Yutaka Ueda

Prognostic factors of lenvatinib plus pembrolizumab therapy for advanced or recurrent endometrial cancer: analysis of a multicenter cohort study in Japan

Abstract Background Lenvatinib plus pembrolizumab (LP) therapy has emerged as an effective treatment for patients with advanced or recurrent endometrial cancer. However, limited data are available regarding its outcomes in real-world settings. This study aimed to identify prognostic factors associated with the efficacy of LP therapy. Methods This multicenter observational study was conducted across 15 institutions in Japan and examined patients with endometrial cancer, including uterine carcinosarcoma, who experienced disease progression after receiving at least one platinum-based chemotherapy, including adjuvant treatment, and subsequently received LP therapy. The prognostic factors for progression-free survival were assessed using a multivariate Cox proportional hazards model. Results A total of 105 patients met the inclusion criteria. Improved progression-free survival was independently associated with performance status of 0 (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.23–0.75), platinum-free interval (PFI) of ≥ 6 months (aHR 0.46, 95% CI 0.28–0.78), histology of grade 1–2 endometrioid carcinoma (aHR 0.52, 95% CI 0.30–0.91), and relative dose intensity during the initial 8 weeks (8w-RDI) of lenvatinib of ≥ 50% (aHR 0.53, 95% CI 0.31–0.91). Patients with PFI of ≥ 6 months also demonstrated improved overall survival (HR 0.44, 95% CI 0.25–0.76) and objective response rate (44.0% versus 20.0%, P  = 0.011) compared with those with PFI of < 6 months. Additionally, 8w-RDI of lenvatinib ≥ 50% was associated with improved overall survival (HR 0.53, 95% CI 0.30–0.92) compared to those with < 50%. Conclusions This study identified several novel prognostic factors for LP therapy. Among them, PFI may inform treatment selection for recurrent endometrial cancer following chemotherapy. Clinical trial registration University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 000049997.

The value of vaginal cytology for postoperative surveillance of endometrial cancer

The value of conducting vaginal cytology surveillance after endometrial cancer (EC) surgery has not been fully established, yet in Japan it is still performed routinely in many institutions. We have retrospectively examined its diagnostic and prognostic values. We studied 759 EC cases that underwent hysterectomy at our hospital in Osaka, Japan from January 2010 to December 2019. Information on the clinicopathological factors at the time of initial and postoperative treatments, and the sites and diagnostic timing of recurrences were extracted from medical records and analyzed. Recurrences from primary EC were observed in 11.2% of the patients (85/759). In 23.5% of the cases (20/85), the recurrence included a vaginal component. The two most common single-sites of recurrence were vagina (14.1%, 12/85) and lung (12.9%, 11/85). The diagnosis of vaginal recurrence was made from symptoms and gynecological examination in 14 of the 20 cases. Only one was diagnosed solely by vaginal cytology; in that case, macroscopic lesions appeared two months after obtaining the abnormal cytology. We found that, in postoperative follow-up surveillance for EC, most cases of vaginal recurrence were first diagnosed by a careful pelvic examination. For current routine postoperative practice, monitoring critical symptoms and conducting careful gynecological examinations has been shown to be more important than cytological examinations.

Adjuvant Chemotherapy for Endometrial Cancer (ACE) trial: A randomized phase II study for advanced endometrial carcinoma

AbstractThis study evaluated the feasibility and efficacy of three postoperative adjuvant chemotherapy regimens for endometrial cancer. Endometrioid cancer patients with intermediate‐risk stage I and II or high‐risk stage III and IV disease were randomly assigned to receive six cycles of either paclitaxel‐epirubicin‐carboplatin (TEC), paclitaxel‐anthracycline (doxorubicin)‐carboplatin (TAC), or dose‐dense paclitaxel‐carboplatin (ddTC). The primary end‐point was the completion rate (CRate) of six cycles of treatment. The secondary end‐points were progression‐free survival (PFS) and overall survival (OS). One hundred and one patients were treated as follows: 33 received TEC, 33 TAC, and 35 ddTC. The CRates for TEC, TAC, and ddTC were 94%, 64%, and 69%, respectively (P = .005). The TEC CRate was significantly higher than for the other two groups. However, the PFS and OS outcomes were not statistically different between the three groups. The 2‐year survival rates were 94%, 97%, and 97% for TEC, TAC, and ddTC, respectively. When compared to the current standard treatments for endometrial cancer, TEC is a promising candidate for a phase III trial based on its significantly superior CRate and equivalent PFS and OS. This study is registered with UMIN Clinical Trials Registry (UMIN000008911).

VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix

ABSTRACT Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high‐grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia‐related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient‐derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two‐dimensional cultures, it significantly suppressed cell proliferation in three‐dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA‐sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial‐related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear‐encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti‐tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.

SLFN11 is a BRCA Independent Biomarker for the Response to Platinum-Based Chemotherapy in High-Grade Serous Ovarian Cancer and Clear Cell Ovarian Carcinoma

Abstract BRCA1/2 mutations are robust biomarkers for platinum-based chemotherapy in epithelial ovarian cancers. However, BRCA1/2 mutations in clear cell ovarian carcinoma (CCC) are less frequent compared with high-grade serous ovarian cancer (HGSC). The discovery of biomarkers that can be applied to CCC is an unmet need in chemotherapy. Schlafen 11 (SLFN11) has attracted attention as a novel sensitizer for DNA-damaging agents including platinum. In this study, we investigated the utility of SLFN11 in HGSC and CCC for platinum-based chemotherapy. SLFN11 expression was analyzed retrospectively by IHC across 326 ovarian cancer samples. The clinicopathologic significance of SLFN11 expression was analyzed across 57 advanced HGSC as a discovery set, 96 advanced HGSC as a validation set, and 57 advanced CCC cases, all of whom received platinum-based chemotherapy. BRCA1/2 mutation was analyzed using targeted-gene sequencing. In the HGSC cohort, the SLFN11-positive and BRCA mutation group showed significantly longer whereas the SLFN11-negative and BRCA wild-type group showed significantly shorter progression-free survival and overall survival. Moreover, SLFN11-positive HGSC shrunk significantly better than SLFN11-negative HGSC after neoadjuvant chemotherapy. Comparable results were obtained with CCC but without consideration of BRCA1/2 mutation due to a small population. Multivariate analysis identified SLFN11 as an independent factor for better survival in HGSC and CCC. The SLFN11-dependent sensitivity to platinum and PARP inhibitors were validated with genetically modified non-HGSC ovarian cancer cell lines. Our study reveals that SLFN11 predicts platinum sensitivity in HGSC and CCC independently of BRCA1/2 mutation status, indicating that SLFN11 assessment can guide treatment selection in HGSC and CCC.

Even though active recommendation for HPV vaccination has restarted, Japan's rates have not recovered

AbstractJapan 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.

Epidemiology of cervical cancer and HPV infection in Asia and Oceania

AbstractCancer 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.

A nationwide birth year‐by‐year analysis of effectiveness of HPV vaccine in Japan

AbstractIn Japan, the age‐adjusted incidence of cervical cancer has been increasing constantly and rapidly among younger women. We set out to accurately confirm the effectiveness of the HPV vaccine in Japan. Data were collected for women born in the fiscal year (FY) 1990 to 1997, who became eligible for their 20‐y‐old cervical cancer screening between the FY 2010 to 2017. The adjusted incidence of cervical intraepithelial neoplasia (CIN)1+ in women born in FY 1990 to 1993, that is those who reached the national vaccination target age prior to the introduction of publicly subsidized HPV vaccinations, referred here after as “the pre‐introduction generation”, was 1.42% (242/17 040). The incidence in the “vaccination generation” (women born in FY 1994 to 1997, that is those who were heavily vaccinated as a group when they were of the nationally targeted age of 13‐16) was 1.66% (135/8020). There was no significant difference between these incidence rates. However, our FY birth year‐by‐year analysis revealed that the incidence of CIN1+ was obviously lower than that predicted based on just the trend for CIN1+ seen in the pre‐introduction generation. Our analysis revealed that the incidence of CIN3+ was obviously lower in the vaccination generation than in the pre‐introduction generation (P = .0008). The incidence of CIN was already tending to increase in both the pre‐introduction and vaccination generations. The changes in CIN incidence by individual birth FY must be examined to accurately determine the actual effects of the HPV vaccine for reducing mild cervical lesions.

Trends and future projections of cervical cancer‐related outcomes in Japan: What happens if the HPV vaccine program is not implemented?

AbstractContrary to other developed countries, in Japan, recent years have seen increases in cervical cancer incidence and mortality among young people. However, the human papillomavirus (HPV) vaccine program, a key measure for avoiding cervical cancer, has been virtually suspended. Temporal changes in cervical cancer profiles in this unique situation have not been fully investigated epidemiologically. Our study aimed to determine the current status and future trends of the incidence and mortality of cervical cancer and precancerous lesions in Japan. Mortality rates of cervical cancer during 1975 to 2016 and incidence rates of cervical cancer and cervical intraepithelial neoplasia (CIN) 3 during 1975 to 2013 were examined using vital statistics and population‐based cancer registry data in Japan. Bayesian age‐period‐cohort analyses were performed to analyze temporal changes of the three cervical cancer‐related outcomes. We also calculated projections to 2028 for the three outcomes, assuming that HPV vaccination coverage and screening rates in Japan would be maintained at the current level after the resumption of the national vaccination program. The risk of occurrence of the three outcomes showed similar changes by birth cohort, peaking in the mid‐1890s to 1900s birth cohorts, declining sharply in the 1940s birth cohort, and persistently increasing in the 1950s and later birth cohorts. Projections to 2028 show increases in cervical cancer incidence and mortality in the 30 to 69 age group, with a particular increase in CIN3 incidence in the 25 to 49 age group, if HPV vaccine programs and screening are not effectively implemented. These findings revealed an increasing cervical disease burden among reproductive age females in Japan.

Overview of laparoscopic surgery for cervical cancer in Japan: Updates after the laparoscopic approach to cervical cancer trial

AbstractLaparoscopic radical hysterectomy (LRH) for cervical cancer has been reported to be similar oncologic outcome compared to abdominal radical hysterectomy (ARH) in many retrospective studies. In Japan, LRH has been covered by insurance since April 2018. In 2018, the same year that LRH became covered by insurance, Ramirez et al. at MD Anderson Cancer Center reported the results of a large phase III laparoscopic approach to cervical cancer trial (LACC trial) on the prognosis of open versus laparoscopic/robot‐assisted minimally invasive radical hysterectomy. The results showed that minimally invasive approaches were associated with a higher rate of recurrence and death. At this point, it is not clear what is wrong with LRH and why it has a poorer prognosis compared to ARH. In this report, after the LACC report, we would like to review the current status of minimally invasive surgery for cervical cancer and future directions.

Effectiveness of human papillomavirus vaccine against cervical precancer in Japan: Multivariate analyses adjusted for sexual activity

AbstractJapanese girls aged 12–16 years are offered free human papillomavirus (HPV) vaccination and cervical cancer screening is conducted with cytology and not HPV testing from the age of 20 years. So far, no study has analyzed the effect of HPV vaccination against cervical precancers considering HPV infection status and sexual activity. We aimed to analyze the vaccine effectiveness (VE) against HPV infection and cytological abnormalities, adjusted for sexual activity. This study comprised women aged 20–26 years who underwent cervical screening in Niigata. We obtained HPV vaccination status from municipal records and a questionnaire along with information concerning sexual activity. Of 5194 women registered for this study, final analyses included 3167 women in the vaccinated group (2821 vaccinated women prior to sexual debut) and 1386 women in the unvaccinated group. HPV 16/18 (0.2% vs 3.5%), 31/45/52 (3.4% vs 6.6%), and 31/33/45/52/58 (5.0% vs 9.3%) positive rates were significantly lower in the vaccinated group (P < 0.001). No women vaccinated before sexual debut had HPV 16/18‐related cytological abnormalities. VE for HPV 16/18 infection and high‐grade cytological abnormalities in women vaccinated prior to sexual debut were 95.8% (95% CI 81.9–99.0%; P < 0.001) and 78.3% (95% CI 11.3–94.7%; P = 0.033), respectively, in multivariate analyses adjusted for age and number of sexual partners. However, analyses of all vaccinated women did not show significant effectiveness against cytological abnormalities. Our results showed the effectiveness of HPV vaccine against high‐grade cervical cytological abnormalities and the importance of the vaccination before sexual debut.

Attitudes and behaviors of obstetricians and gynecologists toward HPV vaccination: a 7-year follow-up survey in Japan

In Japan, the government suspended HPV vaccine recommendation in 2013, resulting in dropping vaccination uptake to almost zero. We conducted four serial surveys on our colleague' attitude to HPV vaccination between 2014 and 2021. Here, we evaluate the result of the survey in 2021 and compare it to previous surveys. The subjects were 567 obstetricians and gynecologists who had been trained in our university hospital or our affiliated hospitals. We used a questionnaire similar in format to those used in 2014, 2017, and 2019. A total of 340 doctors (60.0%) completed the survey. Among them, 93.2% (317/340) of respondents thought that the government should restart HPV vaccination recommendation, and that 63.2% (215/340) think male teenagers should also vaccinate against HPV. The percentage of teenaged daughters inoculated with HPV vaccination after Japanese government had suspended its recommendation was 43.5% (20/46), an increasing trend from the previous surveys. 39 out of the 46 daughters (84.8%) would be expected to receive full HPV vaccination after they take junior high school entrance examination or after 9-valent HPV vaccination is designated as a national routine-immunization. This study revealed increasing number of our colleagues think HPV vaccination is necessary for prevention of cervical cancer. The Japanese government's decision to resume its recommendation of the HPV vaccine in November 2021 will lead to a change in the public's thinking and behavior toward the HPV vaccine.

The Effect of a Web-Based Cervical Cancer Survivor’s Story on Parents' Behavior and Willingness to Consider Human Papillomavirus Vaccination for Daughters: Randomized Controlled Trial

Background Providing adequate information to parents who have children eligible for human papillomavirus (HPV) vaccination is essential to overcoming vaccine hesitancy in Japan, where the government recommendation has been suspended. However, prior trials assessing the effect of brief educational tools have shown only limited effects on increasing the willingness of parents to vaccinate their daughters. Objective The aim of this trial is to assess the effect of a cervical cancer survivor’s story on the willingness of parents to get HPV vaccination for their daughters. Methods In this double-blinded, randomized controlled trial (RCT) implemented online, we enrolled 2175 participants aged 30-59 years in March 2020 via a webpage and provided them with a questionnaire related to the following aspects: awareness regarding HPV infection and HPV vaccination, and willingness for HPV vaccination. Participants were randomly assigned (1:1) to see a short film on a cervical cancer survivor or nothing, stratified by sex (male vs female) and willingness for HPV vaccination prior to randomization (yes vs no). The primary endpoint was the rate of parents who agreed for HPV vaccination for their daughters. The secondary endpoint was the rate of parents who agreed for HPV vaccination for their daughters and the HPV vaccination rate at 3 months. The risk ratio (RR) was used to assess the interventional effect. Results Of 2175 participants, 1266 (58.2%) were men and 909 (41.8%) were women. A total of 191 (8.8%) participants were willing to consider HPV vaccination prior to randomization. Only 339 (15.6%) participants were aware of the benefits of HPV vaccination. In contrast, 562 (25.8%) participants were aware of the adverse events of HPV vaccination. Although only 476 (21.9%) of the respondents displayed a willingness to vaccinate their daughters for HPV, there were 7.5% more respondents in the intervention group with this willingness immediately after watching the short film (RR 1.41, 95% CI 1.20-1.66). In a subanalysis, the willingness in males to vaccinate daughters was significantly higher in the intervention group (RR 1.50, 95% CI 1.25-1.81); however, such a difference was not observed among females (RR 1.21, 95% CI 0.88-1.66). In the follow-up survey at 3 months, 1807 (83.1%) participants responded. Of these, 149 (8.2%) responded that they had had their daughters receive vaccination during the 3 months, even though we could not see the effect of the intervention: 77 (7.9%) in the intervention group and 72 (8.7%) in the control group. Conclusions A cervical cancer survivor’s story increases immediate willingness to consider HPV vaccination, but the effect does not last for 3 months. Furthermore, this narrative approach to parents does not increase vaccination rates in children eligible for HPV vaccination. Trial Registration UMIN Clinical Trials Registry UMIN000039273; https://tinyurl.com/bdzjp4yf

Challenge to improve Japan's deplorable HPV vaccination rate by local government actions

AbstractAimIn Japan, in 2013, following reports of several alleged adverse reactions in young girls following vaccination, the previously successful national human papillomavirus infection (HPV) vaccination program collapsed rapidly. In the 8 years since vaccination rates have hovered near zero. In October of 2020, in an attempt to mitigate this lingering disaster, the Japanese Ministry of Health, Labor, and Welfare (MHLW) agency finally revised its HPV vaccination informational leaflet that was designed to be distributed by local governments nationwide. Prior to this revision, Toyonaka City, in Japan's Osaka province, had already begun sending out their own unique leaflet to girls in the targeted 6th–10th grades. As a preview of how MHLW's revised leaflet might eventually succeed, we have studied the HPV vaccination results from Toyonaka City's experiment.MethodThis study was a population‐based analysis that compared the monthly rates of new vaccinations in girls of a targeted grade school age group. We looked at rates before and after the leaflets were sent by Toyonaka City's Division of Health Promotion and Senior Services.ResultsThe vaccination rates between April 2020 and March 2021 were improved across all grades; 1.2% in 6th grade (p = 0.000185), 2.5% in 7th grade (p < 0.0001), 3.5% in 8th grade (p < 0.0001), 6.8% in 9th grade (p < 0.0001), and a remarkable 16.5% in 10th grade (p < 0.0001).ConclusionWhen a local government sends an HPV informational leaflet targeted at young girls, it can significantly improve their HPV vaccination rates.

Effect of Immersive Virtual Reality on Chemotherapy-Related Side Effects in Patients Receiving Paclitaxel-Carboplatin With or Without Bevacizumab: 2-Arm Randomized Controlled Trial

Abstract Background Symptomatic drug treatment is generally used to treat various side effects associated with paclitaxel-carboplatin (TC) or TC plus bevacizumab (TC+Bev). However, this can lead to increased adverse effects from additional drugs. Immersive virtual reality (iVR) reduces pain and anxiety. Objective This study aimed to investigate the efficacy of iVR in managing side effects associated with TC or TC+Bev therapy. Methods This 2-arm randomized controlled trial included patients with gynecologic cancer scheduled to undergo their first course of TC/TC+Bev. Patients in the intervention group received iVR for approximately 10 minutes/day for 7 consecutive days, starting on the first day of treatment. The primary endpoint was the severity of physical and psychiatric symptoms measured using the Japanese version of the revised Edmonton Symptom Rating System (ESAS-r-J). The secondary endpoint included the proportion of patients who used additional antiemetic medications, the complete response (CR) rate to nausea, and the severity of anxiety, measured using the state-trait anxiety inventory-JYZ (STAI) Y-1. Patients in the nonintervention group received supportive and symptomatic treatments. Results The analysis included 28 and 30 patients in the intervention and nonintervention groups, respectively. The change in ESAS-r-J scores between days 1 and 7 and nausea were significantly worse in the intervention group on day 4 only (P<.001); however, the nonintervention group showed significantly worse scores on days 3, 4, and 5. Depression was not significantly worse in the intervention group on any day other than on day 1; however, the nonintervention group showed significantly worse scores on day 4. The proportion of patients who used additional antiemetic medications from days 2 to 7 was significantly lower in the intervention group than in the nonintervention group (P=.02). Regarding the change in STAI Y-1 on day 1 of TC or TC+Bev therapy, the mean score was significantly lower after the iVR experience than before the experience in the intervention group (from 43.8 to 34.8; P<.001), whereas, in the nonintervention group, no significant difference was observed before and after anticancer drug administration (from 44.9 to 43.9; P=.54). Conclusions iVR may reduce the deterioration of nausea and depression more effectively in patients with gynecologic cancer undergoing TC or TC+Bev therapy than in those undergoing nonintervention, especially in delaying the onset of nausea and accelerating recovery.