Three-year questionnaire study on human papillomavirus vaccination targeting new female college school students: Follow-up to a 2021 report to reveal the impact of a policy change in Japan.

AIM: The purpose of this study was to examine the trend in human papillomavirus (HPV) vaccination rates in Japan before and after a policy change in 2022, involving resumption of active recommendation and start of catch-up vaccination. METHODS: From 2021 to 2023, a web-based questionnaire survey was administered to newly enrolled female college students in Yokohama, Japan. The questionnaire included items such as age, HPV vaccination status, HPV vaccine awareness, and awareness of catch-up vaccination. We compared knowledge about the HPV vaccine and cervical cancer in 2021 and 2023, before and after resumption of the national vaccination program. RESULTS: The HPV vaccination rates were 5.4% in 2021, 7.5% in 2022, and 35.3% in 2023, with a significant upward trend (p < 0.001). A similar upward trend was observed for HPV vaccine awareness (p < 0.001). Comparing 2022 and 2023 after the start of catch-up vaccination, there was no significant difference in awareness of catch-up vaccination (p = 0.669), but there was a significant increase in awareness of free vaccination tickets (p < 0.001). After resumption of the national vaccination program with adoption of the catch-up vaccination program, there was no difference in knowledge of cervical cancer, but there was a difference in knowledge of the HPV vaccine. CONCLUSIONS: Although the HPV vaccination rate has increased after the policy change, it has not recovered to the level before the suspension of active recommendation. It is important for healthcare providers and school educators to actively communicate the safety and effectiveness of the HPV vaccine.

Human Papillomavirus Vaccination by Birth Fiscal Year in Japan.

Importance: The Ministry of Health, Labour, and Welfare (MHLW) of Japan aggregates human papillomavirus (HPV) vaccination data across Japan for each fiscal year (FY) by age at vaccination. Birth FY (BFY)-specific vaccination coverage remains unknown. Objective: To calculate the BFY-specific vaccination coverage for each FY and the cumulative first-dose coverage for each BFY in Japan, to understand the generation-specific vaccination coverage, and to estimate the cumulative first-dose coverage of each BFY that would be achieved by FY 2028 vs World Health Organization (WHO) targets. Design, Setting, and Participants: In this cross-sectional study, MHLW-published national age-specific HPV vaccination numbers and demographic data for female individuals were used to calculate the BFY-specific first-dose coverage for each FY and the BFY-specific cumulative first-dose coverage. It was assumed that the BFYs 2007 to 2012 vaccination coverage in FY 2023 to 2028 would remain the same as the vaccination coverage of the same grade in FY 2022 to estimate the cumulative first-dose coverage that would be achieved by FY 2028. Data analysis was performed from December 2023 to January 2024. Exposure: Two MHLW policy changes were the government's suspension of proactive recommendation for HPV vaccination in June 2013 and the government's resumption of proactive recommendation for HPV vaccination in April 2022. Main Outcomes and Measures: The primary outcome was generation-specific vaccination coverage among female individuals born in BFYs 1994 to 2010 in FYs 2010 to 2022, calculated using reconfigured published data. Results: In this study of vaccination data for 9 414 620 female individuals, the generation-specific vaccination coverage was 71.96% for the vaccination generation (BFYs 1994-1999), 4.62% for the vaccine-suspension generation (BFYs 2000-2003), 16.16% for the generation that received information individually (BFYs 2004-2009), and 2.83% for the vaccine-resumed generation (BFY 2010). HPV routine vaccination coverage was extremely low in BFYs 2000 to 2010 (0.84%-25.21%) vs BFYs 1994 to 1999 (53.31%-79.47%). The cumulative first-dose coverage that was estimated to be achieved in the vaccine-resumed generation by FY 2028 plateaued at 43.16%. Conclusions and Relevance: Even after the resumption of MHLW's proactive recommendations, HPV vaccination coverage has only minimally recovered in Japan. The cumulative first-dose coverage that was estimated to be achieved in the vaccine-resumed generation by FY 2028 is below the WHO target. These findings reveal that stronger cervical cancer control measures are required, particularly for the vaccine-resumed generation, which will plateau at approximately one-half the WHO target values.

Estimation of self-funded human papillomavirus vaccine recipients from Japan's previously assumed "unvaccinated generation".

Precise vaccination data is essential to accurately estimate the effectiveness of the human papillomavirus (HPV) vaccine against HPV-related cancers. In Japan, the number of subsidized HPV vaccinations can be tracked through registries, but the number of self-funded vaccinations has not been tracked. The number of individuals who chose to receive the vaccine at their own expense, despite being ineligible for public subsidies due to their age, is unknown and has been nominally considered to be zero. Our aim is to produce a more accurate estimate of this number using recently released proprietary data. First, we estimated the total number of self-funded HPV vaccinations occurring from 2010 to 2012 using public data from the Ministry of Health, Labour and Welfare and our previously reported data on the number of HPV vaccinations eligible for public subsidy. Second, using proprietary data from the vaccine manufacturer, we calculated the distribution of self-funded vaccination shots by age. Finally, we combined these data to estimate the number of self-funded HPV vaccinations by birth fiscal year (FY) relative to a yearly reference population. We found that 78,264 individuals born in FY1993 and 58,190 born in FY1992 self-funded their vaccinations, representing 13.6% and 10.0% of the reference population, respectively. Additionally, we found that 5%-10% of individuals born from FY1986 to FY1991 self-funded their vaccinations. Our study revealed for the first time that a certain number of individuals from the "HPV unvaccinated generation," ineligible for subsidies due to age restrictions, chose to self-fund their vaccinations.

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.

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.

Epidemiology of cervical cancer and HPV infection in Asia and Oceania.

Cancer will continue to be a major source of morbidity and mortality globally during the foreseeable future. Human papillomavirus (HPV)-related cancer is now a serious problem in both women and men. The most common HPV-related cancer is cervical cancer in females and oropharyngeal cancer in males. Eastern Africa has a high age-standardized incidence of HPV-related cancers, followed in order by Southern Africa, Central Africa, and then the rest of Africa. Among Asian and Oceania countries, Fiji, Papua New Guinea, Solomon Islands, Indonesia, Maldives, and Myanmar have extremely high age-standardized incidences and mortality. Oropharyngeal cancer is less common than cervical cancer, but the age-standardized incidence, for both females and males, is higher in Western Europe, Northern Europe, North America, and Australia/New Zealand. Oropharyngeal cancer incidence rates differ significantly from the rates of cervical cancer within the same countries. In Asia and Oceania, the incidence of oropharyngeal cancer is particularly high among females in Bhutan, Bangladesh, and Australia, and it is highest among males in Bangladesh, New Caledonia, Australia, and French Polynesia. To a certain extent, cervical cancer can be reduced through the development of cervical screening programs and improvements in screening uptake. On the other hand, for oropharyngeal cancer, as of yet, no effective means of cancer screening has been established. Widespread uptake of HPV vaccine will contribute to the reduction of HPV-related cancers in Asia and Oceania, but also in the rest of the world.

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.

Proposal for Classifying the Emetogenicity of Oral Anticancer Agents with a Focus on PARP Inhibitors: A Prospective, Observational, Multicenter Study (JASCC-CINV 2002).

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary.

Suppressed pediatric asthma hospitalizations during the COVID-19 pandemic in Japan, from a national survey.

BACKGROUND: Acute asthma exacerbation in children is often caused by respiratory infections. In this study, a coordinated national surveillance system for acute asthma hospitalizations and causative respiratory infections was established. We herein report recent trends in pediatric acute asthma hospitalizations since the COVID-19 pandemic in Japan. METHODS: Thirty-three sentinel hospitals in Japan registered all of their hospitalized pediatric asthma patients and their causal pathogens. The changes in acute asthma hospitalization in children before and after the onset of the COVID-19 pandemic and whether or not COVID-19 caused acute asthma exacerbation were investigated. RESULTS: From fiscal years 2010-2019, the median number of acute asthma hospitalizations per year was 3524 (2462-4570), but in fiscal years 2020, 2021, and 2022, the numbers were 820, 1,001, and 1,026, respectively (the fiscal year in Japan is April to March). This decrease was observed in all age groups with the exception of the 3- to 6-year group. SARS-CoV-2 was evaluated in 2094 patients from fiscal years 2020-2022, but the first positive case was not detected until February 2022. Since then, only 36 of them have been identified with SARS-CoV-2, none of which required mechanical ventilation. Influenza, RS virus, and human metapneumovirus infections also decreased in FY 2020. In contrast, 24% of patients had not been receiving long-term control medications before admission despite the severity of bronchial asthma. CONCLUSION: SARS-CoV-2 was hardly detected in children with acute asthma hospitalization during the COVID-19 pandemic. This result indicated that SARS-CoV-2 did not induce acute asthma exacerbation in children. Rather, infection control measures implemented against the pandemic may have consequently reduced other respiratory virus infections and thus acute asthma hospitalizations during this period. However, the fact that many hospitalized patients have not been receiving appropriate long-term control medications is a major problem that should be addressed.

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.

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.

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.