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CD109 is a glycosylphosphatidylinositol‑anchored glycoprotein implicated in tumor progression and physiological homeostasis. Although aberrant CD109 expression has been reported in multiple malignancies, its prognostic relevance across cancer types and its potential immunomodulatory roles remain incompletely characterized. We performed an integrative pan-cancer analysis of CD109 using RNA sequencing data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. CD109 expression, genetic alterations, survival associations, and immune infiltration patterns were systematically assessed. Single-cell RNA sequencing (scRNA-seq) data from non-small cell lung cancer (NSCLC) cohorts were analyzed to define cellular CD109 distribution. Functional validation was performed using siRNA-mediated CD109 knockdown in A549 lung adenocarcinoma cells, followed by macrophage co-culture experiments, flow cytometry, qPCR, ELISA, and migration assays. CD109 was markedly upregulated in 15 tumor types and showed heterogeneous prognostic associations across cancers. Elevated CD109 expression was associated predominantly with unfavorable survival in several tumor types, whereas opposite prognostic associations were observed in a subset of cancers. Bioinformatic analysis revealed that high CD109 expression was associated with an immunosuppressive tumor immune microenvironment, characterized by the enrichment of M2-like tumor-associated macrophages (TAMs) and activation of oncogenic signaling axes. Single-cell profiling showed that CD109 was predominantly expressed in malignant cells and a subset of M2 macrophages. Consistent with these clinical and computational insights, functional validation in an in vitro lung cancer model showed that CD109 knockdown in A549 cells significantly suppressed tumor migration and was associated with a shift in macrophage polarization away from a pro-tumorigenic M2 phenotype toward an anti-tumor M1 state. Our study highlights CD109 as a context-dependent biomarker with tumor type specific prognostic relevance and links its expression to immunosuppressive features of the tumor immune microenvironment. These findings suggest that CD109 warrants further investigation as a potential therapeutic target, particularly in tumor contexts characterized by macrophage-associated immunosuppression, although the macrophage-related functional effects observed here were validated in a lung cancer model and require further investigation in additional tumor types.

Histologically normal mammary tissue from breast cancer patients can harbor significant genetic alterations that could precede visible tumor development and influence disease progression. Whole-exome sequencing was performed on 408 samples from 77 breast cancer patients with poor prognosis, 49 patients recruited without prognosis-based selection, and 15 individuals undergoing non-cancer-related mammoplasty. Paired primary tumor and histologically normal mammary gland tissues were analyzed. Variant classification adhered to strict filtering criteria, incorporating allele frequency thresholds, multiple annotation databases, and in silico prediction tools. Duplex sequencing was employed to detect and confirm pathogenic PIK3CA and TP53 variants in normal mammary tissue samples from 11 breast cancer patients with unfavorable prognosis. Statistical analyses included hypergeometric testing, Kaplan-Meier survival analysis, and Cox proportional hazards modeling. Post-zygotic pathogenic variants in cancer-associated genes were significantly more prevalent in normal mammary tissue of poor-prognosis patients (29%) than in unselected patients (12.5%) (p = 0.0008578). Variant presence and per-individual burden were similar across age-matched cohorts and intrinsic subtypes, indicating that subtype composition, germline predisposition and age do not account for the excess UM variant load in BCAP. Truncating variants were exclusive to poor-prognosis cases. Frequently altered genes included AKT1, PIK3CA, PTEN, TBX3, and TP53, with TP53 variants detected only in patients with adverse outcomes. Duplex sequencing confirmed the presence of low-frequency variants (as low as 1.34%) in regions of histologically normal breast tissue from patients with a poor prognosis. Notably, nearly one-quarter of all identified cases (24%, 12/49) harbored pathogenic variants in normal tissue absent from corresponding primary tumors, suggesting that at least some mosaic clones in uninvolved mammary tissue represent independent evolutionary events rather than residual tumor cells. Post-zygotic pathogenic variants are frequent in histologically normal mammary tissue from breast cancer patients, including alterations in key cancer-associated genes. These findings indicate that mosaic clonal changes outside the tumor are more common than previously appreciated and warrant further investigation. Assessing such variants in non-tumorous tissue may, in the future, help refine approaches to breast cancer risk evaluation and management.

Human papillomavirus (HPV) has been investigated as a potential risk factor in breast cancer, but the literature remains inconsistent. Although biological mechanisms involving HPV E6/E7 oncogene activity provide biological plausibility for viral involvement, reproducible evidence in breast tumors is lacking. This study aimed to determine whether high-risk HPV is detectable or transcriptionally active in breast cancer tissues from young women negative for BRCA1/BRCA2 mutations. This retrospective, single-center study included women younger than 50 years with confirmed BRCA1/BRCA2-negative breast cancer. Formalin-fixed, paraffin-embedded tumor specimens were analyzed for high-risk HPV DNA using a PCR-based assay targeting HPV-16, HPV-18, and pooled high-risk genotypes. A subset of tumors with sufficient residual FFPE material and laboratory acceptance for FFPE-based RNA testing also underwent high-risk HPV E6/E7 mRNA analysis to assess transcriptional activity. Ninety women contributed 91 breast cancer specimens. Demographic, reproductive, and pathological features were consistent with typical early-onset breast cancer. High-risk HPV DNA was not detected in any tumor specimen. All mRNA analyses were also negative, indicating absence of transcriptionally active viral oncogene expression. High-risk HPV was neither detectable nor transcriptionally active in breast cancer tissues from young BRCA1/BRCA2-negative women. These findings do not support a role for high-risk HPV in breast carcinogenesis in this population.

In low- and middle-income countries (LMIC), Do-Not-Resuscitate (DNR) discussions are often delayed or omitted, adversely affecting the quality of end-of-life care. Despite the growing recognition of palliative care, limited evidence exists on the timing and determinants of DNR decisions in these settings. To assess the prevalence, temporal trends and predictors of DNR orders among advanced cancer patients receiving palliative care at a tertiary center in Jordan. We conducted a retrospective review of all deceased advanced cancer patients who received palliative care at the King Hussein Cancer Center between 2013 and 2022. Demographic, clinical, and code status data at referral and at death were extracted from medical records. Descriptive statistics, chi-square tests, and t-tests were used to identify patterns and associations. Among 5,264 patients were analyzed, 48.9% female, 79.9% married, and 94.6% Jordanian. The most common cancer types were gastrointestinal (26.5%), breast (16.6%), and genitourinary (14.9%). At referral, 26.4% had a DNR order, increasing to 81% at death. Cancer type was significantly associated with DNR status at death (p < .001), with breast and gastrointestinal cancers more likely to have DNR orders. The proportion of DNR orders at death demonstrated an overall upward trend across the study period. There was a substantial shift from CPR to DNR orders between referral and death primarily influenced by clinical rather than demographic factors. These findings underscore the importance of early advance care planning and targeted training in culturally sensitive end-of-life communication to promote patient-centered decision making.

Systemic inflammation and nutritional issues have been regarded as cancer complications. As indicators of systemic inflammatory responses, neutrophil/lymphocyte ratio (NLR) and prognostic nutritional index (PNI) have been recommended to be used in the prediction of certain cancer-related clinical complications. The purpose of this study is to investigate the effects of PNI and NLR on the prognosis of gastric cancer. From 2010 to 2018, 559 gastric-cancer patients consecutively undergoing radical surgery were involved in this study. A receiver operating characteristic (ROC) analysis was conducted to determine the optimal cut-off values of PNI and NLR. Using these cut-off values, we categorized the patients into high and low PNI/NLR groups, with clinical characteristics of these two groups compared and analyzed. Low PNI and high NLR were both associated with worse OS in univariate analysis (P&#x2009;<&#x2009;0.001 for both). In multivariate analysis, low PNI remained an independent prognostic factor for poor OS (HR&#x2009;=&#x2009;1.502, 95%CI: 1.135-1.987, P&#x2009;=&#x2009;0.004), while NLR did not demonstrate independent prognostic significance in this cohort. In patients with resectable gastric cancer, preoperative PNI was identified as an independent prognostic factor for overall survival, while NLR did not show independent prognostic value in this cohort. These findings suggest that PNI may be useful in preoperative risk assessment and patient counseling. Further studies are needed to validate these results and directly compare the prognostic performance of PNI and NLR.

Endometrial cancer is one of the most common gynecologic malignancies, with increasing evidence suggesting the involvement of immune-related processes rather than direct immune evasion mechanisms in its progression. However, effective immune-related biomarkers for prognostic evaluation and therapeutic targeting remain limited. This study aimed to identify novel immune-associated molecules based on clinical endometrial cancer specimens using integrated proteomic and bioinformatic approaches. Proteomic analysis was performed on tumor and adjacent normal tissues from endometrial cancer patients. Differentially expressed proteins were screened and further analyzed through transcriptomic validation, survival analysis, immune infiltration assessment, and pathway enrichment to explore their clinical relevance and potential functional roles in the tumor immune microenvironment. IMPDH1 was identified as a significantly upregulated protein in endometrial cancer and was associated with unfavorable prognosis. High expression of IMPDH1 was correlated with reduced CD8&#x207a; T cell infiltration and features of an immunosuppressive tumor microenvironment. Functional enrichment suggested its involvement in purine metabolism and a potential role in immune-related processes. This study identifies IMPDH1 as a novel immune-related biomarker in endometrial cancer, with potential value for prognosis and immunotherapy.

Oxidative stress, generated by both endogenous and exogenous agents, can cause DNA lesions that, if not repaired, accumulate as somatic mutations and can contribute to cancer initiation. Here, we explored this problem through the lens of DNA electronic properties, quantified by the vertical ionization potential (vIP) of nucleobase motifs, which reflects their susceptibility to oxidation. We analyzed genome-wide experimental data on oxidative DNA damage and found that the highest damage levels occur in regions with low vIP values, suggesting a causal link between them. The analysis of cancer mutational signatures and their annotated aetiologies revealed strong anticorrelations between mutation frequency and vIP values, particularly in cancers driven by oxidative DNA damage, such as lung cancer. We further computed anticorrelations between vIP values and the frequencies of mutated motifs across coding and non-coding regions and across different mutation types, observing the strongest anticorrelations for silent mutations, consistent with their reduced selective pressure. Moreover, similar anticorrelations were observed for somatic mutations in cancer and normal tissues, as well as for germline mutations, suggesting that they arise from similar mutagenesis processes. This work clarifies how oxidative damage, DNA electronic properties and carcinogenesis are related and help identify genomic regions more prone to mutations.

The internet has become an important source of information for cancer patients. Numerous websites provide nutritional advice that promises benefits for the outcome of cancer therapy. The aim of our study was to evaluate and compare the online information about cancer diets on German- and English-language websites. A patient's online search was simulated using the search engines Google and Bing. Websites were evaluated by means of content and formal criteria according to a standardized instrument. The analysis of 31 websites revealed heterogeneous quality regarding content and formality, distributed evenly among the German- and English-language websites. The quality of content and formality does not correlate with the website's order of appearance in a browser-based search. The high discrepancy in quality of content and formality represents a risk for cancer patients, who are searching for information online. Content of poor quality and formality increases the risk of mal-information and consecutive false decisions on diet. It results in the decline of therapy response, an increased probability of therapeutic toxicity and a poorer prognosis in general. The visibility of high-quality websites needs to be improved.

Participatory approaches (including co-research, co-design, Patient and Public Involvement [PPI], and Participatory Action Research [PAR]) are increasingly being incorporated into digital health innovation. However, their application in cancer-related digital and Artificial Intelligence (AI) tool lifecycle remains insufficiently synthesised, limiting understanding of how participatory approaches influence ethical outcomes, trust, and the real-world implementation of these technologies. This review moves beyond documenting participatory approaches to critically examine how far participation extends across the AI lifecycle, and how this limits ethical and trust-related outcomes. To examine how participatory approaches are used in the lifecycle of digital and AI-based tools for cancer care, and to analyse their ethical and trust-related impacts. A systematic review was conducted following JBI methodology. Searches of PubMed, Embase, Scopus, and ScienceDirect identified studies published in English between 2010 and 2025. The inclusion criteria required empirical research reporting the participatory involvement of patients, survivors, caregivers, or public contributors in the design, development, implementation, or governance of digital or AI tool development for cancer care. Quality appraisal was performed using the CASP checklist. Data were synthesised using a meta-aggregation approach and organised into thematic domains. Of 2,742 records identified, 40 studies met the inclusion criteria. The largest proportion was published in 2024. Co-design emerged as the most frequently used participatory approach, particularly in early development stages (e.g., requirements identification, content co-creation, usability testing), while participatory involvement in later stages, such as implementation, auditing, or governance, was limited. Participation centred primarily on patients/survivors and clinicians, with caregivers and policy-level stakeholders comparatively under-represented. Most studies focused on general digital health technologies such as mobile apps and telehealth, with relatively few addressing AI-specific development components such as model training, validation, or explainability. Very few studies reported explicit measurements of ethical outcomes such as trust, fairness, or transparency. Participatory approaches are widely referenced but remain predominantly concentrated in early design phases of digital tool development. Future research should extend co-research into later lifecycle stages, include broader stakeholder groups beyond patients and clinicians, and systematically capture ethical and trust-related outcomes. These shifts are necessary to move beyond symbolic participation toward demonstrable and equitable impact in the development of digital and AI-enabled technologies for cancer care.

Chronic obstructive pulmonary disease (COPD) remains substantially underdiagnosed, particularly in individuals with mild or early-stage disease. Individuals undergoing lung cancer screening represent a high-risk population due to significant smoking exposure; however, the burden of previously undiagnosed COPD in this real-world clinical setting remains insufficiently characterized. This retrospective observational study included individuals who underwent national lung cancer screening using low-dose computed tomography (LDCT) at a tertiary referral center between September 2019 and December 2022. The study population consisted of individuals referred for pulmonologist consultation after screening, reflecting real-world clinical practice. Participants without a prior diagnosis of COPD who underwent pulmonary function testing were included. Clinical characteristics, pulmonary function parameters, and CT findings were analyzed. Multivariable logistic regression analysis was performed to identify factors associated with previously undiagnosed COPD. Among 279 individuals who underwent pulmonologist consultation, 170 had available spirometry and were included in the analysis. Of these, 63 individuals (37.1%) met spirometric criteria for COPD despite having no prior diagnosis. Participants with previously undiagnosed COPD were more likely to report dyspnea and demonstrated greater physiologic impairment and structural lung abnormalities, including a trend toward lower diffusion capacity and CT-defined emphysema. In multivariable analysis, dyspnea, reduced DLCO, and CT-defined emphysema were independently associated with COPD. A substantial proportion of individuals undergoing lung cancer screening were found to have previously undiagnosed COPD. These findings highlight a gap in real-world screening workflows and support the potential value of integrating spirometry or respiratory assessment into lung cancer screening programs to facilitate early detection and timely management of COPD in high-risk populations.

Breast and cervical cancer represent a significant disease burden. Health care quality measures captured through electronic clinical data systems could be used to assess follow-up of abnormal breast and cervical cancer screening results. The National Committee for Quality Assurance (NCQA) wanted to explore the feasibility of using health plan electronic clinical data systems to develop quality measures for follow-up of abnormal breast and cervical cancer screening test results. NCQA interviewed quality improvement leaders from ten health plans, recruited through a purposive sample representing varying sizes, geographic regions, and commercial, Medicare, and Medicaid product lines. Health plan leaders identified several barriers, including a lack of standardized data integration as well as opportunities such as supporting provider and health system data aggregation and other support. Findings indicate that improved data governance, particularly around data standardization and information technology infrastructure integration, would increase the feasibility of monitoring follow-up after abnormal breast and cervical cancer screening results.

Prostate cancer mortality trends and spatial clustering in Kazakhstan over the last two decades require detailed national and regional assessment using time-trend and spatial statistics.&#x200b; METHODS: A nationwide population-based observational study evaluated prostate cancer deaths (ICD-10 C61) among men in Kazakhstan from 2005 to 2024, calculating crude and age-standardized mortality rates, assessing temporal changes using joinpoint regression, and identifying spatial hot spots/cold spots using Getis-Ord Gi* across five predefined periods (2005-2012, 2013-2017, 2018-2019, 2020-2021, 2022-2024). A total of 7,411 deaths were recorded; the overall crude mortality rate (CMR) was 4.44 per 100,000 men and the age-standardized mortality rate (ASMR) was 6.54 per 100,000 men, with deaths concentrated in ages 65-79 (65-69: 19.2%; 70-74: 22.3%; 75-79: 18.9%) and age-specific mortality peaking at 103.04 per 100,000 in ages 80-84. National joinpoint analysis identified a statistically non-significant, essentially stable trend from 2005 to 2019 (annual percent change [APC]&#x2009;0.7%, p&#x2009;=&#x2009;0.397), followed by a statistically significant accelerated decline from 2019 to 2024 (APC&#x2009;=-8.4%, p&#x2009;<&#x2009;0.001), with an overall average annual percent change (AAPC) of -2.8% (p=0.004) for 2005-2024. Regional ASMR varied substantially (3.1 per 100,000 in Kyzylorda to 10.5 per 100,000 in Almaty city), and mean regional ASMR decreased from 6.57 (2005-2012) to 4.30 (2022-2024) with shifting hot spot/cold spot patterns across periods. Prostate cancer mortality in Kazakhstan declined significantly over 2005-2024, but substantial and evolving geographic disparities persisted, supporting the need for continued surveillance and targeted regional cancer-control actions.

Lipoid pneumonia (LP) is a rare inflammatory lung disease caused by lipid accumulation in alveolar spaces. Its nonspecific clinical and radiological features often lead to misdiagnosis as lung cancer, resulting in potentially avoidable surgical interventions. We conducted a retrospective case series of six patients who underwent surgical resection at our institution between 2019 and 2025 with a preoperative suspicion of lung cancer but were ultimately diagnosed with LP by postoperative histopathology. Clinical presentations, imaging features, tumor marker levels, and pathological findings were analyzed. All six patients had pulmonary nodules or masses highly suggestive of malignancy on chest CT, including ground-glass opacities, spiculated margins, and cystic changes. Two patients had elevated tumor markers (CEA (carcinoembryonic antigen) or NSE (neuron-specific enolase)). Final pathological examination revealed intra-alveolar lipid-laden macrophages, cholesterol clefts, and chronic granulomatous inflammation, consistent with LP. Most patients denied a specific history of lipid aspiration, though one case had a habit of applying intranasal cooling oil. LP can closely mimic lung cancer both radiologically and biochemically. A high index of suspicion is required in patients with atypical pulmonary lesions, even when tumor markers are elevated. Pathological examination remains the gold standard for diagnosis. Early recognition may help avoid potentially avoidable surgery.

This systematic review synthesizes existing literature to identify the current status and key influencing factors related to death anxiety in family caregivers of cancer patients. A comprehensive search was conducted across seven databases-PubMed, Embase, PsycINFO, Scopus, Web of Science, MEDLINE, and CNKI on July 26th, 2025, with no time restrictions applied. The quality of all included studies was assessed using the Joanna Briggs Institute critical appraisal tools for cross-sectional studies. Eighteen studies were included in the systematic review. Based on our analysis, death anxiety among family caregivers of cancer patients may be influenced by the following six categories of factors: (a) personal factors, (b) disease and caregiving-related factors, (c) psychosocial factors, (d) self-regulatory factors, (e) other factors, and (f) actor and partner effects. Several specific protective and risk factors related to death anxiety were also identified. This review categorizes influencing factors, including protective factors, risk factors, and several contested personal variables, associated with death anxiety. There is a need for longitudinal research to further elucidate the dynamic nature of death anxiety over time. Future studies should adopt a dyadic perspective encompassing both cancer patients and their family caregivers to provide comprehensive insights for healthcare professionals and facilitate the development of effective interventions targeting death anxiety.

Breast cancer is the most commonly diagnosed malignancy in women worldwide, and its marked heterogeneity together with the complexity of the tumor microenvironment contributes to substantial variability in therapeutic responses. Although conventional studies have mainly focused on tumor cell-intrinsic alterations, increasing evidence has identified the neuroimmune axis as a critical regulator of breast cancer progression and treatment resistance. The neuroimmune axis involves bidirectional crosstalk between the nervous system and the immune system, mediated by neurotransmitters, neuropeptides, and neurotrophins. These mediators modulate immune cell activity and reshape tumor behaviors, including proliferation, epithelial-mesenchymal transition, angiogenesis, and metastasis, while immune-derived cytokines can in turn remodel neural circuits and sustain a pro-tumor microenvironment. In this review, we summarize the major mechanisms underlying neuroimmune regulation in breast cancer and discuss emerging therapeutic strategies, including repurposing of neuroactive agents, breast-targeted drug delivery systems, neural stimulation combined with immune checkpoint blockade, and microbiota-neuroimmune interventions. We also outline key challenges to clinical translation, such as the spatiotemporal heterogeneity of neuroimmune regulation, the narrow therapeutic window of neuropharmacological agents, and the lack of standardized biomarkers. A deeper understanding of the neuroimmune axis may provide a theoretical basis for precision therapeutic strategies and help improve outcomes, particularly in therapy-resistant subtypes such as triple-negative breast cancer.

Repeat transurethral resection of bladder tumor (TURBT) is recommended in selected patients with newly diagnosed bladder cancer to improve staging accuracy and detect residual disease, but it also increases morbidity and treatment burden. The Vesical Imaging-Reporting and Data System (VI-RADS) has shown high accuracy for predicting muscle invasion, whereas its role in identifying patients who undergo repeat TURBT remains unclear. This study evaluated the clinical value of VI-RADS for predicting repeat TURBT status in primary bladder cancer. This single-center prospective observational study included 59 patients with newly diagnosed primary bladder tumors who underwent preoperative multiparametric magnetic resonance imaging and initial TURBT. VI-RADS scores were assigned by an experienced radiologist blinded to pathological findings. Associations between VI-RADS and clinicopathological variables were examined using Spearman's correlation analysis. Diagnostic performance for predicting repeat TURBT status was assessed by receiver operating characteristic analysis. Univariable and multivariable logistic regression models were used to identify independent predictors of undergoing repeat TURBT. Repeat TURBT was performed in 31 patients (52.5%). Higher VI-RADS categories were more frequently observed among patients who underwent repeat TURBT, whereas lower categories predominated in the single-TURBT group. Among patients undergoing repeat TURBT, residual malignancy was identified in 66.7% of VI-RADS 4 lesions and 88.9% of VI-RADS 5 lesions. VI-RADS correlated significantly with tumor grade, invasion depth, tumor size, and number of surgical procedures. ROC analysis showed modest discriminatory ability for predicting repeat TURBT status (AUC 0.635, 95% CI 0.491-0.778; p&#x2009;=&#x2009;0.066). At a cutoff of VI-RADS&#x2009;&#x2265;&#x2009;3, sensitivity was 70.4% and specificity was 59.4%. In multivariable analysis, only invasion depth at initial TURBT independently predicted repeat TURBT. VI-RADS was associated with pathological tumor severity and with repeat TURBT status, but it did not independently predict undergoing repeat TURBT. These findings support VI-RADS as an adjunctive preoperative tool rather than a stand-alone determinant for repeat resection decisions.

This meta-analysis aimed to systematically evaluate the incidence and risk of dizziness associated with novel endocrine therapies (androgen receptor pathway inhibitors, ARPIs) in patients with advanced prostate cancer. A comprehensive literature search was conducted across PubMed, Web of Science, and ClinicalTrials.gov databases. After screening titles/abstracts and full-texts, 4 eligible randomized controlled trials (RCTs) involving 4267 patients were included. Risk of bias assessment was performed using the Cochrane Risk of Bias (RoB 2) tool. Meta-analysis results indicated that ARPI-based therapy was significantly associated with an increased risk of all-grade dizziness (risk ratio [RR]&#x2009;=&#x2009;1.60, 95% confidence interval [CI]: 1.28-2.00, I2&#x2009;=&#x2009;18.7%, p&#x2009;=&#x2009;0.2955) compared with control. For grade&#x2009;&#x2265;&#x2009;3 dizziness, the pooled RR was 2.03 (95% CI: 0.56-7.29, I2&#x2009;=&#x2009;0.0%, p&#x2009;=&#x2009;0.8165), though statistical significance was not reached. Subgroup analyses by ARPI type (abiraterone [Abi], Abi&#x2009;+&#x2009;enzalutamide [Enz], darolutamide [Dar], Enz) showed no significant differences in dizziness risk among subgroups (p&#x2009;=&#x2009;0.2026). In conclusion, novel endocrine therapy with ARPIs increases the risk of all-grade dizziness in prostate cancer patients, while the risk of severe dizziness remains non-significant. Clinicians should monitor dizziness symptoms during ARPI treatment to optimize patient management.

Eligibility criteria for lung cancer (LC) screening aim to identify long-term smokers who have exceeded a minimum-risk threshold of having LC, while still having sufficiently long remaining life expectancy. For individuals who have once met eligibility criteria (i.e., reached sufficiently high LC risk), a question is whether longer-term smoking cessation and corresponding improvement in other-cause mortality risk could justify a higher maximum screening age for former smokers than for continuing smokers. We performed time-varying Cox models in the EPIC-Heidelberg cohort (N&#x2009;=&#x2009;24,715), using 3-yearly questionnaire data collected between 1994 and 2014 to estimate hazard ratios (HRs) and incidence rates for death by LC or other causes, in relation to age-specific smoking status and eligibility by German LC screening criteria (LCSC). Depending on age, models showed up to 3-fold higher risk of other-cause mortality for recent and LCSC-eligible smokers, relative to never smokers. Among former smokers, those who quit before age 30 or 40 showed no significant difference in other-cause mortality compared with never-smokers, in men and women, respectively. However, at higher quitting ages HRs increased up to about 1.9 for men who stopped at age &#x2265;60, or 1.5 in women who stopped at age 50-<60. Also, depending on age, former smokers who had once met the LCSC, but then quit for >10 years (thereby losing formal screening eligibility), showed HRs of about 1.5&#x2013;3.0 for other-cause mortality in men and 1.3&#x2013;1.9 in women. In both sexes, the absolute incidence rate for other-cause mortality amongst past-eligible smokers age 75-<80 was similar to that for current-eligible smokers of the younger, 70-<75-year age group. For LC, both current and former smoking were associated with persistently increased HRs, even after long-term cessation. For smokers who once met LCSC, but then quit for >10 years the risk of other-causes mortality remains elevated, but less so than for continuing smokers, which may argue for a moderate extension of the maximum age limit for LC screening. Larger studies will be needed to obtain more precise risk estimates.

Hepatocellular carcinoma, the third leading cause of cancer-related deaths globally, presents a critical public health burden in China due to its high incidence and mortality. While targeted therapies and immunotherapies have improved survival in advanced HCC, drug resistance remains a major therapeutic challenge. Recent studies suggest that gefitinib, an EGFR inhibitor, overcomes lenvatinib resistance, yet its mechanistic underpinnings are incompletely understood. To investigate gefitinib's metabolic effects in HCC, we conducted untargeted metabolomic profiling using two separate platforms: gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) with both hydrophilic interaction liquid chromatography (HILIC) and reversed-phase modes. Raw data were processed by Mass Hunter, normalized with internal standards, and analyzed via SIMCA for pattern recognition. Principal component analysis (PCA) of quality control samples and experimental groups (n&#x2009;=&#x2009;6 each) confirmed system stability and clear inter-group separation. Orthogonal projections to latent structures discriminant analysis models were validated by 200 permutation tests. Analysis identified 42 metabolites with VIP >&#x2009;1, of which 25 showed significant alterations (p&#x2009;<&#x2009;0.05) post-gefitinib treatment. KEGG/RaMP-DB enrichment revealed perturbations in four key pathways: arginine-proline metabolism, nitrogen metabolism, branched-chain amino acid biosynthesis, and taurine metabolism. These results delineate gefitinib-induced metabolic reprogramming in HCC cells, providing a foundation for targeting metabolic vulnerabilities to overcome therapy resistance.