Search Results (360)

Background and Objective: Insulinoma-associated protein 1 (INSM1) is a novel immunohistochemical marker with potential utility in identifying neuroendocrine differentiation in lung cancer. Unlike conventional neuroendocrine (NE) markers, INSM1 can potentially serve as a standalone diagnostic biomarker. This study presents the first meta-analysis assessing the diagnostic accuracy of using INSM1 to distinguish LCNEC and SCLC from other lung cancer subtypes, addressing the variability across individual studies. Methods: A systematic review and meta-analysis were conducted to comprehensively evaluate the diagnostic performance of INSM1 in the pathological classification of lung cancer. The online databases PubMed, Web of Science, and Embase were systematically searched for data collection. Studies reporting the sensitivity and specificity of INSM1 in diagnosing LCNEC and SCLC were included. Pooled estimates were calculated using two models: the NSCLC model, which distinguishes LCNEC from other non-small cell lung cancers (NSCLCs), and the lung cancer model, which differentiates both LCNEC and SCLC from non-neuroendocrine (non-NE) lung cancer. Results: Fourteen studies comprising 3,218 specimens were included in this systematic review and meta-analysis. In the NSCLC model, INSM1 demonstrated a pooled sensitivity of 0.67 (95% CI: 0.61–0.73) and specificity of 0.97 (95% CI: 0.96–0.98), with an area under the curve (AUC) of 0.943. In the lung cancer model, the pooled sensitivity and specificity were 0.86 (95% CI: 0.84–0.88) and 0.97 (95% CI: 0.96–0.98), respectively, with an AUC of 0.974. Conclusions: INSM1 demonstrated excellent diagnostic accuracy and consistently high specificity for pulmonary neuroendocrine carcinomas, supporting its utility as a reliable standalone immunohistochemical marker with the potential to replace conventional NE markers in the pathological diagnosis of LCNEC and SCLC. Full article

Non-small cell lung cancer (NSCLC) is a predominant form of lung cancer that is often diagnosed at an advanced metastatic stage. The processes of cancer cell migration and invasion involve epithelial-to-mesenchymal transition (EMT), which is crucial for metastasis. Targeting cancer aggressiveness with effective plant compounds has gained attention as a potential adjuvant therapy. Eurycomanone (ECN), a bioactive quassinoid found in the root of Eurycoma longifolia Jack, has demonstrated anti-cancer activity against various carcinoma cell lines, including human NSCLC cells. This study aimed to investigate the in vitro effects of ECN on the migration and invasion of human NSCLC cells and to elucidate the mechanisms by which ECN modulates the EMT in these cells. Non-toxic doses (≤IC20) of ECN were determined using the MTT assay on two human NSCLC cell lines: A549 and Calu-1. The results from wound healing and transwell migration assays indicated that ECN significantly suppressed the migration of both TGF-β1-induced A549 and Calu-1 cells. ECN exhibited a strong anti-invasive effect, as its non-toxic doses significantly suppressed the TGF-β1-induced invasion of NSCLC cells through Matrigel and decreased the secretion of MMP-2 from these cancer cells. Furthermore, ECN could affect the TGF-β1-induced EMT process in various ways in NSCLC cells. In TGF-β1-induced A549 cells, ECN significantly restored the expression of E-cadherin by inhibiting the Akt signaling pathway. Conversely, in Calu-1, ECN reduced the aggressive phenotype by decreasing the expression of the mesenchymal protein N-cadherin and inhibiting the TGF-β1/Smad pathway. In conclusion, this study demonstrated the anti-invasive activity of eurycomanone from E. longifolia Jack in human NSCLC cells and provided insights into its mechanism of action by suppressing the effects of TGF-β1 signaling on the EMT program. These findings offer scientific evidence to support the potential of ECN as an alternative therapy for metastatic NSCLC. Full article

In recent years, an increasingly important role in the etiopathogenesis of lung cancer has been attributed to genetic predisposition. Current genetic research suggests that the increased risk of this cancer may be due to gene polymorphism within repair genes. In the case of lung cancer, observations about genes involved in the DNA repair system by cutting bases of nitrogen—base excision repair (BER)—seem to be interesting. Most attention has been devoted to the XRCC1 gene, which coordinates the various stages of BER. The aim of this study was to assess the role of the single nucleotide polymorphism Arg399Gln in the XRCC1 gene as a factor influencing the risk of lung cancer. The study involved 118 patients with non-small cell lung cancer (NSCLC). The control group consisted of 60 people who did not have cancer. The study proved that the polymorphism of the XRCC1 gene is characterized by a statistically significant relationship with the onset of cancer. There were no statistically significant differences between the Arg399Gln polymorphism of the XRCC1 gene and risk factors for non-small cell lung cancer, such as age, sex, smoking and its duration, or place of residence, as well as between the histological type of the tumor or its severity. Detailed analysis of three genotypes—Arg/Arg, Arg/Gln, and Gln/Gln—showed that the incidence of particular genotypes in the group of patients was, respectively, 16.10%, 27.12%, and 58.78%. In the case of the Gln/Gln genotype, the most common associated histopathological type was squamous cell carcinoma, and in the case of adenocarcinoma, the most common genotype was Arg/Arg. It was estimated that each Arg allele reduced the chance of tumor occurrence to 0.48 times the reference value, i.e., the Gln/Gln genotype class for the Arg/Gln genotype and the Arg/Gln genotype for the Arg/Arg genotype. The relationship between the male sex and the occurrence of cancer remained insignificant, in contrast to the presence of nicotinism. Studies suggest that the Arg399Gln polymorphism of the XRCC1 gene has limited prognostic significance in non-small cell lung cancer. Full article

Background: Lung cancer, predominantly NSCLC (80%), has a poor prognosis due to late diagnosis and limited treatment efficacy. DMRTA2 (DMRT5), a transcription factor linked to neural/germ cell development, is overexpressed in NSCLC per TCGA data, indicating its potential role in tumorigenesis and as a therapeutic target. Methods: Conduct a comprehensive search of the relevant theoretical foundations. Based on this, differential expression analysis will be performed using the DESeq2 package in R on RNA-seq data from lung adenocarcinoma and lung squamous cell carcinoma in the TCGA database. The research will then employ various methods, including CRISPR genome editing, MTS assay, flow cytometry, Western blot, co-immunoprecipitation, immunofluorescence, and qRT-PCR. Results: Through experimental validation, we found that DMRTA2 mRNA is highly expressed in non-small-cell lung cancer (NSCLC) tissues and is negatively correlated with poor prognosis. DMRTA2 binds to HSP90β, inhibiting the interaction between HSP90β and p53, thereby suppressing p53 ubiquitination and nuclear export. This activates the p53 pathway, inhibiting the proliferation and invasion of lung cancer cells. Conclusions: In NSCLC, DMRTA2 acts as a context-dependent regulator, stabilizing wild-type p53 through competitive HSP90β binding to suppress tumors, while in p53-compromised cells, potentially engaging HSP90β or alternative pathways to promote malignancy. Its dual localization and transport interactions reveal multifunctional, stress-responsive roles beyond transcription. Full article

Poly(ADP-ribose) polymerases (PARP) are a family of enzymes that were proven to play an essential role in the initiation and activation of DNA repair processes in the case of DNA single-strand breaks. The inhibition of PARP enzymes might be a promising option for the treatment of several challenging types of cancers, including triple-negative breast cancer (TNBC) and non-small cell lung carcinoma (NSCLC). This study utilizes several techniques to screen the compound collection of the Leibniz Institute of Plant Biochemistry (IPB) to identify novel hPARP-1 inhibitors. First, an in silico pharmacophore-based docking study was conducted to virtually screen compounds with potential inhibitory effects. To evaluate these compounds in vitro, a cell-free enzyme assay was developed, optimized, and employed to identify hPARP-1 inhibitors, resulting in the discovery of two novel scaffolds represented by compounds 54 and 57, with the latter being the most active one from the compound library. Furthermore, fluorescence microscopy and synergism assays were performed to investigate the cellular and nuclear pathways of hPARP-1 inhibitor 57 and its potential synergistic effect with the DNA-damaging agent temozolomide. The findings suggest that the compound requires further lead optimization to enhance its ability to target the nuclear PARP enzyme effectively. Nonetheless, this new scaffold demonstrated a five-fold higher PARP inhibitory activity at the enzyme level compared to the core structure of olaparib (OLP), phthalazin-1(2H)-one. Full article

Background/Objectives: Lung cancer is the leading cause of cancer-related mortality worldwide. Accurate radiotherapy (RT) planning alongside chemotherapy and immunotherapy is critical for improving treatment outcomes for inoperable non-metastatic cases. Conventional computed tomography (CT)-based planning may be inadequate for accurately identifying tumor margins and the location of nodal disease. We investigated whether ¹⁸F-labeled fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET-CT) imaging can assist in target volume delineation for primary, nodal, and metastatic disease in the RT planning and overall therapeutic planning of patients. Methods: In this single-center, prospective study, we recruited 34 patients with histologically confirmed locally advanced non-small-cell lung carcinoma (NSCLC). All patients underwent ¹⁸F-FDG PET-CT-based RT simulation. Two sequential RT plans were created by the same radiation oncologist: one based on CT alone and the other PET-CT. Planning target volumes (PTVs) and PET-CT-guided adjustments were analyzed to assess their impact. Standardized protocols for immobilization, imaging, target delineation, and dose prescription were applied. Results: A total of 34 patients (31 males and 3 females) were recruited in the study. ¹⁸F-FDG PET-CT detected distant metastases in 7/34 (20.6%) patients, altering the overall therapeutic plan in 4/34 (11.8%) and allowing radical RT in 3 of them who had oligometastatic disease (8.8%). It modified RT planning in 26/34 (76.5%) patients and clarified malignancy in atelectatic areas. Nodal involvement was identified in 3/34 patients (8.8%) and excluded in 3/34 cases, avoiding unnecessary nodal irradiation. Additional involved nodes were revealed in 12/34 (35.3%) patients, requiring dose escalation. Overall, changes to the tumor PTV were made in 23/30 (76.6%) and to the nodal PTV in 19/30 (63.3%) cases (p < 0.0001). Primary tumor and nodal PTVs increased in 20/34 (66.7%) and 13/34 (43.3%), respectively. Conclusions: ¹⁸F-FDG PET-CT significantly improves RT planning by more precisely defining tumor and nodal volumes, identifying undetected lesions, and guiding dose adaptation. Larger long-term studies are required to confirm potential locoregional control and survival improvements. Full article

Background: Organoid cultures have received much attention in recent years due to the promise of patient-derived organoid cultures for exploration of personalized cancer treatment strategies. Organoid cultures have been established from a variety of malignancies; however, lack of a thorough histopathological analysis has limited the acceptance of organoid models as translational tools. Methods: Here, we aimed to establish patient-derived tumor-organoid (PDTO) models from human non-small-cell lung cancer (NSCLC) resection specimens and provide a thorough histopathological evaluation of the cultures. Results: We show that we were able to establish organoid cultures of lung adenocarcinomas (LUADs) and lung squamous cell carcinomas (LUSCs) successfully, and that the organoid cultures of different subtypes of NSCLC preserved the histoarchitecture and growth pattern of the tumors they derive from. Immunohistochemistry and AB-PAS staining confirmed the subtype-specific protein expression pattern and preserved mucin production in LUAD organoids. The genetic abnormalities of the tumors assessed by immunohistochemistry (IHC-P) were preserved in the organoid cultures. Conclusions: Our thorough study reveals conserved PDTO histopathology, supports further exploration, and encourages using PDTO models in translational research projects. PDTO models hold remarkable promise as patient-specific models and may be applied to predict therapy response in cases where molecular–pathological analyses pose significant management dilemmas, and they also may provide a platform for exploring the molecular mechanisms of therapy resistance in a biologically relevant model system. Full article

DNA methylation changes, especially hypermethylation of SOX1 and HOXA9, may serve as biomarkers for diagnosis and prognosis in non-small cell lung carcinoma (NSCLC). This study analyzed the methylation status of SOX1 and HOXA9 in 63 primary NSCLC tumor samples, corresponding normal lung tissues, and circulating blood, using bisulfite pyrosequencing. The relationship between methylation patterns and clinicopathologic features was also explored. SOX1 and HOXA9 promoter methylation levels were significantly higher in tumor tissues compared to normal lung tissues and blood samples. Histological subtypes influenced methylation patterns, with squamous cell carcinomas (SCC) showing higher hypermethylation rates at both loci compared to other NSCLC subtypes. HOXA9 hypermethylation was associated with advanced tumor stage (stages II and III). Gender and smoking status did not correlate with methylation status. These findings highlight the cancer-specific nature of SOX1 and HOXA9 hypermethylation in NSCLC. Further investigation into demographic and molecular factors influencing methylation could enhance the clinical utility of SOX1 and HOXA9 in NSCLC diagnosis and management. Full article

Background/Objectives: Differentiating thoracic malignant tumors, such as epithelioid malignant pleural mesothelioma (EMPM) and non-small-cell lung carcinoma (NSCLC), primarily comprising lung adenocarcinoma (LAC) and lung squamous cell carcinoma (LSCC), remains a challenge in routine pathological diagnosis. This study aimed to evaluate whether podoplanin (PDPN) immunohistochemistry combined with scanning electron microscopy (SEM) using the NanoSuit-correlative light and electron microscopy (CLEM) methods could serve as a reliable tool for distinguishing these thoracic malignancies. Methods/Results: Initially, PDPN expression was assessed by immunohistochemical analysis in 11 EMPM, 100 LAC, and 23 LSCC cases. PDPN positivity was predominantly observed in the cell membrane and was significantly more frequent in EMPM (100%) than in LAC (2%; p < 0.0001) or LSCC (43.5%; p = 0.0018). Subsequently, field emission–SEM (FE-SEM) observations of PDPN-positive sites on immunohistochemical slides, conducted using the NanoSuit-CLEM method, revealed distinctive ultrastructural features. EMPM exhibited densely packed, elongated microvilli, whereas such structures were absent in LAC and LSCC. Furthermore, analysis of thick-cut sections (20 μm) demonstrated extensive microvilli coverage characteristic of EMPM. Conclusions: These findings suggest that the combined approach of PDPN immunohistochemistry and FE-SEM observation of PDPN-positive sites, using the NanoSuit-CLEM method, constitutes an effective diagnostic strategy for enhancing the accuracy of distinguishing EMPM from NSCLCs. Full article

Background/Objectives: The Lung Immune Prognostic Index (LIPI) has emerged as a promising biomarker for predicting outcomes in advanced non-small cell lung cancer (aNSCLC). We assessed whether LIPI, in combination with baseline clinical characteristics, can guide first-line treatment selection between pembrolizumab (P) and pembrolizumab plus platinum-based chemotherapy (PCT) in patients with PD-L1 tumor proportion score (TPS) ≥ 50% and EGFR/ALK/ROS1 wild-type. Methods: A predictive score was developed using baseline clinical variables, including age, sex, smoking status, and LIPI, in a proof-of-concept cohort (n = 241). This model was then validated in an independent cohort of 409 patients. OS was compared between patients treated with P versus PCT, stratified by predictive score. Results: In the proof-of-concept cohort, the median OS was 18.3 months for P and 26.6 months for PCT (p = 0.001). In the validation cohort, the median OS was 28.0 months for P and 22.2 months for PCT (p = 0.062). Stratification using the predictive score showed that patients with high scores (3–5) had improved OS with PCT compared to P (31.2 vs. 25.5 months, p = 0.001), while those with low scores (0–2) derived similar benefits from both treatments. Conclusions: This LIPI-based predictive score may assist in identifying aNSCLC patients who derive greater benefit from chemo-immunotherapy over immunotherapy. Its simplicity and clinical relevance support integration into treatment decision-making, pending prospective validation. Full article

Background: Ambient air pollution is a modifiable determinant of lung cancer survival, affecting early-stage Non-Small Cell Lung Cancer (NSCLC) incidence and mortality. Methods: This retrospective cohort study examined the association between all-cause mortality and exposure to air pollution among stage 1A NSCLC-treated patients from the U.S. National Cancer Registry from 1988 to 2015. The Cox hazard model and Kaplan–Meier survival plots were provided. Air pollutants were included separately and together in the models, accounting for spatiotemporal weather variability affecting air pollution exposure levels pre and post lung cancer diagnosis. Results: NO₂ (above the median sample mean = 25.66 ppb; 12.97 ppb below median), SO₂ (above median sample mean = 3.98 ppb; 1.81 ppb below median), and CO (above median sample mean = 1010.84 ppb; 447.91 ppb below median) air pollutant levels and weather conditions were calculated for county-day units. The median months of survival for those exposed to above-median NO₂ were 27 months (SD = 17.61 months), while the median was 30 months (SD = 15.93 months) for those exposed to below-median levels. Multipollutant analyses indicated that an average monthly NO₂ increase of 1 part per billion (ppb) in the county of NSCLC diagnosis was associated with increases of 4%, 6%, and 9% in the all-cause mortality rate one, three, and five years after diagnosis, respectively; an equivalent increase in SO₂ was associated with increases of 16%, 17%, and 17%; and an increase in CO was associated with increases of 53%, 51%, and 42% Conclusion: It is vital to implement environmental policies that control emissions to reduce preventable deaths in stage 1A NSCLC patients with adenocarcinoma or squamous cell carcinoma histology types who reside in metropolitan areas. Full article

Background/Objectives: Anlotinib is a novel oral antiangiogenic tyrosine kinase inhibitor (TKI) approved as a third-line treatment for advanced non-small-cell lung cancer (NSCLC). However, its efficacy in combination with docetaxel remains incompletely understood. Given the need for effective second-line therapies after platinum-based chemotherapy, this systematic review aims to evaluate the therapeutic potential of anlotinib plus docetaxel in advanced NSCLC. Methods: The PubMed, WOS, Medline, and Scopus databases were screened for published articles up to 12 April 2024. We included RCTs comparing anlotinib plus docetaxel with docetaxel alone in advanced NSCLC after receiving platinum-based chemotherapy, reporting progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) as outcomes for both groups. Results: Our systematic review included three randomized controlled trials (RCTs) with a total of 151 patients in the anlotinib plus docetaxel group and 132 in the docetaxel-only group. Meta-analysis results demonstrated that the combination therapy significantly prolonged PFS (mean difference (MD) = 2.98, 95% confidence interval (CI), 1.95–4.00; p < 0.00001) and improved ORR (risk ratio (RR) = 3.04, 95% CI = 1.77–5.24; p < 0.00001). Additionally, the DCR was notably higher in the combination group (RR = 1.58, 95% CI = 1.34–1.87; p < 0.00001). Conclusions: Anlotinib plus docetaxel appears to be more effective as a second-line treatment of advanced NSCLC than docetaxel in prolonging PFS and increasing ORR and DCR. Full article

Background/Objectives: Paraneoplastic syndromes (PNS), characterized by a large diversity of symptoms, may sometimes be the first clinical feature of a severe underlying disorder such as cancer. Methods: We report the case of a middle-aged male patient with no significant previous medical history, a nonsmoker or alcohol heavy drinker, complaining about generalized, recently onset itch. Given no reasonable explanation of pruritus after dermatological consultation and the unsatisfactory response to treatment, the patient was referred to gastroenterology with the suspicion of a cholestatic liver disease. Results: The abdominal ultrasound examination revealed gallstones and no dilation of the biliary tree. Numerous tests were run and came out negative, except for the slight elevation of C-reactive protein, mild dyslipidemia, and positivity for H. pylori antigen. The gut microbiota displayed important dysbiosis with a significant increase in the histamine-producing bacteria. Given this chronic pruritus became suspicious, thorax and abdominal CT were recommended and performed soon after. A large right mid-thoracic tumor image was found. Bronchoscopy came out negative for a tumor. After the CT-guided biopsy, the tumor turned out not to be a lymphoma, but a non-small cell lung carcinoma (NSCLC). Conclusions: Chronic pruritus was not associated with cholestasis in a patient with gallstone disease, but rather with a PNS, as the first clinical manifestation of NSCLC, triggering many diagnostic and therapeutic challenges. Full article

Background: Despite advances in immunotherapy, non-small-cell lung carcinoma (NSCLC)’s clinical success is limited, possibly due to substantial immunological alterations in advanced cancer patients. This study examines the immunomodulatory effects of sEVs derived from lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) on T cells. Methods: SEVs were isolated from lung cancer cell lines and Jurkat-E6.1. SEV size and morphology were analyzed by NTA and TEM, respectively, while Western blotting confirmed sEV markers. SEV uptake was assessed, followed by resazurin assay, RNA isolation, quantification, cDNA preparation, RT-PCR, nano LC-MS, and bioinformatic analysis, before and after treating Jurkat-E6.1 cells with sEVs from A549 and SKMES1. Results: Cancer-derived sEVs were efficiently internalized by immune cells, reducing T-cell viability. The real-time PCR analysis showed downregulation of KI67, BCL2, BAX, TNFA, IL6, TGFβ, and IL10, suggesting reduced proliferation, dysregulated apoptosis, and impaired inflammatory and immunosuppressive signaling, and the upregulation of GZMB and IL2 suggests retained cytotoxic potential but possibly dysfunctional T-cell activation. Proteomic analysis revealed 39 differentially abundant proteins (DAPs) in ADC-treated T cells and 276 in SCC-treated T cells, with 19 shared DAPs. Gene Ontology (GO) analysis of these DAPs highlighted processes such as sEV biogenesis, metabolic pathways, and regulatory functions, with ADC sEVs influencing NAD metabolism, ECM binding, and oxidoreductase activity, while SCC sEVs affected mRNA stability, amino acid metabolism, and cadherin binding. The cytoplasmic colocalization suggests the presence of these proteins in the cellular and extracellular lumen, indicating the potential of further release of these proteins in the vesicles by T cells. Conclusion: Lung cancer-derived sEVs regulate T-cell activities through immunoregulatory signaling. The molecular interactions between sEVs and immune cells can reveal novel tumor immune regulatory mechanisms and therapeutic targets. Full article

Globally, lung cancer is the most prevalent cause of cancer-related death. There are two large histological groups of lung cancer: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Based on histopathological and molecular features, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the two major histologic subtypes of NSCLC. Various epidemiological and environmental factors are linked with an increased risk of lung cancer. However, these risk factors show disparities in patients with divergent racial and ethnic backgrounds. Interestingly, different populations were found to harbor distinct molecular features as evidenced by variations in genetic mutation profiles. Moreover, diverse histological and molecular progression patterns are identified in lung cancer, which could be crucial in improving diagnosis, prognosis, and therapeutic planning. In concert with a plethora of nuclear genetic alterations, mitochondrial alteration, epigenetic reprogramming, microbial dysbiosis, and immune alteration signatures have been identified in various lung cancer types. This review article provides a comprehensive overview of screening tests and the treatment strategies for NSCLC and SCLC, including surgery, radiation therapy, chemotherapy, targeted therapies, and immunotherapies. Through the unification of these diverse aspects, this review article aspires to a complete understanding of lung cancer’s genomics, biology, microbial landscapes, and racial disparity and seeks to understand the essential role of racial and ethnic factors in lung cancer occurrence and treatment. Full article