Prognostic significance of Ki67 during neoadjuvant chemotherapy in primary unresectable ovarian cancer.

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.

The mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin than to conventional taxane and carboplatin chemotherapy in high grade serous ovarian carcinoma: A survey of Japanese Gynecologic Oncology Group study (JGOG3016A1).

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.

Adjuvant therapy after radical surgery for stage IB-IIB cervical adenocarcinoma with risk factors.

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.

Malignant Struma Ovarii With a Predominant Component of Anaplastic Carcinoma.

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.

Progression-free survival by local investigator versus independent central review: comparative analysis of the AGO-OVAR16 Trial.

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.

Success rate and safety of tumor debulking with diaphragmatic surgery for advanced epithelial ovarian cancer and peritoneal cancer.

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.

Pathology-oriented treatment strategy of malignant ovarian tumor in pregnant women: analysis of 41 cases in Japan.

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.

Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial.

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.

Side population is increased in paclitaxel-resistant ovarian cancer cell lines regardless of resistance to cisplatin.

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.

Short-term serum deprivation confers sensitivity to taxanes in platinum-resistant human ovarian cancer cells.

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.

Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial.

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.

Mitochondrial ultrastructure-associated chemotherapy response in 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.

Favourable prognosis with modified dosing of docetaxel and cisplatin in Japanese patients with ovarian cancer.

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.

Readministration of Platinum Agents in Recurrent Ovarian Cancer Patients Who Developed Hypersensitivity Reactions to Carboplatin.

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.

Survival Following Chemotherapy in Ovarian Clear Cell Carcinoma Is Not Associated with Pathological Misclassification of Tumor Histotype.

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.

Analysis of prognostic factors for patients with leiomyoma treated with uterine arterial embolization.

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.

[Future directions of anticancer drug development in Japan].

At the 13th Oncology Forum, future directions of anticancer drug development in Japan were discussed. Development of anticancer drugs in the 1990s was based on the concept of total cell kill, but now development of molecular targeted drugs becomes the mainstream. Unfortunately, molecular targeted drugs and antibody agents are mostly foreign products and translational research in Japan is poor as it stands now. As future directions of anticancer drug development, international collaborative development is considered essential, but there are various obstacles to the conduct of international collaborative studies. Companies, medical institutions and regulatory agencies must make collaborative efforts to overcome these obstacles. As future development of anticancer agents in individual cancer regions in Japan is considered, gastric cancer therapy is progressing considerably with the advent of S-1 and in the future, development of multi-agent combination therapy including molecular targeted agents is expected. Much progress in colon cancer therapy has been made owing to accumulation of evidence in recent years. Multi-agent chemotherapy combined with antibody agent, which is advancing overseas, is introduced to Japan. Clinical development of combination therapy with a high therapeutic index, including compounds discovered in Japan, is expected in the future. Although conventionally hormone therapy has been considered as first-line treatment of breast cancer and used in combination with chemotherapy, with the advent of antibody agents in recent years, HER2 sensitivity has greatly affected the algorithm of treatment. Future development of molecular targeted drugs and individualised diagnosis using cDNA array, etc. are likely to advance individualisation of treatment. On the other hand, large-scale clinical trials are required to prove a small difference in adjuvant therapy, etc. and accordingly international studies are becoming indispensable. For urological cancers, molecular targeted drugs have been proved effective in renal cancer and future development of molecular targeted drugs for prostate cancer and testicular tumors is desirable. At that time, elucidation of the mechanism of action of molecular targeted drug and strategic drug development designed to increase its efficacy are expected. As a future direction of anticancer drug development, there are many cancers in whose international collaborative studies Japan can participate. Studies of prostate cancer and renal cell carcinoma can be internationalised while internationalisation of studies in ovarian and pancreatic cancers is essential. Phase III should be performed as international collaborative studies and depending on the type of cancer and drug, collaborative studies in an Asian region are effective. When participating in an international collaborative study, Japan needs to recruit subjects at a speed similar to the rest of the world, but differences in medical environment including clinical trials pose a problem. To solve this problem, it is considered effective not only to pursue the Western environment but also to improve staff such as nurses and CRC. The number of Japanese patients necessary for Phase III studies is individual developmental strategy and needs to be examined by both companies and regulatory agencies.

Retrospective analysis of sites of recurrence in stage I epithelial ovarian cancer.

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.

Clinical associations of Trousseau's syndrome associated with cerebral infarction and ovarian cancer.

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.

Differential regulation of the cytotoxicity activity of paclitaxel by orobol and platelet derived growth factor in human ovarian carcinoma cells.

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.