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.

     

The effect of extracellular calcium ion on gene expression of bone-related proteins in human pulp cells

Calcium hydroxide is often used for induction of reparative dentin formation in endodontic treatment. However, little is known about the mechanism by which calcium hydroxide works. The calcium ion (Ca2+) is an important regulator of cell functions. In this study, we examined the effect of extracellular Ca2+ on gene expression of bone-related proteins in human cultured pulp cells in serum-free conditions. A Ca2+ level elevated by 0.7 mM induced an increase in mRNA expression of osteopontin and bone morphogenetic protein (BMP)-2. However, mRNA levels of BMP-4 and alkaline phosphatase decreased under the elevated Ca2+ culture condition. The same concentration of additional magnesium ions had little effect on expressions of the examined bone-related protein mRNAs. These findings suggest that Ca2+ in Ca(OH)2 specifically modulates osteopontin and BMP-2 levels during calcification in pulp.     

Herbal medicine Ninjinyoeito ameliorates ribavirin-induced anemia in chronic hepatitis C： A randomized controlled trial

AIM: Ribavirin (RBV) shows a strong antiviral effect on hepatitis C virus when used in combination with interferon. However, RBV-induced anemia is a major problem in this therapy. It would be of great clinical importance to ameliorate the anemia without reducing the RBV dose. We report here that, Ninjinyoeito (NYT), a herbal medicine can reduce the RBV-induced anemia. METHODS: Twenty-three patients with chronic hepatitis C were treated with interferon alpha 2b plus RBV with (NYT group) or without (control group) NYT by a randomized selection. Eighteen patients completed the treatment schedule, and hemato-biochemical and virological effects were evaluated. RESULTS: There was no significant difference in biochemical and virological responses between the two groups. However, anemia was significantly reduced in the NYT group compared with the control group. The maximal decrease of Hb in the NYT group (2.59±1.10 g/dL) was significantly (P= 0.026) smaller than that in the control group (3.71±0.97 g/dL). There was no significant difference in serum glutathione peroxidase activity, serum RBV concentration, and Thl/Th2 balance between the two groups. There was no specific adverse effect in NYT administration. CONCLUSION: These results suggest that NYT could be used as a supportive remedy to reduce the RBV-induced anemia in the treatment of chronic hepatitis C.     

Pulmonary Mycobacterium massiliense disease with septicemia during immunosuppressive treatment

A 75-year-old man with interstitial pneumonia due to ANCA-related vasculitis requiring immunosuppressive treatment was admitted to our hospital because of fever and rapidly progressive dyspnea. Chest CT showed diffuse ground-glass opacity with infiltration shadow in the bilateral lungs. We established a definitive diagnosis by isolating Mycobacterium massiliense on culture examination of acid-fast bacilli from peripheral blood and sputum. We began to administer CAM, LVFX, AMK, IPM/CS to this patient two weeks after admission. However, he died of respiratory failure and septic shock. There are few case reports of pulmonary lesion with septicemia due to Mycobacterium massiliense.     

Single-step electrochemical deposition of antimicrobial orthopaedic coatings based on a bioactive glass/chitosan/nano-silver composite system

Composite orthopaedic coatings with antibacterial capability containing chitosan, Bioglass® particles (9.8 μm) and silver nanoparticles (Ag-np) were fabricated using a single-step electrophoretic deposition (EPD) technique, and their structural and preliminary in vitro bactericidal and cellular properties were investigated. Stainless steel 316 was used as a standard metallic orthopaedic substrate. The coatings were compared with EPD coatings of chitosan and chitosan/Bioglass®. The ability of chitosan as both a complexing and stabilizing agent was utilized to form uniformly deposited Ag-np. Due to the presence of Bioglass® particles, the coatings were bioactive in terms of forming carbonated hydroxyapatite in simulated body fluid (SBF). Less than 7 wt.% of the incorporated silver was released over the course of 28 days in SBF and the possibility of manipulating the release rate by varying the deposition order of coating layers was shown. The low released concentration of Ag ions (<2.5 ppm) was efficiently antibacterial against Staphyloccocus aureus up to 10 days. Although chitosan and chitosan/Bioglass® coating supported proliferation of MG-63 osteoblast-like cells up to 7 days of culture, chitosan/Bioglass®/Ag-np coatings containing 342 μg of Ag-np showed cytotoxic effects. This was attributed to the relatively high concentration of Ag-np incorporated in the coatings.     

Increase in CD95 (Fas/APO-1)-positive CD4+ and CD8+ T cells in peripheral blood derived from patients with autoimmune hepatitis or chronic hepatitis C with autoimmune phenomena

BACKGROUND: The expressions of CD95 (Fas/APO-1) and Bcl-2 are determinants of apoptosis in normal lymphocytes, and abnormalities in their expressions might contribute to the induction of autoimmunity. In this study, we examined the expressions of CD95 and Bcl-2 on freshly isolated T and B cells from patients with autoimmune hepatitis (AIH) or chronic hepatitis C associated with autoimmune phenomena (CH-C(AI)). METHODS: The CD95 and Bcl-2 expressions within CD4+ T, CD8+ T, and CD19+ B cell subsets were analysed by two-colour flow cytometry. RESULTS: The surface expression of CD95 was significantly high in both the CD4+ T and CD8+ T cell subsets derived from the patients with AIH and those with CH-C(AI), compared with expression in patients with CH-C and normal subjects. The increase in CD95 expression was associated with the phenotypic conversion of naive CD45RO- to primed CD45RO+ CD4+ T cells. Bcl-2 was detected in the vast majority of peripheral T and B cells. There was no significant difference in the percentage of Bcl-2-positive cells in the CD4+ T cell, CD8+ T cell and CD19+ B cell subsets among the patient groups and normal subjects. CONCLUSIONS: These results indicate that an increase in CD4+ T cells expressing CD45RO and CD95 marks an important subset of AIH and CH-C(AI) patients. These expanded CD95+ CD45RO+ primed T cells most likely reflect a continuous antigen-specific or non-specific activation of T lymphocytes, and/or the persistent presence of activated lymphocytes as a consequence of abnormalities in the peripheral deletion of activated lymphocytes. These persistently activated lymphocytes might play a role in the induction of autoimmunity in AIH and CH-C(AI).     

Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology

Controlled proteolytic degradation of specialized junctional structures, corneodesmosomes, by epidermal proteases is an essential process for physiological desquamation of the skin. Corneodesmosin (CDSN) is an extracellular component of corneodesmosomes and, although considerable debate still exists, genetic studies have suggested that the CDSN gene in the major psoriasis-susceptibility locus (PSORS1) may be responsible for susceptibility to psoriasis, a human skin disorder characterized by excessive growth and aberrant differentiation of keratinocytes. CDSN is also expressed in the inner root sheath of hair follicles, and a heterozygous nonsense mutation of the CDSN gene in humans is associated with scalp-specific hair loss of poorly defined etiology. Here, we have investigated the pathogenetic roles of CDSN loss of function in the development of skin diseases by generating a mouse strain with targeted deletion of the Cdsn gene. Cdsn-deficient mouse skin showed detachment of the stratum corneum from the underlying granular layer and/or detachment within the upper granular layers due to the disrupted integrity of the corneodesmosomes. When grafted onto immunodeficient mice, Cdsn-deficient skin showed rapid hair loss together with epidermal abnormalities resembling psoriasis. These results underscore the essential roles of CDSN in hair physiology and suggest functional relevance of CDSN gene polymorphisms to psoriasis susceptibility.     

Immunoelectron microscopic study of corticotropin-releasing factor in the human hypothalamus and pituitary gland

Ultrastructural localization of immunoreactive corticotropin-releasing factor (CRF) was visualized for the first time in the human hypothalamus and pituitary gland with specific antibodies against human/rat CRF. In the hypothalamus most of the positive immunoreactivity to CRF was present in granules with a wide range of diameters, 50-250 nm, in the perikarya of parvocellular neurons in the paraventricular nucleus. Among these, neurosecretory type granules, 100-150 nm in diameter, were dominant, and small vesicles, 50-80 nm in diameter, were sparse. Some of surfaces of rough endoplasmic reticulum and polyribosomes were also positive in some of these cells. CRF-positive reactions were also observed in the nerve fibers of the pituitary stalk and the posterior pituitary gland revealing two types of granules: small vesicles, 50-80 nm in diameter, and neurosecretory granules, 100-150 nm in diameter. These results support the theory that the human CRF, which is identical to rat CRF, is synthesized in parvocellular neurons of paraventricular nucleus, transported in nerve fibers, and controls ACTH secretion in the human anterior lobe of pituitary gland via the portal system.