Search

Aim: The purpose of this study was to investigate whether the Ki67 values were associated with survival for predicting prognosis in patients with advanced ovarian cancer receiving neoadjuvant chemotherapy (NACT)., Methods: Among 17 patients treated with NACT, 13 patients were available for tissue samples from matched pre- and post-therapy tissues. Ki67 scores were transformed to a logarithmic scale for the statistical analyses. The optimal cutoff values of the log-phase Ki67 were assessed by receiver operating characteristic (ROC) analysis. Kaplan-Meier analysis, the log-rank test, and Cox regression analysis were carried out to analyze survival., Results: The Ki67-decrease and post-NACT Ki67 were the independent factors associated with relapse-free survival (RFS) (p < 0.001 and p = 0.003). No association was observed on overall survival. The optimal cutoff values for the Ki67-decrease and the post-NACT Ki67 were 6.67% and 5.46 based on ROC where the area under ROC curves (AUC) were 1.00 (p < 0.001) with the 100% sensitivity and specificity. The median RFS was 537 days in patients showing Ki67-decrease >6.66% or post-NACT Ki67 level <5.46, while it was 224 days in those with Ki67 decrease ≤6.66% or post-NACT Ki67 level ≥5.46 (p = 0.001)., Conclusions: The Ki67-decrease and the lower post-NACT Ki67 are independent factors associated with favorable RFS, indicating that they could be precise biomarker candidates for prognosis in NACT-administered patients with advanced ovarian cancer., (© 2021 Japan Society of Obstetrics and Gynecology.)

Background/aim: Hypersensitivity reactions (HSRs) to carboplatin, a key drug for ovarian cancer patients, are problematic. The aim of this study was to evaluate the efficacy and safety of readministration of platinum agents (PTs) in recurrent ovarian cancer patients who developed HSRs to carboplatin., Patients and Methods: Thirty-one patients with recurrent ovarian cancer who developed HSRs to carboplatin were divided into those who continued to receive PTs in the following cycle (continuation group, n=24) and those in whom either the drug was switched to non-platinum agents (non-PTs) or chemotherapy was ended (discontinuation group, n=7). Outcomes were evaluated based on patients' medical records., Results: The median survival time following HSRs was 28.1 and 15.4 months in the continuation and discontinuation groups, respectively (p=0.018). In the continuation group, a total of 155 cycles of PTs were re-administrated, and 50 cycles (32%) led to recurrent HSRs. There were no recurrent HSRs with a severity of grade 3 or greater., Conclusion: Continuation of PTs in ovarian cancer patients may contribute to improvement in their overall survival without severe recurrent HSRs., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology., Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( N = 5) or had a very short time to progression ( N = 5)., Results: The majority of mixed OCCC ( N = 6, 85.7%) and a small proportion of pure OCCC ( N = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified samples were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( P = 0.0194 and 0.0395, respectively). Mutations in ARID1A, PIK3CA, PPP2R1A , and TP53 were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations., Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome., (©2019 American Association for Cancer Research.)

Objective: Recently, we established new histopathological subtypes of high-grade serous ovarian cancer (HGSOC) that include the mesenchymal transition (MT) type, the immune reactive (IR) type, the solid and proliferative (SP) type and the papillo-glandular (PG) type. Furthermore, we identified that the mesenchymal transcriptome subtype might be sensitive to taxane. We investigated whether these different histopathological subtypes of HGSOC require individualized chemotherapy for optimal treatment., Methods: We conducted the Japanese Gynecologic Oncology Group (JGOG) 3016A1 study, wherein we collected hematoxylin and eosin slides (total n = 201) and performed a histopathological analysis of patients with HGSOC registered in the JGOG3016 study, which compared the efficacy of conventional paclitaxel and carboplatin (TC) and dose-dense TC (ddTC). We analyzed the differences in progression-free survival (PFS) and overall survival (OS) among the four histopathological subtypes. We then compared the PFS between the TC group and the ddTC group for each histopathological subtype., Results: There were significant differences in both PFS and OS among the four histopathological subtypes (p = 0.001 and p < 0.001, respectively). Overall, the MT subtype had the shortest PFS (median 1.4 y) and OS (median 3.6 y). In addition, the MT subtype had a longer PFS in the ddTC group (median 1.8 y) than in the TC group (median 1.2 y) (p = 0.01). Conversely, the other types had no significant difference in PFS when the two regimens were compared., Conclusions: The MT type of HGSOC is sensitive to taxane; therefore, the ddTC regimen is recommended for this histopathological subtype., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Since there have been few large series studies to date, we investigated the relationship between Trousseau's syndrome associated with cerebral infarction and its clinical associations with ovarian cancer., Methods: In this study, we investigated the association between cerebral infarction onset and ovarian cancer. Eight-hundred twenty-seven consecutive ovarian cancer patients from 4 affiliated academic institutions were included in the study over a 12 years period. All patients were histopathologically diagnosed as epithelial ovarian cancer and were analyzed retrospectively., Results: The 27 patients (3.2%) presented with cerebral infarction during the study period, 14 patients onset prior to treatment (1.7%), and 13 patients onset after start of initial treatment (1.5%). Univariate analysis and multivariate analysis was performed for onset of Trousseau's syndrome and various clinical and pathological parameters. There was no statistical significance between the occurrence of Trousseau's syndrome with age or International Federation of Gynecology and Obstetrics (FIGO) stage; however, univariate analysis and multivariate analysis demonstrated a statistically significant association between clear cell carcinoma (CCC) and non-CCC histology., Conclusion: Thus, our results demonstrate that Trousseau's syndrome with cerebral infarction occurred with greater incidence among CCC cases compared to non-CCC cases., Competing Interests: None of the authors have any conflict of interest to disclose., (Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Objective: The aim of the study is to investigate recurrence of stage I epithelial ovarian cancer., Methods: Six hundred two patients diagnosed with stage I epithelial ovarian cancer at 4 hospitals between 2000 and 2013 were retrospectively analyzed. Age, surgical procedure, substage, histologic type, adjuvant chemotherapy, recurrence, initial recurrence site (peritoneal dissemination [P], hematogenous recurrence [H], lymphogenous recurrence [L], and others [O]), and frequency of recurrence at each site were investigated retrospectively., Results: Median age was 54 years and median follow-up was 60 months. The stage was IA in 180 cases (30%), IB in 8 (1%), IC1 in 247 (41%), IC2 in 63 (10%), and IC3 in 104 (17%). Systematic lymph node dissection including both pelvic and para-aortic lymph nodes was performed in 224 patients (37%), and 412 patients (68%) received adjuvant chemotherapy. Recurrence occurred in 70 patients (11.6%). The median time to recurrence was 18 months, and the stage was IA in 13 (19%), IB in 1 (1%), IC1 in 24 (34%), IC2 in 9 (13%), and IC3 in 23 (33%) cases. The numbers of recurrence at the P, H, L, and O sites, including overlapping cases, were 49 (70%), 18 (26%), 9 (13%), and 6 (9%), respectively, and recurrence by peritoneal dissemination in the pelvis occurred in 43 cases (61%)., Conclusion: Recurrence of stage I epithelial ovarian cancer by peritoneal dissemination was frequent, especially in the pelvis. There is a need to elucidate the pathogenesis of peritoneal recurrence and to prepare a treatment strategy to prevent pelvic peritoneal recurrence., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

We identified the stepwise increase of MIB-1 index in a long-surviving malignant peritoneal mesothelioma (MPM) patient with a history of frequent relapse. A 29-year-old Japanese woman showed upper abdominal induration with adnexal tumor. Imaging study with biochemical analyses strongly suggested peritoneal tumor. On primary surgery, all tumors were resected completely without any residual tumor. Histologically, the tumor was diagnosed as MPM, for which she received adjuvant chemotherapy containing platinum agent. Two years later, the tumor relapsed in her pelvic cavity, but was resected completely with hysterectomy and salpingo-oophorectomy. Histologically, the tumor was diagnosed as MPM relapse. She underwent intraperitoneal chemotherapy with cisplatin that achieved progression-free survival of 5 years. However, relapse was detected again in pelvic cavity without any dissemination in upper abdominal cavity. The tumors were completely removed and were revealed to be compatible with MPM. She received gemcitabine and carboplatin chemotherapy. However, 2 years later, the tumor relapsed again in left upper abdominal cavity, for which she wouldn't receive 4th treatment. To investigate the longevity of this patient in association with the histologic findings, the MIB-1 index was examined in the primary and relapse tumors. The rate of MIB-1 index positive cells was calculated by counting 500 cells. MIB-1 indices were 4.2 ± 1.1 (mean ± SE), 11.8 ± 2.3, and 37.3 ± 2.5 in primary, 1st- and 2nd-relapsed tumor, respectively, demonstrating stepwise increase of MIB-1 expression over the surviving time of more than 9 years. Increase in MIB-1 index was not associated with mitotic index but may be indicating drug sensitivity, resulting in >2-year progression-free interval in each relapse., Competing Interests: The authors report no conflicts of interest. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ovarian high-grade serous adenocarcinoma responds well to regular platinum/taxane chemotherapy, while borderline tumor survives and demonstrates persistent disease. A 69-year-old Japanese woman was suspected for having advanced ovarian carcinoma. MRI showed cystic tumor containing solid component of the right adnexal region with massive ascites and peritoneal dissemination. Serum CA125 was elevated to 203 µ/ml; however, no remote metastases were detected. Laparotomy revealed that peritoneal carcinomatosis spreads out to omentum and subphrenic area. Omentum was partially removed with big tumor nodules that histologically demonstrated the high-grade serous adenocarcinoma with positive ascites cytology. After 6 cycles of postoperative chemotherapy with docetaxel and carboplatin, she received second surgery where the known residual bilateral adnexa and all of the persistent tumors were perfectly resected. Pathological examination of the tumor revealed serous borderline tumor with microinvasion and no evidence of residual high-grade serous carcinoma with negative ascites cytology. This is the extremely rare case of concurrent high-grade serous carcinoma and borderline tumor demonstrating differential chemo-sensitivity., Competing Interests: The authors report no conflicts of interest.This patient has already died of disease more than a year ago. At this moment, we could not keep track of the patient’s guardian or next of kin and the written consent could not be available. In the report described here, all personal details of the patient were removed from the case report to ensure that the patient cannot be identified.

Objective: Patients with adeno/adenosquamous carcinoma may have a poorer prognosis than patients with squamous cell carcinoma. Radiotherapy and concurrent chemoradiotherapy are used as adjuvant therapies for cervical cancer, regardless of the histological subtype. The aim of this study was to investigate the prognostic outcome of adjuvant therapy for patients with adeno/adenosquamous carcinoma with pathological risk factors., Methods: The medical records of 135 patients with stage IB-IIB cervical cancer with squamous cell carcinoma or adeno/adenosquamous carcinoma who underwent primary surgery followed by adjuvant therapy were retrospectively reviewed. Patients with a pathologically confirmed bulky tumor (≥4 cm), nodal metastasis and/or parametrium invasion were included in the study., Results: The median follow-up period was 48 (1-132) months. Of the 135 patients, 90 with squamous cell carcinoma and 23 with adeno/adenosquamous carcinoma were treated with adjuvant radiotherapy and concurrent chemoradiotherapy (SCC-RT/CCRT and AC-RT/CCRT groups), and 22 with adeno/adenosquamous carcinoma were treated with adjuvant systemic chemotherapy (AC-CT group). There were no significant differences in clinicopathological factors between the SCC-RT/CCRT and AC-RT/CCRT groups and between the AC-RT/CCRT and AC-CT groups. Progression-free survival was significantly shorter in the AC-RT/CCRT group compared to the SCC-RT/CCRT group (P = 0.002). Adeno/adenosquamous carcinoma histology and multiple lymph node metastasis were independent prognostic factors for shorter progression-free survival in patients treated with adjuvant radiotherapy and concurrent chemoradiotherapy. Progression-free survival was also significantly shorter in the AC-RT/CCRT group compared to the AC-CT group (P = 0.026)., Conclusions: Adjuvant radiotherapy and concurrent chemoradiotherapy may be less effective for patients with adeno/adenosquamous carcinoma than for those with squamous cell carcinoma. Adjuvant systemic chemotherapy may be beneficial for adeno/adenosquamous carcinoma and further studies are warranted., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A cell line, designated NOCC, was established from the ascites of a patient with clear cell adenocarcinoma of the ovary. The cell line has been grown without interruption and continuously propagated by serial passaging (more than 76 times) over 7 years. The cells are spherical to polygonal-shaped, display neoplastic, and pleomorphic features, and grow in a jigsaw puzzle-like pattern while forming monolayers without contact inhibition. The cells proliferate rapidly, but are easily floated as a cell sheet. The population doubling time is about 29 h. The number of chromosomes ranges from 60 to 83. The modal number of chromosomes is 70-74 at the 30th passage. NOCC cells secreted 750.5 ng/ml of VEGF over 3 days of culture. Hypoxia inducible factor-1α (HIF-1α) is a primary regulator of VEGF under hypoxic conditions. NOCC cells were not sensitive to the anticancer drugs BEV, DOX, GEM, ETP, CDDP, or TXT. The graft of NOCC cells to a scid mouse displayed similar histological aspects to the original tumor. Both the NOCC cells and the graft of the NOCC cells gave a positive PAS reaction.

Purpose: Clear cell carcinoma (CCC) is a rare histologic subtype that demonstrates poor outcomes in epithelial ovarian cancer. The Japanese Gynecologic Oncology Group conducted the first randomized phase III, CCC-specific clinical trial that compared irinotecan and cisplatin (CPT-P) with paclitaxel plus carboplatin (TC) in patients with CCC., Patients and Methods: Six hundred sixty-seven patients with stage I to IV CCC of the ovary were randomly assigned to receive irinotecan 60 mg/m(2) on days 1, 8, and 15 plus cisplatin 60 mg/m(2) on day 1 (CPT-P group) every 4 weeks for six cycles or paclitaxel 175 mg/m(2) plus carboplatin area under the curve 6.0 mg/mL/min on day 1 every 3 weeks for six cycles (TC group). The primary end point was progression-free survival. Secondary end points were overall survival, overall response rate, and adverse events., Results: Six hundred nineteen patients were clinically and pathologically eligible for evaluation. With a median follow-up of 44.3 months, 2-year progression-free survival rates were 73.0% in the CPT-P group and 77.6% in TC group (hazard ratio, 1.17; 95% CI, 0.87 to 1.58; P = .85). Two-year overall survival rates were 85.5% with CPT-P and 87.4% with TC (hazard ratio, 1.13; 95% CI, 0.80 to 1.61; one-sided P = .76). Grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently with CPT-P, whereas grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred more frequently with TC., Conclusion: No significant survival benefit was found for CPT-P. Both regimens were well tolerated, but the toxicity profiles differed significantly. Treatment with existing anticancer agents has limitations to improving the prognosis of CCC., (© 2016 by American Society of Clinical Oncology.)

Struma ovarii exhibiting malignant histology are uncommon, and aggressive clinical courses with initial extraovarian spread are even more rare. This report describes a case of malignant struma ovarii with a predominant anaplastic carcinoma component. A 65-yr-old, gravida 2, para 2, female presented with lower abdominal discomfort and pain. She had a 12×10×7.5 cm tumor in the right ovary. Intraoperative diagnosis was high-grade spindle cell tumor. Right salpingo-oophorectomy and hysterectomy were performed. Macroscopically, the tumor invading the right tube was a yellow-white solid mass with focal microcysts containing greenish liquid and focal calcification. The tumor was histologically characterized by a spindle cell and pleomorphic sarcomatous component, and a minor component of benign-looking thyroid tissue with ossification. Immunohistochemically, the sarcomatous component was focally positive for CAM 5.2, EMA, thyroid transcription factor-1, and thyroglobulin, indicating anaplastic carcinoma. The patient was treated with chemotherapy and is alive, yet with tumor, 25 mo after surgery. This is the first case of malignant struma ovarii with a predominant component of anaplastic carcinoma. This type of malignant struma ovarii may lead to diagnostic problems, and sampling and differential diagnosis among sarcomatous ovarian tumors are important for making the correct diagnoses.

Purpose: In advanced epithelial ovarian and peritoneal cancer, residual tumor diameter correlates with prognosis; therefore, maximum debulking and optimal surgery (OS) for residual tumors <1 cm is warranted. Here, we clarified the efficacy of tumor debulking with diaphragmatic surgery (DS)., Methods: In 45 patients with epithelial ovarian or peritoneal cancer who underwent DS (ten, full-thickness resection; 35, stripping) between January 2010 and December 2013 at two related institutions, we retrospectively evaluated OS safety and success by surgical duration, blood loss, complications, hospitalization stay, and residual tumor diameter and site., Results: Blood loss was 4,090.8 and 2,847.9 mL; surgical duration was 485.2 and 479.5 min; hospitalization stay was 21.7 and 24.8 days; and complications included intraoperative thoracotomy in 17 and 7 patients, unexpected thoracotomy in 11 and 3, chest drain insertion in one and three, and pleural effusion in 14 and 7, in the primary debulking surgery (PDS) and interval debulking surgery (IDS) groups, respectively. OS was successful in all patients with complete surgery (CS: no residual tumor) achieved in 16 (50.0%) and 9 (69.2%), residual tumor diameter < 5 mm in 11 (34.4%) and 2 (15.4%), and residual tumor diameter < 1 cm in 5 (15.6%) and 2 (15.4%) in the PDS and IDS groups, respectively., Conclusions: Tumor debulking surgery with DS resulted in controllable blood loss, and OS was successful in all patients without severe complications or postoperative treatment delay. Currently, OS is considered to have very few benefits over CS; thus, the success rate of CS rate should be improved while maintaining safety.

Background: Analysis of progression-free survival (PFS) as the primary endpoint in advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer (AEOC) trials may be confounded by the difficulty of radiologic evaluation of disease progression and the potential for discrepancy between investigator and blinded independent central assessments. PFS as assessed by local investigator (INV) was the primary endpoint of AGO-OVAR16, a randomized, double-blind trial of pazopanib maintenance therapy in AEOC. To confirm the robustness of the primary analysis, PFS was also evaluated by blinded independent central review (BICR)., Methods: Patients with histologically confirmed AEOC (N = 940) were randomized 1:1 to receive pazopanib 800 mg/day or placebo for up to 24 months. Tumor response in the intent-to-treat population was evaluated by CT/MRI every 6 months and analyzed per RECIST 1.0., Results: Pazopanib prolonged PFS versus placebo by INV (median 17.9 vs 12.3 months; hazard ratio [HR] = 0.766, 95% confidence interval [CI]: 0.643-0.911; P = 0.0021). Results for PFS by BICR were similar (median 15.4 vs 11.8 months; HR = 0.802, 95% CI: 0.678-0.949; P = 0.0084). Progression events were recorded later by INV in 23% of pazopanib-treated patients and 17% of placebo-treated patients. The overall concordance between INV and BICR assessments was 84% and 86% in the pazopanib and placebo arms, respectively., Conclusions: By INV and BICR assessments, maintenance therapy with pazopanib in AEOC provided a significantly longer PFS than placebo. The good overall concordance between INV and BICR assessments, as well as HR and P value consistency, supports the reliability of investigator-assessed PFS as the primary endpoint in AGO-OVAR16., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to investigate the impact of the histological findings on the treatment of malignant ovarian tumors in pregnant women., Methods: This is a retrospective study of 41 patients diagnosed and treated for ovarian malignancy during pregnancy between 1985 and 2010., Results: The median age of the study group was 30 years old, ranging from 20 to 41. Thirty-eight (92 %) patients were diagnosed with stage I, and one (2 %) with each of stages II, III, and IV. Twenty-five (61 %) patients had borderline malignancy, 8 (20 %) were diagnosed with epithelial ovarian cancer, 7 (17 %) with germ cell tumor, and one with sex cord stromal tumor. All patients received primary surgery; 7 (17 %) patients had cystectomy, 32 (78 %) had unilateral salpingo-oophorectomy, and 3 (7 %) underwent hysterectomy with bilateral salpingo-oophorectomy. Thirty-one (76 %) patients delivered live newborns; 21 had borderline tumor (84 %), 2 had ovarian cancers (25 %), and 8 had non-epithelial tumor (100 %). Six cases were terminated in order to perform the standard treatment for ovarian malignancy and 2 cases aborted spontaneously., Conclusion: In pregnant women, ovarian cancer is exceptionally less frequent compared with non-pregnant women, i.e. age-matched, statistically-corrected controls based on the Japanese annual report [8/33 (24 %) vs. control (60 %); ovarian cancer/(ovarian cancer + borderline tumor), P = 0.001]. The pregnant women with ovarian cancer chose to prioritize treatment of ovarian cancer at the sacrifice of their babies while those with borderline tumor or non-epithelial tumor were able to successfully deliver live newborns.

Recurrent ovarian cancer following chemotherapy is usually incurable, particularly when the tumor acquires a drug resistance. The present study aimed to define the effect of irradiation on locoregional recurrences and the impact of the factors on the efficacy. The study retrospectively reviewed the clinical records of 61 patients with epithelial ovarian cancer who received irradiation following repeated chemotherapy between 1997 and 2006. A positive-irradiation response was designated as complete response, partial response, minor response or no change (NC). Due to the possible synergistic effect of chemotherapy and irradiation, and the cross-resistance to chemotherapeutic drugs and radiation, the focus was on the treatment break between chemotherapy and radiation, and patients were classified into 3 categories: Category I, ≤1 month; II, 1-6 months; and III, >6 months. The effect of irradiation was analyzed in association with histology, treatment break, recurrent site, irradiation dose and chemosensitivity. The post-irradiation survival time was analyzed by the irradiation response and treatment category. The median biological-effective dose was 60.0 Gy (range, 15.6-72.0 Gy). The sites irradiated included nodal recurrence (36), abdominal (six) and pelvic cavity (five cases). Histologically, serous adenocarcinoma was the most common type of the disease (23 cases) compared to mucinous (four), endometrioid (three), and clear-cell types (six cases). The median survival times were 4.5 months in the radiation responders (13 cases) and 15.3 months in the non-responders (37) (P=0.004). The positive-irradiation response was significantly associated with the treatment break (P=0.026) and chemosensitivity (P=0.007). In conclusion, irradiation for recurrent ovarian cancer produced an improved survival benefit when applied to chemoresponsive, locoregional-recurrent tumors immediately following chemotherapy.

Background: The primary analysis of the JGOG 3016 trial showed that a dose-dense paclitaxel and carboplatin regimen significantly improves progression-free and overall survival compared with the conventional regimen as first-line chemotherapy for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. We report the long-term follow-up results for survival., Methods: This randomised controlled trial was done at 85 centres in Japan. Patients with stage II-IV ovarian cancer were randomly assigned to receive conventional treatment (carboplatin area under the curve [AUC] 6 mg/mL per min and paclitaxel 180 mg/m(2) on day 1) or dose-dense treatment (carboplatin AUC 6 mg/mL per min on day 1 and paclitaxel 80 mg/m(2) on days 1, 8, and 15). The treatments were repeated every 3 weeks for six cycles; responding patients had three additional cycles. The randomisation was done centrally by telephone or fax, stratified by residual disease, stage, and histological type. The primary endpoint was progression-free survival; overall survival was a secondary endpoint. Long-term information on adverse events was not collected. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00226915., Findings: 637 patients were enrolled, of whom 631 were analysed (312 assigned to the dose-dense regimen, 319 to the conventional regimen). Median follow-up was 76·8 months (IQR 68·9-85·6). Median progression-free survival was significantly longer in the dose-dense treatment group than in the conventional treatment group (28·2 months [95% CI 22·3-33·8] vs 17·5 months [15·7-21·7]; hazard ratio [HR] 0·76, 95% CI 0·62-0·91; p=0·0037). Median overall survival was 100·5 months (95% CI 65·2-∞) in the dose-dense treatment group and 62·2 months (52·1-82·6) in the conventional treatment group (HR 0·79, 95% CI 0·63-0·99; p=0·039)., Interpretation: Dose-dense treatment offers better survival than conventional treatment and is a potential new standard of care for first-line chemotherapy for patients with advanced epithelial ovarian cancer., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To test the concept of taxane sequencing, this feasibility trial evaluated maintenance of docetaxel after paclitaxel and carboplatin combination chemotherapy in patients with stage IC-IV ovarian cancer., Methods: All patients received debulking surgery followed by paclitaxel and carboplatin chemotherapy. Attainment of clinically defined complete or partial response was confirmed by image scanning. Maintenance of docetaxel started at an initial dose of 70 mg/m(2) every 4 weeks for 6 cycles and was extended to 10 cycles unless disease progression and/or recurrence during the protocol therapy or unacceptable toxicities were seen., Results: Stage subsets in 20 eligible patients were as follows: IIIB, 2 patients (10%); IIIC, 13 patients (65%); IV, 5 patients (25%). Neutropenia was common (40% with grade 3 or 4) and was most frequent during first or second cycle although the disabling peripheral neuropathy was not observed. Twelve patients completed protocol therapy (6≤cycles), while 8 patients failed to complete 6-cycle chemotherapy, because of progressive disease (5 patients) or grade 4 toxicities (3 patients). Median PFS was 20 months and 3-year PFS rate was 12%. Median overall survival was 39 months and 3-year OS rate was 69%., Conclusion: Six cycles of single-agent docetaxel maintenance chemotherapy is feasible and generally tolerable to women with advanced ovarian cancer who attained a clinically defined response to initial paclitaxel and carboplatin based chemotherapy.

Glycolipid and transporter protein gene expression in ovarian serous carcinoma-derived 2008 cells, and their paclitaxel-resistant Px2 and cisplatin-resistant C13 forms was examined to confirm the previous finding, i.e., that it was characteristically altered in anticancer drug-resistant cells established on continuous cultivation of ovarian carcinoma-derived KF28 cells in the different anticancer drug-containing media. Although the concentrations of lipid constituents in 2008 cells were higher than those in KF28 cells, and the glycolipid compositions were different, the following glycolipids and genes were commonly altered in KF28- and 2008-derived resistant cells. Gb(3)Cer was increased in all resistant cells, irrespective of whether the resistance was to paclitaxel or cisplatin, and expression of the MDR1 gene and gangliosides was enhanced in paclitaxel-resistant cells, but gangliosides were absent in cisplatin-resistant cells. In accord with the decreased amounts of gangliosides in cisplatin-resistant cells, the gene expression and specific activity of GM3 synthase were greatly decreased in cisplatin-resistant cells. Furthermore, paclitaxel- and cisplatin-resistant cells were converted to forms more sensitive to the respective anticancer drugs on cultivation with D-PDMP, an inhibitor of GlcCer synthase, and GM3, respectively, prior to the addition of anticancer drugs, indicating the possible involvement of glycolipids in anticancer drug resistance.

The objective of this study was to ascertain the evidence on ovarian cancer during pregnancy and compile recommendations derived from this information. This was a retrospective study, based on clinical histories from patients diagnosed and treated at 4 independent hospitals for ovarian cancer during pregnancy, between 1992 and 2009. The median age at diagnosis was 30 years (range, 24-41). Out of 10 cases of ovarian cancer, 2 patients showed either bleeding or abdominal pain, while 8 patients were asymptomatic. All 10 cases were diagnosed via ultrasound, and the masses were detected in the first trimester in 7 patients and in the second trimester in 2 patients. Of the diagnosed tumors, 8 cases were epithelial tumors including 6 adenocarcinomas and 2 borderline tumors, and 2 germ cell tumors. The primary ovarian malignancies were at stage I of the disease. Unilateral salpingo-oophorectomy was performed in 9 patients and cystectomy was performed in one patient. Chemotherapy was administered to 4 patients, in 1 case during pregnancy. Neonatal outcome analysis showed a full- or pre-term delivery in 6 cases, abortion in 1 case and therapeutic termination in 3 cases. The majority of cases of ovarian cancer in pregnancy were incidentally detected by ultrasound at an early stage, resulting in good prognosis for the mother and the neonate.

Background: Based on the evidences showing that serum deprivation provokes apoptosis in a variety of cells, we have investigated the effect of serum deprivation on drug sensitivity., Methods: After human ovarian cancer cells were preincubated in 0.5 % serum containing medium for 12 hours, cellular drug sensitivities were determined by colony-forming assay., Results: Serum deprivation treatment resulted in significant increase in paclitaxel sensitivity by factors of mean ± SD, 148.6 ± 28.1 and 10.1 ± 1.0 (n = 3; P < 0.001) fold in platinum-resistant C13 and CP70 cells, respectively. Similarly, serum deprivation induced significant docetaxel sensitivity in these cell lines. However, no enhancement effect of serum deprivation was observed in platinum-sensitive 2008 and A2780 cells. Serum deprivation did not have any effect on the sensitivities to cisplatin, vincristin, and doxorubicin in all of these cells. More than 7-fold increase of apoptotic cells were observed in C13 or CP70 cells when they were treated by serum deprivation followed by paclitaxel compared with the treatment of either serum deprivation or paclitaxel alone. Confocal laser microscopy using rhodamine 123 and flow cytometric analysis with 3,3'-dihexyloxacarbocyanine iodide revealed that serum deprivation decreased mitochondrial membrane potential in C13 or CP70 cells, whereas no change was observed in 2008 and A2780 cells. This indicates that serum deprivation induced depolarization specifically in platinum-resistant cells. Electron microscopy revealed that serum deprivation caused regeneration of mitochondrial matrix structure in C13 or CP70 cells where mitochondria were usually destructed and disappeared., Discussions: These results indicate that serum deprivation confers taxane hypersensitivity specifically in platinum-resistant cells by recovering their impaired mitochondrial functions. The evidence might be clinically beneficial for the development of new chemotherapeutic technology, particularly for the patients with platinum-resistant ovarian cancer.

Objectives: In recent years, cancer stem cells (CSCs) have been reported to be correlated with chemoresistance and may also be enriched in side populations (SPs). In this study, the relationship between resistance to paclitaxel (PTX) and cisplatin (CDDP) and side populations was examined in three parental PTX- and CDDP-sensitive ovarian cancer cell lines (2008, KF28, and TU-OM-1) and several other cell lines derived from these as well as the additional effects of interferon-alpha (INF-α)., Methods: SP of three different parental cell lines and PTX- and/or CDDP-resistant cell lines derived from these was analyzed with flow cytometry. The expression of ABCB1 and ABCG2 in KF28 and its derived cell lines was examined. Additional cell-death effect of INF-α with PTX was also examined., Results: In the three parental cell lines and the PTX-sensitive cell lines derived from these lines, SP was very low. Conversely, in PTX-resistant cell lines, regardless of CDDP resistance, SP increased. ABCB1 was strongly expressed in the PTX-resistant cells, but not in their parental lines, which are sensitive to PTX. While INF-α showed only slight enhancement of the cell-death effect of PTX in PTX-sensitive cells, INF-α itself strongly induced apoptosis in PTX-resistant cells regardless of PTX concentration., Conclusions: The SP could be correlated with resistance to PTX. SP could be a target of INF-α, and resistance to PTX might be overcome by INF-α., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This experiment was conducted to address the question of whether acquired paclitaxel resistance is dependent upon whether it is given as a single brief exposure or as a long-term exposure. PX2 and PX24 were established from 2008 human ovarian cancer cells by 2-h single exposure or 24-h continuous exposure to paclitaxel. PX2 acquired paclitaxel resistance faster than PX24 by twofold. Drug resistant pattern was exposure-time dependent. In 2-h exposure, PX2 showed 53.86 ± 4.96 (mean ± standard deviation [SD]) fold paclitaxel resistance while PX24 showed 9.51 ± 1.01 fold resistance (P = 0.002). In 24-h exposure, PX2 showed 2.31 ± 0.3 fold paclitaxel resistance while PX24 showed 28.17 ± 0.98 fold resistance (P = 0.040). PX2 and PX24 acquired cross-resistance to docetaxel and SN38 and the resistance degrees were significantly higher in PX2 than PX24. They displayed approximately twofold cisplatin collateral sensitivity. PX24 also displayed sensitivity to other platinum drugs, oxaliplatin and ZD0473, whereas PX2 acquired significant resistance to both of them. Although differential tubulin-isotype expressions were noted among 2008, PX2 and PX24, they were not significant. In electron microscopy, prominent, densely stained lysosomes were observed more in the resistant cells than 2008. Two independent, exposure-time dependent paclitaxel-resistant human ovarian carcinoma cell lines were established. Understanding the characteristics of the differential resistance pattern could be clinically beneficial for the selection of second line chemotherapy for relapsed ovarian cancer., (2010 The Authors. Human Cell 2010 Japan Human Cell Society.)

We report a mitochondrial (MT) scoring system related to response to platinum treatment in ovarian cancer (OC). Ultra-thin sections of surgical specimens of primary tumors prepared from 41 OC patients were examined by electron microscopy. The ovarian carcinoma cell line 2008 and its platinum-resistant variant C13 were used as controls. Seven independent MT features, including MT diameter, pattern of cresta structure, electron density, MT distribution, pattern of distribution, ovoid ratio and MT architecture, were examined. Each of the seven parameters was assigned a point score of 0-2 and was summed up with a total score of 14. Clinical response and in vitro sensitivity to platinum, taxane, irinotecan and doxorubicin were evaluated. Clinical information was available for 37 of the 41 cases. Twenty-four cases were stage III and, histologically, 16 serous, 6 endometrioid and 6 clear cell carcinoma were included. All of the patients underwent surgery followed by 6 cycles of taxane and platinum chemotherapy. Fifteen patients exhibited a response, while 22 were resistant to treatment. The total MT score was 5.13±1.13 (mean ± SE) in the 15 responsive cases and 11.41±0.43 in the 22 resistant cases (P<0.001). Receptor operative characteristic (ROC) analysis revealed that the resistant total 'cut-off' score was ≥10 points (P<0.05; AUC=0.86) with 95.5% sensitivity and 80.0% specificity. The MT scoring system correlated well with response to drugs, with the exception of doxorubicin. The progression-free survival (PFS) curves showed an absolute difference in the 6-month PFS of 10% (83 vs. 73%) and in the 12-month PFS of 21% (80 vs. 59%), in favor of patients with low MT scores. This MT scoring system correlates very closely with clinical response as well as cellular sensitivity to chemotherapy, resulting in an association with PFS.

Background: Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer., Methods: Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (180 mg/m(2); 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/mL per min), given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m(2); 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00226915., Findings: 631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=312; conventional regimen, n=319). Median progression-free survival was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3-35.4) than in the conventional treatment group (17.2 months, 15.7-21.1; hazard ratio [HR] 0.71; 95% CI 0.58-0.88; p=0.0015). Overall survival at 3 years was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; p=0.03). 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.0001). The frequencies of other toxic effects were similar between groups., Interpretation: Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer., Funding: Bristol-Myers Squibb.

Apart from typical yolk sac tumors, ovarian tumors with elevated alfa-fetoprotein (AFP) are uncommon and the differential diagnosis needs to consider the hepatoid pattern of a yolk sac tumor, hepatocellular carcinoma metastatic to the ovary, hepatoid carcinoma, and other epithelial ovarian tumors. We report here an AFP-producing ovarian tumor with uncertain pathological diagnosis, which was extremely responsive to chemotherapy. A 59-year-old Japanese woman presented with lower abdominal distension and was found to have a left ovarian mass on pelvic examination and magnetic resonance imaging (MRI) scan. Laboratory tests showed serum AFP, 73 687 ng/ml; carbohydrate antigen 125 (CA125), 1599 U/ml; and carcinoembryonic antigen (CEA), 13.9 ng/ml. Total hysterectomy with bilateral salpingo-oophorectomy, partial omentectomy, and low anterior resection of the rectum was performed, without any residual macroscopic tumor. Microscopically, the tumor was characterized by a hepatoid carcinomatous component composed of solid sheets of large eosinophilic cells with pleomorphic nuclei. The pathological stage was pT2N0M0. Tumor cells were diffusely immunoreactive for AFP and cytokeratin (CAM5.2), but monoclonal CEA and CA19-9 were focally positive in the cytoplasm, while CA125 was negative. The patient was treated postoperatively with three cycles of chemotherapy consisting of bleomycin, etoposide, and cisplatin; with this regimen, serum AFP decreased to 16 ng/ml from 12 600 ng/ml just before the initiation of chemotherapy. The patient received secondary cytoreductive surgery of systemic lymphadenectomy, which revealed no evidence of residual tumor.

Background: The long-term efficacy and safety of docetaxel/cisplatin as first-line chemotherapy in Japanese patients was evaluated in order to find an optional regimen for ovarian cancer., Patients and Methods: Women with surgically resected stage Ic-IV epithelial ovarian cancer were treated with docetaxel 70 mg/m2 and cisplatin 60 mg/m2 every 4 weeks., Results: Ninety women were enrolled of whom 89 (median age, 54 years) received a median of 6 cycles (range 1 to 9). With a median 38 months'follow-up, median progression-free survival was 28 months (95% lower confidence interval, 24 months) in 60 patients with stage III-IV disease. The overall response rate for 20 patients was 45%. Neutropenia was the most common (67%) grade 3/4 toxicity. Major grade 3/4 nonhaematological toxicities were gastrointestinal toxicities (< or = 11%) and fatigue (8%). No grade 3/4 neurotoxicity was observed., Conclusion: The combination of docetaxel/cisplatin is a regimen with favourable progression-free survival for ovarian cancer.

We developed mitochondrial (MT) scoring system based on MT ultrastructural findings in association with response to chemotherapy in ovarian cancer (OC). Ultrathin sections of MT prepared from 28 OC patients before chemotherapy were examined by electron microscopy. Platinum-sensitive ovarian carcinoma cell line 2008 and its resistant variant C13 were used as control cells. Seven independent MT features including, diameter, pattern of cresta structure, electron density, distribution-density and -pattern, ratio of minimal/maximal diameter and MT architecture were examined and were assigned a score between 0 and 2. Twenty-eight cases were primary advanced OC, including 4 recurrent cases. Nine cases were chemosensitive while 19 were resistant. Univariate and multivariate analysis in each factor showed good correlation to chemosensitivity for 2 factors of electron density, distribution pattern. Total score of these 2 factors in 9 sensitive cells was 1.44+/-0.41 (M +/- SE) and was 3.58+/-0.18 in 19 resistant cells (P<0.001). Receptor operative characteristics (ROC) analysis revealed that total 'cut-off' score was 3 point (P<0.05; AUC=0.84). In conclusion, this MT scoring system was excellently correlated to response regardless of histopathologic findings and this strongly suggests that the system is deemed to be of great value as biomarker for the chemosensitivity in OC.

Very few cases of postoperative decubitus have been reported. We report two cases of hip decubitus after myomectomy. Case 1 is a 32-year-old Japanese woman who underwent an uncomplicated myomectomy under the combination of general and epidural anesthesia. Twelve hours after surgery, a palpable soft tissue mass developed in the sacral region. On day 3, the soft tissue mass had disappeared and the patient was discharged on day 8. Case 2 is a 33-year-old woman. Under a combination of spinal and epidural anesthesia, a myomectomy was carried out. On day 1 after surgery, a hard mass with redness was detected. On day 8, decubitus improved and she was discharged. We evaluated the temporal changes in anesthetic level in four independent cases. Eighteen hours after surgery, the anesthetic effect still continued below the L2 level. We conclude that the extended effect of epidural anesthesia might be one of the mechanisms causing postoperative decubitus.

Ovarian small cell carcinoma of hypercalcemic type is a rare neoplasm that typically occurs in young females. We describe three cases of ovarian small cell carcinoma of hypercalcemic type occurring in patients aged 24, 37, and 25 years. The first patient had stage IIc disease and had primary surgery with a left salpingo-oophorectomy and omentectomy, followed by chemotherapy with cisplatin and etoposide. Upon a second relapse, pelvic lymphadenectomy was performed, followed by chemotherapy with docetaxel. She is alive for 4 years without any recurrence after the initial treatment. In vitro drug-sensitivity assay revealed the tumor cells were sensitive to taxane and resistant to irinotecan. The second patient had stage III disease and had primary debulking surgery with bilateral salpingo-oophorectomy, simple hysterectomy, omentectomy, low-anterior resection, and lymphadenectomy, followed by chemotherapy with paclitaxel and carboplatin. Four months after the initial treatment she relapsed and died. The tumor cells were sensitive to platinum, taxane, and doxorubicin, but resistant to irinotecan. The third patient had stage III disease and had right salpingo-oophorectomy, omentectomy, and lymphadenectomy, followed by chemotherapy with cisplatin, cyclophosphamide, and doxorubicin. She relapsed 4 months after completing the chemotherapy and died 5 months after secondary debulking surgery. The tumor cells were sensitive to platinum, taxane, and doxorubicin, but resistant to irinotecan. The drug-sensitivity assays suggested that a non-irinotecan, taxane-containing combination might have been suitable as first-line chemotherapy for these patients. However, an effect of such a regimen was seen in only one patient with early-stage disease, and this questions the validity of chemosensitivity testing.

Objective: The objective of the study was to describe a clinically useful factors index predicting long-term efficacy of uterine artery embolization (UAE)., Study Design: Newly diagnosed patients with uterine leiomyoma wishing to retain their uterus underwent UAE at our institution. Clinical demographics and 4 prognostic factors were recovered from the medical record. A regrowth-free interval (RFI) was calculated for all patients based on leiomyoma regrowth or recurrence of any previously reported symptoms. RFI by prognostic factor was analyzed by the Kaplan-Meier method., Results: Forty-three patients were identified. Two prognostic factors were identified by multivariate analysis: vascularity (dichotomized as hypervascular vs hypovascular; RFI at 2 years, 80% vs 20%, P = .001) and number of nodules (solitary vs multiple; RFI at 2 years, 72% vs 25% at 2 years, P = .001), Conclusion: UAE success may be predicted by 2 preoperative parameters. Further investigation is warranted.

Paclitaxel (PX) binds to and stabilizes tubulin, preventing depolymerization, and resulting in cell death. Based on a previous report showing the activity of phosphatidylinositol kinase (PIK) on tubulin, we investigated the effect of the PI4K inhibitor orobol and the PI3K activator platelet derived growth factor (PDGF) on PX sensitivity. Drug sensitivity was examined by classical colony forming assay. Tubulin isotype expression was determined by semi-quantitative RT-PCR. Microtubule texture was observed by laser confocal microscope using anti-beta-tubulin antibody. Apoptotic activity was estimated by frequency of condensed nuclear chromatin with Hoechst 33342 stain. Orobol enhanced PX sensitivity of human ovarian carcinoma 2008 cells by 18.9+/-1.2-fold (N=3; P<0.01). In contrast, pretreatment with PDGF rendered cells resistant to PX by 2.3+/-0.4-fold (N=3; P<0.01). Neither orobol nor PDGF showed any effect on cell growth. Orobol produced a 2.5-fold sensitization in cisplatin-resistant 2008/C13*5.25 (C13) cells, and PDGF rendered the cells 2.3-fold resistant to PX. Orobol suppressed the beta 4a-tubulin isotype expression by 85% and other isotypes by 20%. In contrast, PDGF induced beta 4a-tubulin isotype expression by 1.3-fold, while it supressed all the other isotypes by 20-40%. Orobol produced thick microtubules and PDGF generated ring condensed microtubules. Orobol promoted PX-induced apoptosis, while PDGF caused 50% reduction of apoptosis. These results indicate that orobol and PDGF regulate PX sensitivity by reciprocally altering the proportion of tubulin isotype expression and PX-induced apoptotic signaling.

One of the mechanisms of cisplatin cell cytotoxicity is the mitochondria-associated induction of apoptosis. The morphological or functional change of mitochondria in cisplatin-resistant cells has already been reported. Herein we present additional data describing the mitochondrial genomic and functional changes in cisplatin- resistant cells. Cisplatin increased the level of apoptotic cells in cisplatin-sensitive human ovarian carcinoma OV 2008 and C13 cells by 3.90+/-1.01 (SD; N=3) (p<0.01)-fold and 2.03+/-0.20 (SD; N=3) (p<0.01)-fold compared to the basal apoptotic level. This indicates a lower level induction of apoptosis by 50% in cisplatin-resistant OV 2008/C13 *5.25 variant (C13) cells. In both cell types, cisplatin cytotoxicity is mostly inhibited by the caspase-9 inhibitor as well as the caspase-3 inhibitor, Ac-DEVD-CHO, suggesting that the mitochondrial downstream event was functioning well in both the C13 cells and in OV 2008 cells. Mitochondrial transmembrane potential (DeltaPsim) determined by flow cytometry using DiOC6-stained cells revealed a significant depolarization of C13 cells as compared to OV 2008 cells. Treatment of these cells with cisplatin or hydrogen peroxide induces complete mitochondrial DNA damage in OV 2008 cells, while only partial DNA-destruction is observed in C13 cells, strongly suggesting that mitochondria are resistant to cisplatin and oxidative stress response. Continuous oxygen consumption of these cells monitored by a multi-channel dissolved oxygen meter is 1.70-fold higher in OV 2008 cells than C13 cells and the oxygen consumption was decreased by 30% in C13 cells, suggesting mitochondrial respiratory malfunction in these cells. The hypothesis generated here is that mitochondrial DNA resistance to cisplatin and oxidative stress response might be one of the main characteristics concerning the lower level of apoptosis induced by cisplatin. However, the mechanism by which the mitochondrial DNA encoded molecule is involved in cisplatin resistance remains to be determined.

Background: The current treatment of patients with recurrent ovarian cancer who have received initial platinum- or taxane-based chemotherapy depends on the results of the initial chemotherapy. The purpose of this study was to evaluate how to make the selection of second-line agents for patients with recurrent ovarian carcinoma initially diagnosed as stage II to IV., Methods: We conducted a retrospective crossover study in patients who received second-line chemotherapy at Jikei University School of Medicine. We evaluated the responses, progression-free survivals, survivals of second-line chemotherapy, and overall survivals after primary surgery for 51 patients. The treatment cohorts were defined as follows: TC1, patients who were given paclitaxel and carboplatin as first-line chemotherapy and who, upon recurrence, were treated with a platinum-based combination as second-line; and TC2, patients who were given a non-taxane-based platinum combination as first-line chemotherapy, followed, at the time of recurrence, with paclitaxel and carboplatin., Results: The response rates of the second-line chemotherapy for the TC1 and TC2 groups were 44% and 25% (P=0.09). The median progression-free survivals of TC1 and TC2 were 12.9 and 6.4 months (P=0.018; hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.16-5.04). The median survivals after second-line chemotherapy for the two groups were 16.8 and 10.4 months (P=0.007; HR, 2.78; 95% CI, 1.33-5.84) and overall survivals after primary surgery were 36.6 and 27.9 months (P=0.007; HR, 2.36; 95% CI, 1.07-5.21)., Conclusion: The TC1 group demonstrated a significantly better response and extension of progression-free survival, as well as significantly better survival after crossover and overall survival after primary surgery. As this was a retrospective analysis, this effect should be considered as hypothesis-generating and assessed prospectively in other trials comparing these two chemotherapy schedules.

The 12 th Oncology Forum discussed the progress and future strategy of cancer prevention in Japan. The National Cancer Center has established a research center for screening focusing on the most common six cancer, stomach, lung, liver, colon, breast and uterus cancer. The program so far had a cumulative detection rate of 3.3%, which is high,and may reflect the selection of subjects. Screening and chemoprevention is also being investigated in prostate cancer, but the issues centre on how to make this widely available. High risk subjects can also be identified for breast cancer. Obesity and family history are especially important. In colorectal cancer studies are evaluating different diets, but general application is not yet possible and the infrastructure to implement any general screening and prevention does not exist. Development of pharmaceutical treatments for prevention is difficult because of the need for very safe treatments, and also because of the length of time needed to carry out studies. Overall, cancer prevention is still in evolution. New approaches are needed, and new infrastructure will be needed at a government level to implement this.

Purpose: We aimed to find key molecules associated with chemoresistance in ovarian cancer using gene expression profiling as a screening tool., Experimental Design: Using two newly established paclitaxel-resistant ovarian cancer cell lines from an original paclitaxel-sensitive cell line and four supersensitive and four refractory surgical ovarian cancer specimens from paclitaxel-based chemotherapy, molecules associated with chemoresistance were screened with gene expression profiling arrays containing 39,000 genes. We further analyzed 44 genes that showed significantly different expressions between paclitaxel-sensitive samples and paclitaxel-resistant samples with permutation tests, which were common in cell lines and patients' tumors., Results: Eight of these genes showed reproducible results with real-time reverse transcription-PCR, of which indoleamine 2,3-dioxygenase gene expression was the most prominent and consistent. Moreover, by immunohistochemical analysis using a total of 24 serous-type ovarian cancer surgical specimens (stage III, n = 21; stage IV, n = 7), excluding samples used for GeneChip analysis, the Kaplan-Meier survival curve showed a clear relationship between indoleamine 2,3-dioxygenase staining patterns and overall survival (log-rank test, P = 0.0001). All patients classified as negative survived without relapse. The 50% survival of patients classified as sporadic, focal, and diffuse was 41, 17, and 11 months, respectively., Conclusion: The indoleamine 2,3-dioxygenase screened with the GeneChip was positively associated with paclitaxel resistance and with impaired survival in patients with serous-type ovarian cancer.

The purpose of cancer screening is to widen the difference between morbidity and mortality of the target cancer. Since 1983 cancer screening has been supported by the Japanese government. Initially it covered gastric and cervical cancer with lung, breast and endometrial cancers supported from 1987 and colorectal cancer in 1992. Since 1998 support for cancer screening has been transferred to local government. It is generally accepted that the uptake of screening services is too low. Estimates for Japan suggest that at best 30% of the eligible population accept the services. In other parts of the world screening is more widely accepted, for example, 67% for breast cancer and 79% for cervical screening in the USA. Barriers within Japan for increasing screening are complex and include, legal, ethical, financial, technical infrastructure, data related matters and the level of understanding and education of the general public. In 2000 the MHLW conducted an evaluation of cancer screening in terms of usefulness and effectiveness. It concluded that fair or better evidence for reduction in mortality existed for cervical cancer (cytology), breast cancer (mammography with clinical examination for women aged > or = 50 years), colorectal cancer (faecal occult blood test), gastric cancer, lung cancer and liver cancer. As a step towards improving screening services and their uptake by the general public a new Research Centre for Cancer Prevention and Screening was established at the National Cancer Centre in October 2003. This and other initiatives will build on the progress of the past 20 years but it is generally agreed that there is still have a long way to go.

We selected ovarian cancer as being the most representative of the gynecologic malignancies since it has the largest number of tumor markers now in clinical use. First, variety of serum tumor markers were developed and regularly used to detect the existence of ovarian cancer and its stage. These markers of monoclonal antibodies could detect three different classes of cell surface antigen. CA 125, CA 130, CA 602 are antibodies raised against the core protein of the proteoglycan molecule, whereas CA 19-9, CA 50, KMO-1 and CA 72-4, STN, CA 546 are antibodies against a different portion of the glycosaminoglycan chain from the core protein. These markers, when combined with another group of tumor markers for discriminating the variety of pathological types of ovarian cancer, might have the potential to provide a better predictive value. Second, biomarkers for the detection of early-stage ovarian cancer are urgently needed and developed also in gynecologic tumors. These include a ovarian cancer-specific proteomic patterns generated by mass spectroscopy and single nucleotide polymorphism (SNP) digital analysis combined with assessment of allelic imbalance. Third, for monitoring the effect of treatment with cytostatic drugs, various types of biomarkers could be used as surrogate markers for the treatment depending on the mechanism of the effects of the drug used. For treatment with Bryostatin, a strong protein kinase C (PKC) stimulator, PKC activity promises to be an effective marker. For the trials with bevacizumab, anti-VEGF antibody, VEGF and its associated bFGF, CD-31, and thrombospondin-1 (TSP-1), are leading candidates for monitoring markers.

Objective: The purpose of this study is to assess the survival experience following systematic lymphadenectomy (LNX) in conjunction with primary but optimal cytoreductive surgery in advanced epithelial ovarian cancer (OC) patients when followed by intensive chemotherapy., Methods: This is a retrospective analysis of all women with OC who were treated in our institution between 1992 and 2000. A total of 98 patients with stages IIIc-IV of OC underwent primary cytoreductive surgery which was 'optimal' (<1 cm residual disease). All patients subsequently received postoperative platinum-containing chemotherapy. Group I, consisting of 51 patients underwent LNX; Group II, consisting of 47 patients did not undergo LNX. The percentage of patients failing to respond to chemotherapy in each group was similar. Each group had statistically equivalent age, stage, regimens of chemotherapy performed, and all other known prognostic factors., Results: No survival benefit could be seen in platinum-sensitive patients. However, in patients who failed to respond to chemotherapy, the 2-year progression-free survival (PFS) (42.8% vs. 14.3%) and overall survival (OS) (51.2% vs. 28.8%) was quite different. LNX significantly improved those of drug-resistant patients when optimal cytoreductive surgery was performed [P = 0.008, risk ratio (rr) = 2.675, 95% confidence interval (CI) = 1.251-5.724]. Cox's proportional analysis shows that LNX was one of the three most significant covariate with the tumor grade and the number of postoperative residual lesions., Conclusions: The results show that LNX might be of benefit in patients who have optimal primary cytoreductive surgery and who do not respond to platinum-based chemotherapy.

Based on presentations on the basic concepts and scientific rationale of anti-angiogenic approaches to cancer therapy and the possible applications in the area of prostate cancer, gastrointestinal cancer, lung cancer and breast cancer it is easy to conclude that development of anti-angiogenic approaches into clinical therapies is extremely challenging. It is now well established that cancer growth is increased by angiogenic factors and that inhibition of angiogenesis decreases growth and metastatic potential. Anti-angiogenic effect can be obtained through interference with multiple targets. Further development of new strategies involving such novel cancer therapies requires wide reaching development of translational research abilities. However, for moving new therapies into the clinic same rigorous criteria need to be applied as is done for traditional therapies. Angiogenesis appear to be a critical factor for development of prostate, gastric, lung and breast cancers. Development of new anti-angiogenic treatment modalities might become very important in these diseases. A critical requirement for the successful clinical development will be the development of imaging techniques that can help evaluate the effect on blood vessel functionality. Such surrogate markers of anti-angiogenic effect will be essential for optimising molecules and doses.

Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.

Objectives: Based on our previous report showing that orobol, a potent phosphatidylinositol 4-kinase (PI4K) inhibitor, produced cisplatin (DDP) sensitivity, we have determined the mechanism of orobol-sensitization effect., Methods and Results: Orobol produced >2-fold DDP sensitivity in human ovarian carcinoma 2008 cells and its DDP-resistant variant 2008/C13*5.25 cells (C13). Because orobol had no effect on conventional mechanisms such as DDP accumulation or cellular metallothionein and glutathione content, we have focused on the apoptotic signaling pathway. Orobol induced a significant increase in apoptosis in DDP-treated cells, as estimated by frequency of condensed nuclear chromatin with Hoechst 33342 stain, although orobol alone did not have any effect on apoptotic potential. The caspase-3-inhibiting peptide Ac-DEVD-CHO completely inhibited the orobol sensitization effect but did not block DDP cell cytotoxicity per se. Orobol rendered both of these cells resistant to rhodamine 123 (Rh) by more than 2.5-fold, indicating significant decrease of mitochondrial membrane potential (DeltaPsim). Confocal laser microscopy of cells stained with the mitochondria (MT)-specific dye Rh revealed that orobol decreased Rh-fluorescent intensity. Electron microscopy of these cells showed that orobol induced swelling and condensation of MT. Orobol suppressed both naturally expressed and the DDP-induced Bcl-2 expression significantly. Orobol and DDP treatment reduced cytochrome c level in MT determined by Western blot analysis, indicating increased amount of cytochrome c release from MT, whereas orobol alone did not alter the amount of cytochrome c in MT., Conclusions: These results indicate that orobol produced DDP sensitivity in human ovarian carcinoma cells by inducing apoptosis through the MT-dependent signaling pathway.

Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important. Use of identical protocols are required for effective bridging. Participations in global phase III trials is the best way of achieving registration in Japan. For successful global trials in Japan it is important to include Japanese investigators in the preparation of the protocol and to recognise the challenges facing such a project. Clinical practice in diagnosis and treatment have many differences, thus it is recommended to have clear and detailed information in the protocol. Hard end points like survival are important since they are not biased by cultural differences. There are clear difficulties with HE or QOL outcomes. The emergence of focus on evidence based medicine is also happening in Japan and will help to harmonize documentation across the world. For large adjuvant or prevention cancer global trials are essential. To facilitate global studies further development of infrastructure is necessary in Japan. Use of electronic data capture web based communication etc. will help overcome communication difficulties. Other improvements that will make Japanese participation in global trials easier and better include establishment of clinical trial centre at each hospital, introduction of trial coordinators or study nurses and an improved collaboration with company staff. A critical issue that also need addressing is agreement of centre target recruitment. We need to introduce a new flexible system in Japan if participation in global trial is to be optimised. If we can address these issues Japanese investigators and collaborative groups should be able to initiate and lead global trials in the future.

Evidence Based Medicine (EBM) is a growing concept in Japan as it is elsewhere. Central to improving the use of EBM is generation of data through well conducted controlled clinical studies. There are many problems associated with conduct of clinical studies after launch in Japan, and many initiatives are ongoing to improve the situation. Development of Clinical Research Coordinators (CRO) and central Data Management centers are key to improving the quality of clinical research in Japan. Currently Japan has an undeveloped legal system with regard to post-launch trials and off-label use of registered drugs. There is no reimbursement for off-label and various restrictions imposed on the recipients of the Ministry of Health, Labour and Welfare's (MHLW) funds. Maybe the biggest problem is the high cost of post-marketing studies sponsored by pharmaceutical manufacturers. A high quality system to support post launch clinical studies need a solid financial base. There is a need for a suitable review system for investigator initiated multi-centre studies, as the current IRB system is not sufficient. There are also challenges regarding the differences, perceived or real, in treatment practice and available registrations in Japan and in the West, causing problems in choosing suitable comparators and study designs. At the present time it is not clear whether investigator initiated trials will be acceptable for registration purposes in Japan. The agreed first priority is to build a suitable and strong infrastructure within the academic community to support researchers to investigate important questions with or without pharmaceutical company support. Despite all these issues, several groundbreaking projects are under way throughout Japan, in many different areas and by different collaborative groups, some with government support. In fact, researcher-initiated clinical trials achieved a rapid growth in Japan in the past year.

Despite improvements in median and overall survival from a combination of improved operation techniques and chemotherapy with platinum-compounds and paclitaxel, long-term survival rates for patients with epithelial ovarian carcinoma remain disappointing, and ongoing efforts are aimed at developing more effective primary therapies. In early ovarian carcinoma, conservative management is used to denote surgery that preserves reproductive potential without compromising curability. With some exceptions, such a strategy may be applicable for women younger than 40, who wish to bear children. A major dilemma facing gynecologic oncologists is to determine whether the accurate staging laparotomy is needed for apparent low-risk stage I ovarian carcinoma and how many cycles of chemotherapy will be needed for high-risk stage I ovarian carcinoma. In advanced ovarian carcinoma, main objectives of salvage therapy include: a improvement in quality of life and symptoms; b. tumor load reduction and survival advantage; c. evaluation of potentially active new drugs to be included in first-line treatment. We need to evaluate the potential benefit on survival of systematic pelvic and para-aortic lymphadenectomy during primary or secondary cytoreductive surgery in patients with advanced ovarian carcinoma. Paclitaxel/cisplatin is considered to be the international standard treatment based on the data of GOG 111 trial showing that paclitaxel/cisplatin has provided a survival benefit better than that of cyclophosphamide/cisplatin. This choice of standard therapy might, however, be questioned based on the results of the largest randomised study, ICON3. There were no statistically significant differences in progression-free or overall survival among paclitaxel/carboplatin and carboplatin only or a platinum combination (cyclophosphamide/doxorubicin/cisplatin). The best selection for adjuvant chemotherapy is still controversial and a large number of studies are now ongoing.

Based on short reviews of lung, gastric, colorectal, prostate, breast and ovarian cancer, there remain significant differences between Japan and the West in the therapeutic regimen for most cancers. Some of the differences are due to differences in stage of disease at diagnosis or historical factors affecting availability of products. In both Japan and the West, there are initiatives to prepare treatment guidelines based on published data. For Japan this initiative is limited by the lack of Japanese clinical trial data or even safety data. When guidelines are prepared from international data, many of the products have limited indications in Japan and therefore not reimbursed. Availability of the most appropriate therapies to Japanese patients will depend on a facilitation of clinical trials in both primary and additional indications. However, the experience in other countries is that, even where data and registration approval are available, guidelines are hard to agree and are not uniformly accepted by prescribers. The ICH E5 guideline on the use of bridging studies to interpolate Western data to Japanese regulatory dossiers provides an opportunity to accelerate availability of new medicines to Japanese prescribers and patients. The use of bridging studies has so far been limited for anti-cancer therapies. Where relevant pharmacodynamic endpoints can be measured, (e.g. aromatase inhibition) there can increase confidence in bridging. The newer types of agent which act to stabilise disease rather than tumour shrinkage present a special problem. In some cases surrogate markers can be valuable but in each case they need to be validated. As globalization continues, an alternative approach is to include a significant cohort of Japanese patients in Japanese patients but this depends on sufficient similarity in the patient population and background therapy. The most significant limitation to either large outcome studies in Japan or for Japanese centers to join international trials has been the environment for conduct of clinical trials. There have been some recent improvements and further progress is expected so that Japanese doctors can play a full role in the evaluation of new therapies.

The management of advanced cancer presents the greatest challenge to physicians involved in oncology. There will usually be a large burden of disease; cure is unlikely; and the needs of the patient in terms of pain control and palliation will also be important over and above the direct treatment of the disease. Different issues will arise depending on the site and pathological type of the cancer. Increasingly over the past few years, treatment protocols and guidelines have been developed for different cancers, but these can only be rough guides rather than definite treatment recommendations. Additionally in most cancers advanced disease offers the opportunity for evaluation of new treatments in Phase II studies and other trials. With the new generation of molecular targeted therapies, such as EGFR inhibitors, striking results are being seen in advanced disease that compare favourably with what has been seen previously. Other agents such as those which attack the tumour vasculature may also have promise in this setting. Palliation is also an important aspect of the management of advanced disease, and pain control in particular is an important component of patient management. In summary, the treatment of advanced disease provides a test bed for new agents, but this need to develop better cancer therapies must be balanced against patient needs for a pain-free and comfortable end to life.