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Objective@#The addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1. @*Methods@#PAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint). @*Results@#Of 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11–1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16–2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab. @*Conclusion@# @*Results@#in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer.
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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. @*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 corresponding 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.
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Objective@#Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of MELK expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines. @*Methods@#Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay.MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients by quantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluated using freshly-isolated primary ovarian cancer cells including spheroid formation condition. @*Results@#MELK mRNA expression was significantly higher in ovarian cancer than in normal ovaries (p<0.001), and high MELK mRNA expression was observed in patients with advanced stage, positive ascites cytology and residual tumor size. Patients with high MELK mRNA expression showed shorter progression-free survival (p=0.001). Expression of MELK was also confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitory concentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167 showed 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 target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.
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Objective@#In this study we sought to investigate the clinical factors that affect postprogression survival (PPS) in patients with recurrent or persistent clear cell carcinoma (CCC).We utilized the JGOG3017/Gynecological Cancer InterGroup data to compare paclitaxel plus carboplatin (TC) and irinotecan plus cisplatin (CPT-P) in the treatment of stages I to IV CCC. @*Methods@#We enrolled 166 patients with recurrent or persistent CCC and assessed the impact of variables, including platinum sensitivity, treatment arm, crossover chemotherapy, primary stage, residual tumor at primary surgery, performance status, ethnicity, and tumor reduction surgery at recurrence on the median of PPS in patients with recurrent or persistent CCC. @*Results@#A total of 77 patients received TC, and 89 patients received CPT-P. The median PPS for patients with platinum-resistant disease was 10.9 months, compared with 18.8 months for patients with platinum-sensitive disease (hazard ratio [HR]=1.88; 95% confidence interval [CI]=1.30–2.72; log-rank p<0.001). In the multivariate analysis, the platinum sensitivity (resistant vs. sensitivity; HR=1.60; p=0.027) and primary stage (p=0.009) were identified as independent predictors of prognosis factors for PPS in recurrent or persistent CCC. @*Conclusions@#Our findings revealed that platinum sensitivity and primary stage are clinical factors that significantly affect PPS in patients with recurrent or persistent CCC as wellas other histologic subtypes of ovarian cancer. PPS in patients with recurrent CCC should establish the basis for future clinical trials in this population.
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Objective@#Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of MELK expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines. @*Methods@#Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay.MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients by quantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluated using freshly-isolated primary ovarian cancer cells including spheroid formation condition. @*Results@#MELK mRNA expression was significantly higher in ovarian cancer than in normal ovaries (p<0.001), and high MELK mRNA expression was observed in patients with advanced stage, positive ascites cytology and residual tumor size. Patients with high MELK mRNA expression showed shorter progression-free survival (p=0.001). Expression of MELK was also confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitory concentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167 showed 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 target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.
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Objective@#In this study we sought to investigate the clinical factors that affect postprogression survival (PPS) in patients with recurrent or persistent clear cell carcinoma (CCC).We utilized the JGOG3017/Gynecological Cancer InterGroup data to compare paclitaxel plus carboplatin (TC) and irinotecan plus cisplatin (CPT-P) in the treatment of stages I to IV CCC. @*Methods@#We enrolled 166 patients with recurrent or persistent CCC and assessed the impact of variables, including platinum sensitivity, treatment arm, crossover chemotherapy, primary stage, residual tumor at primary surgery, performance status, ethnicity, and tumor reduction surgery at recurrence on the median of PPS in patients with recurrent or persistent CCC. @*Results@#A total of 77 patients received TC, and 89 patients received CPT-P. The median PPS for patients with platinum-resistant disease was 10.9 months, compared with 18.8 months for patients with platinum-sensitive disease (hazard ratio [HR]=1.88; 95% confidence interval [CI]=1.30–2.72; log-rank p<0.001). In the multivariate analysis, the platinum sensitivity (resistant vs. sensitivity; HR=1.60; p=0.027) and primary stage (p=0.009) were identified as independent predictors of prognosis factors for PPS in recurrent or persistent CCC. @*Conclusions@#Our findings revealed that platinum sensitivity and primary stage are clinical factors that significantly affect PPS in patients with recurrent or persistent CCC as wellas other histologic subtypes of ovarian cancer. PPS in patients with recurrent CCC should establish the basis for future clinical trials in this population.
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A 41-year-old man was referred to our hospital suffering from pyrexia. Echocardiogram showed diffuse severe hypokinesis of the left ventricle. The patient was treated medically under a diagnosis of acute myocarditis and anticoagulation therapy had been started. However a large mobile thrombus and multiple small thrombi were detected in the left ventricle 2 days after admission. Because of the deterioration of his left ventricular function (LVEF 14%), he was treated medically with careful monitoring of the thrombi by echocardiogram. His left ventricular function started to improve 3 days after admission (LVEF 27%), and then surgical removal of the thrombi was performed through left ventriculotomy. His postoperative course was uneventful. LVEF was improved to 60% at discharge. He is doing well without any signs of embolic event at 2 years postoperatively. Left ventriculotomy is one of the useful methods for removal of left ventricular thrombus associated with acute myocarditis, if the procedure is performed during the recovery phase.
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Homologous blood transfusion may increase generalized inflammation by stimulating a patient's immune system during an open heart operation using cardiopulmonary bypass (CPB). We examined the beneficial effects on lung function of having no homologous blood transfusion during pediatric open heart operations. Thirty-three consecutive patients with ventricular septal defect were divided into (a) an autologous blood transfusion (AB) group (<i>n</i>=16) consisting of patients in whom predonation of autologous blood was undertaken and so homologous blood was not transfused, and (b) a control group (<i>n</i>=17) consisting of patients in whom homologous blood was used with a leukocyte removal filter during and after operation. Patients' age, sex, body weight, and contents of primed solution of the bypass circuit were similar in the 2 groups. Arterial blood gas analysis was carried out several times and the respiratory index (RI) calculated. Postoperative duration of intubation, white blood cell counts, and CRP titer were also compared. RI immediately after CPB did not differ between the AB and control groups, but RIs 3 and 6h after operation were significantly lower in the AB than in the control group (0.43±0.08 vs. 0.79±0.15 and 0.38±0.07 vs. 1.60±0.17). Duration of intubation, white blood cell counts, CRP titer were not statistically different. The results suggest that avoiding transfusion of whole homologous blood elements works effectively for preventing lung dysfunction after CPB.
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A pseudoaneurysm of the ascending aorta is a complication found in aortic valve surgery. A 66-year-old man who had a previous history of aortic valve replacement due to infectious endocarditis was admitted to our hospital suffering from chest pain. Follow-up chest X-ray and transthoracic echocardiogram had revealed no findings of pseudoaneurysm during the intervening period. At admission, computed tomographic scan and transesophageal echocardiogram each showed a Type A acute aortic dissection and a pseudoaneurysm of the ascending aorta. Under cardiopulmonary bypass and deep hypothermic circulatory arrest, an ascending aortic graft replacement was carried out uneventfully. The patient is well 14 months postoperatively. Postoperative examinations following aortic surgery should be performed not only from the view point of cardiac function, but also from that of a pseudoaneurysm.
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A case of combined redo off-pump CABG (OPCAB) with right gastroepiploic artery and abdominal aortic aneurysm repair is reported. A 71-year-old man with a previous history of CABG was admitted for the operation of recurrent angina pectoris and known abdominal aortic aneurysm. Preoperative coronary angiograms showed obstruction of LITA graft for LAD. The operative procedure consisted of redo OPCAB using right gastroepiploic artery as a transdiaphragmatic graft under left antero-lateral thoracotomy and graft replacement of abdominal aortic aneurysm under median laparotomy simultaneously. This strategy has the advantage of avoiding the continuity of median sternotomy and laparotomy and contributes to the minimally invasive procedure in the combined operation.
ABSTRACT
The results of complete graft replacement for thoracoabdominal aortic aneurysm remains unsatisfactory. The operative strategies, including the method of reconstruction of visceral vessels and the protection of abdominal organs and spinal cord, are controversial. Two male patients (53 and 59 years of age) had thoracoabdominal aortic aneurysms including the celiac artery and small abdominal aortic aneurysm in the renal arterial part. They underwent replacement of a large aneurysm using a Dacron prosthesis with reconstruction of the celiac artery. The remaining small aneurysm was wrapped by a bandage of Teflon tape 3mm in width. This wrapping technique was easy to perform and could be sufficiently adapted to the aneurysm preserving visceral arterial branches. The postoperative courses were uneventful. Their postoperative enhanced CTs (41 months and 26 months after surgery, respectively) revealed no enlargement of the wrapped aortic aneurysm and no stenosis of the visceral branches. This result suggests that our wrapping method is useful to reinforce the wall of small aortic aneurysms.