ABSTRACT
EGFR?TKIs have changed the landscape of metastatic NSCLC treatment with a significant improvement in survival of EGFRm patients compared to wild?type EGFR. Even with the newer third generation EGFR TKIs like, Osimertinib, which has proven efficacy against the resistance mutation of EGFRm T790M, progression eventually occurs. There are limited treatment options for patients with metastatic EGFRm NSCLC with other acquired resistance. Therefore, novel therapeutic combination strategies are being researched to overcome potential resistance to EGFR?TKI?targeted therapy. The ICIs targeting the programmed cell death?1 pathway in patients with EGFRm NSCLC were greatly anticipated based on preclinical studies showing increased PD?L1 expression. In clinical settings, this increased expression did not translate into a survival benefit. Treatment with ICIs failed to positively affect EGFRm patients because of multiple reasons: nonsynonymous tumor mutational burden, lower PD?L1 expression in tumors, and cancer cells utilizing alternate immune escape mechanisms. The NCCN guidelines currently do not recommend immunotherapy in patients with metastatic EGFRm NSCLC. Recently, a subgroup analysis in the IMpower150 study provided a signal for overall survival of atezolizumab with bevacizumab plus chemotherapy in EGFRm?TKI progressed patients. Based on these encouraging findings, several combinations of ICIs and EGFR?TKIs are being evaluated in TKI?failed EGFRm patients. These regimens might provide a favorable therapeutic effect by combining higher response rates of TKIs and durable disease control of ICIs. However, further research is warranted to understand the exact underlying molecular and cellular mechanisms responsible for the clinical benefits. In this article, we explored the TKI failed metastatic EGFRm NSCLC, reviewed the available clinical data of ICI use in metastatic EGFRm NSCLC, and discussed its emerging role as a combination regimen in this patient population
ABSTRACT
An interesting feature of neural development in most animal species is that the number of neurons ini-tially produced is greater than the number of neurons belonging to the mature circuits. In the first two weeks of life, a significant number of neurons are eliminated in a short period through apoptosis. Although we have been very clear that in the peripheral nervous system(PNS),neurotrophic factors and apoptosis play an important role in controlling the neurons survival, but the situation in central nervous system (CNS) remains unknown. In the rodent cortex, the peak of apoptosis coincides with spontaneous, synchronous neural activity pattern. In this arti-cle, we review the recent research results which proved the important role of electrical activity in the brain cortex neuron survival, described the function of Ca2+and neurotrophic factors in translating electrical activity into pro-survival signals, and finally discuss the clinical impact of the tight relation between electrical activity and apopto-sis of neurons.