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Background Standard treatments for small cell carcinoma of the cervix (SCCC) have not been established. In this study, we aimed to estimate the optimal treatment strategy for SCCC. Methods This was a multicenter retrospective study. Medical records of patients with pathologically proven SCCC treated between 2003 and 2016 were retrospectively analyzed. Overall survival (OS) was plotted using the Kaplan-Meier method. Log-rank tests and Cox regression analysis were used to assess the differences in survival according to stage, treatment strategy, and chemotherapy regimen. Results Data of 78 patients were collected, and after excluding patients without immunohistopathological staining, 65 patients were evaluated. The median age of the included patients was 47 (range: 24–83) years. The numbers of patients with International Federation of Gynecology and Obstetrics (FIGO) 2018 stages I-IIA, IIB-IVA, IVB were 23 (35%), 34 (52%), and 8 (12%), respectively. Of 53 patients who had undergone chemotherapy, 35 and 18 received SCCC and non-SCCC regimens as their first-line chemotherapy regimen, respectively. The 5-year OS for all patients was 49%, while for patients with FIGO stages I-IIA, IIB-IVA, IVB, it was 60, 50, and 0%, respectively. The 5-year OS rates for patients who underwent treatment with SCCC versus non-SCCC regimens were 59 and 13% (p Conclusion Our results suggest that the application of an SCCC regimen such as EP or IP as first-line chemotherapy for patients with locally advanced SCCC may play a key role in OS. These findings need to be validated in future nationwide, prospective clinical studies.

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P

Background We aimed to compare the detection rate of pelvic sentinel lymph node between the radio-isotope with 99m technetium (99mTc)-labeled phytate and near-infrared fluorescent imaging with indocyanine green in patients with endometrial cancer. Methods This study included 122 patients who had undergone sentinel lymph node mapping using 99mTc and indocyanine green. In the radio-isotope method, sentinel lymph nodes were detected using uterine cervix 99mTc injections the day before surgery. Following injection, the number and locations of the sentinel lymph nodes were evaluated by lymphoscintigraphy. In addition, indocyanine green was injected into the cervix immediately before surgery. Results The overall pelvic sentinel lymph node detection rate (at least one pelvic sentinel lymph node detected) was not significantly different between 99mTc (95.9% [117/122]) and indocyanine green (94.3% [115/122]). Similarly, the bilateral sentinel lymph node detection rate was not significantly different between 99mTc (87.7% [107/122]) and indocyanine green (79.5% [97/122]). More than two sentinel lymph nodes per unilateral pelvic lymph node were found in 12.3% (15/122) and 27% (33/122) of cases with 99mTc and indocyanine green, respectively, in the right pelvic side, and 11.5% (14/122) and 32.8% (40/122) of cases with 99mTc and indocyanine green, respectively, in the left pelvic side. indocyanine green showed that there were significantly more than two sentinel lymph nodes in either the left or right pelvic sentinel lymph nodes (P Conclusion Although indocyanine green is useful for sentinel lymph node identification, we believe it is better to use it in combination with 99mTc until the surgeon is accustomed to it.

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

PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated. METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (N=7,022). Using age-, stage, and site-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors. RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR=1.37; 95% CI=1.10–1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR=1.28; 95 % CI=1.08–1.52, and HR=1.26; 95% CI=1.04–1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS. CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients’ survival.

Background The aim of the current study was to evaluate oncologic outcomes of patients who were treated with salvage hysterectomy (HT), compared to systemic chemotherapy (CT) for persistent cervical cancer after definitive radiotherapy (RT)/ concurrent chemoradiotherapy (CCRT). Methods Patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions from 2005 to 2014 were reviewed retrospectively (n = 317). Those who underwent a HT for persistent cervical cancer after definitive RT/CCRT were matched with propensity scores for patients who underwent systemic CT. Oncologic outcomes between the two groups using a propensity score matched–cohort analysis were compared. Results A total of 142 patients with persistent cervical cancer after definitive RT/CCRT were included after matching (HT: 71, systemic CT: 71). All background factors between HT and CT groups were well balanced. Median overall survival was 3.8 and 1.5 years in the HT and CT groups, respectively (p = 0.00193, hazards ratio [HR] 0.41, 95% confidence interval [CI] 0.23–0.73), Increasing residual tumor size was significantly associated with a high incomplete resection rate (p = 0.016, Odds Ratio 1.11, 95%CI 1.02–1.22). Severe late adverse events occurred in 7 patients (9.9%) in the HT cohort. Conclusion The current study demonstrated that, when compared to systemic CT, the adoption of salvage HT for patients with persistent cervical cancer after definitive RT/CCRT reduced mortality rate by about 60%. This indicates that salvage HT could be curative treatment for those patients. Further prospective clinical trials with regard to salvage HT after RT/CCRT are warranted.

Background 5-Aminolaevulinic acid (5ALA) is a precursor of the strong sensitizer protoporphyrin IX (PpIX) in the heme synthesis pathway. We conducted aclinical trial designed to evaluate the efficacy and safety of 5ALA photodynamic therapy (PDT) using a light-emitting diode (LED) in patients with cervical intraepithelial neoplasia (CIN). Methods Data for 51 CIN patients who underwent 5ALA-PDT between 2012 and 2017 were prospectively analysed. After a 20 % 5ALA jelly formulation was topically applied to the cervix, the region was irradiated with red light at approximately 633 nm to excite PpIX for treatment. We estimated outcomes by cytology, pathology, and human papilloma virus (HPV) testing after PDT. Results Patients underwent two PDT sessions at one-week intervals during outpatient treatment and achieved favourable results without photosensitivity and severe adverse events. Over a long follow-up period, 96.1 % of all patients showed some positive effects, including approximately 70 % with a complete response (CR), 10 % with a partial response, and 15 % with downgrades. The HPV clearance rate in patients with CR was 79.4 %. Recurrence occurred in five patients who mostly remained HPV-positive after PDT. Conclusions Based on our study, topical 5ALA-PDT using an LED light source potentially represents a safe treatment for CIN on an outpatient basis.

The development of cervical cancer is initiated by human papillomavirus (HPV) infection and involves both viral and host genetic factors. Genome-wide association studies (GWAS) of cervical cancer have identified associations in the HLA locus and two loci outside HLA, but the principal genes that control infection and pathogenesis have not been identified. In the present study, we performed GWAS of cervical cancer in East Asian populations, involving 2609 cases and 4712 controls in the discovery stage and 1461 cases and 3295 controls in the follow-up stage. We identified novel-significant associations at 5q14 with the lead single nucleotide polymorphism (SNP) rs59661306 (P = 2.4 × 10-11) and at 7p11 with the lead SNP rs7457728 (P = 1.2 × 10-8). In 5q14, the chromatin region of the GWAS-significant SNPs was found to be in contact with the promoter of the ARRDC3 (arrestin domain-containing 3) gene. In our functional studies, ARRDC3 knockdown in HeLa cells caused significant reductions in both cell growth and susceptibility to HPV16 pseudovirion infection, suggesting that ARRDC3 is involved in the infectious entry of HPV into the cell. Our study advances the understanding of host genes that are responsible for cervical cancer susceptibility and guides future research on HPV infection and cancer development.

ObjectiveThe aim of this study was to compare the outcomes and toxicities of radical hysterectomy (RH) and definitive chemoradiation (CRT) for International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer.Materials and MethodsA retrospective analysis was performed on FIGO stage IIB patients who underwent RH with adjuvant radiotherapy (surgery group) or intended to receive CRT (CRT group). The distributions of disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Propensity score matching (PSM) was performed for the 2 groups based on age, tumor diameter, histological type, and pelvic node metastasis in pretreatment imaging tests.ResultsMedian follow-up times were 58 months in the surgery group (n = 75) and 55 months in the CRT group (n = 65). Propensity score matching identified 37 patients with similar characteristics from each group. Significant differences were observed in the ratio of the chemotherapy combination between the surgery and CRT groups before (47% vs 98%) and after PSM (51% vs 100%). Five-year DFS rates were slightly higher in the surgery group than in the CRT group before PSM (69% vs 58%, P = 0.30) but were similar after PSM (76% vs 82%, P = 0.36). Five-year OS rates were similar between the surgery and CRT groups before (70% vs 75%, P = 0.59) and after PSM (78% vs 77%, P = 0.97). The results of multivariate analyses also showed that neither DFS nor OS was associated with the treatment modalities regardless of PSM. The incidence of late toxicities grade 2 or greater was similar between the surgery and CRT groups before (17% vs 23%, P = 0.31) and after PSM (19% vs 24%, P = 0.78).ConclusionsThe results of this study suggest that RH with adjuvant radiotherapy and definitive CRT are equivalent treatment options for patients with FIGO stage IIB cancer. However, prospective larger studies are needed to confirm this.

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.

Background Medical circumstances in Japanese patients with cancer of the corpus uteri have greatly changed since the late 1990s, including the introduction of concomitant therapy with taxane and platinum. We evaluated changes in survival rates for this cancer following these advances by analyzing data from population-based cancer registries in Japan. Methods Data were available for 8562 cases of cancer of the corpus uteri from six prefectural cancer registries. We defined the two periods of 1993-2000 (1st period) and 2001-2006 (2nd period). Relative survival (RS) in each period was calculated to assess changes using an excess mortality model, with adjustment for age group (15-54, 55-69, and 70-99 years), extent of disease (localized, regional, and distant), and histological subtype. Results Overall 5-year RS improved from 77.7% in the 1st period to 80.2% in the 2nd period, with an excess hazard ratio (EHR) of 0.785 (95% confidence interval [CI], 0.705-0.873). Five-year RS significantly improved in the group aged 55-69 years, in all groups by extent of disease, and in the endometrioid adenocarcinoma group. In particular, 5-year RS significantly improved in patients with endometrioid adenocarcinoma, from 84.5% to 89.7%, with an EHR of 0.698 (95% CI, 0.560-0.870). Conclusion Overall 5-year RS for cancer of the corpus uteri in Japan improved from the 1990s to early 2000s. These improvements might have been aided by the comprehensive medical development of management for this cancer, including the spread of concomitant therapy with taxane and platinum as a standard adjuvant chemotherapy in the early 2000s.

The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.

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.

According to the specified primary objective, a regimen of cisplatin, paclitaxel and bevacizumab was tolerable in Japanese patients and demonstrated encouraging activity in this small single-arm study., Background Adding bevacizumab to chemotherapy for recurrent, persistent or metastatic cervical cancer significantly improved overall survival (primary endpoint), progression-free survival and overall response rate in the randomized Phase III GOG-0240 trial. However, data for bevacizumab-containing therapy are scarce in Japanese patients with advanced cervical cancer. Methods The primary objective of the single-arm multicenter Phase II JO29569 study was to evaluate the tolerability of paclitaxel (135 mg/m2 over 24 h or 175 mg/m2 over 3 h), cisplatin (50 mg/m2) and bevacizumab (15 mg/kg), administered every 3 weeks until disease progression or unacceptable toxicity in Japanese patients with stage IVB, persistent or recurrent cervical cancer. Results The seven treated patients received a median of nine (range 7–12) bevacizumab cycles and six (range 4–12) chemotherapy cycles. None of the predefined adverse events occurred during the tolerability evaluation period. The most common all-grade adverse events were alopecia, hypertension, decreased appetite, nausea and peripheral sensory neuropathy. There were no cases of fistula. The most common grade ≥3 adverse events were hypertension, neutrophil count decreased and neutropenia. Only one patient experienced febrile neutropenia. The overall response rate was 86% (95% confidence interval, 42–100%), including a complete response in one patient. At data cutoff, disease had progressed in one patient; bevacizumab therapy was ongoing in the remaining six. Conclusions According to the specified primary objective, a regimen of cisplatin, paclitaxel and bevacizumab was tolerable in Japanese patients and demonstrated encouraging activity in this small single-arm study. Further study is warranted to confirm the safety and effectiveness of bevacizumab in Japanese patients with cervical cancer.

This study was to analyze patterns and risk factors of relapse after postoperative adjuvant chemotherapy for endometrial cancer.Among patients enrolled in a randomized phase III trial (JGOG2043) investigating the efficacy of adjuvant chemotherapy for endometrial cancer at a high risk of progression, the recurrent patients were studied. Clinical information were collected, and correlation between relapse-related factors and clinicopathological factors were analyzed.Among 193 patients analyzed, 50% had local relapse and 63% had distant relapse. Local relapse involved regional lymph nodes in 30%, while distant relapse involved the abdominal cavity in 42%. Imaging was used to confirm relapse in 83%, and the median disease-free interval (DFI) was 11.5 months. Factors showing a significant correlation with DFI ≤12 months were residual tumor at surgery (p 0.01), Grade 3 histology (p 0.01), and lymph node metastasis (p = 0.03). In contrast, treatment with paclitaxel and carboplatin showed a significant correlation with DFI12 months (p = 0.04). The median post-relapse overall survival (RS) was 23.9 months. In multivariate analysis, CA125 ≥ 100 U/mL prior to relapse (p 0.01), distant metastasis (p 0.01), DFI ≤ 12 months (p = 0.02), and not performing para-aortic lymphadenectomy (p = 0.01) were independently related to poor RS.Relapse of endometrial cancer following adjuvant chemotherapy often occurs by 1 year after treatment, with common relapse sites of the abdominal cavity and regional lymph nodes. Among treatment-related factors, RS was correlated with DFI and para-aortic lymphadenectomy.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

Importance The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer. Objective To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer. Design, Setting, and Participants In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017. Interventions Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL × min) on day 1 every 3 weeks. Main Outcomes and Measures The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection. Results Among 788 eligible patients, the median (SD) age was 59 (22-74) years; 263 patients were assigned to doxorubicin plus cisplatin treatment, 263 patients to docetaxel plus cisplatin treatment, and 262 patients to paclitaxel plus carboplatin treatment. The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187;P = .12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215;P = .67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively. Conclusions and Relevance There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin. Trial Registration UMIN-CTR identifier:UMIN000000522

Background: The number of elderly patients with gynecological cancer in Japan is increasing in line with the aging of society. However, little has been reported on the survival of elderly patients aged 75 or older with gynecological cancer in Japan. Methods: To clarify survival in women aged 75 years or older with gynecological cancer, we analyzed data of 4,089 gynecological cancer cases (cervical cancer, 1,309 cases; endometrial cancer, 1,319 cases; and ovarian cancer, 1,461 cases) in patients aged 75 or older from 21 population-based cancer registries in Japan, diagnosed in 2006-2008. We calculated the net survival (NS) of younger (75-79 years old), older (80-84 years old) and the oldest age group (85-99 years old). We also calculated NS stratified by extent of disease and histological type. Results: Five-year NS of cervical cancer patients was 54.5% in the younger age group, 40.8% in the older age group and 28.2% in the oldest age group. Five-year NS of endometrial cancer patients was 64.5%, 51.6% and 39.0% in the younger, older and oldest age groups, respectively. Five-year NS of ovarian cancer was 34.7%, 18.8% and 8.3%, respectively. Conclusion: We estimated NS in elderly patients aged 75 years or older with gynecological cancers in Japan using data from population-based cancer registries.

Anticancer drug sensitivity affects prognosis in ovarian carcinoma. Previously, we purified spectrin αII and βII tetramers from cisplatin‐resistant ovarian serous adenocarcinoma cells and demonstrated that they contribute to platinum anticancer drug resistance. In this clinical study, we focused on the role of spectrin αII expression. It is our objective to demonstrate the potential of spectrin αII expression as a useful predictor of anticancer drug resistance and postoperative prognosis in epithelial ovarian carcinoma. Spectrin αII expression in the ovarian adenocarcinoma surgical specimens of 193 patients was examined by immunohistochemical staining. Staining strength was scored 3+, regarded as positive expression, and 2+, 1+, and 0, regarded as non‐positive expression. Prognoses obtained from clinical records were evaluated by statistical analysis. In the 193 cases studied, positive spectrin αII expression was associated with worse overall survival when compared with non‐positive expression (P

Background/aim The incidence of delayed chemotherapy-induced nausea and vomiting (CINV), especially nausea, in gynecologic cancer patients who receive paclitaxel and carboplatin (TC) chemotherapy is unclear. We assessed risk factors for delayed CINV in these patients, and examined whether it was controlled with combination antiemetic therapy. Materials and methods Data were pooled from two prospective studies, and compared between the two antiemetic prophylaxis groups using inverse probability of treatment weighted (IPTW) analysis. Results Among the 182 evaluable patients (mean age: 56.2 years), three antiemetics gave better overall control than two for delayed nausea (42.9% vs. 57.4%,) and vomiting (13.8% vs. 34.5%). Risk factor for delayed nausea was age [odds ratio (OR)=0.953; p=0.0898[and use of two antiemetics (vs. three antiemetics) for delayed vomiting (OR=0.304; p=0.0732). Conclusion A combination of three antiemetics controls delayed CINV among patients who undergo TC chemotherapy. Identification of risk factors can facilitate personalized treatments.

Aim The purpose of this study was to develop a scale to assess daily time management capabilities among working patients with diabetes and to test this scale's reliability and validity. Methods A self-administered questionnaire survey was conducted among 277 diabetes outpatients, and data from 220 participants (mean age = 54.3 ± 10.2 years, 76.8% male) were analyzed. Questionnaire items were selected through exploratory factor analysis. During the process of developing the questionnaire, opinions were solicited from experts on education for patients with diabetes, and Cronbach's α was calculated as a coefficient of reliability. Correlations with the Instrument of Diabetes Self-Care Agency (IDSCA) were examined and confirmatory factor analysis was performed to check for validity. Results Adequacy of a 4-factor, 16-item scale was confirmed. Cronbach's α coefficient was ≥.7 for the entire scale and for the subscale items. There was a significant correlation between total IDSCA scores and various factors (r = .280-.469). However, there was no correlation between the "adjustment of life rhythms" and parts of the IDSCA subscale. Conclusion Although some aspects warrant further investigation, the developed scale provides a reliable and valid means of assessing daily time management capabilities among working patients with diabetes, and can thus be applied to help diabetes patients to manage their daily lives.

Objectives The objective of this study was to assess the effect of extensive lymphadenectomy on survival of early-stage cervical cancer patients with radical hysterectomy followed by adjuvant radiotherapy (RT). Materials and Methods A retrospective analysis was performed on early-stage patients with high-risk factors who received radical hysterectomy with lymphadenectomy followed by adjuvant RT. All patients were divided into the less than or equal to 40 dissected pelvic lymph nodes (DPLN ⩽40) and greater than 40 dissected pelvic lymph nodes (DPLN >40) groups to assess the effect of extensive lymphadenectomy. Distributions of disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Significance of survival was assessed by the log-rank test. Cox proportional hazards models were applied to assess the effects of the factors on survival by univariate and multivariate analyses. Results After a median follow-up of 76 months for a total of 178 patients, 5-year DFS of the DPLN >40 group was significantly higher than that of the DPLN ⩽40 group (86% vs 74%, P = 0.045). Five-year OS was comparable between the 2 groups (85% vs 78%, P = 0.49). The multivariate analysis showed that the DPLN ⩽40 group was at a significantly higher risk of recurrence (hazard ratio, 2.3; 95% confidence interval (CI), 1.1–4.8; P = 0.020), whereas OS was not affected by the DPLN group (P = 0.26). Positive pelvic lymph node, parametrial invasion, histological type, and the absence of RT-combined chemotherapy remained significant prognostic factors for lower DFS and OS by the multivariate analysis. Adjusted hazard ratio of DPLN ⩽40 for DFS was 1.2 (95% CI, 0.11–12; P = 0.91) in patients with negative pelvic lymph node (PLN) whereas it was 2.6 (95% CI, 1.1–5.8; P = 0.024) in patients with positive PLN. Conclusions These results suggest that more extensive lymphadenectomy significantly improve the outcomes of patients with positive PLN even followed by adjuvant RT.

Objective Perifosine exhibits anti-tumor activity by inhibiting AKT phosphorylation. The purpose of this phase II basket trial was to evaluate the efficacy and safety of perifosine monotherapy for ovarian, endometrial, and cervical cancers. Methods Recurrent or persistent ovarian, endometrial, or cervical cancer patients were assigned to PIK3CA wild-type or mutant groups. Each patient received 600 mg oral perifosine on day 1 followed by a maintenance dose of 100 mg daily. The primary endpoint was disease control rate; secondary endpoints included response rate, progression-free survival, overall survival, and safety. Immunohistochemical staining and targeted sequencing were used to explore new biomarkers in such patients. Results Sixteen and 5 ovarian, 17 and 7 endometrial, and 18 and 8 cervical cancer patients with PIK3CA wild-type and mutant, respectively, were enrolled. Disease control rates (wild-type/mutant) were 12.5/40.0%, 47.1/14.3%, and 11.1/25.0% in ovarian, endometrial, and cervical cancer, respectively. The most common grade 3/4 toxicities were anemia (22.5%) and anorexia (11.3%). Immunohistochemical staining revealed that the disease control rate in patients with negative phosphatase and tensin homolog (PTEN) expression was 50.0%, and the odds ratio of positive to negative patients was 0.24 in all patients. Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients with PIK3CA mutations and endometrial cancer patients with PIK3CA wild-type; no difference was observed between PIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy.

Medroxyprogesterone acetate (MPA) is used to preserve fertility in patients with Grade 1 endometrial cancer without myometrial invasion (G1EA) and those with atypical endometrial hyperplasia (AEH). However, the efficacy of retreatment with MPA has not been sufficiently established for patients who experience recurrence but wish to retain their fertility. This study aimed to show the effectiveness of MPA treatment and retreatment for AEH and G1EA.A total of 39 patients received MPA treatment between 2005 and 2015, including nine with G1EA and 30 with AEH. The patients received high-dose (600 mg/day) MPA for 26 weeks. If a complete response was not achieved, MPA treatment was continued. After complete remission, if there was a recurrence, the patient was offered a choice of a hysterectomy or retreatment with MPA. The gynecologic and obstetric outcomes were retrospectively analyzed.The median age was 34 years, and the median body mass index was 23.3 kg/mMPA can be effective for G1EA and AEH treatment even when they recur.

Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited. We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer. Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97–1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19–3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03–1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival. In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.

Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients. Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes. Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced). Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival. Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470–3. ©2017 AACR.

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.

Endoglin (CD105), an accessory receptor of transforming growth factor-β, is expressed in vascular endothelial cells. Recently, it was reported that endoglin expression was significantly associated with poorer survival in several cancers. In this study, we evaluated the role of endoglin in uterine leiomyosarcoma. We examined the expression of endoglin in 22 uterine leiomyosarcomas and the association between their expression and the outcome. Additionally, to evaluate the function of endoglin, we used SKN cells, a human uterine leiomyosarcoma cell line. We generated SKN cells stably transfected with plasmids encompassing shRNA targeting endoglin (shEng cells), and compared the ability of proliferation, migration, and invasion to control shRNA-transfected cells (shCon cells). We compared the level of VEGF and matrix metalloproteinases (MMP) in culture supernatants of shEndoglin and shControl cells. Nine patients were endoglin-positive and 13 patients were -negative. The endoglin-positive group had a significantly poorer overall survival and progression-free survival than the endoglin-negative group. In an in vitro study, there was no difference in cell proliferation between shEng and shCon cells. On the other hand, shEng cells showed a lower ability for migration and invasion than shControl cells. The activity of MMP-9 and VEGF level in the supernatant from shEng cells were lower than in shCon cells. In uterine leiomyosarcoma, endoglin expression was associated with a poor prognosis. It was suggested that endoglin up-regulated invasion and VEGF secretion. The investigation of endoglin may lead to a new strategy in uterine leiomyosarcoma therapy.

This study was conducted to assess the long-term clinical outcome for patients with recurrent mucinous epithelial ovarian cancer (RmOC) in comparison with recurrent serous epithelial ovarian cancer (RsOC). Three hundred and eighty-four patients with recurrent ovarian cancer, including 340 RsOC and 44 RmOC patients, were analyzed in this study. The pathological slides were evaluated under central pathological review. The prognostic significance of clinicopathological factors was evaluated employing both uni- and multivariable analysis. The 3- and 5-year postrecurrence survival (PRS) rates of patients with RmOC were 17.3, and 6.9 %, respectively. In contrast, those of patients with RsOC were 29.8 and 18.8 %, respectively. The PRS of patients with RmOC was significantly poorer than that of patients with RsOC (PRS: P = 0.0006). Moreover, either in the presence or absence of a residual tumor (RT) at initial surgery, the PRS of patients with RmOC was markedly poorer than that of patients with RsOC [RT (−): P

Contains fulltext : 174140.pdf (Publisher’s version ) (Closed access) PURPOSE: Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype. METHODS: Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes. RESULTS: History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94. CONCLUSIONS: Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Women with ovarian cancer (OC) often experience relapse and receive further repetitive chemotherapy. The objective of this study was to overview the remaining survival time after the final chemotherapy and to examine influential clinicopathologic indicators in those patients.The medical charts of deceased OC patients who had died of the disease between 2003 and 2012 were retrospectively reviewed. We investigated post-cancer-treatment survival (PCS) defined as the interval between the date of the final chemotherapy and death.In all, 77 patients were enrolled. Three patients (3.9%) had received chemotherapy in the last 2 weeks. Eight (10.4%), 28 (36.4%), and 44 (57.2%) patients had received chemotherapy in the last 30, 60, and 90 days, respectively. There were no differences in either survival after recurrence or overall survival between the shorter (75 days) and longer (≥75 days) PCS groups. On the other hand, patients in the shorter PCS group had significantly fewer chances of referral to a hospice or home-care than those in the latter group (P = 0.035). In multivariable analysis, a poorer performance status, an elevated white blood cell count, and a higher C-reactive protein value were significantly correlated with a shorter PCS (P = 0.004, 0.006 and 0.027, respectively).Half of the patients received chemotherapy within 75 days of death and we did not identify any survival benefit in patients who received chemotherapy near the end of life. We should provide information to patients about their prognosis and discuss the timing of withdrawal from chemotherapy from the early stage of their recurrence.

Radical trachelectomy (RT) is a widely used fertility-sparing treatment for patients with early cervical cancer (CCA). RT, however, is an investigational treatment, and its gynecological and obstetric efficacy are being investigated. We retrospectively assessed the efficacy of abdominal RT (ART) as a fertility-sparing surgery.From 2010 to 2014, patients with stage IA2-IB1 CCA (tumor ≤2 cm) who wished to preserve their fertility underwent ART. The major outcomes were mortality, recurrence, pregnancy complications, and obstetric outcome.Twenty-eight patients received ART. Adjuvant chemotherapy was performed in seven patients because of lymphovascular space invasion. During the median follow-up of 43 months, no recurrences occurred. Twelve women attempted to conceive, and eight of them became pregnant. A total of five children were born, and one baby was full term. Three cases of second trimester, and one case of third trimester preterm births were recorded.Fertility was preserved after ART in a moderate number of patients. The pregnancy and birth rates after ART have been improving, and increasing the full-term birth rate is the next goal. In addition, development of further types of minimally invasive surgery for CCA can be expected.

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.

Background: Clear-cell carcinoma of the ovary (CCC) is often diagnosed at childbearing age, or sometimes during treatment for infertility. Therefore, most young women with early-stage CCC wish to preserve their reproductive and endocrine functions if possible. Methods: Clinicopathologic data collected under the central pathological review system were subjected to survival analyses. We analyzed patients with stage I CCC who underwent fertility-sparing surgery (FSS, n = 16) and compared their long-term survival with those receiving radical surgery (n = 205), or patients with non-CCC undergoing FSS (n = 64). Results: There was no difference in both the overall survival (OS) and disease-free survival (DFS) between patients with CCC who underwent FSS and those who received radical surgery [CCC/FSS (n = 16) versus CCC/radical (n = 205); OS: P= 0.519, DFS: P= 0.265]. Moreover, patients with CCC who underwent FSS did not show a poorer OS and DFS than non-CCC patients who underwent FSS (CCC/FSS versus non-CCC/FSS; OS: P= 0.584, DFS: P= 0.401), or those at the corresponding stage with no CCC. Furthermore, according to the series of patients with CCC in both the current study and four studies in the literature, there was no difference in the recurrence rate between patients with or without CCC who were treated conservatively (CCC/FSS: 13.2% versus non-CCC/FSS: 10.9%, P= 0.614). Conclusions: Although our study did not have sufficient power to yield a definite conclusion, our data suggests that at least patients with stage IA CCC may be treated with FSS.

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.

Benign metastasizing leiomyoma (BML) is a rare disease that is caused by metastasis of a histologically benign leiomyoma that spreads to distant organs. Metastasis commonly follows surgical treatment of myomectomy or hysterectomy for benign uterine leiomyoma. Since the work of Steiner in 1939, several other studies have been published, but a unified view has not emerged regarding the biological nature, pathogenesis, and prognosis of this disease. In particular, a standard treatment has not been established. Here we report a case of BML of the lung and peritoneum in a premenopausal 45-year-old woman who underwent hysterectomy for uterine leiomyoma 10 years earlier. A computed tomography (CT) scan showed multiple pulmonary nodules (maximum size 48 mm) and a solitary intra-peritoneal nodule. The lung nodules were diagnosed as BML following a CT-guided needle biopsy. Histologically, the biopsied tumor was composed of spindle cells without significant atypia, and mitosis was not observed. Immunohistochemically, the tumor cells were strongly positive for smooth muscle actin, desmin, and estrogen receptor, suggesting a uterine leiomyomatous lineage. The patient was treated with a gonadotropin-releasing hormone agonist for 36 months, during which time the nodules reduced in size slightly. No new lesions appeared, and the tumors were stable at 15 months after the cessation of treatment. In conclusion, endocrine therapy can serve as one of the conservative treatments for premenopausal women with BML, rather than surgery.

Background and Objectives There were a few reports of a large number of patients with clear cell adenocarcinoma (CCA) of the ovary because of the low incidence of CCA. This study compared the clinical factors affecting long-term survival of patients with CCA to those with serous cystadenocarcinoma (SCA). Methods One hundred and seventy-eight CCA and 311 SCA patients treated between 1987 and 2000 were retrospectively evaluated. Differences in survival rates were calculated using log-rank test and Cox's proportional hazards analysis was used to identify independent prognostic factors. Results The ratio of stage I was significantly higher than that of SCA. There was no significant difference of 8-year survival rate in each stage between CCA and SCA. However, the patients with stage IIIb or IIIc CCA showed significantly worse prognosis than those with SCA. Positive peritoneal or ascitic cytology, the presence of residual tumor, more than 100 ml ascites were demonstrated to have the significant impact on survival by univariate analysis. Multivariate analysis demonstrated that stage, more than 100 ml ascites, and the presence of residual tumor were significant prognostic factors of CCA overall survival. Conclusions Distribution of stage and substage differed between CCA and SCA in this study. Thus, substaging is quite important for comparison of prognoses between histologies, and CCA showed poorer prognoses than serous adenocarcinoma in stages IIIb and IIIc. J. Surg. Oncol. 2006;94:138–143. © 2006 Wiley-Liss, Inc.

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.

It remains unknown whether the end-of-life (EOL) environment influences survival after anticancer treatment, particularly for gynecologic malignancy.The study's objective was to clarify whether the survival time varied depending on where patients spend the EOL.This retrospective study included patients who received initial oncologic treatment but died due to cancer recurrence and/or progression. The subjects were a cohort of 181 gynecologic malignant tumor cases in a single institution from 2002 to 2008. Measurement was of postcancer treatment survival (PCS), defined as the time interval between the last date of anticancer treatment after recurrence/progression and death from the disease, analyzed on stratification by type of supportive care or where patients spent the EOL.The median survival time was 26.1 (1.0-306.4) months. The distribution of the carcinoma type was as follows: 28.7% of patients with cervical (N=52), 27.6% with endometrial (N=50), and 43.1% with ovarian (N=79) cancer. The median PCS was 13.3 weeks. Patients in the hospice/home care group showed a significantly more favorable PCS than those in the hospital group (log rank: P=0.029). On multivariate analysis, the age (60 versus ≥60) and site of supportive care (hospital versus hospice/home care) retained their significance as independent prognostic factors of poor PCS (age: HR=0.679, 95% CI, 0.496-0.928, P=0.0151; site of supportive care: HR=0.704, 95% CI, 0.511-0.970, P=0.0319).Our current data could be hypothesis generating; it is possible that the EOL environment is a crucial prognostic factor for survival after anticancer treatment.

Objectives This study was conducted to estimate the oncologic outcome of stage I epithelial ovarian carcinoma (EOC) patients after recurrence. Study design After central pathological review and searching of the medical records of multi-institutions, a total of 103 relapsed patients with stage I EOC were analyzed. The major endpoint was postrecurrence survival (PRS). Results The median follow-up for surviving patients was 57.5 (5.7–242.0) months. The median age was 52 (14–89). Among the patients, 19 (18.4%) had FIGO IA disease, and 4 (3.9%) and 80 (77.7%) had IB and IC disease, respectively. Regarding the histological type, the clear-cell type was the most frequently observed ( N = 42: 40.8%). The 3/5-year overall and PRS rates of all patients were 63.7/47.9 and 38.2/24.0%, respectively. The 5-year PRS rates of patients with serous, endometrioid, clear-cell, and mucinous tumors were 44.9, 35.0, 19.8, and 0%, respectively. On stratifying by the histological type, the overall and postrecurrence survival rates of patients with the mucinous/clear-cell types were significantly poorer than in those with the non-mucinous/clear-cell types (OS: P = 0.0253, PRS: P = 0.0016). In multivariate analyses, the FIGO stage (IA/IB vs. IC) and histological type (clear-cell/mucinous vs. non- clear-cell/mucinous) retained their significance as prognostic factors of a poorer PRS {stage IC (vs. IA/B): HR: 2.176 (95% CI: 1.059–4.470), P = 0.0343: clear-cell/mucinous (vs. non- clear-cell/mucinous): HR: 2.486(95% CI: 1.416–4.364), P = 0.0015). Conclusions Even if at stage I, once patients with a mucinous/clear-cell histology experience recurrence, subsequent survival is extremely poor.

We aimed to investigate the possibility of an association between a stem-like hallmark and radiotherapeutic sensitivity in human cervical carcinoma cells.Side-population (SP) cells and non-SP (NSP) cells in HeLa cells were isolated using flow cytometry and Hoechst 33342 efflux. We performed Western blot analysis to evaluate the expression of stem cell markers (CXCR4, Oct3/4, CD133, and SOX2) and apoptosis markers after irradiation. In addition, SP and NSP cells were injected into nude mice and we assessed subcutaneous tumor formation. To examine tolerance of irradiation, colony formation and apoptosis change were confirmed in the SP and NSP cells.SP cells showed a higher expression of CXCR4, Oct3/4, CD133, and SOX2 than NSP cells. The colony size of SP cells cultured on non-coated dishes was larger than that of NSP cells, and NSP cells were easily induced to undergo apoptosis. SP cells tended to form spheroids and showed a higher level of tumorigenicity compared with NSP cells. In addition, nude mice inoculated with SP cells showed greater tumor growth compared with NSP cells. SP cells showed a higher tumorigenicity and lower apoptotic potential, leading to enhanced radiotolerance.Tumor SP cells showed higher-level stem-cell-like characters and radioresistance than NSP cells. SP cells may be useful for new therapeutic approaches for radiation-resistant cervical cancer.

We retrospectively analyzed the clinicopathological features and evaluated the prognostic indicators of recurrence in 132 patients with clear cell adenocarcinoma (CCC) of the ovary at reproductive age. Between 1986 and 2011, as a regional population-based study, clinicopathological data on 132 young patients with CCC, collected under the central pathological review system, were subjected to uni- and multivariable analyses to evaluate recurrence-free survival (RFS). The median age was 40 (27–45) years. The median follow-up period for surviving patients was 46.4 months. During the observation period, there were 16 recurrences in 87 patients with stage I tumors (18.4 %), 8 in 17 with stage II (47.1 %), and 16 in 28 with III–IV (57.1 %). Subsequently, 35 patients died of the disease. Those with stage I or II did not reach the median RFS. The median RFS of stage III–IV was 21.6 months. When analysis was confined to stage I patients, there was no significant difference in the RFS of CCC patients between IA and IC(r) (intraoperative capsule rupture) (P = 0.7957). In contrast, CCC patients with IC excluding IC(r) [IC(non-r)] showed a poorer RFS than those with IC(r) (P

BackgroundIt is controversial whether patients with stage I ovarian clear cell carcinoma (CCC) benefit from postoperative chemotherapy. This study was designed to evaluate the postoperative outcomes associated with the inclusion or exclusion of adjuvant therapy in these patients.MethodsA total of 185 patients who were treated for stage I CCC between 1991 and 2007 were retrospectively evaluated. All of the patients had received comprehensive surgical staging, and their condition had been diagnosed by a central pathological review system. Only one patient with stage IB was excluded from this study.ResultsMedian follow-up time was 62 months (range 7–191 months). Median age was 52 years (30–75 years). There were 41, 93, and 50 patients in stage IA, intraoperative capsule ruptured IC (rupture-IC), and all other-IC groups, respectively. The 5-year recurrence-free survival rates for the substage were 97.6%, 87.8%, and 70.4% (P < 0.001), respectively. Among 134 patients consisting of those in the stage IA and rupture-IC groups, 91 patients received adjuvant chemotherapy (AC) and 43 patients did not (non-AC). There was no significant survival difference in each substage group between the non-AC and AC groups in 5-year recurrence-free survival rate (stage IA, 100% vs 93.8%; rupture-IC, 94.1% vs 86.6%). Multivariate analysis demonstrated that there was no significant prognostic factor for both recurrence and survival among the IA and rupture-IC groups. Postoperative therapy, regimen, and chemotherapy cycles were not significantly affected.ConclusionsThis study indicates that adjuvant chemotherapy does not contribute to the improving prognosis of stage IA ovarian CCC. Whereas the histological type is CCC, the routine adjuvant chemotherapy after comprehensive surgical staging may be unnecessary for patients with at least stage IA.

To estimate the long-term clinical outcome of patients with recurrent clear cell carcinoma (RCCC) of the ovary in comparison with those with recurrent serous adenocarcinoma (RSAC).In this study, 113 patients with RCCC and 365 patients with RSAC were analyzed. The pathological slides were evaluated under central pathological review. End points were the overall survival (OS), postrecurrence survival (PRS), and timing of death of mortality cases.The 5-year OS and PRS rates of patients with RCCC were 22.5 and 13.2%, respectively. In both OS and PRS, the prognosis of patients with RCCC was significantly poorer than that of the patients with RSAC (OS: P = 0.0007; PRS: P0.0001). Moreover, regardless of the status of the residual tumor (RT) at the initial surgery, the OS and PRS of the patients with RCCC were markedly shorter than those with RSAC (RT [-]: OS, P = 0.0005: PRS, P = 0.0002: RT [+]: OS, P0.0001: PRS, P0.0001). In multivariable analysis, the histological type was a significantly poorer prognostic indicator for OS and PRS (OS [RCCC vs RSAC]: hazard ratio, 2.302: 95% confidence interval, 1.723-3.076; P0.0001: PRS [RCCC vs RSAC]; hazard ratio, 2.353: 95% confidence interval, 1.756-3.155; P0.0001). Even in the deceased patients (n = 350), the rate of patients with RCCC dying within 12 months of recurrence was higher than that of RSAC (RCCC, 67.8%; RSAC, 40.7%; [P0.0001]).The long-term clinical outcome of patients with RCCC was extremely poor. We confirmed that RCCC should be investigated as a different malignancy compared with RSAC.

The effect of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced epithelial ovarian cancer (aEOC) who are optimally debulked.Demographic and clinicopathologic data were obtained from the Tokai Ovarian Tumor Study Group between 1986 and 2009. All patients were divided into two groups. Group A (n = 93): (i) patients did not undergo SRL; and (ii) lymph node exploration or sampling was optional. Group B (n = 87): patients underwent SRL. Survival curves were calculated using the Kaplan-Meier method. Differences in survival rates were analyzed using the log-rank test.All pT3-4 aEOC patients were optimally debulked (residual tumor1 cm). The median age was 55 years (range: 18-84). The 5-year progression-free survival (PFS) rates of groups A and B were 46.7 and 41.9%, respectively (P = 0.658). In addition, the 5-year overall survival (OS) rates were 62.9 and 59.0%, respectively (P = 0.853). Subsequently, there was no significant difference in OS and PFS in the two groups stratified to histological type (serous or non-serous type). Furthermore, there was no significant difference in recurrence rates in retroperitoneal lymph nodes regardless of completion of lymphadenectomy.Our data suggest that aEOC patients with optimal cytoreduction who underwent SRL did not show a significant improvement in survival irrespective of each histological type.

Primary ovarian malignant germ cell tumors (OMGCTs) are rare and difficult to diagnose. Immunohistochemistry can help in the diagnosis and development of new management strategies. The aim of this study was to investigate the frequency of CD117, CD133, SALL4, OCT4, TCL1 and glypican-3 marker expression in OMGCTs.We examined the expression of six markers in 87 (85 pure and two mixed OMGCTs) cases of OMGCT using immunohistochemical staining. Staining was graded in a semiquantitative manner as follows: negative (no staining), 1+ (1-30% staining), 2+ (31-60% staining), or 3+ (60% staining).All 27 dysgerminomas and all 31 YSTs showed CD117 expression, with only nine (29%) positively stained in immature teratomas. SALL4 and glypican-3 were strongly positive in 100 and 79.3%, respectively, of YSTs. All dysgerminomas were positive for OCT4, whereas all YSTs and immature teratomas were negative. 100% of dysgerminomas were positive for TCL1, but all immature teratomas were negative. CD133 expression showed generally the same tendency in the 3 OMGCTs.CD117 can be used as a diagnostic marker for dysgerminoma and YST. SALL4 is a more sensitive and specific marker for YSTs than glypican-3. SALL4 and OCT4 are useful in distinguishing YST from dysgerminoma.

Twist, a basic helix-loop-helix transcription factor, promotes cancer cell epithelial-mesenchymal transition and metastasis. Here, we aimed to examine the association between Twist expression and lymphovascular space involvement for early-stage cervical carcinoma. Paraffin sections from 90 patients with stage Ib to IIb cervical carcinoma were immunostained with Twist antibody, and the staining intensities were semiquantitatively evaluated. Of the 90 cervical carcinoma specimens examined in this study, 51 (56.7%) were negative for Twist and 39 (43.3%) were positive for Twist immunoreactivity. The 5-year overall survival rates of patients in the Twist-negative and Twist-positive groups were 98.0% and 75.8%, respectively. Univariate and multivariate analyses demonstrated that Twist expression was an independent prognostic factor for overall survival and recurrence-free survival (univariate: P = .0069 [overall survival], P = .0092 [recurrence-free survival]: multivariate: P = .0118 [overall survival], P = .0118 [recurrence-free survival]). On stratifying based on the negative lymphovascular space involvement status, the overall survival and recurrence-free survival of patients in the Twist-negative group was the same as that of those in the Twist-positive group (log-rank: P = .262 [recurrence-free survival], P = .899 [overall survival]). In contrast, with lymphovascular space involvement, a significantly poorer recurrence-free survival was predicted for patients in the Twist-positive group compared with that in the Twist-negative group (P = .0021). Twelve (75.0%) of 16 patients showing recurrence belonged to the Twist-positive group, and 83.3% (10/12) of them experienced recurrence in distant organs or the peritoneal cavity. This study suggested that the assessment of the Twist immunoreactivity and lymphovascular space involvement may distinguish high- from low-risk patients with locally invasive cervical carcinoma.

Objective In recent years it has been indicated that ecological niches play important roles in the maintenance of cancer stem cells (CSCs). We investigated interactions between peritoneal mesothelial cells and SC-OYST based on the hypothesis that peritoneal mesothelial cells have the potential to provide one of the niches for SC-OYST. Methods We divided NOY1cells into CD133-positive and -negative cells. Using the co-culture of NOY1 and peritoneal mesothelial cells, we compared the expression of CD133, colony formation, and the capacity for migration and invasion. In addition, we assessed the inhibitory effects of AMD3100, a neutralizing antibody against a chemokine receptor (CXCR4). Then, we examined whether AMD3100 affects the tumorigenicity of NOY1-CD133+ cells in vivo. Results When NOY1 cells were co-cultured with peritoneal mesothelial cells, we observed the high-level expression of CD133. The number of colonies of NOY1-CD133+ cells was 2.4 times that of NOY1-CD133− cells. In contrast, on co-culture with peritoneal mesothelial cells, it was 4.3 times. When NOY1 cells were cultivated in the upper layer and peritoneal mesothelial cells were cultivated in the lower chamber, NOY1-CD133+ cells showed a greater capacity for migration and invasion than NOY1-CD133− cells. By adding AMD3100 to the co-culture systems, the colony formation, migration, and invasion of NOY1-CD133+ cells were inhibited. In addition, AMD3100 inhibited the tumorigenicity of NOY1-CD133+ cells in vivo. Conclusions Our data suggest that peritoneal mesothelial cells have the potential to provide one of the niches for NOY1 cells. Investigation of the niches of SC-OYST will help elucidate important targets for therapeutic approaches.

Low-grade endometrial stromal sarcoma (ESS) is a rare tumor. Endocrine treatment is frequently necessary, but treatment details have not been established. Thirteen consecutive patients with low-grade ESS were examined clinicopathologically. All patients underwent surgery, and six were treated with a uniform regimen of medroxyprogesterone acetate (MPA) against residual or recurrent disease. Of the 13 patients, 9 were in stage I, whereas the others were in advanced stages. The median follow-up period was 117 months (range 43–170 months). Six patients, including three with residual peritoneal dissemination and three with recurrent tumors, were treated with MPA. Six months after the initiation of treatment, 3 patients demonstrated a partial response, and 3 patients demonstrated stable disease. The median dosing period was 64 months (range 28–92 months). Five of the patients, including 2 patients who are alive with no evidence of disease and 3 patients who are alive with disease, continue with MPA therapy. The clinicopathological characteristics of the low-grade ESS in this study are consistent with those reported in previous studies. MPA therapy with residual or recurrent disease achieved excellent disease control over a period of 5 years. These results indicate that MPA therapy might be considered as a therapeutic option for residual or recurrent low-grade ESS and perhaps chosen as a first-line therapy.