Survival Of Non-small Cell Lung Cancer Patients Research Articles

Immunotherapy and Radiotherapy for Older Patients with Locally Advanced Non-Metastatic Non-Small-Cell Lung Cancer Who Are Not Candidates for or Decline Surgery and Chemotherapy: A Practical Proposal by the International Geriatric Radiotherapy Group.

The standard of care for locally advanced non-small-cell lung cancer (NSCLC) is either surgery combined with chemotherapy pre- or postoperatively or concurrent chemotherapy and radiotherapy. However, older and frail patients may not be candidates for surgery and chemotherapy due to the high mortality risk and are frequently referred to radiotherapy alone, which is better tolerated but carries a high risk of disease recurrence. Recently, immunotherapy with immune checkpoint inhibitors (ICIs) may induce a high response rate among cancer patients with positive programmed death ligand 1 (PD-L1) expression. Immunotherapy is also well tolerated among older patients. Laboratory and clinical studies have reported synergy between radiotherapy and ICI. The combination of ICI and radiotherapy may improve local control and survival for NSCLC patients who are not candidates for surgery and chemotherapy or decline these two modalities. The International Geriatric Radiotherapy Group proposes a protocol combining radiotherapy and immunotherapy based on the presence or absence of PD-L1 to optimize the survival of those patients.

Triple therapy boosts survival in NSCLC patients with brain metastases: a retrospective cohort study of chemotherapy, ICIs, and antiangiogenic agents

BackgroundTreatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood–brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival.MethodsIn this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher’s exact test, and survival curves were estimated with the Kaplan–Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk.ResultsFrom an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43–0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18–0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683).ConclusionOur study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population.

Survival prognostic factors in nonsmall cell lung cancer patients with simultaneous brain metastases and poor performance status at initial presentation

PurposeAlthough the treatment of nonsmall cell lung cancer (NSCLC) has rapidly progressed recently, there is little evidence of treatment for patients with symptomatic brain metastases (BM) and poor performance status (PS). However, in symptomatic BM patients, appropriate upfront intracranial treatment can often lead to rapid improvement in PS and effective systemic therapy. Thus, this study investigated the prognostic factors for the survival of poor PS NSCLC patients with synchronous BM. MethodsData of patients with BM and Karnofsky PS (KPS) ≤70 at the first diagnosis of NSCLC who were treated in our hospital between January 2017 and December 2021 were reviewed. Patient survival was compared among patients stratified by type of first-line regimen of systemic treatment. Correlations between patient characteristics and survival were examined. ResultsFifty patients receiving aggressive treatment were enrolled. The median survival times for tyrosine kinase inhibitor (TKI), immune checkpoint inhibitor (ICI), and chemotherapy alone groups were 19 (95% confidence interval [CI], 2.8–68.5), 19 (3.0–62.0), and 13 (1.2–24.8) months, respectively. Survival in the TKI and ICI groups was significantly longer than in the chemotherapy alone group (p = 0.046, TKI vs. chemo; p = 0.022, ICI vs. chemo; p = 0.023). Both sex and type of systemic treatment correlated to survival time on univariate analysis. Chemotherapy alone for systemic treatment [p = 0.034; hazard ratio (HR), 0.44 (0.20–0.94)] remained significant for predicting overall survival in the multivariate analysis. ConclusionEven in patients with poor PS and BM at the initial diagnosis of NSCLC, the ICI group had a survival time comparable to that of the TKI group when combined with tailor-made intracranial treatment. There is a subgroup in the patient population that was previously considered unsuitable for ICI, whose PS improves with individualized intracranial treatment, and who may benefit from immunotherapy.

RILPL2 as a potential biomarker for predicting enhanced Tcell infiltration in non-small cell lung cancer.

Our previous bioinformatics analysis has revealed that Rab-interacting lysosomal protein-like 2 (RILPL2) is associated with tumor immune microenvironment in non-small cell lung cancer (NSCLC). In our study, we collected 140 patients with primary NSCLC to verify the RILPL2 expression and its prognostic value, the relationship between RILPL2 expression and CD4+, CD8+T cell infiltration. A total of 140 patients who had been diagnosed with primary NSCLC (including 66 lung adenocarcinomas and 74 lung squamous cell carcinomas) were enrolled in our study. Immunohistochemical (IHC) staining was performed to analyze the expression of RILPL2, CD4, and CD8 in these patients. Compared with peri-cancer tissues, the RILPL2 expression in NSCLC tissues was significantly lower (P < 0.0001). RILPL2 expression was significantly related to clinical stage (P = 0.019), and low RILPL2 expression indicated higher stage. Low RILPL2 expression predicted worse overall survival (OS) in NSCLC patients (P = 0.017). Correlational analyses revealed that RILPL2 expression was significantly positively correlated with CD4+T cell infiltration in NSCLC (R = 0.294, P < 0.001), LUAD subgroup (R = 0.256, P = 0.038), and LUSC subgroup (R = 0.333, P = 0.004); RILPL2 expression was also significantly positively correlated with CD8+ T cell infiltration in NSCLC (R = 0.263, P = 0.002), LUAD subgroup (R = 0.280, P = 0.023), and LUSC subgroup (R = 0.250, P = 0.031).In conclusion, RILPL2 expression was downregulated in NSCLC; low RILPL2 expression was significantly related to higher stage and worse prognosis; RILPL2 expression was significantly positively correlated with CD4+, CD8+T cell infiltration.

Effect of SBRT plus immunotherapy on immune status and survival quality of NSCLC patients: A study of combined radiotherapy and immunotherapy.

non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer populations. Stereotactic radiotherapy (SBRT) is mainly suitable for early NSCLC patients who are not suitable for surgery or refuse surgery. To analyze the effects of stereotactic radiotherapy (SBRT) plus immunotherapy for non-small cell lung cancer (NSCLC) patients on their immune status and survival quality. NSCLC patients admitted to our hospital from 2019-2022 were divided into 61 cases in control group (SBRT) and 60 cases in observation group (SBRT plus immunotherapy) by the randomized numerical table method to compare the efficacy, the level of tumor markers in the serum, the level and activity of the immune cells in the peripheral blood and the Kahlil's functional status (KPS) scores. The observation group had a higher efficacy rate than that of the control group (P< 0.05). There was no statistical difference between the two groups in serum tumor marker content, immune cell level and activity in peripheral blood and KPS score before treatment (P> 0.05). After treatment, serum tumor markers were lower than those in control group, and immune cell level, NK cell-related activity and KPS score were higher than those in control group (P< 0.05). SBRT plus immunotherapy can reduce the level of various tumor markers, improve the immune status and quality of survival for NSCLC patients.

Physical performance and plasma metabolic profile as potential prognostic factors in metastatic lung cancer patients.

Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non-small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells. This prospective cohort study included 55 metastatic NSCLC patients and seven age-matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis. We observed a higher survival rate in NSCLC patients with high performance in the timed up-and-go (+320%; p = .007), sit-to-stand (+256%; p = .01) and six-minute walking (+323%; p = .002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p > .05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (-54.2%; p < .0001) and cell proliferation (-44.9%; p = .007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance. These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.

No survival benefit of primary tumor resection for non-small cell lung cancer patients with unexpectedly detected pleural disseminated nodules in the era of targeted therapy.

Non-small cell lung cancer (NSCLC) patients with pleural dissemination are generally contraindicated for surgery. This study aimed to investigate the survival benefits of primary tumor resection for NSCLC patients with unexpectedly detected pleural disseminated nodules during thoracotomy in the era of targeted therapy. Of the 4984 patients with NSCLC who underwent surgery without induction therapy between 2000 and 2021, we retrospectively evaluated 90 (1.8%) patients with unexpectedly detected pleural disseminated nodule. Survival analyses were performed with Kaplan-Meier methods and Cox proportional hazards regression. Among the evaluated patients, 58 were male, the median age was 67, and 77 (86%) were diagnosed with adenocarcinoma. Exploratory thoracotomy was performed in 21 (23%), and primary tumor resection was performed in 69 (77%) patients, including pneumonectomy in four, lobectomy in 39, and sublobar resection in 26. Epidermal growth factor receptor gene mutation and anaplastic lymphoma kinase rearrangement were detected in 33 (37%) and 4 (4%) cases, respectively. Among them, 31 patients received targeted therapy. The overall survival (OS) was not significantly different between patients with primary tumor resection and exploratory thoracotomy (5-year OS rate: 30.2% vs. 27.8%, p = 0.81). Multivariable analysis revealed that sex (p = 0.02) and targeted therapy (p < 0.01) were independent prognostic factors for OS. Survival outcomes in patients who received targeted therapy were significantly better regardless of primary tumor resection. Primary tumor resection might not affect the survival in NSCLC patients with unexpectedly detected pleural disseminated nodules in the era of targeted therapy.

18F-Fluorodeoxyglucose Positron Emission Tomography-Based Risk Score Model for Prediction of Five-Year Survival Outcome after Curative Resection of Non-Small-Cell Lung Cancer.

The aim of our retrospective study is to develop and assess an imaging-based model utilizing 18F-FDG PET parameters for predicting the five-year survival in non-small-cell lung cancer (NSCLC) patients after curative surgery. A total of 361 NSCLC patients who underwent curative surgery were assigned to the training set (n = 253) and the test set (n = 108). The LASSO regression model was used to construct a PET-based risk score for predicting five-year survival. A hybrid model that combined the PET-based risk score and clinical variables was developed using multivariate logistic regression analysis. The predictive performance was determined by the area under the curve (AUC). The individual features with the best predictive performances were co-occurrence_contrast (AUC = 0.675) and SUL peak (AUC = 0.671). The PET-based risk score was identified as an independent predictor after adjusting for clinical variables (OR 5.231, 95% CI 1.987-6.932; p = 0.009). The hybrid model, which integrated clinical variables, significantly outperformed the PET-based risk score alone in predictive accuracy (AUC = 0.771 vs. 0.696, p = 0.022), a finding that was consistent in the test set. The PET-based risk score, especially when integrated with clinical variables, demonstrates good predictive ability for five-year survival in NSCLC patients following curative surgery.

Effect of &lt;i&gt;VEGF&lt;/i&gt; gene polymorphism on the survival of a patient with non-small cell lung cancer

Currently, much attention is paid to studying the vascular endothelial growth factor (VEGF) that stimulates angiogenesis, as a potential target for antiangiogenic therapy. The purpose of this work was to study the effect of polymorphic variants rs2010963 (G-634C), rs699947 (A-2578C), and rs3025039 (C+936T) of the VEGF gene, encoding a vascular endothelial growth factor, on the overall (OS) and adjusted survival (AS) of patients with non-small cell lung cancer (NSCLC) at stages I–III. The effect of VEGF rs699947 polymorphic variants on the extent of tumor spread was shown. A connection between AS and polymorphic variants rs2010963 (G-634C) and rs699947 (A-2578C) was established. The one-year adjusted survival (AS) in the -634G/C genotype carriers was 81.9 ± 3.9 %; in the -634G/G genotype carriers – 92.8 ± 2.5 %; and p = 0.016 was the significance level. Two-year AS was as follows: in the carriers of the -634G/C genotype was 70.4 ± 4.6 %; in the carriers of the -634G/G genotype – 84.3 ± 3.5 %; and p = 0.015. Three-year AS: in the carriers of the -634G/ genotype C was 63.0 ± 4.9 %; in the carriers of the -634G/G genotype – 76.7 ± 4.1 %; and p = 0.029. One-year and two-year AS in the carriers of the -2578A/A genotype was significantly higher than in the carriers of the -2578C/C genotype (p = 0.015 and p = 0.042 respectively). The identified influence of the polymorphic variants rs2010963 and rs699947 on the survival of NSCLC patients during the first three years after the established diagnosis shows a need to use knowledge about the genetic characteristics of a tumor during therapy.

The Effect of PET/CT-Derived Parameters on the Prediction of Survival in Lung Cancer Patients

Background: The ability to predict the survival of patients with non-small cell lung cancer (NSCLC) can provide a basis for individualized treatment and follow-up. Determination of positron emission tomography/computed tomography (PET/CT) parameters, i.e., maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), may improve predictions of survival for NSCLC patients. Objectives: To determine the relationship between the PET/CT-derived parameters SUVmax, SUVmean, MTV, and TLG and survival in NSCLC patients. Patients and Methods: Patients with NSCLC diagnosed at our clinic between January 2019 and October 2020 were evaluated retrospectively using data obtained from the electronic database. The study population consisted of 132 patients over 18 years of age who had a PET/CT scan before receiving any treatment for NSCLC. During their initial PET/CT evaluation, SUVmax, SUVmean, MTV, and TLG were calculated. Correlations between the variables were analyzed using Spearman’s correlation test, and the associations of the variables with patient survival were determined using the Cox proportional hazards regression model. Results: The overall 2-year survival rate of the patients was 36.6%. In the univariate analysis, MTV and TLG, but not SUVmax or SUVmean, were significantly associated with survival (P = 0.8, P = 0.003, and P = 0.045, respectively). In the multivariate analysis, MTV was related to a higher risk of death in patients with adenocarcinoma, lymph node involvement, or distant metastasis. By contrast, TLG was associated with a lower risk of death in patients with adenocarcinoma (ACA) or distant metastasis. Conclusion: Among the parameters obtained in PET/CT studies, SUVmax and SUVmean were not related to the survival of patients with NSCLC. However, MTV was associated with a higher risk of death, while TLG was associated with a lower risk of death in patients with adenocarcinoma or distant metastasis. Further studies with larger samples are needed to validate these results.

Circ_0060060 Accelerates Metastasis of Non-Small-Cell Lung Carcinoma by Upregulating FUT8

We aimed to elucidate the diagnostic and prognostic values of Circ_0060060 in non-small-cell lung cancer (NSCLC), and its regulatory effect on FUT8. Relative levels of Circ_0060060 and FUT8 were examined in NSCLC and adjacent tissues. Clinical information of recruited NSCLC patients was collected for assessing the prognostic value of Circ_0060060. Regulatory effects of Circ_0060060 and FUT8 on in vitro proliferative and migratory abilities of NSCLC were examined by cell counting kit-8 (CCK-8) and transwell assay, respectively. Finally, the interaction between Circ_0060060 and FUT8 was determined via dual-luciferase reporter assay and Pearson correlation test. Circ_0060060 and FUT8 were upregulated in NSCLC tissues. High level of Circ_0060060 or FUT8 predicted higher incidences of distant metastasis and worse overall survival in NSCLC patients. in vitro evidences have shown the roles of Circ_0060060 and FUT8 in stimulating proliferative and migratory abilities of PC-9 and SPC-A1 cells. Circ_0060060 directly targeted FUT8 and positively regulated its level. Circ_0060060 and FUT8 are effective diagnostic markers of NSCLC. Circ_0060060 stimulates proliferative and migratory abilities of NSCLC by regulating FUT8.

Racial disparities in the immunotherapeutic outcomes of patients with non-small cell lung cancer (NSCLC): An in-depth systematic review and meta-analysis.

1579 Background: The utilization of immunotherapy has become prevalent in the therapeutic approach to non-small cell lung cancer (NSCLC), owing to its association with enhanced survival outcomes. Nevertheless, a notable gap exists in the available information regarding potential variations in the survival benefits of immunotherapy based on the racial demographics of NSCLC patients. Methods: A systematic search for articles published until January 2023 was performed on PubMed, EMBASE, and Google Scholar databases. Articles that aligned with the research objective were included, while non-English articles, case reports, conference abstracts, studies combining immunotherapy with other cancer therapies, and studies on small-cell lung cancer were excluded. Data required for review and analysis was independently abstracted into separate Excel files by two reviewers. Furthermore, Statistical analyses were performed using the Review Manager software, and the methodological quality evaluation was done using the Newcastle Ottawa Scale. Results: Seven cohort studies were used for review and analysis. A subgroup analysis of data from these studies showed that Black/African American and Asian NSCLC patients receiving immunotherapy had improved overall survival (OS) than White patients (HR: 0.84; 95% CI: 0.75 – 0.95; p = 0.006 and HR: 0.53; 95% CI: 0.30 – 0.93; p = 0.03, respectively). However, the difference in OS is statistically insignificant when Hispanic patients are compared with white patients (HR: 0.68; 95% CI: 0.46 – 1.00; p = 0.05). On the other hand, the subgroup analyses did not demonstrate any significant difference in progression-free survival (PFS) when comparing Black/African American, Asian or Hispanic patients to White patients (HR: 0.93; 95% CI: 0.79 – 1.09; p = 0.35, HR: 0.89; 95% CI: 0.51 – 1.55; p = 0.69, and HR: 1.01; 95% CI: 0.82 – 1.23; p = 0.96, respectively). Conclusions: Among non-small cell lung cancer (NSCLC) patients undergoing immunotherapeutic interventions, it is discerned that Black/African American and Asian individuals exhibit superior overall survival (OS) outcomes compared to their White counterparts. However, it is noteworthy that the observed racial disparity does not appear to exert a discernible influence on the progression-free survival (PFS) of NSCLC patients subjected to immunotherapy.

Different genetic profiles contribute to worse overall survival in patients with leptomeningeal metastases of non-small-cell lung cancer.

To assess the genetic characteristics of central nervous system (CNS) metastases from non-small-cell lung cancer (NSCLC), we gathered the genetic profiles of brain metastases (BM) and leptomeningeal metastases (LM). Our objective was to identify genetic factors contributing to poorer overall survival (OS) in NSCLC patients with LM. This study included 25 consecutive patients with BM and 52 patients with LM from Guangdong Sanjiu Brain Hospital. All participants underwent 168-target panel sequencing. Among the 25 patients with BM, TP53 was the most frequently mutated gene (44%), followed by driver genes such as EGFR and BRAF (40% and 20%, respectively). In patients with BM, EGFR_amp and CDK4 were also frequently mutated, with rates of 20% and 16%, respectively. The genetic landscape of patients with LM differed, with the top mutated genes being EGFR, TP53, EGFR_amp, CDKN2A, CCNE1, CDK4, PMS2, and PIK3CA, with mutation rates of 77%, 69%, 31%, 29%, 13%, 13%, 13%, and 12%, respectively. In our study, patients with LM exhibited significantly worse OS compared to those with BM (p = 0.029). The mutation rates of TP53, EGFR_amp, and CDKN2A varied between patients with LM and those with BM, at 69.23% vs. 44%, 30.77% vs. 20%, and 28.85% vs. 12%, respectively. Further exploration revealed that patients with BM with TP53 mutations had a shorter OS than patients without TP53 mutations (p = 0.014). Similarly, patients with LM and TP53 mutations presented with worse OS than those without TP53 mutations (p = 0.0067). LM patients with CDKN2A deletions had worse OS than those without CDKN2A deletions (p = 0.037). Additionally, patients with EGFR_amp had a shorter OS than those without EGFR_amp (p = 0.044). Patients with LM exhibited significantly worse OS than those with BM. Gene signatures, such as TP53, EGFR_amp, and CDKN2A, may account for shorter outcomes in patients with LM.

Prognostic factors and predictive model construction in patients with non-small cell lung cancer: a retrospective study

ObjectiveThe purpose of this study was to construct a nomogram model based on the general characteristics, histological features, pathological and immunohistochemical results, and inflammatory and nutritional indicators of patients so as to effectively predict the overall survival (OS) and progression-free survival (PFS) of patients with non-small cell lung cancer (NSCLC) after surgery.MethodsPatients with NSCLC who received surgical treatment in our hospital from January 2017 to June 2021 were selected as the study subjects. The predictors of OS and PFS were evaluated by univariate and multivariable Cox regression analysis using the Cox proportional risk model. Based on the results of multi-factor Cox proportional risk regression analysis, a nomogram model was established using the R survival package. The bootstrap method (repeated sampling for 1 000 times) was used to internally verify the nomogram model, and C-index was used to represent the prediction performance of the nomogram model. The calibration graph method was used to visually represent its prediction compliance, and decision curve analysis (DCA) was used to evaluate the application value of the model.ResultsUnivariate and multivariate analyses were used to identify independent prognostic factors and to construct a nomogram of postoperative survival and disease progression in operable NSCLC patients, with C-index values of 0.927 (907–0.947) and 0.944 (0.922–0.966), respectively. The results showed that the model had high predictive performance. Calibration curves for 1-year, 2-year, and 3-year OS and PFS show a high degree of agreement between the predicted probability and the actual observed probability. In addition, the results of the DCA curve show that the model has good clinical application value.ConclusionWe established a predictive model of survival prognosis and disease progression in patients with non-small cell lung cancer after surgery, which has good predictive performance and can guide clinicians to make the best clinical decision.

Chemosensitizing effect of pentoxifylline in sensitive and multidrug-resistant non-small cell lung cancer cells.

Aim: Multidrug resistance (MDR) is frequent in non-small cell lung cancer (NSCLC) patients, which can be due to its fibrotic stroma. This work explores the combination of pentoxifylline, an anti-fibrotic and chitinase 3-like-1 (CHI3L1) inhibitor drug, with conventional chemotherapy to improve NSCLC treatment. Methods: The effect of pentoxifylline in the expression levels of P-glycoprotein (P-gp), CHI3L1 and its main downstream proteins, as well as on cell death, cell cycle profile, and P-gp activity was studied in two pairs of sensitive and MDR counterpart NSCLC cell lines (NCI-H460/NCI-H460/R and A549/A549-CDR2). Association studies between CHI3L1 gene expression and NSCLC patients' survival were performed using The Cancer Genome Atlas (TCGA) analysis. The sensitizing effect of pentoxifylline to different drug regimens was evaluated in both sensitive and MDR NSCLC cell lines. The cytotoxicity of the drug combinations was assessed in MCF10A non-tumorigenic cells. Results: Pentoxifylline slightly decreased the expression levels of CHI3L1, β-catenin and signal transducer and activator of transcription 3 (STAT3), and caused a significant increase in the G1 phase of the cell cycle in both pairs of NSCLC cell lines. A significant increase in the % of cell death was observed in the sensitive NCI-H460 cell line. TCGA analysis revealed that high levels of CHI3L1 are associated with low overall survival (OS) in NSCLC patients treated with vinorelbine. Moreover, pentoxifylline sensitized both pairs of sensitive and MDR NSCLC cell lines to the different drug regimens, without causing significant toxicity to non-tumorigenic cells. Conclusion: This study suggests the possibility of combining pentoxifylline with chemotherapy to increase NSCLC therapeutic response, even in cases of MDR.

Dysregulation of peripheral and intratumoral KLRG1+ CD8+T cells is associated with immune evasion in patients with non-small-cell lung cancer

ObjectivesKiller cell lectin like receptor G1 (KLRG1) is identified as a co-inhibitory receptor for NK cells and antigen-experienced T cells. The role of KLRG1 in immune regulation in patients with non-small cell lung cancer (NSCLC) remains poorly understood. Materials and MethodsWe measured the proportion and immune function of KLRG1+CD8+T cells derived from peripheral blood in patients with NSCLC by flow cytometry. Besides, using data from the gene expression profiles and single-cell sequencing, we explored the expression and immune role of KLRG1 in tumor tissues of patients with NSCLC. We further determined the prognostic value of KLRG1 in terms of overall survival (OS) in NSCLC patients. ResultsWe found that the proportion of KLRG1+CD8+T cells in peripheral blood significantly increased in patients with NSCLC as compared to those with benign pulmonary nodules and healthy donors. Peripheral KLRG1+CD8+T cell proportion was increased in elder subjects compared to that in younger ones, implying an immunosenescence phenotype. Moreover, the KLRG1+CD8+T cell levels were positively correlated with tumor size and TNM stage in the NSCLC cohort. In vitro stimulation experiments demonstrated that the KLRG1+CD8+T cells from peripheral blood expressed higher levels of Granzyme B and perforin than the KLRG1−CD8+ T cells. However, single-cell RNA sequencing data revealed that the KLRG1+CD8+ T cells were less infiltrated in tumor microenvironment and exhibited impaired cytotoxicity. The KLRG1 gene expression levels were significantly lower in tumor tissues than that in normal lung tissues, and were inversely correlated with CDH1 expression levels. Moreover, higher expression of CDH1 in tumor tissues predicted worse overall survival only in patients with KLRG1-high expression, but not in the KLRG1-low subset. ConclusionThis study demonstrates that KLRG1+CD8+T cells were associated with tumor immune evasion in NSCLC and suggests KLRG1 as a potential immunotherapy target.

Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia

ObjectivesIn this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes. Materials and methodsThe efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial. ResultsOf the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35–3.46]; ICIs vs docetaxel, 1.49 [1.21–1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07–0.64]). ConclusionsAfter platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

Immunotherapy combined with cranial radiotherapy for driver-negative non-small-cell lung cancer brain metastases: a retrospective study.

Background: This study assesses immune checkpoint inhibitors' efficacy for non-small-cell lung cancer (NSCLC) with brain metastases (BM) and explores the role of cranial radiation therapy (CRT) in the immunotherapy era. Methods: The retrospective analysis screened NSCLC patients with BMs from July 2018 to December 2021. Treatment involved chemotherapy combined with immune checkpoint inhibitors as the first-line, with patients divided into CRT and non-CRT groups. Overall survival (OS), progression-free survival and intracranial progression-free survival were calculated and compared. Results: Among 113 patients, 74 who received CRT had significantly better median OS (not reached vs 15.31months), particularly among those with one to three BMs. Factors correlating with better OS included CRT, PD-L1 expression and diagnosis-specific graded prognostic assessment scores. Conclusion: Integrating CRT with anti-PD-1 therapy notably enhanced long-term survival in NSCLC patients with BMs.

CD146 Promotes EMT-Mediated Migration and Invasion of NSCLC via PI3K/Akt Signaling Pathway.

Recurrence and metastasis are the main causes of non-small cell lung cancer (NSCLC)-related death. CD146 has been identified as a potential risk factor for poor prognosis, closely related to the distant metastasis and drug resistance in various cancers. However, the clinical significance of CD146 in NSCLC requires further investigation. This study explored the correlation between CD146 expression and clinical variables using tumor tissue samples collected from our hospital. CD146 expression levels in NSCLC cell lines and tissues were assessed and compared using immunohistochemistry, real-time polymerase chain reaction (RT-qPCR), flow cytometry, and western blot analysis. The invasion and migration capabilities of tumor cells were determined using transwell and wound healing assays. The levels of proteins related to epithelial-mesenchymal transition (EMT) as well as the underlying PI3K/Akt signaling pathway was measured by western blotting. We discovered that CD146 expression is significantly associated with the EMT signaling pathway. High CD146 expression predicted lymph node metastasis, metastasis to distant organs, advanced Tumor, Node, Metastasis (TNM) staging, and poor survival in NSCLC patients. Wound healing and transwell assays showed that knocking down CD146 significantly suppressed cell migration along with cell invasion in NSCLC, whereas overexpressing CD146 notably enhanced these processes. Western blot analysis revealed significantly reduced levels of N-cadherin, vimentin, snail, twist, PI3K, and AKT phosphorylation in shCD146 H460 cells compared to vector control cells. Treatment with PI3K inhibitor PI3K-IN-1 increased E-cadherin expression levels but reduced N-cadherin, Twist, Vimentin, PI3K, and AKT phosphorylation levels in pcDNA3.1-CD146 A549 cells compared with the vector control cells. CD146 expression acts as a prognostic risk factor for adverse outcomes in NSCLC, promoting invasion and metastasis by activating the EMT through the PI3K/Akt signaling pathway. These findings underscore the potential therapeutic strategies targeting CD146, offering new treatment options for NSCLC patients, especially those at risk of metastasis.

CD137+ and regulatory T cells as independent prognostic factors of survival in advanced non-oncogene addicted NSCLC patients treated with immunotherapy as first-line

BackgroundImmune checkpoint inhibitors (ICIs), administered alone or combined with chemotherapy, are the standard of care in advanced non-oncogene addicted Non-Small Cell Lung Cancer (NSCLC). Despite these treatments' success, most long-term survival benefit is restricted to approximately 20% of patients, highlighting the need to identify novel biomarkers to optimize treatment strategies. In several solid tumors, immune soluble factors, the activatory CD137+ Tcells, and the immunosuppressive cell subsets Tregs and MDSCs (PMN(Lox1+)-MDSC and M-MDSCs) correlated with responses to ICIs and clinical outcomes thus becoming appealing predictive and prognostic factors. This study investigated the role of distinct CD137+ Tcell subsets, Tregs, MDSCs, and immune-soluble factors in NSCLC patients as possible biomarkers.MethodsThe levels of T cells, MDSCs and soluble factors were evaluated in 89 metastatic NSCLC patients who underwent ICIs as first- or second-line treatment. T cell analysis was performed by cytoflurimetry evaluating Tregs and different CD137+ Tcell subsets also combined with CD3+, CD8+, PD1+, and Ki67+ markers. Circulating cytokines and immune checkpoints were also evaluated by Luminex analysis. All these parameters were correlated with several clinical factors (age, sex, smoking status, PS and TPS), response to therapy, PFS , and OS . The analyses were conducted in the overall population and in patients treated with ICIs as first-line (naïve patients).ResultsIn both groups of patients, high levels of circulating CD137+ and CD137+PD1+ T cells (total, CD4 and CD8) and the soluble factor LAG3 positively correlated with response to therapy. In naïve patients, PMN(Lox1+)-MDSCs negatively correlated with clinical response, and a high percentage of Tregs was associated with favorable survival. Moreover, the balance between Treg/CD137+ Tcells or PMN(Lox1+)-MDSC/CD137+ Tcells was higher in non-responding patients and was associated with poor survival. CD137+ Tcells and Tregs resulted as two positive independent prognostic factors.ConclusionHigh levels of CD137+, CD137+PD1+ Tcells and sLAG3 could predict the response to ICIs in NSCLC patients independently by previous therapy. Combining the evaluation of CD137+ Tcells and Tregs also as Treg/CD137+ T cells ratio it is possible to identify naive patients with longer survival.