Exosomal microRNAs have recently been studied as the potential diagnostic marker for various malignancies, including hepatocellular carcinoma (HCC). The aim of this study was to investigate serum exosomal microRNA profiles as HCC diagnostic marker. Transmission electron microscopy and Western blot were used to identify serum exosomes. Deep sequencing was performed to screen differentially expressed microRNAs between HCC (n = 5) and liver cirrhosis (LC, n = 5) groups. Three upregulated and two downregulated microRNAs were selected for qPCR analysis. The levels of selected microRNAs were normalized to Caenorhabditis elegans miR‐39 microRNA mimics. Serum exosomal level of miR‐122, miR‐148a, and miR‐1246 was further analyzed and significantly higher in HCC than LC and normal control (NC) groups (P < 0.001), but not different from chronic hepatitis group (P > 0.05). The receiver operating characteristic curve was used to evaluate the diagnostic performance of candidate microRNAs. Area under the curve (AUC) of miR‐148a was 0.891 [95% confidence interval (CI), 0.809–0.947] in discriminating HCC from LC, remarkably higher than alpha‐fetoprotein (AFP) (AUC: 0.712, 95% CI: 0.607–0.803). Binary logistic regression was adopted to establish the diagnostic model for discriminating HCC from LC. And the combination of miR‐122, miR‐148a, and AFP increased the AUC to 0.931 (95% CI, 0.857–0.973), which can also be applied for distinguishing early HCC from LC. miR‐122 was the best for differentiating HCC from NC (AUC: 0.990, 95% CI, 0.945–1.000). These data suggest that serum exosomal microRNAs signature or their combination with traditional biomarker may be used as a suitable peripheral screening tool for HCC.

Background: This study is to investigate the effects and resistance mechanisms of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients carrying rare EGFR exon 19 deletion-insertion (19delins) mutations. Methods: The next generation sequencing (NGS) data of 1783 patients diagnosed as advanced NSCLC from November 2017 to September 2020 were successively and retrospectively reviewed. 41 patients with EGFR 19delins and 41 patients with EGFR exon 19 deletion (19del) were enrolled in this study, who were given first generation EGFR TKIs as first-line therapy. Results: 17 mutation types of EGFR 19delins were identified in this study, L747_P753delinsS (10/41) and L747_A750delinsP (9/41) were the most frequent mutation types, followed by L747_T751delinsP (6/41) and E746_S752delinsV (3/41). Under the same baseline characteristics, median progression-free survival (mPFS) was similar in patients with EGFR 19delins to those with EGFR 19del (10.4 months vs. 13.1 months, p=0.1076). Interestingly, patients with L747_T751delinsP had a better mPFS than those with other variants (18.7 months vs. 13.1 months, p=0.035). No significant difference in mPFS was found among the three groups of gefitinib, icotinib, and erlotinb with 14.7 months, 10.9 months, and 13.1 months (p>0.05). After progression from first-line EGFR TKIs, both EGFR 19delins and EGFR 19del had similar rates of developing resistance mechanisms including EGFR T790M mutation (45.8% vs. 57.8%). Patients acquiring T790M mutation received osimeritinib as second-line treatment, and the mPFS was similar between the groups of EGFR 19delins (n=8) and EGFR 19del (n=10): 12.0 months vs. 12.2 months (p=0.97). Conclusion: Our results indicate that patients with uncommon EGFR 19delins can also benefit from first-generation EGFR TKIs treatment, having similar treatment responses and survival outcomes to those with EGFR 19del, even similar clinical outcomes from osimeritinib upon acquiring T790M resistance mutation.

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Background Anaplastic lymphoma kinase (ALK) fusion is a prognostic indicator for patients with non‐small cell lung cancer (NSCLC) receiving tyrosine kinase inhibitors (TKIs). The real‐world data of ALK TKIs remain a major concern. Methods Patients with ALK‐positive advanced NSCLC, who received crizotinib or alectinib treatment in first line, were retrospectively reviewed. ALK status was detected using immunohistochemistry (IHC) or next‐generation sequencing (NGS). Clinical outcomes have been comprehensively analyzed between TKIs, ALK fusions, EML4‐ALK variants, and next‐generation TKIs after crizotinib failure. Results One hundred sixty‐eight patients were successively enrolled (crizotinib, n = 109; alctinib, n = 59). Alectinib showed consistent superiority in progressive‐free survival (PFS) over crizotinib (hazard ratio [HR]: 0.43, 95% confidential interval [CI]: 0.24–0.77, p = 0.004). Multivariate Cox regression showed chemotherapy (CT) prior to TKIs or synchronous chemotherapy seemed not to improve PFS compared to ALK inhibitors alone (p > 0.05). And, alectinib was superior to crizotinib in prolonging intracranial PFS (HR 0.12, 95% CI: 0.03–0.49, p = 0.003). Patients in EML4 group had a better prognosis than those in non‐EML4 group after alectinib administration (HR 0.13, 95% CI: 0.03–0.60, p = 0.009). TP53 co‐mutations were relatively common (34.0%) and associated with adverse outcome in ALK‐positive patients (adjusted HR 2.22, 95% CI: 1.00–4.92, p = 0.049). After crizotinib failure, 33 patients received a sequential application of next‐generation ALK TKIs. Compared to ceritinib and brigatinib, alectinib might have better PFS (p = 0.043). Conclusion Our results revealed alectinib had better PFS and higher intracranial efficacy compared to crizotinib in ALK‐positive NSCLC, and might improve PFS by comparison with ceritinib and brigatinib after crizotinib failure.