A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L).

OBJECTIVES: Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. METHODS: The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA. RESULTS: The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively. CONCLUSIONS: This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.

Bone formation by human umbilical cord perivascular cells.

We investigated the possibility of employing human umbilical perivascular cells (HUCPVCs) within the context of finding an alternative source of mesenchymal stromal cells (MSC) for bone tissue engineering. Since it has previously been reported that conditioned medium (CM) from osteogenic bone marrow (BM) MSCs can potentiate osteogenic differentiation in a secondary cell population, we also employed BM-MSCs to generate CM to stimulate osteogenesis in the HUCPVCs. The BM-MSCs were a commercially available immortalized human cell line. In vitro assays showed negligible levels of osteogenic gene expression in HUCPVCs compared to BM-MSC, but alkaline phosphatase was detected when HUCPVC were cultured in osteogenic medium in the presence of CM from BM-MSC. An in vivo assay employing a rat calvarial osteotomy defect, together with a collagen sponge scaffold, showed that HUCPVCs provided statistically significant bony repair compared to controls. BM-MSC loaded scaffolds were not statistically different from either controls or HUCPVCs. The addition of BM-MSC CM to HUCPVCs also produced no statistically significant difference to the bone formed by HUCPVCs alone. Our results demonstrate that the in vitro assays employed did not predict in vivo outcomes, and that the BM-MSC cell line employed, or CM from such cells, provided no osteogenic advantage over the use of HUCPVCs alone.

A simple, safe bimanual technique for subincisional cortex aspiration.

We developed a bimanual manipulation technique to facilitate the removal of the subincisional lens cortex in small-incision phacoemulsification cataract surgery. A separate aspiration handpiece, not connected to an aspiration tube, is passed into the anterior chamber through a side-port corneal incision. Under irrigation with a standard infusion/aspiration (I/A) handpiece through a tunnel incision, the cortex is stripped off with the separate handpiece and removed with the I/A handpiece. In 227 eyes, subincisional cortex removal and subsequent capsule polishing was performed safely with the separate handpiece. Rupture of the posterior lens capsule occurred in 3 high-risk eyes.

Mechanics of curved plasma membrane vesicles: resting shapes, membrane curvature, and in-plane shear elasticity.

Highly curved cell membrane structures, such as plasmalemmal vesicles (caveolae) and clathrin-coated pits, facilitate many cell functions, including the clustering of membrane receptors and transport of specific extracellular macromolecules by endothelial cells. These structures are subject to large mechanical deformations when the plasma membrane is stretched and subject to a change of its curvature. To enhance our understanding of plasmalemmal vesicles we need to improve the understanding of the mechanics in regions of high membrane curvatures. We examine here, theoretically, the shapes of plasmalemmal vesicles assuming that they consist of three membrane domains: an inner domain with high curvature, an outer domain with moderate curvature, and an outermost flat domain, all in the unstressed state. We assume the membrane properties are the same in these domains with membrane bending elasticity as well as in-plane shear elasticity. Special emphasis is placed on the effects of membrane curvature and in-plane shear elasticity on the mechanics of vesicle during unfolding by application of membrane tension. The vesicle shapes were computed by minimization of bending and in-plane shear strain energy. Mechanically stable vesicles were identified with characteristic membrane necks. Upon stretch of the membrane, the vesicle necks disappeared relatively abruptly leading to membrane shapes that consist of curved indentations. While the resting shape of vesicles is predominantly affected by the membrane spontaneous curvatures, the membrane shear elasticity (for a range of values recorded in the red cell membrane) makes a significant contribution as the vesicle is subject to stretch and unfolding. The membrane tension required to unfold the vesicle is sensitive with respect to its shape, especially as the vesicle becomes fully unfolded and approaches a relative flat shape.

[Different effects of exercise training in patients with myocardial infarction with or without diabetes mellitus].

OBJECTIVES: This study investigated whether myocardial infarction patients with diabetes mellitus had lower heart rate reserve to exercise by measuring the increment in heart rate (HR) divided by the increment of norepinephrine (NE) concentration from rest to peak exercise (delta HR/log delta NE). The difference in exercise training effects was also investigated. METHODS: The 148 patients after myocardial infarction were divided into two groups, the DM group (n = 34) and the non-DM group (n = 114). Cardiopulmonary exercise testing was performed in each subject at 1 and 3 months after the onset. Blood samples were taken at rest and immediately after peak exercise, rest brain natriuretic peptide, rest and peak norepinephrine were analyzed. Exercise training was performed from 1 to 3 months after the onset. RESULTS: Resting heart rates were significantly higher in the DM group than in the non-DM group both at 1 and 3 months although peak heart rates were not significantly different. Peak oxygen uptake were lower in the DM group both at 1 and 3 months after onset of myocardial infarction compared to the non-DM group. End-tidal carbon dioxide pressure was lower and the rate of increase of minute ventilation to carbon dioxide output was higher in the DM group. Plasma brain natriuretic peptide was higher in the DM group. delta HR/log delta NE was 19.4 +/- 4.0 in the DM group and 22.2 +/- 5.6 in the non-DM group (p < 0.01), and increased in only the non-DM group. delta HR/log delta NE was more closely correlated with peak oxygen uptake in the DM group than in the non-DM group. CONCLUSIONS: Impaired response to exercise training may be caused, in part, by impaired heart rate reserve to exercise in patients with diabetes mellitus.

Relationship between impaired chronotropic response, cardiac output during exercise, and exercise tolerance in patients with chronic heart failure.

The present study was undertaken to investigate the relationship between the extent of impaired chronotropic response and cardiac output during exercise, and exercise tolerance in patients with chronic heart failure. The subjects consisted of 24 patients (mean 60.1 +/- 14.0 years) who had mild chronotropic incompetence. Cardiopulmonary exercise testing was performed in all patients, and heart rate (HR), anaerobic threshold (AT), maximum oxygen uptake (peak VO2), slope of the regression line relating the ventilatory equivalent to carbon dioxide output (VE/VCO2 slope), and exercise time were measured. Cardiac output (CO) was measured by a thoracic bioimpedance method and cardiac index (CI) was calculated. Plasma norepinephrine (NE) was measured at rest and immediately after the exercise test. The changes in HR, NE, and CI from the resting state to immediately after exercise were calculated as deltaHR, deltaNE, and deltaCI, respectively. The deltaNE was converted to a logarithmic scale and deltaHR/log deltaNE was used as a parameter of HR response to sympathetic nerve stimulation. The results were as follows: HR and NE in the resting state had no correlation with AT and with peak VO2. DeltaHR/log deltaNE correlated positively with both AT and peak VO2, and negatively with the VE/CO2 slope. DeltaHR/log deltaNE correlated positively with peak CI, %deltaCI, and deltaCI/exercise time. The data suggest that one of the mechanisms of low exercise tolerance in chronic heart failure patients was due to an inadequate increase in CO response against exercise caused by an impaired HR response to increased NE.