The efficacy of postoperative radiotherapy in resected pâ ¢A-N2 EGFR mutant and wild-type lung adenocarcinoma.

The resected pⅢA-N2 non-small-cell lung cancer (NSCLC) patients who could benefit from postoperative radiotherapy (PORT) are not well-defined. The study explored the role of PORT on EGFR mutant and wild-type NSCLC patients. We retrospectively searched for resected pIIIA-N2 lung adenocarcinoma patients who underwent EGFR mutation testing. 80 patients with EGFR wild-type and 85 patients with EGFR mutation were included. 62 patients received PORT. In overall population, the median disease-free survival (DFS) was improved in PORT arm compared to non-PORT arm (22.9 vs. 16.1 months; p = 0.036), along with higher 2-year locoregional recurrence-free survival (LRFS) rate (88.3% vs. 69.3%; p = 0.004). In EGFR wild-type patients, PORT was associated with a longer median DFS (23.3 vs. 17.2 months; p = 0.044), and a higher 2-year LRFS rate (86.8% vs. 61.9%; p = 0.012). In EGFR mutant patients, PORT was not significantly correlated with improved survival outcomes. EGFR wild-type may a biomarker to identify the cohort that benefits from PORT.

Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial.

Importance: For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective: To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Interventions: Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Results: Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Conclusions: Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

Increased coexpression of PD-L1 and IDO1 is associated with poor overall survival in patients with NK/T-cell lymphoma.

Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma.

Case report: Pathological complete response induced by immunochemotherapy in a case of Pulmonary Sarcomatoid Carcinoma staged IIIA-N2.

Pulmonary sarcomatoid carcinoma (PSC) represents a rare and highly aggressive variant of lung cancer, characterized by its recalcitrance to conventional therapeutic modalities and the attendant dismal prognosis it confers. Recent breakthroughs in immunotherapy have presented novel prospects for PSC patients; nevertheless, the utility of neoadjuvant/conversional immunotherapy in the context of PSC remains ambiguous. In this report, we present a middle-aged male presenting with Stage III PSC, notable for its high expression of the programmed death-ligand 1 (PD-L1), initially deemed as non-resectable for sizeable tumor mass and multiple lymph nodes metastases. The patient underwent a transformation to a resectable state after a regimen of three cycles of platinum-based chemotherapy plus immunotherapy. Following definitive surgical resection, the individual realized a pathological complete response (pCR), culminating in a significant prolongation of event-free survival (EFS). This case underscores the viability of employing immunochemotherapy as a neoadjuvant/conversional strategy for chosen cases of PSC.

Predicting the overall survival and progression-free survival of nasopharyngeal carcinoma patients based on hemoglobin, albumin, and globulin ratio and classical clinicopathological parameters.

BACKGROUND: Serum biomarkers have a significant impact on the prediction of treatment outcomes in patients diagnosed with nasopharyngeal carcinoma (NPC). The primary aim of this study was to develop and validate a nomogram that incorporates hemoglobin, albumin, and globulin ratio (HAGR) and clinical data to accurately forecast treatment outcomes in patients with NPC. METHODS: A total of 796 patients diagnosed with NPC were included in the study. RESULTS: The results of the multivariate Cox analysis revealed that TNM stage and HAGR were found to be significant independent prognostic factors for OS and PFS. Furthermore, the utilization of the nomogram demonstrated a significant improvement in the evaluation of OS, PFS compared with the eighth TNM staging system. Additionally, the implementation of Kaplan-Meier curves and decision curve analysis curves further confirmed the discriminability and clinical effectiveness of the nomogram. CONCLUSIONS: The HAGR, an innovative prognostic factor grounded in the realm of immunonutrition, has emerged as a promising prognostic marker for both OS and PFS in individuals afflicted with NPC.

Nomograms based on the lymphocyte-albumin-neutrophil ratio (LANR) for predicting the prognosis of nasopharyngeal carcinoma patients after definitive radiotherapy.

Much evidence has accumulated to show that inflammation and nutritional status are associated with the prognosis of patients with various cancers. The present study was designed to explore the prognostic role of the LANR in NPC patients receiving definitive radiotherapy and to construct a nomogram for predicting patient survival. This study retrospectively reviewed 805 NPC patients (604 in the training cohort and 201 in the validation cohort) who received definitive radiotherapy between January 2013 and December 2019. The clinical data and pretreatment laboratory test data, including lymphocyte count, neutrophil count, and serum ALB concentration, were collected for all patients. The LANR was calculated as the albumin × lymphocyte/neutrophil ratio. Patients in the training cohort and validation cohort were categorized into high-LANR and low-LANR groups according to the corresponding cutoff values. The independent prognostic factors for overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), and metastasis-free survival (MFS) were evaluated by univariate and multivariate Cox regression analyses, and a nomogram was subsequently constructed. The performance of the nomogram was evaluated by the concordance index (C-index) and calibration curve. A low LANR (< 14.3) was independently associated with worse OS, PFS and MFS in NPC patients. A prognostic prediction nomogram was established based on T stage, N stage, Eastern Cooperative Oncology Group (ECOG) score, treatment modality, and LANR and was validated. The C-indices of the nomograms for OS and PFS in the training cohort were 0.729 and 0.72, respectively. The C-indices of the nomograms for OS and PFS in the validation cohort were 0.694 and 0.695, respectively. The calibration curve revealed good consistency between the actual survival and the nomogram prediction. Patients with NPC with low pretreatment LANR had a poor prognosis. The nomogram established on the basis of the LANR was efficient and clinically useful for predicting survival in NPC patients who underwent definitive radiotherapy.

Prognostic significance of pan-immune-inflammation value (PIV) in nasopharyngeal carcinoma patients.

Background: Blood-based immune-inflammation indexes have been widely used to predict survival in a variety of cancers. In this research, we seeked to evaluate a novel immune-inflammation marker, named the pan-immune-inflammation value (PIV), in patients with nasopharyngeal carcinoma (NPC) undergoing definitive radiotherapy. Methods: A group of 377 patients with NPC was retrospectived analyzed. Clinical data and laboratory data were collected. Receiver operating characteristic (ROC) curve analysis was performed in order to determine the optimal PIV cut-off value. Survival curves were estimated by Kaplan-Meier method, and prognostic variables were identified using a Cox regression model. Additionally, we developed a nomogram and assessed its acuracy using the concordance index (C-index) and a calibration curve. Results: The optimal PIV cut-off value was 146.24 according to ROC analysis. High PIV was related to poorer Eastern Cooperative Oncology Group Performance Status (ECOG PS) score (p = 0.017), more advanced T (p＜0.001) and clinical stages (p = 0.024). In univariate analysis, older Age, poorer ECOG PS, higher Epstein-Barr virus DNA (EBV-DNA), advanced T, N and clinical stage, and higher PIV levels were related to patients' poorer overall survival (OS). Poorer ECOG PS, higher EBV-DNA, later T stage, later clinical stage, and higher PIV were associated with patients' poorer progression free survival (PFS). Male sex and later T stage were associated with patients' poorer locoregional recurrence free survival (LRRFS). Poorer ECOG PS, higher EBV-DNA, later T stage, later clinical stage, and higher PIV were associated with patients' poorer distant metastasis free survival (DMFS). Multivariate analysis demonstrated that PIV was an independent prognostic index for OS (HR 2.231, 95 % CI 1.241-4.011, P = 0.007), PFS (HR 1.664, 95 % CI 1.003-2.760, P = 0.049), and DMFS(HR 2.081, 95 % CI 1.071-4.044, P = 0.031). Nomogram C-indexes for the nomogram of OS were 0.684, and PFS were 0.62, respectively. Survival predictions and actual survival were consistent according to the calibration curve. Conclusions: Pre-treatment PIV is a promising biomarker for predicting survival in patients with NPC.

Development and validation of a nomogram for predicting the overall survival in non-small cell lung cancer patients with liver metastasis.

Background: Among all metastatic lesions in non-small cell lung cancer (NSCLC), liver metastasis (LM) is the most lethal site with a median survival of less than 5 months. Few studies exclusively report on prognostic factors for these unique patients. We aimed to construct and validate a practical model to predict the prognosis of NSCLC patients with LM. Methods: Cases of NSCLC with LM diagnosed between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database, and were randomly split into training and validation cohort (7:3). The overall survival (OS) was measured from diagnosis until date of death or last follow-up. Cox regression analyses were performed to identify potential predictors of the model. A nomogram incorporating those independent factors was constructed and validated by the concordance index (C-index) and calibration plots. The decision curve analysis (DCA) and a risk stratification system were used to evaluate its clinical value. Results: A total of 2,367 cases were selected for analysis and randomized to the training cohort (n=1,677) and the validation cohort (n=690). The patients were mainly male (59.3%), married (83.1%) and White (77.3%). Apart from LM, 54.2%, 26.7%, and 36.7% of patients also present with bone, brain, and lung metastases, respectively. The median follow-up was 4.0 months for all patients and 23 months for alive cases. The median OS was 5 months [interquartile range (IQR), 2-11 months]. Sex, age, race, grade, T stage, bone metastasis, brain metastasis, surgery, and chemotherapy were identified as the independent risk factors of the OS and used to develop the nomogram. The calibration curves exhibited excellent agreement between the predicted and actual survival in both the training and validation set, with a C-index of 0.700 [95% confidence interval (CI): 0.684-0.716] and 0.677 (95% CI: 0.653-0.701), respectively. The DCA and the risk classification system further supported that the prediction model was clinically effective. Conclusions: This is the first study to build a prediction model for NSCLC patients with LM. It aids in treatment decisions, focused care, and physician-patient communication. The global prospective data is needed to further improve this model.

Klotho improves cardiac fibrosis, inflammatory cytokines, ferroptosis, and oxidative stress in mice with myocardial infarction

The anti-aging protein Klotho has been associated with cardiovascular health protection. Nevertheless, the protective mechanism remains unknown. The present study is aimed at exploring the effect of Klotho on cardiac remodeling and its potential mechanism in mice with myocardial infarction (MI). We used left anterior coronary artery descending ligation to develop an MI model for in vivo analyses. In contrast, H9C2 cells and cardiac fibroblasts were used to establish the oxygen–glucose deprivation (OGD) model in in vitro analyses. In vivo and in vitro models were treated with Klotho. Compound C, an AMPK signaling inhibitor, was used to determine whether Klotho’s effects are mediated through the AMPK/mTOR signaling pathway. Echocardiography, Masson trichrome staining, immunofluorescence, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot were used to detect the related indicators. The findings of the in vivo model indicate that Klotho treatment improved the mice’s cardiac function, reduced cardiac fibrosis, and attenuated myocardial inflammatory factors, ferroptosis, and oxidative stress. The results of the in vitro model were in line with the findings of in vivo modeling. An AMPK inhibitor, Compound C, reversed all these effects. In conclusion, Klotho potentially improves cardiac remodeling in MI mice by regulating AMPK/mTOR signaling, demonstrating Klotho as an effective MI therapeutic agent. (AU)

Exosomal ITGB6 from dormant lung adenocarcinoma cells activates cancer-associated fibroblasts by KLF10 positive feedback loop and the TGF-ß pathway.

Background: Dormant cancer cells are commonly known to play a pivotal role in cancer recurrence and metastasis. However, the mechanism of tumor dormancy and recurrence remains largely unknown. This study aimed to investigate the mechanism by which exosomes derived from dormant lung adenocarcinoma (LUAD) cells activate cancer-associated fibroblasts (CAFs) to reconstruct the extracellular matrix (ECM), providing a novel idea for decoding the mechanism of tumor dormancy. Methods: In this study, high-dose cisplatin was used to induce the dormant LUAD cells. Exosomes were extracted from the culture supernatant of normal and dormant cancer cells. The effects of selected exosomal proteins on the fibroblasts were evaluated. RNA-seq for fibroblasts and exosomal proteomics for normal and dormant cancer cells were used to identify and verify the mechanism of activating fibroblasts. Results: We demonstrated that exosomes derived from dormant A549 cells could be taken by fibroblasts. Exosomal ITGB6 transferred into fibroblasts induced the activation of CAFs by activating the KLF10 positive feedback loop and transforming growth factor ß (TGF-ß) pathway. High ITGB6 expression was associated with activation of the TGF-ß pathway and ECM remodeling. Conclusions: In all, we demonstrated that CAFs were activated by exosomes from dormant lung cancer cells and reconstruct ECM. ITGB6 may be a critical molecule for activating the TGF-ß pathway and remodeling ECM.