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Background Bevacizumab (Bev) plays the central role of the adjuvant therapy for patients with ovarian carcinoma. The aim of our study was to examine whether differences in the administration of Bev influence the prognosis of patients. Methods Patients with ovarian carcinoma who received treatment at two hospitals between 1999 and 2020 were identified. Patients treated with weekly low-dose administration of Bev (100 mg Bev on days 1 and 8 and 200 mg Bev on day 15, monthly) at one hospital (group A) and those with monthly high-dose administration of Bev (15 mg/kg of Bev on day 1, monthly) at another hospital (group B) were retrospectively compared. Results Among the total patients, 44 were assigned to group A and 33 were assigned to group B. More patients in group A had advanced disease (p = 0.03) and a lower dose of Bev at the first time during the first cycle administration (p p p = 0.03). Stable duration was longer in group A than in group B (p p = 0.01) and nonhematological toxicities such as hypertension (p p p Conclusions Weekly low-dose administration of Bev might improve prognosis and decrease the frequency of adverse effects associated with this drug although the prospective study was needed to get corroboration.

Almost a quarter of a century has passed since the term sarcopenia was defined. Sarcopenia is recognized as a poor prognostic factor in a variety of cancer types. In ovarian cancer, it remains controversial whether sarcopenia affects prognosis and how it should be evaluated. The present study aimed to evaluate the association between the volume of the psoas major muscle and survival in patients with epithelial ovarian cancer. Medical charts of patients with epithelial ovarian cancer who received first-line chemotherapy with paclitaxel and carboplatin at the National Defense Medical College Hospital (Tokorozawa, Japan) between April 2010 and January 2015 were retrospectively reviewed. The bilateral psoas major muscle areas at the fifth lumbar vertebra were measured using computed tomography images. The Institutional Review Board at National Defense Medical College Hospital (Tokorozawa, Japan) approved the study protocol. A total of 72 patients with epithelial ovarian cancer who received combination therapy with paclitaxel and carboplatin were identified and enrolled. The median psoas muscle index (PMI; psoas muscle major cross-sectional area divided by height squared) was 5.4 cm2/m2 (range, 3.3-10.0). Patients with higher PMI had significantly improved overall survival (OS) compared with those with lower PMI [log-rank test P=0.014; hazard ratio (HR), 2.61; 95% confidence interval (CI), 1.21-6.06]. Multivariate analysis for OS revealed that lower PMI was an independent unfavorable prognostic factor (HR, 3.87; 95% CI, 1.37-12.1; P=0.0098). The volume of psoas major muscle mass could be a potential biomarker for prognosis in patients with epithelial ovarian cancer.

Objective: The pretreatment neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have been reported to be useful as markers for prognostic factors and metastasis in several cancers. The aim of this study was to identify the predictor of lymph node (LN) metastasis by pretreatment NLR and PLR in patients with endometrial cancer. Methods: Medical charts of the patients with endometrial cancers that received primary surgery at our hospital between 2007 and 2013 were retrospectively analyzed. The cutoff value was calculated from the receiver operating characteristics (ROC) curve. Clinicopathological parameters including inflammatory markers were evaluated for LN metastasis using multiple logistic regression analysis. Results: Among 197 patients enrolled in the study, LN metastasis was observed in 25 patients (13%). ROC curves demonstrated that the best cutoff value of NLR for predicting LN metastasis was 2.18 and that of PLR was 206. In univariate analysis, several pathological factors, NLR, and PLR were identified as predictors of LN metastasis. In multiple logistic regression analysis, lymphovascular invasion and NLR were found to be significantly correlated with LN metastasis (p = 0.002, 0.039). Conclusion: A higher pretreatment NLR was identified as a predictor of LN metastasis in endometrial cancers. Although further study is needed to confirm the results, NLR could be a candidate clinical marker for detection of LN metastasis.

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au–S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm−1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm−1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance., Graphical abstract Image 1, Highlights • Cystathionine-γ-lyase predicts post-operative chemoresistance in ovarian cancer. • SERS visualizes on-tissue polysulfides in non-responders against chemotherapy. • Polysulfides ameliorate cisplatin-induced DNA damages to block cancer cell death. • Ambroxol degrades polysulfides to unlock chemoresistance in vitro and in vivo.

Almost all primary epithelial ovarian cancers (EOC) respond to platinum-based chemotherapy; however, more than half of advanced cases develop recurrence. EOC has four major histologic subtypes: serous, endometrioid, clear cell, and mucinous tumors. Key genetic characteristics were determined according to these pathologic subtypes. High-grade serous carcinoma had four subtypes according to genetic profile. Clear cell and mucinous carcinomas had a lower response rate to platinum-based therapy. In the chapter, genetic analysis of drug sensitivity of EOC would be discussed for the clinical setting.

To compare a cohort of patients with platinum-resistant recurrent ovarian cancer (PROC) treated with bevacizumab and gemcitabine (Bev–Gem) to that of patients treated only with gemcitabine (Gem). Between 2011 and 2017, we identified the Bev–Gem and Gem PROC groups. The regimen included 1000 mg/m2 of Gem on days 1, 8, and 15, and 15 mg/m2 of Bev on day 1, every 4 weeks. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the administration of Bev–Gem or Gem until disease progression or death. The Bev–Gem and Gem groups included 18 and 29 patients, respectively. More patients had advanced stage disease in the Bev–Gem group (p = 0.048); no other characteristics differed between the groups. The response rates [ratio of complete remission (CR) to partial remission (PR)] of Bev–Gem and Gem were 38.9 and 3.4%, respectively (p

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au-S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm

The aim of the present study was to identify clinicopathological factors in long-term survivors following ovarian cancer recurrence. The patients who achieved longer survival after recurrence (n=18) and those who succumbed to the disease earlier (n=47) were identified and analyzed. There were no significant differences in age, performance status, stage distribution or histology between the two groups. Additionally, no significant difference was observed in progression-free survival after primary therapy. Multivariate analyses revealed that the predictive factors for long-term survival were i) secondary debulking surgery (OR=13.3; 95% CI: 1.39–226.7), ii) favourable response rate of second-line chemotherapy (OR=46.5; 95% CI: 1.84–313-4), and iii) ≥3 regimens after first recurrence (OR=9.01; 95% CI: 1.28–117.7). This study revealed that prolonged post-progression survival was associated with post-recurrence treatment. Therefore, appropriate selection of secondary debulking surgery and better chemotherapeutic response may lead to prolonged post-progression survival in recurrent ovarian cancer patients.

Recently, generic drugs of paclitaxel have been commonly used mainly by economic reasons; however, predictive factors for toxicities are not fully determined. Hypersensitivity reaction (HSR) is one of the most important adverse events in the paclitaxel-based therapy, and sometimes leads to lethal condition. The aim of the study was to identify predictors for HSR in patients treated with paclitaxel-based regimens. All the patients treated with chemotherapy including paclitaxel at our hospital between 1998 and 2013 were retrospectively evaluated. Clinicopathological factors of the patients that developed HSR and those without HSR were compared, and predictive factors for HSR were identified. Among 414 patients enrolled in the study, 26 patients (6.3%) developed HSR. Multivariate analyses showed that younger age (odds ratio 6.31), a history of allergy (odds ratio 3.79), and short-course premedication (odds ratio 14.1) were identified as predictive factors for HSR. There was no significant difference in the incidence of HSR between original paclitaxel and generic drug. The incidence of HSR was higher as the number of these predictors was accumulated. Three factors were identified as predictive factors for HSR: younger age, a history of allergy, and short-course premedication. Accumulation of these factors increased the incidence of HSR; however, the use of generic drug was not associated HSR in gynecologic cancer patients.

Objective: Most of the endometrial carcinomas are detected in early stages and have a better prognosis; however, predictive factors for recurrence have not been determined. Methods: Patients with grade 1 endometrioid carcinoma (EG1) according to the 2014 WHO criteria at FIGO 2009 stage IA that were identified through scanning medical charts were included, and we assessed whether the presence of uterine serous carcinoma (SC) component which comprised less than 5% of the total volume using the ovarian two-tiered grading system could be a recurrent risk factor in these patients. Results: Among 126 cases which met inclusion criteria, 12 cases had SC. SC tumors were divided into 2 groups: SC resembling high-grade serous carcinoma (HGSC) and SC resembling low-grade serous carcinoma (LGSC). Five (3.9%) cases had HGSC and 7 (5.6%) cases had LGSC. Recurrence was observed in 3 of all cases (2.3%): 2 cases with HGSC, and 1 case with LGSC. Regarding several clinicopathological factors, only the presence of SC was associated with recurrence. The sensitivity and specificity to predict recurrence using this system were 100 and 93%, respectively. Conclusion: The identification of SC using the ovarian two-tiered grading system could be an accurate predictor of recurrence in stage IA EG1.

Objective: The aim of the present study was to assess whether hysterectomy with wider resection could improve survival by preventing local recurrence. Methods: Medical charts of the patients with clinical stage I/II endometrial cancers treated at our hospital between 1990 and 2009 were retrospectively analyzed. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and adverse effects according to the type of hysterectomy. Results: A total of 247 patients were identified: 46 patients treated with total abdominal hysterectomy (TAH group) and 201 patients with modified radical hysterectomy (mRH group). No significant differences were observed in OS (p = 0.52) and PFS (p = 0.67) between the two groups. Also, there was no significant difference in the distribution of recurrent sites between the two groups. The patients treated with mRH had a longer operation time and more frequently developed severe adverse events, such as blood loss and lymphedema. Conclusion: In our cohorts, there were no significant differences in both PFS and OS according to surgical procedures, and the mRH group more frequently developed severe adverse events. Overall, clinical benefit was not obtained by mRH in patients with clinical stage I/II endometrial carcinomas.

Objective: The clinical significance of lymphocyte infiltration (LI) at the invasive front in endometrial carcinomas (EC) has not been determined. The aim of the current study was to evaluate the association between zone formation of LI at the invasive front of the tumor margin and prognoses of the patients with EC. Methods: All available pathological slides of the enrolled cases were reviewed, and the degree of LI at the invasive front was categorized into 2 groups: strong LI and weak LI. Clinical significance of LI was evaluated retrospectively. Results: A total of 333 cases with EC were enrolled in the study: 225 cases with weak LI and 108 cases with strong LI. Weak LI was more frequently observed in the patients with grade1/2 endometrioid EC. Multivariate analyses for progression-free survival (PFS) and overall survival (OS) revealed that weak LI was identified as an independent worse prognostic factor for OS (p = 0.004) in addition to PFS (p = 0.022). Conclusion: Weak LI at the invasive front of the tumor margin was associated with worse prognoses in EC. Although further studies are needed, it is suggested that LI could be a biomarker of prognoses in EC.

Background/aim The purpose of this study was to compare the clinical behavior of several grades of endometrioid carcinoma (EC) compared to high-grade serous carcinoma (HGSC), based on World Health Organization 2014 criteria. Materials and methods Clinicopathological features were compared between all grades of EC and HGSC, and between HGSC and either grade 1/2 or grade 3 EC. Results Sixty-five patients with EC and 214 with HGSC were identified. Among patients with EC, 56 displayed 1/2 EC and nine had grade 3 EC. The progression-free (PFS) and overall (OS) survival of patients with grade 1/2 EC were better than of those of patients with HGSC; however, PFS and OS did not statistically differ between patients with grade 3 EC and those with HGSC. Grade 1/2 EC, but not grade 3, was a better prognostic factor compared with HGSC. Conclusion A grading system for EC would be beneficial for the accurate prognosis of ovarian cancer.

Background/aim To investigate whether XIAP down-regulation and autophagy inhibition sensitize ovarian clear cell cancer cells to cisplatin. Materials and methods The ovarian clear cancer cell line KK was used for in vitro analysis. Hydroxychloroquine (HCQ) and phenoxodiol (PXD) or embelin were used as autophagy and XIAP inhibitors, respectively. Non-specific and XIAP-specific siRNAs were transfected using Lipofectamine. Cytotoxicity was assessed by MTT assays. Protein expression was confirmed by western blotting. Results In KK, down-regulation of XIAP using specific siRNAs together with HCQ treatment enhanced the anti-tumor effect of cisplatin. Although embelin sensitized KK to cisplatin through XIAP down-regulation, it induced autophagy. However, PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition. Expression of Atg7, Atg12, and Beclin 1 was decreased after PXD treatment. Conclusion PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition and could be a new candidate for ovarian clear cell carcinoma treatment.

Objective In 2014 World Health Organization criteria, seromucinous carcinoma was defined as a new histological subtype in ovarian carcinomas, but "seromucinous carcinoma" was not defined in endometrial carcinomas. The aim of this study was to identify seromucinous carcinoma resembling ovarian seromucinous carcinoma in endometrial carcinomas, and to evaluate the clinical significance for prognoses of the patients. Methods Central pathological review was conducted for patients with endometrioid carcinoma of the endometrium treated by primary surgery at our hospital between 1990 and 2013. Results Among 340 cases included in the study, no case had all tumor cells resembling ovarian seromucinous carcinoma in all specimens, and 31 cases (9.1%) had seromucinous component in combination with endometrioid carcinomas. Immunohistochemical analysis revealed seromucinous component had positive reactivity for cytokeratin (CK) 7, and negative reactivity for CK20 and caudal type homeobox 2 (CDX2) in all cases. Seromucinous component showed lower immunoreactivity of estrogen receptor and progesterone receptor, compared with endometrioid carcinoma component. Progression-free survival of the cases with seromucinous component was better than those without seromucinous component (p=0.049). Conclusion Seromucinous component was identified in approximately 10% of endometrioid carcinoma, and could be a histological predictor for prognosis.

The clinical significance of coexistence of endometriosis (EM) in ovarian clear cell carcinoma (CCC) has not yet been determined. The aim of the present study was to analyze the correlation of endometriosis with clinicopathological factors in CCC. The cases with CCC that received primary debulking surgery at the present hospital between 1990 and 2013 were identified. Retrospective analysis was conducted to evaluate the association between complications with EM and clinicopathological features in CCC. Of the 105 cases enrolled in the study, 45 cases were complicated with EM, and 60 cases did not have EM (non-EM). The patients with EM were diagnosed at a younger age (P=0.03), and at earlier stages (P

Aim To determine whether CD44, which is associated with tumor growth and metastasis, is related to carcinogenesis and prognosis in ovarian mucinous carcinomas (MACs). Materials and methods Tissue blocks from 71 patients with benign mucinous ovarian tumors were used in the study: 35 were from patients with borderline mucinous ovarian tumors, and 60 from patients with MACs. Immunochemical analysis was performed to evaluate the expression of CD44 and examine its association with tumorigenesis and survival. Results Compared to benign tumors, borderline tumors had high CD44 expression levels (p=0.047). Conversely, MACs had lower expression than borderline tumors (p=0.032). Progression-free and overall survival of patients with MAC with low CD44 expression were worse than those of patients with high expression (p=0.04 and p=0.02, respectively). Conclusion Malignant transformation of mucinous tumors is associated with changes in CD44 expression, with low expression level being a prognostic factor in MAC.

High-temperature-required protein A2 (HtrA2) is one of the serine proteases related to apoptosis. HtrA2 protein expression has been associated with cisplatin resistance and poor prognosis in ovarian serous adenocarcinoma (SAC). The aim of this study was to understand the influence of HtrA2 on repeated treatment with cisplatin. The change in HtrA2 expression in 31 ovarian cancers was investigated by immunohistochemical analysis, before and after cisplatin-based chemotherapy, and the association between HtrA2 expression after chemotherapy and prognosis was analyzed. The association between the change in HtrA2 and proteins associated with LATS1 in ovarian serous cancer cell lines after repeated treatment with cisplatin was evaluated in vitro. In immunohistochemical analysis, repeated cisplatin treatment induced downregulation of HtrA2 protein expression, before and after cisplatin-based chemotherapy in SAC. Progression-free survival and overall survival of SAC with low expression of HtrA2 were worse than those with high expression. In vitro analysis using cisplatin-sensitive ovarian cancer cell lines, KF28, and cisplatin-resistant cancer cell lines, KFr13, obtained from KF28 by repeated cisplatin treatment, showed that HtrA2 protein expression was lower in KFr13 than in KF28. Furthermore, KFr13 had a higher invasive capacity than KF28. Next, downregulation of HtrA2 transfected with an HtrA2-specific siRNA in KF28 had not only cisplatin resistance, but also more invasive capacity than those with non-specific siRNA. Repeated treatment with cisplatin downregulated the HtrA2 protein, which led to cisplatin resistance and increased invasive capacity. Thus, HtrA2 might be a biomarker of response to cisplatin treatment and prognosis, after cisplatin-based chemotherapy.

We aimed to retrospectively evaluate the efficacy and toxicity of an irinotecan hydrochloride (CPT) and nedaplatin (N) combination therapy for recurrent and refractory endometrial carcinoma, administered based on UGT1A1 genotype. Between 2009 and 2017, 21 patients who received CPT-N therapy for recurrent endometrial carcinoma as second- or third-line chemotherapy at our hospital were identified. The CPT-N regimen included 40–70 mg/m2 of CPT-11 on days 1, 8, and 15, and 50 mg/m2 of nedaplatin on day 1, q4 weeks. The median patient age was 63 years. The number of prior chemotherapeutic regimens ranged from 1 to 2. Two patients had prior pelvic irradiation. The response rate [ratio of complete remission (CR) to partial remission (PR)] of CPT-N therapy was 3 of 21 (14.3%), and clinical benefit rate (CBR) [the combined percentages of CR, PR, and stable disease (SD)] was 9 of 21 (42.8%). Toxicities included grade 3 neutropenia [4 (19.0%) cases], grade 3 febrile neutropenia [2 (9.5%) cases], and grade 3 diarrhea [3 (14.3%) cases]; all resolved with conservative treatment. Patients with a wild-type UGT1A1 status received higher doses of CPT-11 (p = 0.048) and had similar RR and CBR compared to those with a UGT1A1*6 and *28 status. There were no significant differences in frequencies of hematological or non-hematological toxicities, regardless of UGT1A1 status. The CPT-N regimen for recurrent and refractory endometrial carcinoma had tolerable side effects and significant efficacy. This regimen is a viable treatment option for endometrial carcinoma.

The activation of JAK2/STAT3 pathway has been reported to have critical roles in several solid tumors. The present study aimed to evaluate the correlation between JAK2/STAT3 activation and clinicopathological parameters in ovarian cancer types. Tissue microarrays made from the patients treated at the National Defense Medical College Hospital between 1984 and 2008 were evaluated using immunohistochemical (IHC) stainings. Medical charts of these patients including IHC results were retrospectively analyzed, and prognostic factors for progression-free survival and overall survival were evaluated. Among 341 enrolled patients, positive expression of p-STAT3 was observed in 95 cases (28%). Positive p-STAT3 was an independent worse prognostic factor for overall survival in all the cases. Additionally, p-STAT3 expression was related with overall survival in patients with clear-cell histology, but not in serous histology. The effect of an inhibitor of STAT3, niclosamide, was evaluated in ovarian clear-cell cancer cells, and niclosamide treatment decreased expression of p-STAT3, leading to increased apoptosis in a dose-dependent manner in vitro. The activation of JAK2/STAT3 pathway had significant impact on survival of ovarian cancers, especially for the cases with clear-cell histology. Although further analyses are needed, suppression of this pathway could be a candidate for the treatment of ovarian cancers.

Non-platinum single agents are usually used for patients with platinum-resistant recurrent ovarian cancers (ROC). However, the efficacy of these drugs is limited. The aim of the present study was to evaluate the efficacy and adverse events (AE) of combination therapy with irinotecan and platinum (CPT-Pt) for ROC. A total of 28 platinum-resistant or refractory patients with ROC treated with CPT-Pt at the National Defense Medical College Hospital institution between 2002 and 2012 were identified. All patients received taxane and carboplatin (TC) as a first-line treatment and relapsed within 6 months after completion of TC, or progressed during TC therapy. The median age was 59 years (range, 16-78), and median number of CPT-Pt therapy cycles was 5.5 (range, 2-16). The overall response rate was 14%, with a complete response (CR) in 2 patients and partial response (PR) in 2 patients. Stable disease (SD) for >3 months was observed in 15 patients (54%), resulting in a clinical benefit rate (CBR = CR + PR + SD) of 68%. The median progression-free survival and overall survival were 8 and 15 months, respectively. Fifteen cases (68%) developed grade 3/4 hematological AE and 3 cases (11%) developed non-hematological grade 3/4 AE, which were resolved by conservative management or dose reduction. Platinum re-treatment with irinotecan for platinum refractory or resistant ROC may be a candidate in such clinical settings.

OBJECTIVE Ovarian clear cell carcinoma (CCC) is one of histological subtypes showing poor prognosis due to chemoresistance. The association of autophagy-related proteins and clinical implementation in CCC has not been determined. METHODS The present study investigated whether expression of autophagy-related protein, light chain 3A (LC3A), was related with prognoses in the patients with CCC using immuno-histochemical stainings, and whether inhibition of autophagy modified the sensitivity to cisplatin in CCC cells in vitro. RESULTS High expression of autophagy-related protein, LC3A, was detected in 78 cases (78%) in all CCC cases. The patients with high LC3A expression showed significantly lower response rate to primary chemotherapy (17% vs. 100%, p

e17124 Background: The immunotherapy drug, nivolumab, is now approved for several metastatic cancers, and has resulted in responses previously not seen with these cancers. Molecular targeting agents, such as mammalian target of rapamycin (mTOR) inhibitor, have also recently been shown to have modest activity for endometrial cancers, however, the efficacy was limited. The present retrospective analysis is to evaluate the efficacy of Nivolumab alone or combination with molecular targeting agents for recurrent and refractory endometrial cancers. Methods: A retrospective evaluation for medical charts of the patients were conducted: (a) the cases with histologically confirmed endometrial cancers, (b) those that had recurrent diseases, (c) diagnosed as refractory for the previous chemotherapy, (d) those that were treated with combination therapy using tri-weekly Nivolumab (100mg/body, every 3 weeks) alone, or combination with molecular targeting agents. The association with serum markers and response was also investigated. Results: A total of 16 patients were identified: 5 cases with endometrioid G1/2, 4 cases with endometrioid G3, and the 6 cases with serous, and one case with mucinous histology. Median age was 61 years old (range:43-76), and median number of the previous chemotherapy was 4 regimens (range:1-5). Combined drugs included everolimus (n = 9), temozolomide (n = 1), trametinib (n = 1), and nintedanib (n = 1). Among 12 cases with evaluable disease, a complete response over 20 months was observed in one case: a case with endometrial carcinoma G2 treated with Nivolumab and evelorimus (5mg/day, continuously). Stable disease more than three months was achieved in 8 cases (67%), and clinical benefit rate (CR+SD > 3months) was achieved in 75% of the cases. Median progression-free survival was 5 months (range: 3-20+). Non-hematological adverse events included general fatigue, mucositis, dysgeusia, skin rash, edema, and liver dysfunction, but the toxicity greater than grade2 was observed and in a case with liver dysfunction (G3). There was no significant relationship between response and serum levels of VEGF, p53, and IL-6, however, clinical benefit was observed in higher abundance of endometrioid histology compared with serous subtype (86% vs. 50%). Conclusions: Combination therapy using Nivolumab with evelolimus could be a candidate for recurrent and refractory endometrial cancers. Biomarker analyses for the responders are mandatory for further investigation for larger clinical studies.

11051 Background: Uterine sarcomas are associated with poor prognosis snce the complete remission is extreme rare. Therefore, treatment with chemotherapy including eribulin or trabectedin, hormone therapy or molecular-targeted therapy including pazopanib or olaratumab was expectd, but the effect is not satisfactory. Thus, we evaluated the effects of temozoromide (T), derivateives of dacarbazine, and bevacizumab (B) (TB) containing or not cabozantinib (C), a multikinase inhibitor of MET, AXL, RET and VEGFR2 (TBC) in heavily pretreated cases of uterine sarcomas. Methods: From 2009 to 2018, 29 patients (pts) with heavily pretreated uterine sarcomas were enrolled. Fifteen of 29 patients were treated with T (80mg/body/day) and B (2mg/kg; days1, 8 and 15, q 4 weeks) (TB). Since 2013, C (140mg/body/week) was added to TB (TBC, n = 14). Treatment was continued until disease progression and/or unmanageable toxicities. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) v1.1, and adverse events were assessed by common terminology criteria for adverse events (CTCAE) v4.0. Results: Seven pts (24 %) had carcinosarcoma, fifteen (52 %) had leiomyosarcoma, five (17 %) had undifferentiated uterine sarcoma, one (3 %) had adenosarcoma, and one (3 %) had uterine sarcoma-not other specified. Twenty-three of 29 pts were subjected to response evaluation. Five pts (22 %) had complete response (CR), three (13 %) had partial response, six (26 %) had stable disease (SD). The response rate (RR: CR+PR) and disease-control rate (DCR: CR+PR+SD) were 35 % and 70 %, respectively. The median progression-free survival was 6.5 (2-89) months. When adding C to T and B, DCR was improved from 64 % (TB) to 75% (TBC). Median administration of cycles is 7 (TB) and 5 (TBC). There were 2 dead cases from perforation, but toxicity was almost mild and manageable. Conclusions: We have experienced 5 cases of CR by TB or TBC. Moreover, addition of C to T and B resulted in better disease-control rate. Compared to other reported treatment, TB combined with C could be substantially effective in cases with heavily pretreated uterine sarcomas. These results warrant further prospective and randomized studies.

e17059 Background: Eribulin is a candidate for paclitaxel-refractory breast cancers, and Bevacizmab (B) is known to enhance efficacy of anti-cancer agents in ovarian cancers. A combination therapy using weekly administration of B with eribulin and oxaliplatin (EriOX) in relapsed patients with platinum-resistant and refactory ovarian carcinomas (PR-ROC) was evaluated retrospectively, and the association with response and serum biomarkers was investigated. Methods: Medical charts of the patients who met the criteria shown below were identified: (a) histologically confirmed epithelial ovarian cancer (b) diagnosed as platinum-resistant ovarian cancer (c) treated with weekly-B-EriOX consisting of B (2mg/kg), eribulin (1mg/m2), and oxaliplatin (30mg/m2), three weeks on and one week off, q4weeks (d) written informed consent. Biomarker analyses including serum VEGF, BNP, p53, and IL-6 were also conducted. Results: A total of 34 patients were treated with weekly-B-EriOX. Median age of the patients was 58.5 years (range: 35-76), and median number of previous regimen was 4(range: 2-9). Overall, two patients (6%) had a complete response (CR), 8 patients (24%) had a partial remission (PR) and 16 patients (47%) had a stable disease (SD). The response rate and clinical benefit rate (CR+PR+SD) were 29% and 76%, respectively. Median progression-free survival was 4 months (range: 1-27+). Hematological adverse effects (AE) with grade 3/4 were observed in 4 patients (11%). Non-hematological AE greater than grade 2 was observed in one case: hypo albuminemia and edema, which were manageable and tolerable. The patients with elevation of serum mutated p53 protein and IL-6 had poorer prognosis. Conclusions: Weekly B and EriOX administration showed a remarkable response for patients with PR-ROC. Elevation of serum mutated p53 protein and IL-6 could be biomarkers for this regimen. These results warrant further prospective studies with additional biomarker analyses.

2592 Background: Cancer cachexia occurs in more than half of cancer patients and can be the primary cause of death for at least 20% of all patients. Cancer cachexia also lowers quality of life in cancer survivors due to a severe loss of skeletal muscle mass. Although a multitude of cytokines have been implicated in facilitating a cachectic state, the correlation of serum IL-6 and cancer-induced muscle wasting in gynecologic cancer patients has not been elucidated. Methods: The correlation between serum level of IL-6 and skeletal muscle volume in the patients with gynecologic cancers that received multiple lines of therapy was retrospectively evaluated. We used the psoas muscle index [PMI (cm2/m2)], the psoas major muscle area at the fifth lumber level divided by the height squared, measured using digital axial CT images, for the value of skeletal muscle volume. The level of IL-6 cut-off for elevation was defined as more than 12.0 pg/mL. The comparison of the survival distributions from the day of IL-6 measuaments was made using a log-rank test. Results: A total of 74 cases were assessed for the serum IL-6 and PMI: 32 cases with Mullerian cancers, 24 cases with endometrial cancers, 13 cases with cervical cancers, and 5 patients with others. The group with elevated IL-6 were associated with the lower PMI (t-test, p = 0.0154). The patients with IL-6 elevation had significantly worse survival compared with those with normal IL-6 (1y-OS; 31% vs. 80%, p < 0.0001). In 28 patients with more than two-point measurements of IL-6, the patients with the decrease to the level of IL-6 cut-off had favorable survival compared with those without the decrease (6m-OS; 100% vs. 52%, p = 0.0069). Conclusions: Serum level of IL-6 could be a sentinel biomarker for cancer-induced sarcopenia in the patients with gynecologic cancers. Additionally, IL-6 could be a biomarker to determine further continuation of aggressive chemotherapy for the patients that had received multiple lines of chemotherapy.

In this study, we aimed to determine whether the presence of poorly differentiated histologic components in ovarian clear cell adenocarcinoma (CCA) affects patient prognosis. Pathologic slides from 159 patients with CCA were studied, and the tumors were classified as Por(+) in the event of poorly differentiated histology; that is, if solid masses or cords, or individual infiltrating tumor cells with little or no glandular/papillary differentiation were present in >5% of the tumor area examined. All other tumors were classified as Por(-). The prognostic value and interobserver reproducibility of this assignment were analyzed. The agreement level in the assignment between 2 pathologists was 93.7% (κ=0.86). After a consensus was reached, 53 (33%) and 106 (67%) tumors were classified as Por(+) and Por(-), respectively. Patients with Por(+) tumors showed a significantly worse outcome than those with Por(-) tumors, both in the early stages (stages I/II, 5-year survival rate 53.9% vs. 96.3%, P

e17562Background: Although most of gynecologic cancers receive platinum-containing chemotherapy after the first surgical procedure, the most cases eventually relapse and develop to platinum-resista...

Background: To investigate the effects of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28, *6 and *27 in patients with gynecologic cancer who received chemotherapy with irinotecan and cisplatin. Methods: Patients eligible for this study had cervical or ovarian cancer treated with chemotherapy; a course of the regimen consisted of 60 mg/m2 of irinotecan on days 1, 8 and 15, and 60 mg/m2 of cisplatin on day 1 every 4 weeks. UGT1A1 polymorphisms and toxicities were analyzed. Results: From March 2007 to December 2007, 30 Japanese patients were enrolled; 24 ovarian carcinoma patients and 6 cervical cancer patients. The following genotypes of UGT1A1 were found: wild type in 17 patients (57%), *28 in 4 patients (13%), *6 in 8 patients (27%), *28*6 in 1 case (3%) and no case of *27 (0%). Grade 3/4 neutropenia, thrombocytopenia and diarrhea were significantly more frequent in *6 patients compared with wild-type patients. Also, in *6 patients irinotecan administration on days 8 or 15 was significantly more often omitted due to toxicities. In patients with *28 or *28*6, side effects were similar to those in patients with *6. Conclusion: In addition to UGT1A1*28, UGT1A1*6 might also be a key candidate to determine the dose of combination chemotherapy with irinotecan and cisplatin.

5550 Background: Eribulin is a candidate for paclitaxel-refractory breast cancers, and Bevacizumab (B) is known to enhance efficacy of anti-cancer agents in ovarian cancers. A phase II study to evaluate weekly administration of B with eribulin and oxaliplatin (EriOX) in patients with platinum-resistant and refractory ovarian carcinomas (PR-ROC) was performed. Methods: Eligible patients were as follows: (a) ECOG PS = 0~2 (b) histologically confirmed epithelial ovarian cancer (c) diagnosed as platinum-resistant ovarian cancer (d) written informed consent. Patients were treated with weekly-B-EriOX consisting of B (2mg/kg), eribulin (1mg/m2) and oxaliplatin (30mg/m2), three weeks on and on week off, q4weeks. The study was conducted using two-stage design of Simon (type I error = 0.05, power = 0.9, true response rate = 25%). Biomarker analyses including serum VEGF, BNP, p53, IL-6, and Her-2 were also conducted. Results: A total of 34 patients were enrolled in the present study: 13 cases in the first-stage, and additional 21 cases in the second-stage. There were 3 responders (≧2) in the first-stage, and the protocol was proceeded to the second-stage. Median age of the patient was 58.5 years (range: 35-76), and median number of previous regimen was 4 (range: 2-9). Overall, two patients (6%) had a complete response (CR), 8 patients (24%) had a partial remission (PR) and 16 patients (47%) had a stable disease (SD). The response rate and clinical benefit rate (CR+PR+SD) were 29% and 76%, respectively. Median progression-free survival was 4 months (range: 1-27+). Hematological adverse effects (AE) with grade 3/4 were observed in 4 patients (11%). Non-hematological AE greater than grade2 was observed in one case: hypo albuminemia and edema, which were manageable and tolerable. As there were 10 responders (≧6), the protocol was considered for additional investigation. The Patients with elevated serum mutated p53 / IL-6 showed lower response and worse prognoses. Conclusions: Weekly B and EriOX administration was considered for additional investigation for patients with PR-ROC. Serum mutated p53 protein and/or IL-6 could be biomarkers in PR-ROC patients treated with weekly B and EriOX.

Among the 161 cases of pT1 ovarian cancer treated at our hospital during the last 25 years, the impact of systematic lymphadenectomy was evaluated in 93 cases of the pT1N0M0 group(N0 group), 59 cases of the pT1NxM0(Nx group), and 9 cases of the pT1N1M0(N1 group). Significantly greater relapse-free survival(RFS)and overall survival(OS)were observed in 108 cases of the N0+N1 group compared to the Nx group(p=0. 006, p=0. 02). Multivariate analysis showed that systematic lymphadenectomy was a significant prognostic factor(hazard ratio 0. 473(95%CI, 0. 235-0. 951; p=0. 036). The present study suggested the systematic lymphadenectomy had a significant therapeutic effect on pT1 stage ovarian cancers.

Palliative therapy is usually employed for the treatment of metastatic or relapsed cervical cancer. Many agents including cisplatin have been used for fighting the tumor; however, the gold standard therapy has not yet been confirmed.Two cases of recurrent metastatic or refractory cervical cancer successfully treated with weekly administration of bevacizumab (2 mg/kg), paclitaxel (80 mg/m(2)), and carboplatin (area under the curve (AUC) = 2.0) are presented. 1 course of the therapy consisted of weekly paclitaxel/carboplatin on days 1, 8, and 15 and weekly bevacizumab on days 1, 8, 15, and 21, q28 days. Complete remission was observed after 3-4 courses of the therapy. Hematologic and non-hematologic toxicities higher than grade 3 were not observed during the chemotherapy. In both cases, there was no evidence of disease more than 10 months after the therapy.Weekly administration of bevacizumab and paclitaxel/carboplatin has potential activity in recurrent, metastatic, and refractory cervical carcinomas. These findings warrant further trials in such clinical settings.

Recent reports showed that bevacizumab, a humanized recombinant antibody binding to vascular endothelial growth factor (VEGF), harbored a significant activity in advanced or recurrent epithelial ovarian cancers. However, life-threatening complications including arterial thrombosis, pulmonary hemorrhage, and gastrointestinal perforation (GIP) are not negligible. A Japanese case of bowel perforation associated with bevacizumab treatment in heavily pretreated ovarian cancers is reported. The case affected with refractory ovarian cancer had no signs of bowel obstruction and bowel thickness which are now recognized as risk factors of GIP associated with bevacizumab. After obtaining a written informed consent, a combination of weekly paclitaxel and weekly bevacizumab was administered as the fourth-line therapy. After nine cycles of the regimen, the case developed GIP, although the recurrent tumor showed a stable disease. After conservative therapy for two months, the patient died. The case was severely pretreated; however, there seemed to be no risk factors for GIP. Therefore, we do recommend that special cautions are required for the bevacizumab- based chemotherapy, especially severely pretreated ovarian cancer patients.

To investigate the effects of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28, *6 and *27 in patients with gynecologic cancer who received chemotherapy with irinotecan and cisplatin.Patients eligible for this study had cervical or ovarian cancer treated with chemotherapy; a course of the regimen consisted of 60 mg/m(2) of irinotecan on days 1, 8 and 15, and 60 mg/m(2) of cisplatin on day 1 every 4 weeks. UGT1A1 polymorphisms and toxicities were analyzed.From March 2007 to December 2007, 30 Japanese patients were enrolled; 24 ovarian carcinoma patients and 6 cervical cancer patients. The following genotypes of UGT1A1 were found: wild type in 17 patients (57%), *28 in 4 patients (13%), *6 in 8 patients (27%), *28*6 in 1 case (3%) and no case of *27 (0%). Grade 3/4 neutropenia, thrombocytopenia and diarrhea were significantly more frequent in *6 patients compared with wild-type patients. Also, in *6 patients irinotecan administration on days 8 or 15 was significantly more often omitted due to toxicities. In patients with *28 or *28*6, side effects were similar to those in patients with *6.In addition to UGT1A1*28, UGT1A1*6 might also be a key candidate to determine the dose of combination chemotherapy with irinotecan and cisplatin.

Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing a resistance to chemotherapy and resulting in poor prognosis. Our aim was to evaluate the effects of complete surgical procedures followed by adjuvant chemotherapy for CCC patients whose tumors were confined to the ovary (pT1M0). During the period of 1987-2005, 56 patients with stage I CCC were identified and two cases were excluded due to retroperitoneal lymph node metastasis. A total of 54 patients were enrolled in the study and divided into two groups: Group A (n=38, 1993-2005) underwent complete surgical staging including pelvic and para-aortic lymphadenectomy. Group B (n=16, 1987-1992) underwent a hysterectomy, bilateral salpingo-oopherectomy, omentectomy without comprehensive lymphadenectomy. Every patient received six courses of adjuvant chemotherapy using a platinum agent. Survival analysis was estimated by the Kaplan-Meier method and prognostic factors were evaluated using a Cox regression model. The clinical characteristics of the two groups were similar, except for the rate of conventional platinum-based chemotherapy (p=0.02). Multiple regression survival analysis revealed that the completion of a comprehensive staging operation was the only independent factor for progression-free survival of stage I CCC patients (p=0.03) and that the chemotherapeutic regimen was not a prognostic factor (p=0.43). The present study indicates that we should accomplish complete surgical staging procedures for CCC confined to the ovary.

We occasionally encountered clear cell adenofibromatous (CCAF) components coexisting in the ovarian clear cell adenocarcinoma (CCA). To reveal the clinicopathologic significance of CCAF components in CCA, we classified 67 cases of surgically resected CCA into CCA with and without CCAF components [CCAF(+) and (-) groups], and compared clinicopathologic parameters, that is, patient age, clinical stage, the degree of optimal cytoreduction, patient outcome, histologic grade and Ki-67 labeling index of the CCA, and the presence of endometriosis, between these 2 groups. Fourteen cases (21%) and 53 cases were classified as CCAF(+) and CCAF(-) groups, respectively. Of these 14 CCAF(+) cases, the CCAF components with atypia were observed adjacent to the CCAF components without atypia in 10, and adjacent to the obvious CCAs in 13 cases. In comparison with the CCAF(-) group, the CCAF(+) group showed a higher frequency of histologically low-grade tumors [93% (13 of 14) vs. 43% (23 of 53), P=0.0027], a lower Ki-67 labeling index (mean 35.9% vs. 44.0%, P=0.0492), and better patient prognosis (5-year survival 78.8% vs. 49.3%, P=0.0277). Endometriosis was much less frequent in the CCAF(+) group than in the CCAF(-) group [14.7% (2 of 14) vs. 67.9% (36 of 53), P=0.00096]. Multivariate analysis identified only optimal cytoreduction as independent favorable prognostic factor. These results suggest that CCAF besides endometriosis is associated with the development of CCA, and that the CCAF(+) group may be a distinct subgroup of CCA with less aggressive biologic behavior.

5603 Background: Eribulin, inhibiting a protein component of tubulin, is a candidate for paclitaxel-refractory breast cancers, and Bevacizumab (B) is known to enhance efficacy of anti-cancer agents...

5583 Background: Recurrent clear cell carcinoma (RCCC) of the ovary showed exceedingly chemo-resistant phenotype, especially in the case with recurrent or refractory to previous therapy. A phase II...