Keiichiro Nakamura

CD63 as a potential biomarker for patients with ovarian cancer

Exosomes play an important role in regulating physiological processes and mediating the systemic dissemination of various types of cancer. We investigated the association of exosomal tetraspanins CD9, CD63, and CD81 in patients with ovarian cancer (OC). We measured the plasma tetraspanins CD9, CD63, and CD81 by enzyme-linked immunosorbent assay in 91 patients who underwent treatment for OC between April 2018 and March 2024. Additionally, we analyzed clinical pathologic factors, chemotherapy response, and prognosis. In terms of stages, CD63 expression was significantly higher in patients with stage IV compared to those with stage I OC (p = 0.003). In terms of histological type, CD63 expression was significantly higher in high-grade serous carcinoma (HGSC) than in clear cell carcinoma (CCC) with OC (p = 0.009). Furthermore, CD63 levels were significantly higher in advanced-stage, HGSC than in patients with early-stage, non-HGSC and early-stage, HGSC OC (p = 0.045 and p = 0.002, respectively). In the Neoadjuvant chemotherapy (NAC) of 12 patients with OC assessed as having either a partial response (PR) or complete response (CR), CD63 was significantly decreased (p = 0.043), whereas perforin was significantly increased (p = 0.001). In the NAC of 16 patients with OC, CD63 of the response rate to chemotherapy tended to differ between the progressive disease (PD) and PR/CR groups (p = 0.056). A moderate inverse correlation was observed between CD63 and perforin levels (R = 0.638, R CD63 could be a potential biomarker for all types of OC patients.

Lymphadenectomy and chemotherapy are effective treatments for patients with 2023 international federation of gynecology and obstetrics stage IIC-high risk endometrial cancer in Japan

Abstract Background In early-stage endometrial cancer (EC), the treatment of aggressive histological subtypes (endometrioid carcinoma grade 3, serous carcinoma, clear-cell carcinoma, undifferentiated carcinoma, mixed carcinoma, and carcinosarcoma) is controversial. We aimed to investigate the treatment of patients with International Federation of Gynecology and Obstetrics (FIGO) stage IC and stage IIC EC according to the 2023 classification. Methods We retrospectively identified patients with FIGO 2023 stage IC, IIC-intermediate risk (IIC-I), and IIC-high risk (IIC-H) EC who underwent adjuvant therapy or observation after surgery at eight medical institutions from 2004 to 2023. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier estimates and univariate and multivariate analyses. Results The PFS and OS were significantly worse in patients with FIGO 2023 stage IIC-H EC than in those with FIGO 2023 stage IIC-I EC (PFS: p = 0.008 and OS: p = 0.006). According to the FIGO 2023 stage IIC-H classification, lymphadenectomy and chemotherapy resulted in better prognoses regarding both PFS and OS (p < 0.001 for both) than other treatments. Our findings suggest that lymphadenectomy and chemotherapy effectively reduced vaginal stump and lymph node metastases in FIGO 2023 stage IIC-H EC (p < 0.001 and p = 0.008, respectively). Furthermore, in the multivariate analysis, not undergoing lymphadenectomy or chemotherapy were independent predictors of recurrence and poor prognoses in patients with FIGO 2023 stage IIC-H EC (p < 0.001 and p = 0.031, respectively). Conclusion Lymphadenectomy and chemotherapy resulted in better prognoses regarding both recurrence and survival in patients with FIGO 2023 stage IIC high-risk EC.

Efficacy and safety of olaparib, olaparib plus bevacizumab and niraparib maintenance treatment in Japanese patients with platinum-sensitive advanced ovarian cancer

Abstract Objective To investigate whether maintenance treatment could be safely and effectively performed with olaparib, olaparib plus bevacizumab and niraparib in platinum-sensitive advanced ovarian cancer at multiple institutions in Japan. Methods We investigated progression-free survival and adverse events in 117 patients with platinum-sensitive advanced ovarian cancer treated with maintenance therapy. Results The median progression-free survival of 117 patients was 20.1 months. Patients with germline BRCA pathogenic variants had a significantly better prognosis than the other groups (P < 0.001). Furthermore, in the multivariate analysis, stage IV (P = 0.016) and germline BRCA wild-type (P ≤ 0.001) were significantly associated with worse progression-free survival in patients with advanced ovarian cancer. Regarding adverse events, all three types of maintenance treatment were significantly worse than chemotherapy given before maintenance treatment with respect to renal function (olaparib, P = 0.037; olaparib plus bevacizumab, P < 0.001; and niraparib, P = 0.016). Conclusion Maintenance treatment was performed effectively and safely. Renal function deterioration is likely to occur during maintenance treatment, and careful administration is important in platinum-sensitive advanced ovarian cancer.

Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan

AbstractTo obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012‐2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2‐3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type‐specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type‐specific RCs between CIN1 and CIN2‐3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type‐specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2‐3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2‐3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01‐4.98), followed by HPV31 (2.51, 1.54‐5.24), HPV18 (2.43, 1.59‐4.32), HPV35 (1.56, 0.43‐8.36), HPV33 (1.01, 0.49‐3.31), HPV52 (0.99, 0.76‐1.33), and HPV58 (0.97, 0.75‐1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71‐2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14‐0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9‐valent vaccine contributed to 89.7% (95% CI, 88.7‐90.7) of CIN2‐3/AIS and 93.8% (95% CI, 92.4‐95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9‐valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.

Human papillomavirus vaccine effectiveness by age at first vaccination among Japanese women

AbstractIn Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12‐16 years, and catch‐up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2‐3 (CIN2‐3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine‐targeted types HPV16 or HPV18 to CIN2‐3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12‐15 years (n = 36), 16‐18 years (n = 23), 19–22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P < .001). This finding was supported by age at first sexual intercourse; among women with CIN2‐3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2‐3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P = .004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12‐14 years and catch‐up vaccination for adolescents aged 18 years and younger in Japan.

Human papillomavirus vaccine impact on invasive cervical cancer in Japan: Preliminary results from cancer statistics and the MINT study

AbstractThe first prophylactic vaccine against human papillomavirus (HPV) 16 and HPV18 was licensed in Japan in 2009. HPV vaccine effectiveness against high‐grade cervical lesions has been demonstrated among young Japanese women, but evidence of its effects on invasive cervical cancer (ICC) is lacking. Using data from two different cancer registries, we compared recent trends of new ICC cases by age group using Poisson regression analysis. We also analyzed time trends in HPV16/18 prevalence among 1414 Japanese women aged <40 years newly diagnosed with ICC in the past decade. Based on the population‐based cancer registry, the incidence of ICC among young women aged 20–29 years showed a significant decline from 3.6 to 2.8 per 100 000 women‐years during 2016–2019, but no similar decline was observed for older age groups (p < 0.01). Similarly, using data from the gynecological cancer registry of the Japan Society of Obstetrics and Gynecology, the annual number of ICCs among women aged 20–29 years also decreased from 256 cases to 135 cases during 2011–2020 (p < 0.0001). Furthermore, a declining trend in HPV16/18 prevalence in ICC was observed only among women aged 20–29 years during 2017–2022 (90.5%–64.7%, p = 0.05; Cochran–Armitage trend test). This is the first report to suggest population‐level effects of HPV vaccination on ICC in Japan. Although the declining trend in HPV16/18 prevalence among young women with ICC supports a causal linkage between vaccination and results from cancer registries, further studies are warranted to confirm that our findings are attributable to vaccination.