Evaluation of the effect of sagging correction calibration errors in radiotherapy software on image matching

To investigate the impact of sagging correction calibration errors in radiotherapy software on image matching. Three software applications were used, with and without a polymethyl methacrylate rod supporting the ball bearings (BB). The calibration error for sagging correction across nine flex maps (FMs) was determined by shifting the BB positions along the Left–Right (LR), Gun–Target (GT), and Up–Down (UD) directions from the reference point. Lucy and pelvic phantom cone-beam computed tomography (CBCT) images underwent auto-matching after modifying each FM. Image deformation was assessed in orthogonal CBCT planes, and the correlations among BB shift magnitude, deformation vector value, and differences in auto-matching were analyzed. The average difference in analysis results among the three softwares for the Winston–Lutz test was within 0.1 mm. The determination coefficients (R2) between the BB shift amount and Lucy phantom matching error in each FM were 0.99, 0.99, and 1.00 in the LR-, GT-, and UD-directions, respectively. The pelvis phantom demonstrated no cross-correlation in the GT direction during auto-matching error evaluation using each FM. The correlation coefficient (r) between the BB shift and the deformation vector value was 0.95 on average for all image planes. Slight differences were observed among software in the evaluation of the Winston–Lutz test. The sagging correction calibration error in the radiotherapy imaging system was caused by an auto-matching error of the phantom and deformation of CBCT images

A Construction of a Superior and an Inferior Function to the Gerber-Shiu Function

application/pdfLet the surplus process {R(t)} of a company be the jump diffusion model (Ⅰ.1). The company goes to ruin at a moment τ ≡ {t > 0 : R(t) < 0}, where the surplus R(τ−) immediately prior to τ, and the deficit |R(τ)| are important quantities. Then given a suitable penalty function W(y, z) of y, z ≥ 0, the severity of ruin is measured by the Gerber-Shiu function ψ(x) = Ex[e−ατ W(R(τ−), | R(τ)|) ], in which α ≥ 0 is a discount rate. ψ is a powerful tool in the risk theory. However it is hard to obtain ψ of an explicit form except very special claim size distributions F. Therefore for general F and W, we present a method to construct an explicit superior function ΨU and an explicit inferior ΨL with constants BU and BL, such that ψ(x) ≤ ΨU(x) for 0 ≤ x ≤ BU, and ψ(x) ≥ ΨL(x) for 0 ≤ x ≤ BL. As examples of general F, we consider the followings and compute the above BU, ΨU and etc. in each case: 1. a truncated exponential distribution, which imitates to contract a reinsure, 2. and, a step function type F, which imitates a practical claim size distribution,departmental bulletin pape

Coronary angioplasty ameliorates hypoperfusion-induced endothelial dysfunction in patients with stable angina pectoris

Objectives.This study sought to investigate the effect of coronary angioplasty on chronic hypoperfusion-induced endothelial dysfunction in patients with coronary heart disease.Background.The endothelium is an important component for organ flow regulation. Ischemia with or without reperfusion is known to cause endothelial dysfunction. We tested the hypothesis that chronic hypoperfusion impairs endothelial function in the angiographically normal coronary artery segment distal to stenosis and that the impairment by chronic hypoperfusion is reduced by coronary angioplasty.Methods.In 13 patients with stable angina pectoris, substance P (10, 30 and 100 pmol) and nitroglycerin (200 μg) were sequentially infused into the coronary artery in a cumulative manner on the day after coronary angioplasty. In 10 of these patients, vascular responses to these agents were again investigated 3 months after angioplasty. Changes in vascular diameter were evaluated in vessels located proximal and distal to the target lesion, both of which were angiographically normal, by performing computer-assisted quantitative coronary angiography. In five patients, the transstenotic pressure gradient was also measured with a pressure sensor-mounted guide wire before angioplasty.Results.On the day after angioplasty, the magnitude of dilation by substance P in distal segments was significantly less than that in proximal segments and inversely correlated with the transstenotic pressure gradient (p < 0.05) and lesion stenosis (p < 0.05). There was no difference in nitroglycerin-induced vasodilation between the two vessel segment groups. Three months later, the impaired response to substance P in the distal segment was restored to normal.Conclusions.We conclude that chronic hypoperfusion impairs endothelium-dependent dilation of coronary artery distal to critical stenosis in patients with ischemic heart disease and that coronary angioplasty ameliorates the endothelial dysfunction within 3 months

Hepatocyte growth factor reduces susceptibility to an irreversible epidermal growth factor receptor inhibitor in EGFR-T790M mutant lung cancer

金沢大学附属病院がん高度先進治療センターPurpose: The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the most frequent cause of acquired resistance to the reversible EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, in lung cancer. Irreversible EGFR-TKIs are expected to overcome the reversible EGFR-TKI resistance of lung cancer harboring T790M mutation in EGFR. However, it is clear that resistance may also develop to this class of inhibitors. We showed previously that hepatocyte growth factor (HGF) induced gefitinib resistance of lung cancer harboring EGFR-activating mutations. Here, we investigated whether HGF induced resistance to the irreversible EGFR-TKI, CL-387,785, in lung cancer cells (H1975) harboring both L858R activating mutation and T790M secondary mutation in EGFR. Experimental Design: CL-387,785 sensitivity and signal transduction in H1975 cells were examined in the presence or absence of HGF or HGF-producing fibroblasts with or without HGF-MET inhibitors. Results: HGF reduced susceptibility to CL-387,785 in H1975 cells. Western blotting and small interfering RNA analyses indicated that HGF-induced hyposensitivity was mediated by the MET/phosphoinositide 3-kinase/Akt signaling pathway independent of EGFR, ErbB2, ErbB3, and ErbB4. Hyposensitivity of H1975 cells to CL-387,785 was also induced by coculture with high-level HGF-producing lung fibroblasts. The hyposensitivity was abrogated by treatment with anti-HGF neutralizing antibody, HGF antagonist NK4, or MET-TKI. Conclusions: We showed HGF-mediated hyposensitivity as a novel mechanism of resistance to irreversible EGFR-TKIs. It will be clinically valuable to investigate the involvement of HGF-MET-mediated signaling in de novo and acquired resistance to irreversible EGFR-TKIs in lung cancer harboring T790M mutation in EGFR. ©2010 AACR

An Expansion Formula to the Gerber-Shiu Function

application/pdfIn order to incorporate the effects of operational risks and economic fluctuations, we define the surplus process {R(t)} of an insurance company, by 　　　jump diffusion model R(t) = x + t + σB(t) −ΣN(t)k=0Uk, x≥ 0. (See (Ⅰ.6) for more informations). The company goes to ruin at a moment of τ ≡ inf{t >0 : R(t) < 0}. When it occurs, important quantities are the surplus R(τ−) immediately prior to τ, and the deficit |R(τ)|. Therefore, given a suitable penalty function W(z, y)for y, z ≥ 0, the severity of ruin is defined by 　　　the Gerber-Shiu function ψ(x) = Ex[e−ατ W( R(τ−), | R(τ) |) ], where α ≥ 0 is a fixed discount rate. 　One of main topics on the risk theory is to analyze ψ, because ψ can be various quantities related to the risk theory. To this end, we present an expansion formula to ψ under a general claim size distribution and a general W. In the special case of σ = 0, W ≡ 1,and α = 0, our formula becomes to the Pollaczek-Khintchine formula whose usefulness is well known.departmental bulletin pape

Met Kinase Inhibitor E7050 Reverses Three Different Mechanisms of Hepatocyte Growth Factor-induced Tyrosine Kinase Inhibitor Resistance in EGFR Mutant Lung Cancer

PURPOSE: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant lung cancer cells by activating Met and the downstream PI3K/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. EXPERIMENTAL DESIGN: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR-mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion, and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into SCID mice and the therapeutic effects of E7050 plus gefitinib were assayed. RESULTS: E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. CONCLUSIONS: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs