Objective:To evaluate the impact of deep learning image reconstruction (DLIR) on quantitatively assessing emphysema, air trapping and small airway dysfunction in chronic obstructive pulmonary disease (COPD) using low-dose inspiratory-expiratory chest CT. Methods:Sixty-nine COPD patients underwent low-dose inspiratory-expiratory chest CT scans and pulmonary function tests (PFT) were prospectively enrolled. The CT images were reconstructed using 50% adaptive statistical iterative reconstruction (ASiR-V), DLIR-high (DLIR-H), medium (DLIR-M), and low (DLIR-L) strengths. The volumes and its percentages (relative to whole lung) characterizing emphysema, air trapping and small airway dysfunction were quantified on the inspiratory-expiratory CT scans. Results:The total dose-length product was 128.99 ± 39.00 mGy·cm. For all patients, emphysema parameters were lowest for DLIR-H and highest for ASiR-V; small airway dysfunction parameters were highest with DLIR-H and lowest with ASiR-V; air trapping parameters were lowest with ASiR-V; highest with DLIR-M. Emphysema parameters demonstrated moderate negative correlations with FEV1/FVC (r = -0.570 to -0.649, all p < 0.001). Air trapping and small airway dysfunction parameters showed weak negative correlations with MEF25%, MEF50%, and MEF75% (r = -0.320 to -0.381, all p < 0.001). When differentiating GOLD I-II from III-IV, all parameters showed AUC values ranging from 0.69 to 0.76, without statistically differences among reconstructions (DeLong's test, p > 0.05), while the optimal thresholds varied across reconstructions. Conclusion:In low-dose inspiratory-expiratory chest CT, DLIR may alter the lung function-related CT parameters compared to ASiR-V, but does not affect their correlations with PFTs or their efficacies in GOLD grading.
Introduction:Ground-based walking training is an aerobic exercise used in supervised pulmonary rehabilitation (PR). Physical activity (PA) interventions typically promote step counts, but it is unclear whether community-based walking intensity can be targeted as aerobic exercise. This randomized controlled trial evaluated a web-based, pedometer-mediated PA intervention designed to increase walking amount and intensity. Material and Methods:Participants with COPD who had never enrolled in PR were randomized 1:1 to control or intervention. The intervention included individualized step-count goals, iterative feedback, educational content, and an online community forum. The Fitbit Inspire Heart Rate objectively monitored daily step counts. Participants were instructed to achieve step-count goals with as many steps of moderate-intensity as possible guided by a modified Borg rating of 4-5 for dyspnea. The primary outcome was change in PA measured as average daily step count at 12 weeks. Aerobic intensity was assessed by the Rapid Assessment of PA Questionnaire which uses self-reported moderate or vigorous PA to categorize responders as underactive or active. Linear mixed-effects models (PROC MIXED, SAS v9.4), adjusting for group, time, group*time, FEV1%predicted, enrollment season, and study modality (eg, in-person, virtual, hybrid), assessed between-group change. Results:Participants (57 intervention, 52 control) were 97% male, mean age 73±7 years, and baseline FEV1 73±23% predicted. Baseline daily steps were 4,222±1,929 (intervention) and 4,851±2,637 (control). Intervention participants increased average daily steps by 1,410 steps/day more than controls (p=0.005). The intervention group showed greater transitions from underactive to active intensity (between-group: p=0.025), with 20 (41%) moving to active status (within-group: p=0.001). Conclusion:Technology-mediated community-based walking increased PA amount and intensity. These findings support further evaluation of this intervention as a potential option for ground-based walking training with objective measurement of exercise intensity.
Chronic obstructive pulmonary disease (COPD) is a prevalent and devastating condition responsible for substantial morbidity and mortality in the United States (US). Although the burden of cardiopulmonary (CP) comorbidity in COPD is increasingly known, CP risk remains frequently under-recognized and suboptimally managed in routine clinical practice. Definitions of CP risk in COPD vary across the literature and clinical settings. CP risk may be broadly defined as the risk of serious respiratory and/or cardiovascular events in patients with COPD, including COPD exacerbations, myocardial infarction, stroke, heart failure decompensation, arrhythmia, and death. While current clinical guidelines recognize comorbidity, there remain no clear protocols for screening, risk assessment, or a coordinated multidisciplinary approach to address the CP risk in patients with COPD. To address these gaps, a multidisciplinary expert panel developed consensus-based guidance through an iterative process incorporating an expert-led narrative review supported by targeted desk searches alongside multiple rounds of expert input. This paper identifies critical gaps in the management of CP risk among patients with COPD in the US and outlines actionable steps towards improvement of care. Actionable recommendations include encouraging earlier screening and risk assessment to identify patients at risk of exacerbations and improving patient access to multidisciplinary teams, prompting earlier initiation or optimization of evidence-based treatment. Furthermore, implementation of fully coordinated treatment strategies through primary care settings and increasing the use of preventative strategies in the clinic such as spirometry, vaccination, and smoking cessation are recommended. By shifting to proactive, multidisciplinary care, healthcare practitioners can better address the complex needs of patients with COPD to reduce their CP risk and improve individual and population-level outcomes.
Background:Chronic obstructive pulmonary disease (COPD) often coexists with lung cancer, worsening clinical outcomes. This study aimed to develop machine learning models for early COPD screening in lung cancer patients using clinical variables and a novel systemic coagulation-inflammation index (SCI). Methods:We retrospectively enrolled 1016 patients, extracting demographic, smoking, vital, and laboratory data. After feature selection with Boruta and least absolute shrinkage and selection operator (LASSO), six models-logistic regression, decision tree (DT), multilayer perceptron (MLP), support vector machine (SVM), gradient boosting decision tree (GBDT), and extreme gradient boosting (XGBoost)-were trained on 70% of the data and tested on 30%. Model performance was assessed with area under the curve (AUC), accuracy, sensitivity, specificity, precision, F1 score, and calibration, while SHapley Additive exPlanations (SHAP) and contour plots helped interpret the best model and explore predictor interactions. Results:Among the 1,016 patients, 182 (17.9%) had concomitant COPD. Boruta and LASSO identified 8 key predictors: age, historical smoking index (HSI), SCI, eosinophils (EOS), bicarbonate (HCO3 -), sex, lymphocytes (LYM), and hemoglobin (HGB). The GBDT model showed the best performance, with an area under the curve (AUC) of 0.74 (95% CI: 0.69-0.80) and moderate sensitivity (0.68) and specificity (0.66). SHAP analysis revealed age, HSI, and SCI as major risk factors, with contour plots indicating a synergistic effect between SCI, age, and HSI on COPD risk. Conclusion:A GBDT-based model built from routine clinical variables and SCI showed moderate discrimination for identifying patients with lung cancer at high risk of concomitant COPD.
Background:Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality, and integrated stress response (ISR) participates in its progression. Traditional COPD diagnosis relies mainly on GOLD criteria, while ISR-based auxiliary molecular markers are still lacking. This study aimed to comprehensively analyze and identify ISR-related biomarkers in COPD, and to uncover their underlying molecular mechanisms. Methods:COPD data were obtained from the GEO database. Biomarkers were identified and validated through a comprehensive approach, including differential expression analysis, machine learning algorithms, expression level verification, and receiver operating characteristic (ROC) curve analysis. Moreover, a nomogram was applied to construct an ISR-related predictive model for COPD. Enrichment analysis, immune infiltration analysis, molecular regulatory network, and drug prediction were performed to further confirm the regulatory roles of biomarkers. Furthermore, the expression patterns of biomarkers in core cells were investigated using dataset GSE173896. Furthermore, Western blotting was employed to detect the protein expression levels of biomarkers in clinical samples. Results:Overall, 2 biomarkers (MYC and BAG3) were identified as significantly associated with ISR in COPD. A predictive nomogram constructed based on MYC and BAG3 demonstrated excellent diagnostic performance, with an area under the curve (AUC) value of 0.799. The biomarkers were significantly enriched in the MAPK signaling pathway and cell cycle. Notably, biomarkers were positively correlated with effector memory CD4 T cells and eosinophils. Subsequently, 36 microRNAs (miRNAs) (like hsa-miR-4699-3p), 260 transcription factors (TFs) (like SNAI2, ZBTB43, and ZNF395) and 9 drugs (like staurosporine and N-acetyl-L-cysteine) were associated with the biomarkers. Moreover, significant changes in MYC and BAG3 expression were observed during T cell differentiation. Clinically, MYC and BAG3 were significantly upregulated in COPD tissues, with protein levels increased by 58.4% and 252.2% respectively. Conclusion:This study identified and preliminarily verified ISR-associated MYC and BAG3, offering novel molecular references to complement conventional COPD clinical assessment.
Background:Advanced chronic obstructive pulmonary disease (COPD) is associated with multimorbidity and substantial healthcare use. However, sex differences in documented multimorbidity and healthcare use near the end of life remain insufficiently understood. Methods:This retrospective population-based cohort study used routinely collected administrative and clinical data from Clalit Health Services, Israel. The study included deceased patients with advanced COPD during 2016-2020 and 2022-2023. The year 2021 was excluded a priori as the period designated in the study protocol to minimize distortion in healthcare utilization, and mortality patterns; 2020 remained part of the prespecified observation window. The cohort comprised 2261 patients aged ≥55 years who met an operational definition requiring documented COPD, FEV1/FVC <0.70, FEV1 <50% predicted, and at least two opioid prescriptions or dispensations during the final year of life. The opioid criterion was not considered a stand-alone diagnostic criterion or evidence of refractory dyspnea. Women and men were compared regarding demographic characteristics, multimorbidity, selected healthcare-use indicators, coded palliative care encounters, and time from first documented COPD diagnosis to death. Results:The cohort included 547 women and 1714 men. Women were older and more frequently had dementia and rheumatic/connective tissue disease. Men more frequently had myocardial infarction, renal disease, peripheral vascular disease, and diabetes. Men had more documented procedures, although the effect size was small. The mean Charlson Comorbidity Index differed by 0.44 points, of uncertain clinical importance. Coded palliative care encounters were rare and available only for small subsamples. Median time from first documented COPD diagnosis to death was 33 months among women and 29 months among men, without a statistically significant difference (log-rank p=0.328). Conclusion:Sex differences were observed primarily in documented multimorbidity. Healthcare-use and palliative-care findings were partial and descriptive and should not be interpreted as complete end-of-life trajectories or causal effects of sex.
Background:Anemia is common in chronic obstructive pulmonary disease (COPD) and may be influenced by air pollution-related metal accumulation. However, the biological links among air pollution, intracellular metals, immune gene expression, and erythrocyte alterations remain unclear. Methods:We examined associations between air pollutants, intracellular metals, gene expression, and erythrocyte indices in sixty-one COPD patients and ten healthy controls. Annual exposures to particulate matter with aerodynamic diameter ≤10 µm (PM10), ≤2.5 µm (PM2.5), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were estimated using land use regression. Metals were quantified by inductively coupled plasma mass spectrometry (ICP-MS) and single-cell ICP-MS. Gene expression in peripheral blood mononuclear cells (PBMCs) was profiled by RNA sequencing. Results:In COPD, PM2.5 was associated with higher red blood cell (RBC) count (β = 0.0314×106 cells/µL; 95% confidence interval (CI): 0.0066 ~ 0.0561) and ln(red cell distribution width) (β = 0.0051; 95% CI: 0.0003 ~ 0.0098). PM2.5 was also associated with higher ln(chromium (Cr)) in PBMCs (β = 0.0632; 95% CI: 0.0124 ~ 0.1139), ln(zinc (Zn)) in RBCs (β = 0.1338; 95% CI: 0.0388 ~ 0.2288), and ln(cadmium (Cd)) in RBCs (β = 0.1297; 95% CI: 0.0125 ~ 0.2469). RBC Cr, Cd, lead, and vanadium were positively associated with hemoglobin, hematocrit, and mean corpuscular volume. In PBMCs, Cr, Cd, Zn, and single-cell iron were associated with ALPL, CXCR1, and PI3 expression. Anemic COPD patients showed upregulation of IFI27 and TRAV38-1 and downregulation of DEFA1, PI3, CXCR1, and ALPL. Conclusion:Intracellular metals, particularly Cr and Cd, were associated with immune-related gene expression profiles and anemia-related erythrocyte indices in COPD. These findings suggest potential biological associations among air pollution exposure, intracellular metal burden, immune dysregulation, and hematologic alterations in COPD.
Purpose:We compared salivary metabolomic signatures from patients with stable COPD across a range of severity of airflow obstruction with healthy controls. Patients and Methods:In this exploratory study, 47 people with COPD and 48 age-matched, healthy controls, provided saliva that was assessed by flow infusion electrospray mass spectrometry (FIE-MS). Spectra were interrogated using an open-source library DIMEpy package. Results:Four potential biomarkers identified the presence of COPD with a sensitivity of 73% and specificity of 72%. Six metabolites predicted the level of airflow obstruction, FEV1% in the COPD cohort (P < 0.001, R2 > 0.3, AUC > 0.7), whilst a range of multivariate approaches targeted six metabolites linked to COPD stage of severity (P < 0.001, AUC > 0.7). Identification of the metabolites suggested changes in pterin biosynthesis, lipid processing, nucleotide metabolism and melatonin in COPD patients. Conclusion:This proof-of-concept study shows metabolic fingerprinting of saliva samples is feasible and can differentiate patients with COPD from people (including smokers) without COPD and correlates with COPD severity as defined by level of airflow obstruction. Metabolic fingerprinting also offers insights into the metabolic pathways involved in COPD aetiology.
Claudin 18 isoform 2 (CLDN18.2) has emerged as a clinically validated therapeutic target in gastric and gastroesophageal junction (GEJ) adenocarcinoma following the regulatory approval of zolbetuximab in combination with first-line chemotherapy. Accurate prevalence data at the clinically validated immunohistochemical threshold are essential for patient selection, healthcare resource planning, and treatment strategy. Reported prevalence estimates vary widely across studies due to differences in populations, methodologies, and immunohistochemical protocols. This systematic review and meta-analysis aimed to generate a robust pooled prevalence estimate of CLDN18.2 expression at the threshold used in pivotal phase III trials. PubMed, Embase, and the Cochrane Library were searched from database inception through March 12th, 2026. Studies reporting CLDN18.2 expression in gastric or gastroesophageal junction adenocarcinoma using the ≥ 75
Immunotherapy has changed the therapeutic approach to advanced gastric cancer (AGC) and has shown survival benefits compared with standard chemotherapy. However, in clinical practice, its use remains heterogeneous. Differences in diagnostic pathways, organisational aspects, and regional settings may lead to delays in treatment access. This study aimed to analyse these issues and to describe possible shared strategies to improve the use of immunotherapy in AGC in Italy. The analysis was performed in two steps. First, a focus group comprising 13 oncologists and pathologists from 5 national reference centres was organised to collect information on the use of immunotherapy biomarker tests and the main barriers encountered in daily practice. Based on the topics emerging from this discussion, a second step was conducted using a consensus questionnaire. The questionnaire was sent to a multidisciplinary group composed of 19 oncologists, pathologists, surgeons, pharmacists, and endoscopists. Several common problems were reported during the focus group discussion. These included delays in biomarker testing, differences in pre-analytical procedures among centres, the absence of shared quality indicators, and difficulties in tracking tissue samples, especially when samples were sent from outside hospitals. In addition, limited interaction among different specialists was frequently mentioned. The results of the questionnaire indicated a high level of agreement on several proposed actions, such as the evaluation of regional differences, the use of organisational models already adopted in some Italian oncology networks, the introduction of new biomarkers together with dedicated training activities, and the use of digital tools to support the discussion of complex cases. All survey items reached the predefined consensus threshold. This study identified several organizational and diagnostic challenges affecting the implementation of immunotherapy in AGC. Participants highlighted a number of potential priorities for improvement, including optimization of diagnostic workflows, stronger multidisciplinary collaboration, and greater coordination across centres. These findings may inform future initiatives aimed at reducing variability in clinical practice and supporting equitable access to innovative treatments.
Appendiceal adenocarcinoma is a rare malignancy with a high risk of peritoneal recurrence, especially in locally advanced stages. While intraoperative systemic chemotherapy (ISC) is standard for metastatic disease, its role in non-metastatic Stage II–III patients remains controversial. This study aimed to evaluate the survival benefit of ISC in this population. We conducted a retrospective cohort study using the National Cancer Database (2006–2022). Patients with clinical Stage II–III (T4, N0–2) appendiceal adenocarcinoma who underwent surgical resection were included. Overall survival (OS) was compared between patients who received ISC and controls using Kaplan-Meier statistics and multivariable Cox proportional hazard models. A total of 616 patients were identified, 130 (21.1
Tumor-agnostic targeted therapy has expanded precision oncology by allowing selected molecular alterations to guide treatment across conventional organ boundaries. In gastrointestinal (GI) cancers, however, actionability is not uniformly independent of histology. This narrative review examines NTRK and RET fusions as paradigmatic tumor-agnostic targets and contrasts them with histology-tuned or GI-specific fusion-directed strategies, particularly NRG1 fusion-positive pancreatic adenocarcinoma and cholangiocarcinoma. Targeted PubMed/MEDLINE and regulatory-agency searches were updated through August 3, 2026. In the initial 55-patient larotrectinib analysis, ORR was 75
CLDN18.2 is specifically overexpressed in gastric cancer tissues and represents an important emerging therapeutic target in gastriccancer treatment. Bispecific antibodies (BsAbs), a class of antibody-based therapeutics capable of simultaneously targeting two antigensites, have recently entered clinical development for the treatment of CLDN18.2-positive gastric cancer. This review systematicallysummarizes the molecular designs, functional subtypes, and clinical development of CLDN18.2-related BsAbs, while analyzing currentchallenges and potential optimization strategies. Currently, CLDN18.2-related BsAbs that have entered clinical development mainlycomprise three categories: T-cell engagers, T-cell costimulators, and immune checkpoint-blocking BsAbs. These agents havedemonstrated preliminary antitumor activity in later-line monotherapy and first-line combination therapy settings, with generallymanageable safety profiles. Optimization of target combinations, precise patient selection, strategies to overcome efficacy limitations, and improved safety management represent important directions for enhancing the therapeutic value of BsAb-based approaches.
The incorporation of immune checkpoint inhibitors (ICIs) into first-line therapy has changed the treatment landscape of advanced gastric and gastroesophageal junction cancer. This review summarizes the clinical evidence for chemotherapy after prior ICI exposure, discusses potential biological mechanisms, and considers practical treatment sequencing in the ICI era. We conducted a targeted narrative review of PubMed/MEDLINE and major oncology congress proceedings through July 19, 2026. Original clinical studies reporting outcomes of systemic chemotherapy after prior ICI exposure in advanced gastric or gastroesophageal junction cancer were prioritized, with selected evidence from other tumor types and mechanistic studies included for context. Retrospective and observational studies suggest that chemotherapy after anti-PD-1 therapy can retain clinically meaningful activity, although the evidence is heterogeneous and largely non-randomized. Taxane plus ramucirumab is the most extensively studied post-ICI regimen, but available data in the contemporary first-line-ICI setting do not establish superiority over other guideline-supported second-line options. Whether favorable outcomes reflect true immunologic chemosensitization, residual immune activation interacting with subsequent cytotoxic or anti-angiogenic therapy, or patient selection remains unresolved. Current evidence supports individualized selection among guideline-recommended second-line regimens, including taxane plus ramucirumab, single-agent taxane, and irinotecan, after first-line fluoropyrimidine/platinum plus ICI. Prospective post-ICI validation and biomarker-integrated studies are needed.
Purpose:Experimental studies suggest that lithium may modulate emphysema-related tissue injury through activation of the WNT/β-catenin signaling pathway. However, clinical data examining the relationship between lithium exposure and emphysema burden remain limited. This study aimed to investigate the association between long-term lithium use and CT-derived emphysema burden in smokers with bipolar disorder. Patients and Methods:This retrospective observational study included 67 smokers with bipolar disorder who had received lithium treatment for at least 5 years and 71 matched controls with similar demographic and smoking characteristics. Quantitative emphysema measurements were obtained from thoracic computed tomography using low attenuation area percentage (LAA%). Multivariable linear regression analyses were performed adjusting for age, sex, BMI, and smoking exposure. Results:Right, left, and total lung LAA% values were lower in the lithium-treated group than in controls (7.53% vs 10.11%, p=0.009; 7.73% vs 10.02%, p=0.019; and 7.64% vs 10.07%, p=0.011, respectively). In multivariable analysis, lithium treatment remained independently associated with lower total LAA% after adjustment for age, sex, body mass index, and smoking exposure (B = -2.636, standardized β = -0.236, 95% CI -4.537 to -0.736; p = 0.007). Weak inverse correlations between serum lithium concentrations and emphysema measurements were observed in unadjusted analyses but were no longer significant after multivariable adjustment. Conclusion:Long-term lithium exposure was associated with lower CT-derived emphysema burden in smokers with bipolar disorder. Given the observational design and potential influence of inspiratory effort during CT acquisition, these findings should be considered hypothesis-generating rather than evidence of a protective effect. Prospective longitudinal and mechanistic studies are warranted to clarify the relationship between lithium exposure and smoking-related parenchymal lung injury.
Background:The systemic immune-inflammation index (SII) is derived from routine blood counts, but its incremental value for disease-specific early readmission after acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains uncertain. We evaluated the association between admission SII and 90-day AECOPD-related unplanned readmission and its value beyond available clinical variables. Methods:This single-center retrospective development cohort included 207 unique patients hospitalized for AECOPD from January 2024 to January 2025; only the first eligible hospitalization per patient was analyzed. Readmissions were ascertained from electronic records and structured telephone follow-up completed on June 30, 2025. SII was calculated from the first blood count obtained within 24 hours of arrival. Logistic regression, receiver operating characteristic analysis, 1000-resample bootstrap internal validation, calibration assessment and decision curve analysis were performed. Bootstrap validation assessed optimism in discrimination, calibration and net benefit. Results:Seventy-eight patients (37.7%) experienced AECOPD-related unplanned readmission within 90 days. Each 500-unit increase in SII was associated with higher adjusted odds of readmission (odds ratio 1.329, 95% confidence interval 1.153-1.530; p < 0.001). Apparent AUC was 0.809 (95% confidence interval 0.742-0.869) for the integrated model versus 0.752 (0.678-0.821) for the limited clinical model. The absolute increase was 0.057 (bootstrap 95% confidence interval 0.014-0.101), and adding SII improved model fit (likelihood-ratio p < 0.001). Optimism-corrected AUC, calibration intercept and slope were 0.785, -0.003 and 0.874. Otherwise identical NLR and PLR models had corrected AUCs of 0.775 and 0.765; pairwise differences were inconclusive. Conclusion:Higher admission SII was associated with 90-day AECOPD-related unplanned readmission and improved discrimination beyond a limited clinical model. These exploratory single-center findings require external validation, recalibration and prospective impact assessment before clinical implementation.
Objective:This study aimed to construct a biopsychosocial network model of dyspnea-related fear in older adults with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), identify central and bridge nodes within the psychological system, and explore structural associations linking fear symptoms to emotional distress and functional impairment. Methods:A total of 317 hospitalized older adults with AECOPD were enrolled. Eight variables were assessed, including fear of dyspnea (Fear-D), fear of activity (Fear-A), anxiety (Anx), depression (Dep), psychological resilience (Psy-R), self-efficacy (Self-E), social support (Social-S), and activities of daily living (ADL). Gaussian Graphical Models (GGM) were estimated using EBICglasso. Centrality indices, bridge strength, node predictability (R2), and non-parametric bootstrap procedures were applied to evaluate network stability and accuracy. Results:Anxiety demonstrated the highest expected influence (z = 1.34), functioning as the most central node. Fear-D and Fear-A formed a cohesive dyad (edge weight = 0.51), while Anx and Dep exhibited the strongest edge (0.76). Protective factors (Self-E and Psy-R) showed negative associations with fear and anxiety nodes and significant bridge strength across communities. ADL was structurally embedded between psychological and emotional domains. Network stability analysis confirmed high robustness (CS coefficient > 0.70). The topology reflects a "indicating a structured pattern of fear-emotion co-occurrence and resource-related associations" configuration. Social support (Social-S) demonstrated near-zero centrality, suggesting minimal structural integration within the network under acute hospitalization conditions. Conclusion:Dyspnea-related fear in older AECOPD patients operates within a structured pattern of emotional and resource co-occurrence rather than a simple linear fear-disability pathway. Anxiety serves as the most central node, whereas self-efficacy functions as a cross-domain bridge node. Targeting high-centrality emotional nodes and strengthening resource bridges may optimize precision psychological intervention in AECOPD.
Claudin 18 isoform 2 (CLDN18.2) has emerged as a clinically actionable target in gastric and gastroesophageal junction adenocarcinoma. Zolbetuximab plus chemotherapy established the first validated CLDN18.2-directed strategy, but also highlighted clinically important limitations: incomplete primary sensitivity, spatial and temporal heterogeneity of antigen expression, gastrointestinal toxicity, uncertain biomarker persistence after treatment, and the absence of an evidence-based sequence after progression. These limitations have accelerated development of antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies, T-cell engagers, and rational combinations with chemotherapy or immune checkpoint blockade. This review summarizes current evidence through July 2026, examines plausible mechanisms of resistance and biomarker evolution, and proposes a cautious, modality-specific framework for future clinical development. Updated clinical data support proof of concept across multiple modalities. IBI343, an exatecan-based ADC, has shown antitumor activity with predominantly hematologic toxicity; vedotin-based ADCs demonstrate a different linker-payload profile with additional concern for microtubule-related cumulative toxicity. Randomized phase II data with satricabtagene autoleucel have established progression-free survival benefit over treatment of physician's choice in previously treated disease, although lymphodepletion-related cytopenias and cytokine-release syndrome require specialized infrastructure. Early studies of givastomig and IBI389 further support immune-engaging approaches. Tissue immunohistochemistry remains the reference method for treatment selection; circulating tumor DNA cannot currently reproduce membranous protein intensity or spatial distribution, and liquid-biopsy approaches for CLDN18.2 reassessment remain investigational.
The Advanced Lung Cancer Inflammation Index (ALI) combines body mass index, serum albumin, and the neutrophil-to-lymphocyte ratio, but overlaps with many other prognostic scores in pancreatic ductal adenocarcinoma (PDAC). We evaluated whether ALI is independently prognostic in de novo metastatic PDAC and whether it adds information beyond performance status and established scores. In this single-centre retrospective cohort of patients with de novo metastatic PDAC diagnosed between 2019 and 2023, ALI was calculated at diagnosis. It was compared head-to-head with NLR, PNI, mGPS, CONUT, SII, PLR, LMR, and HALP using Harrell’s concordance index (C-index), and its incremental value over a clinical model (ECOG performance status, CA 19 − 9, liver metastasis, age) was quantified with bootstrap internal validation. Of 102 patients, 101 were analysable (47 deaths; median follow-up 14.3 months). Low ALI (≤ 26.4) was associated with shorter median overall survival than high ALI (10.6 vs. 21.8 months; hazard ratio 1.97; p = 0.025), but this was not independent after multivariable adjustment for performance status (adjusted hazard ratio 1.62, 95
