FTO blocks RNA translational activity via the loss of N6-methyladenosine methylation at 5' UTR regulated by RBM5 in cisplatin-resistant NSCLC.

N6-methyladenosine (m6A) methylation has been widely regarded in numerous biological functions including CR. Nonetheless, the molecular process of m6A methylation behind CR in non-small cell lung cancer (NSCLC) has no apparent significance. We identified in this study that the expression of FTO alpha-ketoglutarate dependent dioxygenase (FTO) was downregulated in CR NSCLC tissues and cells in vivo and in vitro. Additionally, RIP-seq indicated that loss of FTO contributed to the elevated m6A methylation at 5'-untranslated region of RNAs which were closely connected with tumor resistance and malignancy, and FTO exerted to exclude the recruitment of eIF3A to these target genes in CR NSCLC. Moreover, FTO-enriched transcripts displayed a reduced translational capability in CR NSCLC compared to the regular NSCLC cells. Finally, we also identified RNA binding motif protein 5 (RBM5) that could specially interact with FTO in regular NSCLC compared to CR NSCLC. Deficiency of RBM5 resulted in the abnormal recognition of transcripts by FTO, and led to the translation silencing of genes associated with CR such as ATP7A, ERCC1, CD99, CDKN3, XRCC5, and NOL3. Taken together, our data characterized FTO as a novel translation regulator and revealed the molecular mechanism on gene translation through the synergistic effects with RBM5 and m6A methylation in CR NSCLC cells.

Diagnostic and prognostic nomograms for laryngeal carcinoma patients with lung metastasis: a SEER-based study.

PURPOSE: To establish two nomograms to quantify the risk of lung metastasis (LM) in laryngeal carcinoma (LC) and predict the overall survival of LC patients with LM. METHODS: Totally 9515 LC patients diagnosed histologically from 2000 to 2019 were collected from the Surveillance, Epidemiology, and End Results database. The independent diagnostic factors for LM in LC patients and prognostic factors for LC patients with LM were identified by logistic and Cox regression analysis, respectively. Nomograms were established based on regression coefficients and evaluated by receiver operating characteristic curve, calibration curves, and decision curve analysis. RESULTS: Patients with supraglottis, higher pathological grade, higher N stage, and distant metastasis (bone, brain, or liver) were more likely to have LM (P < 0.05). Chemotherapy, surgery and radiotherapy were independent factors of the overall survival of LC patients with LM (P < 0.05). The area under curve of diagnostic nomogram were 0.834 and 0.816 in the training and validation cohort respectively. For the prognostic nomogram, the area under curves of 1-, 2-, and 3-years were 0.735, 0.734, and 0.709 in the training cohort and 0.705, 0.803, and 0.809 in the validation cohort. The calibration curves and decision curve analysis indicated good performance of the nomograms. CONCLUSION: Distant metastasis (bone, brain, or liver) and N stage should be considered for prediction of LM in LC patients. Chemotherapy is the most significant influencing prognostic factor improving the survival of LC patients with LM. Two nomograms may benefit for providing better precautionary measures and treatment decision.

PD-1 inhibitors plus chemotherapy as first-line therapy for stage IV ESCC.

To evaluate the anti-tumor efficacy and tolerability of programmed cell death protein 1 (PD-1) inhibitors plus chemotherapy versus chemotherapy alone as first-line therapy for unresectable esophageal squamous cell carcinoma (ESCC) patients at stage IV in a real-world cohort. All unresectable ESCC patients at stage IV who initiated first-line therapy with PD-1 inhibitors plus chemotherapy between August 2018 and March 2021 in a general hospital in China were retrospectively analyzed in this study. Propensity score matching (1:1) with control patients receiving chemotherapy alone was performed. Overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method. In this study, fifty patients (n = 25 each group) were included, all of whom could be evaluated for efficacy. PD-1 inhibitors plus chemotherapy exhibited better OS than chemotherapy alone (median 15.8 vs 12.4 months, hazard ratio [HR] 0.46 [95% CI 0.23-0.95]; P = 0.036). The median PFS for the PD-1 inhibitors plus chemotherapy group was 8.7 months compared with 6.1 months for the chemotherapy group (HR 0.48 [95% CI 0.26-0.90]; P = 0.014). Adverse events (AEs) of grade 3 or above related to treatment were found in 24.0% and 32.0% of the PD-1 inhibitors plus chemotherapy and chemotherapy alone groups, respectively. PD-1 inhibitors plus chemotherapy exhibited durable anti-tumor activity and relatively controllable safety as first-line therapy for unresectable ESCC patients at stage IV, but these results need to be confirmed by further research.

High-dose versus standard-dose radiotherapy in concurrent chemoradiotherapy for inoperable esophageal cancer: A systematic review and meta-analysis.

PURPOSE: The aim of this study was to evaluate the effectiveness and safety of high-dose (HD-RT) versus standard-dose radiotherapy (SD-RT) in concurrent chemoradiotherapy (CCRT) for inoperable esophageal cancer (EC) patients. METHODS: A systematic search of the literature was conducted by screening PubMed, Web of Science, EMBASE and Cochrane Library databases before October 7, 2022 to collect controlled clinical studies of high-dose (≥60 Gy) and standard-dose (50-50.4 Gy) radiation in CCRT for EC. For statistical analysis, a fixed-effects model was used to synthesize HR and OR if there was no significant heterogeneity among studies; otherwise, a random-effects model was employed. RESULTS: There were ten studies with 4625 patients included in the study, 3667 of whom (79.3%) were esophageal squamous cell carcinoma (ESCC). The HD-RT group had no significant benefits in overall survival (OS) (HR = 0.88, 95% confidence interval [CI] = 0.74-1.05, P = 0.16) and progression-free survival (HR = 0.84, 95%CI = 0.67-1.04, P = 0.12) in total EC patients, compared with SD-RT group. However, in ESCC subgroup analysis, compared with SD-RT group, a better OS was observed in the HD-RT group (HR = 0.78, 95%CI = 0.70-0.88, P < 0.0001). CONCLUSION: Compared with the radiation dose of 50-50.4 Gy, the increase of radiation dose (≥60 Gy) did not achieve benefits in survival for inoperable EC patients receiving CCRT. However, in patients with ESCC, high dose (≥60 Gy) of radiation probably improved OS.

Efficacy and safety of anti-PD-1 antibody plus chemoradiotherapy in locally advanced esophageal squamous cancer.

Objective: To compare effects and adverse events of anti-programmed cell death protein 1 (anti-PD-1) antibody combined with chemoradiotherapy (CRT) and CRT alone as the initial treatment in locally advanced esophageal squamous cell carcinoma (ESCC). Methods: We retrospectively reviewed locally advanced ESCC patients who received Anti-PD-1+CRT as initial treatment at 3 institutions. Primary outcomes of interest were progression-free survival (PFS) and overall survival (OS); secondary outcomes were objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and treatment-related adverse events (AEs) including immune-related adverse events (irAEs). Results: At data cutoff, 81 patients were included (30 Anti-PD-1+CRT, 51 CRT). Median follow-up was 31.4 months. Anti-PD-1+CRT resulted in significant improvements in PFS (median, 18.6 vs. 11.8 months, HR 0.48 [95% CI, 0.29-0.80], P = 0.008), and OS (median, 27.7 vs. 17.4 months, HR 0.37 [95% CI, 0.22-0.63], P = 0.002), compared with CRT in ESCC. The ORR and DCR of patients treated with Anti-PD-1+CRT were also significantly higher than those treated with CRT (80.0% vs. 56.9%, P = 0.034), (100% vs. 82.4%, P = 0.023), respectively. Anti-PD-1+CRT had better durable response compared with CRT, with DoR (median,17.3 vs. 11.1 months, P = 0.022). Treatment-related adverse event incidence was similar between the two groups (any Grade, 93.3% vs. 92.2%; ≥Grade 3, 50.0% vs. 33.3%). Conclusion: Anti-PD-1 plus chemoradiotherapy demonstrated promising antitumor activity and was well tolerated in locally advanced ESCC.

Anti-programmed death ligand 1 immunotherapy in patients with limited-stage small cell lung cancer: a real-world exploratory study.

The aim of this study was to investigate the safety and efficacy of anti-programmed death ligand 1 (PD-L1) immunotherapy plus chemoradiotherapy for patients with limited-stage small cell lung cancer (LS-SCLC) in clinical practice. Patients with LS-SCLC treated with anti-PD-L1 (atezolizumab/durvalumab) plus chemoradiotherapy (CRT) as the initial treatment at three general hospitals between March 2020 and December 2021 were retrospectively analysed. 1:2 propensity score matching for controls that receive CRT only was performed. Clinical data (age, sex, history of cancer treatment, adverse events, etc.) were collected to evaluate toxicity, progression-free survival (PFS) and objective response rate (ORR). Researchers used univariate Chi-squared analyses to determine if anti-PD-L1 immunotherapy had a significant association with toxicity or ORR. Kaplan-Meier survival analysis, and the log-rank test were used to compare survival curves between the two groups. In the anti-PD-L1 plus CRT and CRT groups, 15 and 30 patients were analyzed; median follow-up was 16.39 months and 16.64 months, respectively. Incidence of toxicity between the two groups was similar and there were no new safety signals. Anti-PD-L1 immunotherapy significantly improved PFS (P = 0.02). The median PFS was not reached in the anti-PD-L1 plus CRT group versus 8.18 months [95% confidence interval (CI), 6.14-10.22 months] in the CRT group. The ORR were 93.33% and 76.67%, respectively (P = 0.34). This study supports adding anti-PD-L1 immunotherapy (atezolizumab/durvalumab) to CRT as an initial treatment option in patients with LS-SCLC for its favorable safety profile and efficacy.