Survival outcomes of targeted and immune consolidation therapies in locally advanced unresectable lung adenocarcinoma.

BACKGROUND: Locally advanced non-small cell lung cancer (LA-NSCLC) presents unique challenges due to its progression and tumor heterogeneity. The effectiveness of consolidation therapies, particularly in patients with gene mutations, remains an area of active investigation. METHODS: In this retrospective cohort study, we examined data from 3,454 patients with unresectable lung adenocarcinoma (LUAD), narrowing our focus to 242 individuals with stage II/III. We gathered patient data, such as demographics, ECOG status, histology, treatment specifics, and gene expression, from patients in China. The study's primary outcome was overall survival (OS), while progression-free survival (PFS) served as the secondary outcome. RESULTS: In this study, 50 % of the 242 patients underwent only radical chemoradiotherapy, with 45.87 % (111/242) exhibiting driver gene mutations, predominantly EGFR (58.57 %), followed by KRAS and ALK. Patients with mutations who received either targeted or immune consolidation therapy demonstrated a significantly longer median PFS (42.97 months vs. 24.87 months, p = 0.014) and improved OS (not reached vs. 24.37 months, p = 0.006), compared to those without consolidation therapy. Targeted therapy in mutant patients resulted in an extended median PFS (42.87 months) compared to immune therapy (27.03 months, p = 0.029), with no significant difference in OS. Median PFS and OS were similar between mutant and wild-type patients receiving immune therapy (p = 0.380 and p = 0.928, respectively). CONCLUSION: This study underscores the efficacy of targeted consolidation therapy in enhancing PFS in LUAD patients with genetic mutations. It also shows that immune consolidation therapy provides similar survival benefits to mutant and wild-type patients. Future research should focus on optimizing these therapies for improved patient outcomes.

Primary versus acquired epidermal growth factor receptor Thr790Met mutant non-small cell lung cancer: clinical features and prognoses.

PURPOSE: This study aimed to identify the impact of epidermal growth factor receptor (EGFR) T790M mutations on clinical characteristics and prognosis. METHODS: Retrospective analyses were conducted on the differences on clinicopathological features and prognosis between primary and acquired T790M mutations. Subgroup analyses were performed for primary T790M coexisting with other mutations. RESULTS: Patients with primary T790M mutations showed a 60.53% (23/38) incidence of concurrent L858R mutations, 18.42% (7/38) for 19del mutations and a 21.05% (8/38) occurrence of brain metastases. Conversely, those with acquired T790M mutations demonstrated respective frequencies of 36.53% (61/167), 58.68% (98/167) and 44.31% (74/167), with all comparisons yielding p < 0.05. The median overall survival differed significantly between the two groups, with a duration of 33 months for patients with primary T790M mutations as compared to 48 months for those with acquired mutations (p = 0.030). Notably, among patients with L858R co-mutations, when treated with third-generation EGFR-TKIs, those with acquired T790M mutations experienced a significantly prolonged median time to treatment failure compared to those with primary mutations (17 months vs. 9 months, p = 0.009). CONCLUSION: Patients with primary T790M have unique molecular features and had worse prognosis compared with acquired T790M. Resistance to third-generation EGFR-TKIs seems to be associated with the presence of EGFR co-mutations.

Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

MATTE: a pipeline of transcriptome module alignment for anti-noise phenotype-gene-related analysis.

A phenotype may be associated with multiple genes that interact with each other in the form of a gene module or network. How to identify these relationships is one important aspect of comparative transcriptomics. However, it is still a challenge to align gene modules associated with different phenotypes. Although several studies attempted to address this issue in different aspects, a general framework is still needed. In this study, we introduce Module Alignment of TranscripTomE (MATTE), a novel approach to analyze transcriptomics data and identify differences in a modular manner. MATTE assumes that gene interactions modulate a phenotype and models phenotype differences as gene location changes. Specifically, we first represented genes by a relative differential expression to reduce the influence of noise in omics data. Meanwhile, clustering and aligning are combined to depict gene differences in a modular way robustly. The results show that MATTE outperformed state-of-the-art methods in identifying differentially expressed genes under noise in gene expression. In particular, MATTE could also deal with single-cell ribonucleic acid-seq data to extract the best cell-type marker genes compared to other methods. Additionally, we demonstrate how MATTE supports the discovery of biologically significant genes and modules, and facilitates downstream analyses to gain insight into breast cancer. The source code of MATTE and case analysis are available at https://github.com/zjupgx/MATTE.

Inflammatory biomarkers as predictors of immune activation to different irradiated sites and short-term efficacy in advanced squamous cell esophageal carcinoma received radioimmunotherapy.

Purpose: The present study aimed to compare immune activation among different irradiated sites and identify potential short-term efficacy prognostic factors in patients with advanced squamous cell esophageal carcinoma (ESCC) who received radiotherapy (RT) and immunotherapy. Patients and methods: We recorded the clinical characteristics, blood cell counts, and derived blood index ratios, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), at three time points (before, during, and after RT) in 121 patients with advanced ESCC who had received RT and immunotherapy. Chi-square test and univariate and multivariate logistic regression analyses were used to calculate the relationships among inflammatory biomarkers (IBs), irradiated sites, and short-term efficacy. Results: Delta-IBs were calculated as (medio-IBs - pre-IBs) ÷ pre-IBs. The medians of delta-LMR, and delta-ALC were the highest, whereas the median of delta-SII was the lowest in patients with brain radiation. Treatment responses were observed within 3 months after RT or until the beginning of the next line therapy, and the disease control rate (DCR) was 75.2%. The areas under the receiver operating characteristic curve (AUCs) for delta-NLR and delta-SII were 0.723 (p = 0.001) and 0.725 (p < 0.001), respectively. Multivariate logistic regression analysis showed that the treatment lines of immunotherapy (odds ratio [OR], 4.852; 95% confidence interval [CI], 1.595-14.759; p = 0.005) and delta-SII (OR, 5.252; 95% CI, 1.048-26.320; p = 0.044) were independent indicators of short-term efficacy. Conclusion: In this study, we found that RT to the brain had a stronger immune activation effect than RT to extracranial organs. We also found that earlier-line immunotherapy plus RT and a decrease in SII during RT may generate better short-term efficacy in advanced ESCC.

Proteomic profiling of gastric cancer with peritoneal metastasis identifies a protein signature associated with immune microenvironment and patient outcome.

BACKGROUND: Peritoneal metastasis (PM) frequently occurs in patients with gastric cancer (GC) and is a major cause of mortality. Risk stratification for PM can optimize decision making in GC treatment. METHODS: A total of 25 GC patients (13 with synchronous, 6 with metachronous PM and 6 PM-free) were included in this study. Quantitative proteomics by high-depth tandem mass tags labeling and whole-exome sequencing were conducted in primary GC and PM samples. Proteomic signature and prognostic model were established by machine learning algorithms in PM and PM-free GC, then validated in two external cohorts. Tumor-infiltrating immune cells in GC were analyzed by CIBERSORT. RESULTS: Heterogeneity between paired primary and PM samples was observed at both genomic and proteomic levels. Compared to primary GC, proteome of PM samples was enriched in RNA binding and extracellular exosomes. 641 differently expressed proteins (DEPs) between primary GC of PM group and PM-free group were screened, which were enriched in extracellular exosome and cell adhesion pathways. Subsequently, a ten-protein signature was derived based on DEPs by machine learning. This signature was significantly associated with patient prognosis in internal cohort and two external proteomic datasets of diffuse and mixed type GC. Tumor-infiltrating immune cell analysis showed that the signature was associated with immune microenvironment of GC. CONCLUSIONS: We characterized proteomic features that were informative for PM progression of GC. A protein signature associated with immune microenvironment and patient outcome was derived, and it could guide risk stratification and individualized treatment.

Cardiac Substructures Dosimetric Predictors for Cardiac Toxicity After Definitive Radiotherapy in Esophageal Cancer.

PURPOSE: To investigate the predictive value of the cardiac substructures (CSs) dosimetric parameters for cardiac toxicity after definitive radiation therapy in locally advanced esophageal cancer. METHODS AND MATERIALS: Between August 2010 and January 2016, 716 patients with stage 2-3 esophageal cancer receiving definitive radiation therapy at 2 institutions were divided into training (n = 432) and external validation (n = 284) cohorts. Dose-volume histogram parameters for the whole heart (WH) and CSs were extracted. Competing risks and Cox regressions analyses were performed. The predictive performance of the models was evaluated using the area under the receiver operating characteristic curve (AUC) and the Brier score. RESULTS: With a median follow-up of 93 months, 68 patients (15.7%) developed grade ≥3 cardiac events (G3+ CEs), with a median of 13.5 months to the first event. Multivariable analysis showed left ventricle, left anterior descending (LAD), and mean left circumflex (LCX) variables were significantly associated with G3+ CEs. The AUCs and Brier scores demonstrated favorable predictive accuracies of the models integrating these CS variables when predicting G3+ CEs in the training and validation cohorts. However, compared with the WH variables, the CS variables did not significantly improve the prediction of G3+ CEs. Nevertheless, when G3+ acute coronary syndrome and/or congestive heart failure (ACS/CHF) CE was the outcome of interest, models based on the LAD or LCX variables were superior to the WH variable models in training and validation cohorts. CONCLUSIONS: Models based on CS variables showed favorable predictive accuracy for G3+ CEs. The LAD and LCX variables significantly improved the prediction of G3+ ACS/CHF events compared with the WH variables. Radiation doses to CSs, such as LCX and LAD, should be monitored to help reduce the occurrence of significant CEs in patients with esophageal cancer undergoing definitive radiation therapy.

Predicting Prognosis and Adverse Events by Hematologic Markers in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Treated with Neoadjuvant Chemoradiotherapy.

PURPOSE: Our purpose was to evaluate the association between hematologic markers and mortality and adverse events in patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT). PATIENTS AND METHODS: A total of 311 patients with ESCC treated with nCRT from 2012 to 2014 were enrolled retrospectively. The Kaplan-Meier method with a Log rank test was used to calculate five-year overall survival (OS). Receiver operating characteristic (ROC) curves were plotted to determine the cut-off values for hematologic markers. Multivariate analysis was performed using Cox regression analysis model. Model performance was evaluated by predicted nomogram, concordance index (C-index) and calibration curve. RESULTS: Median follow-up was 22 months. High pretreatment platelet to lymphocyte ratio (PLR, p = 0.047) and systemic immune-inflammation index (SII, p = 0.027) were significantly associated with pathologic complete response (pCR). In multivariate analysis, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, invasion depth, lymph node metastasis, PLR, and SII were independent factors to predict five-year OS. Multivariate analysis showed a lower neutrophil to lymphocyte ratio (NLR) at baseline (p = 0.007) was significantly associated with development of grade ≥3 hematologic toxicity, and none of inflammatory biomarkers could predict grade ≥3 non-hematologic toxicity or radiation pneumonitis (RP). CONCLUSION: SII and PLR were independent indicators to predict prognosis in patients with ESCC treated with nCRT, and a lower NLR at baseline was an independent indicator to predict grade ≥3 hematologic toxicity.

Heart Dosimetric Parameters Were Associated With Cardiac Events and Overall Survival for Patients With Locally Advanced Esophageal Cancer Receiving Definitive Radiotherapy.

Objectives: The aim of this study was to assess the association between heart dosimetric parameters and cardiac events or overall survival (OS) for patients with stage III esophageal cancer receiving definitive radiotherapy. Materials and Methods: Patients with stage III esophageal cancer receiving definitive radiotherapy at our hospital from 2011 to 2013 were enrolled retrospectively. The primary endpoint was grade ≥ 2 cardiac events, and the second endpoint was 5-year OS. Competing risk analysis and Cox regressions analysis were performed to evaluate the association between heart dose and cardiac events or OS. Results: Three hundred forty-six patients were analyzed. Median follow-up was 30 months. Median prescribed dose was 60 Gy. Seventy-eight patients (22.5%) had 91 grade ≥ 2 cardiac events, at a median of 14 months to first event. Thirty-three patients (9.5%) had 42 grade ≥ 3 cardiac events. Of the 78 patients with grade ≥ 2 cardiac events, 70 (89.7%) had the first cardiac events that occurred within first 3 years after radiotherapy. Multivariable analysis showed that preexisting ischemic heart disease [hazard ratio (HR), 2.26; 95% confidence interval (CI), 1.26-4.06; p = 0.006] and mean heart dose (HR, 1.12; 95% CI, 1.04-1.20; p = 0.002) were significantly associated with increased risk of grade ≥ 2 cardiac events. Disease progression (HR, 2.60; 95% CI, 1.82-3.70; p < 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (HR, 0.71; 95% CI, 0.56-0.91; p = 0.007), heart volume receiving ≥ 5 Gy (V5, HR, 1.01; 95% CI, 1.00-1.03; p = 0.035), and gross tumor volume (GTV; HR, 1.00; 95% CI, 1.00-1.00; p = 0.020) were significant predictors of 5-year OS on multivariable analysis. Conclusion: Higher heart dose was significantly associated with an increased cardiac event rate and a worse OS outcome for patients with stage III esophageal cancer treated with definitive radiotherapy. Most of the first cardiac events occurred within first 3 years after treatment.

Left Ventricular Systolic Dysfunction Is a Possible Independent Risk Factor of Radiation Pneumonitis in Locally Advanced Lung Cancer Patients.

Objectives: To assess the association between left ventricular (LV) systolic and diastolic dysfunction and grade ≥2 radiation pneumonitis (RP) for locally advanced lung cancer patients receiving definitive radiotherapy. Materials and Methods: A retrospective analysis was carried out for 260 lung cancer patients treated with definitive radiotherapy between 2015 and 2017. RP was evaluated according to Radiation Therapy Oncology Group (RTOG) toxicity criteria. Logistic regression analysis, 10-fold cross validation, and external validation were performed. The prediction model's discriminative performance was evaluated using the area under the receiver operating characteristic curve (AUC), and calibration of the model was assessed by the Hosmer-Lemeshow test and the calibration curve. Results: Within the first 6 months after radiotherapy, 70 patients (26.9%) developed grade ≥2 RP. Reduced left ventricular ejection fraction (LVEF) before radiotherapy was detected in 53 patients (20.4%). The odds ratio (OR) of developing RP for patients with LVEF <50% was 3.42 [p < 0.001, 95% confidence interval (CI), 1.85-6.32]. Multivariate analysis showed that forced expiratory volume in the first second/forced vital capacity (FEV1/FVC), LVEF, Eastern Cooperative Oncology Group (ECOG) performance status, chemotherapy, and mean lung dose (MLD) were significantly associated with grade ≥2 RP. The AUC of a model including the above five variables was 0.835 (95% CI, 0.778-0.891) on 10-fold cross validation and 0.742 (95% CI, 0.633-0.851) on the external validation set. The p-value for the Hosmer-Lemeshow test was 0.656 on 10-fold cross validation and 0.534 on the external validation set. Conclusion: LV systolic dysfunction is a possible independent risk factor for RP in locally advanced lung cancer patients receiving definitive radiotherapy.