Prognosis of unresected versus resected early-stage pulmonary carcinoid tumors ≤3 cm in size: A population-based study.

PURPOSE: The observation-based prognosis, rather than resection, for small carcinoid tumors is still unclear. This lack of clarity has important implications for counseling elderly patients or patients for whom surgical resection poses a high risk. This study compared the outcomes of observation and surgical resection in patients with pulmonary carcinoid (PC) tumors ≤3 cm in size without metastasis. METHODS: Data of patients with PC tumors with ≤3 cm in diameter and without lymph node and distant metastases were retrieved from Surveillance, Epidemiology, and End Results (SEER) registry. To reduce the inherent bias of retrospective studies, propensity score matching analysis was performed. Overall survival (OS) and lung carcinoid-specific survival (LCSS) were analyzed using Kaplan-Meier plots. Multivariate analysis was used to determine predictors of LCSS in different size subgroups. RESULTS: In total, 4552 patients with early-stage PCs ≤3 cm in diameter, including 435 (9.56%) who were observed and 4117 (90.44%) treated by surgery, were recruited. Patients with surgery had significantly better OS and LCSS than those who were observed. However, patients with observation had comparable LCSS to those with surgery for PCs with tumor diameters ≤1 cm. Multivariate analysis indicated that surgical resection was an independent prognostic factor for LCSS in 1 cm < tumors ≤2 cm, and 2 cm < tumors ≤3 cm groups, but not for tumors ≤1 cm in diameter. CONCLUSION: Surgical resection of small PCs is associated with a survival advantage over observation. However, for early PCs ≤1 cm in diameter, observation may be considered in patients with high risk for surgical resection.

GJB3: a comprehensive biomarker in pan-cancer prognosis and immunotherapy prediction.

BACKGROUND: A wide range of connexins are situated between normal-normal cells, cancer-cancer cells, and cancer-normal cells. Abnormalities in connexin expression are typically accompanied by cancer development; however, no systematic studies have examined the role of Gap Junction Protein Beta 3 (GJB3) in the context of tumor progression and immunity, especially when considering a broad range of cancer types. METHODS: In this study, data on GJB3 expression were gathered from Genotype-Tissue Expression, Cancer Cell Line Encyclopedia, and The Cancer Genome Atlas databases. Then, we analyzed the relationship between GJB3 expression and tumor characteristics. In vitro experiments using colony formation, EdU, CCK8, transwell migration assays, immunohistochemistry and western blot were performed to investigate the function of GJB3 in tumor progression of various cell lines. A drug sensitivity analysis of GJB3 was performed using the Genomics of Drug Sensitivity in Cancer database. RESULT: Our findings demonstrate that GJB3 is widely expressed in various cancers and correlates significantly with disease stages, patient survival, immunotherapy response, and pharmaceutical guidance. Additionally, GJB3 plays a role in different cancer pathways, as well as in different immune and molecular subtypes of cancer. Co-expression of GJB3 with immune checkpoint genes was observed. Further experiments showed that knockdown of GJB3 inhibited the PI3K/AKT pathway and resulted in reduced proliferation, migration, and viability of different cancer cells. CONCLUSION: Overall, GJB3 shows potential as a molecular biomarker and therapeutic target for various cancers, particularly lung adenocarcinomas, mesothelioma, pancreatic adenocarcinoma. Thus, GJB3 may represent a new therapeutic target for a wide range of cancers.

Response of a Novel KANK1::ALK Fusion to Alectinib in an Advanced Lung Adenocarcinoma: A Case Report.

More than 90 distinct fusion partners of ALK rearrangement have been identified. Different ALK fusions may exhibit different sensitivities to ALK tyrosine kinase inhibitors. The emergence of rare fusions poses significant challenges to targeted therapies. This study aimed to investigate the response of KANK1::ALK fusion to alectinib in an advanced lung adenocarcinoma. A novel KANK1::ALK fusion was identified by next-generation sequencing (NGS) and Ventana immunohistochemistry assessments. A 73-year-old woman who had never smoked was admitted with hemoptysis in May 2020. PET/CT revealed a nodule in the left upper lobe, with bilateral pulmonary and multiple lymph node metastases. The upper lobe nodule of the left lung was diagnosed as adenocarcinoma through bronchofiberscopy biopsy, resulting in a clinical diagnosis of stage IVA (cT1c,N3,M1a). Because the biopsy tissue was insufficient for NGS analysis, a blood-based genetic analysis was performed, revealing the presence of KRAS p.Q61R mutations. The patient received carboplatin and pemetrexed with pembrolizumab as first-line therapy, followed by maintenance therapy of pembrolizumab monotherapy. Although the tumor initially showed significant shrinkage, it unfortunately progressed further after 11 months. Subsequently, the patient was given carboplatin and pemetrexed with pembrolizumab again, but the tumor progression continued. An NGS using a rebiopsy of the left upper lobe tumor suggested a KANK1::ALK fusion. Alectinib was prescribed in January 2022, and a durable partial response was observed after 18 months. ALK rearrangements were observed in the broader spectrum of lung cancers. This study provided a potential treatment option for patients with KANK1::ALK fusions. Further studies are needed to understand the function of these fusions.

The nomogram for the prediction of overall survival after surgery in patients in early-stage NSCLC based on SEER database and external validation cohort.

BACKGROUND & AIMS: Currently, there is a lack of effective tools for predicting the prognostic outcome of early-stage lung cancer after surgery. We aim to create a nomogram model to help clinicians assess the risk of postoperative recurrence or metastasis. MATERIALS AND METHODS: This work obtained 16,459 NSCLC patients based on SEER database from 2010 to 2015. In addition, we also enrolled 385 NSCLC patients (2017/01-2019/06) into external validation cohort at Tianjin Medical University General Hospital. Univariable as well as multivariable Cox regression was carried out for identifying factors independently predicting OS. In addition, we built a nomogram by incorporating the above prognostic factors for the prediction of OS. RESULTS: Tumor size was positively correlated with the risk of poor differentiation. Advanced age, male and adenocarcinoma patients were factors independently predicting poor prognosis. The risk of white race is higher, followed by Black race, Asians and Indians, which is consistent with previous study. Chemotherapy is negatively related to prognostic outcome in patients of Stage IA NSCLC and positively related to that in those of Stage IB NSCLC. Lymph node dissection can reduce the postoperative mortality of patients. AUCs of the nomograms for 1, 2, and 3-year OS was 0.705, 0.712, and 0.714 for training cohort, while those were 0.684, 0.688, and 0.688 for validation cohort. CONCLUSIONS: The nomogram could be used as a tool to predict the postoperative prognosis of patients with Stage I non-small cell lung cancer.

Identification of multiple organ metastasis-associated hub mRNA/miRNA signatures in non-small cell lung cancer.

Metastasis remains major cause of treatment failure in non-small cell lung cancer (NSCLC). A comprehensive characterization of the transcriptomic landscape of NSCLC-cells with organ-specific metastatic potentials would advance our understanding of NSCLC metastasis process. In this study, we established NSCLC bone-metastatic (BoM), brain-metastatic (BrM), and lymph-metastatic (LnM) cells by an in vivo spontaneous metastatic model. Subsequently, by analyzing the entire transcriptomic profiles of BoM, BrM, LnM, LuM, in comparison with their parental cell line L9981, we identified miR-660-5p as a key driver that is associated with NSCLC progression and distant metastasis, potentially through its targeting of LIMCH1, SMARCA5 and TPP2. In addition, a six-gene signature (ADRB2, DPYSL2, IL7R, LIMCH1, PIK3R1, and SOX2) was subsequently established to predict NSCLC metastasis based on differentially expressed genes, three of which (DPYSL2, PIK3R1, LIMCH1) along with the transcriptional factors RB1 and TP63, were ultimately validated by experiments. Taken together, aberrant gene signature and miRNA can serve as biomarkers for predicting NSCLC distant metastasis, and targeting them could potentially contribute to the development of novel therapeutic strategies.

A Review of Biomarkers and Their Clinical Impact in Resected Early-Stage Non-Small-Cell Lung Cancer.

The postoperative survival of early-stage non-small-cell lung cancer (NSCLC) patients remains unsatisfactory. In this review, we examined the relevant literature to ascertain the prognostic effect of related indicators on early-stage NSCLC. The prognostic effects of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), mesenchymal-epithelial transition (MET), C-ros oncogene 1 (ROS1), or tumour protein p53 (TP53) alterations in resected NSCLC remains debatable. Kirsten rat sarcoma viral oncogene homologue (KRAS) alterations indicate unfavourable outcomes in early-stage NSCLC. Meanwhile, adjuvant or neoadjuvant EGFR-targeted agents can substantially improve prognosis in early-stage NSCLC with EGFR alterations. Based on the summary of current studies, resected NSCLC patients with overexpression of programmed death-ligand 1 (PD-L1) had worsening survival. Conversely, PD-L1 or PD-1 inhibitors can substantially improve patient survival. Considering blood biomarkers, perioperative peripheral venous circulating tumour cells (CTCs) and pulmonary venous CTCs predicted unfavourable prognoses and led to distant metastases. Similarly, patients with detectable perioperative circulating tumour DNA (ctDNA) also had reduced survival. Moreover, patients with perioperatively elevated carcinoembryonic antigen (CEA) in the circulation predicted significantly worse survival outcomes. In the future, we will incorporate mutated genes, immune checkpoints, and blood-based biomarkers by applying artificial intelligence (AI) to construct prognostic models that predict patient survival accurately and guide individualised treatment.

Lobe-specific analysis of perioperative chemotherapy for non-small cell lung cancer patients.

OBJECTIVES: Perioperative cisplatin-based chemotherapy decreases the risk of death over surgery alone and is a standard of care. Here, we examined perioperative chemotherapy indications for stage IB-III non-small cell lung cancer (NSCLC) patients according to lobe-specific analysis. METHODS: Resectable NSCLC patients with stage IB-III who received perioperative chemotherapy with and without radiotherapy after lung resection were identified from the SEER database. Propensity score matching (PSM) analysis was performed to reduce the inherent bias of retrospective studies. The Kaplan-Meier method and log-rank tests were used to assess the differences in overall survival (OS). RESULTS: The study enrolled 23,844 patients before PSM. The perioperative chemotherapy group had better OS than the nonperioperative chemotherapy group in stage IB-III NSCLC patients before and after PSM. However, subgroup analysis according to stage demonstrated that perioperative chemotherapy did not markedly benefit patients with stage IB. Furthermore, lobar subgroup analysis did not show survival advantages in primary tumors located in either the right middle lobe in stages II and III NSCLC or the right lower lobe in stage III NSCLC. CONCLUSIONS: Lobe-specific perioperative chemotherapy is recommended in NSCLC patients. For stage IB NSCLC, right middle lobe NSCLC from stage IB-III and right lower lobe NSCLC from stage III, perioperative chemotherapy might not confer survival benefits.

PD­1/PD­L1 immune checkpoint inhibitors in neoadjuvant therapy for solid tumors (Review).

A comprehensive search regarding programmed cell death protein 1 (PD­1)/programmed death­ligand 1 (PD­L1) inhibitor monotherapy or combination therapy in neoadjuvant settings of 11 types of solid cancer was performed using the PubMed, Cochrane and Embase databases, and the abstracts of various conferences were screened. Data presented in 99 clinical trials indicated that preoperative treatment with PD­1/PD­L1 combined therapy, particularly immunotherapy plus chemotherapy, could achieve a higher objective response rate, a higher major pathologic response rate and a higher pathologic complete response rate, as well as a lower number of immune­related adverse events compared with PD­1/PD­L1 monotherapy or dual immunotherapy. Although PD­1/PD­L1 inhibitor combination caused more treatment­related adverse events (TRAEs) in patients, most of the TRAEs were acceptable and did not cause marked delays in operation. The data suggest that patients with pathological remission after neoadjuvant immunotherapy exhibit improved postoperative disease­free survival compared with those without pathological remission. Further studies are still required to evaluate the long­term survival benefit of neoadjuvant immunotherapy.

Clinical significance of preoperative neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in the prognosis of resected early-stage patients with non-small cell lung cancer: A meta-analysis.

BACKGROUND: Poor prognosis is linked to peripheral blood levels of preoperative platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in many advanced cancers. Nevertheless, whether the correlation exists in resected early-stage cases with non-small cell lung cancer (NSCLC) stays controversial. Consequently, we performed a meta-analysis to explore the preoperative NLR and PLR's prognostic significance in early-stage patients with NSCLC undergoing curative surgery. METHODS: Relevant studies that validated the link between preoperative NLR or PLR and survival results were found via the proceeding databases: PubMed, Embase, Cochrane Library, and Web of Science. The merged 95% confidence interval (CI) and hazard ratio (HR) was employed to validate the link between the NLR or PLR's index and overall survival (OS) and disease-free survival (DFS) in resected NSCLC cases. We used sensitivity and subgroup analyses to assess the studies' heterogeneity. RESULTS: An overall of 21 studies were attributed to the meta-analysis. The findings indicated that great preoperative NLR was considerably correlated with poor DFS (HR = 1.58, 95% CI: 1.37-1.82, p < 0.001) and poor OS (HR = 1.51, 95% CI: 1.33-1.72, p < 0.001), respectively. Subgroup analyses were in line with the pooled findings. In aspect of PLR, raised PLR was indicative of inferior DFS (HR = 1.28, 95% CI: 1.04-1.58, p = 0.021) and OS (HR = 1.37, 95% CI: 1.18-1.60, p < 0.001). In the subgroup analyses between PLR and DFS, only subgroups with a sample size <300 (HR = 1.67, 95% CI: 1.15-2.43, p = 0.008) and TNM staging of mixed (I-II) (HR = 1.47, 95% CI: 1.04-2.07, p = 0.028) showed that the link between high PLR and poor DFS was significant. CONCLUSIONS: Preoperative elevated NLR and PLR may act as prognostic biomarkers in resected early-stage NSCLC cases and are therefore valuable for guiding postoperative adjuvant treatment.

Identification of a novel oxidative stress-related prognostic model in lung adenocarcinoma.

Background: Oxidative stress (OxS) participates in a variety of biological processes, and is considered to be related to the occurrence and progression of many tumors; however, the potential diagnostic value of OxS in lung cancer remains unclear. Methods: The clinicopathological and transcriptome data for lung adenocarcinoma (LUAD) were collected from TCGA and GEO database. LASSO regression was used to construct a prognostic risk model. The prognostic significance of the OxS-related genes was explored using a Kaplan-Meier plotter database. The prediction performance of the risk model was shown in both the TCGA and GSE68465 cohorts. The qRT-PCR was performed to explore the expression of genes. CCK-8, Edu and transwell assays were conducted to analyze the role of CAT on cell proliferation migration and invasion in lung cancer. Immune infiltration was evaluated by CIBERSORT and mutational landscape was displayed in the TCGA database. Moreover, the relationship between risk score with drug sensitivity was investigated by pRRophetic. Results: We identified a prognosis related risk model based on a four OxS gene signature in LUAD, including CYP2D6, FM O 3, CAT, and GAPDH. The survival analysis and ROC curve indicated good predictive power of the model in both the TCGA and GEO cohorts. LUAD patients in the high-risk group had a shorter OS compared to the low-risk group. QRT-PCR result showed that the expression of four genes was consistent with previous analysis in cell lines. Moreover, overexpression of CAT could decrease the proliferation, invasion and migration of lung cancer cells. The Cox regression analysis showed that the risk score could be used as an independent prognostic factor for OS. LUAD patients in the high-risk score group exhibited a higher tumor mutation burden and risk score were closely related to tumor associated immune cell infiltration, as well as the expression of immune checkpoint molecules. Both the high- and low-risk groups have significant differences in sensitivity to some common chemotherapy drugs, such as Paclitaxel, Docetaxel, and Vinblastine, which may contribute to clinical treatment decisions. Conclusion: We established a robust OxS-related prognostic model, which may contribute to individualized immunotherapeutic strategies in LUAD.

The Profile and Clinical Significance of ITGB2 Expression in Non-Small-Cell Lung Cancer.

Integrins are involved in extracellular and intracellular signaling and are often aberrantly expressed in tumors. Integrin beta 2 (ITGB2) has previously been demonstrated to be correlated with the host defense. However, the expression profile and role of ITGB2 in non-small-cell lung cancer (NSCLC) remain unclear. Here, we found that the genetic alterations in ITGB2 was predominated by gene mutation and copy number deletion using cBioPortal analysis, and its expression was downregulated in the NSCLC tissues, as validated by the UALCAN, TCGA, and GEO databases and our tissue samples. Kaplan-Meier (KM) plotter analysis revealed that patients with a lower ITGB2 expression had a shorter overall survival (OS) time (p = 0.01). Moreover, 1089 differentially expressed genes (DEGs) in the NSCLC tissues were screened using the TCGA database. The GO and KEGG enrichment analysis showed that the DEGs were closely associated with immune processes and cell adhesion. The protein-protein interaction (PPI) network revealed that 10 of 15 EMT-related genes among the DEGs might lead to the metastasis of NSCLC. Concomitantly, the expression of ITGB2 was positively correlated with the infiltration of Treg cells and Myeloid-derived suppressor cells (MDSC). Biologically, the ectopic expression of ITGB2 significantly inhibited the proliferation and metastasis of NSCLC cells. Mechanistically, we demonstrated that ITGB2 suppressed the expression of N-cadherin, Vimentin, Slug, Snail, and Twist, while it promoted E-cadherin expression, according to gain-of-function studies. In conclusion, ITGB2 can inhibit the proliferation and migration of NSCLC cells, leading to a poor prognosis, via epithelial-mesenchymal transition (EMT) signaling.

Comprehensive analyses of one-carbon metabolism related genes and their association with prognosis, tumor microenvironment, chemotherapy resistance and immunotherapy in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and is a global public health concern. One-carbon (1C) metabolism plays a crucial role in the occurrence and development of multiple cancer types. However, there are limited studies investigating 1C metabolism in LUAD. This study aims to evaluate the prognostic value of 1C metabolism-related genes in LUAD and to explore the potential correlation of these genes with gene methylation, the tumor microenvironment, and immunotherapy. Methods: We identified 26 1C metabolism-related genes and performed a Kaplan-Meier and Cox regression analysis to evaluate the prognostic value of these genes. Consensus clustering was further performed to determine the 1C metabolism-related gene patterns in LUAD. The clinical and molecular characteristics of subgroups were investigated based on consensus clustering. CIBERSORT and ssGSEA algorithms were used to calculate the relative infiltration levels of multiple immune cell subsets. The relationship between 1C metabolism-related genes and drug sensitivity to immunotherapy was evaluated using the CellMiner database and IMvigor210 cohort, respectively. Results: The expression levels of 23 1C metabolism-related genes were significantly different between LUAD tumor tissues and normal tissues. Seventeen of these genes were related to prognosis. Two clusters (cluster 1 and cluster 2) were identified among 497 LUAD samples based on the expression of 7 prognosis-related genes. Distinct expression patterns were observed between the two clusters. Compared to cluster 2, cluster 1 was characterized by inferior overall survival (OS) (median OS = 41 vs. 60 months, p = 0.00031), increased tumor mutation burden (15.8 vs. 7.5 mut/Mb, p < 0.001), high expression of PD-1 (p < 0.001) and PD-L1 (p < 0.001), as well as enhanced immune infiltration. 1C metabolism-related genes were positively correlated with the expression of methylation enzymes, and a lower methylation level was observed in cluster 1 (p = 0.0062). Patients in cluster 1 were resistant to chemotherapy drugs including pemetrexed, gemcitabine, paclitaxel, etoposide, oxaliplatin, and carboplatin. The specific expression pattern of 1C metabolism-related genes was correlated with a better OS in patients treated with immunotherapy (median OS: 11.2 vs. 7.8 months, p = 0.0034). Conclusion: This study highlights that 1C metabolism is correlated with the prognosis of LUAD patients and immunotherapy efficacy. Our findings provide novel insights into the role of 1C metabolism in the occurrence, development, and treatment of LUAD, and can assist in guiding immunotherapy for LUAD patients.