgery eight months after the injury, reducted the lateral malleolus anatomically, and fixed it with a plate. Postoperatively, the pain improved rapidly, and the bone marrow edema had almost disappeared on an MRI. In this case, we think rotational instability of the ankle mortise caused abnormal pressure and continuous stress on the medial malleolus after injury, which may have contributed to persistent medial ankle pain.

Parental gender influences their intention to HPV vaccinate their children, and the association between HPV and COVID-19 vaccination intentions.

Purpose: The coronavirus disease of 2019 (COVID-19) pandemic has increased public awareness of infectious diseases and interest in vaccines, including the human papilloma virus (HPV) vaccine. We investigated differences between parental gender and intentions to vaccinate their child for HPV and COVID-19. Methods: We analyzed data from Japan's COVID-19 and Society Internet Survey (JACSIS), a web-based cross-sectional survey of 2,444 respondents in 2021. Results: Females were more knowledgeable and more afraid of HPV and COVID-19 than males. The proportions of females in favor of, or against, HPV vaccination was higher than among males. The fathers' intention for HPV vaccination was significantly associated with the child's gender, knowledge regarding HPV, and intention to inoculate with the COVID-19 vaccine. The mothers' intention was also associated with her knowledge of HPV and her intention to seek the COVID-19 vaccine, but it included a greater fear of HPV infection. Both male and female parents favored the COVID-19 vaccine over the HPV vaccine. Parents approving of COVID-19 vaccination believed in the overall efficacy of vaccines and were more receptive to opinions from the administration and physicians, even if the parent was currently against HPV vaccination. Conclusions: Mothers were more knowledgeable about HPV and more favorable to vaccinate their child for HPV than fathers. The intention to have children COVID-19 vaccinated was also higher than for HPV vaccination. During this period of heightened public interest in vaccines due to the COVID-19 pandemic, this is a good time to educate and inform the public about HPV.

Maternal Autistic Traits and Adverse Birth Outcomes.

Importance: Women with a high level of autistic traits in the general population may experience larger health disparities during pregnancy, particularly women diagnosed with autism spectrum disorder (ASD), which in turn may be associated with increased risk of adverse birth outcomes. Objective: To investigate the association between maternal autistic traits and the risk of adverse birth outcomes in the general population. Design, Setting, and Participants: This cohort study included mothers of singletons from a nationwide, multicenter prospective birth cohort, the Japan Environmental Children's Study. Expecting mothers were recruited between January 2011 and March 2014. Data were analyzed between June 2021 and November 2023. Exposures: Autistic traits were self-reported during the second and third trimesters using the short form of the Autism-Spectrum Quotient Japanese version (AQ-J10) (score range, 0-10; clinical range, ≥7). Main Outcomes and Measures: Data on preterm birth (<37 weeks' gestation) and neonates born small for gestational age (SGA) were transcribed from medical records. Additional analysis of gestational age groups (very preterm birth, <32 weeks' gestation; moderate-to-late preterm birth, 32-36 weeks' gestation) was also performed. Results: Among 87 687 women (mean [SD] age, 31.2 [5.0] years) included in the study, 2350 (2.7%) had AQ-J10 scores within the clinical range yet only 18 (0.02%) were diagnosed with ASD. A higher AQ-J10 score was associated with an increased risk of all birth outcomes, including preterm births (relative risk [RR] per 1-SD increase, 1.06; 95% CI, 1.03-1.09), moderate-to-late preterm births (RR per 1-SD increase, 1.05; 95% CI, 1.01-1.08), very preterm births (RR per 1-SD increase, 1.16; 95% CI, 1.06-1.26), and child born SGA (RR per 1-SD increase, 1.04; 95% CI, 1.01-1.06) after adjusting for maternal and pregnancy-related factors. The risks of all outcomes increased with higher AQ-J10 scores; compared with women below the clinical range, women within the clinical range had greater risk of preterm births (RR, 1.16; 95% CI, 1.07-1.26), moderate-to-late preterm births (RR, 1.12; 95% CI, 1.03-1.22), very preterm births (RR, 1.49; 95% CI, 1.18-1.89), and a child born SGA (RR, 1.11; 95% CI, 1.04-1.19). Conclusions and Relevance: In this cohort study, higher level of maternal autistic traits was associated with increased risk of adverse birth outcomes, particularly very preterm birth. Acknowledging the risks and providing tailored and timely antenatal care support to women with a high level of autistic traits in the general population, particularly women with autistic traits within the clinical range, regardless of formal diagnosis, is warranted.

An autopsy case of intravascular large B-cell lymphoma showing a rapid transition to embolic strokes with occlusion of the major cerebral arteries.

Intravascular large B-cell lymphoma can induce central nervous system manifestations, including strokes, due to small-vessel occlusion caused by lymphoma cells. However, involvement in large-sized vessels is rare. Here, we present an unusual autopsy case of an 88-year-old man showing a rapid transition from multiple strokes due to small vessel occlusion, typical of intravascular lymphoma, to progressive embolic strokes caused by the occlusion of major cerebral arteries. Magnetic resonance angiography demonstrated the major cerebral arteries associated with those multiple progressive strokes, including the right posterior cerebral artery, left anterior cerebral artery, and right middle cerebral artery, but the detectability was poor. A random skin biopsy at the abdomen confirmed the diagnosis of intravascular large B-cell lymphoma. The patient died 106 days after hospitalization despite intensive treatment. An autopsy revealed broad liquefactive necrosis in the area governed by the major cerebral arteries and multiple small infarctions caused by intravascular lymphoma cells in the small-sized vessels. In addition, the major cerebral arteries showed multiple thromboembolism with partial organization and clusters of intravascular lymphoma cells. Notably, those cells were shown aggregated and attached along the vascular wall of the basilar artery, which might have caused focal hypercoagulation in the near vessels. This aggregation might have disseminated widely in the other major cerebral arteries. Moreover, the cluster of intravascular lymphoma cells in the basilar artery was positive for tumor necrosis factor α, and similar histopathology findings were observed in the splenic veins. However, the pathogenesis of this rare phenomenon involving these cells remains unknown. From a clinical perspective, we should consider the possibility that intravascular lymphoma cells may provoke similar progressive embolic strokes.

Neurodevelopmental outcomes at age 3 years after moderate preterm, late preterm and early term birth: the Japan Environment and Children's Study.

OBJECTIVE: To assess the association between gestational age classification at birth and the risk of neurodevelopmental impairments at age 3 years. DESIGN: Cohort study using the Japan Environment and Children's Study database. PATIENTS: A total of 86 138 singleton children born without physical abnormalities at 32-41 weeks of gestation enrolled between January 2011 and March 2014. MAIN OUTCOME MEASURES: Neurodevelopmental impairment, evaluated using the Ages and Stages Questionnaire (third edition). METHODS: Logistic regression analysis was used to evaluate the risk of neurodevelopmental impairment in moderate preterm, late preterm and early term children compared with term children after adjusting for socioeconomic and perinatal factors. RESULTS: The respective adjusted ORs (95% CIs) of incidence of scores below the cut-off value (<-2.0 SD) at age 3 years for moderate preterm, late preterm and early term births, compared with full-term births, were as follows: communication, 2.40 (1.54 to 3.73), 1.43 (1.19 to 1.72) and 1.11 (1.01 to 1.21); gross motor, 2.55 (1.69 to 3.85), 1.62 (1.36 to 1.93) and 1.20 (1.10 to 1.30); fine motor, 1.93 (1.34 to 2.78), 1.55 (1.35 to 1.77) and 1.08 (1.01 to 1.15); problem solving, 1.80 (1.22 to 2.68), 1.36 (1.19 to 1.56) and 1.07 (1.00 to 1.14) and personal-social, 2.09 (1.29 to 3.40), 1.32 (1.07 to 1.63) and 1.00 (0.91 to 1.11). CONCLUSION: Moderate preterm, late preterm and early term births were associated with developmental impairment at age 3 years compared with full-term births, with increasing prematurity. Careful follow-up of non-full-term children by paediatricians and other healthcare providers is necessary for early detection of neurodevelopmental impairment and implementation of available intervention.

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.

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.

Clonal Origin and Lineage Ambiguity in Mixed Neuroendocrine Carcinoma of the Uterine Cervix.

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitro and in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state.

Tumor cell-expressed lipolysis-stimulated lipoprotein receptor negatively regulates T-cell function.

Lipolysis-stimulated lipoprotein receptor (LSR) is known as a lipoprotein receptor. LSR is expressed in various solid tumors, including epithelial ovarian, gastric, and colon cancers. High LSR expression is significantly associated with poor prognosis, but its role in cancer has not been fully elucidated. LSR belongs to the Ig protein superfamily, which is conserved in B7 family. Here, we assessed LSR as a novel immune checkpoint molecule. We developed a novel anti-LSR antibody (#27-6 mF-18) that defects antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activity. The #27-6 mF-18 cross-reacts with both human and mouse LSR. We found that LSR was expressed on 4T1 murine breast cancer cell line. The #27-6 mF-18 exhibited antitumor effects against the 4T1 syngeneic tumor model, a poor immunogenic model refractory to treatment with anti-PD-1 or anti-CTLA-4 antibodies. Compared with control antibody-treated mice, mice treated with #27-6 mF-18 showed significantly increased numbers of CD8+ T cells and a ratio of activated CD8+ T cells infiltrated in the tumor tissue. This antitumor effect was abrogated by CD8+ T-cell depletion through anti-CD8 antibody treatment, indicating that LSR negatively regulates tumor immunity by repressing CD8+ T cells. These findings show that LSR negatively regulates T-cell immune activity. LSR targeting could provide immune checkpoint inhibitors for cancer immunotherapy.