Objective:To investigate the correlation between pre- and post-treatment changing trends in peripheral blood inflammatory markers and efficacy and their predictive value for prognosis in non-small cell lung cancer (NSCLC) patients treated with the first-line immunotherapy plus chemotherapy.Methods:The clinical data of NSCLC patients admitted to the Department of Radiation and Chemotherapy for Lung Oncology, Zhongnan Hospital of Wuhan University from October 2018 to May 2023 were retrospectively analyzed. The χ2 test was used to analyze the correlation between the changing trend of peripheral blood inflammatory markers and the efficacy of immunotherapy plus chemotherapy. The influencing factors of objective response rate (ORR) were assessed using binary logistic regression analysis. Kaplan-Meier survival curve and Cox proportional hazards model were used to analyze the prognostic value of the changing trend of peripheral blood inflammation markers on patients' prognosis. Results:A total of 102 NSCLC patients treated with first-line immunotherapy plus chemotherapy were included. The proportion of patients with bone metastases was higher in the lymphocyte to monocyte ratio (LMR) decreased group ( n=50) than that in the increased group ( n=52) ( χ2=4.28, P=0.039), whereas the pathological type of patients in the platelet to lymphocyte ratio (PLR) decreased group ( n=51) was more common in squamous carcinoma compared to patients in the increased group ( n=51) ( χ2=18.99, P<0.001), and a higher proportion of patients in the prognostic nutritional index (PNI) decreased group ( n=46) was female than that in the increased group ( n=56) ( χ2=4.29, P=0.038), with statistically significant differences. The 2-cycle objective response rate (ORR) of patients in the LMR increased and decreased groups was 63.5% (33/52) and 44.0% (22/50) ( χ2=3.89, P=0.049), the 2-cycle ORR of patients in the neutrophil to lymphocyte ratio (NLR) increased ( n=24) and decreased ( n=78) groups was 29.2% (7/24) and 61.5% (48/78) ( χ2=7.74, P=0.005), and the 2-cycle ORR for patients in the systemic immune inflammatory index (SII) increased group ( n=27) and decreased group ( n=75) was 33.3% (9/27) and 61.3% (46/75) ( χ2=6.26, P=0.012), with statistically significant differences. Multivariate analysis showed that the changing trend of inflammatory markers in peripheral blood were not related to ORR. The Kaplan-Meier survival curve indicated that patients in the group with SII decreased had longer median progression-free survival (PFS) (not reached vs. 7.1 months, χ2=9.35, P=0.002) and median overall survival (OS) (not reached vs. 16.6 months, χ2=11.08, P<0.001) than those in the SII increased group, and patients in the NLR decreased group had longer median OS (not reached vs. 22.2 months, χ2=4.56, P=0.033) than that in the NLR increased group. Univariate analysis suggested that both brain and bone metastasis ( HR=4.04, 95% CI: 1.23-13.35, P=0.022), increased SII ( HR=2.83, 95% CI: 1.41-5.66, P=0.003) were found to be significant factors affecting the PFS of NSCLC patients, both brain and bone metastasis ( HR=3.47, 95% CI: 1.05-11.45, P=0.041), increased NLR ( HR=2.17, 95% CI: 1.05-4.51, P=0.037) and increased SII ( HR=3.12, 95% CI: 1.54-6.30, P=0.002) were found to be significant factors affecting the OS of NSCLC patients. Multivariate analysis demonstrated that both brain and bone metastasis ( HR=4.32, 95% CI: 1.30-14.40, P=0.017) and increased SII ( HR=2.89, 95% CI: 1.44-5.81, P=0.003) were independent risk factors for PFS in NSCLC patients, both brain and bone metastasis ( HR=3.76, 95% CI: 1.13-12.50, P=0.031) and increased SII ( HR=3.47, 95% CI: 1.28-9.41, P=0.014) remained independent risk factors for OS in patients with NSCLC. Conclusion:The changing trend of peripheral blood inflammatory markers of NSCLC patients cannot independently predict the efficacy of 2-cycle immunotherapy plus chemotherapy. Both brain and bone metastasis, as well as the changing trend of SII can be used as important indicators to predict PFS and OS in advanced NSCLC patients treated with first-line immunotherapy plus chemotherapy. The simultaneous occurrence of brain and bone metastasis and SII increased suggest poor prognosis of NSCLC patients.

Objective:To explore the correlation between SAM domain and HD domain-containing protein 1 (SAMHD1) and programmed death-ligand 1 (PD-L1) expression in lung adenocarcinoma.Methods:The expression of SAMHD1 in lung adenocarcinoma and its effect on prognosis were analyzed by online database GEPIA and Kaplan-Meier Plotter. The expression of SAMHD1 in lung adenocarcinoma cell lines was detected by quantitative real-time PCR (qPCR) and Western blotting. SAMHD1 gene was silenced in H1975, H1299 and LLC cells by small interfering RNA transfection and lentivirus infection, respectively. The mRNA and protein expression levels of PD-L1 in lung adenocarcinoma cells of control group, siSAMHD1-1 group and siSAMHD1-2 group were detected by qPCR and Western blotting. The membrane PD-L1 level was detected by flow cytometry. A mouse lung adenocarcinoma xenograft model was constructed. The PD-L1 levels in the tumor tissues of control group and shSAMHD1 group were detected by immunohistochemistry. Cell proliferation activities of the control, siSAMHD1-1 and siSAMHD1-2 groups were detected by CCK-8 assays.Results:The GEPIA database results showed that the mRNA expression of SAMHD1 in lung adenocarcinoma was lower than that in normal lung tissue (4.81±0.90 vs. 5.99±0.76, t=20.67, P<0.001) . The median overall survival time of patients with high SAMHD1 expression was significantly longer than that of patients with low SAMHD1 expression (109.0 months vs. 87.7 months, χ2=26.83, P=0.002) . The relative mRNA expression levels of SAMHD1 in A549, PC9, H1299 and H1975 cells were 1.00±0.02, 0.75±0.05, 3.49±0.19 and 7.25±0.38 ( F=589.00, P<0.001) , and the relative protein expression levels were 1.00±0.06, 0.34±0.07, 1.67±0.22 and 2.11±0.63 ( F=15.79, P=0.001) . In H1975 cells, the relative mRNA levels of PD-L1 in the control, siSAMHD1-1 and siSAMHD1-2 groups were 1.00±0.00, 1.54±0.26 and 2.89±0.13 ( F=102.30, P<0.001) , and the relative protein expression levels were 1.00±0.01, 1.50±0.10 and 1.52±0.33 ( F=6.65, P=0.030) . In H1299 cells, the relative mRNA levels of PD-L1 in the three groups were 1.00±0.08, 1.63±0.03 and 2.14±0.03 ( F=368.80, P<0.001) , and the relative protein levels of PD-L1 were 1.00±0.07, 1.88±0.35 and 2.05±0.38 ( F=10.66, P=0.011) . The expression level of PD-L1 in the siSAMHD1-1 and siSAMHD1-2 groups was higher than that in the control group (all P<0.05) . Flow cytometry results showed that in H1975 cells, the fluorescence intensity of membrane PD-L1 in the control, siSAMHD1-1 and siSAMHD1-2 groups were 246.83±27.59, 325.60±8.00 and 308.93±7.60 ( F=17.56, P=0.003) , and in H1299 cells, the fluorescence intensity of membrane PD-L1 in the three groups were 959.00±6.25, 1 084.33±7.64 and 1 085.33±21.22 ( F=86.74, P<0.001) . The fluorescence intensity of PD-L1 in the siSAMHD1-1 group and siSAMHD1-2 group was higher than that in the control group (all P<0.05) . In xenograft mouse model, the H-SCORE of PD-L1 in the shSAMHD1 group was higher than that in the control group (7.99±1.10 vs. 4.49±0.43, t=5.13, P=0.007) . The proliferative activities of H1975 cells in the control group, siSAMHD1-1 group and siSAMHD1-2 group at 72 h were 0.50±0.02, 0.75±0.05 and 0.73±0.06 ( F=25.01, P=0.001) . The proliferative activities of H1299 cells in the three groups at 72 h were 0.80±0.01, 1.00±0.04 and 0.93±0.07 ( F=13.90, P=0.006) . The cell proliferation activity in the siSAMHD1-1 group and siSAMHD1-2 group was higher than that in the control group (all P<0.05) . Conclusion:SAMHD1 silencing induces PD-L1 expression in lung adenocarcinoma.

Novel cancer immunotherapy can treat tumors through regulating innate immunity and adaptive immune system. cGMP-AMP synthase (cGAS) is a key regulator of innate immune response to both exogenous and endogenous DNA. After recognizing the cytoplasmic DNA, cGAS produces the second messenger cyclic GMP-AMP (cGAMP), which subsequently combines with the adaptor STING (also known as MITA, MPYS and ERIS) to mediate innate immunity by inducing the production of type I interferons and inflammatory cytokines. Recent studies have revealed that the cGAS/STING signaling pathway can be activated by tumor-derived DNA and by-products of genomic instability and affect the incidence and development of tumors, which plays a critical role in the natural antitumor immunity across cancer types and immune checkpoint blockade therapy. In this article, current understanding of cGAS/STING signaling pathway in tumors was summarized, the pivotal role in tumor immunity and radiotherapy was highlighted, and the potential targeted or alternative therapy of this signaling pathway was reviewed.

Objective:To investigate the effect and mechanism of Myosin X on the radiosensitivity of non-small cell lung cancer (NSCLC) cell line H1975 in vitro. Methods:Western blot was applied to detect the expression level of Myosin X expression. The H1975 cell line with stable knockout of Myosin X (KO group) and infected with control virus (NC group) were constucted by using CRISPR/Cas9 technique. The knockout efficiency was validated. The radiosensitivity of two cell lines was measured by colony formation assay and single-hit multi-target model. γ-H 2AX focus formation test and RNA sequencing (RNAseq) analysis were employed to identify the regulatory mechanism of the radiosensitivity of lung cancer cell lines mediated by Myosin X. Results:The expression level of Myosin X in the H1975 cells was significantly up-regulated than those in other NSCLC cell lines (all P<0.01). The lentiviral vector of Myosin X sgRNA-Lenti-CRISPR v2 was successfully constructed. After the puromycin screening, H1975 cell lines with complete knockout of Myosin X and control cell lines (NC group) were obtained. Colony formation assay demonstrated that compared with the NC group, the radiosensitivity in the KO group was significantly higher (The D 0 value was decreased from 1.28 Gy to 1.03 Gy, SF 2 decreased from 0.29 to 0.21, and the sensitization ratio was 1.24). The γ-H 2AX focus formation test showed that the number of damage focus formed at 1 h and 6 h after irradiation in the KO group was significantly larger than that in the NC group ( P<0.05. RNAseq analysis indicated that the expression level of ISLR in the KO group was significantly down-regulated than that IN the NC group ( P<0.05). Conclusion:Knockout of Myosin X can increase the radiosensitivity of H1975 cells probably by interfering the repair of DNA double-strand damage and down-regulating the expression level of ISLR.

Lung cancer is the leading cause of cancer death worldwide as well as in China. For many years, conventional oncologic treatments such as surgery, chemotherapy, and radiotherapy (RT) have dominated the field of non-small cell lung cancer (NSCLC). The recent introduction of immunotherapy in clinical practice, led to a paradigm shift in lung cancer as in many other solid tumors. Recent pre-clinical and clinical data have shown RT may also modify antitumor immune responses through induction of immunogenic cell death and reprogramming of the tumor microenvironment. This has led many to reexamine RT as a partner therapy to immuno-oncology treatments and investigate their potential synergy in an exponentially growing number of clinical trials. Clinical trials combining radiotherapy and immunotherapy are attracting major attention, experts were invited to discuss frontier and controversial academic topics: (1) Recent developments of clinical synergy between radiation and immune checkpoint inhibitors (ICIs) in the treatment of NSCLC; (2) Will immunotherapy and radiotherapy increase the toxicity risk for cancer patients; (3) How to cope the mixed responses/disassociated responses phenomenon in checkpoint inhibition therapy to NSCLC with local ablative therapy; (4) Combining radiotherapy and immunotherapy in the treatment of NSCLC brain metastases.

Objective:To explore the appropriate radiotherapy time and method in the treatment of patients with brain metastases (BM) due to from non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation.Methods:Totally 69 EGFR-mutant NSCLC patients with BM treated in Zhongnan Hospital of Wuhan University from January 2014 to September 2018 were retrospectively reviewed. The patients were divided into two groups according to the time of brain radiotherapy, including the upfront radiotherapy group ( n=45) who received concurrent brain radiotherapy and EGFR-tyrosine kinase inhibitors(TKI)treatments and deferred radiotherapy group ( n=24) who received brain radiotherapy after intracranial progression during EGFR-TKI treatment. The upfront radiotherapy group was further divided into two groups, the group treated with WBRT concurrent with EGFR-TKI ( n=20) and the group treated with SRS concurrent with EGFR-TKI ( n=25). Overall survival (OS), progression-free survival (PFS) and intracranial progression-free survival (iPFS) time were evaluated. Results:The median OS of 69 patients was 31.2 months. For the upfront and deferred radiotherapy groups, the 1-, 2- year OS were 95%, 64% and 80%, 35%, the difference between the two groups was statistically significant. On subgroup analysis, the upfront WBRT, upfront SRS and deferred radiotherapy groups 1-, 2- year OS were 95%, 96%, 80% and 42%, 88%, 35%. Moreover, the upfront SRS group was associated with improved OS relative to the deferred radiotherapy group ( HR: 0.10, 95% CI: 0.23-0.46, P=0.003), but the upfront WBRT and deferred radiotherapy groups shared similar OS ( HR: 0.54, 95% CI: 0.21-1.32, P=0.180). There were no significant difference in iPFS and PFS between the upfront and deferred radiotherapy groups( P>0.05). Conclusions:Upfront brain radiotherapy prolonged the survival of BM patients metastasized from EGFR-mutant NSCLC. SRS concurrent with EGFR-TKI may be superior to WBRT concurrent with EGFR-TKI in the treatment of BM metastasized from EGFR-mutant NSCLC.

Objective:To investigate the outcomes of limited stage small cell lung cancer (L-SCLC) undergoing surgical therapy and to explore the value of adjuvant therapy for those patients.Methods:A retrospective analysis was initialed for the L-SCLC patients who underwent the surgical treatment in the Zhongnan Hospital of Wuhan University from January 2012 to December 2018. The median disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method. Cox regression was used to explore the prognostic factors.Results:A total of 44 patients were included in our study. The median DFS was 25 months, 1- and 2-year DFS rate were 70.2% and 51.9%, respectively. The median OS was 41 months, 1- and 2- year OS rate were 88.4% and 69.9%, respectively. Multivariate analysis showed male ( RR=6.56, P=0.03), T3-4 ( RR=6.23, P=0.01), pathological lymph node metastasis ( RR=6.52, P=0.03) and adjuvant radiotherapy ( RR=0.13, P=0.002) were associated with disease relapse significantly. Moreover, pathological lymph node metastasis ( RR=3.62, P=0.01) coupled with sufficient adjuvant chemotherapy (≥4 cycles) ( RR=0.12, P=0.01) were independent prognostic factors of OS. Conclusions:Surgical therapy may be an alternative primary treatment for L-SCLC. Additional adjuvant radiotherapy can reduce the risk of recurrence. Giving sufficient course of adjuvant chemotherapy can improve OS.

Objective:To investigate the outcomes of limited stage small cell lung cancer (L-SCLC) undergoing surgical therapy and to explore the value of adjuvant therapy for those patients.Methods:A retrospective analysis was initialed for the L-SCLC patients who underwent the surgical treatment in the Zhongnan Hospital of Wuhan University from January 2012 to December 2018. The median disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method. Cox regression was used to explore the prognostic factors.Results:A total of 44 patients were included in our study. The median DFS was 25 months, 1- and 2-year DFS rate were 70.2% and 51.9%, respectively. The median OS was 41 months, 1- and 2- year OS rate were 88.4% and 69.9%, respectively. Multivariate analysis showed male ( RR=6.56, P=0.03), T3-4 ( RR=6.23, P=0.01), pathological lymph node metastasis ( RR=6.52, P=0.03) and adjuvant radiotherapy ( RR=0.13, P=0.002) were associated with disease relapse significantly. Moreover, pathological lymph node metastasis ( RR=3.62, P=0.01) coupled with sufficient adjuvant chemotherapy (≥4 cycles) ( RR=0.12, P=0.01) were independent prognostic factors of OS. Conclusions:Surgical therapy may be an alternative primary treatment for L-SCLC. Additional adjuvant radiotherapy can reduce the risk of recurrence. Giving sufficient course of adjuvant chemotherapy can improve OS.

Objective To analyze the clinical efficacy and prognosis of stereotactic body radiation therapy (SBRT) for pulmonary oligometastases.Methods Medical records of 104 patients with SBRT for pulmonary oligometastases in our hospital between 2012 and 2018 were retrospectively reviewed.SBRT was performed by intensity modulated radiation therapy (IMRT) technique before December 2015,and by helical tomotherapy (HT) technique in others.The local control (LC),progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.Cox-regression was used for univariate analyses and multivariate analyses.The radiotherapy-related adverse events were evaluated by NCICTCAE V4.0.Results The 1-,2-and 3-year LC rates were 86.6％,75.9％ and 72.3％,respectively.The 1-,2-and 3-year PFS rates were 40.9％,28.4％ and 22.1％,respectively.The 1-,2-and 3-year OS rates were 75.9％,53.2％ and 43.53％,respectively.The median OS time was 26.6 months.Multivariate analyses showed that the pathologic type of primary tumor,the volume of lung oligometastases and the carcino-embryonic antigen (CEA) level before SBRT were the independent prognostic factors of LC (x2 =28.66,P＜0.05).The way of tumor progression after SBRT was the independent prognostic factor of OS (x2=40.01,P＜0.05).Meanwhile,there were no significant differences in the LC and OS between HTSBRT and IMRT-SBRT.Radiation pneumonitis was the major adverse event of SBRT (n =25,24.04％).Less than 7％ patients experienced grade 2 and above radiation pneumonitis.Conclusions SBRT shows high local control rates and tolerable adverse events in the treatment of pulmonary oligometastases.There were no significant differences in the clinical efficacy and adverse events between HT-SBRT and IMRT-SBRT,which means they are all suitable for clinical application.

Primary central nervous system lymphoma (PCNSL) is a type of extranodal non-Hodgkin lymphoma.Whole brain radiation therapy (WBRT) combined with high-dose methotrexate is the standard treatment.Although PCNSL patients are sensitive to radiation therapy,the duration of response is relatively short and it is likely to provoke delayed neurotoxicity,especially in the elderly patients.Reduced-dose WBRT and autologous stem cell transplantation (ASCT) can lower the risk of neutotoxicity,whereas the clinical efficacy remains to be validated.For the elderly patients with PCNSL,application of WBRT in the first-line treatment should be cautiously considered.