Novel biomarkers are imperative for predicting radioactive iodine (RAI) avidity in metastatic lesions of differentiated thyroid carcinoma, and mechanisms regulating RAI uptake remain incompletely understood. This study aimed to identify distinct serum metabolic profiles in papillary thyroid carcinoma (PTC) patients with non-131I-avid disease and elucidate underlying molecular mechanisms. Serum samples from 94 PTC patients were analyzed using gas chromatography–time-of-flight mass spectrometry. Patients were stratified into the non-131I-avid pulmonary metastases group (n = 30), the 131I-avid pulmonary metastases group (n = 31), and the remnant ablation group (n = 33). Principal component analysis and orthogonal partial least squares-discriminant analysis was employed for classification and biomarker identification. Differential metabolites were visualized via heatmap and evaluated for diagnostic potential using receiver operating characteristic curve analysis. Pathway enrichment analysis utilized the KEGG database. Sixty metabolites were significantly dysregulated between non-131I-avid and 131I-avid groups: 54 elevated (fold change (FC) range: 1.17–4.81) and 6 reduced (FC range: 0.31–0.82) in the non-131I-avid cohort. Ten metabolites demonstrated a high predictive power for non-131I-avid pulmonary metastatic PTC (AUC > 0.9; P < 0.001). Pathway analysis identified linoleic acid (LA) metabolism as the most significantly altered pathway (impact factor = 1.0). Mechanistically, LA competitively inhibited the binding of the endoplasmic reticulum (ER) stress-responsive transcription factor ATF4 to the sodium–iodide symporter (NIS) promoter, suppressing NIS transcription. Serum metabolomic profiling effectively discriminates PTC patients with pulmonary metastases based on 131I avidity. Our findings demonstrate that LA attenuates NIS expression by inhibiting ER stress-mediated ATF4 activation in PTC. This work provides novel mechanistic insights into non-131I-avid metastatic PTC development and identifies potential diagnostic biomarkers and therapeutic targets.

BACKGROUND:Wogonin, a bioactive flavonoid from Scutellaria baicalensis Georgi, exhibits broad-spectrum anticancer effects. However, whether wogonin exerts antitumor effects in thyroid cancer (TC) or reverses drug resistance remains unknown. METHODS:The antitumor effects of wogonin were evaluated in thyroid cancer cells and in xenograft models. RNA-sequencing, molecular docking, molecular dynamics, cellular thermal shift assay, and surface plasmon resonance were used to identify molecular targets. Lenvatinib-resistant cells were established to investigate the potential of wogonin in reversing acquired resistance. RESULTS:Wogonin inhibited TC cell proliferation, induced apoptosis and suppressed tumor growth in a dose-dependent manner. Biophysical and computational methods showed that wogonin binds to the extracellular domain of the platelet-derived growth factor receptor beta (PDGFRB), leading to its downregulation and inactivation of the PI3K/AKT pathway. Furthermore, PDGFRB overexpression was associated with acquired lenvatinib resistance, and wogonin contributed to resensitization to lenvatinib by reducing PDGFRB. CONCLUSION:Wogonin exerts remarkable antitumor effects against TC by binding to PDGFRB, leading to its downregulation, and subsequently suppressing the PI3K/AKT pathway. Furthermore, PDGFRB upregulation contributes to lenvatinib resistance in TC, while wogonin partially reverses this resistance in a PDGFRB-dependent manner.

OBJECTIVE:Accurate segmentation of Multiple Myeloma (MM) lesions from PET/CT is critical for prognosis but challenging due to lesion heterogeneity and cross-modal frequency discrepancies. This study aims to develop a robust, parameter-efficient framework to address these complexities. METHODS:We introduce a Cross-Modal Dual-Wavelet Fusion Network with a Frozen SAM Decoder. Unlike standard adaptations, we replace the heavy SAM image encoder with a custom dual-branch wavelet encoder. This design explicitly aligns high-frequency anatomical edges from CT with low-frequency metabolic cues from PET via a "decompose-and-inject" mechanism. Furthermore, we freeze the pre-trained SAM mask decoder to leverage robust geometric priors and employ a lightweight Tiny Pseudo Decoder for auxiliary boundary supervision. RESULTS:Extensive experiments on an in-house MM dataset (N=161) and the public HECKTOR 2022 dataset demonstrate that our method achieves Dice scores of 0.8323 and 0.8465, respectively, significantly outperforming state-of-the-art baselines including nnU-Net and MedSAM ($p < 0.05$). Notably, the model requires only 10.28M parameters-a $\approx$96% reduction compared to the standard SAM (271.24 M)-while maintaining superior accuracy. CONCLUSION:The proposed framework effectively bridges the gap between lightweight deployment and high-performance cross-modal segmentation. SIGNIFICANCE:The approach offers a practical, lightweight alternative for PET/CT segmentation, facilitating deployment in clinical workflows by combining strong accuracy, cross-dataset generalizability, and markedly improved computational efficiency. The model code is available at https://github.com/HanXinfun/DualwaveSAM.

PurposeThis randomized controlled trial aimed to determine if Lugol’s solution following radioactive iodine (RAI) therapy enhances the efficacy of ablation and mitigates radiation-induced toxicity in patients with differentiated thyroid cancer.MethodsIn this prospective study, 97 patients were enrolled and randomized to control group (RAI) and test group (RAI + Lugol’s solution). The primary endpoint was the rate of successful ablation. The secondary endpoint was short-term (d3 and d10) and long-term (6- to 9-month after RAI therapy) adverse events (AEs).ResultsThe rate of negative DxWBS was similar between control and test group (93.3% vs. 91.2%, p = 0.748). At the 6- to 9-month follow-up, while the successful ablation rate (sTg <1 ng/mL) was numerically higher in the test group compared to the controls (82.8% vs. 66.7%, p=0.131), applying a stricter stimulated thyroglobulin (sTg) cutoff (<0.2 ng/mL) revealed a statistically significant advantage for the test group (65.7% vs. 40.0%, p = 0.041). Uni- and multi-variate analysis showed Lugol’s Solution administration significantly correlated with lower level of sTg at the 6- to 9-month follow-up. The two groups exhibited comparable short-term AEs rates (46% vs. 34%, p = 0.230) and profiles. The most common AEs included neck swelling, pain, loss of appetite and dry mouth. However, the control group reported 2 cases of long-term AEs, whereas none were observed in the test cohort.ConclusionIn this preliminary study, the addition of Lugol’s Solution following RAI showed non-inferior ablation efficacy with a numerically lower incidence of long-term AEs, despite numerically higher short-term AE rates.Clinical trial informationIt was registered at Chinese Clinical Trial Registry with identifier ChiCTR1900027705 at November 24th, 2019.

ObjectivePostoperative hypoparathyroidism remains a common complication after total thyroidectomy. This study aimed to assess whether combining near-infrared autofluorescence (NIRAF) imaging with carbon nanoparticle suspension (CN) improves parathyroid gland (PG) identification and functional preservation in patients undergoing total thyroidectomy for papillary thyroid carcinoma (PTC).MethodsA total of 80 patients with PTC undergoing total thyroidectomy with central neck dissection (CND) were randomly divided into two groups. The CN group (n = 40) received CN alone to distinguish PGs, whereas the NIRAF + CN group (n = 40) underwent combined CN and NIRAF imaging for PG identification. Data collected included operative time, counts of identified, incidentally removed, and autotransplanted PGs, and lymph nodes numbers. Serum calcium and parathyroid hormone (PTH) levels were compared preoperatively and postoperatively (on day 1, and at 1, 3, and 6 months) between groups.ResultsThe NIRAF + CN group identified significantly more PGs than the CN group (147/160 [91.9%] vs. 135/160 [84.4%], p = 0.028), with a lower rate of incidentally removed PGs (5.0% vs. 15.0%, p = 0.263) and a higher autotransplantation rate (20.0% vs. 15.0%, p = 0.770). On postoperative day 1, serum PTH levels were significantly higher in the NIRAF + CN group (19.86 ± 11.15 pg/mL) than in the CN group (13.82 ± 9.13 pg/mL, p = 0.010), while calcium levels and PTH at later time points (1, 3, 6 months) showed no significant intergroup differences. The incidence of transient hypoparathyroidism was 25.0% in the NIRAF + CN group vs. 37.5% in the CN group (p = 0.228), and permanent hypoparathyroidism occurred in 2.5% of the NIRAF + CN group compared with 7.5% of the CN group (p = 0.615).ConclusionsThe combined use of NIRAF and CN enhances intraoperative PG preservation and improves early parathyroid function.

Developing novel radiopharmaceuticals for cancer theranostics has recently attracted extensive interest. Bifunctional chelators are key components of many radiometal-based radiopharmaceuticals. For the established 68Ga/177Lu theranostic pair, the commonly used chelator DOTA suffers from some issues, such as the requirement for heating during radiolabeling and slow chelation kinetics. The limitations highlight the need to develop new bifunctional chelators. Methods: The novel macrocyclic chelator 2-[11,27-bis(carboxymethyl)-34,36-dihydroxy-7,23-dimethyl-3,11,19,27,33,35-hexaazapentacyclo[27.3.1.15,9113,17121,25]hexatriaconta-1(33),5(36),6,8,13,15,17(35),21(34),22,24,29,31-dodecaen-3-yl]acetic acid (Dar3A) was synthesized and modified with a pendant arm for bioconjugation. A comprehensive comparison with DOTA was performed, including titration experiments to assess thermodynamic stability and radiolabeling studies to evaluate the efficiency of 68Ga and 177Lu labeling. For a proof of concept, Dar3A was conjugated with a fibroblast activation protein-targeted moiety derived from fibroblast activation protein inhibitor-04 and radiolabeled with 68Ga to prepare [68Ga]Ga-SMIC-3101. The resulting 68Ga-labeled radiotracer was further evaluated in cellular assays, animal models, and human subjects (3 healthy volunteers and 1 patient with esophageal cancer). Results: Dar3A exhibited superior radiolabeling efficiency with 68Ga and 177Lu compared with DOTA, and [68Ga]Ga-SMIC-3101 was obtained with a molar activity of 28.7 MBq/nmol. In U87MG tumor-bearing mice, [68Ga]Ga-SMIC-3101 exhibited enhanced tumor uptake (12.73 ± 1.68 and 10.64 ± 2.88 %ID/g at 2 and 4 h, respectively), significantly exceeding that of DOTA-based [68Ga]Ga-FAPI-04 (0.66 ± 0.22 and 0.51 ± 0.10 %ID/g, respectively). Moreover, the first-in-human study demonstrated that [68Ga]Ga-SMIC-3101 was safe, with physiologic excretion occurring primarily via the hepatobiliary system, and clearly visualized primary and metastatic esophageal cancer lesions. Conclusion: Dar3A is a promising bifunctional chelator for radiolabeling and bioconjugation, supporting theranostic radiopharmaceutical development.

As a pivotal therapeutic approach following surgery, chemoradiotherapy, and molecular targeted therapy, tumor immunotherapy has revolutionized survival outcomes for cancer patients, with immune checkpoint inhibitors (ICIs) demonstrating remarkable efficacy in clinical practice. However, challenges such as Immunotherapy resistance and significant individual variability in response persist, underscoring the critical need for precise tumor assessment and identification of benefit populations to achieve precision and personalization in immunotherapy. Multi-omics technologies, by integrating multidimensional data from genomics, transcriptomics, proteomics, metabolomics, and radiomics, enable comprehensive analysis of tumor development mechanisms, tumor microenvironment characteristics, and immunotherapy response patterns at molecular, cellular, tissue, and systemic levels. This review systematically examines the current applications, clinical value, and future prospects of multi-omics in tumor immunotherapy, with a focus on the development and utilization of radiomics in immunotherapy efficacy evaluation and prognostic prediction, thereby providing theoretical foundations and technical support for the precise implementation of tumor immunotherapy.

Intraoperative preservation of parathyroid glands (PGs) remained a significant challenge in thyroidectomy. Recently, deep learning has demonstrated considerable potential in medical applications. We proposed a novel intraoperative method for PG identification. We developed a localization subnet based on YOLOX and a novel semantic segmentation model termed Trans-U-HRNet, collectively termed PG-AI. The dataset included 976 images from 121 patients undergoing open thyroidectomy, with images from 101 patients randomly split 8:2 for training and internal validation. PG detection was quantified using PG-AI, and its performance was visually compared with near-infrared autofluorescence (NIRAF) imaging and assessments by surgeons with varying experience levels. PG-AI achieved an accuracy of 91.1

PurposeTo investigate the impact of adrenal metastases (AM) of differentiated thyroid cancer (DTC) through the comparison of clinicopathological characteristics and prognoses between DTC patients with AM and those with other distant metastatic sites.MethodsWe retrospectively analyzed the records of 84 DTC patients (28 DTC patients with AM and 56 with other metastatic sites) who underwent surgery and 131I therapy based on a review of the Shanghai Sixth People’s Hospital medical records from September 2014 to January 2025. Univariate analysis with the log-rank test was performed to evaluate survival outcomes and prognostic factors of overall survival (OS), while parameters with a P-value < 0.05 were further subjected to multivariate analysis using the Cox proportional hazards model.ResultsA total of 84 patients with DTC were enrolled in this study, among whom 28 were diagnosed with AM and 56 with distant metastases at other sites. All patients in both groups received radioactive iodine therapy. The proportion of radioactive iodine-refractory DTC (RAIR-DTC) was significantly higher in the DTC with AM (DTC-AM) group (71.43% vs. 44.64%). The median time of follow-up of the DTC patients with AM and those without was 29.6 months (5.0-112.5 months) and 69.3 months (10.4-146.7 months), respectively. At the end of follow-up, 10 patients (35.71%) died in the DTC-AM group, while 8 patients (14.29%) died in the non-DTC-AM group. The 5- and 10-year OS rates of the DTC-AM group were 65.31% and 46.65% versus 92.88% and 78.23% in the non-DTC-AM group. The presence of AM, advanced age at diagnosis of distant metastases (≥60y) and large maximal primary tumor size (≥4cm) were independently associated with poor survival (all P<0.05).ConclusionPatients with DTC-AM are characterized by a higher proportion of advanced age at diagnosis of distant metastases, larger primary tumor size, a predominance of multiple synchronous distant metastatic sites, a higher rate of RAIR-DTC, and more frequent use of tyrosine kinase inhibitor therapy. AM exerted a significant negative impact on the prognoses of DTC patients. The occurrence of AM, advanced age at diagnosis of distant metastases (≥60y) and large maximal primary tumor size (≥4cm) were independent risk factors for unfavorable prognoses of DTC patients with distant metastases.

The optimal dose of adjuvant radioiodine(131I) therapy for differentiated thyroid cancer (DTC) remains controversial. This study aimed to determine the efficacy and prognostic impact of two doses of adjuvant 131I therapy (3.7 GBq and 5.55 GBq) in DTC patients with unexplained TSH-stimulated Tg(sTg) elevation. Data for eligible patients with DTC who received adjuvant 131I therapy at our institution between January 2015 and December 2016 were retrospectively reviewed. The results of dynamic risk assessment of persistent and recurrent disease (PRD) and recurrence-free survival (RFS) were compared between the 3.7 GBq and 5.55 GBq 131I groups using the chi-squared test, Fisher’s exact test, log-rank test, and a Cox proportional hazards model. In total, 224 patients with DTC were enrolled. Six months after adjuvant 131I therapy, 132 patients(58.9

Objective:An accurate assessment of 131I accumulation capacity in lung metastases of differentiated thyroid cancer (DTC) is pivotal for guiding radioiodine therapy and avoiding ineffective 131I administration. This study aimed to develop a deep convolutional neural network (DCNN) model to predict 131I uptake in lung metastases of DTC before radioiodine therapy. Methods:In this retrospective, multicenter, population-based cohort study, we collected chest CT image datasets for DTC patients with lung metastases from three hospitals in China. Pulmonary metastases were classified into two categories based on the post therapeutic 131I whole-body scan: 131I-avid (positive 131I uptake) and non-131I-avid (negative 131I uptake). For DCNN model development, patients were assigned to the primary dataset (140 patients with 131I-avid, 121 with non-131I-avid). For model validation, patients were assigned to the internal validation dataset (36 patients with 131I-avid, 23 with non-131I-avid), external validation dataset 1 (25 patients with 131I-avid, 18 with non-131I-avid), and external validation dataset 2 (23 patients with 131I-avid, 18 with non-131I-avid). Using these datasets, we assessed the performance of our model, ResNeSt50, and compared it with two models: Inception V3 and ResNet50. Results:Compared to Inception V3 and ResNet50, our model, ResNeSt50, demonstrated the highest prediction performance in the internal (area under the curve [AUC] = 0.722, 95% confidence interval [CI] = 0.716-0.725), external validation dataset 1 (AUC = 0.720, 95% CI = 0.691-0.749), and external validation dataset 2 (AUC = 0.731, 95% CI = 0.713-0.748). Conclusion:We developed a simple and robust DCNN model for predicting the 131I uptake in lung metastases of DTC before radioiodine therapy, which can provide improved screening for patients who may benefit from 131I therapy. Trial registration:Chinese Clinical Trial Registry (ChiCTR), ChiCTR1800018047. Registered on 28 August 2018.

Objective Pleural metastasis (PM) is rare in patients with differentiated thyroid cancer (DTC). Radioiodine (131I) therapy has been the main treatment for postoperative metastasis and recurrence of DTC. However, clinical data on PM from DTC are limited. This study investigated the clinicopathological characteristics of patients with PM from DTC that were treated surgically and with 131I therapy and evaluated their long-term prognosis and prognostic factors. Methods A review of the Shanghai Sixth People’s Hospital medical records from 2010 to 2023 identified PM in 27 of 14,473 patients with DTC. Overall survival (OS) was assessed by the Kaplan–Meier method. Results The prevalence of PM in DTC was 1.87‰ (27/14,473). The median age at the time of initial diagnosis of PM was 59 years (range: 34–79). At the end of follow-up, eight patients (29.63%) had disease progression (PD), four (14.81%) had a partial response, and the remainder had stable disease; no patient achieved complete response. Twelve patients (44.44%) died, and 15 (55.56%) survived. Thirteen patients (48.15%) did not show 131I avidity, and 16 (59.26%) had radioiodine-refractory DTC (RR-DTC). Twenty patients (74.07%) had malignant pleural effusion (MPE), which was large in 11 cases (40.74%) and moderate in two. More-than-moderate MPE (P = 0.031), lack of 131I avidity (P = 0.041) and RR-DTC (P = 0.030) were significantly associated with worse 5-year OS in patients with PM of DTC. Conclusions PM is rare in DTC. Lack of 131I avidity, RR-DTC and more-than-moderate MPE are associated with poor OS in patients with DTC and PM.

Multiple myeloma (MM) is a heterogeneous malignancy with prognosis significantly affected by high-risk cytogenetic abnormalities (HRCAs). Traditional detection using fluorescence in situ hybridisation is invasive and limited in capturing disease heterogeneity. We aimed to develop and validate radiomics model based on pretreatment [18F] fluoro-deoxyglucose (FDG) positron emission tomography/computed tomographic (18F-FDG PET/CT) imaging to non-invasively predict HRCAs in newly diagnosed MM patients. Among the 42 candidate models, the Decision Tree classifier utilizing PET active lesions features demonstrated optimal performance in the validation cohort, exhibiting excellent predictive ability (Area Under the Curve (AUC) = 0.89), significantly outperforming the PET metrics model (AUC = 0.84) and clinical model (AUC = 0.74). SHapley Additive exPlanations analysis identified the PET-derived feature as the most important contributor to the model’s predictive capacity. The model stratified patients into high-risk and low-risk groups, with the high-risk group exhibiting significantly worse PFS and OS (median PFS: high-risk 24.5 months vs. low-risk 29 months; p = 0.0360; median OS: high-risk 33.5 months vs. low-risk 50 months; p = 0.0023). As a non-invasive imaging biomarker, PET/CT radiomics holds potential for predicting high-risk cytogenetic status and facilitating patient prognosis stratification Further large-scale, multi-center prospective validations are essential to confirm its utility for personalized therapeutic decision-making in MM.

Prostate specific membrane antigen (PSMA) ligands play significant roles in the radiotheranositcs of prostate cancer (PC), but also face challenges of false negative results and lesion loss, especially when encountering bone metastases. Aiming at prostate cancer bone metastasis (PCBM) and taking integrin alpha 2 beta 1 as the second target of PSMA, in this work we constructed two hetero-bivalent agents (lIP-L and cIP-L). The added diagnostic value of integrin alpha 2 beta 1 to PSMA was firstly evaluated using RNA of 512 PC patient and 52 healthy individuals as analysis sample. PET tracers ([68Ga]Ga-lIP-L and [68Ga]Ga-cIP-L) and internal irradiation therapy drug (IRT, [177Lu]LucIP-L) were then developed. Dual-receptor specificity and affinity were determined on PC-3 and LNCaP cell. Biodistribution and circulation behaviors were investigated. PET imaging and IRT were performed on PC-3 and LNCaP tumor-bearing mice. [68Ga]Ga-lIP-L and [68Ga]Ga-cIP-L demonstrated high affinity and specificity to both integrin alpha 2 beta 1 and PSMA. Moreover, [68Ga]Ga-cIP-L showed capacity to monitor the development of bone metastases and identify bone metastases including metastases at spine, rib, tibia, vertebra and skull at very small and early stage. Last but not least, [177Lu]Lu-cIP-L also demonstrated dual-target specificity and showed strong antitumor effects on both PC-3 and LNCaP tumors. Hence, we considered that lIP-L and cIP-L showed great potential to be translated as powerful radiotheranostic tools for the early and accurate detection/treatment of prostate cancer.

ObjectiveNear-infrared autofluorescence (NIRAF) imaging shows promise in identifying parathyroid gland (PG) during surgery. However, the clinical application of NIRAF faces challenges due to the heterogeneous fluorescence intensity (FI) of PGs observed in different thyroid and parathyroid diseases. This study aimed to evaluate the effectiveness of NIRAF in PG detection and to analyze the FI of PGs in patients with various thyroid and parathyroid diseases.MethodsA total of 105 patients undergoing thyroidectomy and parathyroidectomy were enrolled. Intraoperative NIRAF imaging was used to detect PGs, and the FI values were quantified using ImageJ software. Normal PGs were grouped according to the pathological results of ipsilateral thyroid diseases. Compare and analyze the FI values of normal and diseased PGs.ResultsA total of 239 PGs were detected during surgery. 225 PGs were identified by NIRAF. The NIRAF identification rate was significantly higher than visual identification (94.1% vs. 81.2%, p < 0.001). NIRAF demonstrated high performance in PG identification, with sensitivity, specificity, and positive predictive values and negative predictive values to predict PGs were 95.4%, 77.5%, 90.5% and 88.1%, respectively. The FI of PGs was higher in patients with papillary thyroid carcinoma (1.39 ± 0.21), follicular nodules of thyroid (1.45 ± 0.25), nodular thyroid gland (1.36 ± 0.19) than in those with hyperthyroidism (1.06 ± 0.28) and primary hyperparathyroidism (1.17 ± 0.23). Superior PGs in Stage I exhibited higher FI compared to PGs in Stage II (p = 0.025). In Stage II, the FI of inferior PGs was significantly higher than that of superior PGs (p < 0.001). The FI of PGs in both Stage I and II was significantly higher than in Stage III.ConclusionsNIRAF demonstrates high efficiency in identifying PGs across various surgical stages, outperforming conventional visual identification. The FI of superior and inferior PGs exhibits significant variability across different intraoperative stages. Surgeons should exercise caution when identifying PGs in patients with primary hyperparathyroidism and hyperthyroidism, as these conditions are associated with lower FI compared to other thyroid diseases.

Native ligand-derived peptides have significantly advanced the development of targeting ligands in radiopharmaceutical discovery and design. Herein, we report the first attempt to develop novel mesenchymal–epithelial transition factor (c-MET) targeted peptide positron emission tomography (PET) probes based on the endogenous biomolecule, hepatocyte growth factor (HGF). Three c-MET targeted peptides were designed from the N-terminal and kringle 1 domain (NK1: 32–207 amino acid residues) of HGF. Then they were conjugated with chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with [68Ga]GaCl3. The resulted [68Ga]Ga-labelled probes, [68Ga]Ga-DOTA-K1, [68Ga]Ga-DOTA-A-C5, and [68Ga]Ga-DOTA-A-M8 were evaluated in vitro and in vivo. Among three PET probes, [68Ga]Ga-DOTA-A-M8 exhibited a high affinity for c-MET (IC50 = 5.43 nM) and demonstrated specific and high uptake in c-MET highly expressing HCT-116 cells. Small animal PET/CT imaging clearly visualized the tumor with good contrast using [68Ga]Ga-DOTA-A-M8 over 120 min. Quantitative analysis of PET images revealed tumor uptake of [68Ga]Ga-DOTA-A-M8 at 30 min post-injection was 2.91 ± 0.20

As an important tumor-associated carbohydrate antigen, the Thomsen-Friedenreich (T or TF) antigen has become an attractive target for tumor diagnosis and treatment. However, there has been very limited success in developing peptide- and small-molecule-based radiopharmaceuticals for this important target. Currently, only 64Cu-NO2A-TFpep has been reported as a radiolabeled peptide targeting the TF antigen, and it shows a low tumor-to-liver ratio due to 64Cu retention in the liver. In this study, a novel PET probe targeting the TF antigen (DOTA-TFpep) was synthesized using 2,2',2″,2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) chelator for increasing the hydrophilic property and for radiolabeling with different radionuclides. DOTA-TFpep was then radiolabeled with 68Ga for positron emission tomography (PET) imaging of breast tumors expressing the TF antigen. 68Ga-DOTA-TFpep was confirmed by radio-HPLC with a purity greater than 98% and high stability in PBS. Immunofluorescence analysis confirmed the TF antigen expression of 4T1 and K1 cell lines. Cell uptake studies confirmed its targeting specificity. Further in vivo biodistribution studies in high (4T1) and low (K1) TF antigen-expression xenograft models demonstrated the favorable pharmacokinetics property of the probe. PET imaging and biodistribution showed that 68Ga-DOTA-TFpep exhibited specific tumor uptake. Moreover, compared with the widely studied 64Cu-NO2A-TFpep, 68Ga-DOTA-TFpep showed lower liver uptake and a higher tumor-to-liver ratio (1.31 ± 0.20 for 64Cu-NO2A-TFpep and 0.48 ± 0.15 for 68Ga-DOTA-TFpep at 120 min after injection). In summary, this study demonstrates the synthesis and evaluation of the TF antigen-targeting probe 68Ga-DOTA-TFpep. It shows favorable in vivo tumor imaging properties, highlighting it as a promising molecular probe targeting the TF antigen.

Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131I to construct the bulk of RDC (131I-ER). Floxuridine was mixed with 131I-ER to develop a hydrogen bond-driving supermolecular RDC system (131I-ER-Fu NPs). The carrier-free 131I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects. In vivo imaging also revealed its application for tumor localization of nonsmall cell lung cancer (NSCLC) and screening of patients suitable for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. We considered that 131I-ER-Fu NPs showed potentials as an integrated platform for the radiotheranostics of NSCLC.

Background In patients with non-distant metastatic PTC and TERT-p mutation being a rare entity at initial diagnosis, it is unclear whether 131I treatment is effective and can reduce the risk of recurrence after surgery. The objective of this study was to determine the clinical characteristics, effectiveness of radioiodine (131I), and recurrence-free survival (RFS) in patients with non-distant metastatic papillary thyroid cancer (PTC) and TERT-p mutation at initial diagnosis. Patients and Methods A retrospective observational review of clinical data collected between January 2016 and December 2023. One hundred and thirteen patients with non-distant metastatic PTC and TERT-p mutation at initial diagnosis were included.Therapeutic efficacy was evaluated using the dynamic risk stratification. Recurrence-free survival (RFS) was assessed using the Kaplan-Meier method and a Cox proportional hazards model. Results: One hundred and thirteen patients were were included.Sixty-two patients (54.9%) received postoperative 131I and 51 (45.1%) did not. There was a significant association between the American Thyroid Association (ATA) risk stratification and whether or not there was an acceptable response at the end of follow-up (p=0.001). There were significant associations of structural disease and TERT-p mutation with extra-thyroidal extension (p=0.003) and ATA risk stratification (p<0.001). Multivariate analyses indicated that age ≥55 years at initial diagnosis, N1b stage, and high-risk stratification were independent prognostic factors for RFS (p=0.014, p=0.003, and p=0.045, respectively). Conclusions: 131I treatment may have no effect on RFS in patients with non-distant metastatic PTC and TERT-p mutation at initial diagnosis.

Background Effective treatment for patients with advanced thyroid cancer is lacking. Metabolism reprogramming is required for cancer to undergo oncogenic transformation and rapid tumorigenic growth. Glutamine is frequently used by cancer cells for active bioenergetic and biosynthetic needs. This study aims to investigate whether targeting glutamine metabolism is a promising therapeutic strategy for thyroid cancer. Methods The expression of glutaminase (GLS) and glutamate dehydrogenase (GDH) in thyroid cancer tissues was evaluated by immunohistochemistry, and glutamine metabolism-related genes were assessed using real time-qPCR and western blotting. The effects of glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) on thyroid cancer cells were determined by CCK-8, clone formation assay, Edu incorporation assay, flow cytometry, and Transwell assay. The mechanistic study was performed by real time-qPCR, western blotting, Seahorse assay, and gas chromatography–mass spectrometer assay. The effect of DON prodrug (JHU-083) on thyroid cancer in vivo was assessed using xenograft tumor models in BALB/c nude mice. Results GLS and GDH were over-expressed in thyroid cancer tissues, and GLS expression was positively associated with lymph-node metastasis and TNM stage. The growth of thyroid cancer cells was significantly inhibited when cultured in glutamine-free medium. Targeting glutamine metabolism with DON inhibited the proliferation of thyroid cancer cells. DON treatment did not promote apoptosis, but increased the proportion of cells in the S phase, accompanied by the decreased expression of cyclin-dependent kinase 2 and cyclin A. DON treatment also significantly inhibited the migration and invasion of thyroid cancer cells by reducing the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Non-essential amino acids, including proline, alanine, aspartate, asparagine, and glycine, were reduced in thyroid cancer cells treated with DON, which could explain the decrease of proteins involved in migration, invasion, and cell cycle. The efficacy and safety of DON prodrug (JHU-083) for thyroid cancer treatment were verified in a mouse model. In addition to suppressing the proliferation and metastasis potential of thyroid cancer in vivo, enhanced innate immune response was also observed in JHU-083-treated xenograft tumors as a result of decreased expression of cluster of differentiation 47 and programmed cell death ligand 1. Conclusions Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.