Analyses of progression pattern of acquired resistance to osimertinib and the effect of salvage therapy in advanced lung cancer / 肿瘤研究与临床

Objective:To investigate the progression pattern of acquired resistance to osimertinib and the treatment method as well as the therapeutic effect of salvage therapy in advanced lung cancer patients with epidermal growth factor receptor (EGFR) sensitive mutation or T790M mutation after the treatment of tyrosine-kinase inhibitor (TKI).Methods:The data of 145 patients with advanced lung cancer treated with osimertinib in Jiangsu Cancer Hospital between April 2017 (the approval time of osimertinib in China) and May 2019 were collected. At the last follow-up (December 2019), a total of 87 (60.0%) patients had acquired resistance to osimertinib, 61 (70.1%) of whom received salvage treatment; for patients with dramatic progression after resistance, chemotherapy was mainly given in the salvage therapy; for patients with gradual or local progression after resistance, the continuing targeted drug therapy and the local therapy were given. Imaging evaluation and Kaplan-Meier method were used to analyze the progression pattern of acquired resistance to osimertinib and the survival status, and to compare the salvage treatment results among subgroups.Results:The median follow-up time of 61 patients receiving salvage therapy was 11 months (4-32 months), among which 58 (95.1%) patients again had resistance to osimertinib, and 24 (39.3%) patients died of lung cancer. The median progression-free survival (PFS) time and overall survival (OS) time for the whole cohort was 2.5 months (95% CI 2.1-3.0 months) and 19.0 months (95% CI 13.7-26.3 months), respectively. The 1-year and 2-year OS rate was 72.1% and 41.7%, respectively. Among 61 patients receiving salvage therapy, 8 (13.1%) , 30 (49.2%) and 23 (37.7%) cases had dramatic progression, gradual progression and local progression, respectively; when given timely and proper salvage treatment, there were no statistically differences in PFS and OS of the patients in the above three subgroups (all P>0.05). There were no statistically differences in PFS and OS between patients receiving local therapy (24 cases) and patients not receiving local therapy (37 cases) after the progression occurred (all P>0.05). Among 58 patients with resistance to osimertinib again after the salvage therapy, 6 patients with gradual or local progression had more than 6-mouth PFS after the salvage therapy. Conclusions:Dramatic, gradual and local progression are the main patterns in patients with acquired resistance to osimertinib. The therapeutic efficacy of salvage therapy still shows some disappointing results.

MiR-122 exerts anti-proliferative and apoptotic effects on nasopharyngeal carcinoma cells via the PI3K/AKT signaling pathway.

To investigate the effects of microRNA-122 (miR-122) on the proliferation and apoptosis of nasopharyngeal carcinoma (NPC) HONE-1 cells, and its correlation with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Human NPC cell line (HONE-1) was transfected with miR-122 inhibitor (anti-miR-122 group), negative controls (vector control group) via lipofectamines, and HONE-1 cell lines undergoing no transfection were selected (non-transfection group). The expression of miR-122, cell proliferation, apoptosis, and expressions of PI3K/AKT pathway and downstream target proteins in the three groups were determined using fluorescence quantitative polymerase chain reaction (qPCR), cell counting kit-8 (CCK8), immunofluorescence (IF) and Western blotting, respectively. The expression of miR-122 in the anti-miR-122 group was significantly lower than corresponding expressions in the non-transfection and vector control groups after 48h of transfection (p <0.05). The proliferation of cells in the anti-miR-122 group was significantly reduced with time after transfection (p <0.05). After 48h of transfection, the extent of apoptosis in the anti-miR-122 group (47.11 ± 1.95%) was significantly higher than that in normal control (7.37 ± 0.82%) and vector control group (8.54 ± 0.96%; p <0.05). There were no significant differences in the expressions of PI3K, AKT, mTOR protein, and the downstream signal proteins (p70S6K and 4E-BP1) in the three groups (p >0.05). However, the expressions of phosphorylated forms of these proteins were significantly lower in the anti-miR-122 group than in the non-transfection and vector control groups (p <0.05). IF results revealed that there were no significant differences in the fluorescence intensity value of PI3K and Akt among the three groups of patients (p>0.05). Inhibition of the expression of miR-122 in NPC suppresses the proliferation, and promotes their apoptosis through the PI3K/AKT signal transduction pathway.

A dose volume analysis of brain stem injury after intensity-modulated radiotherapy in patients with nasopharyngeal carcinoma / 中华放射肿瘤学杂志

Objective To investigate the relationship between the incidence of radiation-induced brain stem injury after intensity-modulated radiotherapy (IMRT) and the radiation dose volume in patients with nasopharyngeal carcinoma.Methods A retrospective analysis was performed on the data of 258 patients newly diagnosed with nasopharyngeal carcinoma who received IMRT in our group from 2005 to 2013.The radiation dose per unit volume of brain stem was analyzed.The relationship between the incidence of brain stem injury induced by IMRT and the radiation dose volume was studied.The survival rate was calculated using the Kaplan-Meier method.The factors influencing the radiation-induced brain stem injury were analyzed using the Cox regression model.Results Two patients with stage T3 disease and three patients with T4 disease had radiation-induced brain stem injury.The 3-and 5-year injury incidence rates were 1.6％ and 2.4％,respectively.The latency ranged between 9 and 58 months,with a median latency of 19 months.The median D1％ and Dmax for the brain stem were 54.24 and 59.22 Gy in all patients,54.31 and 59.45 Gy in patients with stage T3 disease,and 61.29 and 66.37 Gy in patients with stage T4 disease,respectively.In the five patients with brain stem injury,the D1％ and Dmax were larger than 60 and 63 Gy,respectively.The univariate analysis showed that the incidence of radiation-induced brain stem injury was correlated with D1％,Dmax,D0.1 cm3,D0.5 cm3,and D1.0 cm3 (all P=0.01).The incidence of radiation-induced brain stem injury was significantly lower in patients with D1％,Dmax,D0.1 cm3,D0.5 cm3,and D1.0 cm3 no larger than 60,63,60,58,and 56 Gy,respectively (all P =0.00).Conclusions The incidence of radiation-induced brain stem injury after IMRT is relatively low in patients with nasopharyngeal carcinoma.Strict control of the dose to the brain stem may help to reduce the incidence of brain stem injury and improve the long-term quality of life.