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.

Significance of tumor size and number of positive nodes in patients with FIGO 2018 stage IIIC1 cervical cancer.

OBJECTIVE: This study aimed to investigate the prognostic significance of tumor size and number of positive pelvic lymph nodes (PLN) in International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIIC1 cervical cancer patients. METHODS: Clinical data from 626 women with cervical cancer treated at Osaka International Cancer Center in 2010-2020 were retrospectively reviewed. Using the cutoff value obtained on the receiver operating characteristic analysis, the prognostic significance of tumor size and number of positive PLN in stage IIIC1 patients was first evaluated via uni- and multivariate analyses. Then, the impact of incorporating tumor size and number of positive PLN into the FIGO staging system was investigated using the Kaplan-Meier method. RESULTS: Among 196 women with Stage IIIC1 disease, larger tumors (>4 cm) and multiple PLN metastases (≥4) were independent predictors of progression-free survival (PFS) in patients with stage IIIC1 cervical cancer. The PFS of patients with stage IIIC1 disease was inversely associated with the number of risk factors. Although patients with stage IIIC1 disease had significantly increased survival rates compared to those with stage IIIA or IIIB disease in the original FIGO 2018 staging system, this reversal phenomenon was resolved by incorporating larger tumors (>4 cm) and multiple PLN metastases (≥4) into the revised staging system. CONCLUSIONS: Incorporating tumor size and number of metastatic lymph nodes into the FIGO staging system allows additional risk stratification for women with stage IIIC1 cervical cancer and improves survival prediction performance.

Trends in incidence and hormonal management of endometrial cancer during potentially reproductive age in Japan: a population-based study.

BACKGROUND: We aimed to investigate the trends in the incidence and treatment of endometrial cancer (EC) during potentially reproductive age in Japan, with a special focus on the relative oncologic safety of hormonal therapy (HT) over surgery. METHODS: This population-based retrospective cohort study was conducted using data from the Osaka Cancer Registry from 2004 to 2018. Women with EC were first identified and then distributions of age, stage, histology, and initial treatment were examined. Then, the relative oncologic safety of HT over surgery in patients under the age of 50 years was evaluated. RESULTS: Among the 9417 patients with EC, 1937 were diagnosed during their potentially reproductive age (< 50 years). The incidence of EC during potentially reproductive age has increased from 18.5% in 2004-2011 to 21.9% in 2012-2018. ECs during potentially reproductive age more frequently displayed favorable characteristics, such as endometrioid histology, and lower histological grade than those in non-potentially reproductive age. Among the 1223 patients diagnosed with localized endometrioid EC, 74 cases (6.0%) received HT as an initial treatment, while 1100 cases (90.0%) underwent surgery as their initial treatment. When the two treatment groups were compared, there was no significant difference in overall survival (p = 0.3713). The estimated 5-year survival rates were 100 and 98.8% in the HT and surgery groups, respectively. CONCLUSION: EC is increasingly diagnosed during potentially reproductive age in Japan. The use of HT as an initial treatment is increasing, and achieved comparable survival outcomes to urgery against localized endometrioid EC during the potentially reproductive age.

Extraovarian seromucinous borderline tumor: Case report and literature review.

Seromucinous borderline tumors (SMBT) are papillary neoplasms without invasive capabilities. Originally categorized as ovarian tumors, SMBT, being an endometriosis-related tumor, can manifest beyond the ovaries. To date, only four cases of extraovarian SMBT have been documented in literature. In this report, we present our experience with the first case of SMBT in the uterine cervix, which exhibited highly elevated CA19-9 levels. The patient, initially clinically diagnosed with cervical cancer, underwent treatment with radical hysterectomy and was later pathologically diagnosed with SMBT of the uterine cervix. While extraovarian SMBT, especially in the uterine cervix, is extremely rare, this condition should be considered in patients with cervical masses lacking pathological evidence of malignant disease but displaying elevated CA19-9 levels.

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

The 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.

Evaluation of survival outcomes between minimally invasive and open surgery in the treatment of early-stage endometrial cancer: a population-based study in Osaka Japan.

OBJECTIVE: To compare the oncological outcomes between Japanese women who underwent minimally invasive surgery and those who underwent open surgery for early-stage endometrial cancer. METHODS: This population-based retrospective cohort study was conducted using data from the Osaka Cancer Registry from 2011 to 2018. Surgically treated patients for localized (uterine-confined) endometrial cancer were identified. Patients were classified into two groups according to the type of surgery (minimally invasive surgery group and open-surgery group), pathological risk factors (low-risk and high-risk), and year of diagnosis (Group 1, 2011-14; Group 2, 2015-18). Overall survival was compared between the minimally invasive surgery and open-surgery groups. RESULTS: In the analyses including all patients, there was no difference in overall survival between the minimally invasive surgery and open-surgery groups (P = 0.0797). The 4-year overall survival rate was 97.1 and 95.7% in the minimally invasive surgery and open-surgery groups, respectively. When investigated according to pathological risks, there were no differences in overall survival between the minimally invasive surgery and open-surgery groups in both the low- and high-risk groups. In the low-risk group, the 4-year overall survival rates in the minimally invasive surgery and open-surgery groups were 97.7 and 96.5%, respectively. In the high-risk group, the 4-year overall survival rates in the minimally invasive surgery and open-surgery groups were 91.2 and 93.2%, respectively. Similarly, there were no differences in overall survival between the minimally invasive surgery and open-surgery groups in both Group 1 (P = 0.4479 in low-risk and P = 0.1826 in high-risk groups) and Group 2 (P = 0.1750 in low-risk and P = 0.0799 in high-risk groups). CONCLUSION: Our study provides epidemiological evidence that minimally invasive surgery is an effective alternative to open surgery in Japanese patients with early-stage endometrial cancer.

Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial.

BACKGROUND: The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma. METHODS: Patients with previously untreated stage III-IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients. RESULTS: Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18-1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy. CONCLUSIONS: Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

Impact of lymphadenectomy in patients with locally recurrent or persistent cervical cancer treated with salvage hysterectomy.

AIM: To investigate the role of lymphadenectomy (LND) in locally recurrent or persistent cervical cancer patients treated with salvage hysterectomy. METHODS: Locally recurrent or persistent cervical cancer patients treated with salvage hysterectomy, with or without LND, were identified. Patients were divided into two groups according to the status of radiologic evidence of lymph node metastasis, and the impact of LND was investigated by evaluating postoperative survival. RESULTS: This study included 72 patients; 48 did not show radiological evidence of lymph node metastasis (Group 1) while 24 did (Group 2). Overall, the addition of LND to salvage hysterectomy resulted in increased postoperative complications. In Group 1, salvage hysterectomy plus LND resulted in the identification of five cases with false-negative lymph nodes (19.2%), but showed no advantage over salvage hysterectomy alone in terms of postoperative survival. In Group 2, all patients underwent LND, which resulted in the identification of eight cases with false-positive nodes (33.3%), and reasonably long postoperative survival. The estimated 3-year postoperative survival rate in this group was 39.7%. CONCLUSION: Including LND in salvage hysterectomy allows for precise lymph node staging but increases risk of postoperative complications. However, considering the inability to improve survival, LND should not be performed during salvage hysterectomy in patients without radiological evidence of lymph node metastasis. In patients with radiological evidence of lymph node metastasis, salvage hysterectomy plus LND can only be performed in those who understand the risk of postoperative complications and the limited evidence supporting its survival advantage.

Efficacy and safety of standard of care with/without bevacizumab for platinum-resistant ovarian/fallopian tube/peritoneal cancer previously treated with bevacizumab: The Japanese Gynecologic Oncology Group study JGOG3023.

We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum-resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open-label, phase II trial (JGOG3023), patients were randomized 1:1 to a single-agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m2 administered intravenously], topotecan [1.25 mg/m2 intravenously], paclitaxel [80 mg/m2 intravenously], or gemcitabine [1000 mg/m2 intravenously]) or single-agent chemotherapy + bevacizumab (15 mg/m2 intravenously). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator-assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32-0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38-1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment-related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification.

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

In 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.

Regional differences in human papillomavirus type 52 prevalence among Japanese women with cervical intraepithelial neoplasia†.

Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48-2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83-1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines.

Risk assessment in the patients with uterine cervical cancer harboring intermediate risk factors after radical hysterectomy: a multicenter, retrospective analysis by the Japanese Gynecologic Oncology Group.

BACKGROUND: Adjuvant therapy is usually considered for surgically treated patients with uterine cervical cancer harboring intermediate risk (IR) factors such as large tumor diameter, stromal invasion to the outer half, and lymphovascular space invasion (LVSI). However, the indications and types of adjuvant therapy for the IR group remain controversial. This study aimed to analyze the differences in patient outcomes in the IR group to provide novel insights for tailoring adjuvant therapy. METHODS: Data from 6192 patients with cervical cancer who underwent radical hysterectomy at 116 institutions belonging to the Japanese Gynecologic Oncology Group were reviewed. RESULTS: In total, 1688 patients were classified into the IR group, of whom 37.3% did not receive adjuvant therapy. Conversely, approximately equal proportions of the remaining patients received adjuvant radiotherapy, concurrent chemoradiotherapy, and chemotherapy. Patients with all three risk factors showed worse overall survival than those with one or two risk factors. In addition to LVSI, non-squamous cell carcinoma histology, and vaginal invasion were identified as independent risk factors for both recurrence and mortality in multivariate analyses. Tumor diameter greater than 40 mm and surgical center volume were identified as independent risk factors for recurrence. Stromal invasion to the outer half and ovarian metastasis were identified as independent risk factors for mortality. CONCLUSIONS: This study revealed the significant differences in prognosis in the IR group. The indications for adjuvant therapy should be further studied, focusing on conventional risk factors and other pathological findings.

Oncologic outcomes in elderly patients who underwent hysterectomy for endometrial cancer: a multi-institutional survey in Kinki District, Japan.

BACKGROUND: The goal of this study is to assess the oncologic outcomes of elderly patients who underwent hysterectomy for endometrial cancer across three variables: hysterectomy approach, lymph node resection, and adjuvant therapy. METHODS: Hospital records of patients aged ≥ 70 years who underwent hysterectomy for endometrial cancer were obtained from 19 institutions. Patients were categorized into three risk groups: low, intermediate, and high. In each group, disease-free survival and overall survival were compared according to hysterectomy approach, lymph node resection, and adjuvant therapy using Kaplan-Meier method. Cox regression analysis with a 95% confidence interval was performed to estimate relative risk (RR) of death. RESULTS: A total of 1246 patients were included. In the low-risk group, the adjusted RR for death for minimally invasive surgery (MIS) versus laparotomy and lymph node resection versus no lymph node resection were 0.64 (0.24-1.72) and 0.52 (0.24-1.12), respectively. In the intermediate-risk group, the adjusted RR for death for MIS versus laparotomy, lymph node resection versus no lymph node resection, and adjuvant therapy versus no adjuvant therapy were 0.80 (0.36-1.77), 0.60 (0.37-0.98), and 0.89 (0.55-1.46), respectively. In the high-risk group, the adjusted RRs for death for lymph node resection versus no lymph node resection and adjuvant therapy versus no adjuvant therapy were 0.56 (0.37-0.86) and 0.60 (0.38-0.96), respectively. CONCLUSIONS: MIS is not inferior to laparotomy in uterine-confined diseases. Lymph node resection improved the outcome for all disease stages and histological types. In contrast, adjuvant therapy improved the outcomes only in high-risk patients.

Primary Fallopian Tube Carcinoma Presenting with a Massive Inguinal Tumor: A Case Report and Literature Review.

Primary fallopian tube carcinoma (PFTC) has characteristics similar to those of ovarian carcinoma. The typical course of PFTC metastasis includes peritoneal dissemination and pelvic and paraaortic lymph node metastasis, while inguinal lymph node metastasis is rare. Moreover, the initial presentation of PFTC with an inguinal tumor is extremely rare. A 77-year-old postmenopausal woman presented with a massive 12-cm inguinal subcutaneous tumor. After tumor resection, histopathological and immunohistochemical analysis showed that the tumor was a high-grade serous carcinoma of gynecological origin. Subsequent surgery for total hysterectomy with bilateral salpingo-oophorectomy revealed that the tumor developed in the fallopian tube. She received adjuvant chemotherapy with carboplatin and paclitaxel, followed by maintenance therapy with niraparib. There has been no recurrence or metastasis 9 months after the second surgery. We reviewed the literature for cases of PFTC and ovarian carcinoma that initially presented with an inguinal tumor. In compliance with the Preferred Reporting Items for Systematic Reviews guidelines, a systematic literature search was performed through 31 January 2022 using the PubMed and Google scholar databases and identified 14 cases. In half of them, it was difficult to identify the primary site using preoperative imaging modalities. Disease recurrence occurred in two cases; thus, the prognosis of this type of PFTC appears to be good.

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE-100.

Interim results from the two-cohort, phase 2 KEYNOTE-100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4-11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE-100. Patients with epithelial ROC had received either 1-3 prior chemotherapy lines and had platinum-free interval or treatment-free interval (PFI; TFI) of 3-12 months (cohort A) or 4-6 prior chemotherapy lines and had PFI/TFI of ≥3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand-1 (PD-L1) tumor expression. The relationship between PD-L1 expression (measured as combined positive score [CPS]) and ORR was assessed. Twenty-one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37-78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III-IV disease. ORR was 19.0% (95% CI, 5.4-41.9) and seemed to increase with increasing PD-L1 expression. A total of 13 (61.9%) patients had treatment-related adverse events (TRAE), and 5 (23.8%) had grade 3-4 TRAE. There were no treatment-related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD-L1 expression among some patients with higher ORR.

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

To 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.

Dedifferentiation of neuroendocrine carcinoma of the uterine cervix in hypoxia.

Neuroendocrine carcinoma of small cell type (SCNEC) is a rare pathological subtype in cervical cancer, which has a worse prognosis than other histological cell types. Due to its low incidence and the lack of experimental platforms, the molecular characteristics of SCNEC in the cervix remain largely unknown. Using the cancer tissue-originated spheroid (CTOS) method-an ex vivo 3D culture system that preserves the differentiation status of the original tumors-we established a panel of CTOS lines of SCNEC. We demonstrated that xenograft tumors and CTOSs, respectively, exhibited substantial intra-tumor and intra-CTOS variation in the expression levels of chromogranin A (CHGA), a neuroendocrine tumor marker. Since hypoxia affects differentiation in various tumors and in stem cells, we also investigated how hypoxia affected neuroendocrine differentiation of SCNEC of the uterine cervix. In the CTOS line cerv21, hypoxia suppressed expression of the neuroendocrine markers CHGA and synaptophysin (SYP). Flow cytometry analysis using CD99 (a membrane protein marker of SCNEC) revealed decreased CD99 expression in a subset of cells under hypoxic conditions. These expression changes were attenuated by HIF-1α knockdown, and by a Notch inhibitor, suggesting that these molecules played a role in the regulation of neuroendocrine differentiation. The examined SCNEC markers were suppressed under hypoxia in multiple CTOS lines. Overall, our present results indicated that neuroendocrine differentiation in SCNEC of the uterus is a variable phenotype, and that hypoxia may be one of the factors regulating the differentiation status.

Reduction in HPV16/18 prevalence among young women with high-grade cervical lesions following the Japanese HPV vaccination program.

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12-16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population-level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1-3 (CIN1-3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012-2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6-year period were observed in CIN1 (50.0% to 0.0%, Ptrend  < .0001) and CIN2-3/AIS (83.3% to 45.0%, Ptrend  = .07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18-attributable CIN2-3/AIS from 47.7% to 33.0% (P = .003): from 43.5% to 12.5% as routine vaccination (P = .08) and from 47.8% to 36.7% as catch-up vaccination (P = .04). The HPV16/18 prevalence in CIN2-3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P = .02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18-positive CIN/AIS in Japan; however, our data did not support catch-up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government's suspension of its vaccine recommendation could benefit from receiving catch-up vaccination before age 20 years.

Bevacizumab combined with platinum-taxane chemotherapy as first-line treatment for advanced ovarian cancer: a prospective observational study of safety and efficacy in Japanese patients (JGOG3022 trial).

BACKGROUND: This was the first large-scale prospective observational Japanese study evaluating the safety and efficacy of bevacizumab combined with paclitaxel and carboplatin for newly diagnosed advanced ovarian cancer. METHODS: Patients were prospectively enrolled in the primary analysis cohort if they had Stage III or IV epithelial ovarian/fallopian tube/primary peritoneal cancer and were scheduled to receive paclitaxel plus carboplatin every 3 weeks in Cycles 1-6 and bevacizumab every 3 weeks in Cycles 2-22. Primary endpoints were bevacizumab-specific adverse events and adverse events ≥ Grade 3. Secondary endpoints were progression-free survival (PFS) and the response rate. RESULTS: Among 346 patients enrolled, 293 patients formed the primary analysis cohort. Regarding bevacizumab-specific adverse events ≥ grade 3, incidence rates of thromboembolic events (1.4%), gastrointestinal perforation (0.3%), fistula (0.7%), wound dehiscence (0%), and bleeding (0%) were very low. While incidence rates of hypertension (23.2%) and proteinuria (12.6%) were high, all such events were tolerable. No patient with prior bowel resection developed perforation or fistula. Median PFS was 16.3 months (95% CI 14.5-18.9). The response rate was 77.5% (95% CI 67.4-85.7). The response rate was 63.6% in patients with clear cell carcinoma, which tended to be better than previously reported. The median platinum-free interval was 11.5 months, and the platinum-resistant recurrence rate was 24.5%. CONCLUSIONS: Combining bevacizumab with chemotherapy was tolerable and efficacy was acceptable in Japanese patients with advanced epithelial ovarian cancer. Bevacizumab seems to reduce platinum-resistant recurrence and is promising for clear cell carcinoma.

Identifying a candidate population for ovarian conservation in young women with clinical stage IB-IIB cervical cancer.

This study seeks to identify risk factors associated with ovarian metastasis and to characterize a population with minimum risk of ovarian metastasis in young women with stage IB-IIB cervical cancer. This was a nation-wide multicenter retrospective study in Japan examining consecutive cases of surgically-treated women with clinical stage IB-IIB cervical cancer who had oophorectomy at radical hysterectomy (n = 5,697). Multivariable analysis was performed to identify independent risk factors for ovarian metastasis. Ovarian metastasis was seen in 70 (1.2%, 95% confidence interval 0.9-1.5) cases. In the entire cohort, adenocarcinoma, lympho-vascular space invasion, uterine corpus tumor invasion, and pelvic/para-aortic nodal metastases remained independent risk factors for ovarian metastasis (all, adjusted-p < 0.05). In a sensitivity analysis of 3,165 women aged <50 years (ovarian metastasis, 1.0%), adenocarcinoma, parametrial tumor involvement, uterine corpus tumor involvement, and pelvic/para-aortic nodal metastases remained independent risk factors for ovarian metastasis (all, adjusted-P < 0.05). In the absence of these five risk factors (representing 46.1% of women aged <50 years), the incidence of ovarian metastasis was 0.14%. With the presence of adenocarcinoma alone (representing 18.9% of women aged <50 years), the incidence of ovarian metastasis was 0.17% and was not associated with increased risk of ovarian metastasis compared to the subgroup without any risk factors (p = 0.87). In conclusion, nearly two thirds of women aged <50 years with clinical stage IB-IIB cervical cancer had no risk factor for ovarian metastasis or had adenocarcinoma alone: these subgroups had ovarian metastasis rates of around 0.1% and may be a candidate population for ovarian conservation at surgical treatment.