Impact of chrono-radiotherapy on the prognosis and treatment-related toxicity in patients with locally advanced nasopharyngeal carcinoma: A multicenter propensity-matched study.

The timing of radiotherapy (RT) delivery has been reported to affect both cancer survival and treatment toxicity. However, the association among the timing of RT delivery, survival, and toxicity in locally advanced nasopharyngeal carcinoma (LA-NPC) has not been investigated. We retrospectively reviewed patients diagnosed with LA-NPC who received definitive RT at multiple institutions. The median RT delivery daytime was categorized as morning (DAY) and night (NIGHT). Seasonal variations were classified into the darker half of the year (WINTER) and brighter half (SUMMER) according to the sunshine duration. Cohorts were balanced according to baseline characteristics using propensity score matching (PSM). Survival and toxicity outcomes were evaluated using Cox regression models. A total of 355 patients were included, with 194/161 in DAY/NIGHT and 187/168 in WINTER/SUMMER groups. RT delivered during the daytime prolonged the 5-year overall survival (OS) (90.6% vs. 80.0%, p = 0.009). However, the significance of the trend was lost after PSM (p = 0.068). After PSM analysis, the DAY cohort derived a greater benefit in 5-year progression-free survival (PFS) (85.6% vs. 73.4%, p = 0.021) and distant metastasis-free survival (DMFS) (89.2% vs. 80.8%, p = 0.051) in comparison with the NIGHT subgroup. Moreover, multivariate analysis showed that daytime RT was an independent prognostic factor for OS, PFS, and DMFS. Furthermore, daytime RT delivery was associated with an increase in the incidence of leukopenia and radiation dermatitis. RT delivery in SUMMER influenced only the OS significantly (before PSM: p = 0.051; after PSM: p = 0.034). There was no association between toxicity and the timing of RT delivery by season. In LA-NPC, the daytime of radical RT served as an independent prognostic factor. Furthermore, RT administered in the morning resulted in more severe toxic side effects than that at night, which needs to be confirmed in a future study.

Activation of the IL-17 signalling pathway by the CXCL17-GPR35 axis affects drug resistance and colorectal cancer tumorigenesis.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and drug resistance following prolonged treatment leads to downregulation of the efficacy of chemotherapy against CRC. CXCL17 is an inflammatory factor that plays a crucial role in tumorigenesis. However, the function of the CXCL17-GPR35 axis in CRC and resistance to chemotherapy is not entirely clear. Bioinformatic analysis was used to identify differentially expressed genes (DEGs) in oxaliplatin (OXA)-resistant CRC tumour tissues compared to OXA-sensitive counterparts. To further determine the function of CXCL17 in taxol-resistant CRC cells (HCT15), proliferation, migration, invasion, cell cycle, and apoptosis were analysed by CCK-8, wound healing, Transwell®, and flow cytometry assays, respectively. In addition, RNA sequencing, western blotting, CCK-8, wound healing, and Transwell® assays were used to further identify and confirm the downstream effects of CXCL17 regulation on taxol resistance. Our study found that CXCL17 and GPR35 were upregulated in OXA-resistant tumour tissues compared to in OXA-sensitive tissues. CXCL17 silencing significantly decreased the viability, migration, and invasion of taxol-resistant CRC cells. CXCL17 silencing arrested taxol-resistant CRC cells in the G2/M phase and promoted apoptosis. The IL-17 signalling pathway is involved in regulation of the CXCL17-GPR35 biological axis in HCT15 cells, and the addition of IL-17A distinctly reversed the decreased proliferation, migration, and the enhanced apoptosis of HCT15 cells upon CXCL17 deletion. In summary, these findings demonstrate that the CXCL17-GPR35 axis and IL-17 signalling pathway are involved in mediating CRC tumorigenesis and drug-resistance. Inhibition of the CXCL17-GPR35 axis and IL-17 may hence be promising therapeutic targets for CRC resistance to OXA.

Impact of Smoking on Response to the First-Line Treatment of Advanced ALK-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis.

Background: The impact of smoking on the efficacy of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treatment is controversial and has not been systematically explored in the first-line setting. We performed a systematic review based on a pairwise meta-analysis and a Bayesian network meta-analysis (NMA) to address this issue. Methods: PubMed, Embase, Web of Science, Cochrane Library, Clinical-Trials.gov, and other resources were searched until 5 January 2022. Progression-free survival (PFS) was considered the main outcome of interest. Randomized controlled trials with smoking status analysis were included. Cochrane Risk of Bias Tool was performed to assess the risk of bias. Random effects models were adopted conservatively in meta-analysis. The NMA was performed in a Bayesian framework using the "gemtc" version 1.0-1 package of R-4.1.2 software. Results: A total of 2,484 patients from nine studies were eligible for this study, with 1,547 never-smokers (62.3%) and 937 smokers (37.7%). In a pairwise meta-analysis, in the overall population, no significant difference was found between never-smokers and smokers. However, in the subgroup analyses based on crizotinib-controlled studies, anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) derived better PFS in the smoking group over the never-smoking group in the Asian population (HR = 0.17, 95%CI = 0.09-0.31 in the smoking group, HR = 0.39, 95%CI = 0.24-0.65 in the never-smoking group, p = 0.04, low quality of evidence). In NMA, among never-smokers, lorlatinib ranked the highest for PFS (SUCRA = 96.2%), but no significant superiority was found among the new-generation ALK-TKIs except for ceritinib. In smokers, low-dose alectinib performed best (SUCRA = 95.5%) and also demonstrated a significant superiority over ensartinib (HR = 0.23, 95%CI = 0.08-0.68, very low quality of evidence), brigatinib (HR = 0.38, 95%CI = 0.14-0.99, low quality of evidence), ceritinib (HR = 0.24, 95%CI = 0.09-0.66, low quality of evidence), crizotinib (HR = 0.18, 95%CI = 0.08-0.41, moderate quality of evidence), and chemotherapy (HR = 0.11, 95%CI = 0.05-0.28, low quality of evidence). Conclusion: In general, smoking may not affect the treatment efficacy of advanced ALK-positive NSCLC in the first-line setting. However, alectinib may perform better in the smoking Asian population. Moreover, lorlatinib in never-smokers and low-dose alectinib in smokers could be considered optimal first-line therapy for advanced ALK-positive NSCLC. Acceptable limitations of evidence, such as study risk of bias, inconsistency, and imprecision, were present in this NMA.