PurposeThe role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC) has not been clarified. A pooled analysis of prospective clinical trials was conducted to evaluate the efficacy and safety of neoadjuvant EGFR-TKI therapy.MethodsThe PubMed, Embase, Web of Science, and Cochrane Library databases, as well as meeting abstracts were searched for prospective clinical trials evaluating the efficacy and safety of neoadjuvant EGFR-TKI for treatment of EGFR-mutant NSCLC. The main outcomes included the objective response rate (ORR), downstaging rate, surgical resection rate (SRR), pathologic complete response (pCR) rate, progression-free survival (PFS), and adverse events.ResultsA total of five, phase II, prospective, clinical trials involving 124 patients with resectable or potentially resectable EGFR-mutant NSCLC treated with neoadjuvant erlotinib or gefitinib treatment were included in this pooled analysis. The median neoadjuvant medication time was 42 (range, 21–56) days and the median time of response evaluation was 45 (range, 42–56) days. The pooled ORR was 58.5% [95% confidence interval (CI), 45.5%–71.8%] and the surgical resection and complete resection (R0) rates were 79.9% (95% CI, 65.3%–94.5%) and 64.3% (95% CI, 43.8%–84.8%), respectively. In the stage IIIA subgroup (n = 68), the pooled ORR, SRR, and R0 rate were 51.4%, 72.9%, and 57.0%, respectively, while the downstaging and pCR rates were 14.0% and 0.0%, respectively. The pooled median PFS and overall survival were 13.2 and 41.9 months, respectively. Of the most common grade 3/4 adverse events in the overall group, the incidences of hepatotoxicity and skin rash were 5.3% and 14.7%, respectively. The most commonly reported postoperative complications were lung infection, arrhythmia, and pneumothorax.ConclusionNeoadjuvant EGFR-TKI therapy provides a feasible treatment modality for patients with resectable or potentially resectable EGFR-mutant NSCLC, with satisfactory surgical outcomes and low toxicity. Although further phase III clinical trials are needed to confirm these findings, it is necessary to explore the feasibility of a more effective EGFR-TKI combination neoadjuvant therapy given the modest downgrade and pCR rates for EGFR-TKI alone.

A meta-analysis was performed to compare KRAS gene mutations in colorectal cancer tissue samples with primary and metastatic colorectal cancers. A total of 19 publications with 986 paired primary and distant metastases and 171 paired primary and lymph node metastases showed that KRAS genotype was highly concordant in primary and distant metastatic tumors, indicating that either type of tumor tissue could be useful as a source to detect KRAS mutations for selection of anti-EGFR therapy. However, lymph-node-metastatic tumors might not be suitable for diagnostic analysis of KRAS mutations due to an obvious discordant rate between primary and lymph-node-metastatic tumors.

In vertebrates, the primary sex-determining signals that initiate sexual development are remarkably diverse, ranging from complete genetic to environmental cues. However, no sex determination-related genes have been functionally identified in reptiles. Here, we characterized a conserved DM domain gene, Dmrt1, in Chinese soft-shelled turtle Pelodiscus sinensis (P. sinensis), which exhibits ZZ/ZW sex chromosomes. Dmrt1 exhibited early male-specific embryonic expression, preceding the onset of gonadal sex differentiation. The expression of Dmrt1 was induced in ZW embryonic gonads that were masculinized by aromatase inhibitor treatment. Dmrt1 knockdown in ZZ embryos by RNA interference resulted in male to female sex reversal, characterized by obvious feminization of gonads, significant down-regulation of testicular markers Amh and Sox9, and remarkable up-regulation of ovarian regulators, Cyp19a1 and Foxl2. Conversely, ectopic expression of Dmrt1 led to largely masculinized genetic females, production of Amh and Sox9, and a decline in Cyp19a1 and Foxl2. These findings demonstrate that Dmrt1 is both necessary and sufficient to initiate testicular development, thereby acting as an upstream regulator of the male pathway in P. sinensis.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

PurposeThe purpose of this meta-analysis was to explore the influences of pretreatment de novo and posttreatment-acquired epidermal growth factor receptor (EGFR) T790M mutations in patients with advanced non-small cell lung cancer (NSCLC) who had received tyrosine kinase inhibitors (TKIs).MethodsWe searched PubMed, Embase, and the China National Knowledge Infrastructure database for eligible literature. Data were extracted to assess the hazard ratios (HRs) for progression-free survival (PFS), overall survival (OS), and post-progression survival (PPS) and the relative ratios (RRs) for objective response rate (ORR).ResultsThis meta-analysis included 22 studies comprising 1,462 patients with NSCLC who harbored activating EGFR mutations and were treated with EGFR-TKIs. Compared to pretreatment T790M mutation-negative NSCLC, pretreatment T790M mutation-positive NSCLC was associated with decreased PFS (HR 2.23, P<0.001) and OS (HR 1.55, P=0.003). A trend toward significance of worsening ORR (RR 0.86, P=0.051) was evident. The acquired T790M mutation was correlated with improved PFS (HR 0.75, P=0.006) and PPS (HR 0.57, P<0.001), compared to patients without the T790M mutation who progressed after EGFR-TKI treatment. There were no significant differences in OS or ORR between patients with acquired T790M mutation-positive and T790M mutation-negative NSCLC. However, in the tumor tissue rebiopsy subgroup, patients with acquired T790M mutation had improved OS (HR 0.60, P<0.001) compared to T790M mutation-negative patients. In the plasma ctDNA subgroup, acquired T790M mutation decreased the OS (HR 1.87, P<0.001).ConclusionPretreatment T790M mutation was associated with worse PFS and OS in patients with advanced NSCLC treated with EGFR-TKIs, while acquired T790M mutation was associated with longer PFS and PPS than T790M mutation-negative NSCLC. The effects on OS were different between acquired T790M mutation detected from rebiopsy of tumor tissue and that detected from plasma ctDNA.

Non-small cell lung cancer (NSCLC) is frequently associated with oncogenic driver mutations, which play an important role in carcinogenesis and cancer progression. Targeting epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase rearrangements has become standard therapy for patients with these aberrations because of the greater improvement of survival, tolerance, and quality-of-life compared to chemotherapy. Clinical trials for emerging therapies that target other less common driver genes are generating mixed results. Here, we review the literature on rare drivers in NSCLC with frequencies lower than 5% (e.g., ROS1, RET, MET, BRAF, NTRK, HER2, NRG1, FGFR1, PIK3CA, DDR2, and EGFR exon 20 insertions). In summary, targeting rare oncogenic drivers in NSCLC has achieved some success. With the development of new inhibitors that target these rare drivers, the spectrum of targeted therapy has been expanded, although acquired resistance is still an unavoidable problem.

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BackgroundPrevious studies have indicated that enhancement of autophagy lysosome pathway may be beneficial for Parkinson’s disease (PD), in which aberrant accumulation of aggregated/misfolded proteins and mitochondrial dysfunction are considered as crucial pathogenesis. Recently, a number of studies have suggested the neuroprotective effects of lithium in models of several neurodegenerative diseases including PD. However, the exact mechanisms underlying this neuroprotection remain unclear. In our study, rotenone-exposed SH-SY5Y cells were used as an in vitro parkinsonian model to assess the autophagy-enhancing effect of lithium and the underlying mechanisms were further investigated.ResultsSimilar to the common used autophagy enhancer rapamycin (Rap, 0.2 μM), lithium (LiCl, 10 mM) significantly recovered the shrinkage of SH-SY5Y cells, and alleviated rotenone-induced cell apoptosis, mitochondrial membrane potential reduction and reactive oxygen species accumulation. Furthermore, the protective effects induced by LiCl were partially blocked by the co-treatment of autophagy inhibitors such as 3-methyladenine (3-MA, 10 mM) or chloroquine (CHL, 10 μM). Moreover, 3-MA or Chl suppressed LiCl-induced autophagy in the immunoblot assay. In addition, the co-localization of LC3 and mitochondria and the preservation of mitochondrial function within LiCl-treated cells were observed, confirming that the damaged mitochondria were cleared through autophagy (mitophagy).ConclusionsThese findings suggested that lithium exerted neuroprotection against rotenone-induced injuries partially through the autophagy pathway. Pharmacologically induction of autophagy by lithium may represent a novel therapeutic strategy as a disease-modifier in PD.