Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).

Abbreviations

CIs

confidence intervals

ctDNA

circulating tumor DNA

ddPCR

droplet digital PCR

EGFR

epidermal growth factor receptor

MFs

mutant fractions

NGS

next‐generation sequencing

NSCLC

non‐small cell lung cancer

ORR

overall response rate

OS

overall survival

PD

progressive disease

PFS

progression‐free survival

PR

partial response

SD

stable disease

TKI

tyrosine kinase inhibitor

     

Rapid Synthesis and Formation Mechanism of Core-Shell-Structured La-Doped SrTiO3 with a Nb-Doped Shell

To provide a convenient and practical synthesis process for metal ion doping on the surface of nanoparticles in an assembled nanostructure, core-shell-structured La-doped SrTiO₃ nanocubes with a Nb-doped surface layer were synthesized via a rapid synthesis combining a rapid sol-precipitation and hydrothermal process. The La-doped SrTiO₃ nanocubes were formed at room temperature by a rapid dissolution of NaOH pellets during the rapid sol-precipitation process, and the Nb-doped surface (shell) along with Nb-rich edges formed on the core nanocubes via the hydrothermal process. The formation mechanism of the core-shell-structured nanocubes and their shape evolution as a function of the Nb doping level were investigated. The synthesized core-shell-structured nanocubes could be arranged face-to-face on a SiO₂/Si substrate by a slow evaporation process, and this nanostructured 10 μm thick thin film showed a smooth surface.     

Mechanical stress enhances production of cytokines in human periodontal ligament cells induced by Porphyromonas gingivalis

Objective

We have previously reported that human periodontal ligament (hPDL) cells produced many kinds of cytokines as a result of bacterial stimulation, including stimulation with Porphyromonas gingivalis (P. gingivalis). However, the effects of mechanical stress on cytokine production in hPDL cells stimulated by periodontopathogenic bacteria are not clearly understood. In this study, we investigated the effects of mechanical stress on the production of inflammatory cytokines in hPDL cells induced by stimulation with P. gingivalis.

Methods

The hPDL cells were exposed to various levels of mechanical stress (1, 6, 10 and 50 MPa) and costimulated with mechanical stress and P. gingivalis for 24 h. Cytokine mRNA expressions were determined by RT-PCR. Cytokines in the culture supernatant were assessed by ELISA, and morphologic changes in hPDL cells were observed.

Results

The expressions of interleukin (IL)-6, IL-8 and tumor necrosis factor-α mRNA were observed in hPDL cells after exposure to mechanical stress. Moreover, the production of IL-6 and IL-8 increased significantly after exposure to mechanical stress ranging from 1 to 10 MPa. The amount of IL-8 in the culture supernatants of hPDL cells costimulated with P. gingivalis and mechanical stress was significantly higher than the expected additive amount. The morphology of hPDL cells did not change after exposure to 6 MPa, but these cells were partly detached from the Petri dish after exposure to 50 MPa.

Conclusions

These results suggest that local inflammation of the periodontal ligament may be induced mainly by periodontal bacteria, and mechanical stress may promote local inflammation.     

Overcorrection in vertical alveolar distraction osteogenesis for dental implants

A decrease in bone height following alveolar distraction osteogenesis (DO) before implant placement is common, and can be severe when alveolar DO is performed soon after surgical intervention. The aim of this study was to investigate the decrease in bone height after vertical alveolar DO and determine the need for overcorrection with implant placement. Thirty-five patients (17 males and 18 females, mean age 43.9 years) underwent 38 procedures with successful placement of 141 dental implants. Alveolar ridge height was evaluated using digital orthopantomographic radiographs taken shortly after the end of distraction, at consolidation and before implant placement. The mean distraction was 9.7 mm. The total vertical alveolar bone decrease was 2.1mm (21%) during the consolidation period and 3.6mm (37%) at implant placement. Although the 20 sites with a healthy alveolus (surgery >6 months) had bone reductions of 1.5 and 2.5mm (15 and 25%) the 18 sites at which alveolar DO was performed within 6 months (mean 3.0) of surgical intervention had much greater bone loss of 2.7 and 4.8mm (28 and 50%), respectively ((**)P<0.01). These results indicate that any alveolar DO protocol should include a waiting period after the surgical intervention, as well as consider an overcorrection of more than 25% within the limits of the applied surgical protocol.     

Induction of Sca-1 in the duct cells of the mouse submandibular gland by obstruction of the main excretory duct

The effect of ligation of the main excretory duct (MED) of the mouse submandibular gland (SMG) on the expression of Sca-1, a stem cell antigen, was examined by Western blotting and immunohistochemistry. By Western blotting, the expression of Sca-1 with a molecular weight of 18 kDa was identified in the normal gland. At 1 day post-ligation, the expression level of Sca-1 was strongly increased in the experimental gland and weakly in the contralateral gland, and such expression in both glands decreased at 6 days. By immunohistochemistry, Sca-1 was detected weakly in the apical membrane of excretory duct (ED) cells of the SMG under the normal condition. By duct ligation, Sca-1 became expressed strongly in most cells of the two major duct systems, i.e., the striated duct (SD) and granular convoluted tubules (GCT), but was not detected in the acinar (Ac) cells. By fluorescence-activated cell sorter (FACS) analysis, the number of side population (SP) cells in this gland was found to be increased by ligation. These results imply that Sca-1-positive cells may have a role in the duct cell proliferation in the regeneration step elicited by MED ligation-induced injury.     

Echocardiographic changes in diastolic filling and stroke volume during postural alterations and ankle exercise in a patient with congenital defect of the pericardium

Journal of Echocardiography -     

Transesophageal Doppler echocardiographic assessment of pulmonary venous flow pattern in subjects without cardiovascular disease

This study was designed to assess pulmonary venous flow dynamics using transesophageal Doppler echocardiography. Under general anesthesia, we studied 54 surgical patients with no history or physical evidence of cardiac disorders. In all patients pulmonary venous flow was easily identified by transesophageal color flow mapping. Pulmonary venous flow pattern, which was obtained clearly in 85% (4654) of patients by transesophageal pulsed Doppler echocardiography, was tri- or quadriphasic. The first wave, which was often biphasic in elderly patients, occurred during ventricular systole (S wave). The second wave occurred in diastole during the early ventricular filling phase of mitral flow (D wave). The third wave was reverse flow toward the pulmonary vein during atrial contraction (A wave). The following variables were measured: the peak flow velocities of each wave (PFVs, PFVd, PFVa), and the ratio of PFVs to PFVd (PFV(S/D)). The PFVd correlated with age (r=?0.56, P<0.001), indicating age-related decrease. The PFV(S/D) correlated with age (r=0.61, p<0.001), indicating age-related increase. These results would indicate that the contribution of pulmonary venous flow during diastole to total pulmonary venous flow decreases with age. Our data suggest that age-related diastolic dysfunction of the left ventricle would affect pulmonary venous flow dynamics and that left atrial storage volume during ventricular systole would increase with age.     

Differential diagnosis of gastric ulcer and gastric cancer in elderly patients

Along with the growing elderly population, patients with gastric ulcers caused by low-dose aspirin have increased. Gastric cancer is also common among the elderly population, but is sometimes difficult to distinguish from gastric ulcers, especially those stemming from aspirin use. To differentiate the diagnostic symptoms of gastric ulcers and gastric cancers in elderly patients, we compared the endoscopic findings of 198 subjects (92 benign ulcers and 106 cancers) aged 65 years and older. Despite their benign nature, aspirin-induced ulcers tended to have more irregularity of the ulcer edge and heterogeneous formation of regenerating epithelium than ulcer unrelated to aspirin. Asking about the use of low-dose aspirin is therefore important when confronted with such lesions in elderly patients.