Background and Purpose-The intraluminal suture technique for producing middle cerebral artery occlusion in rodents is the most commonly used method for modeling focal cerebral ischemia associated with clinical ischemic stroke. Synchrotron radiation angiography may provide a novel solution to directly monitor the success of middle cerebral artery occlusion. Methods-Twenty adult Sprague-Dawley rats for middle cerebral artery occlusion models were prepared randomly with different suture head silicone coating. In vivo imaging was performed at beam line BL13W1, Shanghai Synchrotron Radiation Facility, Shanghai, China. Results-Silicone-coated suture was superior to uncoated suture for producing consistent brain infarction. Additionally, silicone coating length was an important variable controlling the extent of the ischemic lesion: infarcts affected predominantly the caudate-putamen with large variability (Ͻ2 mm), both the cortex and caudate-putamen (2-3.3 mm), and most of the hemisphere, including the hypothalamus (Ͼ3.3 mm). Conclusions-Synchrotron radiation angiography provides a useful tool to observe hemodynamic changes after middle cerebral artery occlusion, and the physical properties of suture are critical to the success of the middle cerebral artery occlusion model. (Stroke. 2012;43:888-891.)Key Words: angiography Ⅲ middle cerebral artery occlusion Ⅲ synchrotron radiation T he focal cerebral ischemia model involves the occlusion of the middle cerebral artery (MCAO) and typically results in localized brain infarction, which recapitulates many of the pathophysiological and histopathologic features of stroke. The most common technique for MCAO is the intraluminal filament model. 1 However, 1 limitation of the suture model is its high variability in infarct size. 2 Factors that contribute to such variation include differences in animal strain and weight, method of anesthesia, blood pressure, brain and body temperature, brain vascular anatomy, suture material, duration, and site of occlusion. Physical properties of the filament are important because it is the key factor that affects lesion volume 3 ; however, there is no direct evidence to confirm this principle. 4,5 Regional cerebral blood flow can be measured using autoradiography and laser Doppler flowmetry to confirm successful MCAO, but neither method can dynamically monitor changes of cerebral blood flow in deeper tissue during ischemia-reperfusion. 6,7 Synchrotron radiation angiography (SRA) may represent a novel solution to directly and dynamically monitor MCAO. 8 In the present study, we used SRA to examine if the coating length was critical for producing a highly reproducible stroke model. Materials and Methods Experimental GroupsAnimal procedures were approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University, Shanghai, China. Twenty male Sprague-Dawley rats (SLAC, Shanghai, China) weighing 270 to 350 g were divided into 4 groups randomly (nϭ5/group). The sutures with different physical properties were used in 4 groups t...
Background: Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triplenegative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. Methods: The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m 2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m 2 , days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m 2 days 1 and 8 every 3 weeks). Results: Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). Conclusion: Eribulin 1.1 mg/m 2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. Trial registration: ClinicalTrials.gov, NCT02120469. Registered
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