Efficacy of immunotherapy in RET fusion-positive NSCLC: A meta-analysis.

Background: The Rearranged during Transfection (RET) gene represents a rare driver mutation in non-small cell lung cancer (NSCLC) occurring in only 1 %-2 % of cases, with implications in targeted carcinogenesis. Despite the significant efficacy demonstrated by immunotherapy in advanced NSCLC with wild-type driver genes, its validation in RET fusion-positive patients is yet to be established. Objectives: This meta-analysis aims to systematically evaluate the effectiveness of immunotherapy in patients with RET fusion-positive NSCLC. Data sources: and Methods: PubMed and Web of Science databases were systematically searched for relevant studies. Outcomes including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were extracted for further analysis. Results: Ten real-world evidence (RWE) studies involving 7145 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 24.0 % and 61.0 %, respectively. Regarding survival analysis, the pooled median PFS and median OS were 4.17 months [95 % confidence interval (CI): 3.40-5.02) and 17.22 months (95 % CI: 11.58-23.91)], respectively. Subgroup analyses showed that immunotherapies plus chemotherapy were superior to single-immunotherapy in terms of ORR, DCR, and median PFS, which were 43 % (95 % CI: 31%-55 %) vs. 17 % (95 % CI: 11%-25 %), 74 % (95 % CI: 60%-84 %) vs. 45 % (95 % CI: 31%-59 %) and 6.69 months (95 % CI: 4.91-8.93) vs. 2.96 months (95 % CI: 2.25-3.78), respectively. Conclusions: To date, RET fusions appear to be associated with poor response to immunotherapy in NSCLC patients, and immunotherapy combined with chemotherapy seems to offer greater clinical benefits than mono-immunotherapy.

Serum cytokine analysis in a cohort of advanced non-small cell lung cancer treated with PD-1 inhibitors reveals predictive markers of CXCL12.

Background: The circulating predictive factors for the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) remain elusive. We aimed to assess the predictive value of circulating cytokines for outcomes. Methods: Serum samples of 102 advanced-stage NSCLC patients who underwent immunotherapy were collected at baseline. The relative levels of 37 cytokines were detected. PD-L1 expression was also analyzed. Results: Higher serum CXCL12 levels (top 33%) were a poor predictive biomarker for durable clinical benefit (DCB) (23.5% vs. 72.1%, p<0.001), progression-free survival (PFS) (3.76 vs. 14.40 months; p<0.001) and overall survival (OS) (12.20 vs. 44.84 months; p=0.008). Compared with PD-L1-negative patients, PD-L1-positive patients had a significantly higher objective response rate (ORR) (70.0% vs. 28.8%, p<0.001) and a prolonged mPFS (25.35 vs. 4.64 months, p=0.003) and tended to have an increased mOS (44.84 vs. 20.42 months, p=0.087). A signature comprising PD-L1<1% and the top 33% CXCL12 level was associated with the lowest ORR (27.3% vs. 73.7%, p<0.001) and DCB (27.3% vs. 73.7%, p<0.001) and the worst mPFS (2.44 vs. 25.35 months, p<0.001) and mOS (11.97 vs. 44.84 months, p=0.007). Area under the curve (AUC) analyses of PD-L1 expression, CXCL12 level and PD-L1 expression plus CXCL12 level to predict DCB or no durable benefit (NDB) showed AUC values of 0.680, 0.719 and 0.794, respectively. Conclusion: Our findings suggest that serum cytokine CXCL12 levels can predict the outcomes of patients with NSCLC receiving ICI. Moreover, the combination of CXCL12 levels and PD-L1 status can predict outcomes with a significantly improved discriminatory power.

LncRNAs and related molecular basis in malignant pleural mesothelioma: Challenges and potential.

Malignant pleural mesothelioma (MPM) is a rare but invasive cancer, which mainly arises from mesothelial tissues of pleura, peritoneum and pericardium. Despite significant advances in treatments, the prognosis of MPM patients remains poor, and the 5-year survival rate is less than 10%. Therefore, it is urgent to explore novel therapeutic targets for the treatment of MPM. Growing evidence has indicated that long non-coding RNAs (lncRNAs) potentially could be promising therapeutic targets for numerous cancers. In this regard, lncRNAs might also potentially therapeutic targets for MPM. Recent advances have been made to investigate the molecular basis of MPM. This review first provides a comprehensive overview of roles of lncRNAs in MPM and then discusses the relationship between molecular basis of MPM and MPM-related lncRNAs to implement them as promising therapeutic targets for MPM.

Real-world treatment and prognostic factors for survival in ALK+ non-small cell lung cancer (NSCLC) patients with brain metastases in China.

BACKGROUND: To explore the efficacy and prognostic factors of different treatment modalities on anaplastic lymphoma kinase (ALK)+ non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). METHODS: A total of 86 patients were enrolled into the study. They were divided into two cohorts based on their history of treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) prior to the incidence of BMs. ALK-TKI-naïve patients with BMs were included in cohort 1 (n = 59); patients who developed BMs after ALK-TKIs treatment were enrolled in cohort 2 (n = 27). Prognostic factors related with overall survival (OS) when treated with ALK-TKIs were assessed in multivariable analysis. RESULTS: With a median follow-up of 41.8 months, the median OS was 34.8 months. In cohort 1, the OS, intracranial progression-free survival (iPFS), and progression-free survival (PFS) were 38.7 months (95% CI: 23.3 to 54.1), 18.5 months (95% CI: 9.6 to 27.4), and 19.1 months (95% CI: 13.7 to 24.5), respectively. Significantly improved OS and iPFS were noted in those patients in which second-generation ALK-TKIs versus crizotinib were initiated (OS: not reached vs. 29.0 months, p = 0.040; iPFS: 22.8 vs. 11.9 months, p = 0.035). In cohort 2, patients who experienced BMs as a result of the treatment failure of ALK-TKIs had a median OS of 27.1 months. Considerable duration of stable disease in patients with measurable BMs was observed (iPFS: 11.5 months, 95% CI: 4.4 to 18.6; PFS: 12.2 months, 95% CI: 3.2 to 21.1). CONCLUSION: Second-generation ALK-TKIs further improved the duration of intracranial response and survival in ALK+ NSCLC patients with BMs in a real-world setting. The potent intracranial efficacy of second-generation ALK-TKIs might generate the lowered urgency of local treatment.

The Efficacy of PD-1/PD-L1 Inhibitors in Patients with Liver Metastasis of Non-Small Cell Lung Cancer: A Real-World Study.

BACKGROUND: A controversy exists regarding the efficacy of programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) inhibitors for patients with non-small cell lung cancer (NSCLC) and liver metastases. Our study retrospectively evaluated the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients with liver metastases. METHODS: This retrospective study included 1627 lung cancer patients who received immunotherapy. Among 648 patients who had advanced NSCLC and received PD-1/PD-L1 inhibitors, 61 had liver metastases and 587 did not have. We analyzed patient characteristics, progression-free survival (PFS) and overall survival (OS). An exploratory analysis of biomarkers including CD4, CD8 and CD68 for efficacy in patients with liver metastases was also performed. RESULTS: In liver metastasis patients receiving PD-1/PD-L1 inhibitors, the objective response rate (ORR) was 29.5%, the disease control rate (DCR) was 72.1%, PFS was 6.4 months and OS was 15.2 months, which were all worse than those of patients without liver metastases (ORR: 35.8%; DCR: 81.8%; PFS: 7.9 months, p = 0.001; OS: 20.6 months, p = 0.008). When compared to non-liver lesions, the ORR (26.2 vs. 39.3%) and DCR (75.4 vs. 88.5%) of liver lesions were lower. During the analysis of PD-L1 expression, 27 PD-L1-positive patients had a longer PFS than 21 patients in the negative group (p = 0.012). Being PD-L1 positive was the independent prognostic indicators for PFS (p = 0.006). Additionally, the PD-L1 and CD8 dual-positive group responded favorably to PD-1/PD-L1 inhibitors. CONCLUSIONS: PD-1/PD-L1 inhibitors are effective in liver metastasis-NSCLC patients. However, the efficacy is inferior when compared to those of patients without liver metastases. In NSCLC patients with liver metastases, PD-L1 expression and CD8+ T cell infiltration can predict the response of PD-1/PD-L1-directed immunotherapy.

Real-world utilization of PD-1/PD-L1 inhibitors with palliative radiotherapy in patients with metastatic non-small cell lung cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) blockade plus radiotherapy may be a promising strategy to improve the prognosis of patients with metastatic non-small cell lung cancer (NSCLC). However, the optimum combined scheme, treatment time of radiotherapy, and irradiated lesion have not been fully determined. METHODS: A total of 321 metastatic NSCLC patients treated with immunotherapy were identified. Among them, 107 patients received PD-1/PD-ligand 1 (PD-L1) inhibitors with radiotherapy, while the remaining cases did not receive radiotherapy. Data on overall survival (OS), progression-free survival (PFS), treatment response and adverse events were collected. Comparisons based on type of radiation, timing of radiotherapy and number of irradiated lesions were performed. RESULTS: The median OS in PD-1/PD-L1 inhibitors plus radiotherapy was longer than in nonradiotherapy (22.8 vs. 16.6 months, p = 0.022). The median PFS showed a similar trend in this study (9.4 vs. 6.2 months, p = 0.042). Moreover, the combined strategy demonstrated a superior disease control rate and abscopal control rate versus without radiotherapy (both p ≤ 0.001). Further multivariate analysis in the immunotherapy and radiotherapy groups revealed that age below 65 (p = 0.004), Eastern Cooperative Oncology Group performance scores of 0-1 (p = 0.001), oligometastasis (p = 0.006), concurrent combination (p = 0.002), and treated with SRT (p = 0.013) were associated with longer OS. There was a similar incidence of adverse events between the two groups (both p ≥ 0.05). CONCLUSIONS: The combination of PD-1/PD-L1 inhibitors plus palliative radiotherapy demonstrated favorable survival and good tolerability in metastatic NSCLC patients.

The Novel Tumor Microenvironment-Related Prognostic Gene AIF1 May Influence Immune Infiltrates and is Correlated with TIGIT in Esophageal Cancer.

BACKGROUND: Esophageal carcinoma (EC) is the sixth most common cause of cancer-related mortality worldwide. Studying the associations of the tumor microenvironment (TME) with pathology and prognosis would illustrate the underlying mechanism of prognostic prediction and provide novel targets for immunotherapy in the treatment of EC. METHODS: Transcriptomic profiles of 159 EC patients were obtained from The Cancer Genome Atlas (TCGA) database. Stromal and immune scores were calculated using the ESTIMATE algorithm. Differentially expressed genes (DEGs) were identified by the optimal score cutoff. Functional enrichments were analyzed by DAVID, while prognostic genes were explored using the Kaplan-Meier method. Validation analysis was performed using immunohistochemistry in tissue microarrays containing samples from 145 EC patients. Multiplex immunofluorescence staining was performed to detect a panel of 6 immune markers, including T-cell immunoreceptor with Ig and ITIM domains (TIGIT), in 90 EC patients. RESULTS: Immune scores significantly increased with increasing age, while stromal scores were dramatically elevated with increasing tumor stage. Fifteen TME-related DEGs including allograft inflammatory factor 1 (AIF1) were identified as prognostic factors of EC. Furthermore, the validation cohort indicated that AIF1 was negatively associated with the prognosis of esophageal squamous cell carcinoma patients. Subsequent analyses suggested that AIF1 may affect immune infiltrates, including T cells and natural-killer cells. Moreover, a correlation between AIF1 and TIGIT was identified. CONCLUSIONS: These results indicate that the TME-related gene AIF1 is a promising predictor of prognosis and is related to immune infiltrates and TIGIT expression in EC. However, further mechanistic studies are needed.

Efficacy of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer and brain metastases: A real-world retrospective study in China.

BACKGROUND: There is only limited knowledge of the treatment responses and clinical outcomes of immune checkpoint inhibitors (ICIs) in driver gene-negative non-small cell lung cancer (NSCLC) patients with brain metastases (BM). This study aims to assess the efficacy of immunotherapy in these patients in a real world setting. METHODS: NSCLC-BM patients without driver gene mutations who received ICIs were retrospectively identified between July 2017 and December 2019. The primary observation endpoint was intracranial objective response rate (iORR), and secondary objectives were objective response rate (ORR), intracranial and systemic progression-free survival (iPFS, PFS), and overall survival (OS). RESULTS: We reviewed 1578 patients with lung cancer and BM. According to the exclusion criteria, 41 patients were finally enrolled. Among these 41 patients, iORR was 36.6% (95% confidence interval [CI] = 21.2%-52.0%), whereas iPFS was 6.8 (95% CI = 3.32-10.35) months. Additionally, ORR, PFS, and OS were 24.4% (95% CI = 10.7%-38.1%), 6.2 (95% CI = 4.57-7.83) months and 13.7 (95% CI = 11.20-16.26) months, respectively. ICIs combined with concurrent radiotherapy group exhibited preferred iORR (p = 0.030) compared with no radiotherapy group, and ICIs plus chemotherapy showed improved OS (p = 0.024) compared to ICI monotherapy. Moreover, the lines of ICI treatment ≥2 (p = 0.005) and derived neutrophil-to-lymphocyte ratio (dNLR) ≥3 (p = 0.010) were independently negative factors for OS. CONCLUSION: In NSCLC-BMs patients lacking driver genes, ICIs exhibited an effective drug regime. A combination of ICIs with concurrent radiotherapy showed a better intracranial response, whereas ICIs plus chemotherapy were associated with superior OS.

KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup.

Lung cancer, the leading cause of cancer-related deaths worldwide, can be classified into small cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is the most common histological type, accounting for 85% of all lung cancers. Kirsten rat sarcoma viral oncogene (KRAS) mutations, common in NSCLC, are associated with poor prognosis, likely due to poor responses to most systemic therapies and lack of targeted drugs. The latest published clinical trial data on new small-molecule KRAS G12C inhibitors, AMG510 and MRTX849, indicate that these molecules may potentially help treat KRAS-mutant NSCLC. Simultaneously, within the immuno-therapeutic process, immune efficacy has been observed in those patients who have KRAS mutations. In this article, the pathogenesis, treatment status, progress of immunotherapy, and targeted therapy of KRAS-mutant NSCLC are reviewed.

[Analysis of the variation and changes of Yersinia enterocolitica in Ningxia area from 1984 to 2011].

OBJECTIVE: To analyze the genetic evolution and bacterial type changes of Yersinia enterocolitica in the Ningxia area between year 1984 and 2011. METHODS: A total of 296 strains of Yersinia enterocolitica was collected from diarrhea patients, pig, rodents, sheep and dogs between year 1984 and 2011. The serotype, biotype, ail, ystA, ystB, yadA, virF and other toxic genes were detected. The PFGE subtypes of serotype O:3 and O:9 strains and the cluster features were analyzed. RESULTS: Out of 296 Yersinia enterocolitica strains, pig was the main host, accounting for 65.20% (193/296), followed by rodents, accounting for 32.43% (96/296). Serotype and biotype had their own respective dominant types in different periods. During 1984 and 1985, 2 strains of serotype O:3 and 3 strains of serotype O:9 were isolated, all belonged to biotype 3. Because of lack of strains, there were no obvious dominant types found. Between 1997 and 1999, 177 strains of serotype O:9 Yersinia enterocolitica were isolated as the dominant strain; and there were 178 strains of biotype 2 Yersinia enterocolitica were found. During 2007 and 2011, 54 strains of serotype O:3 Yersinia enterocolitica were isolated as dominant strain; followed by 26 strains of serotype O:5. There were separately 44 and 59 strains of biotype 1A and biotype 3. The PCR test divided the 248 strains into 4 types, including pathogenic strains as type I (ail(+), ystA(+), ystB(-), yadA(+), virF(+)). The PFGE divided the serotype O:3 into 12 types, in which K6GN11C30021 and K6GN11C30012 were the dominant types, accounting for 63.64% (42/66). The serotype O:9 were divided into 14 types, in which K6GN11C90010, K6GN11C90008, K6GN11C30018 and K6GN11C90003 were the dominant types, accounting for 89.01% (162/182). CONCLUSION: The different serotypes of isolated strains in Ningxia district showed different dominant bacteria in different periods; while the biotypes also changed with serotypes. The Yersinia enterocolitica isolated from different years showed great variation.

[Characteristics of Yersinia enterocolitica genes isolated in Ningxia Hui autonomous region from 1997 to 2010].

OBJECTIVE: To investigate the distribution of virulent genes of Yersinia enterocolitica (Y. enterocolitica) in Ningxia Hui autonomous region and the characteristics of the molecular patterns of Y. enterocolitica. METHODS: 283 strains of Y. enterocolitica were isolated in Ningxia Hui autonomous region between year 1997 and 2010. The genes ail, ystA, ystB, yadA and virF were analyzed by PCR method; the chromosomal DNA of Y. enterocolitica was digested by restriction endonucleases NotI and processed by pulsed-field gel electrophoreses (PFGE); and then the cluster analysis were conducted by BioNumeric computer software towards the above results. RESULTS: Of all, 209 strains of serotypes O:3 and O:9 Y.enterocolitica showed positive virulence of genes ail, ystA, yadA and virF; 97.6% (204/209) of which, the ystB virulence were negative. The virulence of all genes in serotype O:8 and serum-unclassified strains were negative. 9 out of 11 strains of serotype O:5 Y. enterocolitica showed negative virulence of the above five genes. By PFGE, according to the NotI Macrorestriction Map on chromosomal DNA, the 29 strains of serotype O:3 Y. enterocolitica were divided into 12 PFGE patterns, 2 of which were dominant patterns which could be found in over 5 strains; and the 180 strains of serotype O:9 Y. enterocolitica were divided into 13 patterns, 4 of which were dominant patterns which existed in over 10 strains; which were isolated individually from pigs and house mouse, pigs and dogs as well as pigs and wild rabbits. CONCLUSION: Y.enterocolitica serotypes O:3 and O:9 were pathogenic in Ningxia, and serotype O:3 becomes predominant gradually. O:5, O:8 and serum-unclassified serotypes were non-pathogenic.