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Background: In patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC), epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment has shown a good response. Subsequent treatments jeopardize the ability to determine the effect of first-line chemotherapy on overall survival (OS). Therefore, using patient-level data, we aimed to study the associations of progression-free survival (PFS) and post-progression survival (PPS) with OS after first-line EGFR-TKI treatment in patients with EGFR-mutated NSCLC., Methods: Between November 2006 and December 2016, we analyzed 92 patients with EGFR-mutated NSCLC treated with first-line EGFR-TKI. The correlations of PFS and PPS with OS were analyzed for each patient., Results: Spearman's rank correlation and linear regression analyzes showed that PPS correlated highly with OS (r = 0.85, P < 0.05, R 2 = 0.75), whereas PFS correlated weakly with OS (r = 0.76, P < 0.05, R 2 = 0.50). The best responses after first-line and second-line treatments were significantly associated with PPS., Conclusions: PPS has a higher impact on OS than PFS in patients with EGFR-mutated NSCLC treated with first-line EGFR-TKIs. These outcomes suggest that the OS in this patient group may be affected by treatments following first-line chemotherapy; however, this remains to be verified in prospective trials., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background Monoallelic mutations of GHR have been described in idiopathic short stature (ISS), although the significance of these remain unclear. We report a case of ISS with novel monoallelic S219L mutation of GHR and discuss the possible significance of monoallelic GHR mutation in ISS. Case presentation The proband, a 13.9-year-old Japanese boy, had severe short stature (-3.8 standard deviation [SD]). Serum insulin-like growth factor (IGF)-I level and growth hormone (GH) secretion was normal. His parents were nonconsanguineous and had normal stature. Genetic analyses revealed a novel monoallelic missense variation in exon 7 of GHR (S219L). The proband's mother had the same variation. S219L might be the novel mutation judging from there being no registration of it as a single-nucleotide polymorphism (SNP) in any database, evolutional conservation of Ser219, in silico analyses, and computational molecular visualization analysis. Furthermore, a review of the literature showed that the median height of missense mutation carriers of GHR was relatively low. Conclusions We propose the possibility that monoallelic mutation of GHR increases the susceptibility to short stature.

Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

Objective: Vanishing white matter disease (VWM) is a chronic, progressive leukoencephalopathy associated with episodes of rapid deterioration following minor stress events such as head traumas or infectious disorders. The white matter of the patients with VWM exhibits characteristic radiological findings., Method: The genes encoding all five subunits of eukaryotic translation initiation factor 2B (EIF2B) were analyzed in patients, who were tentatively diagnosed with VWM, by Sanger sequencing., Results: Seven mutations were identified in the genes encoding the subunits 1, 2, 4, and 5 of EIF2B. Among them, one mutation (p.V83E) in the subunit 2 (EIF2B2) was recurrently identified in three alleles, indicating the most common mutation in Japanese patients with VWM. Two patients were homozygous, and the other four patients were compound heterozygous., Conclusion: All patients showed white matter abnormalities with various degrees. One patient showed manifestations of end-stage VWM disease. Some patients showed late onset and slow progression associated with brain magnetic resonance imaging displaying T2 high intensity only in the deep white matter. There was clinical heterogeneity among patients with VWM., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)