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.

     

Aspects of interleukin-8 gene expression by gingival and dermal fibroblasts stimulated with interleukin-1beta or tumour necrosis factor alpha

Fibroblast-derived interleukin (IL)-8 is thought to have an important role in the orchestration of immuno-participant cells infiltrating the skin and gingiva in response to continuously recurring bacterial infection. Therefore, the IL-8 gene expression should be under tight regulatory control and it might be temporally and spatially limited in inflammatory tissue. The purpose of this study was to examine the aspect of the IL-8 gene expression by fibroblasts stimulated with pro-inflammatory cytokines, IL-1beta and TNF-alpha. In situ hybridisation revealed that fibroblasts did not express IL-8 mRNA whereas keratinocytes and endothelial cells did in IL-1beta- or TNF-alpha-injected mice skin. However, cultured mouse dermal fibroblasts expressed not only IL-8 but also IL-1beta mRNA without stimulation by exogenous IL-1beta and TNF-alpha, and the expression was not enhanced by the exogenous cytokines. A similar result was obtained in late-passage human gingival fibroblasts. These results suggest that fibroblasts remain insensitive to IL-1beta and TNF-alpha so as to induce the IL-8 gene expression in non-inflammatory mice skin. Mouse dermal and late-passage human gingival fibroblasts in vitro are likely to be altered in phenotype into IL-8-producing cells along with the production of IL-1beta. In skin inflammation and periodontal diseases, fibroblasts may express the IL-8 gene even without an exogenous cytokine, IL-1beta or TNF-alpha, during their proliferation similar to the situation in our culture system.     

Three‐dimensional structures of bacteriophage neck subunits are shared in Podoviridae,Siphoviridae and Myoviridae

Tailed bacteriophages (Caudovirales) are divided into three families: Myoviridae with long contractile tails, Siphoviridae with long noncontractile tails and Podoviridae with short noncontractile tails. All have an icosahedral head with a portal vertex connected to a neck structure followed by a tail. Bacteriophage Mu belongs to the Myoviridae family. Herein, the gp29 portal subunit and neck subunits gp35, gp36 and gp37 of the Mu phage were purified to elucidate their arrangement in the neck. Both gp29 and gp36 were monomeric in solution, like the corresponding subunits of Podoviridae P22 and Siphoviridae SPP1. X‐ray crystal structure of gp36 showed structural similarity to neck subunits of Siphoviridae and Podoviridae. The gp36 structure has a characteristic aromatic hydrophobic core, and the structure of the ring form of the Mu phage connector deduced from the Siphoviridae and Podoviridae connector showed that this feature builds the contact surface between gp36 subunits. Structural comparison with the neck of Siphoviridae and Podoviridae also implies direct interaction between gp36 and gp29. Because gp35 and gp36 form a stable complex, we predict that the head‐portal ring (gp29), the connector complex (gp36 and gp35), the tail terminator (gp37) and the tube (gp40) are arranged in the Mu phage neck in this order.     

The first recognized patient withLegionella pneumophila serogroup 9 pneumonia in Japan

A 77-year-old female was admitted because of high fever, cough and sputum. She had been receiving corticosteroid therapy for 4 years for multiple myeloma and was immunosuppressed. A physical examination on admission showed coarse crackles in the right lower lung field, a chest radiograph showed consolidation in the right middle and lower lung fields, and a blood gas analysis revealed marked hypoxemia. The patient was diagnosed as having refractory pneumonia associated with acute respiratory failure and treated with intravenous cefmetazole followed by imipenem. On hospital day 5, erythromycin therapy was started because of a poor response to the previous antibiotics. The patient became afebrile on the tenth day and was in good health on day 15. A sputum culture on day 4 revealed aLegionella organism on Wadowsky-Yee-Okuda medium, which was subsequently confirmed to beLegionella pneumophila by a DNA hybridization test. This strain was identified at the Centers for Disease Control (Atlanta, GA, USA) by slide agglutination asL. pneumophila serogroup 9. Although our patient's symptoms are not apparently different from those caused by other serogroup strains ofL. pneumophila, this is the first recognized patient with culture-provenL. pneumophila serogroup 9 pneumonia in Japan. The clinical course of the disease and the diagnostic difficulties in identifying this type of pneumonia are discussed.     

Deficiency in systemic interleukin-1 receptor antagonist production as an operative risk factor in malnourished elderly patients with colorectal carcinoma

OBJECTIVE: Aging and tumor-related malnutrition are associated with increased inflammatory cytokine levels. However, it is unclear whether this influences the outcomes of surgery. We explored the relationships between cytokines and surgical complications among patients undergoing surgery for colorectal cancer. DESIGN: Laboratory experiment. SETTING: Surgery department of school of medicine. PATIENTS: One hundred patients with colorectal cancer. INTERVENTIONS: The perioperative circulating levels of interleukin (IL)-1beta, IL-6, and IL-1 receptor antagonist (Ra) were determined, and the numbers of circulating lymphocytes and neutrophils were counted. MEASUREMENTS AND MAIN RESULTS: Trends toward increasing postoperative infection were observed among patients who were older and had lower body mass index. Preoperative IL-1Ra and intraoperative blood loss, however, remained the only two independent predictors of postoperative infection. Clinically, patients with low preoperative IL-1Ra most frequently were the elderly with low body mass index. Postoperatively, elderly patients with low body mass index showed an exaggerated IL-6 response, followed by an exaggerated postoperative inflammatory response and increased postoperative loss of body weight. In contrast, normal immunoreactivity was preserved in well-nourished elderly patients. CONCLUSIONS: In colorectal cancer patients undergoing surgery, low preoperative IL-1Ra is associated with postoperative infection. In our patient population, lower IL-1Ra level is commonly observed in the elderly with low body mass index. These findings suggest that postoperative infection, frequently seen in the nutritionally deficient elderly, may be the result of defective immunoinflammatory adaptation system.     

Improved short-term memory and increased expression of NR2B observed in senescence-accelerated mouse (SAM) P6

The increased dopamine and serotonin were suggested [Niimi et al., 2008. Emotional behavior and expression pattern of tyrosine hydroxylase and tryptophan hydroxylase in senescence-accelerated mouse (SAM) P6 mice. Behav. Brain Res. 188, 329-336], and as these monoamines are well known to influence working memory processes, SAMP6 may show improved working memory. We found that spatial Y-maze memory and non-spatial novel object recognition memory of SAMP6 were improved compared with those of senescence-accelerated mouse resistant 1 (SAMR1). Among molecules known to be related with memory processes other than dopamine and serotonin, we focused on N-methyl-d-aspartate (NMDA) receptors. Animals treated with (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a NMDA receptor antagonist, were subjected to the Y-maze and novel object recognition tests to examine whether NMDA receptors are associated with the improved short-term memory of SAMP6. CPP (10mg/kg) significantly impaired the spontaneous alternation behavior and the exploratory preference of SAMR1, whereas no significant effect was seen in SAMP6 in either of these behavioral tests. Western blot analyses revealed increased expression of NMDA receptor (NR) subunit 2B in forebrain of SAMP6 compared with SAMR1, while there was no difference in the levels of NR1 and NR2A between SAMR1 and SAMP6. Our results indicate that increased expression of NR2B in forebrain of SAMP6 is one of the causes of the improved short-term memory of SAMP6.     

Effect of a late evening snack on outpatients with liver cirrhosis

Aims: We have reported that one-week administration of a late evening snack (LES) improved not only malnutrition but also glucose intolerance in hospitalized patients with liver cirrhosis. Thus, we investigated whether long-term LES administration to outpatients for 3 months could reproduce the results obtained from hospitalized patients, especially improved glucose intolerance. If this treatment aggravated glucose intolerance, we tried to find any marker predicting this aggravation before the treatment. Methods: Outpatients were prescribed one pack of oral supplementation of a branched-chain amino acid (BCAA)-enriched nutrient, Aminoleban EN (210 kCal) as a LES without dietician supervision. Both before LES administration and after 3 months, glucose tolerance and liver function were examined using a 75 g oral glucose tolerance test (OGTT), biochemical parameters in blood and the relationship between glucose tolerance (area under the curve (AUC)) and the following serum markers. Results: Branched-chain amino acid/tyrosine ratio (BTR), the number of red blood cells (RBC), and hematocrit (Ht) significantly increased, with significant reduction of blood NH(3) level in patients with a blood glucose level less than 200 mg/dL 2 h after 75 g OGTT. However, the increase of AUC was seen after 3 months of LES administration in patients who had blood glucose higher than 200 mg/dL 2 h after 75 g OGTT. AUC weakly correlated positively with serum 7S collagen and negatively with choline esterase (ChE) and albumin (Alb). Conclusion: 75 g OGTT is a useful marker to predict the worst outcome and avoid the adverse effect of LES treatment in liver cirrhosis patients if performed without adequate nutrient conduct by a dietician.