Taichi Mizushima

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.

Impact of MED12 mutation and CDK8 activity on uterine leiomyoma growth and response to gonadotropin-releasing hormone agonist treatment

MED12 exon 2 mutation is the most frequent mutation associated with uterine leiomyomas. MED12 wild-type leiomyomas have a higher growth potential than mutant leiomyomas, suggesting that the mutation limits leiomyoma growth. MED12 forms a complex with CDK8 and is involved in the phosphorylation of RNA polymerase II, playing a role in transcriptional regulation. However, its mechanism of action in leiomyoma growth is not clear. We aimed to clarify the relationship between MED12 mutation status, response to gonadotropin-releasing hormone (GnRH) agonist treatment, and CDK8 activity in leiomyomas. We also examined the effects of CDK8 inhibitors on primary cultured uterine leiomyoma cells. We classified 44 surgically removed uterine leiomyomas into four groups according to GnRH agonist use and MED12 mutation status. CDK8 was co-immunoprecipitated from leiomyoma tissue extracts using MED12 antibody to test its kinase activity in vitro , and the amount of phosphorylated substrate was measured. Cell proliferation and apoptosis of primary cultured MED12 wild-type leiomyoma cells were evaluated in the presence of a CDK8 inhibitor and sex steroid hormones. Of the 44 leiomyomas tested, 11 MED12 wild-type leiomyomas without preoperative GnRH agonist treatment had significantly higher CDK8 activity than nine GnRH agonist-treated MED12 wild-type leiomyomas and 15 leiomyomas with MED12 mutations without GnRH agonist treatment. Treatment of primary cultured MED12 wild-type cells with CDK8 inhibitors significantly inhibited cell growth and increased apoptosis. MED12 wild-type leiomyoma cells without GnRH agonist treatment showed high CDK8 activity, and inhibition of CDK8 activity suppressed cell growth in vitro .

Risk factors for positive cervical cytology during early pregnancy screening and awareness of positive cytological results in Japan: a report from the Pregnant Women Health Initiative

Objective Cervical cancer screening rates are low in Japan. Therefore, when a woman is pregnant, this is a good opportunity to visit an obstetrics and gynecology clinic to have cervical cytology. This study aimed to clarify the association between cervical cancer screening and the management of pregnant women’s health. Methods We prospectively examined the relationships between cervical cytological results during prenatal checkups and the following factors: participant’s background, cytological sampling instruments, and awareness of cytological results. Results Of the 2725 participants, 71 showed abnormal results defined as atypical squamous cells of undetermined significance or higher grade (ASC-US+). ASC-US+ detection rates were higher in smokers, younger participants, those with a low education, those without cancer screening in the past 2 years, and those who received cytology using a spatula or brush. A multivariable logistic regression analysis identified smoking (adjusted odds ratio: 2.99 [95% confidence interval: 1.41–6.33]) and a spatula/brush (adjusted odds ratio: 2.46 [95% confidence interval: 1.09–5.53]) as independent variables associated with detecting ASC-US+. Among the participants, 39.4% (28/71) self-reported “no abnormalities,” despite obtaining an ASC-US+ result. Conclusions Pre-pregnancy smoking and cytological sampling tools may contribute to detecting ASC-US+. Patients with detected abnormalities need accurate information and reliable follow-up.

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.

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.