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Abstract Background Endometrial cancer (EC) is a common gynecologic malignancy and patients with advanced and recurrent EC have a poor prognosis. Although chemotherapy is administered for those patients, the efficacy of current chemotherapy is limited. Therefore, it is necessary to develop novel therapeutic agents for EC. In this study, we focused on lipolysis-stimulated lipoprotein receptor (LSR), a membrane protein highly expressed in EC cells, and developed a chimeric chicken–mouse anti-LSR monoclonal antibody (mAb). This study investigated the antitumor effect of an anti-LSR mAb and the function of LSR in EC. Methods We examined the expression of LSR in 228 patients with EC using immunohistochemistry and divided them into two groups: high-LSR (n = 153) and low-LSR groups (n = 75). We developed a novel anti-LSR mAb and assessed its antitumor activity in an EC cell xenograft mouse model. Pathway enrichment analysis was performed using protein expression data of EC samples. LSR-knockdown EC cell lines (HEC1 and HEC116) were generated by transfected with small interfering RNA and used for assays in vitro. Results High expression of LSR was associated with poor overall survival (hazard ratio: 3.53, 95% confidence interval: 1.35–9.24, p = 0.01), advanced stage disease (p = 0.045), deep myometrial invasion (p = 0.045), and distant metastasis (p

Girls born in 2001 became eligible for subsidized HPV vaccination when they reached 12 years old in 2013, but that was the year when the Japanese MHLW suspended its official governmental recommendation for HPV vaccination. Those girls will now reach 20 years of age this year, 2021, and they will become eligible for cervical cancer screening. We report on the effects of an educational intervention with an information sheet about their current unvaccinated defenselessness for HPV and the necessity for early and repeated cervical cancer screening as a way to improve their intention to have that screening and their attitude toward HPV vaccination. Among the educated women, 75.2% had a positive intention toward having cervical cancer screening, 24.8% had a negative intention. Educational intervention can significantly promote the intention of having cervical cancer screening in women who had experienced the suspension of the MHLW’s official recommendation for HPV vaccination. As a result of this simple intervention, they were more likely to think that HPV vaccination was needed for themselves.

In Japan, the government’s recommendation for the HPV vaccine has been suspended for almost 8 years. A questionnaire survey was conducted in the Tsubaki Women’s Clinic, Matsuyama, Japan, to examine responses of the mothers of girls eligible for HPV vaccine before and after their doctor provided them an informative leaflet explaining the need for cervical cancer prevention. Among the 53 mothers who admitted to imposing some preconditions before being willing to encourage their daughters’ HPV vaccination, 21 (40%) mothers became more willing to vaccinate their daughters immediately after receiving the cervical cancer prevention linkage explanation provided by their doctor, and seven of the mothers (33%) even returned to the clinic to get their daughter vaccinated during our study period. Logistical regression analysis revealed that having initial preconditions required for their daughters’ HPV vaccination was an independent variable influencing the mothers’ change of willingness to get their daughters vaccinated immediately after receiving the explanation using the leaflet. We have found that to achieve maximum effectiveness, we can use an appropriate leaflet even under suspension of the governmental recommendation. Our future efforts should be focused on those mothers who are less likely to impose preconditions on their daughter’s vaccination.

Abstract Background The retained products of conception (RPOC) and related conditions (RPOC-ARC) are the main cause of secondary postpartum hemorrhage (sPPH), but there is no clear consensus for their management. The purpose of this study was to characterize those RPOC-ARC that require invasive treatment and those that could be managed more conservatively. Methods We retrospectively analyzed 96 cases of RPOC-ARC that occurred after miscarriage, abortion, or delivery at a gestational age between 12 and 42 completed weeks, that were managed within our institution from May 2015 to August 2020. We reviewed the associations between the occurrence of sPPH requiring invasive treatment with clinical factors such as the maternal background and the characteristics of the lesions. Results The range of gestational age at delivery in our study was 12–21 weeks in 61 cases, 22–36 in 5, and 37 or later in 30. Among them, nine cases required invasive procedures for treatment. The onset of sPPH was within one month of delivery in all but two cases, with a median of 24 days (range 9–47). We found significant differences between requirements for invasive versus non-invasive strategies according to gestational age at delivery, assisted reproductive technology (ART) pregnancy, amount of blood loss at delivery, and the long axis of the RPOC-ARC lesion (p = 0.028, p = 0.009, p = 0.004, and p = 0.002, respectively). Multivariate analysis showed that only the long axis of the lesion showed a significant difference (p = 0.029). The Receiver Operating Characteristic (ROC) curve for predicting the need for invasive strategies using the long axis of the lesion showed that with a cutoff of 4.4 cm, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) was 87.5, 90.0, 43.8, and 98.7%, respectively. Conclusion The long axis of the RPOC-ARC is a simple indicator for predicting which sPPH will require invasive procedures, which use is rare in cases with lesions less than 4.4 cm or those occurring after the first postpartum month. Conservative management should be considered in such cases.

In Japan, the governmental recommendation for HPV vaccination was suspended in June 2013 because of media reports of so-called adverse vaccine events. The HPV vaccination rate in Japan prior to this suspension was almost 70%, but fell afterward to almost zero. To explore ways to bolster HPV vaccination, between 2014 and 2019 we conducted three serial surveys of the opinions of obstetricians and gynecologists about HPV vaccination. This study aimed to discuss the changing attitudes found in this 5-year follow-up survey. In August 2014, January 2017, and June 2019, we posted questionnaires to about 570 obstetricians and gynecologists practicing in Osaka, Japan. All three surveys used the same structured and closed-ended questionnaire, including questions about their personal opinions regarding HPV vaccination. We compared our new results to those of the previous two surveys. The response rate for the latest survey was 51.1% (293/573), which was equivalent to the previous two surveys. Among the responders, 83.3% (244/293) now thought that the Japanese government should restart its HPV vaccine recommendation, and 84.6% (248/293) were already recommending HPV vaccines for teenagers in their daily care. Eleven of 30 doctors (36.7%) had their own teenage daughters vaccinated against HPV after the suspension of recommendation. The rate has maintained an increasing trend from the previous two surveys. This study indicated that the attitude of obstetricians and gynecologists in Japan toward HPV vaccination has changed positively over 5 years. The results should serve as an encouragement to resume the governmental recommendation of HPV vaccines.

Human papillomavirus (HPV) vaccine has been used to prevent chronic HPV infection, which accounts for cervical cancer. Japanese Ministry of Health, Labor and Welfare (MHLW) conducted an HPV vaccination campaign in 2010 and the Obstetrical Gynecological Society of Osaka initiated a multicenter, prospective cohort study in Osaka, Japan – OCEAN (Osaka Clinical resEArch of HPV vacciNe) study – to investigate the oncogenic HPV prevalence and the long-term protection rate of HPV vaccine. A total of 2814 participants were enrolled on their visit for HPV vaccination between 12 and 18 years old. Among them, 102 participants received HPV/Pap co-test as primary cancer screening at the age of 20–21. We compared the prevalence in two groups (the vaccinated and the unvaccinated group). HPV infection ratio was significantly lower in the vaccinated group compared to the unvaccinated (12.9% vs. 19.7%; p = .04). In particular, HPV 16 and 18 were not detected in the vaccinated group, while 4.9% of participants in the unvaccinated group were infected (p = .001), suggesting that vaccination provided effective protection against high-risk types of HPV. The cross-protection effect of HPV vaccines was also observed against HPV 31, 45, and 52. Although HPV vaccines were not contributed to the reduction of cervical intraepithelial neoplasia 1 (CIN) (p = .28), CIN2 or worse was not observed in vaccinated group. Our research showed that at the age of 20–21, HPV vaccine inhibited the infection of high-risk HPV and had impacted on the development to CIN2 or worse in Japan.

Preeclampsia is one of the most common as well as most severe complications of pregnancy, characterized by new-onset hypertension and proteinuria or other organ dysfunction. It predominantly occurs after 20 weeks of gestation. Very rarely, it can be triggered earlier in some specific situations. Here we report a case of fetal triploidy presenting as an extraordinarily early-onset preeclampsia. A healthy 36-year-old multiparous woman who had conceived naturally was hospitalized due to acute-onset severe hypertension accompanied by proteinuria at 18 weeks of gestation. Laboratory testing ruled out the presence of underlying maternal disease. Ultrasound findings, including multicystic large placenta and multiple fetal anomalies, strongly suggested fetal triploidy. Maternal ovaries showed hyperreactio luteinalis. The soluble fms-like tyrosine kinase-1/ placental growth factor (sFlt-1/PlGF) ratio was elevated, at 270. Medical abortion was carried out at 19 weeks of gestation; thereafter, her symptoms quickly resolved. Fetal triploidy was confirmed by genetic testing. We should be aware that fetal disorders including triploidy as well as pre-existing maternal diseases can provoke such very early-onset preeclampsia. Fetal ultrasound evaluation is critical and the sFlt-1/PlGF ratio is important for prompt diagnosis and management to prevent adverse maternal outcomes associated with atypical preeclampsia before 20 weeks of gestation.

Summary: Turning non-inflamed (cold) tumors into inflamed (hot) tumors is important for maximizing the effect of immune checkpoint inhibitors (ICIs) against malignancies. We showed that lactate, a product of the Warburg effect, inhibited the efficacy of ICIs and suppressed IL-12 p40 expression in dendritic cells (DCs) through reducing NF-κB p65, p50, and c-Rel DNA-binding activity to the IL-12 p40 promoter. Additionally, lactate promoted the expression of early growth response protein 1 (EGR1), whose expression was increased in human invasive melanoma compared with non-invasive melanoma. We also found that EGR1 interacts with serum response factor (SRF) and represses the expression of CD80 in DCs. These findings suggest that lactate and its induced EGR1 are key factors that turn hot tumors into cold tumors and may represent targets in cancer treatment with ICIs.

In 2013, the Ministry of Health, Labor, and Welfare (MHLW) in Japan announced a suspension of the governmental recommendation for routine HPV vaccinations. In 2020, MHLW started individual notifications of HPV vaccine to the targeted girls. In April 2022, the governmental recommendation was restarted, and catch-up vaccinations started. We evaluated the benefits and limitations of the MHLW’s new vaccination strategies by estimating the lifetime risk for cervical cancer for each birth FY under different scenarios to suggest a measure for the vaccine suspension generation. It was revealed that catch-up immunization coverage among the unvaccinated must reach as high as 90% in FY2022, when the program begins, in order to reduce the risk of the females already over the targeted ages to the same level or lower than that of women born in FY1994-1999 who had high HPV vaccination rates. For women whose vaccination coverage waned because of their birth FYs, strong recommendations for cervical cancer screening should be implemented.

Abstract In Japan, a housing plan has been established involving mainly high‐rise housing and standardization. However, there have been few analyses and studies of the relationship and harmony between people and the natural environment based on the relationship between the residence and the surrounding environment. This paper aims to grasp the environmental perception of residents formed by the arrangement and building plans of settlements, focusing on the resident's residential floor and the location of the dwelling unit, classified as inland side facing land or coastal side facing water. We also explore cognitive characteristics from the constituent and cognitive domain areas of each cognitive domain and perform comparative analysis. Furthermore, we analyze the changes in the cognitive domain caused by vertical displacement of residential floor, aiming to grasp the effect of dwelling unit location and residential floor on formation of environmental perception in high‐rise residences.

Abstract The risk of uterine rupture in subsequent pregnancy is 1%‐12% in patients with prior classical uterine incision. Management of mild/moderate abdominal pain without an obvious abnormal finding before 36 weeks is challenging owing to fetal immaturity.

In Japan, government subsidies for human papillomavirus (HPV) vaccination of girls aged 13–16 commenced in 2010. By early 2013, vaccination had become a widely accepted national immunization program. However, in June of 2013, the Ministry of Health, Labor, and Welfare (MHLW), the government’s lead agency, suspended its recommendation for vaccination in response to reports of adverse vaccine events. The rate of HPV vaccination quickly dropped from 70% to almost zero, where it has lingered for eight years. In 2020, a new 9-valent HPV vaccine was licensed in Japan. The momentum seemed to be building for the resumption of HPV vaccinations, yet Japanese mothers remain widely hesitant about vaccinating their daughters, despite the well-proven safety and efficacy of the HPV vaccines. The Japanese government and our educational and medical institutions must work harder as a team to inform our parents and their children about the life-saving benefits of the HPV vaccine, and at the same time, we must respond to all their concerns and questions. The vaccine hesitancy of unvaccinated women born in 2000 and thereafter is a natural consequence of the suspension of the government‘s recommendation. We must also take every possible measure to reduce the significant risk for cervical cancer these women have.

We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological “cold tumor” to “hot tumor”.

Squamous cell carcinoma (SCC) accounts for approximately 95% of the malignant tumors of the vaginal vulva and is mostly found in elderly women. The future numbers of patients with vulvar SCC is expected to rise, mainly because of the proportional increase in the average age of the general population. Two different pathways for vulvar SCC have been put forth. The first pathway is triggered by infection with a high-risk-type Human Papillomavirus (HPV). Integration of the HPV DNA into the host genome leads to the development of a typical vulvar intraepithelial neoplasia (VIN), accompanied with overexpression of p14ARF and p16INK4A. This lesion subsequently forms a warty- or basaloid-type SCC. The HPV vaccine is a promising new tool for prevention of this HPV related SCC of the vulva. The second pathway is HPV-independent. Keratinizing SCC develops within a background of lichen sclerosus (LS) through a differentiated VIN. It has a different set of genetic alterations than those in the first pathway, including p53 mutations, allelic imbalances (AI), and microsatellite instability (MSI). Further clinical and basic research is still required to understand and prevent vulvar SCC. Capsule. Two pathway for pathogenesis of squamous cell carcinoma of the value are reviewed.

Combination therapy with BRAF and MEK inhibitors (BRAF/MEKi) has shown significantly prolonged progression-free survival (PFS) and overall survival (OS) for BRAF mutated melanoma. Over 90% of the activating mutations are BRAFV600E or BRAFV600K changes. There are no reports of BRAFV600R in Japanese patients with melanoma. The third most common BRAF mutation is BRAFV600R. In this case, we detected the BRAFV600R mutation with FoundationOne CDx in a Japanese patient with melanoma.. The patient was treated with BRAF/MEKi and maintained stable disease status for 1 year. [ABSTRACT FROM AUTHOR]

We analyzed the clonality and human papillomavirus (HPV) infection status of concurrent glandular and squamous lesions and adenosquamous carcinomas of the uterine cervix to clarify their histogenesis. The glandular and squamous components were clonally different from each other in 7 informative concurrent lesions. HPV was episomal in 2 polyclonal glandular dysplasias (GDs). HPV was in a mixed integrated-episomal form in a monoclonal GD, an adenocarcinoma in situ, and an adenocarcinoma. Both tumor components were monoclonal in origin in 6 adenosquamous carcinomas, with identical patterns of X-chromosomal inactivation and types and physical status of HPV. These results imply that the concurrent glandular and squamous lesions are formed separately, whereas adenosquamous carcinoma is more likely to be a combination tumor of monoclonal origin, and that integration of HPV has an important role in the progression from polyclonal GD through monoclonal expansion to adenocarcinoma in situ and adenocarcinoma. [ABSTRACT FROM AUTHOR]

A 54-year-old woman, who was severely malnourished and awaiting lung transplantation for chronic respiratory failure, was given nutritional support by home parenteral nutrition (HPN). The patient’s emaciated state was further compromised by the fact that she had undergone a distal gastrectomy 4 years earlier. We decided that HPN was indicated because her oral intake was so poor and drinking enteral formula reduced her appetite. After 1 year of HPN, her body weight increased and her nutritional, anthropometric, and biochemical values were well maintained by the time of transplantation. Moreover, her progress after lung transplantation was remarkably good, indicating the effectiveness of nutritional support by HPN during the protracted waiting period. [ABSTRACT FROM AUTHOR]

Purpose. While many retrospective and prospective observational studies have shown laparoscopic surgery to be less invasive than conventional open surgery, this issue has not been evaluated by objective parameters. Currently available clinical parameters, such as the day of first ambulation, the day food intake is commenced, and the length of postoperative hospital stay, are subjective. The purpose of this study was to investigate whether measuring postoperative physical activity with an accelerometer is a useful parameter for evaluating postoperative recovery after surgical stress. Methods. The subjects included 20 patients who underwent laparoscopic partial gastrectomy (LPG group), 35 patients who underwent open distal gastrectomy (ODG group), and 20 patients who underwent open total gastrectomy (OTG group). The cumulative acceleration of voluntary movement, measured by an Active tracer AC-301 (ACT) accelerometer for 7 days postoperatively, was compared among these three groups. Results. The cumulative acceleration of physical activity for 24?h was significantly better in the LPG group than in the ODG and OTG groups on each postoperative day. The recovery time, defined as the day that cumulative acceleration had recovered to more than 90% of the preoperative level, was significantly shorter in the LPG group (2.8 ? 0.9 days) than in the ODG (6.6 ? 2.1 days) and OTG (7.8 ? 1.2 days) groups. Conclusion. These results showed that convalescence differed with the degree of surgical stress, and that measurement of the cumulative acceleration of voluntary movement by using an accelerometer could be a useful objective and quantitative parameter for evaluating postoperative recovery. [ABSTRACT FROM AUTHOR]

Previous reports proposed the concept and criteria of epidermotropic metastatic malignant melanoma (EMMM): (a) dermal involvement equal to or broader than the epidermal involvement, (b) atypical melanocytes within the dermis, (c) thinning of the epidermis, (d) widening of the papillary dermis with an epithelial collarette, and (e) vascular invasion of atypical melanocytes. However, it remains unclear whether EMMM also involves the mucosal epithelium. In this case, the patient was diagnosed with EMMM based on the histopathological findings of the patient's multiple skin lesions and clinical course. The patient also developed metastasis to the hypopharynx. Although histopathological findings of the lesion suggested the possibility of melanoma in situ, as the lesion included atypical melanocytes in the mucosal epithelium, the clinical course supported the diagnosis of hypopharyngeal metastasis from EMMM. This case suggests that EMMM may have epitheliotropic features not only in the skin but also in the mucosa. [ABSTRACT FROM AUTHOR]

Methyl-CpG binding domain protein 3 (MBD3) belongs to the methyl-CpG binding protein family. MBD3 facilitates the initiation of neural stem cell reprogramming. Melanoma originates in melanocytes derived from neural crest stem cells; therefore, we investigated the role of MBD3 in melanoma. MBD3 was overexpressed in melanoma compared with pigmented nevi. MBD3 knockdown had no effect on the proliferation of melanoma cells (A375 and A2058 cells). Contrarily, it significantly reduced the migration and invasion of A375 cells, but had no significant effect on A2058 cells. Furthermore, MBD3 knockdown reduced N-cadherin protein levels and matrix metalloproteinase-2 (MMP-2) activity in A375 cells, but had no significant effect on A2058 cells. Based on these results, the MBD3 expression level may be a useful biomarker for the diagnosis of melanoma. Thus, MBD3 has potential as a novel therapeutic target for some melanoma patients. [ABSTRACT FROM AUTHOR]