Search Results (13,400)

4-aminoquinazoline derivatives exhibit unique physiological activities, including antitumor, anti-inflammatory, and antibacterial biological activities. Afatinib (BIBW-2992), the representative tyrosine kinase inhibitor, has been developed for the treatment of non-small cell lung cancer. Following our expanded medical chemistry research program, we report a novel 4-aminoquinazoline derivative named JSLN-P (1), (5S)-5-[(2-(5-bromo-2-methoxyphenyl) quinazolin-4-ylamino)methyl]-3-(3-fluoro-4-morpholino phenyl) oxazolidin-2-one, aimed for developing new drugs with antiglioma properties. The title compound JSLN-P (1) was successfully synthesized by amination approaches following benzylamination and oxazolone cyclization, further condensation with 4-(4-bromo-2-fluorophenyl) morpholine, reduction in debenzylation and halogenated amination of quinazolin. The structure of JSLN-P (1) was confirmed by ¹H and ¹³C nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Full article

Background/Objectives: The EGFR T790M mutation drives lung cancer resistance by sterically hindering inhibitors and restoring ATP affinity. As C797S mutations render covalent inhibitors obsolete, novel non-covalent strategies are critical. This study identifies inhibitors that redefine the mutant methionine sulfur as a primary stabilizing anchor rather than a liability. Methods: A generative AI framework (DrugEx) sampled 100,000 molecules, prioritized via QSAR classification (ROC-AUC: 0.91 ± 0.01) and Applicability Domain (AD) mapping. The workflow was de-risked through retrospective benchmarking against the DUD-E database (35,590 molecules), achieving a 1% Enrichment Factor of 5.19. Lead candidates underwent 100 ns all-atom molecular dynamics (MD) simulations. Mechanistic stability was quantified via Free Energy Landscape (FEL) analysis and ensemble-averaged MM-GBSA binding free energy calculations. Results: Candidate 106 demonstrated exceptional mutation tolerance by redistributing interactions toward the Met790 sulfur atom. MD analysis confirmed potency is dictated by successful recruitment of the thioether environment, locking the complex within a narrow thermodynamic basin. Candidate 106 maintained stable binding (−11.0 kcal/mol) corroborated by an equipotent MM-GBSA ΔG_bind of −50.51 kcal/mol in the mutant system, driven by persistent π-sulfur contacts (85% occupancy). Conclusions: These results indicates that potential T790M resistance bypass is achievable by exploiting the gatekeeper methionine’s electronic environment. This modeled mutation-aware framework provides a candidate non-covalent strategy to be validated in future wet-lab campaigns. Full article

Background: This study aimed to comprehensively investigate the complex association between the use of fluoroquinolone (FQ) antibiotics and cancer risk, with a specific focus on patients with interstitial lung disease (ILD)—a unique clinical population characterized by a high inflammatory burden and a high susceptibility to infections. Methods: We conducted a large-scale retrospective cohort study using a high-quality clinical database. A total of 7906 matched patients (3953 pairs) were included after propensity score matching (PSM). Three complementary statistical models were applied: the standard Cox proportional hazards model, the time-dependent Cox regression model, and the Fine–Gray competing-risks model, to provide a multidimensional assessment of cancer risk. Results: A total of 7906 matched patients (3953 pairs) were followed. After strictly defining the index date to eliminate immortal time bias, FQ exposure was associated with an increased risk of all-cause cancer in the standard Cox model (adjusted HR 1.45; 95% CI, 1.20–1.76) and the competing risk model (adjusted SHR 1.28; 95% CI, 1.06–1.55). Site-specific analyses revealed elevated risks for certain malignancies, notably prostate cancer. Importantly, when modeled as a continuous variable, the cumulative dose of fluoroquinolones showed no significant dose–response relationship with overall cancer risk (adjusted HR 0.99; 95% CI, 0.99–1.00). Conclusions: After correcting for immortal time bias, the previously hypothesized protective effect of fluoroquinolones on cancer risk was not observed. The increased risk observed in categorical models, coupled with a lack of a continuous dose–response, strongly suggests that these findings are driven by confounding by indication and reverse causation (i.e., frequent infections masking undiagnosed malignancies or reflecting severe underlying ILD), rather than a direct pharmacological effect. Full article

Background/Objectives: Due to its rapidly aging population, lung cancer is expected to become the second most common and deadliest cancer in Japan. Although surgery is the primary treatment for early-stage non-small cell lung cancer (NSCLC), advances in radiation therapy technology mean that stereotactic body radiation therapy (SBRT) is also a viable option for elderly patients with various underlying health conditions. Methods: We conducted a retrospective analysis to evaluate the outcomes of SBRT in 50 consecutive elderly patients (37 of whom were aged 80 and older) with early-stage peripheral NSCLC (Tis~T2aN0M0), who were treated with SBRT at our hospital and received a total dose of 55 Gy in four fractions. Results: The three-year overall, disease-free and cause-specific survival rates for all patients were 73.2%, 88.5% and 91.4%, respectively. For patients aged 80 years and older, these rates were 77.5%, 90.6% and 91.4%, respectively. There was no local recurrence. Hematogenous metastases were observed in four patients. However, hilar and subcarinal lymph node metastases developed in only one patient. Grade 2 pneumonitis and chest wall injuries (CWIs) were observed in two and five patients, respectively. Patients with larger tumors had a significantly higher incidence of chest wall injuries. Conclusions: SBRT at a total dose of 55 Gy in four fractions can achieve safe and satisfactory outcomes for early-stage peripheral NSCLC, even in patients aged 80 years and older. While CWIs were limited to Grade 2, attention to the chest wall dose is advisable when treating tumors adjacent to the chest wall. Full article

Background: Gastroesophageal reflux disease (GERD) is a common problem that affects patients. The constant irritation of the esophageal mucosa, in addition to the potential aspiration, has been suggested as a predisposing factor for lung cancer (LC). This study aims to investigate the association between GERD and LC. Methods: An electronic search was conducted on EMBASE, CENTRAL, and PubMed databases from inception through November 2025. Studies evaluating the association between GERD and lung cancer in adult populations were included. Reviews, non-English articles, pediatric studies, and non-human studies were excluded. Twelve studies involving 2,900,965 patients met the inclusion criteria. Three types of common and random effect meta-analyses were utilized, namely meta-analysis of proportion, log(HR) and log(OR) models. Included studies were examined for risk of bias using the Newcastle–Ottawa scale. Results: Twelve articles describing 2,900,965 patients were found to be fit for inclusion. Male and female sexes were equally represented. On average, patients were 57.67 ± 10.02 years of age. Pooled proportion of co-occurring LC and GERD in patients was estimated at 64% [95% C.I.: 15–95%; p = 0.02], with significant heterogeneity (I² = 96.8%, p < 0.01). Among studies calculating for hazard ratio (HR), an estimated pooled log(HR) of 1.01 [95% C.I.: 0.36–2.8; p = 0.98] with significant data heterogeneity (I² = 88%, p < 0.01) was found. In comparison, five studies included estimates of odds ratio (OR), which resulted in a pooled log(OR) of 1.32 [95% C.I.: 1.2–1.46; p < 0.01], with less heterogeneity (I² = 59.1%) which was marginally significant (p = 0.04). Conclusions: Our findings may suggest a possible association between LC and GERD; however, estimates were discordant across effect measures and heterogeneity was substantial, so this association should be interpreted with caution. Full article

Lung, breast, colorectal and prostate cancer account for over 41% of global cancer incidence and 39% of mortality, yet durable control of advanced disease remains limited. Plant secondary metabolites are promising multitarget leads, but their polypharmacological mechanisms cannot be captured by single-target approaches, and the evidence across these four cancers has not been synthesised within a unified framework. This review provides an integrated comparative analysis of network-pharmacology studies of plant-derived anticancer compounds across the four cancers, cataloguing phytochemical profiles, identifying shared and cancer-specific targets, quantifying the concordance between computational predictions and experimental validation, and appraising the translational gap. A systematic search of biomedical databases (2016–2026) identified 101 peer-reviewed studies (40 breast, 33 colorectal, 24 lung, and 14 prostate) combining network pharmacology with experimental validation. AKT1, EGFR, TP53, STAT3, MAPK1/3, CASP3, and HSP90AA1 recurred as cross-cancer hub genes, with the phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase pathways most frequently implicated. Cancer-specific signatures comprised the androgen receptor in prostate, the oestrogen receptor and human epidermal growth factor receptor 2 in breast, β-catenin/Wnt in colorectal, and the epidermal growth factor receptor/RAS axis with epithelial-to-mesenchymal transition effectors in lung cancer. Flavonoids, terpenoids, alkaloids, and polyphenols predominated. The persistent validation gap remains the principal barrier to translation. Full article

Background and Clinical Significance: Brain metastases in non-small cell lung cancer (NSCLC) carry a poor prognosis, particularly in patients lacking targetable driver mutations or significant programmed death-ligand 1 (PD-L1) expression. Durable intracranial control exceeding five years is uncommon in this population and the factors that determine exceptional therapeutic response remain incompletely understood; Case Presentation: We report a 59-year-old male with pathological stage pT3N1 solid-type pulmonary adenocarcinoma (EGFR wild-type, ALK wild-type, PD-L1 <1%) who developed two sequential brain metastases following right upper lobectomy and adjuvant pembrolizumab plus pemetrexed-carboplatin. The first lesion was treated with single-fraction stereotactic radiosurgery (SRS, 10 Gy); a second metastasis identified 18 months later was managed with focal radiotherapy (8 Gy, single fraction) followed by whole-brain radiotherapy (24 Gy in 12 fractions). Local progression of the second metastasis in 2024 prompted successful surgical resection via right occipital craniotomy. Over a follow-up exceeding five years, the patient achieved sustained intracranial disease control, preserved neurological function, and maintained quality of life. Notably, no clinically apparent neurocognitive deterioration was documented on routine clinical follow-up, despite whole-brain irradiation without hippocampal sparing; formal neuropsychological testing was not performed; Conclusions: This case demonstrates that durable intracranial control may be achievable through carefully sequenced multimodal therapy—including stereotactic radiosurgery, whole-brain radiotherapy, and neurosurgical resection—even in biologically unfavorable NSCLC. The absence of clinically apparent neurocognitive deterioration on routine follow-up after WBRT raises hypothesis-generating questions regarding interindividual variability in radiation tolerance; this observation must be interpreted in the absence of formal neuropsychological testing and prospective hippocampal dosimetry. A multidisciplinary, individualized approach integrating radiotherapy, systemic therapy, and neurosurgery remains essential in this setting. Full article

Background/Objectives: Intraoperative molecular imaging (IMI) enables real-time visualization of tumor biology during surgery using fluorescent probes and near-infrared imaging systems. As lung cancer screening increases detection of small and nonpalpable pulmonary nodules, conventional localization and margin assessment techniques remain limited, particularly during minimally invasive surgery. This review summarizes the technical foundations, imaging agents, clinical applications, and future directions of IMI in thoracic oncology. Methods: We performed a narrative review to synthesize current evidence regarding the technical foundations, molecular imaging agents, clinical applications, and future directions of intraoperative molecular imaging in thoracic oncology. Given the multidisciplinary scope of the field, a narrative approach was selected to integrate mechanistic, translational, and clinical evidence rather than to answer a single narrowly defined clinical question. Results: IMI generates dynamic intraoperative contrast based on preferential probe accumulation or activation within malignant tissue. Current approaches include non-specific fluorophores such as indocyanine green, activatable probes targeting tumor-associated proteases or acidic microenvironments, and receptor-targeted agents such as pafolacianine. Across prospective studies and multicenter trials, IMI improved localization of nonpalpable lesions, identified occult synchronous malignancies, and enhanced intraoperative margin assessment, frequently altering surgical management. Phase 2 and 3 studies of folate receptor-targeted imaging demonstrated clinically significant findings in a substantial proportion of patients, including lesions not detected by conventional imaging or palpation. However, performance remains dependent on tumor biology, target expression, lesion depth, and optical constraints. Conclusions: IMI represents an emerging transition from anatomy-guided toward biology-informed thoracic surgery by providing real-time molecular information during resection. Current evidence supports its role as a complementary intraoperative technology that augments conventional imaging and surgical techniques, particularly for small, peripheral, and nonpalpable lesions. Full article

Opioids are frequently prescribed for cancer pain management, yet accumulating evidence suggests that opioid exposure may be associated with inferior outcomes in patients also undergoing treatment with immune checkpoint inhibitors (ICIs). To synthesize mechanistic and clinical evidence linking opioids to the PD-1/PD-L1 axis, the literature was searched up to 18 January 2026, with study selection and data extraction focused on (i) cancer-cell and immune-cell effects of opioid agonism or antagonism on PD-1/PD-L1 biology, and (ii) clinical studies reporting ICI outcomes (progression-free survival, overall survival, or treatment duration) with concomitant opioid exposure. Preclinical studies support multiple, non-mutually exclusive mechanisms: opioids can induce PD-L1 in tumour cells, modulate innate-inflammatory pathways (including TLR4-linked cascades), promote dysfunctional T-cell phenotypes that reduce responsiveness to PD-1 blockade, and show context- and opioid-dependent effects. Clinical cohorts and meta-analytic datasets in non-small cell lung cancer and other tumour types report associations between opioid exposure (including higher morphine-equivalent dosing) and worse ICI outcomes. The intersection of opioid signaling with PD-1/PD-L1 biology likely operates across cancer cell-intrinsic and immune cell-intrinsic pathways, providing a mechanistic rationale for prospective evaluation of opioid-sparing strategies and/or peripheral opioid antagonism as adjuncts to checkpoint blockade. Full article

Boron Neutron Capture Therapy (BNCT), as a promising oncological modality, enables the specific therapy of tumor cells while minimizing damage to healthy tissues. It has emerged as a critical strategy for combating refractory malignancies such as glioma, breast cancer, lung cancer, and hepatocellular carcinoma. The development of efficient boron carriers is fundamental to realizing the clinical potential of BNCT. This review systematically traces the evolutionary trajectory of boron carriers, from first-generation soluble borates and second-generation agents to third-generation actively targeted formulations, with a particular focus on the current state of nanoparticle-based carriers. It provides a detailed analysis of the structural properties, boron-loading advantages, targeting modification strategies, and key research findings associated with various nanoplatforms, including liposomes, polymers, dendrimers, boron carbide nanoparticles, and gold nanoparticles. Furthermore, by examining specific tumor cell targets such as folate receptors and integrin receptors, the review elucidates the mechanisms by which nanocarriers achieve tumor boron enrichment through both the enhanced permeability and retention (EPR) effect and ligand-mediated active targeting. The review also critically assesses current challenges in the field, including targeting efficacy, boron loading capacity, in vivo retention, and biocompatibility. Finally, it summarizes emerging strategies—such as multi-target modification, combination immunotherapy, theranostics, and the induction of tumor cell pyroptosis—and provides a forward-looking perspective on future developments, aiming to inform the rational design of next-generation BNCT boron carriers with high targeting specificity, high boron payload, and low toxicity. Full article

Background: Lung cancer carries a high psychosocial burden. Tobacco use, the stigma attached to the disease, and coping strategies are thought to interact and shape psychological outcomes, yet they have rarely been examined together. This review aimed to synthesise the evidence on the relationship between tobacco use, lung cancer stigma, and coping, and how these factors interact and influence patients’ psychological outcomes. Methods: Following the PRISMA 2020 guideline, PubMed/MEDLINE and Dialnet were searched (window 2014–April 2026) for empirical studies conducted in adults with lung cancer that addressed stigma, coping, or relevant psychological outcomes (e.g., anxiety, depression, distress, or quality of life). Study selection and data extraction were performed independently by two reviewers, with discrepancies resolved by consensus and, where needed, by a third reviewer. Methodological quality was appraised with design-specific tools (JBI for cross-sectional and cohort studies, CASP for qualitative studies, and COSMIN-oriented criteria for the psychometric study). Given the clinical and methodological heterogeneity, a structured narrative synthesis was conducted following the SWiM guideline. The protocol was registered in the Open Science Framework. Results: Twenty-four studies were included. Stigma was prevalent and consistently associated with depression, anxiety, distress, and poorer quality of life, with longitudinal evidence indicating that stigma precedes and predicts distress. Internalised stigma (guilt, shame, self-blame) was the facet most strongly linked to depression and anxiety. Smoking history graded stigma intensity (current > former > never smokers) but did not determine it, since clinically significant stigma also affected never-smokers. Adaptive coping (e.g., fighting spirit, positive reappraisal) and social support were consistently associated with better psychological adjustment and quality of life, while maladaptive coping (e.g., helplessness, avoidance, anxious preoccupation) was associated with worse outcomes; cross-sectional evidence further indicated that coping modes mediated the relationship between stigma and quality of life and that social support and self-compassion attenuated the impact of stigma on distress. Conclusions: Internalised stigma is a central, modifiable psychosocial stressor in lung cancer that affects smokers and never-smokers alike. Systematic screening for stigma, coping, and social support, together with non-stigmatising care, is warranted. Full article

Current research primarily focuses on post-treatment resistance, leaving the immediate impact of cisplatin on the tumor–immune interaction poorly understood. Tumor cells were co-cultured with immune cells to assess immune cell activation. The correlation with RAB27A/B and CD274 expression levels in non-small cell lung cancer (NSCLC) were analyzed using TCGA. The relationship between RAB27A/B and the tumor microenvironment was assessed by TIMER2.0. Cisplatin significantly increased PD-L1 mRNA levels and surface protein expression, detected by qPCR, flow cytometry and confocal microscopy. In the co-culture assay, cisplatin-induced cell surface PD-L1 protein levels inhibited the activation of Jukat T-cells. Cisplatin also upregulated genes associated with exosome secretion and increased total exosome particle counts and secretion per cell. Pretreatment with GW4869, an exosome release inhibitor, significantly enhanced cisplatin sensitivity in HCC827 cells. While GW4869 reduced intracellular RAB27A/B and EV PD-L1 levels, it did not alter cellular PD-L1 expression. Bioinformatic analysis further revealed that high RAB27A/B expression correlates with poor 5-year survival in NSCLC and is negatively associated with CD8+ T-cell activation, while positively correlating with cancer-associated fibroblasts. Both RAB27A and RAB27B gene expression levels positively correlated with CD274. Conclusions: RAB27A and RAB27B may be crucial proteins in modulating cisplatin-induced exosomal PD-L1 levels and the tumor microenvironment. Full article

Systematic endoscopic mediastinal lymph node staging is imperative to most accurately define the extent of LN involvement in patients with locally advanced (cN2) NSCLC. It provides the most accurate nodal information in comparison to imaging techniques and is the most likely investigation to differentiate N2a from N2b disease. Accumulation of evidence to validate the prognostic, and potentially the predictive value of accurately defining N2a and N2b N-status will be supported by more consistent and more comprehensive mediastinal endoscopic staging in this group, aided by more detailed (synoptic) reporting. We identify proposed solutions for enhancement of systematic staging in patients with N2 NSCLC, including routine performance of systematic lymph node assessment, with sampling of all LN > 6 mm, addition of EUS-B-FNA where possible, and use of synoptic reporting to reduce variance in care and enable performance monitoring. Full article

Clinical outcomes remain heterogeneous among patients with unresectable stage III non-small cell lung cancer treated with definitive chemoradiotherapy. We evaluated the prognostic value of the systemic immune-inflammation index (SII) and explored survival outcomes according to the concurrent chemotherapy backbone in this setting. This retrospective study included 101 patients treated with definitive chemoradiotherapy before consolidation durvalumab became standard practice. Baseline SII was calculated using routine blood counts. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan–Meier method and Cox proportional hazards models. With a median follow-up of 40.6 months, patients with low SII had significantly longer OS (26.1 vs. 10.9 months, p = 0.004) and PFS (15.6 vs. 7.2 months, p = 0.018) than those with high SII. Elevated SII remained independently associated with inferior OS in multivariable analysis (HR 1.99, 95% CI 1.21–3.27, p = 0.007). Although survival was numerically longer with cisplatin/etoposide than with carboplatin/paclitaxel, the difference was not statistically significant. Subgroup analysis according to SII level and chemotherapy regimen showed the poorest outcomes among patients with high SII receiving carboplatin/paclitaxel. These findings support the prognostic value of SII and suggest a potential role for risk stratification in patients with unresectable stage III NSCLC undergoing definitive chemoradiotherapy in the pre-durvalumab era. Full article