Introduction:Circulating immune cells serve as readily accessible biomarkers in cancer patients. Some of them, such as neutrophils, lymphocytes as well as the neutrophil to lymphocyte ratio (NLR), have been validated as prognostic indicators of disease outcome whereas the significance of others remains controversial due to conflicting findings. Moreover, the interplay and correlation among these markers have not been thoroughly investigated nor has their dynamic course during chemotherapy. Methods:Blood was collected from 16 healthy donors and 90 patients receiving first line chemotherapy for metastatic colorectal cancer before, during and after chemotherapy. Neutrophils, lymphocytes, circulating CD4+CD25+FOXP3+ regulatory T lymphocytes (Tregs), monocytic myeloid derived suppressor cells (mMDSCs), polymorphonuclear myeloid derived suppressor cells (pMDSCs) and other exploratory myeloid subsets were immunophenotyped and quantified with flow cytometry. Their frequencies were compared between healthy donors and patients and correlated with each other and with clinical parameters. Associations with progression-free and overall survival were evaluated using Cox proportional hazards regression and longitudinal changes in immune cell populations during chemotherapy were analyzed using linear mixed-effects models. Results:Circulating Tregs were significantly reduced in patients with high neutrophil counts (7% vs 17%, p=0.04), increased significantly during treatment in responders, particularly in patients achieving complete or partial response (+16%, p = 0.003) but did not demonstrate prognostic significance. pMDSCs were further stratified by CD16 expression into a CD16+ subset associated with favorable outcome and a CD16dim/- subset enriched in patients demonstrating poor prognosis. Frequency of circulating mMDSCs was modestly increased in patients but retained adverse prognostic significance (HR 1.98, CI 1.04-3.78, p=0.039) and correlated with the CD16dim/- pMDSC fraction. Mature CD15+CD33- polymorphonuclear cells were significantly expanded in patients (79% vs 73%, p=0.003) and correlated with adverse clinical features, whereas lower levels correlated with improved survival (HR 0.54, CI 0.3-0.98, p=0.045). Rare HLA-DR+CD16+ granulocytic subset demonstrated significantly reduced levels in patients compared to healthy donors while their kinetics during treatment also correlated inversely with disease burden. Discussion:Circulating immune cell subsets in metastatic colorectal cancer exhibit considerable baseline heterogeneity and distinct immune kinetics during chemotherapy. Our findings demonstrate that conventional leukocyte populations, when evaluated individually, together with detailed immunophenotyping provide complementary prognostic information, revealing previously unappreciated heterogeneity within major immune cell populations and a network of novel interrelationships among circulating immune cells. Together, these observations support comprehensive immune profiling as a promising approach for future biomarker development and immune-based patient stratification.

BackgroundThe spatial distribution and functional heterogeneity of tumor-infiltrating lymphocytes (TILs) significantly impact patient outcomes in non-small cell lung cancer (NSCLC). While T cell factor 1 (TCF1) expressing TILs have emerged as key players in sustaining anti-tumor immunity, their subset characterization, localization, and clinical significance within the tumor microenvironment remain poorly defined.MethodWe performed multiplex immunohistochemistry and immunofluorescence to characterize TCF1+ immune cell subsets, in 102 NSCLC tumors, separately analyzing the tumor center (TC) and invasive front (IF). We integrated this data with publicly available single-cell RNA-sequencing datasets and clinical outcome analyses.ResultsCD4+ T cells and CD79α+ B cells, dominate the TCF1+ landscape, while CD8+ T cells constitute a minority of TCF1+ immune cells, particularly in the TC. We demonstrated the presence of tumor-infiltrating IgG+/IgA+ plasma cells co-expressing TCF1. PD1+TCF1- cells were more frequent than PD1+TCF1+ cells both in the TC and IF, reflecting that terminally differentiated exhausted TILs predominate within the tumor microenvironment. Survival analyses revealed significantly different prognostic impact of TILs including TCF1-expressing cells based on topography. Multivariate analysis showed that increased CD8+TCF1+ cells (HR: 2.5; p=0.039) and increased TCF1 expression by cancer cells (HR: 2,7; p=0.041) in the TC and CD4+TCF1+ cells (HR: 0.4; p=0.043) in the IF emerged as negative and positive independent prognostic markers for Disease-free survival (DFS), respectively. Integrating PD-L1 expression with TILs, PD-L1 immunopositivity was correlated with increased CD8+ and PD1+TCF1- cell infiltration and was associated with favorable DFS especially in the TC.ConclusionsOur findings support a more refined framework for TCF1+ TIL assessment and TCF1 expression across cellular populations in the tumor microenvironment, with implications for prognostication in operable NSCLC.

Immunotherapy has revolutionized the management of patients with cancer. Immune checkpoint inhibition (ICI) is a promising treatment option that targets the molecular mechanisms that cancer cells exploit to prevent immune-mediated elimination. ICI therapy can cause exceptional long-term tumor remissions, in some cases, even after treatment discontinuation. Despite its success, many patients acquire resistance or fail to respond due to immune escape mechanisms mediated by the tumor and its microenvironment. Pre-existing immunity status of individuals seems to play a fundamental role in immunotherapy response and eventually tumor progression, as it orchestrates tumor-immune interactions. Different immune cell subsets, both in the tumor microenvironment and the peripheral blood, are established mediators that contribute to immune escape in various tumor types. Based on these findings, the elucidation of the mechanisms implicated in the regulation of these immune cells has become a priority for investigators focused on improving the efficacy of ICI. This will be essential for identifying responders as well as for developing novel therapeutic modalities to improve clinical outcomes. Herein, we summarize preclinical and clinical evidence proposing a predictive role of pre-existing immunity for clinical responses to immunotherapies.

e23524 Background: Soft tissue sarcomas are heterogeneous mesenchymal malignancies with overlapping histology, making diagnosis challenging. According to World Health Organization (WHO) classification of STS and bone sarcomas, >150 recurrent fusions have emerged as central diagnostic hallmarks for many sarcoma entities. RNA-based next-generation sequencing, particularly RNA-exome sequencing, enables sensitive detection of known and novel fusion transcripts with precise breakpoint characterization, and comprehensive molecular profiling even from limited tissue samples. The aim of this study was to assess the diagnostic utility of exome-capture RNA sequencing compared to targeted RNA next-generation sequencing for the detection of sarcoma-associated gene fusions, particularly in cases with challenging histology or negative results on targeted fusion panels. Methods: Total RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue using the MagMAX FFPE DNA/RNA Ultra Kit (Thermo Fisher Scientific). RNA-exome libraries were prepared with the NadPrep Total RNA to DNA – EZ DNA Library Preparation Kit (Nanodigmbio) and sequenced on the DNBSEQ-T7 platform (MGI Tech). Fusion transcript detection was performed using SeqPilot, complemented by bioinformatic tools STAR-Fusion and FusionInspector. In parallel, targeted RNA NGS libraries were generated using a custom sarcoma fusion panel, sequenced on the Ion GeneStudio S5 Prime System (Thermo Fisher Scientific) and analysed via the Torrent Suite software. Results: A total of 143 samples from patients with various histological subtypes of sarcoma were analyzed using a custom sarcoma panel (Ion AmpliSeq). Sarcoma-associated rearrangements were identified in 34% of cases (49/143). The most frequently detected alteration was the EWSR1::FLI1 fusion, observed in 7.7% of samples, a well-established molecular hallmark of Ewing sarcoma. Subsequently, 24 samples that were negative by the custom sarcoma panel were further analyzed using the RNA exome panel. In addition, in 17% (4/24) of cases, detection of TFE3::ASPSCR1 , HEY1::NCOA2 , FGFR1::WHSC1L1 , and EWSR1-NR4A3 fusions aided histological classification and confirmed the initial sarcoma diagnosis. Conclusions: RNA-exome sequencing provided additional diagnostic yield in panel-negative cases, enabling the detection of clinically informative fusions that supported or refined histological classification. These findings highlight the significant role of RNA-exome sequencing in the molecular diagnosis of STSs, particularly in diagnostically challenging cases, and support its integration into advanced diagnostic workflows. Nevertheless, prior review by sarcoma-expert pathologists remains essential to determine the appropriate indication for NGS testing.

Background/Objectives: Advanced prostate cancer (PCa) evolves through adaptive mechanisms that sustain tumor growth despite the suppression of androgen receptor (AR) signaling. Accumulating evidence identifies activation of the hepatocyte growth factor (HGF)/MET pathway as a potential driver of PCa progression in advanced disease states characterized by AR-independence and therapeutic resistance. We review the biological and clinical evidence supporting MET as a context-dependent therapeutic target and discuss its implications for patient selection and combination strategies. Methods: A comprehensive narrative review of preclinical, translational, and clinical studies evaluating MET-directed therapies for PCa was performed. Results: Aberrant activation of the HGF-MET axis is frequently driven by autonomous paracrine and autocrine loops that sustain pathway activation during disease progression. MET overexpression is associated with adverse pathological features, increased tumor aggressiveness, bone metastasis, lineage plasticity, and resistance to AR-targeted treatments. Preclinical studies have demonstrated that AR suppression, tumor hypoxia and tumor-microenvironment interactions promote MET upregulation, supporting AR-independent growth and epithelial-to-mesenchymal transition. Clinical trials of MET inhibitors have shown modest activity as monotherapies, with the most consistent biological effects observed in bone-dominant disease. Recent studies indicate greater therapeutic potential when MET inhibition is incorporated into rational combination strategies targeting complementary molecular pathways. Emerging data further indicate that MET activation characterizes a biologically aggressive, AR-low or neuroendocrine-like disease state. These findings support a transition from empiric use of MET inhibitors toward precision, context-driven therapeutic development. Conclusions: MET is not a universal therapeutic target but defines a clinically relevant subset of aggressive, AR-indifferent PCa. Future development should focus on biomarker-guided patient selection and rational combination strategies. Integration of molecular profiling, imaging, and liquid biopsy approaches will be essential to identify patients most likely to benefit from MET-directed interventions.

In view of the shifting standard of care for non-small cell lung cancer (NSCLC), we aimed to capture the evolution of the epidemiological and systemic treatment (ST) landscape in Greece. This non-interventional, single-country, multicenter, retrospective study, collected high-level aggregate data for adult patients who were newly diagnosed with histologically/cytologically confirmed Stage I-IV NSCLC between 01-Jan-2016 and 31-Dec-2020 (index period) at leading oncology clinics across the country. Overall, 10,644 patients were newly diagnosed with NSCLC during the entire 5-year index period at the 18 participating sites (63.8

BACKGROUND:Chemotherapy-related symptom burden and psychological distress may significantly influence patients' perceptions of treatment convenience and satisfaction, yet evidence in the Greek oncology population remains limited. METHODS:A cross-sectional study was conducted among 150 cancer patients receiving chemotherapy in a tertiary hospital. Data were collected using CCSQ, ESAS-r, PHQ-2, GAD-2, and WHO-5. Pearson correlations and multiple linear regression analyses were performed. RESULTS:Higher levels of depressive symptoms and anxiety were significantly associated with lower chemotherapy convenience and satisfaction (e.g., PHQ-2: r = -0.659 to -0.584, p < 0.001; GAD-2: r = -0.623 to -0.469, p < 0.001). Depressed mood emerged as a significant negative predictor of convenience (β = -0.39, p = 0.015) and concerns (β = -0.39, p = 0.005), while anxiety independently predicted satisfaction (β = 0.45, p = 0.007). CONCLUSIONS:Chemotherapy experience is strongly associated with psychological and symptom burden. These findings highlight the importance of integrating psychosocial assessment into routine oncology care.

Background: Small-cell lung cancer (SCLC) is an aggressive type of lung cancer, and several factors are currently used to predict poor outcomes, including performance status (PS), extensive-stage disease, male sex, advanced age, and elevated lactate dehydrogenase (LDH) levels. In this study, we aimed to explore the role of Tegs and inflammatory indices, such as CRP and NLR, in predicting response to immunotherapy. Methods: Fifty-one therapy-naïve ES-SCLC patients and ten healthy donors were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with fluorochrome-conjugated monoclonal antibodies. Multicolor flow cytometry was performed to determine the levels of CD8+ T cells and CD4+ Tregs, as well as their correlation with inflammatory indices and clinical outcomes. Results: ES-SCLC patients harbored higher percentages of CD8+ Teffs (p = 0.005) and FOXP3+ Tregs (p < 0.0001) in circulation before therapy compared with healthy donors. In addition, high levels of CD3+CD8+ T effectors were associated with longer PFS (p = 0.018) and longer OS (p = 0.012) compared with patients bearing low levels, while Tregs were not found to be predictive. More importantly, a survival benefit was observed in ES-SCLC patients with a low Treg/Teff ratio, as longer OS was observed in those with high percentages of CD8+ Teffs and low FOXP3+CTLA-4+ Tregs (p = 0.014) compared with those bearing low CD8+ Teffs and high FOXP3+CTLA-4+ Tregs. A low Treg/Teff ratio was further associated with low eosinophil levels and a low NLR before treatment initiation. Conclusions: These findings suggest a novel, easily obtainable blood-based signature that may help predict response to ICIs in ES-SCLC patients.

Background: Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has improved outcomes in non-small cell lung cancer (NSCLC), although reliable biomarkers for predicting benefit are still limited. Methods: In this exploratory study, we conducted a longitudinal analysis of the peripheral T-cell receptor (TCR) β repertoire in 28 patients with unresectable stage IIIb non-small cell lung cancer (NSCLC) who received anti-PD-L1 immunotherapy following chemoradiotherapy. Blood samples were collected at baseline and three months after treatment initiation. Results: At the cohort level, global TCR repertoire features such as diversity and richness did not change significantly over time. However, when looking at individual patients, more specific patterns became evident. Patients could be broadly separated based on changes in clonotype richness, with reductions generally accompanied by lower diversity and decreased convergent TCR frequency. We also observed differences in TRBV gene usage in relation to clinical outcome, with higher TRBV20-1 and lower TRBV28 frequencies tending to associate with improved survival and delayed disease progression. Interestingly, the disappearance of dominant clonotypes from the peripheral blood during treatment was linked to longer progression-free survival (PFS). In addition, patients with higher baseline blood plasma tumor mutational burden (bTMB) showed greater clonotype richness and were more likely to exhibit this clonotype loss. The combination of high bTMB and clonotype disappearance identified a subgroup of patients with particularly favorable outcomes. Conclusions: Overall, these results suggest that early responses to PD-L1 blockade may be reflected less in global TCR repertoire shifts, including clonality and diversity measures, and more in subtle changes in clonotype composition and dynamics, since the frequencies of certain TRBV genes and the disappearance of dominant clonotypes following ICB were associated with clinical outcomes integrating TCR profiling with bTMB and could therefore help refine patient stratification and improve the understanding of immune responses in NSCLC. Nevertheless, due to the small number of recruited patients, our study is exploratory and hypothesis-generating, and further validation in larger patient cohorts is warranted.

Background Immune checkpoint inhibitors (ICIs) have improved survival in advanced NSCLC; yet the trajectory of objective physical performance during immunotherapy remains poorly characterized. Pulmonary rehabilitation (PR) has not been evaluated in this setting in randomized trials. Research Question Does supervised pulmonary rehabilitation modify functional capacity and multidimensional physical performance during first-line immunotherapy for advanced NSCLC? Study Design and Methods In this randomized controlled trial, patients with stage IV NSCLC initiating first-line ICI-based therapy were randomized 1:1 to supervised PR or usual care for 8 weeks. The primary outcome was change in 6-minute walk distance (6MWD). Secondary outcomes included multidimensional physical performance, symptom burden, and health-related quality of life. Exploratory outcomes included inflammatory biomarkers and oncologic endpoints. Results Of 148 individuals screened, 48 were randomized (PR, n = 24; usual care, n = 24). At 8 weeks, supervised PR significantly improved 6-minute walk distance compared with usual care (adjusted mean difference, 25.8 m; 95% CI, 10.1–41.5 m; p = .002). Significant between-group differences favoring PR were observed in lower-extremity performance (SPPB), quadriceps strength, fine motor dexterity, respiratory symptom burden (CAT), anxiety, and depressive symptoms. Participants receiving usual care demonstrated decline across multiple functional domains despite stable ECOG performance status. No between-group differences were observed in inflammatory biomarkers. Exploratory analyses demonstrated a trend toward longer progression-free survival (median, 15.0 vs 10.0 months) in the pulmonary rehabilitation group; however, the study was not powered to detect differences in survival outcomes. Interpretation Among patients receiving first-line ICI-based therapy for advanced NSCLC, early functional deterioration occurred despite stable ECOG performance status, indicating that oncologic stability does not necessarily reflect physiologic stability. Supervised PR modified functional trajectories during active treatment in this randomized trial, supporting early rehabilitation as an integral component of immunotherapy care rather than a survivorship intervention.

Abstract Background: DNA damage and genomic instability represent hallmarks of cancer. Tumors with defects in repairing double strand breaks have been shown to respond to platinum compounds, immune checkpoint inhibitors (ICI) and PARP inhibitors. We have previously reported that 28% of early-stage Non-Small Cell Lung Cancer (NSCLC) patients present high Genomic Scarring Score (h-GSS), an indicator of genomic instability, while patient-derived xenografts from those patients respond favorably to olaparib. The aim of this study was to investigate the immune landscape of h-GSS early-stage and metastatic NSCLC patients, and to assess their clinical outcome. Material and Methods: Sixty-seven (early stage I-III) and 52 (stage IV) patients with no actionable genomic alteration were enrolled in the study. Their GSS was assessed using a commercial panel (AmoyDx® HRD Complete), which also identifies mutations in 20 homologous recombination repair (HRR) genes. PD-L1 expression (tumor proportion score-TPS) and early and late exhausted (TCF1+PD1+ and TCF1-PD1+, respectively) CD8+ cells were assessed using immunohistochemistry. All patients with early-stage disease received platinum-based adjuvant chemotherapy while stage IV patients received immunotherapy-based regimens. Results: h-GSS was detected in tumors from 28/67 (41.8%) patients with stage I-III NSCLC and in 16/52 (30.8%) with stage IV. TP53 mutations (TP53mut) were observed in 27/28 (96.4%) and 22/39 (56.4%) of stage I-III h-GSS and l-GSS tumors, respectively (p<0.001), and in 12/16 (75.0%) and 15/34 (44.1%) of h-GSS and l-GSS tumors stage IV tumors, respectively (p=0.067). Early-stage but not stage IV TP53mut patients presented a better DFI and OS, compared to wild-type TP53 tumors (p=0.002 and 0.026, respectively). Early-stage h-GSS/TP53mut and l-GSS/TP53mut patients had better DFI (p=0.012 and p=0.002, respectively) compared to l-GSS/TP53wt counterparts, whereas only the h-GSS/TP53mut status was associated with a better OS (p=0.031). PD-L1 expression in l-GSS but not in h-GSS stage IV tumors was associated with a significantly better OS (HR=0.2, 95%CI: 0.1-0.6, p=0.009). Finally, there was a statistical trend towards an increased density of both PD1+TCF1+ (0.067) and PD1+TCF1- (0.054) exhausted tumor-infiltrating lymphocytes in h-GSS compared to l-GSS tumors in patients with stage IV disease. Conclusions: The findings of this study clearly suggest that genomic instability in NSCLC, as assessed by GSS, could become an important tool for better stratification of patients regarding prognosis and treatment choice. Citation Format: Panteleimon Konstantoulakis, Georgia Christopoulou, Apostolos Klinakis, Katerina Tsilingiri, Ioannis Vatselas, Natalia Asimakopoulou, Vassilis Georgoulias, Ioannis Pateras, Konstantinos Ntostoglou, Georgios Christodoulopoulos, Athanasios Kotsakis, Vasiliki Anastasopoulou, Dora Hatzidaki, Abdriani Harpidou, Emilia Tsaroucha, Gary Karponi. Clinical outcome of patients with early stage and metastatic non-small cell lung cancer (NSCLCa) harboring high genomic scarring score (GSS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2431.

11010 Background: Cancer-related cognitive impairment (CRCI, “chemobrain”) is a common condition among patients (pts) receiving adjuvant chemotherapy (CT) and has been shown to negatively affect quality of life (QoL). However, the clinical relevance of early CRCI beyond symptom burden remains poorly characterized. We evaluated whether early CRCI is associated with compromised delivery of adjuvant CT, including reduced relative dose intensity (RDI). Methods: This prospective study was conducted at the University Hospital of Larissa and represents an expanded analysis of a previously reported population with treatment delivery endpoints. Pts with early stage (ES) breast (BC) or colorectal (CRC) cancer scheduled to receive adjuvant CT containing taxanes or oxaliplatin, respectively, were eligible for this study (C1). Two control groups were included: ES cancer pts that were not eligible for adjuvant CT (C2) and age-matched healthy controls (C3). Eligibility criteria included age > 45 years and fluency in Greek; pts with pre-existing dementia or anxiety disorders were excluded. C1 pts were assessed at baseline and every 3 months (mo) up to 12 mo after CT initiation, while C2 and C3 were assessed at 3-mo intervals. CRCI was evaluated using the Greek Version of Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). Early CRCI was defined as a ≥10-point decline in total FACT-Cog score at 3 mo after CT initiation, in the absence of severe anemia (CTCAE grade ≥3). Treatment delivery outcomes included RDI (reduced RDI: < 85%), treatment delays, CT discontinuation, unplanned healthcare use and CT-related neurotoxicity (ntx). Results: Overall, 164 pts were included in C1 (111 BC, 63 CRC), 61 in C2 (38 BC, 23 CRC) and 25 in C3. Early CRCI was observed in a substantial proportion of pts receiving adjuvant CT (99/164, 60%). Pts with early CRCI were significantly more likely to receive reduced CT dose intensity compared to those without CRCI (OR 3.27, 95% CI 1.34-7.98). Early CRCI was also associated with an increased risk of clinically relevant concurrent treatment-related ntx (CTCAE grade > 1; OR 4.05, 95% CI 1.81-9.08). CT discontinuation occurred more frequently among pts with early CRCI than among those without CRCI (12% vs 3%). In addition, these pts more frequently experienced treatment delays and unplanned healthcare use. These associations were independent of baseline ECOG PS. Early CRCI persisted beyond 3 mo in a substantial proportion of affected pts during follow up, while cognitive scores remained stable among controls. Conclusions: In this expanded cohort, early CRCI was associated with reduced RDI and higher rates of treatment discontinuation. Beyond its impact on QoL, early CRCI identifies a vulnerable subgroup of pts at risk for compromised treatment delivery and may represent a clinically actionable target for risk-adapted supportive strategies aimed at preserving curative-intent treatment intensity.

Background Artificial intelligence (AI) has the potential to improve cancer care. Its implementation must align with patients’ needs, values, and lived experiences. This study aimed to explore perspectives from patient advocates representing patient organizations, including individuals with experience of melanoma, bladder and lung cancer, and to co-develop recommendations to support the ethical, patient-centered, and practical integration of AI in oncology. Methods Semi‑structured interviews were conducted with 18 patient advocates from patient organizations within the MULTIR network to explore current challenges in cancer care, perceptions of the benefits and risks of AI, and conditions for its trustworthy, sustainable and equitable adoption. Findings were reviewed and refined through a series of webinars, enabling participants to validate and strengthen the resulting recommendations. Results Participants identified key benefits and risks associated with AI and formulated six main recommendations targeting developers, policymakers, regulators, and researchers. These include: ensuring clear, accessible, and transparent communication about AI; strengthening training and capacity-building for healthcare professionals and patient organizations; demonstrating tangible clinical and patient-level benefits; developing secure, robust, and interoperable data infrastructures; reinforcing ethical and regulatory frameworks; and ensuring the sustained and meaningful involvement of patient organizations throughout AI development, implementation, and evaluation processes. Conclusion These recommendations provide actionable, patient-informed directions for advancing the integration of AI in cancer care. Although grounded in insights from specific cancer communities, they are broadly applicable across oncology. Progress will require the structured integration of patient organizations and experiential knowledge into governance, research, and implementation processes, in order to support more equitable, trustworthy, and patient-centered AI-enabled health systems. Policy Summary The recommendations have implications for European policies on healthcare regulation, digital health infrastructure, and data governance. They highlight the importance of capacity building, stakeholder engagement, and embedding principles of equitable access, responsible implementation, and patient‑centered governance of AI‑enabled health services.

Background:Monocarboxylate transporters (MCTs) facilitate lactate transfer and support cancer cell survival and metastasis. MCT1 and MCT4 expression has been associated with poor prognosis and resistance to therapy with tyrosine kinase inhibitors. Objectives:This pilot study examined the relevance of MCT1 and MCT4 expression in circulating tumour cells (CTCs) isolated from non-small cell lung cancer (NSCLC) patients during osimertinib treatment through single-cell analysis. Design:Fifty-three NSCLC patients were enrolled at three different time points: baseline (n = 53), post-first cycle (n = 20) and progressive disease (PD; n = 21), to evaluate MCT1 and MCT4 expression in patients' samples. Methods:CTCs were isolated with the ISET platform. MCT1/MCT4 expression was assessed using immunofluorescence triple staining experiments and confocal laser scanning microscopy. Results:CTCs were detected in 75% (40/53), 40% (8/20) and 29% (6/21) of patients at baseline, post-first cycle and PD, respectively. Among cytokeratin (CK)-positive patients, MCT1 was overexpressed at all time points in a significant percentage: 67% (18/27) at baseline, 57% (4/7) at post-first cycle and 50% (2/4) at PD. Similarly, MCT4 was overexpressed in 55% (16/29), 50% (2/4) and 60% (3/5) of cases, respectively. Statistical analysis revealed that the (CK+MCT1-CD45-) phenotype was associated with worse progression-free survival [PFS; log rank, p = 0.041, hazard ratio (HR) = 1.971] and overall survival (log rank, p = 0.028; HR = 2.288) of the patients. Conversely, the presence of ⩾3 MCT4+ CTCs was correlated with poorer PFS (log rank, p = 0.042, HR = 4.189). Significant inverse correlations were observed between MCT1 and MCT4 expression, implying their distinct biological roles. Conclusion:MCT1 and MCT4 are overexpressed in CTCs from NSCLC patients, supporting their potential as prognostic biomarkers and therapeutic targets.

This scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. It summarizes advances in fibroblast activation protein inhibitor (FAPI) positron emission tomography (PET) for oncologic and fibroinflammatory diseases. FAP is expressed broadly on activated mesenchymal cells—including cancer-associated fibroblasts (CAFs) and myofibroblasts within desmoplastic tumor stroma, FAP-positive tumor cells in selected sarcomas, and activated fibroblasts in chronic fibroinflammatory disorders such as rheumatoid arthritis, Crohn’s disease, and organ fibrosis. By targeting these activated fibroblasts, [68Ga]- and [18F]-labeled FAPI tracers provide high tumor-to-background contrast, particularly in desmoplastic and stromal-rich cancers. Compared with [18F]FDG, FAPI PET demonstrates superior lesion conspicuity in selected malignancies and enables a streamlined, non-fasting imaging workflow. Beyond oncology, FAPI PET is emerging as a promising tool for assessing cardiac fibrosis, pulmonary inflammation, and autoimmune conditions characterized by fibroblast activation. A systematic literature search of PubMed and Scopus was performed for peer-reviewed publications from 1 January 2018 to 28 February 2026. Inclusion criteria encompassed original studies, systematic reviews, meta-analyses, clinical guidelines, case series, and case reports reporting on FAPI-targeted PET in human subjects or translational models, published in English. After screening, 256 sources met the eligibility criteria and are included. The development of standardized SNMMI/EANM imaging protocols, along with ongoing multicenter trials and the first prospective phase 2 clinical trial of 68Ga-FAPI-46 PET with histopathological confirmation, now supports the reproducible implementation of FAPI PET across institutions. FAPI PET demonstrates strong translational potential, largely due to its favorable biodistribution, safety profile, and theranostic flexibility. However, its widespread use in routine clinical practice is contingent upon large-scale clinical validation, structured reader training, and formal regulatory approval. In conclusion, FAPI PET represents a maturing molecular imaging platform targeting activated fibroblasts across oncologic and fibroinflammatory diseases. Its widespread adoption into clinical practice requires large-scale prospective trials, reader training, standardized reporting, and regulatory approval—all of which are now actively underway.

Introduction:Novel predictive biomarkers are needed to optimize immunotherapy-based treatment response in non-small cell lung carcinoma (NSCLC). T cell modulatory features may limit the ability of T cells to mount effective anti-tumor responses and could predict immune fitness and responsiveness to therapy. We investigated the prognostic and predictive value of CD8+ T cells with an exhausted phenotype, specifically those co-expressing Programmed Death 1 (PD-1) and T cell factor 1 (TCF-1), in peripheral blood of NSCLC patients before any systemic treatment. Methods:Two patient cohorts were analyzed: a) 32 patients with early and locally advanced disease (stage I-IIIA; cohort A) who did not receive immunotherapy, and b) 47 patients with advanced disease (stage IIIB-IV) who received chemo-immunotherapy. Multicolor flow cytometry was used to assess CD8+ T cell subpopulations co-expressing PD-1 and TCF-1. Results:PD-1+TCF1+ progenitor (early) exhausted T cells were found at high frequencies in all NSCLC patients compared with healthy donors, regardless of tumor stage. In cohort A, patients with high levels of CD3+CD8+PD-1+TCF1+ T cells had significantly improved DFS (p= 0.038), while those with high CD3+CD8+PD-1+TCF1- T cells had significantly worse DFS (p= 0.028). In cohort B, high levels of CD3+CD8+PD-1+TCF1+ T cells were associated with shorter PFS (p= 0.027). No association with OS was observed in cohort A. Conversely, in cohort B, high CD3+CD8+PD-1+TCF1+ T cell levels correlated with shorter OS (p= 0.045), while high CD3+CD8+PD-1+TCF1- T cell levels correlated with longer OS (p= 0.010). Conclusion:Therefore, here we show that circulating PD-1⁺TCF1+ T cells correlated differentially with treatment outcome in early and late NSCLC stage patients.