Search

OBJECTIVE. Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS. Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS. At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10(−9)) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10(−9)). SNP rs6902488 at 6p25.2 (r(2) = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP

Objective This multicenter phase II Japanese Gynecologic Oncology Group study (JGOG1067) was designed to evaluate the efficacy and safety of postoperative chemotherapy in patients with node-positive cervical cancer. Methods Patients with stage IB–IIA squamous cervical cancer who underwent radical hysterectomy and were confirmed to have pelvic lymph node metastasis were eligible for this study. The patients postoperatively received irinotecan (CPT-11; 60mg/m 2 intravenously on days 1 and 8) and nedaplatin (NDP; 80mg/m 2 intravenously on day 1). Chemotherapy administration commenced within 6weeks after surgery and was repeated every 28days for up to 5cycles. The primary endpoint of this study was the 2-year recurrence-free survival (RFS) rate. The secondary endpoints were the 5-year overall survival (OS) rate, 5-year RFS rate, and adverse events such as complications of chemotherapy and lower-limb edema. Results Sixty-two patients were analyzed according to our protocol, among whom 55 (88.7%) completed 5cycles of scheduled treatment. The median follow-up period was 66.1months (range, 16.8–96.6months). The 2-year and 5-year RFS rates were 87.1% (95% confidence interval [CI]: 75.9–99.3) and 77.2% (95% CI: 64.5–85.8), respectively. Fourteen patients (22.5%) experienced recurrence during the follow-up period, 8 of whom died of the disease. The 5-year OS rate in this study was 86.5% (95% CI: 74.8–93.0). Only 9.7% of the patients experienced lymphedema in their legs. Conclusion Postoperative chemotherapy without radiotherapy was found to be very effective in high-risk patients with node-positive cervical cancer.

Background Photodynamic therapy (PDT) is known as a minimally invasive treatment for cancer. 5-Aminolevulinic acid (ALA) is a precursor of the photosensitizing agent protoporphyrin IX (PpIX). Patients with ovarian clear-cell carcinoma (CCC) have poorer prognoses than those of patients with other histological CCC types. We evaluated the efficacy of ALA-PDT on CCC cells in vitro. Methods We used seven human CCC cell lines to measure the cytotoxicity of ALA-PDT. PpIX production in cancer cells was measured using a micro-plate reader. Quantitative real-time PCR was performed to assess the mRNA levels of genes involved in the accumulation of PpIX in cancer cells. Additionally, we measured the enhancement in cytotoxicity with the use of an ABCG2 inhibitor. Results We found that three cell lines were highly sensitive to ALA-PDT. In contrast, one cell line was resistant to ALA-PDT. The cytotoxicity of ALA-PDT varied among CCC cell lines. The IC50 values of ALA-PDT for the CCC cell lines had a wide range (30–882 μM). The cytotoxicity of ALA-PDT was correlated with the intracellular PpIX accumulation. The cell lines sensitive to ALA-PDT expressed PEPT1 (an ALA uptake transporter). The cell line resistant to ALA-PDT expressed ABCG2 (a PpIX export transporter). In the resistant cell line, a combination treatment with both ALA and an ABCG2 inhibitor resulted in the promotion of cytotoxic sensitivity. Conclusion The present study revealed the efficacy of ALA-PDT against CCC with chemoresistance in vitro.

Purpose We aimed to determine appropriate treatment guidelines for patients with stages I–II high-grade neuroendocrine carcinomas (HGNEC) of the uterine cervix in a multicenter retrospective study. Patients and methods We reviewed the clinicopathological features and prognoses of 93 patients with HGNEC of International Federation of Gynecology and Obstetrics (FIGO) stages I and II. All patients were diagnosed with HGNEC by central pathological review. Results The median overall survival (OS) and disease-free survival (DFS) were 111.3months and 47.4months, respectively. Eighty-eight patients underwent radical surgery, and five had definitive radiotherapy. The hazard ratio (HR) for death after definitive radiotherapy to death after radical surgery was 4.74 (95% confidence interval [CI], 1.01–15.90). Of the surgery group, 18 received neoadjuvant chemotherapy. Pathological prognostic factors and optimal adjuvant therapies were evaluated for the 70 patients. Forty-one patients received adjuvant chemotherapy with etoposide–platinum (EP) or irinotecan–platinum (CPT–P). Multivariate analyses identified the invasion of lymphovascular spaces as a significant prognostic factor for both OS and DFS. Pelvic lymph node metastasis was also a prognostic factor for DFS. Adjuvant chemotherapy with an EP or CPT–P regimen appeared to improve DFS (HR=0.27, 95% CI, 0.10–0.69). A trend toward improved OS was also observed, but was not statistically significant (HR=0.39, 95% CI, 0.15–1.01). Conclusion Radical surgery followed by adjuvant chemotherapy with an EP or CPT–P regimen was optimal treatment for stages I and II HGNEC of the uterine cervix.

Objectives We reviewed the clinical outcomes of patients with early-stage epithelial ovarian cancer (EOC) who had undergone fertility-sparing surgery (FSS) to assess recurrence-free survival (RFS). Study design After central pathological review and scanning of the medical records of multiple institutions, a total of 94 patients with stage I EOC (IA: 43 and IC: 51) treated with FSS were analyzed. IC substages were defined as follows: intraoperative spillage (IC1), preoperative capsule rupture or surface invasion (IC2), and positive cytology results (IC3). Results The median age was 30.5 (13–40) years. The median follow-up time was 66.6 months. Fourteen patients (14.9%) showed carcinoma recurrence. Eleven (11.7%) patients died of the disease. The total 5-year RFS rate including all women who received FSS was 84.3%. There was no significant difference in RFS between patients with IC1 and those with stage IA ( P =0.9411). In contrast, the RFS rate of patients with IC2/3 was significantly poorer than in patients with stage IA (IA vs. IC2/3: P =0.0487, IC1 vs. IC2/3: P =0.0471). In further analyses according to each histological type and grade, the RFS rate of subjects with the mucinous type was the same as that of those with a clear-cell histology ( P =0.3350). There was a significant difference in RFS of patients with grade 1 (G1) and G2–3 ( P =0.0004). To eliminate selection bias from a number of clinicopathologic factors as thoroughly as possible, the age, FIGO stage, histological type, grade, and postoperative adjuvant chemotherapy were entered into multivariate RFS analyses. Cox multivariable analysis showed that the substage group and grade were independent prognostic factors for RFS. Conclusions Confined to young women with intraoperative rupture, FSS may be proposed, if without tumor-associated dense adhesion. However, those with preoperative rupture, surface invasion, and positive cytology showed a greater risk of recurrence, suggesting that they are not recommended candidates. Although patients with G2–3 tumors showed a poorer prognosis than those with G1, the number of these subjects was so small that the current results should be reconfirmed in the next study.

Objective We analyzed a large number of stage I clear cell carcinoma of the ovary (CCC) patients to estimate the survival impact of the capsule status in stage I CCC patients, particularly in comparison with non-CCC patients. Methods Clinicopathologic data on 564 patients with stage I epithelial ovarian cancer (EOC) collected under the central pathological review system were subjected to uni- and multivariable analyses to evaluate the disease-free survival (DFS) and overall survival (OS). Results There was no significant difference in both the OS and DFS of CCC patients between IA and IC(ir) (intraoperative capsule rupture) {IA vs. IC(ir); OS: P =0.1402, DFS: P =0.2701}. In contrast, CCC patients at IC(non-ir) {IC excluding for IC(ir), such as preoperative capsule rupture, positive ascites/washing, and surface involvement} showed a poorer OS and DFS than those at IC(ir), or those at the corresponding stage in non-CCC. In multivariable analysis, the capsule status was an independent prognostic factor of a poor OS and DFS {OS: HR, 2.832; 95% CI 1.156–6.938; P =0.023; DFS: HR, 4.327; 95% CI, 1.937–9.667; P =0.0004)} {In contrast, non-CCC: N.S. (OS/DFS)}. Furthermore, in CCC patients, intraperitoneal recurrences were more frequently observed in IC(non-ir) CCC than IA or IC(ir) CCC ( P =0.0083) {In contrast, non-CCC: N.S. }. Conclusion This study suggests that CCC patients other than those with intraoperative capsule rupture show a considerable risk for mortality despite adjuvant chemotherapy.

The purpose of this study was to clarify the clinical outcome of patients with stage IA mucinous epithelial ovarian cancer (mEOC) treated with fertility-sparing surgery (FSS).After a central pathological review and search of the medical records from multiple institutions, a total of 148 stage I mEOC patients were retrospectively evaluated in the current study. All mEOC patients were divided into three groups: group A (FSS; age, 40≥); groups B and C {radical surgery; age, 40≥ (B); 40(C)}. Survival analysis was performed among these three groups using Kaplan-Meier methods.The median follow-up time of all mEOC patients was 71.6 (4.8-448.3) months. Among the 41 patients in group A, 27 patients (65.9%) had IA disease, and 14 (34.1%) had IC disease. Five-year overall survival (OS) and disease-free survival (DFS) rates of patients in the groups were as follows: group A, 97.3% (OS)/90.5% (DFS); group B, 94.4% (OS)/94.4% (DFS); group C; 97.3% (OS)/89.3% (DFS). Collectively, there was no significant difference in OS or DFS among these groups even though they were stratified to each substage (IA/IC) (OS, P=0.180; DFS, P=0.445, respectively). Furthermore, in multivariate analyses, the surgical procedure was not an independent prognostic factor for either OS or DFS (OS, HR: 0.340, 95% CI: 0.034-3.775, P=0.352; DFS, HR: 0.660, 95% CI: 0.142-3.070, P=0.596).Patients with stage I mEOC treated with FSS did not necessarily show a poorer prognosis than those receiving radical surgery.

Objective Angiotensin II recently has been reported to promote the growth of several kinds of cells. In this study, we investigated the effect of angiotensin II on cervical carcinoma cells. Study design The expression of angiotensin II type I receptor was examined by immunohistochemistry in normal and neoplastic cervical tissues. Invasion assay was examined in Siha cells (cervical squamous cell carcinoma) and vascular endothelial growth factor levels were assayed with a vascular endothelial growth factor enzyme-linked immunosorbent assay kit. Results Mean staining intensity level was stronger in invasive carcinoma cells than in normal, dysplasia, and carcinoma in situ tissues. Angiotensin II induced the secretion of vascular endothelial growth factor from Siha cells. Furthermore, angiotensin II promoted the invasive potential of Siha cells. These effects were reversed by the addition of anti–human vascular endothelial growth factor antibody and candesartan (antagonist of angiotensin II type I receptor). Conclusion Angiotensin II is involved in the progression of cervical carcinoma, because it induces the secretion of vascular endothelial growth factor through angiotensin II type I receptor, which results in the increased invasiveness of carcinoma cells.