Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B)

Background

Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.

Methods

Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.

Results

Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.

Conclusion

Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

     

Outflow graft anastomosis site design could be correlated to aortic valve regurgitation under left ventricular assist device support

Aortic valve regurgitation (AR) is a critical complication during circulatory support with a left ventricular assist device (LVAD). The time-course of AR and related factors, including outflow graft anastomosis site design, were investigated. Twenty-three patients who had continuous-flow LVAD implantation and were supported for more than 6 months were investigated. AR grade (none, 0; trivial, 0.5; mild, 1; mild-moderate, 1.5; moderate, 2; moderate-severe, 2.5; severe, 3) and aortic valve opening were evaluated with echocardiography. Computed tomography was performed to all the patients postoperatively. The angle of the outflow graft to the aorta (O-A angle, parallel 0; tangent 90°, 0–180°), aortic diameter at the anastomosis site, sino-tubular junction (STJ) diameter, distance between the STJ and the anastomosis site, and distance between the anastomosis site and the brachiocephalic artery were measured. The patients’ age was 38?±?11 years. Support duration was 686?±?354 days. Mean AR grade after continuous-flow LVAD implantation was increased to around mild and was maintained thereafter. No patient needed any intervention to the aortic valve. The aortic valves of 82.6% of patients were closed continuously. The O-A angle (83?±?14) was positively correlated with maximum AR grade (p?=?0.0095). The O-A angle was significantly smaller in patients with maximum AR grade of 1 or less (77?±?9°) than in those with 1.5 or greater (94?±?15°, p?=?0.021). The other CT measurements had no correlation with AR grade. In conclusion, the O-A angle was correlated with AR grade progression. The O-A angle appears to be one of the important factors related to AR under continuous-flow LVAD support.     

Identification of stimulation site of pacemaker lead using tissue tracking method

Purpose We aimed to identify the electrical stimulation sites of pacemaker leads using a tissue tracking method of tissue Doppler imaging. Methods The study group consisted of 30 patients who had undergone permanent pacemaker implantation. During tissue Doppler imaging, the initial contraction site was seen as a red area stimulated by the pacemaker lead. This red area was analyzed precisely using time–distance curves generated by tissue tracking. Results The initial contraction site of the myocardium was located in the interventricular septum in seven patients and in the apical portion of the right ventricle in 11 patients. Furthermore, analysis of time–distance curves demonstrated that one point within the red area started to move earlier than the others. Conclusion The site of electrical stimulation within the myocardium can be determined from the time–distance curves generated by the tissue tracking method. A summary of this paper was presented at the 77th Conference of the Japan Society of Ultrasonics in Medicine (Tochigi, April 2004)     

Detection of Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum DNAs in urine from asymptomatic healthy young Japanese men

The aim of this study was to estimate the detection rates of Mycoplasma and Ureaplasma, which are presumptive causes of sexually transmitted diseases (STDs), in young men in Sapporo, Japan. In addition, we examined the associations among Chlamydia trachomatis, Mycoplasma, and Ureaplasma. A survey of 100 asymptomatic healthy male volunteers was carried out. C. trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum in first-voided urine specimens were detected by polymerase chain reaction assay. Detection rates were 1% for M. genitalium, 4% for M. hominis, 12% for U. urealyticum, and 23% for U. parvum. C. trachomatis was detected in 6% of samples. No M. hominis, U. urealyticum, or U. parvum was detected simultaneously in any sample positive for C. trachomatis. The detection rate of urinary M. genitalium was extremely low, which is similar to previous reports from Japan. The detection rates of urethral U. urealyticum and U. parvum were significantly related to sexual activity. We need to determine whether these pathogens have a role in the sexual transmission of disease or just in colonization.     

Evidence for nonclonal hematopoietic progenitor cell populations in bone marrow of patients with myelodysplastic syndromes

Clonality of marrow hematopoietic progenitor cells in myelodysplastic syndromes (MDS) was analyzed by X-chromosome inactivation pattern using polymerase chain reaction (PCR). Five female patients were included in this study; two with refractory anemia (RA) and three with RA with excess blasts (RAEB). They were heterozygous for BstXI restriction fragment length polymorphisms (RFLP) of the X-chromosome-linked phosphoglycerate kinase (PGK) gene. In each patient, erythroid and nonerythroid colonies, grown in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF), exhibited no remarkable difference in clonal constitution. Two patients showed only one methylation pattern, suggesting the monoclonal origin of hematopoietic progenitor cells. Colonies of two other patients exhibited predominant and minor methylation patterns in PGK gene, indicating that nonclonal progenitor cells remain a minor population. The bone marrow of one patient appeared to contain a greater proportion of nonclonal progenitors. Stem cell factor (SCF), a potent colony- stimulating factor, enhanced both erythroid and nonerythroid colony formation. However, it did not notably alter the clonal constitutions. We conclude that nonclonal hematopoietic progenitor cells can persist in a substantial number of MDS patients.     

Mechanical properties of nerve roots and rami radiculares isolated from fresh pig spinal cords

No reports have described experiments designed to determine the strength characteristics of spinal nerve roots and rami radiculares for the purpose of explaining the complexity of symptoms of medullary cone lesions and cauda equina syndrome. In this study, to explain the pathogenesis of cauda equina syndrome, monoaxial tensile tests were performed to determine the strength characteristics of spinal nerve roots and rami radiculares, and analysis was conducted to evaluate the stress-strain relationship and strength characteristics. Using the same tensile test device, the nerve root and ramus radiculares isolated from the spinal cords of pigs were subjected to the tensile test and stress relaxation test at load strain rates of 0.1, 1, 10, and 100 s^-1 under identical settings. The tensile strength of the nerve root was not rate dependent, while the ramus radiculares tensile strength tended to decrease as the strain rate increased. These findings provide important insights into cauda equina symptoms, radiculopathy, and clinical symptoms of the medullary cone.     

Enhanced constitutive invasion activity in human nontumorigenic keratinocytes exposed to a low level of barium for a long time

We have recently demonstrated that exposure to barium for a short time (≤4 days) and at a low level (5 µM = 687 µg/L) promotes invasion of human nontumorigenic HaCaT cells, which have characteristics similar to those of normal keratinocytes, suggesting that exposure to barium for a short time enhances malignant characteristics. Here we examined the effect of exposure to low level of barium for a long time, a condition mimicking the exposure to barium through well water, on malignant characteristics of HaCaT keratinocytes. Constitutive invasion activity, focal adhesion kinase (FAK) protein expression and activity, and matrix metalloproteinase 14 (MMP14) protein expression in primary cultured normal human epidermal keratinocytes, HaCaT keratinocytes, and HSC5 and A431 human squamous cell carcinoma cells were augmented following an increase in malignancy grade of the cells. Constitutive invasion activity, FAK phosphorylation, and MMP14 expression levels of HaCaT keratinocytes after treatment with 5 µM barium for 4 months were significantly higher than those of control untreated HaCaT keratinocytes. Taken together, our results suggest that exposure to a low level of barium for a long time enhances constitutive malignant characteristics of HaCaT keratinocytes via regulatory molecules (FAK and MMP14) for invasion. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 161–167, 2015.