RESUMO
Background: Lung cancer is the leading cause of cancer-related death, and non-small-cell lung cancer (NSCLC) is the predominant subtype. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are widely used to treat stage IV NSCLC. This study systematically reviewed the literature to clarify the impact of PD-1/PD-L1 inhibitor treatment on the survival of patients with stage III NSCLC. Methods: Randomized phase III clinical trials of PD-1/PD-L1 inhibitors administered to patients with stage III NSCLC that were written in English and published between November 2012 and November 2022 were eligible for review. The sources of information were the MEDLINE database (last consulted on December 26, 2022), ScienceDirect website (last consulted on December 26, 2022), and CENTRAL register (last consulted on December 27, 2022). The outcomes of interest were overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and event-free survival (EFS). Risk of bias assessments were performed according to the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The findings have been assessed for certainty according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines. Results: Fourteen eligible studies and 2788 participants were included in the review. The key characteristics used to group the participants were disease histology, percentage of PD-L1 expression in cancer cells, and timeline of therapy. OS and PFS were improved (risk ratio [RR]: 0.85; 95% confidence interval [CI]: 0.75-0.96 and RR: 0.75; 95% CI: 0.70-0.86, respectively) based on the use of PD-L1 inhibitors after chemoradiation and OS was improved using first-line PD-1 inhibitors plus chemotherapy in non-squamous NSCLC (RR: 0.40; 95% CI: 0.17-0.95), with the GRADE results indicating moderate quality of evidence. Conclusion: This review highlights the OS and PFS benefits of PD-L1 inhibitors in stage III NSCLC when used after chemoradiation and OS benefits of first-line PD-1 inhibitors added to chemotherapy in non-squamous stage III disease.
RESUMO
BACKGROUND: Primary Sjogren's syndrome (SS) is an autoimmune disease with a strong predilection for lymphoma development, with earlier disease onset being postulated as an independent risk factor for this complication. Variations of the Leukocyte immunoglobulin-like receptor A3(LILRA3) gene have been previously shown to increase susceptibility for both SS and non-Hodgkin B-cell lymphoma (B-NHL) in the general population. We aimed to investigate whether variations of the LILRA3 gene could predispose for lymphoma development in the context of SS. METHODS: Study population, all of Greek origin, included 101 SS cases with a current or previous diagnosis of lymphoma (SS-lymphoma, SS-L) and 301 primary SS patients not complicated by lymphoma (SS-non-lymphoma, SS-nL). All SS patients fulfilled the 2016 SS American College of Rheumatology/European league against Rheumatism (ACR/EULAR) classification criteria. A total of 381 healthy controls (HC) of similar age/sex/race distribution were also included. On the basis of the age of SS onset and the presence or absence of adverse predictors for lymphoma development, SS patients were further stratified into younger (≤40 years) and older (>40 years) age of disease onset, as well as into high/medium and low risk groups. Polymerase chain reaction (PCR) was implemented for the detection of the following LILRA3 gene variants: homozygous non-deleted or functional wild type (+/+) heterozygous (+/-) and homozygous deleted (-/-). LILRA3 serum protein levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 85 individuals (29 SS-L, 35 SS-nL patients and 21 HC). RESULTS: While no statistically significant differences were detected in the overall frequency of LILRA3 gene variants between SS-L, SS-nL and HC groups, LILRA3 serum protein levels were increased in the SS-L group compared to HC (1.27 ± 1.34 vs. 0.38 ± 0.34 ng/mL, p-value: 0.004). After stratification according to the age of SS onset and history of lymphoma, as well as the presence or absence of adverse predictors for lymphoma development, the prevalence of the functional LILRA3 gene variant was found to be significantly increased in the young onset SS-L group compared to the HC of similar age and sex distribution (100% vs. 82.9%, p = 0.03), as well as in the high/medium risk SS compared to the low risk SS (91.3 vs. 78.3%, p = 0.0012). Of note, young onset SS-L and SS-nL groups displayed higher LILRA3 serum levels compared to their older counterparts (p-values: 0.007 and 0.0005, respectively). CONCLUSION: The functional LILRA3 gene variant increases susceptibility to SS-related lymphoma development in patients with a disease onset of <40 years old, implying that genetically determined deranged immune responses in younger SS individuals could underly their pronounced risk for lymphoma development.