Compound EGFR mutations, defined as double or multiple mutations in the EGFR tyrosine kinase domain, are frequently detected with advances in sequencing technology but its clinical significance is unclear. This study analyzed 61 cases of EGFR mutation positive lung adenocarcinoma using next-generation sequencing (NGS) based repeated deep sequencing panel of 16 genes that contain actionable mutations and investigated clinical implication of compound EGFR mutations. Compound EGFR mutation was detected in 15 (24.6%) of 61 cases of EGFR mutation-positive lung adenocarcinoma. The majority (12/15) of compound mutations are combination of the atypical mutation and typical mutations such as exon19 deletion, L858R or G719X substitutions, or exon 20 insertion whereas 3 were combinations of rare atypical mutations. The patients with compound mutation showed shorter overall survival than those with simple mutations (83.7 vs. 72.8 mo; P = 0.020, Breslow test). Among the 115 missense mutations discovered in the tested genes, a few number of actionable mutations were detected irrelevant to the subtype of EGFR mutations, including ALK rearrangement, BCL2L11 intron 2 deletion, KRAS c.35G>A, PIK3CA c.1633G>A which are possible target of crizotinib, BH3 mimetics, MEK inhibitors, and PI3K-tyrosine kinase inhibitors, respectively. 31 missense mutations were detected in the cases with simple mutations whereas 84 in those with compound mutation, showing that the cases with compound missense mutation have higher burden of missense mutations (P = 0.001, independent sample t-test). Compound EGFR mutations are detected at a high frequency using NGS-based repeated deep sequencing. Because patients with compound EGFR mutations showed poor clinical outcomes, they should be closely monitored during follow-up.

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Background Diagnostic cutoff points for sarcopenia in chest computed tomography (CT) have not been established although CT is widely used for investigating skeletal muscles. This study aimed to determine reference values for sarcopenia of thoracic skeletal muscles acquired from chest CT scans and to analyse variables related to sarcopenia using the cutoff values determined in a general Asian population. Methods We retrospectively reviewed chest CT scans of 4470 participants (mean age 54.8 ± 9.9 years, 65.8% male) performed at a check‐up centre in South Korea (January 2016–August 2017). To determine cutoffs, 335 participants aged 19–39 years (mean age 35.2 ± 3.6 years, 75.2% male) were selected as the healthy and younger reference group, and 4135 participants aged ≥40 years (mean age 56.4 ± 8.4 years, 65.1% male) were selected as the study group. We measured the following: cross‐sectional area (CSA) of the pectoralis, intercostalis, paraspinal, serratus, and latissimus muscles at the 4th vertebral region (T4CSA); T4CSA divided by height2 (T4MI); pectoralis muscle area (PMCSA); and PMCSA divided by height2 (PMI) at the 4th vertebral region. Sarcopenia cutoff was defined as sex‐specific values of less than −2 SD below the mean from the reference group. Results In the reference group, T4CSA, T4MI, PMCSA, and PMI cutoffs for sarcopenia were 100.06cm2, 33.69cm2/m2, 29.00cm2, and 10.17cm2/m2 in male, and 66.93cm2, 26.01cm2/m2, 18.29cm2, and 7.31cm2/m2 in female, respectively. The prevalence of sarcopenia in the study group measured with T4CSA, T4MI, PMCSA and PMI cutoffs were 11.4%, 8.7%, 8.5%, and 10.1%, respectively. Correlations were observed between appendicular skeletal mass divided by height2 measured by bioelectrical impedance analysis (BIA) and T4CSA (r = 0.82; P < 0.001)/T4MI (r = 0.68; P < 0.001), and ASM/height2 measured by BIA and PMCSA (r = 0.72; P < 0.001)/PMI (r = 0.63; P < 0.001). In the multivariate logistic regression models, sarcopenia defined by T4CSA/T4MI were related to age [odds ratio (95% confidence interval), P‐values: 1.09 (1.07–1.11), <0.001/1.05 (1.04–1.07), <0.001] and diabetes [1.60 (1.14–2.25), 0.007/1.47 (1.01–2.14), 0.043]. Sarcopenia defined by PMCSA/PMI were related to age [1.09 (1.08–1.10), <0.001/1.05 (1.03–1.06), <0.001], male sex [0.23 (0.18–0.30), <0.001/0.47 (0.32–0.71), <0.001], diabetes [2.30 (1.73–3.05), <0.001/1.63 (1.15–2.32), 0.007], history of cancer [2.51 (1.78–3.55), <0.001/1.61 (1.04–2.48), 0.033], and sufficient physical activity [0.67 (0.50–0.89), 0.007/0.74 (0.56–0.99), 0.042]. Conclusions The reference cutoff values of a general population reported here will enable sex‐specific standardization of thoracic muscle mass quantification and sarcopenia assessment.

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Cancer is the leading cause of death in the Republic of Korea and cancer death accounts for 27.8% of the total deaths, which is not only a social issue but also a concern for the public. Among the cancer death rates, lung cancer mortality account for 34 deaths per 100,000 populations, making it the number one cancer death rate. In a preliminary report on cancer death in 2012, the lung cancer mortality ratio showed the regional variation indicating that there were differences in the qualitative level and the structure among the medical care benefit agency and in the assessment of the treatment process. Therefore, the Health Insurance Review and Assessment Service (HIRA) had begun evaluation of the assessment of lung cancer treatment since 2014 to improve the quality of lung cancer care through evaluation and feeds back the results of lung cancer care process. In this report, authors described the current Indicators for the lung cancer adequacy assessment proposed by HIRA and results of the evaluation reported in 2017.

Background: Intratumoral heterogeneity is a cause of drug resistance that leads to treatment failure. We investigated the clinical implication of intratumoral heterogeneity inferred from the number of subclones that constituted a tumor and reasoned the etiology of subclonal expansion using RNA sequencing data.Methods: Simple nucleotide variation, clinical data, copy number variation, and RNA-sequencing data from 481 The Cancer Genome Atlas-Lung Squamous Cell Carcinoma (TCGA-LUSC) cases were obtained from the Genomic Data Commons data portal. Clonal status was estimated from the allele frequency of the mutated genes using the SciClone package. Results:The number of subclones that comprised a tumor had a positive correlation with the total mutations in a tumor (σ=0.477, P-value <0.001) and tumor stage (σ=0.111, P-value <0.015). Male LUSC tumors had a higher probability of having more subclones than female tumors (2.28 vs. 1.89, P-value =0.002, Welch Two Sample t-test). On comparing the gene expression in the tumors that were comprised of five subclones with those of a single clone, 291 genes were found to be upregulated and 102 genes were found to be downregulated in the five subclone tumors. The upregulated genes included UGT1A10, SRY, FDCSP, MRLM, and EREG, in order of magnitude of upregulation, and the biologic function of the upregulated genes was strongly enriched for the positive regulation of immune processes and inflammatory responses.Conclusions: Male LUSC tumors were composed of a greater number of subclones than female tumors. The tumors with large numbers of subclones had overexpressed genes that positively regulated the immune processes and inflammatory responses more than tumors that consisted of a single clone.

Background: Although the use of radial endobronchial ultrasound (R-EBUS) with a guide sheath has shown improved diagnostic capability in peripheral pulmonary lesions, its utility is still low due to variable performance. To overcome its limitation, we evaluated the feasibility and efficacy of R-EBUS combined with transbronchial biopsy (TBB) under fluoroscopic guidance. Methods: We retrospectively reviewed medical records of 74 patients with nonsmall cell lung cancer (NSCLC) who underwent R-EBUS combined with TBB or TBB alone as a diagnostic technique. Subjects were grouped according to the diagnostic modality used (R-EBUS combined with TBB vs. TBB alone). Each group was matched for age, sex, and location of the biopsy. The chi-square test and paired t-test were used to compare characteristics and identify factors that affected the diagnostic yield. Results: The mean age of the study cohort was 67.4 AE 12.8 years, with 21 (56.8%) men and 16 (43.2%) women in each group. The lesion size was significantly smaller in the R-EBUS group (23.6 vs. 33.9, P < 0.001). The diagnostic yield with the combined use of R-EBUS and TBB (27/37, 72.9%) was significantly higher than that with standard TBB alone (22/37, 59.4%). Lung lesions with a positive bronchus sign were associated with a higher diagnostic yield (odds ratio = 3.52 [1.17-10.62]; P = 0.025). Conclusions: The combination of R-EBUS with TBB resulted in a higher diagnostic yield than either technique alone. Thus, the addition of R-EBUS biopsy would be helpful to improve the diagnostic yield of TBB. Key points Significant findings of the study: The combination of R-EBUS with TBB under fluoroscopic guidance improved the diagnostic yield of PPLs compared to TBB alone. A tissue diagnosis was more likely in pulmonary lesions with the air-bronchus sign. What this study adds: The use of R-EBUS could help improve the low diagnostic yield of TBB under fluoroscopic guidance without increasing the incidence of complications.

Osimertinib is a third-generation epidermal growth factor receptor and tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of lung adenocarcinoma patients harboring EGFR mutations. However, acquired resistance to this targeted therapy is inevitable, leading to disease relapse within a few years. Therefore, understanding the molecular mechanisms of osimertinib resistance and identifying novel targets to overcome such resistance are unmet needs of cancer patients. Here, we investigated the efficacy of two novel CDK12/13 inhibitors, AU-15506 and AU-16770, in osimertinib-resistant EGFR mutant lung adenocarcinoma cells in culture and xenograft models in vivo. We demonstrate that these drugs, either alone or in combination with osimertinib, are potent inhibitors of osimertinib-resistant as well as -sensitive lung adenocarcinoma cells in culture. Interestingly, only the CDK12/13 inhibitor in combination with osimertinib, although not as monotherapy, suppresses the growth of resistant tumors in xenograft models in vivo. Taken together, the results of this study suggest that inhibition of CDK12/13 in combination with osimertinib has the potential to overcome osimertinib resistance in EGFR mutant lung adenocarcinoma patients.