Tumor-infiltrating neutrophils and peripheral neutrophil-to-lymphocyte ratio conversely predicted the prognosis of patients with non-small cell lung cancer.

Increasing evidence indicates that neutrophil-associated prognostic markers, such as, tumor-associated neutrophils (TANs), neutrophil-to-T cell ratio (NTR) and neutrophil-to-lymphocyte ratio (NLR), are strongly correlated with the survival of patients with non-small cell lung cancer (NSCLC). However, either the association or the difference in their predictive efficacies remains unknown. To this aim, we investigated the influence of intratumoural TANs and peripheral NLR on the clinical outcome of NSCLC patients using tumor tissues, peripheral blood indexes, and clinicopathological data of 133 patients diagnosed with NSCLC. Additionally, Kendall correlation analysis was performed to identify the association between TANs and NLR. Our results revealed that intratumoural TANs were effective prognostic factors for favorable overall survival (OS), but were not associated with disease-free survival (DFS) in the subgroup analysis of 84 postoperative patients and progression-free survival (PFS) in 49 non-resectable NSCLC patients. Elevated NTR also indicated favorable prognosis, with high intratumoural NTR being correlated with prolonged OS and high stromal NTR being correlated with prolonged DFS. In contrast, peripheral NLR predicted dismal OS and DFS of patients receiving curative surgery. Furthermore, neither intratumoural nor stromal TANs were found to be associated with NLR, indicating that they were independent inflammatory indexes in predicting the prognosis of NSCLC. In conclusion, we discovered that TANs and NLR independently and oppositely predicted the clinical outcome of NSCLC patients, providing new sights on the role of neutrophil in tumor biology and survival prediction.

ANK2 as a novel predictive biomarker for immune checkpoint inhibitors and its correlation with antitumor immunity in lung adenocarcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to significantly improve the survival of patients with advanced lung adenocarcinoma (LUAD). However, only limited proportion of patients could benefit from ICIs. Novel biomarkers with strong predictability are needed for clinicians to maximize the efficacy of ICIs. Our study aimed to identify potential biomarkers predicting ICIs efficacy in LUAD. METHODS: The Cancer Genome Atlas (TCGA) PanCancer Atlas studies in cBioportal were used to evaluate the mutation frequency of ANK2 across multiple cancers. Clinical and mutational data for LUAD from ICIs-treated cohorts (Hellmann et al. and Rizvi et al.) were collected to explore the correlation between ANK2 mutation and clinical outcomes. In addition, the relationship between ANK2 expression and clinical outcomes was analyzed using LUAD data from TCGA and Gene Expression Omnibus. Furthermore, the impact of ANK2 mutation and expression on the tumor immune microenvironment of LUAD was analyzed using TCGA and TISIDB databases. RESULTS: Patients with ANK2 mutation benefited more from ICIs. In ICIs-treated cohort, prolonged progression-free survival (PFS) (median PFS: NR (not reached) vs. 5.42 months, HR (hazard ratio) 0.31, 95% CI 0.18-0.54; P = 0.0037), improved complete response rate (17.65% vs. 1.85%, P = 0.0402), and improved objective response rate (64.71% vs. 24.07%, P = 0.0033) were observed in LUAD patients with ANK2 mutation compared to their wild-type counterparts. Regarding ANK2 expression, it was observed that ANK2 expression was decreased in LUAD (P < 0.05) and a higher level of ANK2 expression was associated with longer overall survival (HR 0.69, 95% CI 0.52-0.92; P = 0.012) in TCGA LUAD cohort. Moreover, ANK2 mutation or higher ANK2 expression correlated with enhanced antitumor immunity and "hot" tumor microenvironment in LUAD, which could be potential mechanisms that ANK2 mutation facilitated ICIs therapy and patients with higher ANK2 expression survived longer. CONCLUSION: Our findings suggest that ANK2 mutation or increased ANK2 expression may serve as a favorable biomarker for the efficacy of ICIs in patients with LUAD.

Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors.

Background: Although immune checkpoint inhibitors (ICIs) generally show poor therapeutic efficacy in patients with epidermal growth factor receptor (EGFR) mutations, certain research indicate that a small proportion of these patients do respond to ICIs. The present study sought to identify the features of patients with EGFR mutations who might benefit from ICIs from multiple studies and discussed the optimal treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. Methods: The profiles of 114 advanced NSCLC patients with EGFR mutations who received ICIs treatment were retrospectively reviewed. EGFR subtypes, programmed cell death ligand 1 (PD-L1) expression, and clinical characteristics regarding their impact on the efficacy of ICIs were investigated. Results: Patients with major EGFR mutations (L858R or 19Del) had a shorter progression-free survival (PFS) and a lower objective response rate (ORR) as compared to patients with rare (20ins or G719X) and other EGFR mutations. Although not statistically significant, median overall survival (OS) tended to be longer in patients with negative (<1%) PD-L1 expression than with positive (≥1%) PD-L1 expression (15.61 vs. 7.40 months, p = 0.138). Median PFS and OS were significantly shorter in heavily treated patients (prior lines of therapy ≥3 lines vs. <3 lines: mPFS, 1.80 vs. 2.50 months, p = 0.003; mOS, 6.70 vs. 14.00 months, p = 0.031). ORR was also lower in patients who had received ≥3 prior lines of therapy compared to in those <3 prior lines of therapy (0.00% vs. 21.67%, p = 0.002). Conclusion: Patients with major EGFR mutations showed poorer responses to ICIs than those with rare EGFR mutations. EGFR-mutated patients with lower PD-L1 expression showed a trend towards a longer OS after receiving ICIs. ICIs should be administered as early as possible to previously treated EGFR-mutated NSCLC patients. ICI-based combined therapies may be a direction for treatment of these patient subtypes in the future.

Comparison of the efficacy and safety of first-line treatments based on clinicopathological characteristics for patients with advanced epidermal growth factor receptor mutated non-small-cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: A growing number of regimens have been approved as first-line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer. However, the optimal regimen has not been determined, especially for patients with different clinicopathological characteristics. Therefore, we performed this meta-analysis to compare the efficacy and safety of first-line treatments for patients with EGFR-mutated NSCLC based on clinicopathological characteristics, thereby providing evidence for individual patient clinical decision-making. METHODS: The PubMed, Embase, Cochrane Library databases, and abstracts of ASCO, ESMO, and WCLC were searched from inception to 3 June 2021 to identify eligible randomized controlled trials (RCTs). The outcomes of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3 or higher adverse events (≥3AEs) were compared and ranked based on various clinicopathological characteristics among 14 regimens by network meta-analysis (NMA) and the surface under the cumulative ranking curve (SUCRA), respectively. RESULTS: 25 RCTs were included, with a total of 6965 patients and 14 treatment regimens. The primary endpoint of all RCTs was PFS, and OS, ORR, and ≥3AEs were secondary endpoints. Regarding overall patients, the most distinct PFS benefit was observed in osimertinib (OSI), with the fewest ≥3AEs, whereas gefitinib plus pemetrexed-based chemotherapy (GEF+PB) provided the greatest benefit for OS. When considering EGFR mutation type, aumolertinib (AUM) and GEF+PB could be the optimal regimens in terms of PFS for patients with EGFR 19DEL and EGFR 21L858R, respectively. Notably, the efficacy of the 14 regimens for PFS varied across clinicopathological characteristics, with GEP+PB ranking first in Eastern Cooperative Oncology Group performance status (ECOG PS)= 1, Asian, age＜65 and smoking subgroups, with AUM ranking first in ECOG PS= 0 and female subgroups, with ICO+PB ranking first in age ≥65 and no smoking subgroups, and with AFA+CET ranking first in the male subgroup. In terms of brain metastases, third-generation EGFR-TKI showed obvious superiority, with AUM and OSI optimally prolonging PFS in patients with and without brain metastases, respectively. In addition, GEF+PB is a superior alternative, ranking second in terms of PFS regardless of the presence of brain metastases. CONCLUSIONS: OSI and GEF+PB were the most two effective first-line regimens for overall patients, ranking first in PFS and OS, respectively. GEF+PB ranked first in terms of PFS in subgroups of EGFR 21L858R, ECOG PS= 1, Asian, age <65, and smoking. Meanwhile, AUM in subgroups of EGFR 19DEL, ECOG PS= 0, female, brain metastasis, OSI in the subgroup of without brain metastasis, ICO+PB in no smoking subgroup, and AFA+CET in male subgroup were the best options as for their evident superiority in PFS.

Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma.

Background: The emergence of immune checkpoint inhibitors (ICIs) has significantly improved the clinical outcomes of patients with metastatic melanoma. However, survival benefits are only observed in a subset of patients. The fibroblast growth factor receptor (FGFR) family genes are frequently mutated in melanoma, yet their impacts on the efficacy of ICIs remain unclear. Our study aimed to explore the association of FGFR mutations with ICIs efficacy in metastatic melanoma. Methods: The Cancer Genome Atlas (TCGA) data (PanCancer Atlas, skin cutaneous melanoma (SKCM), n = 448) in cBioPortal were collected as a TCGA cohort to investigate the association between FGFR mutations and prognosis of melanoma patients. To explore the impact of FGFR mutations on the efficacy of ICIs in melanoma, clinical and tumor whole-exome sequencing (WES) data of four ICI-treated studies from cBioPortal were consolidated as an ICIs-treated cohort. Moreover, the relationship between FGFR mutations and immunogenicity (tumor mutation burden (TMB), neo-antigen load (NAL), mismatch repair (MMR)-related genes and DNA damage repair (DDR)-related genes) of melanoma was evaluated utilizing data from the ICIs-treated cohort. The influence of FGFR mutations on the tumor immune microenvironment (TIME) of melanoma was also analyzed using the TCGA cohort. Results: In the TCGA cohort, survival in melanoma patients with or without FGFR mutations was nearly equivalent. In the ICIs-treated cohort, patients with FGFR mutations had better survival than those without (median overall survival: 60.00 vs. 31.00 months; hazard ratio: 0.58, 95% CI: 0.42-0.80; P = 0.0051). Besides, the objective response rate was higher for patients harboring FGFR mutations (55.56%) compared to wild-type patients (22.40%) (P = 0.0076). Mechanistically, it was revealed that FGFR mutations correlated with increased immunogenicity (e.g., TMB, NAL, MMR-related gene mutations and DDR-related gene mutations). Meanwhile, FGFR mutant melanoma tended to exhibit an enhanced antitumor TIME compared with its wild-type counterparts. Conclusions: Our study demonstrated that FGFR mutations is a promising biomarker in stratifying patients with advanced melanoma who might benefit from ICIs therapy.

M2 macrophages reduce the effect of gefitinib by activating AKT/mTOR in gefitinib-resistant cell lines HCC827/GR.

BACKGROUND: The biological behavior of cells change after they develop drug resistance, and the degree of resistance will be affected by the tumor microenvironment. Here, we aimed to explore the changes in the biological behavior of tumors and to observe the differences in the release of cytokines and chemokines which can influence the tumor microenvironment. We also aimed to study how TKIs-resistant cell lines recruit macrophages to reduce the sensitivity of the cells following gefitinib administration. METHODS: We generated and maintained gefitinib-resistant cell lines to study the differences between gefitinib-sensitive cell lines according to clone formation, cell growth curve analysis, whole-exome sequencing, and qPCR ARRAY technology. We used the WNT/ß-catenin inhibitor, WNT/ß-catenin activator and overexpression ß-catenin lentivirus to observe the changes in CCL2. M2 macrophages and gefitinib-resistant cell lines HCC827/GR were cocultured to detect the viability gefitinib for inducing cell death. RESULTS: The proliferation and migratory activities were much more pronounced in HCC827/GR cells. CCL2 expression was also enhanced and regulated by ß-catenin in HCC827/GR. CCL2 promoted the chemotactic ability of M2 macrophages. M2 macrophages reduced the antitumor effect of gefitinib treatment by activating AKT/mTOR. CONCLUSIONS: Gefitinib-resistant cell lines have stronger proliferation and migration capabilities, and attract macrophages by releasing more CCL2 to reduce the sensitivity of cells to gefitinib.

[Cochlear implant approach in children patients with sigmoid sinus antedisplacement].

OBJECTIVE: To summarize the operation approach and management during cochlear implant operation in children with sigmoid sinus antedisplacement. METHOD: Five hundred and thirty-eight profound hearing loss children were performed auditory and imagiological examinations before cochlear implant. We analyzed the location of the sigmoid sinus from the high resolution CT scan and then performed cochlear implant to all these patients. RESULT: In all these 538 cochlear implant children, 4 cases (0.74%) had significant sigmoid sinus antedisplacement which cause the operation more difficult, 64 cases (11.9%) had slight sigmoid sinus antedisplacement which did not impact the ordinary cochlear implant procedures. CONCLUSION: Significant sigmoid sinus antedisplacement that impact cochlear implant operative procedures were seldom happen in children. In 538 cochlear implant children of our center, 4 cases had significant sigmoid sinus antedisplacement that impact cochlear implant operative procedures, we successfully complete these 4 operation through removal of the incus and abrasive reduction the posterior wall of bony external acoustic meatus.