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.

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.

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.

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.

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.

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.

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.

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.

Effectiveness of catch-up and routine program of the 9-valent vaccine on cervical cancer risk reduction in Japan.

In 2013, the national human papillomavirus (HPV) immunization program began. However, in June 2013, Japan's Ministry of Health, Labor and Welfare (MHLW) announced a "temporary" suspension of its recommendation for the human papillomavirus vaccine. Finally, in November 2021, the MHLW ended its suspension of the recommendation of the HPV vaccine. To address the 9-year gap in HPV vaccinations the suspension had caused, the MHLW conducted a program of catch-up vaccinations from April 2022 to March 2025. Finally, in April 2023, the 9-valent HPV vaccine was approved for both the routine and catch-up vaccination programs in Japan. In this study, we investigated the potential effects of the introduction of the 9-valent vaccine on the increased risk of cervical cancer in females born after fiscal year (FY) 2000. We estimated the lifetime relative risk of cervical cancer incidence and death using the improved routine and catch-up vaccination rates after the recent resumption of the governmental recommendation for women and girls to have the HPV vaccination. These relative risks were calculated using a lifetime risk of 1.000 for cervical cancer incidence and death for females born in FY 1993. We predicted that even if a 90% vaccination rate were to be achieved by FY 2024 with the 9-valent vaccine among women born between FY 2000 and FY 2005, the risk would remain higher than for the vaccination generation. Therefore, for women born between FY 2000 and FY 2005, it will be necessary to significantly improve the cervical cancer screening rate to compensate for this increased risk.

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.

Intentions for catch-up HPV vaccination in Japan: an internet survey.

PURPOSE: In Japan, Japan's Ministry of Health, Labor, and Welfare decided to suspend govermental recommendation for HPV vaccination in FY 2013. The HPV vaccination rate for those born in FY 2000 or thereafter declined dramatically. In 2021, the "suspension of recommendation" ended. The catch-up vaccinations for the unvaccinated have been offered nationwide from FY 2022 to FY 2024. We aimed to quantify the vaccination intentions and characteristics of those young women now eligible for catch-up vaccination.  METHODS: In February of 2022, we conducted an internet survey targeted women who were born in 1997-2004 but who had not yet been HPV vaccinated. RESULTS: We received 1,648 valid responses. 41.6% of the respondents wanted to uptake the catch-up HPV vaccination, 29.7% were undecided, and 28.7% did not want to be vaccinated. The intention to uptake catch-up HPV vaccination was associated with a good history of gynecological visits, intention to receive cervical cancer screening, sexual activity, degree of anxiety about cervical cancer, familiarity with problems associated with cervical cancer, experience with vaccination recommendations, and knowledge about cervical cancer (p < 0.05, respectively). In the vaccinated generation, the proportion of the group that did not want to be vaccinated was significantly higher (p < 0.05). In the vaccine-suspended generation, the proportion of the group that wanted to be vaccinated was significantly higher (p < 0.05). CONCLUSION: Our survey revealed that catch-up vaccination intentions differed depending on the vaccination environment. It is necessary for all organizations involved with HPV vaccination, such as government, medical institutions, and educational institutions, to make recommendations based on an understanding of the characteristics of the "vaccinated generation" and the "vaccine-suspended generation".

Prenatal exposure to selenium, mercury, and manganese during pregnancy and allergic diseases in early childhood: The Japan Environment and Children's study.

BACKGROUND: Prenatal exposure to metallic elements may adversely affect early childhood health. However, more evidence is needed as population-based cohort studies are currently limited. OBJECTIVES: We aimed to examine the associations between prenatal metallic (mercury, selenium, and manganese) exposure and the risk of allergic diseases in early childhood until three years of age. METHODS: The data from 94,794 mother-infant pairs, who participated in the Japan Environment and Children's study, were used in this study. Prenatal metallic element exposure was measured in maternal blood collected during mid-pregnancy. The incidence of atopic dermatitis, food allergies, asthma, and allergic rhinitis during the first three years of life was prospectively investigated using self-reports of physician-diagnosed allergies. A multivariable modified Poisson regression model was used to estimate the cumulative incidence ratio and their 95% confidence intervals of allergic diseases associated with prenatal exposure to mercury, selenium, and manganese. We further evaluated the interaction between mercury and selenium exposures in this association. RESULTS: We confirmed 26,238 cases of childhood allergic diseases: atopic dermatitis, food allergies, asthma, and allergic rhinitis in 9,715 (10.3%), 10,897 (11.5%), and 9,857 (10.4%), 4,630 (4.9%), respectively. No association was found between prenatal mercury or manganese exposure and the risk of allergic diseases. Prenatal selenium exposure was inversely associated with atopic dermatitis, food allergies, allergic rhinitis, and any allergic diseases, but not with asthma. These inverse associations were more pronounced for lower mercury exposures than for higher exposures. CONCLUSIONS: Our findings suggest that prenatal exposure to selenium may be beneficial for reducing the risk of atopic dermatitis, food allergies, allergic rhinitis, and any allergic diseases in early childhood, especially with lower prenatal mercury exposure.

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.

Intracorporeal colpotomy using the Gutclamper as a novel clamping device to prevent tumor spillage during laparoscopic radical hysterectomy for cervical cancer.

INTRODUCTION: Tumor cell spillage during the colpotomy has been suspected as one reason for poor oncologic outcomes in laparoscopic radical hysterectomy (LRH) for cervical cancer. To prevent such tumor spillage in LRH, we focused on use of a Gutclamper which is a device originally designed to clamp the colon and rectum during colorectal resections. MATERIALS AND SURGICAL TECHNIQUE: A woman with stage IB1 cervical cancer underwent LRH using the Gutclamper. The Gutclamper was inserted into the abdominal cavity via 5-mm trocar, the vagina was clamped, and an intracorporeal colpotomy was performed caudal to this device. DISCUSSION: The Gutclamper can be used to clamp the vaginal canal and avoid the exposure of cervical tumor, regardless of the surgeon's skills or patient conditions. An intracorporeal colpotomy using the Gutclamper can contribute to the standardization of LRH.

A questionnaire survey on the prevention of HPV infection among females and males who came of age in Japan under various scenarios of HPV vaccine recommendation.

The Japanese Ministry of Health, Labor and Welfare (MHLW) temporarily suspended recommendation for HPV vaccinations for girls in June 2013. It resumed its recommendation in November 2021. To compensate for eight years of lost overage, a 'catch-up HPV vaccination' program began in April 2022. To determine intervention needs in regards to HPV vaccine hesitancy, from October 13 2021 to April 31 2022, we surveyed 12-28 year-old vaccine-eligible males and females (281 males, 583 females). We investigated the gender and 'vaccine generational' differences in attitudes, perceptions, and future intentions regarding HPV vaccination. Two generations were defined by the vaccine recommendation environment they grew up in. The 'vaccine generation' was born in FY 1994-1999; the 'vaccine-suspension generation' born in FY 2000-2009. Knowledge regarding the HPV vaccine correlated significantly with being female, of the vaccination generation, a medical student, and having received the COVID-19 vaccine. There was a significant 'generational' difference in terms of approval of the MHLW's recommendation resumption. The attitudes, perceptions, and future intentions of Japan's two generation groups are unique and should be dealt with accordingly. HPV vaccination promotion should consider the strong gender differences we identified. As an extension of the anti-cervical cancer program, HPV vaccinations for boys should begin immediately. Our study of their unique outlooks will contribute to the discussion surrounding that implementation.

Continuous Administration of Anti-VEGFA Antibody Upregulates PAI-1 Secretion from Ovarian Cancer Cells via miR-143-3p Downregulation.

Although bevacizumab (BEV) plays a key role in ovarian cancer treatment, BEV resistance is often observed in clinical settings. This study aimed to identify the genes responsible for BEV resistance. C57BL/6 mice inoculated with ID-8 murine ovarian cancer cells were treated with anti-VEGFA antibody or IgG (control) twice weekly for 4 weeks. The mice were sacrificed, then, RNA was extracted from the disseminated tumors. qRT-PCR assays were performed to identify angiogenesis-related genes and miRNAs that were altered by anti-VEGFA treatment. SERPINE1/PAI-1 was found to be upregulated during BEV treatment. Therefore, we focused on miRNAs to elucidate the mechanism underlying the upregulation of PAI-1 during BEV treatment. Kaplan-Meier plotter analysis revealed that higher expression levels of SERPINE1/PAI-1 were associated with poor prognoses among BEV-treated patients, suggesting that SERPINE1/PAI may be involved in the acquisition of BEV resistance. miRNA microarray analysis followed by in silico and functional assays revealed that miR-143-3p targeted SERPINE1 and negatively regulated PAI-1 expression. The transfection of miR-143-3p suppressed PAI-1 secretion from ovarian cancer cells and inhibited in vitro angiogenesis in HUVECs. Next, miR-143-3p-overexpressing ES2 cells were intraperitoneally injected into BALB/c nude mice. ES2-miR-143-3p cells downregulated PAI-1 production, attenuated angiogenesis, and significantly inhibited intraperitoneal tumor growth following treatment with anti-VEGFA antibody. Continuous anti-VEGFA treatment downregulated miR-143-3p expression, which upregulated PAI-1 and activated an alternative angiogenic pathway in ovarian cancer. In conclusion, the substitution of this miRNA during BEV treatment may help overcome BEV resistance, and this may be used as a novel treatment strategy in clinical settings. IMPLICATIONS: Continuous administration of VEGFA antibody upregulates SERPINE1/PAI-1 expression via the downregulation of miR-143-3p, which contributes to acquiring bevacizumab resistance in ovarian cancer.