Non-linear relationship between baseline fasting blood glucose and mortality in peritoneal dialysis patients, a retrospective cohort study

BackgroundThe relationship between baseline fasting blood glucose (bFBG) and mortality in peritoneal dialysis (PD) patients has been the subject of debate, with limited exploration of the non-linear relationship between bFBG and death in these patients.MethodsThis retrospective study categorized patients into four groups based on their bFBG using quartiles. Baseline clinical data at the initiation of dialysis were compared. Survival curves were plotted, and subgroup analyses were stratified by relevant covariates. To address the non-linear relationship, curve fitting and a threshold effect analysis were performed.ResultsThe study included 379 PD patients with a median follow-up of 41.8 (22.6, 60.1) months. The COX proportional hazards model showed an association between bFBG and the risk of death after adjusting for confounding factors [hazard ratio (HR): 1.22, 95% CI: 1.05−1.41, P = 0.009]. Stratified analyses indicated a stable correlation between bFBG and mortality. The Kaplan-Meier curve analysis revealed significant differences in survival rates among different groups based on bFBG levels (P < 0.01). The curve fitting analysis revealed a U-shaped relationship between bFBG and mortality, with an inflection point at approximately 5.1 mmol/L.ConclusionOur study has demonstrated a non-linear relationship between bFBG and mortality in PD patients. Additionally, we have found that the optimal bFBG value associated with the lowest risk of mortality is approximately 5.1 mmol/L

Peripheral T-cell subsets in radiofrequency ablation for tumors from different origins

Backgrounds: Radiofrequency ablation (RFA) is known to destroy tumoral tissue and activate immune cells. This study aimed to investigate the impact of RFA on peripheral T-cell responses and its relationship with tumor origin and hepatitis status. Methods: A retrospective analysis was conducted on 62 patients with various types of tumors, including hepatocellular carcinoma, colorectal cancer, lung cancer, breast cancer, and others, who underwent RFA treatment between June 2017 and December 2018. Blood samples were collected before and one day after RFA treatment. The peripheral T-cell subsets were measured by flow cytometry, and their changes were analyzed. Results: The study found a decrease in the CD4+CD8-and CD4-CD8+ T-cell subsets after RFA, but no significant changes were observed in the populations of CD4+CD8+ and the CD4+CD8-/CD4-CD8+ ratio. Furthermore, no significant differences were observed in peripheral T-cell subsets concerning tumor type or hepatitis status. Conclusions: The study suggests that RFA treatment may have a short-term impact on peripheral T-cell responses, characterized by a decrease in certain T-cell subsets. However, these changes do not seem to be related to the tumor type or hepatitis status of the patients

Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization

The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer (NSCLC). Constitutively active EGFR mutations, including in-frame deletion in exon 19 and L858R point mutation in exon 21, contribute about 90% of all EGFR-activating mutations in NSCLC. Although oral EGFR-tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic clinical efficacy with significantly prolonged progression-free survival in patients harboring these EGFR-activating mutations, most of these patients will eventually develop acquired resistance. Researchers have recently named genomic instability as one of the hallmarks of cancer. Genomic instability usually involves a transient phase of polyploidization, in particular tetraploidization. Tetraploid cells can undergo asymmetric cell division or chromosome loss, leading to tumor heterogeneity and multidrug resistance. Therefore, identification of signaling pathways involved in tetraploidization is crucial in overcoming drug resistance. In our present study, we found that gefitinib could activate YAP-MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib-resistance cells. Using p38 MAPK inhibitors, SB203580 and losmapimod, we could eliminate gefitinib-induced tetraploidization and overcome gefitinib-resistance. In addition, shRNA approach to knockdown p38α MAPK could prevent tetraploidy formation and showed significant inhibition of cancer cell growth. Finally, in an in vivo study, losmapimod could successfully overcome gefitinib resistance using an in-house established patient-derived xenograft (PDX) mouse model. Overall, these findings suggest that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC

Alectinib as first-line treatment for advanced ALK-positive non-small cell lung cancer in the real-world setting: preliminary analysis in a Chinese cohort

Background: Tyrosine kinase inhibitors (TKIs) have been a major advance in the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) which have been substantiated in clinical trials. However, real-world data on first-line alectinib in a Chinese patient population are limited. Methods: We enrolled patients diagnosed with advanced ALK-positive NSCLC treated with first-line alectinib at 8 centers in China, including cases with symptomatic or active CNS metastases. Continuation of alectinib was permitted after local or gradual progression at the treating clinician's discretion. Time-to-treatment failure (TTF) was defined as the period from the start of alectinib to discontinuation for any cause including disease progression, death, adverse events and patient's preference. We defined longer EML4-ALK variants as containing EML4 fusions to at least exon 13 and shorter variants had EML4 fusions up to exon 6. Results: Of the 110 patients included, 26.4% had Eastern Cooperative Oncology Group Performance Status (ECOG) ≥2 points. The objective response rate (ORR) was 88.5% [95% confidence interval (CI): 79.9-94.3%] and median tumor shrinkage rate was 60% (range, 0-100%) in patients with target lesions. For patients with measurable central nervous system (CNS) metastases, the CNS-ORR was 92.9% (95% CI: 66.1-99.8%), additionally, 80% (8/10) of patients experienced significant improvement in CNS-related symptoms following alectinib treatment. With a median follow-up of 18.3 months, the estimated 2-year progression-free survival (PFS) rate and 2-year treatment failure-free rate were 81.1% (95% CI: 71.5-87.7%) and 81.0% (95% CI: 70.6-88.0%) respectively. Grade 3-4 adverse events occurred in 6.4% and only 2 patients (1.8%) permanently discontinued alectinib due to adverse events. Multivariate analysis indicated that patients with metastases in ≥3 distant organs and a tumor reduction rate ≤50% demonstrated more unfavorable mPFS than their counterparts. Furthermore, patients carrying longer variants showed superior mPFS to those with shorter variants (not reached vs. 24.2 months, hazard ratio =0.17, 95% CI: 0.04-0.68, P=0.004). Conclusions: Alectinib showed substantial efficacy and an excellent safety profile in a real-world setting of Chinese patients. Clinical outcomes and long-term survival still require longer follow-up. Tumors with shorter EML4 fusion variants, more extensive metastases and less reduction in tumor lesions may require more aggressive strategies