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Takashi Motohashi,Akira Yabuno,Hiroshi Michimae,Tetsuro Ohishi,Miwa Nonaka,Masashi Takano,Shin Nishio,Hiroyuki Fujiwara,Keiichi Fujiwara,Eiji Kondo,Toru Sugiyama,Tsutomu Tabata 대한부인종양학회 2021 Journal of Gynecologic Oncology Vol.32 No.1
Objective: The standard dose for pegylated liposomal doxorubicin (PLD) is 50 mg/m2every 4weeks. While 40 mg/m2has recently been used in clinical practice, evidence supporting thisuse remains lacking. Methods: This phase III randomized, non-inferiority study compared progression free survival (PFS) for patients with platinum-resistant ovarian carcinoma between anexperimental arm (40 mg/m2PLD) and a standard arm (50 mg/m2PLD) until 10 courses,disease progression or unacceptable toxicity. Eligible patients had received ≤2 prior lines. Stratification was by performance status and PFS of prior chemotherapy (<3 months versus ≥3months). The primary endpoint was PFS and secondary endpoints were overall survival (OS),toxicity profile, clinical response and tolerability. The total number of patients was 470. Results: The trial was prematurely closed due to slow recruitment, with 272 patients randomizedto the experimental arm (n=137) and standard arm (n=135). Final analysis was performed with234 deaths and 269 events for PFS. In the experimental arm vs. standard arm, median PFS was4.0 months vs. 4.0 months (hazard ratio [HR]=1.065; 95% confidence interval [CI]=0.830–1.366)and median OS was 14.0 months vs. 14.0 months (HR=1.078; 95% CI=0.831–1.397). Hematologictoxicity and oral cavity mucositis (≥grade 2) were more frequent in the standard arm than in theexperimental arm, but no difference was seen in ≥grade 2 hand-foot skin reaction. Conclusion: Non-inferiority of 2 PLD dosing schedule was not confirmed because the trialwas closed prematurely. However, recommendation of dose reduction of PLD should bebased both on efficacy and safety. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000003130
Yuji Ikeda,Sho Sato,Akira Yabuno,Daisuke Shintani,Aiko Ogasawara,Maiko Miwa,Makda Zewde,Takashi Miyamoto,Keiichi Fujiwara,Yusuke Nakamura,Kosei Hasegawa 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.6
Objective: Maternal embryonic leucine zipper kinase (MELK) is receiving an attentionas a therapeutic target in various types of cancers. In this study, we aimed to evaluate theprognostic significance of MELK expression in ovarian cancer using clinical samples, andassessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derivedovarian cancer cells as well as cell lines. Methods: Expression levels of MELK in 11 ovarian cancer cell lines were confirmed bywestern blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients byquantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluatedusing freshly-isolated primary ovarian cancer cells including spheroid formation condition. Results: MELK mRNA expression was significantly higher in ovarian cancer than in normalovaries (p<0.001), and high MELK mRNA expression was observed in patients with advancedstage, positive ascites cytology and residual tumor size. Patients with high MELK mRNAexpression showed shorter progression-free survival (p=0.001). Expression of MELK wasalso confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitoryconcentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167showed significant growth inhibitory effect against patient-derived ovarian cancer cells,regardless of their tumor locations, histologic subtypes and stages. Conclusions: We demonstrated MELK as both a prognostic marker and a therapeutic targetfor ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may bean effective approach to treat ovarian cancer patients.
Aiko Ogasawara,Taro Hihara,Daisuke Shintani,Akira Yabuno,Yuji Ikeda,Kenji Tai,Keiichi Fujiwara,Keisuke Watanabe,Kosei Hasegawa 대한암학회 2020 Cancer Research and Treatment Vol.52 No.4
Purpose Circulating tumor DNA (ctDNA) is an attractive source for liquid biopsy to understand molecular phenotypes of a tumor non-invasively, which is also expected to be both a diagnostic and prognostic marker. PIK3CA and KRAS are among the most frequently mutated genes in epithelial ovarian cancer (EOC). In addition, their hotspot mutations have already been identified and are ready for a highly sensitive analysis. Our aim is to clarify the significance of PIK3CA and KRAS mutations in the plasma of EOC patients as tumor-informed ctDNA. Materials and Methods We screened 306 patients with ovarian tumors for somatic PIK3CA or KRAS mutations. A total of 85 EOC patients had somatic PIK3CA and/or KRAS mutations, and the correspon-ding mutations were subsequently analyzed using a droplet digital polymerase chain reaction in their plasma. Results The detection rates for ctDNA were 27% in EOC patients. Advanced stage and positive peritoneal cytology were associated with higher frequency of ctDNA detection. Preoperative ctDNA detection was found to be an indicator of outcomes, and multivariate analysis revealed that ctDNA remained an independent risk factor for recurrence (p=0.010). Moreover, we assessed the mutation frequency in matched plasma before surgery and at recurrence from 17 patients, and found six patients had higher mutation rates in cell-free DNA at recurrence compared to that at primary diagnosis. Conclusion The presence of ctDNA at diagnosis was an indicator for recurrence, which suggests potential tumor spread even when tumors were localized at the time of diagnosis.