Tumor-to-background Ratio Research Articles

Abstract B017: Combining baseline microenvironment biomarkers with hypoxia imaging to predict radiochemotherapy outcomes in head and neck cancer

Abstract Background: Hypoxia contributes to tumor therapy resistance and it can be evaluated through imaging, such as [18F]fluoromisonidazole (FMISO)-PET, or hypoxia-associated gene expression profiling, among other modalities. Integrating imaging with tumor microenvironment features may provide a more comprehensive prognostic assessment. This study evaluates the prognostic value of combining FMISO-PET hypoxia imaging with baseline gene expression profiles in head and neck squamous cell carcinoma (HNSCC) patients undergoing radiochemotherapy (RCTx). Methods FMISO-PET images were obtained at baseline and at weeks 1, 2, and 5 during RCTx to assess tumor-to-background ratios (TBR) and hypoxic volumes (HV). Gene expression from pre-treatment biopsies was analyzed using Affymetrix microarrays. Gene set enrichment analysis of cancer hallmarks was conducted, and cell type fractions were imputed using CIBERSORTx. Correlation and LASSO analyses were conducted to identify baseline gene expression and cell type fractions associated with hypoxia imaging at baseline and during RCTx. Cox regression models were used to integrate imaging and gene expression data for predicting loco-regional tumor control (LRC). Results Baseline Epithelial to Mesenchymal Transition and Hypoxia gene sets were strongly correlated with hypoxia imaging parameters at week 2. A LASSO model identified baseline gene expression associated with FMISO-PET parameters (TBRpeak, HV16, and residual hypoxia) at week 2, indicating a predisposition for hypoxia persistence. AKR1A1, PITPNB, CTSK, and PEF1 gene expression levels were associated with LRC. In the tumor microenvironment, CD4 memory resting T cells and fibroblasts at baseline correlated with hypoxia imaging at weeks 1 and 2, with high levels of these cell fractions linked to decreased LRC. The fibroblast cell fraction positively correlated with CTSK transcript levels (Spearman ρ = 0.59, p < 0.05). K-means clustering based on CTSK and fibroblast levels identified patient subgroups with distinct LRC outcomes (HR [95% CI]: 3.491 [1.165-10.46], p = 0.0256). Importantly, clustering remained an independent predictor of LRC when analyzed with baseline FMISO TBRpeak and HV16 in multivariate Cox regression (HR [95% CI]: 3.883 [1.224-12.321], p = 0.0213). However, when TBRpeak and HV16 at week 2 were included in the model, the impact of the fibroblast cell fraction/CTSK clustering was attenuated (HR [95% CI]: 2.899 [0.918-9.156], p = 0.0697). Conclusion This study highlights the potential for integrating baseline tumor microenvironment markers, such as fibroblast fraction and CTSK expression, with dynamic hypoxia imaging to improve HNSCC prognostic accuracy. High fibroblast cell fraction and CTSK levels at baseline may predispose tumors to treatment-resistant hypoxia, confirmed by persistent hypoxia measured by FMISO-PET at week 2 . By capturing both predisposition to and hypoxia imaging, this approach may enhance the personalization of radiochemotherapy for high-risk HNSCC patients. Citation Format: María J. Besso, Verena Bitto, Cristina Conde-Lopez, Mareike Roscher, Steffen Löck, Annett Linge, Mechthild Krause, Michael Baumann, Ina Kurth. Combining baseline microenvironment biomarkers with hypoxia imaging to predict radiochemotherapy outcomes in head and neck cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B017.

Prognostic and diagnostic value of [18F]FDG, 11C-acetate, and [68Ga]Ga-FAPI-04 PET/CT for hepatocellular carcinoma.

To assess the prognostic value of Fluorine 18-labeled fluorodeoxyglucose [18F]FDG, gallium 68-labeled fibroblast-activation protein inhibitor-04 [68Ga]Ga-FAPI-04, 11C-acetate in hepatocellular carcinoma (HCC) and evaluate the potential usefulness and advantages of different combinations for accurate diagnosis. Thirty-six patients with suspected hepatic masses were prospectively enrolled from May 2021 to September 2022 and underwent [18F]FDG, [68Ga]Ga-FAPI-04, and 11C-acetate PET/CT scans before surgery. PET/CT results and histopathologic examinations were independently interpreted by two radiologists and pathologists, respectively. Kaplan-Meier overall survival curves were calculated and the sensitivity among [18F]FDG, 11C-acetate, [68Ga]Ga-FAPI-04, and different combinations were compared. Of the 36 included patients (mean age, 59 years ± 10 (standard deviation)), 29 were diagnosed with HCC, four with non-HCC malignant tumors, and three with benign tumors. Patients with HCC lesions negative for 11C-acetate or [68Ga]Ga-FAPI-04 exhibited poorer overall survival. Out of 36 patients, 44 HCC lesions were detected. The dual-tracer [68Ga]Ga-FAPI-04/11C-acetate exhibited the highest sensitivity (39 of 44 lesions (88.6%)) among all schemes. HCC lesions with higher histological grade and microvascular invasion (MVI) showed higher maximum standardized uptake value (SUVmax) and tumor-to-background ratio (TBR) of [18F]FDG, but no evidence of significant differences was found in [68Ga]Ga-FAPI-04 and 11C-acetate PET/CT. Higher expression of fibroblast activation protein (FAP) showed higher uptake of [68Ga]Ga-FAPI-04 and [18F]FDG. [68Ga]Ga-FAPI-04 and 11C-acetate PET/CT exhibited good predictive value for HCC patients, with their combination showing the highest sensitivity for HCC detection, suggesting potential for improved diagnostic protocols. Question What are the prognostic and diagnostic values of PET/CT tracers, including [18F]FDG, [68Ga]FAPI-04, and 11C-acetate? Findings Hepatocellular carcinoma, with differing findings across [18F]FDG, [68Ga]GaFAPI-04, and 11C-acetate PET/CT, showed varied prognoses; [68Ga]GaFAPI-04 and 11C-acetate combined offered the highest detection sensitivity. Clinical relevance Evaluating the prognostic value and diagnostic efficacy of different tracer combinations in patients with hepatocellular carcinoma helps to guide the optimal selection of tracers in clinical practice.

Assessment of viable tumours by [68Ga]Ga-FAPI-04 PET/CT after local regional treatment in patients with hepatocellular carcinoma.

To investigate the efficacy of [68Ga]Ga-FAPI-04 PET/CT for assessing viable tumours (VTs) after local regional treatment (LRT) in hepatocellular carcinoma (HCC) patients. The related imaging features of HCC after LRT are preliminarily discussed. A cohort of 37 LRT patients with HCC (encompassing 51 lesions) was retrospectively included from a prospective parent study (ChiCTR2000039099), and sequential PET/CT using [18F]FDG and [68Ga]Ga-FAPI-04 was performed. The diagnostic accuracies of [68Ga]Ga-FAPI-04 and [18F]FDG PET/CT and multiphasic CT/MRI for detecting VTs after LRT were calculated and analysed. Pathological examination was considered the gold standard for VT diagnosis, and clinical follow-up was used as the reference standard. The SUVmax and tumour-to-background ratio (TBR) derived from [18F]FDG and [68Ga]Ga-FAPI-04 PET/CT were calculated and compared. Moreover, the SUVmax, target-to-normal liver ratio (TNR) of VT, tumour necrosis (TN), benign rim (BR), and normal liver (NL) from different imaging modalities after LRT for HCC were compared. Both the sensitivity (96.0% [24/25] vs. 36.0% [9/25], p < 0.001) and accuracy (94.1%, [48/51] vs. 68.6% [35/51], p = 0.004) of [68Ga]Ga-FAPI-04 PET/CT for detecting VTs after LRT were greater than those of [18F]FDG PET/CT, whereas their specificities were comparable (92.3% [24/26] vs. 100% [26/26]). Notably, [68Ga]Ga-FAPI-04 PET/CT had a greater SUVmax (9.80 vs. 3.60) and TBR (9.93 vs. 1.57) than [18F]FDG PET/CT in VT patients (all p < 0.001). Furthermore, VT had a greater SUVmax and TNR than did TN, BR, and NL on [68Ga]Ga-FAPI-04 PET/CT (all p < 0.001) and exhibited morphologic nodular, mass-like, or irregular tracer uptake. Although no significant differences were observed for VT detection (all p > 0.05), [68Ga]Ga-FAPI-04 PET/CT and multiphasic CT/MRI complemented each other in some cases. [68Ga]Ga-FAPI-04 PET/CT not only presented higher sensitivity and accuracy than [18F]FDG PET/CT for diagnosing VTs after LRT for HCC but also showed comparable diagnostic accuracy and complementary roles with multiphasic CT/MRI. Overall, [68Ga]Ga-FAPI-04 PET/CT may play an essential role in surveillance after LRT for HCC. Chinese Clinical Trial Registry ChiCTR2000039099. Registered 17 October 2020.

First Clinical Experience of 68Ga-FAPI PET/CT in Tertiary Cancer Center: Identifying Pearls and Pitfalls.

Background/Objectives: Over the past four years, 68Ga-fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) has been established at a tertiary cancer care facility in Jordan. This retrospective study aims to explore tracer uptake metrics across various epithelial neoplasms, identify diagnostic pitfalls associated with 68Ga-FAPI PET/CT, and evaluate the influence of 68Ga-FAPI PET/CT staging results on changes in therapeutic intent compared to gold standard molecular imaging modalities. Methods: A total of 48 patients with biopsy-confirmed solid tumors underwent 77 68Ga-FAPI PET/CT examinations for molecular imaging assessment, encompassing neoplasms originating from the gastrointestinal tract, head and neck, hepatobiliary system, pancreas, breast, and lung. Results: Notably, pancreaticobiliary tumors exhibited the highest tracer uptake, with mean maximum standardized uptake values (SUVmax) and tumor-to-background ratios (TBR) surpassing 10. A comparative sub-analysis of 68Ga-FAPI PET metrics in 20 treatment-naïve patients revealed a significant correlation between 68Ga-FAPI uptake metrics and tumor grade (Spearman's rho 0.83; p = 0.00001). Importantly, the results from 68Ga-FAPI PET/CT influenced treatment decisions in 35.5% of the cases, primarily resulting in an escalation of management plans. A total of 220 diagnostic challenges were identified across 88.3% of the scans, predominantly within the musculoskeletal system, attributed to degenerative changes (99 observations). Conclusions: This comprehensive analysis highlights the potential significance of 68Ga-FAPI PET/CT in oncological imaging and treatment strategy, while also emphasizing the necessity for meticulous interpretation to mitigate diagnostic challenges.

SVCT2-targeted PET imaging agent for the evaluation of LN metastasis of thyroid cancer.

Cervical lymph node (LN) metastasis is highly prevalent in thyroid cancer (TC). However, the lack of diagnostic modalities that enable real-time assessment of LN metastasis remains a challenge in providing efficient clinical decision-making and optimal patient care. Sodium-ascorbate co-transporters (SVCTs) have shown high expression levels in TC, presenting a potential target for visualizing LN metastasis. In this study, we successfully prepared [18F]FAA, targeting SVCT2, with high radiochemical yield. Subsequently, we demonstrated a significantly high expression of SVCT2 in LN metastasis compared to normal tissues. Then, we demonstrated that [18F]FAA exhibited a significant and specific uptake in TC cells expressing SVCT2. Biodistribution and micro-PET/CT imaging in tumor and lymphadenitis model mice indicated significant [18F]FAA uptake in tumors but not in regions of LN inflammation. Preliminary clinical investigations revealed that [18F]FAA detected a greater number of LN metastatic lesions with higher mean SUVmax and tumor-to-background ratio (TBR) than [18F]FDG. These results highlight the potential of [18F]FAA as a non-invasive imaging agent for accurately detecting LN metastasis in TC.

18F−Prostate−Specific Membrane Antigen PET/CT imaging for potentially resectable pancreatic cancer (PANSCAN−2): a phase I/II study

BackgroundCurrent diagnostic imaging modalities have limited ability to differentiate between malignant and benign pancreaticobiliary disease, and lack accuracy in detecting lymph node metastases. 18F-Prostate-Specific Membrane Antigen (PSMA) PET/CT is an imaging modality used for staging of prostate cancer, but has incidentally also identified PSMA-avid pancreatic lesions, histologically characterized as pancreatic ductal adenocarcinoma (PDAC). This phase I/II study aimed to assess the feasibility of 18F-PSMA PET/CT to detect PDAC.MethodsSeventeen patients with clinically resectable PDAC underwent 18F-PSMA PET/CT prior to surgical resection. Images were analyzed both visually and (semi)quantitatively by deriving the maximum standardized uptake value (SUVmax) and tumor-to-background ratio (TBR). TBR was defined as the ratio between SUVmax of the primary tumor divided by SUVmax of the aortic blood pool. Finally, tracer uptake on PET was correlated to tissue expression of PSMA in surgical specimens.ResultsOut of 17 PSMA PET/CT scans, 13 scans demonstrated positive PSMA tracer uptake, with a mean SUVmax of 5.0 ± 1.3. The suspected primary tumor was detectable (TBR ≥ 2) with a mean TBR of 3.3 ± 1.3. For histologically confirmed PDAC, mean SUVmax and mean TBR were 4.9 ± 1.2 and 3.3 ± 1.5, respectively. Although eight patients had histologically confirmed regional lymph node metastases and two patients had distant metastases, none of these metastases demonstrated 18F-PSMA uptake. There was no correlation between 18F-PSMA PET/CT SUVmax and tissue expression of PSMA in surgical specimens.Conclusions18F-PSMA PET/CT was able to detect several pancreaticobiliary cancers, including PDAC. However, uptake was generally low, not specific to PDAC and no tracer uptake was observed in lymph node or distant metastases. The added value of PSMA PET in this setting appears to be limited.Trial registrationThe trial is registered as PANSCAN-2 in the European Clinical Trials Database (EudraCT number: 2020–002185-14).Graphical

Do you know your PSMA-tracer? Variability in the biodistribution of different PSMA ligands and its potential impact on defining PSMA-positivity prior to PSMA-targeted therapy

BackgroundIn clinical practice, several radiopharmaceuticals are used for PSMA-PET imaging, each with distinct biodistribution patterns. This may impact treatment decisions and outcomes, as eligibility for PSMA-directed radioligand therapy is usually assessed by comparing tumoral uptake to normal liver uptake as a reference. In this study, we aimed to compare tracer uptake intraindividually in various reference regions including liver, parotid gland and spleen as well as the respective tumor-to-background ratios (TBR) of different 18F-labeled PSMA ligands to today’s standard radiopharmaceutical 68Ga-PSMA-11 in a series of patients with biochemical recurrence of prostate cancer who underwent a dual PSMA-PET examination as part of an individualized diagnostic approach.ResultsDifferences in background activity among different PSMA-PET tracers lead to variations in tumor-to-background ratios (TBR). In [18F]F-DCFPyL-PET, TBR with the liver as the reference organ (TBRliver) was comparable to [68Ga]Ga-PSMA-11-PET, while [18F]F-PSMA-1007-PET and [18F]F-JK-PSMA-7-PET showed significantly lower values. Using the parotid gland as the reference (TBRparotidgland), [18F]F-DCFPyL-PET exhibited significantly higher values, whereas [18F]F-PSMA-1007-PET and [18F]F-JK-PSMA-7-PET were comparable. For the spleen (TBRspleen), [18F]F-JK-PSMA-7-PET was comparable, but [18F]F-DCFPyL-PET and [18F]F-PSMA-1007-PET showed significantly higher and lower values, respectively. An additional Bland-Altman analyses revealed low bias for [18F]F-DCFPyL-PET in TBRparotidgland, whereas significant differences in TBRliver and TBRspleen for the other tracers resulted in higher bias.ConclusionDifferent PSMA-PET tracers exhibit distinct biodistribution patterns, leading to variations in tumor-to-background ratios (TBR) in reference organs such as the liver, parotid gland, and spleen. Patient selection for PSMA-directed radioligand therapy is currently based on a semiquantitative approach using the liver as a reference region in [68Ga]Ga-PSMA-11-PET. Thus, the use of alternative [18F]-labeled tracers may result in under- or overestimation of a patient’s suitability for therapy. This highlights the importance of a comprehensive understanding of the differences in tracer-specific uptake behavior for accurate decisions regarding PSMA-expression levels. However, as the patient cohort in this study is at earlier disease stages, the generalizability of these findings to later-stage patients remains unclear and requires further investigation.

Optical molecular imaging in oral- and oropharyngeal squamous cell carcinoma using a novel uPAR-targeting near-infrared imaging agent FG001 (ICG-Glu-Glu-AE105): An explorative phase II clinical trial.

Background: In oral and oropharyngeal squamous cell carcinoma (OSCC, OPSCC), frequent inadequate surgical margins highlight the importance of precise intraoperative identification and delineation of cancerous tissue for improving patient outcomes. Methods: A prospective, open-label, single-center, single dose, exploratory phase II clinical trial (EudraCT 2022-001361-12) to assess the efficacy of the novel uPAR-targeting near-infrared imaging agent, FG001, for intraoperative detection of OSCC and OPSCC. Macroscopic tumor detection was quantified with sensitivity and intraoperative tumor-to-background ratio (TBR). Microscopic tumor-specificity was assessed by analysis of morphological co-localization between tumor tissue, uPAR-expression, and optical signal. Blood samples were collected up to 44 hours post-injection to further characterize the pharmacokinetic profile of the agent. The trial was conducted with close safety monitoring. Results: Sixteen patients undergoing primary surgical resection were systemically administered 36 mg (n = 4), 16 mg (n = 8), or 4 mg (n = 4) of FG001 the evening prior to surgery. Intraoperatively, using a near-infrared imaging system, real-time optical imaging successfully identified all 16 tumors (sensitivity: 100%, mean TBR: 2.99 range: 2.02 - 3.95), and tumor-specificity was confirmed by histology. Clinical neck metastasis was detected with optical imaging. The maximal plasma concentrations were measured after 1 hour, and the half-life of FG001 was 12 hours. No drug-related or serious adverse events were observed. Conclusions: FG001 holds great potential for optical molecular imaging of OSCC and OPSCC. Further trials are warranted to explore FG001 for intraoperative margin delineation and as a decision-making tool.

Evaluating the diagnostic value of 18F-FAPI-04 PET/CT in various malignant tumors: a head-to-head comparison with 18F-FDG PET/CT.

This study aims to evaluate the diagnostic efficacy of 18F-fibroblast activation protein inhibitor-04 (18F-FAPI-04) PET/CT for various malignant tumors and compare it head-to-head with 18F-FDG PET/CT. This single-center, prospective study continuously recruited patients with suspected or confirmed malignant tumors for concurrent 18F-FDG and 18F-FAPI-04 PET/CT scans from April 2022 to October 2023. The pathological diagnosis or clinical follow-up served as the reference standard. The Z-test for two proportions was used to compare the sensitivity, specificity, and accuracy of tumor diagnosis between the two imaging agents. Wilcoxon signed-rank tests were employed to compare the uptake of the two radiotracers and the tumor-to-background ratio (TBR) differences in tumors. The study involved 15 types of tumors and included 88 patients, comprising 53 males and 39 females, with an average age of 57.7 ± 10.8 years. In patient-based analysis, 18F-FAPI-04 PET/CT demonstrated higher diagnostic accuracy than 18F-FDG PET/CT for both initial staging and restaging patients (77.4% vs 56.6%, p = 0.0389; 94.3% vs 54.3%, p < 0.001), prompting treatment plan adjustments in 17% of restaged patients. The lesion-based analysis revealed comparable diagnostic accuracy of 18F-FAPI-04 PET/CT and 18F-FDG PET/CT for primary tumors (78.9% vs 75.4%, p = 0.8234), while showing superior accuracy for residual/recurrent tumors, lymph node metastases, and distant metastases compared to 18F-FDG PET/CT (100.0% vs 50.0%, p = 0.002; 98.8% vs 86.0%, p < 0.001; 98.3% vs 79.3%, p < 0.001). 18F-FAPI-04 PET/CT exhibits higher uptake and TBR in most tumors demonstrating superior diagnostic efficacy for primary lesions, residual/recurrent disease, and metastases compared to 18F-FDG PET/CT, particularly beneficial for restaging post-treatment patients.

Synthesis and Evaluation of 99mTc-Labeled l-Aspartic Acid as a EuK Polymer Linker for Targeting PSMA to a Novel SPECT Tumor Tracer.

The development of novel tracers targeting prostate-specific membrane antigen (PSMA) has great potential for improving the diagnosis and treatment of prostate cancer (PCa). This study aimed to improve the absolute tumor uptake and tumor-to-background ratios (TBRs) of this novel PSMA tracer by increasing the number of pharmacophores, Glu-urea-Lys (EuK), that specifically bind to PSMA. We successfully synthesized four radioligands and prepared a total of 12 stable radiotracers by coordinating 99mTc with various coligands. [99mTc]Tc-EUKD-EDDA showed the best pharmacokinetic properties both in vitro and in vivo. It effectively increased the absolute uptake in tumors and resulted in good tumor retention. Rapid clearance in nontarget organs resulted in high TBRs. High-contrast SPECT/CT images were obtained within 2-6 h after injection, suggesting that [99mTc]Tc-EUKD-EDDA has great application potential in time-lapse imaging of PCa, which is important for improving the diagnostic accuracy of PCa in clinical practice.

Comparative Study of [18F]AlF-LNC1007, [18F]FDG, and [18F]AlF-NOTA-FAPI-04 PET/CT in Breast Cancer Diagnosis: A Methodological Exploration and Analytical Insight.

Objective: To compare the diagnostic value of [18F]AlF-LNC1007, [18F]FDG, and [18F]AlF-NOTA-FAPI-04 PET/CT in breast cancer. Methods: 33 patients with highly suspected or already diagnosed but untreated breast cancer were enrolled in the study and underwent [18F]AlF-LNC1007 (30 patients), [18F]FDG (22 patients), and [18F]AlF-NOTA-FAPI-04 (8 patients) PET/CT. Quantitative measurements included the SUVmax and tumor-to-background ratio (TBR) for all lesions and background tissues. The Chi-square test was used for intergroup diagnostic efficacy, and the Wilcoxon test was used for intergroup SUVmax or TBR. Diagnostic efficacy for lymph node metastasis was evaluated using receiver operating characteristic (ROC) analysis. Results: Compared to [18F]FDG, [18F]AlF-LNC1007 had a higher positive predictive value (100% vs 91%, P = 0.0004) in lymph node metastases (42 vs 46) and higher sensitivity (100 vs 76%, P = 0.0003) in bone metastases (33 vs 25) but lower sensitivity (93 vs 100%, P = 0.001) in liver metastases. Apart from liver metastases, [18F]AlF-LNC1007 PET/CT had higher SUVmax in primary tumor and other metastases, with no statistical difference in TBR. Compared to [18F]AlF-NOTA-FAPI-04 PET/CT, [18F]AlF-LNC1007 had less false-positive and a higher positive predictive value in bone metastases (99 vs 95%, P = 0.0003) but had lower SUVmax(P < 0.01) in all primary and metastases lesions. The TBR difference between [18F]AlF-LNC1007 and [18F]AlF-NOTA-FAPI-04 was statistically significant only in bone metastases (5.97 vs 5.02, P = 0.001). The comparison of lymph node detection efficacy between [18F]AlF-LNC1007 and [18F]FDG PET/CT showed significant differences in SUVmax cutoff values for diagnosing lymph node metastases (2.62 vs 3.90), sensitivity (95.2% vs 66.67), and specificity (100% vs 85.00) (all P < 0.001). Conclusion: [18F]AlF-LNC1007 demonstrated superior efficacy compared to [18F]FDG and [18F]AlF-NOTA-FAPI-04 and higher uptake than [18F]FDG in primary tumor, lymph node and bone metastases, and higher TBR than [18F]AlF-NOTA-FAPI-04, especially in bone metastases. [18F]AlF-LNC1007 also showed high specificity in differentiating inflammatory and metastatic lymph nodes.

18F-FET PET/CT can aid in diagnosing patients with indeterminate MRI findings for brain tumors: a prospective study.

This prospective study aimed to evaluate the diagnostic value of fluorine-18-labeled fluoroethyltyrosine (18F-FET) positron emission tomography (PET)/computed tomography (CT) in diagnosing brain tumors within an Asian patient population. Patients suspected of having primary or recurrent brain tumors were prospectively recruited. Each patient underwent 18F-FET and fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT on separate days within 1week. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy to compare the diagnostic performance of the two PET scans. The standardized uptake value (SUV) and tumor-to-background ratio (TBR) of the lesions were determined using static images. Additionally, time-activity curves (TACs) and time-to-peak (TTP) were generated from the dynamic PET images. From September 2019 to December 2023, 33 subjects were enrolled for reasons including suspected brain tumors (n = 20) or suspicious glioma recurrence (n = 8) on magnetic resonance imaging (MRI) and restaging for glioma (n = 5). Among the patients with suspected brain tumors or glioma recurrence on MRI, 25% had false-positive results. 18F-FET PET/CT accurately identified 86% of these false positives. The sensitivity, specificity, PPV, NPV, and accuracy of visual interpretation of 18F-FET PET/CT were 96.2%, 85.7%, 96.2%, 85.7%, and 93.9%, respectively. The corresponding 18F-FDG PET/CT values were 73.1%, 71.4%, 90.5%, 41.7%, and 72.7%. 18F-FET PET/CT demonstrated significantly higher sensitivity and accuracy than 18F-FDG PET (p = 0.031 and p = 0.030, respectively). Using TBRmean as an adjunct reference index enhanced the diagnostic accuracy of 18F-FET PET/CT, achieving a sensitivity and NPV of 100%. Wash-out TAC or TTP < 20min was associated with a PPV of 100% for brain tumors. 18F-FET PET/CT appears to be a valuable tool for assessing brain tumors with indeterminate MRI findings in this Asian cohort. 18F-FET PET/CT offers benefits over 18F-FDG PET in differentiating brain tumors from nontumor brain lesions, particularly when using semiquantitative analysis with TBR. This study was registered on CinicalTrial.gov (NCT06563024).

Synthesis and preclinical evaluation of [18F]AlF-NOTA-Asp2-PEG2-JR11 as a novel antagonist radioligand for PET imaging of somatostatin receptor.

Somatostatin receptor (SSTR) antagonists have recently emerged as preferable radiotracers for SSTR-targeted imaging and therapy. This study aimed to design a novel SSTR antagonist, [18F]AlF-NOTA-Asp2-PEG2-JR11, and compare its preclinical performance with the previously reported antagonist, [18F]AlF-NOTA-JR11, and the agonist [68Ga]Ga-DOTA-TATE. [18F]AlF-NOTA-Asp2-PEG2-JR11 was synthesized via a one-step radiolabeling process involving [18F]AlF chelation. The binding affinity, internalization, and cellular uptake were evaluated using AR42J/SSTR + cells. Biodistribution and PET/CT imaging were conducted in mice bearing xenografted AR42J/SSTR + or HCT116/SSTR- tumor xenografts. [18F]AlF-NOTA-Asp2-PEG2-JR11 was manually synthesized within 30min with an uncorrected radiochemical yield of 39.56 ± 3.25% (n > 5) and radiochemical purity (RCP) exceeding 99% (n > 5). [18F]AlF-NOTA-Asp2-PEG2-JR11 demonstrated excellent in vivo stability over 2h (RCP > 95%). Among AR42J cells, [18F]AlF-NOTA-Asp2-PEG2-JR11 exhibited high affinity, specific uptake, and low internalization, similar to [18F]AlF-NOTA-JR11. Biodistribution and micro-PET/CT imaging studies revealed comparable tumor uptake between [18F]AlF-NOTA-Asp2-PEG2-JR11 and [18F]AlF-NOTA-JR11 (9.26 ± 0.49 vs. 10.18 ± 0.82%ID/g, p = 0.147) at 60min post-injection (p.i), both were significantly higher than [68Ga]Ga-DOTA-TATE (6.79 ± 0.29%ID/g, p = 0.001). Co-injecting the corresponding inhibitor significantly reduced the tumor uptake of all three tracers. Notably, [18F]AlF-NOTA-Asp2-PEG2-JR11 reached peak tumor uptake at 30min p.i. and exhibited the lowest uptake and fastest clearance in most normal organs, including the kidney, bone, liver, and muscle, resulting in the highest and increasing tumor-to-background ratios (TBR) over time among the three tracers. The synthesis of [18F]AlF-NOTA-Asp2-PEG2-JR11 is efficient, with high radiochemical yield and RCP. [18F]AlF-NOTA-Asp2-PEG2-JR11 exhibits excellent in vivo stability, high tumor uptake, and superior TBR, making it a promising potential tracer for imaging SSTR-positive tumors.

NIMG-80. IMPACT OF KETOGENIC DIET ON MOLECULAR METABOLIC IMAGING WITH [18F]FDG AND [18F]DASA-23 POSITRON EMISSION TOMOGRAPHY IN A PATIENT WITH GLIOBLASTOMA

Abstract The standard-of-care for neuroimaging in patients with glioblastoma is contrast-enhanced MRI, which does not provide tumor metabolism information. Although [18F]FDG PET is used to image tumor metabolism in many solid organ cancers, it has limited benefit in atients with brain tumors due to the high level of glucose uptake in normal brain cells. [18F]DASA-23 is a novel PET radiotracer that assesses the levels of pyruvate kinase M2 (PKM2), a protein highly expressed in cancer cells, which undergo aberrant glycolysis. Despite [18F]DASA-23 having a higher tumor-to-background ratio (TBR) of standardized uptake values (SUVs) in the brain compared to [18F]FDG, both may be susceptible to altered carbohydrate metabolism in the setting of a ketogenic diet (KD). We report the case of a patient with glioblastoma on a KD, whose [18F]FDG and [18F]DASA-23 PET brain scans were limited in identifying disease progression (PD). Background was defined as the white matter contralateral to the tumor, at the level of the centrum semiovale, for TBR of SUVmax. A 39-year-old man was diagnosed with right temporal glioblastoma after previous diagnoses of grade 2 gliofibrillary oligodendroglioma (age 20) and grade 3 anaplastic oligodendroglioma (age 22). He began a KD after the glioblastoma diagnosis. 21 months later, TBR on [18F]DASA-23 PET was 1.38. One month later, surveillance brain MRI showed PD. Ten days later, TBR on [18F]FDG PET was 1.03. The patient died 15 months later. Despite MRI-based PD, the TBR of each radiotracer was not markedly elevated, although the [18F]DASA-23 TBR 1-month pre-PD was 34% greater than the [18F]FDG PET TBR 10-days post-PD. This may suggest a limitation of metabolic imaging by PET in the setting of a KD, and provide an opportunity to develop novel PET radiotracers that are not susceptible to the patient’s diet.

Head-to-head study of [18F]FAPI-04 PET/CT and [18F]FDG PET/CT for non-invasive assessment of liver cancer and its immunohistochemical markers

ObjectiveTo compare the performance of [18F]FDG and [18F]FAPI-04 in PET/CT evaluation for liver cancer lesions, with a further exploration of the associations between PET semiquantitative data and immunohistochemical markers to liver cancer.MethodsPatients with suspected malignant liver lesions (MLL) underwent [18F]FDG and [18F]FAPI-04 PET/CT scanning. Liver lesions were visually classified as positive or negative based on their uptake level exceeding that of adjacent normal liver tissue. SUVmax and tumor-to-background ratio (TBR) were recorded for semi-quantitative analysis. Sensitivity, specificity and accuracy of each tracer were determined using pathological findings as the gold standard. Furthermore, immunohistochemical analysis provided the molecular characteristics of all MLLs. Comprehensive analysis explored correlations between these molecular markers and PET semiquantitative parameters (SUVmax andTBR) to identify potential associations.ResultsThe study enrolled 44 patients, with 39 confirmed cases of MLL, comprising 28 hepatocellular carcinomas (HCC) and 11 intrahepatic cholangiocarcinomas (ICC). For MLL detection, [18F]FAPI-04 and [18F]FDG exhibited sensitivities of 84.6% (33/39) and 76.9% (30/39), specificitiesy of 60% (3/5) and 100%(5/5), and accuracy of 81.8% (36/44) and 79.5%(35/44). Across all liver lesions, [18F]FAPI-04 significantly surpassed [18F]FDG in SUVmax(10.54 ± 6.72 VS. 7.68 ± 6.79) and TBR(4.35 ± 3.78 Vs. 3.17 ± 3.05). Notably, [18F]FAPI-04 displayed markebly elevated SUVmax in benign liver lesions (BLLs) (P = 0.032), HCCs (P = 0.005), and ICCs (P = 0.011). Lesions with hepatocyte negativity (P = 0.023), CD34 negativity(P = 0.044), and high Ki67 expression (> 30%) (P = 0.001) had higher SUVmax on [18F]FAPI-04. Additionally, ARG-1-negative lesions demonstrated higher TBR on [18F]FAPI-04 than ARG-1-positive lesions(P = 0.018). No significant SUVmax/TBR differences were observed with [18F]FDG based on these markers. A linear relationship was identified between Ki67 scores and SUVmax of [18F]FAPI-04 (R = 0.603, P < 0.001).Conclusion[18F]FAPI-04 exhibits superior performance over [18F]FDG in PET/CT evaluation of liver cancer, characterized by increased sensitivity and SUVmax/TBR. Significant correlations with molecular markers, including Ki67, suggest [18F]FAPI-04’s potential for characterizing liver cancer subtypes and assessing tumor proliferation. However, further research is required to validate these findings and their clinical significance.Trial registrationNCT05485792, Registered 01 August 2022.

FET PET to differentiate between post-treatment changes and recurrence in high-grade gliomas: a single center multidisciplinary clinic controlled study.

The clinico-radiological dilemma in post-treatment high-grade gliomas, between disease recurrence (TR) and treatment-related changes (TRC), still persists. FET (Fluoro-ethyl-tyrosine) PET has been extensively used as problem-solving modality for cases where MR imaging is inconclusive. We incorporated a systematic imaging and clinical follow-up algorithm in a multi-disciplinary clinic (MDC) setting to analyse our cohort of FET PET in post-treatment gliomas. We retrospectively analyzed 171 patients of post-treatment grade III and IV glioma with equivocal findings on MRI. 185-222 MBq of 18F-FET was injected and dedicated static imaging of brain was performed at 20min. TBR (Tumor to background ratio) was used as semi-quantitative parameter. Cutoff of 2.5 was used for image interpretation. Imaging findings were confirmed with histopathological diagnosis, wherever available or in a multidisciplinary joint clinic based on serial imaging. 121 of 171 patients showed recurrent disease on FET PET, on follow up, 109 were confirmed with recurrence; 7 patients showed TRC, whereas 5 were treated with bevacizumab, with no further clinico-radiological deterioration, thus confirming TRC. 50 patients showed TRC on FET PET, on follow up on follow up, 40 were confirmed as true-negative. 10 patients who showed TBR less than 2.5 had confirmed TR on subsequent MR imaging. The overall sensitivity and specificity was 91.6 and 76.9% respectively, with a diagnostic accuracy of 87.13%. There is potential for FET PET to be used along with MRI in the post treatment algorithm of high-grade glial tumors.

Synthesis, preclinical assessment, and first-in-human study of [18F]d4-FET for brain tumor imaging.

Tumor-to-background ratio (TBR) is a critical metric in oncologic PET imaging. This study aims to enhance the TBR of [18F]FET in brain tumor imaging by substituting deuterium ("D") for hydrogen ("H"), thereby improving the diagnostic sensitivity and accuracy. [18F]d4-FET was synthesised by two automated radiochemistry modules. Biodistribution studies and imaging efficacy were evaluated in vivo and ex vivo in rodent models, while metabolic stability and radiation dosimetry were assessed in non-human primates. Additionally, preliminary imaging evaluations were carried out in five brain tumor patients: three glioma patients underwent imaging with both [18F]d4-FET and [18F]FET, and two patients with brain metastases were imaged using [18F]d4-FET and [18F]FDG. [18F]d4-FET demonstrated high radiochemical purity and yield. PET/MRIin rodent models demonstrated superior TBR for [18F]d4-FET compared to [18F]FET, and autoradiography showed tumor margins that correlated well with pathological extents. Studies in cynomolgus monkeys indicated comparable in vivo stability and effective dose with [18F]FET. In glioma patients, [18F]d4-FET showed enhanced TBR, while in patients with brain metastases, [18F]d4-FET displayed superior lesion delineation compared to [18F]FDG, especially in smaller metastatic sites. We successfully synthesized the novel PET radiotracer [18F]d4-FET, which retains the advantageous properties of [18F]FET while potentially enhancing TBR for glioma imaging. Preliminary studies indicate excellent stability, efficacy, and sensitivity of [18F]d4-FET, suggesting its potential in clinical evaluations of brain tumors. ChiCTR2400081576, registration date: 2024-03-05, https://www.chictr.org.cn/bin/project/edit?pid=206162.

First-in-human study of dosimetry, safety and efficacy for [177Lu]Lu-P15-073: a novel bisphosphonate-based radioligand therapy (RLT) agent for bone metastases.

Bisphosphonates are pivotal in managing bone tumors by inhibiting bone resorption. This study investigates the therapeutic potential of [177Lu]Lu-P15-073, a novel bisphosphonate, for radioligand therapy (RLT) in bone metastases. Ten patients (age 35 to 75) with confirmed bone metastases underwent therapy with a single dose of [177Lu]Lu-P15-073 (1,225 ± 84 MBq, or 33 ± 2 mCi). Prior to treatment, bone metastases were verified via [99mTc]Tc-MDP bone scans. Serial planar whole-body scans monitored biodistribution over a 14-day period. Dosimetry was assessed for major organs and tumor lesions, while safety was evaluated through blood biomarkers and pain scores. Serial planar whole-body scans demonstrated rapid and substantial accumulation of [177Lu]Lu-P15-073 in bone metastases, with minimal uptake in blood and other organs. The absorbed dose in the critical organ, red marrow, was measured at (0.034 ± 0.010 mSv/MBq), with a notably low normalized effective dose (0.013 ± 0.005 mSv/MBq) compared to other 177Lu-labeled bisphosphonates. Persistent high uptake in bone metastases was observed, resulting in elevated tumor doses (median 3.12Gy/GBq). Patients exhibited favorable tolerance to [177Lu]Lu-P15-073 therapy, with no new instances of side effects. Additionally, 87.5% (7/8) of patients experienced a significant reduction in pain scale (numerical rating scale, NRS, from 5.1 ± 2.3 to 3.0 ± 1.8). The tumor-background ratio (TBRmean) of [99mTc]Tc-MDP correlated significantly with [177Lu]Lu-P15-073 uptake (P < 0.01), indicating its potential for prediction of absorbed dose. This study demonstrates the safety, dosimetry, and efficacy of a single therapeutic dose of [177Lu]Lu-P15-073 in bone metastases. The treatment was well-tolerated with no severe adverse events. These findings suggest that [177Lu]Lu-P15-073 holds promise as a novel RLT agent for bone metastases.

β-galactosidase instructed in situ self-assembly fluorogenic probe for prolonged and accurate imaging of ovarian tumor

Fluorescent probes are essential for optical imaging and have been extensively employed for precise cancer diagnosis studies. β-galactosidase (β-gal) serves as a primary biomarker for ovarian cancer and has been utilized to develop imaging probes for accurate tumor diagnosis. However, traditional small molecular probes have limitations in terms of rapid diffusion and metabolic clearance from the target lesion, resulting in a short imaging window and compromised tumor-to-background ratios (TBR). Herein, we integrated an enzyme-instructed in situ self-assembly strategy to construct Gal-IRFF, a small molecule-based activatable near-infrared (NIR) fluorogenic probe. Upon cleavage by endogenous β-gal overexpressed in ovarian cancer cells, IRFF exhibited enhanced NIR fluorescence signals and self-assembled into nanoparticles through intermolecular interactions of the Phe-Phe (FF) dipeptide moiety, which facilitated probe accumulation and retention within the tumor lesion. Compared with the small molecule probe Gal-IR, our proposed self-assembly probe Gal-IRFF demonstrated a lower limit of detection (LOD) towards β-gal and showed remarkable improvements in distribution and retention time within SKOV3 cells in vitro and tumors in vivo, thereby providing a long-term imaging window for real-time monitoring β-gal levels in ovarian tumors. Therefore, this study highlights the potential of an enzyme-instructed self-assembly fluorogenic probe design approach for achieving precise tumor diagnosis in vivo.

Preclinical evaluation and first-in-human study of [18F]AlF-FAP-NUR for PET imaging cancer-associated fibroblasts

BackgroundFibroblast activation protein (FAP) has gained attention as a promising molecular target with potential utility for cancer diagnosis and therapy. [68Ga]Ga-labeled FAP-targeting peptides have been successfully applied to positron emission tomography (PET) imaging of various tumor types. To meet the applicable demand for peptide-based FAP tracers with high patient throughput, we herein report the radiosynthesis, preclinical evaluation, and the first-in-human imaging of a novel [18F]F-labeled FAP-targeting peptide.Results[18F]AlF-FAP-NUR was automatedly prepared within 45 min with a non-decay corrected radiochemical yield of 18.73 ± 4.25% (n = 3). Compared to [68Ga]Ga-FAP-2286, the [18F]F-labeled peptide demonstrated more rapid, higher levels of cellular uptake and internalization, and lower levels of cellular efflux in HT1080-FAP cells. Micro-PET imaging and biodistribution studies conducted on xenograft mice models revealed a similar distribution pattern between the two tracers. However, [18F]AlF-FAP-NUR demonstrated significantly higher tumor-specific uptake resulting in improved Tumor-Background Ratios (TBRs). In the patients, a significant accumulation of [18F]AlF-FAP-NUR was found in the primary tumor. High uptake of the tracer within the bladder indicated that its major route of excretion was through urine.ConclusionsBased on the physical imaging properties and longer half-life of [18F]F, [18F]AlF-FAP-NUR exhibited promising characteristics such as enhanced tumor-specific accumulation and elevated TBRs, which made it a viable candidate for further clinical investigation.Trial registrationwww.Chictr.org.cn, ChiCTR2300076976 Retrospectively registered 25 October 2023. at, URL: https://www.chictr.org.cn/showproj.html?proj=206753.