Etsuko Miyagi

Risk-reducing mastectomy and salpingo-oophorectomy in women with hereditary breast and ovarian cancer: a single-institute experience following coverage by Japanese national medical insurance

Abstract Background Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are preventive options for women with hereditary breast and ovarian cancer (HBOC). The Japanese national medical insurance began covering RRM and RRSO for patients with HBOC in April 2020. Methods We retrospectively analyzed 59 individuals with pathogenic germline variants (PGVs) from 55 families diagnosed with HBOC between 2010 and 2024 to assess the prevalence of RRM and RRSO after April 2020. Results The median age at diagnosis was 50 years. Ten individuals (16.9%) were diagnosed before April 2020, whereas 49 (83.1%) were diagnosed afterward. PGVs included BRCA1 (28 individuals) and BRCA2 (31 individuals). The most common cancer was breast cancer (74.6%), followed by ovarian (13.6%), and pancreatic cancer (3.3%); 15.3% had no cancer history. RRM was performed in 19 of 41 individuals (46.3%), with the highest rate observed among BRCA1 PGV individuals (55.0%). RRSO was conducted in 30 of 41 individuals (73.1%), with higher rates among BRCA1 and BRCA2 PGV individuals. None of the individuals without a history of breast and/or ovarian cancer underwent these procedures. The median age was 50 for RRM and 49 for RRSO. Most surgeries (64.7% for RRM and 76.0% for RRSO) occurred within a year of genetic testing. Multivariate analysis showed that breast cancer history was strongly associated with RRM. Conclusions National insurance coverage has enhanced access to genetic testing and preventive surgeries, with 46.3% and 73.1% undergoing RRM and RRSO, respectively. However, individuals without a cancer history remain underrepresented.

Assessment of tissue factor pathway inhibitor 2 (TFPI2) as a novel serum marker for malignant tumors of the ovary before and after treatment: A case‐control study

AbstractAimTissue factor pathway inhibitor 2 (TFPI2) is a preoperative biomarker that was developed to discriminate ovarian benign tumors from cancer and is covered by health insurance in Japan. The purpose of this study was to evaluate how the TFPI2 changes after treatment.MethodsSerum levels of TFPI2 (cut off 191 pg/mL) and CA125 (cut off 35 U/mL) before and after primary debulking surgery in patients with ovarian malignant tumors were evaluated among recurrent and nonrecurrent cases, respectively.ResultsA total of 46 cases were analyzed, including 11 borderline tumors, 13 clear cell carcinomas, 15 serous carcinomas, 4 endometrioid carcinomas, and 3 mucinous carcinomas. Among 37 patients without recurrence, the preoperative mean levels of TFPI2 (235.3 pg/mL, range: 78.3–607.7) and CA125 (1125.5 U/mL, range: 6.2–6272.0) were higher than the cutoff values. The mean minimum level of TFPI2 decreased to below the cutoff (150.2 pg/mL, range 56.4–471.1) at 3 months or more after primary debulking surgeries. The postoperative TFPI2 level exceeded the cutoff in 11 out of 37 patients without recurrence (29.7%); however, the postoperative TFPI2 level decreased in 8 patients. The mean maximum levels of TFPI2 and CA125 in 9 patients after recurrence were 492.6 pg/mL and 727.4 U/mL, respectively. Moreover, the mean TFPI2 level was higher than the preoperative one (421.5 pg/mL), different from CA125 (2903.8 U/mL).ConclusionsOur results suggest the clinical validity of TFPI2 as a serum tumor marker for postoperative recurrence screening among malignant ovarian tumors.

Inspection for micrometastasis is essential for predicting the prognosis of serous endometrial intraepithelial carcinoma: Case report and literature review

AbstractSerous endometrial intraepithelial carcinoma is the precursor of invasive uterine serous carcinoma. Here, we present two cases of serous endometrial intraepithelial carcinoma with omental micrometastasis and discuss their clinical significance. Two menopausal patients with abnormal endometrial biopsy findings underwent hysterectomy and comprehensive surgical staging (bilateral salpingo‐oophorectomy, omentectomy, and pelvic and para‐aortic lymphadenectomy). Although gross examination failed to detect tumors, the pathological diagnosis was serous endometrial intraepithelial carcinoma. Both patients had omental micrometastasis; they were diagnosed with International Federation of Gynecology and Obstetrics stage IVB disease and received postoperative chemotherapy. One patient died of the carcinoma 9 months after the hysterectomy, and the other had a recurrence of carcinoma 17 months after the end of the initial therapy. The present cases and literature review highlight the importance of meticulous inspection for micrometastasis in the abdominal cavity, including the omentum and peritoneum, for predicting prognosis.

Human papillomavirus vaccine to prevent CIN3 or worse (CIN3+): A nationwide case–control study in Japan

AbstractAn increase in cervical cancer incidence has been reported in Japan. The Ministry of Health, Labor, and Welfare of Japan has resumed the active recommendation of regular HPV vaccines in 2022. In Japan, the preventive effect of CIN3+ in the real world has not yet been demonstrated in age‐adjusted cohort or case–control studies. This study aimed to estimate the effect of the HPV vaccine against CIN3+ in Japanese women. This nationwide case–control study from April 2013 to March 2020 targeted women aged 20–26 years old at the time of cervical screening. We compared HPV vaccination exposure between those with abnormal and those with normal cytology. Abnormal cytology was classified into cervical intraepithelial neoplasia (CIN)1+, CIN2+, and CIN3+. We calculated the odds ratio (OR) and 95% confidence interval (CI) of the above endpoints and vaccination exposure using the conditional logistic regression model and estimated vaccine effectiveness using the formula (1 −OR) × 100. A total of 2790 cases and 13,990 controls (one‐to‐five matching) were eligible in 37 municipalities in Japan. In this study, 61 CIN3 (2.2%) and 10 squamous cell carcinomas (SCC) (0.4%) were found. The OR for CIN3+ versus controls was 0.14 (95% CI, 0.03–0.75), equating to a vaccine effectiveness of 86%. Of the 10 patients who had SCC none were vaccinated. This nationwide case–control study in Japan demonstrated a substantial risk reduction in CIN3+ among women who did versus those who did not receive HPV vaccination.

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

Abstract 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.

Is there a need for screening of cervical HPV infections and carcinoma?

Antenatal cervical screening aims to detect cervical intraepithelial neoplasms as precancerous lesions and invasive cervical cancer. Whether this screening is performed routinely during pregnancy varies depending on each country's screening participation rates, guidelines, and the risks to the pregnant woman. In some countries with the high rate of routinely implemented cervical screening among the target women, women are recommended to defer cervical screening intentionally to post-delivery, though having screening in consultation with physicians may be possible if routine screening overlaps. However, when cervical screening rate in fertile women is low and the incidence of cervical cancer is high, cervical screening during pregnancy may play an important role in the early detection of cervical cancer. Cervical screening using high-risk human papillomavirus (HPV) testing is accepted worldwide as a highly sensitive and objective test method, and it should replace traditional primary cervical cytology in the future. However, the benefits and disadvantages of using HPV testing in pregnant women is unclear because a false positive rate may be increased due to pregnant women being generally under an immunosuppressed condition.

Validation of tissue factor pathway inhibitor 2 as a specific biomarker for preoperative prediction of clear cell carcinoma of the ovary

Abstract Background Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinoma (CCC) from borderline ovarian tumors (BOTs) and non-clear cell epithelial ovarian cancers (EOCs). Here, we examined the performance of TFPI2 for preoperative diagnosis of CCC. Methods Serum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCC from BOTs, other EOCs, and benign lesions were compared. Results A total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%). In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II–IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCC from BOTs and other EOCs was improved from 43.5 to 71.0% when combined with CA125. Conclusions High specificity of TFPI2 for preoperative detection of CCC was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 may contribute substantially to precise prediction of intractable CCC.

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.

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.

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

Long‐term effectiveness of HPV vaccination against HPV infection in young Japanese women: Real‐world data

AbstractIn Japan, public funding for HPV vaccination began in 2010 for girls aged 13–16 years (birth cohort years 1994–1997) and women born in 1994 who turned 25 in 2019. We aimed to verify the long‐term effectiveness of the bivalent HPV vaccine in women aged 25 years. Subjects were women aged 25–26 years who underwent cervical cancer screening and HPV testing in Niigata from 2019 to 2020 (birth cohort years 1993–1994). Information on vaccination status and sexual behavior was obtained from a questionnaire and municipal records. We compared the HPV infection rates of the vaccinated and unvaccinated groups. Of the 429 registrants, 150 (35.0%) and 279 (65.0%) were vaccinated and unvaccinated, respectively. The average period from HPV vaccination to HPV testing was 102.7 months (8.6 years), with a median of 103 months (range 92–109 months). The HPV high‐risk infection rate was 21.3% (32/150) in the vaccinated group and 23.7% (66/279) in the unvaccinated group (P = 0.63). The HPV16/18 infection rate was 0% (0/150) in the vaccinated group and 5.4% (15/279) in the unvaccinated group, showing a significant difference (P = 0.0018), and the vaccine effectiveness was 100%. The cross‐protective type HPV31/45/52 infection rate in the vaccinated group was significantly lower than that in the unvaccinated group (3.3% vs. 10.0%, P = 0.013). There was no significant difference in the mean age at sexual debut and the number of previous sexual partners between the two groups. We have demonstrated the long‐term 9‐year effectiveness of the bivalent vaccine against HPV infection for the first time in Japan.

Efficacy and Safety of Concurrent Chemoradiotherapy as First‐Line Treatment for Stage IVB Cervical Cancer: A Single‐Center Retrospective Observational Study

ABSTRACT Aim To evaluate the efficacy and safety of concurrent chemoradiotherapy prior to systemic chemotherapy in patients with stage IVB cervical cancer. Methods This retrospective observational study included 40 patients diagnosed with stage IVB cervical cancer who received concurrent chemoradiotherapy as first‐line therapy at the Yokohama City University Hospital between 2007 and 2021. The evaluated outcomes included concurrent chemoradiotherapy response rate, chemotherapy initiation rate, adverse events, and overall survival. Results The disease control rate of concurrent chemoradiotherapy was 72.5%, with no significant differences across the subgroups defined by the number of metastatic sites, presence of out‐of‐field lesions, parenchymal involvement, or histological subtype. Systemic chemotherapy was initiated in 89% of the patients, with a median interval of 39 days after concurrent chemoradiotherapy completion, except in one patient (3.6%) due to disease progression. Including recurrent cases, 91% of patients ultimately received systemic chemotherapy. Grade 3 or higher toxicity that significantly delayed chemotherapy initiation occurred in only one patient (3.6%). The median overall survival was 23 months, with no significant differences based on lesion distribution, parenchymal involvement, histological subtype, or metastatic burden. Conclusions Concurrent chemoradiotherapy may be a feasible first‐line treatment option for stage IVB cervical cancer with manageable toxicity, acceptable disease control, and the potential to allow a timely transition to systemic chemotherapy.

Validation of the 2023 FIGO staging system and its concordance with the JSGO guidelines in endometrial cancer: A multi‐institutional retrospective study in Japan

Abstract Aim To validate the prognostic accuracy of the 2023 FIGO staging system and assess its alignment with the Japan Society of Gynecologic Oncology (JSGO) guidelines for endometrial cancer treatment. Methods This retrospective cohort study included 1207 patients with endometrial cancer treated at four academic hospitals in Kanagawa, Japan, between 2018 and 2022. Patients were reclassified according to the FIGO 2023 system and the JSGO recurrence risk categories. Primary endpoints included stage migration, recurrence risk (RR), overall survival (OS), and concordance between the two classification systems. Results Under FIGO 2023, the stage distribution was: I, 741 (61.4%); II, 203 (16.8%); III, 149 (12.3%); and IV, 114 (9.4%), with stage migration observed in 36.3% of cases. The FIGO 2023 system provided clearer stratification of 3‐year RR than FIGO 2009, with the RR gap widening from 80.0% to 90.1%. Sixteen patients (3.5%) with stage IA3 were classified as high risk by JSGO criteria, while 14.4% of patients considered high risk by JSGO were downstaged under FIGO 2023. Additionally, 46 patients (19.6%) with FIGO stage IA were reclassified as intermediate risk owing to focal lymphovascular space invasion (LVSI). Substantial LVSI was significantly associated with recurrence and poor prognosis (3‐year OS rates: none 94.3%, focal 89.9%, and substantial 40.7%; p  < 0.05). Molecular testing was limited: p53 in 30.2%, MSI in 5.9%, and POLE was not available. Conclusions FIGO 2023 improves prognostic precision. Incorporating LVSI extent and molecular data may refine JSGO classifications and support more individualized adjuvant therapy strategies.

Tissue factor pathway inhibitor-2 inhibits integrin β1 activation and focal adhesion formation and suppresses peritoneal ovarian cancer dissemination in mice

Tissue factor pathway inhibitor-2 (TFPI2) is a Kunitz-type serine protease inhibitor and an ovarian clear cell carcinoma (CCC) biomarker. TFPI2 is expressed in several cancers and exerts tumor-suppressive effects; however, the role of TFPI2 in the CCC cell phenotype remains unclear. Therefore, in this study, we investigated the function of TFPI2 by establishing a gene knockout (KO) in ES-2 CCC cells and observed the change in phenotypes in vitro and in vivo. TFPI2 KO inhibited ES-2 cell proliferation, increased extracellular matrix protein adhesion, enhanced focal adhesion formation and activated integrin β1 cell surface clustering in vitro, and markedly increased ES-2 tumor growth and dissemination in the peritoneal cavity of a mouse xenograft model. These findings suggest a novel function of TFPI2 expression in suppressing the formation of focal adhesions in CCC cells, potentially by activating integrin β1. This function plays a role in the peritoneal growth characteristics of CCC cells.