Search Results (606)

Background/Objectives: Retinoic acid receptor γ (RARγ), encoded by RARG, is increasingly recognized as a cancer-associated regulator through aberrant expression in multiple solid tumors and recurrent gene rearrangements in acute myeloid leukemia. While the oncogenic relevance of RARγ is well established, the potential involvement of its N-terminal activation function-1 (AF1) domain in human cancer remains poorly characterized. Previous biochemical studies demonstrated that phosphorylation of Ser66 and Ser68 in RARγ2, corresponding to Ser77 and Ser79 in canonical RARγ1, is required for ligand-dependent receptor activation, ubiquitination, and proteasome-mediated degradation. Methods: To determine whether this experimentally validated phosphoregulatory region is altered in human cancer, we interrogated the Catalogue of Somatic Mutations in Cancer (COSMIC v104, GRCh38) at single-residue resolution. Mutation data were integrated with clinical and pathological information obtained from the corresponding primary publications and public annotation resources. Results: Rare somatic mutations affecting the AF1 phosphoregulatory region were identified, including the missense variants p.S77L and p.S79L, the nonsense variant p.S79*, and the in-frame insertion p.S77_P78insLQ. These alterations occurred in independent epithelial malignancies, including cervical neuroendocrine carcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, bladder carcinoma, and gastric neuroendocrine carcinoma. Notably, the truncating p.S79* mutation was detected in five spatially distinct regions of a single EGFR-mutant lung adenocarcinoma, consistent with an early clonal event during tumor evolution. Rare cancer-associated mutations affect a previously characterized AF1 phosphoregulatory module of RARγ. These findings extend established RARγ regulatory biology into the context of human malignancy and broaden the spectrum of reported cancer-associated RARG alterations. While the functional consequences of these rare variants remain unknown, their occurrence within residues known to regulate receptor activation and turnover highlights the AF1 phosphoregulatory region as a candidate for future mechanistic investigation. Full article

LIM and calponin homology domain-containing protein 1 (LIMCH1) has recently gained attention as a functionally perplexing factor in human cancers, with studies attributing both tumor-suppressive and tumor-promoting properties that defy simple categorization. Originally described as an actin-associated cytoskeletal protein that promotes non-muscle myosin-IIA (NM-IIA) activity and thereby curtails cell migration, LIMCH1 has more recently been linked to diverse oncogenic pathways across a range of tumor types. In lung adenocarcinoma and clear-cell renal cell carcinoma, diminished LIMCH1 expression is associated with more aggressive clinical behavior and reduced overall survival, aligning with a tumor-suppressive role. By comparison, in triple-negative and invasive breast cancers and in cervical squamous cell carcinoma, increased LIMCH1 expression correlates with enhanced metastatic spread, immune escape, and unfavorable outcomes, suggesting a pro-oncogenic function. In this review, findings from over 30 published studies are integrated with an original TCGA pan-cancer expression and survival analysis to propose that LIMCH1 is best understood as a context-dependent conditional regulator rather than as a classical tumor suppressor or oncogene. Based on the available evidence, we propose a hypothesis-generating conceptual framework in which its ultimate phenotypic effect is shaped by three interacting contextual determinants: (i) TP53 mutation status (determining whether the HUWE1-p53 axis is intact); (ii) tumor matrix stiffness (modulating actomyosin contractility and migration mode); and (iii) upstream signaling cues (e.g., MAPK/ERK, TGFβ). Of note, other tumor-lineage and microenvironmental factors may also contribute and warrant further investigation. This framework resolves the apparent functional duality of LIMCH1 in a cancer type-specific manner and provides critical guidance for future mechanistic research, standardized detection workflows, and the clinical translation of LIMCH1-based biomarkers. Full article

Adhesion G protein-coupled receptor D1 (ADGRD1), formerly known as GPR133, has been implicated in tumor-associated signaling; however, its histology-specific clinicopathologic and prognostic significance in non-small cell lung cancer (NSCLC) remains incompletely characterized. Clinical and survival data from The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) and lung squamous cell carcinoma (TCGA-LUSC) cohorts were integrated with harmonized gene-expression data obtained from the Genomic Data Commons (GDC). ADGRD1 expression was dichotomized using a cohort-specific median cutoff and additionally analyzed as a continuous standardized variable. Clinicopathologic associations, Pearson correlations with prespecified subtype-associated genes, Kaplan–Meier survival analyses, and univariate and multivariable Cox proportional hazards regression analyses were performed. Benjamini–Hochberg false-discovery-rate correction was applied to molecular correlation analyses. Independent validation was performed using GSE30219 and GSE50081, followed by random-effects meta-analysis and proportional hazards sensitivity analyses. High ADGRD1 expression was associated with favorable overall survival (OS) in LUAD in both univariate (HR = 0.542, 95% CI = 0.400–0.734, p < 0.001) and clinically adjusted Cox analyses (HR = 0.543, 95% CI = 0.398–0.740, p < 0.001). Continuous-expression analyses showed concordant results, and the association remained significant in an additional LUAD model incorporating EGFR mutation status (HR = 0.611, 95% CI = 0.391–0.956, p = 0.031). High ADGRD1 expression was also associated with favorable recurrence-free survival (RFS) in LUAD. In contrast, high ADGRD1 expression was associated with adverse OS in LUSC in both univariate (HR = 1.444, 95% CI = 1.099–1.898, p = 0.008) and clinically adjusted analyses (HR = 1.501, 95% CI = 1.137–1.982, p = 0.004), whereas RFS was not significantly different. After false-discovery-rate correction, ADGRD1 correlated positively with TP53 expression in LUAD and inversely with CDKN2A, SOX2, and PIK3CA in LUSC. Independent GEO validation supported the favorable LUAD association (pooled HR = 0.675, 95% CI = 0.538–0.847, p < 0.001), whereas the adverse LUSC association was not independently reproduced (pooled HR = 0.909, 95% CI = 0.686–1.204, p = 0.504). ADGRD1 shows histology-dependent prognostic associations in NSCLC. Its favorable association with survival in LUAD was robust across dichotomized and continuous analyses, multivariable adjustment, EGFR-mutation sensitivity analysis, and independent GEO cohorts. In contrast, the adverse association observed in TCGA-LUSC was not reproduced externally. These findings support further evaluation of ADGRD1 as a subtype-specific prognostic marker, particularly in LUAD. Full article

Background/Objectives: Outcomes in non–small cell lung cancer (NSCLC) remain heterogeneous, even within stage and molecular subtypes. We evaluated whether a Computational Histology Artificial Intelligence (CHAI) biomarker, derived solely from the diagnostic hematoxylin-and-eosin (H&E) whole-slide image (WSI), provides prognostic information independent of established clinicopathologic factors. Methods: Using The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) projects, 914 patients with an evaluable diagnostic digitized whole-slide images (WSI) and outcomes data were stratified by stage and histology and randomly split into a development set (30%, N = 270) and a held-out validation set (70%, N = 644). A CHAI histologic signature was developed and locked on the development set and applied without modification to the validation set. In development, image features were extracted from H&E-stained WSIs and used to train a Cox proportional hazards model to output a CHAI prognostic biomarker score and then dichotomized into high (CHAI positive (+))- and low (CHAI negative (−))-risk groups. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free interval (PFI). Associations were assessed by Kaplan–Meier and Cox proportional-hazards models and adjusted for traditional clinicopathologic and genomic variables. Results: A total of 644 patients were included in the validation cohort. Median age was 68 (IQR: 60–74), 388 (60%) were male, 317 (49%) had LUAD, 327 (51%) had LUSC, and 57 (9%) were never smokers. CHAI-positive patients had significantly worse OS than CHAI-negative patients (3-year OS: 53% vs. 69%; log-rank p < 0.001). The biomarker remained significantly associated with OS (HR 1.70, 95% CI 1.29–2.24, p < 0.001) and PFI (HR 1.39, 95% CI 1.05–1.84, p = 0.023) in multivariable analysis. The effect was consistent across both histologies, and a model combining the CHAI score with clinicopathologic variables was well-calibrated in validation. The biomarker was not associated with stage, age, sex, or histologic subtype, and its adjusted prognostic effect was unchanged after relevant genomic alterations were added to the model. CHAI-positive tumors were, however, enriched for KRAS mutations (21% vs. 11% wild-type, p adjusted = 0.005). Conclusions: An H&E-only CHAI NSCLC biomarker was developed and provided independent prognostic stratification in a held-out NSCLC validation cohort. Such a biomarker has the potential to refine risk stratification in NSCLC. Full article

Lung cancer is the leading cause of cancer-related mortality worldwide, yet the majority of cases are diagnosed at advanced stages when a cure is rarely achievable. Low-dose computed tomography (LDCT) screening in high-risk populations reduces lung cancer mortality by 20–24% in randomised trials, but fewer than 20% of eligible adults in the United States undergo annual screening. We conducted a structured narrative review of PubMed, Embase, and the Cochrane Library for studies published between January 2002 and March 2026, supplemented by review of current clinical guidelines from the USPSTF, NCCN, ACS, CHEST, and ERS. Evidence from the National Lung Screening Trial (NLST) and the NELSON trial establishes the mortality benefit of LDCT screening, though both trials have important methodological limitations that affect generalisability. The NLST predominantly detected non-small cell lung cancer (NSCLC), particularly adenocarcinoma and squamous cell carcinoma, while small cell lung cancer (SCLC) was infrequently screen detected and showed no survival benefit from early detection. Guideline eligibility criteria have progressively broadened, and multivariable risk model-based selection using the PLCOm2012 now demonstrates superiority over categorical smoking thresholds in prospective validation cohorts, with the added benefit of reducing racial and ethnic eligibility disparities. Overdiagnosis estimates have declined substantially with extended follow-up, reaching 7% when observation exceeds five years. Implementation remains critically deficient: patient stigma, provider knowledge gaps, structural barriers, and inadequate electronic health record infrastructure collectively account for screening uptake below 20%. Integrating smoking cessation into screening encounters is evidence-based and cost-effective. Artificial intelligence tools show promising performance in nodule detection and risk prediction, but lack the prospective external validation required for routine clinical deployment. The field has established efficacy; the urgent challenge is now effectiveness at scale. Transitioning to risk model-based eligibility, expanding access to underserved populations, and mandating cessation integration represent the three highest-priority actions. A research agenda addressing never-smoker screening, personalised intervals, and robust AI validation must proceed in parallel. Full article

Background and Objectives: Non-small cell lung cancer (NSCLC) comprises biologically distinct histologic subtypes, including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We evaluated whether the prognostic association of cyclin-dependent kinase-like 2 (CDKL2) differs by histology. Materials and Methods: TCGA CDKL2 expression was linked to harmonized clinical data. The primary analysis used a pooled multivariable Cox model with continuous standardized CDKL2 expression, histology, and a CDKL2 × histology interaction, adjusted for age, sex, pathologic stage, and smoking. Additional analyses assessed model assumptions, tumor purity, tumor-versus-normal expression, KEGG pathways, the tumor microenvironment, and single-cell RNA sequencing. External evaluation used GSE30219. Results: The primary TCGA cohort included 943 patients (471 LUAD, 472 LUSC; 375 deaths). Higher CDKL2 expression was associated with lower mortality in LUAD (HR per 1 pooled SD = 0.721, 95% CI 0.603–0.862, p < 0.001) but higher mortality in LUSC (HR = 1.237, 95% CI 1.011–1.515, p = 0.039), with a significant interaction (HR = 1.717, p < 0.001) persisting after tumor-purity adjustment. CDKL2-low tumors were enriched for cell-cycle, DNA-replication, proteasome, and DNA-repair programs. Single-cell analyses showed predominant epithelial detection and greater malignant-cell CDKL2 detection in LUAD. In GSE30219, the favorable LUAD association was supported in a median-split-adjusted analysis of 207073_at (HR = 0.473, 95% CI 0.250–0.897, p = 0.022), whereas the corresponding continuous estimate was directionally favorable but nonsignificant; 236331_at was nonsignificant in both models; neither probe supported the adverse LUSC association or histology interaction. Conclusions: Higher CDKL2 expression showed a favorable prognostic association in LUAD, with consistent TCGA sensitivity analyses and limited but suggestive independent-cohort support. The adverse LUSC association remains preliminary, and CDKL2 should be regarded as a candidate prognostically associated marker rather than an established clinical biomarker. Full article

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically “cold” tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3Kγ, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites. Full article

Background and Clinical Significance: This paper presents a case of Vogt–Koyanagi–Harada (VKH)-like disease following nivolumab and ipilimumab therapy for squamous cell carcinoma of the lung, complicated by transient type 1 macular neovascularisation (MNV). Case Presentation: A 67-year-old man presented with reduced visual acuity, more pronounced in the left eye, accompanied by headache and neurosensory hearing loss for 10 days. He had been receiving combination therapy with nivolumab and ipilimumab for approximately nine weeks. Slit-lamp examination and multimodal imaging revealed multiple serous retinal detachments, choroidal folds, and bacillary layer detachment. A bilateral VKH-like syndrome was considered the most likely diagnosis, consistent with an immune-related adverse event (irAE). High-dose systemic corticosteroids were initiated, resulting in marked anatomical improvement and recovery of visual acuity. Following multidisciplinary discussion with the patient’s oncologist, ipilimumab was permanently discontinued and nivolumab was rechallenged in combination with chemotherapy after resolution of the ocular adverse events, given the progression of the underlying malignancy. Notably, optical coherence tomography angiography (OCTA) additionally demonstrated a type 1 non-exudative MNV, which resolved spontaneously during follow-up. Conclusions: Nivolumab and ipilimumab, targeting PD-1 and CTLA-4, respectively, are effective anticancer therapies but may induce immune-related adverse events involving the eye. VKH-like disease is a rare but potentially vision-threatening complication. Early recognition and prompt treatment are essential for favourable visual outcomes. In summary, this is a rare case of VKH-like disease associated with nivolumab and ipilimumab therapy, complicated by transient inflammatory type 1 MNV. Clear guidelines are needed regarding management of ocular immune-related adverse events and decisions on continuation or discontinuation of life-prolonging immunotherapy. Full article

Background/Objectives: Loss of phosphatase and tensin homolog (PTEN) activity is a frequent feature of non-small-cell lung cancer (NSCLC), and epigenetic repression may contribute to its reduced expression. This study investigated the effects of 5-aza-2′-deoxycytidine (5-aza-dC) on PTEN, DNA methyltransferase 1 (DNMT1), PTEN promoter methylation-specific amplification patterns, and miR-148a-3p expression in NSCLC models. Methods: Publicly available cancer-genomics datasets were analyzed to compare PTEN and DNMT1 transcript abundance and to assess the association between PTEN methylation and transcript abundance in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). A549 and H460 cells were exposed to 2.5 or 5 µM 5-aza-dC for 72 h. Reverse-transcription quantitative PCR (RT-qPCR), Western blotting, methylation-specific PCR (MSP-PCR), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to evaluate RNA expression, protein abundance, methylation-specific amplification, and metabolic activity, respectively. Results: Bioinformatic analyses showed lower PTEN and higher DNMT1 expression in both NSCLC subtypes, together with inverse associations between PTEN methylation and transcript abundance. In both cell lines, 5-aza-dC reduced MTT metabolic activity and DNMT1 expression. PTEN mRNA and protein abundance increased significantly at 5 µM, whereas no significant changes were detected at 2.5 µM. MSP-PCR revealed persistent heterogeneous PTEN methylation-specific amplification patterns without clear evidence of progressive promoter demethylation. miR-148a-3p exhibited a biphasic response in A549 cells but remained unchanged in H460 cells. Conclusions: These findings support an association between 5-aza-dC exposure, increased PTEN expression, and reduced DNMT1 expression in NSCLC cells. Quantitative methylation analysis and mechanistic validation are required to clarify the contribution of miR-148a-3p to this regulatory association. Full article

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies. Full article

Background: Squamous cell carcinomas (SCCs) share squamous differentiation and may engage the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway, although their causes, biology, and treatment differ by anatomical site. We evaluated tumor response, short-term survival, and grade 3–4 adverse events after neoadjuvant immune-checkpoint blockade, with or without chemotherapy, followed by surgery. Methods: A comprehensive search of PubMed, Embase, the Cochrane Library, and clinical trial registries was conducted from inception to October 2024. Prospective and retrospective studies evaluating neoadjuvant immunotherapy, with or without chemotherapy, before surgery in patients with SCC were included. In mixed-histology studies, data were eligible only when SCC outcomes could be extracted separately. Pooled proportions and 95% confidence intervals (CIs) were estimated with random-effects models. Results: A total of 44 studies involving 2586 patients with six anatomical SCC groups were included. The pooled objective response rate (ORR) was 0.70 (95% CI, 0.59–0.80), clinical complete response (cCR) rate was 0.17 (95% CI, 0.10–0.28), and pathological complete response (pCR) rate was 0.30 (95% CI, 0.27–0.34). The pooled 1-year progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS) rates were 0.82 (95% CI, 0.79–0.86), 0.86 (95% CI, 0.75–0.92), and 0.92 (95% CI, 0.90–0.93), respectively. The pooled incidence of grade 3–4 adverse events was 0.18 (95% CI, 0.14–0.23). Because the PD-L1 subgroup contained only one study for most outcomes, checkpoint-target subgroup findings were considered exploratory. Conclusions: Existing predominantly single-arm evidence suggests antitumor activity of neoadjuvant immune-checkpoint blockade, with or without chemotherapy, in selected patients with resectable SCC. Because esophageal SCC accounted for most studies and clinical heterogeneity was substantial, these pooled proportions should not be interpreted as comparative effects or as evidence of uniform benefit across SCC sites. Full article

Background: Metronomic chemotherapy (MCT), understood as continuous, low-dose cytotoxic administration without prolonged drug-free intervals, has become an established strategy in several solid tumors, acting primarily through antiangiogenic, immunomodulatory, and direct cytostatic mechanisms rather than replication-dependent cytotoxicity. Despite an expanding evidence base, including positive randomized trials, validated predictive biomarkers of response remain unavailable. Methods: We searched PubMed/MEDLINE, Embase, and ClinicalTrials.gov (January 2000 to July 2026) for phase II/III randomized trials, prospective cohorts, and selected retrospective analyses of MCT in breast cancer, head and neck squamous cell carcinoma, NSCLC, and mCRC, and extracted biomarker data from embedded translational substudies of eligible trials. Results: In breast cancer, phase III SYSUCC-001 (adjuvant metronomic capecitabine, improved DFS in TNBC) and MECCA (metronomic capecitabine plus aromatase inhibitor in HR+/HER2− disease) provide the strongest evidence, supported by randomized phase II data for the VEX regimen (METEORA-II) and MCT-anti-PD-1 combinations. TEMPO LUNG established metronomic vinorelbine as effective in platinum-unfit NSCLC, while CAIRO3 confirmed metronomic capecitabine–bevacizumab as an effective mCRC maintenance therapy. Most recently, the phase III TMC-I trial extended positive randomized evidence to head and neck cancer. Candidate biomarkers span angiogenic, immune, tumor proliferative, molecular, pharmacodynamic cytokine, on-treatment clinical (adverse-event-based), and gut–microbiome domains, with FOXC1, circulating endothelial cell kinetics, VEGF pathway markers, and regulatory T-cell dynamics among the most promising; however, none has been prospectively validated in a dedicated confirmatory trial. Conclusions: MCT has moved from empirical use to an evidence-based strategy across multiple tumor types, but the lack of validated predictive biomarkers limits informed patient selection. Future trials should incorporate biomarker-driven designs, particularly FOXC1, endothelial cell kinetics, and immune profiling as co-primary objectives. Defining an MCT-sensitive biological phenotype remains the key translational challenge for the field. Full article

Background: Cetuximab-based therapies continue to play an important role in the management of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) despite the increasing use of immunotherapy. However, data regarding treatment outcomes and prognostic factors remain limited. This study aimed to evaluate treatment outcomes and prognostic factors associated with survival in patients with R/M HNSCC treated with cetuximab-based regimens. Methods: This retrospective single-center cohort study included patients with recurrent/metastatic HNSCC who received cetuximab-based systemic therapy at the Department of Medical Oncology, Manisa Celal Bayar University Faculty of Medicine, between May 2012 and September 2025. Demographic, clinical, laboratory, and PET/CT data were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with survival were evaluated using univariable and multivariable Cox proportional hazards regression analyses. Results: A total of 57 patients were included in the study. The median age was 65 years, and 91.2% of patients were male. Most patients had ECOG performance status 0–1 (94.7%) and stage IV disease (71.9%). The larynx was the most common primary tumor site (50.9%), while distant lymph node metastasis (63.2%) and lung metastasis (61.4%) were the predominant metastatic sites. Median PFS and OS were 4.6 months and 13.8 months, respectively. Kaplan–Meier analysis demonstrated that patients with a body mass index (BMI) > 25 had longer OS, whereas chronic kidney disease (CKD), primary tumor localization, and best response to first-line treatment were significantly associated with survival. In multivariable Cox regression analysis, chronic kidney disease (CKD) (HR: 5.15, p = 0.004), oral cavity primary tumor localization (HR: 2.55, p = 0.013), progressive disease as the best response to first-line treatment (HR: 4.44, p < 0.001) and the absence of grade 1–2 cetuximab-related dermatologic toxicity (HR: 3.20, p = 0.027) remained independent adverse prognostic factors. BMI was not independently associated with survival in multivariable analysis. Conclusions: Cetuximab-based therapy demonstrated clinically meaningful activity in patients with R/M HNSCC. Comorbidities, primary tumor localization, the absence of grade 1–2 cetuximab-related dermatologic toxicity and treatment response appear to substantially influence survival outcomes. Larger prospective studies are warranted to validate these findings. Full article

Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in metastatic non-small cell lung cancer (NSCLC), yet only a subset of patients derives durable benefit, suggesting that host and tumor-related factors may modify treatment efficacy. The renin–angiotensin system has been implicated in regulation of the tumor microenvironment, and angiotensin-converting enzyme inhibitors (ACEIs) have therefore been proposed as potential modulators of immunotherapy response. Material and methods: We conducted a retrospective observational cohort study including patients with advanced metastatic NSCLC treated in the first-line setting with treatment-based immunotherapy, with or without chemotherapy, between January 2017 and September 2025. Chronic ACEI exposure was defined as continuous use for at least two years prior to initiation of immunotherapy. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier estimates and compared using the log-rank test, and multivariable Cox proportional hazards models were adjusted. Results: Among 446 eligible patients, 71 (16%) received ACEIs and 375 (84%) did not. The median age of the cohort was 67.5 years, and 70% were male. Adenocarcinoma was the predominant histology (67.7%), and most patients received chemo–immunotherapy (81.6%), while 18.4% received immunotherapy alone. PD-L1 expression ≥ 1% was present in 59.2% of patients. In the overall cohort, median PFS and OS were 12 and 15 months, respectively. Median OS was 17 months in the ACEI group compared with 14 months in the non-ACEI group (log-rank p < 0.047), while median PFS was 14 months versus 11 months, respectively (p = 0.066). The survival advantage was more pronounced for OS than for PFS and remained consistent after adjustment for clinical characteristics including age, sex, ECOG performance status, smoking status, histology, treatment regimen, and PD-L1 expression. Conclusions: These findings suggest that chronic ACE inhibitor use may be associated with improved outcomes in metastatic NSCLC patients treated with immune checkpoint inhibitors. Full article

Background and Objectives: Environmental exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a potential contributor to cancer-related biological variability; however, human biomonitoring data in oncology populations remain limited. The present study aimed to assess urinary concentrations of selected phenolic EDCs and their associations with cardiometabolic, hematological, inflammatory, and survival-related parameters in patients with advanced lung cancer. Materials and Methods: A total of 190 patients diagnosed with stage IIIB/IV lung cancer were included in this study. Urinary concentrations of bisphenol A (BPA), bisphenol S (BPS), triclosan (TCS), and resorcinol (RCO) were determined using validated analytical methods. Associations between exposure biomarkers and clinical laboratory parameters were evaluated using sex-stratified statistical analyses and regression models adjusted for age and body mass index. Results: TCS was the most frequently quantified compound (29.47%), followed by BPS (27.37%), RCO (11.58%), and BPA (7.89%). Higher odds of TCS quantification were observed in patients with lung adenocarcinoma and a higher probability of BPA quantification in patients with squamous-cell carcinoma. Sex-specific exposure patterns were observed, with higher BPA and BPS concentrations measured among female patients. Exposure to phenolic EDCs was associated with alterations in kidney function biomarkers, liver enzyme activity, inflammatory cell profiles, and anthropometric indicators. In particular, BPA and BPS showed associations with renal function markers and systemic inflammatory parameters, while TCS exposure was related to reduced leukocyte subpopulations. Survival analysis demonstrates borderline associations for BPA between exposure groups. Conclusions: These findings provide novel human biomonitoring evidence linking exposure to phenolic endocrine-disrupting chemicals with systemic metabolic and inflammatory variability in patients with advanced lung cancer. The observed associations support the biological plausibility that environmental endocrine disruptors may contribute to interindividual heterogeneity in cancer-related physiological responses. Full article