Numerous clinical trials on mesothelin (MSLN)-targeted antibodies have provided preliminary evidence supporting their clinical translation, highlighting the importance of patient screening. Although anti-MSLN chimeric antigen receptor T (CAR-T) cell therapy has not been approved by the Food and Drug Administration (FDA) for solid tumor treatment yet, its high expression across various malignancies has made it a major research focus. Prescreening patients suitable for anti-MSLN CAR-T cell therapy may boost both treatment efficacy and safety. The ScFv component of anti-MSLN CAR-T cells retains MSLN targeting capability and serves as a suitable molecular precursor for probe development. In this study, the positron-emitting nuclide 89Zr was utilized to label the antibody fragment MA4 (comprising the ScFv segment of MSLN fused with the human Fc segment), while a mouse monoclonal antibody (Sino Biological, 13128-MM08) served as a control, enabling the development of two immunoPET probes for MSLN imaging. Following purification, 89Zr-MA4 exhibited high radiochemical purity (>99%) and molar activity (24.2-31.9 GBq/μmol) and maintained >95% radiochemical purity over 6 days in both PBS and 5% human serum albumin (HSA). In the MSLN strongly positive LS174T tumor model, the 89Zr-MA4 probe demonstrated expedited tissue penetration and tumor accumulation. The immunohistochemical analysis revealed that LS174T tumors exhibited strong positivity for MSLN, whereas the U87MG group demonstrated only mild expression. Dosage estimation studies have determined that the effective dose of 89Zr-MA4 is 0.142 mSv/MBq, which complies with established safety standards. Overall, both probes exhibit robust in vitro stability and demonstrate feasibility for MSLN-targeted imaging in vivo.

The clinical utility of 18F-fluoroglutamine (18F-FGln) PET/CT for characterizing metabolic heterogeneity and improving lung cancer staging remains underexplored. In this prospective study, 31 patients with 36 primary lung lesions underwent dual-tracer (18F-FDG/18F-FGln) PET/CT. A metastatic cohort (n = 28) was analyzed for distant staging. Diagnostic performance was assessed using ROC analysis, logistic regression, and radiomic texture parameters (volume, mass, CT histogram features). For primary lesions, 18F-FDG showed marginally higher detection rates (86.1

TPS282 Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is an emerging treatment modality for metastatic castration-resistant prostate cancer (mCRPC). However, many agents targeting PSMA have resulted in quality of life-limiting toxicities, such as xerostomia, due to expression of PSMA in salivary glands and other organs. [ 225 Ac]Ac-FL-020 is a next-generation, PSMA alpha radioconjugate developed using the proprietary UniRDC linker-chelator technology designed to optimize biodistribution. It is intended for the treatment of patients with mCRPC and aims to enhance tumor uptake while sparing radiosensitive organs, such as salivary glands, thus potentially leading to an improved therapeutic window. Methods: ProTACT (FL-020-001) is a first-in-human, open-label, multicenter Phase 1 study investigating the safety, tolerability, and preliminary anti-tumor activity of [ 225 Ac]Ac-FL-020 in patients with advanced PSMA-positive mCRPC. This study consists of 2 parts: dose escalation (Part 1) and dose expansion (Part 2). Patients eligible for enrollment must be aged ≥18 years and have: histologically confirmed mCRPC, evidence of disease progression, ≥1 PSMA-positive lesion (uptake higher than liver) on PSMA positron-emission tomography/computed tomography imaging, an Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function. Prior treatment with androgen receptor signaling inhibitors or CYP17 inhibitors and ≥1 taxane-based chemotherapy is required, unless declined by the patient. Prior therapy with Lu-177 is allowed. Patients with extensive PSMA-negative disease are excluded. [ 225 Ac]Ac-FL-020 will be administered intravenously at the assigned dose every 6 weeks for up to 6 cycles. In Part 1, 5 eligible patients will receive 185 ± 20 MBq of [ 111 In]In-FL-020 for dosimetry evaluation ≥8 days prior to first dose of [ 225 Ac]Ac-FL-020. Part 1 will apply a Bayesian logistic regression model (BLRM) with overdose control to guide dose-escalation decisions. Dose cohorts of 1–3 patients (for Cohorts 1 and 2) and 3–6 patients (for Cohorts 3 and beyond) will evaluate ascending dose levels from 1–10 MBq to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D). Once the RP2D is established, 18 additional patients will be enrolled in Part 2 to further assess safety and explore early signals of efficacy. Primary endpoints include incidence of dose-limiting toxicities and type, frequency, and severity of adverse events/serious adverse events. Secondary endpoints include overall response rate, disease control rate, radiological progression-free survival, and pharmacokinetic parameters (eg, maximum plasma concentration). The study intends to enroll patients in Australia, Turkey, the United States, and China. Clinical trial information: NCT06492122 .

Tumor uptake stratified by CEA levels

Correlation between [68Ga]Ga-CTR-FAPI uptake and FAP expression

The transmembrane glycoprotein CD146, overexpressed in solid tumors and tumor vasculature, is a compelling target reinforced by CD146-targeting antibody-drug conjugates (ADCs) in clinical trials. This development underscores the unmet need for noninvasive imaging tools to guide patient selection. Here, we report the first [68Ga]Ga-labeled peptide-based molecular imaging agents targeting CD146: [68Ga]Ga-DOTA-P1 and [68Ga]Ga-DOTA-P2. Both probes were reliably synthesized with radiochemical yield >90% within 15 min and radiochemical purity exceeding 95% (n = 5). [68Ga]Ga-DOTA-P1 and [68Ga]Ga-DOTA-P2 have good in vitro stability, and high affinity for CD146-positive cell, with Kd values of 152.3 nM and 205.1 nM, respectively. In vitro cellular assays demonstrated specific binding, and fluorescence imaging with the analog FITC-P1 visually confirmed robust CD146-mediated cellular uptake. In vivo PET/CT imaging demonstrated rapid tumor uptake and tissue excretion. A375 model showed a higher tumor-to-muscle ratio (5.33  ±  0.58) with [68Ga]Ga-DOTA-P1 at 30 min, whereas [68Ga]Ga-DOTA-P2 produced lower contrast (2.55  ±  0.58) due to its slower blood clearance; in addition, the imaging ability of [68Ga]Ga-DOTA-P1 was also verified in another CD146-positive model (SK-Mel-28). An immunohistochemical test was performed to assess CD146 distribution, showing low expression in normal tissues versus positive membrane-localized expression in A375 and SK-Mel-28 tumors. This work establishes [68Ga]Ga-DOTA-P1 as a rapid, high-contrast imaging tool for CD146-expressing malignancies, offering a practical strategy for noninvasive patient stratification in the era of targeted CD146 therapies.

Objective:Early detection of synergistic cardiotoxicity induced by sequential anthracycline and programmed cell death protein 1(PD-1)inhibitor therapy remains challenging because conventional assessments identify late-stage functional impairment.This study aimed to determine the sensitive imaging probe for early therapy-associated cardiotoxicity and validate findings using integrated positron emission tomography/magnetic resonance imaging(PET/MRI). Methods:Cardiotoxicity was assessed in mouse models treated with PD-1 inhibitor or sequential doxorubicin(DOX)and PD-1 inhibitor therapy.Serial biodistribution analyses of 18F-fluorodeoxyglucose(18F-FDG),18F-fibroblast activation protein inhibitor(18F-FAPI),99mTc-methoxyisobutylisonitrile(99mTc-MIBI),and 11C-acetate were performed.Histopathological evaluation assessed inflammation,mitochondrial injury,and fibrosis.Findings were validated in a prospective lymphoma cohort receiving sequential anthracycline and PD-1 inhibitor therapy using integrated 18F-FDG PET/MRI.Myocardial maximum standardized uptake value(SUVmax),strain parameters,tissue mapping indices,and electrocardiographic(ECG)changes were analyzed. Results:Sequential DOX and PD-1 inhibitor therapy induced an early increase in myocardial 18F-FDG uptake in mice before preceding systolic dysfunction.Histopathological examination confirmed inflammatory cell infiltration and mitochondrial swelling without extracellular matrix remodeling.In contrast,uptake of 18F-FAPI,99mTc-MIBI,and 11C-acetate remained unchanged.In patients with lymphoma,myocardial SUVmax was significantly higher in patients with ECG abnormalities[ECG(+)]than in those without ECG abnormalities[ECG(-)],whereas global longitudinal strain,global radial strain,and global circumferential strain were significantly reduced(all P<0.05).After the third PD-1 cycle,myocardial SUVmax remained elevated in ECG(+)patients,whereas strain parameters declined after 5-6 cycles,suggesting that metabolic alterations precede functional impairment.SUVmax_heart demonstrated the highest diagnostic accuracy for cardiotoxicity[cutoff=3.0;area under the curve(AUC)=0.873;sensitivity=93.3%;specificity=80.0%]. Conclusions:Cardiac 18F-FDG PET/MRI enables early detection of synergistic cardiotoxicity induced by DOX and PD-1 inhibitors before structural or functional deterioration occurs.SUVmax_heart may serve as an imaging biomarker for risk stratification and timely cardioprotective intervention.

Rationale and Objectives Accurately predicting tumor response to neoadjuvant immunochemotherapy (NICT) and patient prognosis remains challenging in esophageal cancer. This study aimed to explore the value of 18F-FDG PET/CT in predicting the pathological response and prognosis of patients with resectable esophageal squamous cell carcinoma (ESCC) undergoing NICT. Materials and Methods Patients who underwent NICT between January 2020 and April 2024 were retrospectively analyzed. 18F-FDG PET/CT scans were performed before (scan-1) and after NICT (scan-2). Parameters derived from 18F-FDG PET/CT and enhanced CT were analyzed for response evaluation and survival prediction. The pathological tumor regression grade served as the gold standard for response evaluation. Results Among the 94 patients, 41 patients (43.6%) achieved a major pathological response (MPR). 18F-FDG PET/CT identified more responders than CT. Compared with non-MPR patients, those achieving MPR demonstrated significantly lower uptake on scan-2 and a greater relative reduction (Δ%) between scan-1 and scan-2. The SUVmax of scan-2 demonstrated the best predictive performance for MPR (AUC = 0.829). The SULpeak of scan-2 showed the highest sensitivity for predicting MPR (90.2%). Multivariate analysis indicated that CPS, SUVmax-2, and ΔSUVmax% were independent predictors of MPR, while pathological stage, PERCIST, and TLG-2 were independent predictors of PFS; further, the pathological stage, PERCIST, and ΔMTV% were independent predictors of OS. Patients with TLG-2 < 8.1 or ΔMTV% > 75.5% indicated better treatment response and longer survival. Conclusion Parameters after NICT and their changes before and after treatment were valuable in identifying patients achieving MPR and predicting prognosis. 18F-FDG PET/CT is a potentially valuable method for predicting the pathological response to NICT and the prognosis of resectable ESCC. Take-home Message Metabolic parameters after NICT and their changes from baseline were valuable for identifying MPR and predicting prognosis.Post-treatment SUVmax and SULpeak may serve as effective predictors of MPR, while a favorable PERCIST or lower TLG-2 relates to improved PFS, and a favorable PERCIST or higher ΔMTV% correlates with prolonged OS.

The transmembrane glycoprotein CD146, overexpressed in solid tumors and tumor vasculature, is a compelling target reinforced by CD146-targeting antibody-drug conjugates (ADCs) in clinical trials. This development underscores the unmet need for noninvasive imaging tools to guide patient selection. Here, we report the first [Ga-68]Ga-labeled peptide-based molecular imaging agents targeting CD146: [Ga-68]Ga-DOTA-P1 and [Ga-68]Ga-DOTA-P2. Both probes were reliably synthesized with radiochemical yield >90% within 15 min and radiochemical purity exceeding 95% (n = 5). [Ga-68]Ga-DOTA-P1 and [Ga-68]Ga-DOTA-P2 have good in vitro stability, and high affinity for CD146-positive cell, with K-d values of 152.3 nM and 205.1 nM, respectively. In vitro cellular assays demonstrated specific binding, and fluorescence imaging with the analog FITC-P1 visually confirmed robust CD146-mediated cellular uptake. In vivo PET/CT imaging demonstrated rapid tumor uptake and tissue excretion. A375 model showed a higher tumor-to-muscle ratio (5.33 +/- 0.58) with [Ga-68]Ga-DOTA-P1 at 30 min, whereas [Ga-68]Ga-DOTA-P2 produced lower contrast (2.55 +/- 0.58) due to its slower blood clearance; in addition, the imaging ability of [Ga-68]Ga-DOTA-P1 was also verified in another CD146-positive model (SK-Mel-28). An immunohistochemical test was performed to assess CD146 distribution, showing low expression in normal tissues versus positive membrane-localized expression in A375 and SK-Mel-28 tumors. This work establishes [Ga-68]Ga-DOTA-P1 as a rapid, high-contrast imaging tool for CD146-expressing malignancies, offering a practical strategy for noninvasive patient stratification in the era of targeted CD146 therapies.

Radiopharmaceutical-based imaging and targeted radionuclide therapy are often limited by heterogeneous or absent molecular targets in tumors. Here, we present a stiffness-responsive mesenchymal stem cell (MSC)-assisted relayed tumor-targeting (SMART) platform that converts matrix stiffness into a programmable molecular entry point for radiotheranostics. Engineered MSCs sense elevated mechanical stiffness within the tumor microenvironment and induce localized expression of synthetic biomarkers, thereby enabling radiopharmaceutical targeting independent of endogenous target availability. As a proof of concept, SMART-driven expression of prostate-specific membrane antigen (PSMA) enables sensitive tumor detection by 68Ga-PSMA-617 positron emission tomography (PET) and effective treatment with 177Lu-AB-PSMA-617 across multiple tumor models, with improved sensitivity and reduced off-target uptake compared with conventional 18F-fluorodeoxyglucose PET. This platform is readily adaptable to alternative synthetic targets and induced pluripotent stem cell (iPSC)-derived MSCs. By translating a universal physical feature of tumors into an actionable molecular signature, SMART expands the scope of precision radiotheranostics beyond native biomarkers.

Patient-based and region-based detection rates

PD-1/PD-L1 and VEGF pathways jointly mediate T-cell dysfunction and immune suppression, limiting the efficacy of immune checkpoint inhibitors. We developed an 89Zr-labeled bispecific immuno-PET probe, 89Zr-JS207, for noninvasive imaging of PD-1 and VEGF in tumors. 89Zr-JS207 was prepared via p-isothiocyanatobenzyl-desferrioxamine (p-NCS-Bz-DFO) conjugation with high radiochemical purity (>99%) and excellent in vitro stability (>95% at 240 h). It showed high affinity for PD-1 (Kd = 6.92 nM) and VEGF-A (Kd = 82.48 nM), with an elimination half-life of 35.14 h. Micro-PET/CT in humanized mice revealed specific tumor uptake blockable by cold JS207, and stronger tumor retention than monospecific probe. NIRF imaging and IHC validated these findings. 89Zr-JS207 enables dual-targeted imaging with favorable pharmacokinetics, holding great potential for patient stratification and therapeutic monitoring in bispecific antibody immunotherapy.

Tumor uptake stratified by newly diagnosed or persistent MTC

5050 Background: [ 225 Ac]Ac-FL-020 is a next-generation, prostate-specific membrane antigen (PSMA) alpha radioconjugate developed using the proprietary UniRDC linker-chelator technology designed to optimize biodistribution. [ 225 Ac]Ac-FL-020 is intended for treating patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and aims to enhance tumor uptake while sparing radiosensitive organs, such as salivary glands, thus potentially leading to an improved therapeutic window. Methods: ProTACT (FL-020-001) is a first-in-human, open-label, multicenter Phase 1 study investigating the safety, tolerability, and preliminary anti-tumor activity of [ 225 Ac]Ac-FL-020 in pts with advanced PSMA-positive mCRPC. This study consists of: Bayesian dose escalation (Part 1) and dose expansion (Part 2). Eligible pts must have: histologically confirmed mCRPC, evidence of disease progression, and ≥1 PSMA-positron emission tomography positive lesion (uptake higher than liver). Prior androgen receptor signaling inhibitors or CYP17 inhibitors and ≥1 taxane-based chemotherapy is required, unless declined by the pt. Prior Lu-177 is allowed. Pts with extensive PSMA-negative disease are excluded. Dose cohorts of 1 to 3 pts (for Cohorts 1 and 2) and dose cohorts of 3 to 6 pts (for Cohorts 3+) will evaluate ascending dose levels from 1 to 10 MBq (intravenous; every 6 weeks; x 6 cycles) to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D). Once the RP2D is established, 18 additional pts will be enrolled in Part 2 to further assess safety and early signals of efficacy. Results: As of 2 Jan 2026, 15 eligible pts have received [ 225 Ac]Ac-FL-020 (maximum dose/cycle: 5 MBq). No dose-limiting toxicities have been observed. Most frequent adverse events (AEs) were fatigue (10 pts), nausea and dry mouth (7 pts each), constipation and anemia (4 pts each). Grade (G)3+ AEs were reported for 6 pts, all G3+ AEs occurred in one pt each. One pt at 1 MBq had G3 anemia and 1 pt at 5 MBq had G3 anemia and G3 thrombocytopenia, both considered related to disease progression with bone marrow infiltration and unrelated to [ 225 Ac]Ac-FL-020. As of the cutoff date, 11 pts remain on treatment and 4 pts discontinued treatment prematurely, 3 due to disease progression and 1 due to G2 dry mouth. Another 6 pts reported dry mouth, all were G1. No renal toxicities or decline in renal function was observed. As of 6 Jan 2026, 1 of 3 pts at 3 MBq showed a reduction in baseline prostate-specific antigen (PSA) > 80% after 3 cycles and 2 of 6 pts at 5 MBq showed a reduction in PSA > 50% after 1 cycle. Conclusions: These initial findings support the feasibility and tolerability of [ 225 Ac]Ac-FL-020 administration in heavily pretreated pts with mCRPC with a few notable PSA responses. The RP2D has not yet been reached, and dose escalation continues. Clinical trial information: NCT06492122 .

Representativeness of study participants

Detection rate of patients with calcitonin >2000 pg/ml

OBJECTIVE:Quantitative imaging-based dosimetry is essential for optimizing [177Lu]Lu-DOTATATE peptide receptor radionuclide therapy (PRRT), yet full multi-time-point (MTP) SPECT/CT is difficult to implement in routine clinical practice. This study proposes a hybrid planar-SPECT framework for organ-level TIA estimation and STP-constrained voxel-level Monte Carlo dose analysis from a single post-therapy SPECT/CT acquisition. APPROACH:The proposed framework integrates single-time-point (STP) SPECT/CT with serial planar imaging to derive organ-level time-integrated activities (TIAs). A physics-informed support vector regression (SVR) model is incorporated to refine planar-to-SPECT scaling factors and improve the robustness of planar-derived activity quantification. The resulting organ TIAs are used to scale the fixed within-organ STP SPECT pattern and generate voxelized TIA maps as source distributions for Monte Carlo (MC)-based dose calculation. The method is evaluated against reference MTP SPECT/CT data in 11 patients and further applied to a separate cohort of 23 patients to explore vertebral dose heterogeneity and its association with hematologic toxicity. MAIN RESULTS:Hybrid dosimetry showed good agreement with MTP SPECT/CT, with organ-level errors of approximately 10-15%. The SVR-based refinement modestly reduced scaling bias, particularly in anatomically challenging structures. Voxel-level vertebral dose heterogeneity metrics showed moderate but exploratory correlations with hematologic toxicity (ρ ≈ 0.4-0.5) after false-discovery-rate correction, whereas conventional organ-averaged dose metrics showed no significant association. SIGNIFICANCE:The proposed hybrid planar-SPECT framework supports clinically feasible organ-level dosimetry from a reduced acquisition protocol. The resulting voxelized maps provide STP-constrained approximate source distributions for MC dose calculation and exploratory characterization of spatial dose heterogeneity, rather than reconstructions of time-varying MTP voxel kinetics. The SVR improvement observed in the 11-patient internal validation remains preliminary, requiring larger cohorts for robustness and external validation for generalizability.

Melanoma, a malignant tumour originating from melanin-producing melanocytes, poses a significant threat to human health, including cutaneous melanoma and uveal melanoma (UM). Although surgical resection remains a primary treatment modality, radiotherapy has emerged as another therapeutic option, particularly for UM. Nevertheless, the adverse effects induced by radiotherapy are considerably pronounced. In this study, we identified WT-161, a selective histone deacetylase 6 (HDAC6) inhibitor, as a potent radiosensitizer for melanoma therapy through high-throughput drug screening. Mechanistically, inhibition of HDAC6 disrupted its interaction with DNA damage repair proteins (DDB2 and DEK) and suppressed gene expression in the DNA damage repair pathway, leading to the accumulation of irradiation-induced DNA damage and tumour regression. Our findings establish HDAC6 as a predictive biomarker for radiation response in melanoma and demonstrate that pharmacological inhibition of HDAC6 with WT-161 could expand the clinical utility of radiotherapy in patients with UM.

Tumor uptake stratified by calcitonin levels

The immune checkpoint programmed ligand 1 (PD-L1) is expressed in various solid tumors and is associated with immunotherapy prognosis. Dynamic assessment of PDL1 expression levels helps identify patients who may benefit from immunotherapy. Atezolizumab is a monoclonal antibody that targets PD-L1 and is used in the treatment of various hematologic malignancies and solid tumors. However, research on colon cancer is lacking. Approximately 85% of colorectal cancer (CRC) patients have the MSS/pMMR (Microsatellite Stable/proficient Mismatch Repair) subtype, which lacks ideal biomarkers for precise and dynamic screening of potential immune-responsive subpopulations and for predicting combination therapy strategies. Currently, the assessment of PD-L1 is limited to biopsy samples. Molecular immuno-PET imaging can provide an effective solution for guiding clinical immunotherapy selection.This study describes the development of 89Zr-DFO-atezolizumab, a PD-L1-targeted immuno-imaging agent, and its evaluation in terms of in vitro and in vivo specificity as well as pharmacokinetics. Tumor uptake and heterogeneity were quantified in mouse models via immuno-PET imaging. PET/CT scans using 89Zr-DFO-atezolizumab revealed a significant difference in tumor uptake between the MC38hPD-L1 model and the MC38 model, and cold anti-atezolizumab effectively blocked this uptake. The preliminary dosimetry study indicated that the organs receiving higher doses are the spleen and the liver. Preclinical PET/CT imaging with 89Zr-DFO-atezolizumab reveals its potential for the non-invasive detection of PD-L1-positive CRC tumors, which holds potential significance for understanding tumor heterogeneity and monitoring early PD-L1 expression changes induced by therapy.