Value of [18F]AlF-NOTA-FAPI-04 PET/CT for differential diagnosis of malignant and various inflammatory lung lesions: comparison with [18F]FDG PET/CT.

OBJECTIVE: Uptake of the imaging tracers [18F]AlF-NOTA-FAPI-04 and [18F]FDG varies in some inflammatory lesions, which may result in false-positive findings for malignancy on PET/CT. Our aim was to compare the [18F]AlF-NOTA-FAPI-04 and [18F]FDG PET/CT imaging features of malignant and various inflammatory lung lesions and to analyze their value for differential diagnosis. METHODS: We retrospectively analyzed [18F]AlF-NOTA-FAPI-04 PET/CT scans from 67 cancer patients taken between December 2020 and January 2022, as well as the scans of 32 patients who also underwent [18F]FDG PET/CT imaging. The maximum and mean standardized uptake values (SUVmax and SUVmean, respectively) and lesion-to-background ratio (LBR) were calculated. The predictive capabilities of semiquantitative PET/CT parameters were analyzed by receiver operating characteristic curve analysis. RESULTS: A total of 70 inflammatory and 37 malignant lung lesions were evaluated by [18F]AlF­NOTA­FAPI­04 PET/CT, and 33 inflammatory and 26 malignant lung lesions also were evaluated by [18F]FDG PET/CT. Inflammatory lesions exhibited lower [18F]AlF-NOTA-FAPI-04 and [18F]FDG uptake compared to malignant lesions, with statistically significant differences in SUVmax, SUVmean, and LBR (all p < 0.001). [18F]AlF-NOTA-FAPI-04 uptake also varied among different types of inflammatory lesions (SUVmax, p = 0.005; SUVmean, p = 0.008; LBR, p < 0.001), with the highest uptake observed in bronchiectasis with infection, followed by postobstructive pneumonia, and the lowest in pneumonia. [18F]FDG uptake was higher in postobstructive pneumonia than in pneumonia (SUVmax, p = 0.009; SUVmean, p = 0.016; LBR, p = 0.004). CONCLUSION: [18F]AlF-NOTA-FAPI-04/[18F]FDG PET/CT showed significantly lower uptake in inflammatory lesions than malignancies as well as variation in different types of inflammatory lesions, and thus, may be valuable for distinguishing malignant and various inflammatory findings. CLINICAL RELEVANCE STATEMENT: Our study confirmed that the uptake of [18F]AlF-NOTA-FAPI-04/[18F]FDG PET/CT in inflammatory and malignant lung lesions is different, which is beneficial to distinguish inflammatory and malignant lung lesions in clinic. KEY POINTS: • Malignant and different inflammatory lung lesions showed varying degrees of uptake of [18F]AlF-NOTA-FAPI-04 and [18F]FDG. • Inflammatory lung lesions showed significantly less uptake than malignancies, and uptake varied among different types of inflammatory lesions. • Both types of PET/CT could differentiate malignant and various inflammatory lung findings.

Features of the TCR repertoire associate with patients' clinical and molecular characteristics in acute myeloid leukemia.

Background: Allogeneic hematopoietic stem cell transplant remains the most effective strategy for patients with high-risk acute myeloid leukemia (AML). Leukemia-specific neoantigens presented by the major histocompatibility complexes (MHCs) are recognized by the T cell receptors (TCR) triggering the graft-versus-leukemia effect. A unique TCR signature is generated by a complex V(D)J rearrangement process to form TCR capable of binding to the peptide-MHC. The generated TCR repertoire undergoes dynamic changes with disease progression and treatment. Method: Here we applied two different computational tools (TRUST4 and MIXCR) to extract the TCR sequences from RNA-seq data from The Cancer Genome Atlas (TCGA) and examine the association between features of the TCR repertoire in adult patients with AML and their clinical and molecular characteristics. Results: We found that only ~30% of identified TCR CDR3s were shared by the two computational tools. Yet, patterns of TCR associations with patients' clinical and molecular characteristics based on data obtained from either tool were similar. The numbers of unique TCR clones were highly correlated with patients' white blood cell counts, bone marrow blast percentage, and peripheral blood blast percentage. Multivariable regressions of TCRA and TCRB median normalized number of unique clones with mutational status of AML patients using TRUST4 showed significant association of TCRA or TCRB with WT1 mutations, WBC count, %BM blast, and sex (adjusted in TCRB model). We observed a correlation between TCRA/B number of unique clones and the expression of T cells inhibitory signal genes (TIGIT, LAG3, CTLA-4) and foxp3, but not IL2RA, CD69 and TNFRSF9 suggestive of exhausted T cell phenotypes in AML. Conclusion: Benchmarking of computational tools is needed to increase the accuracy of the identified clones. The utilization of RNA-seq data enables identification of highly abundant TCRs and correlating these clones with patients' clinical and molecular characteristics. This study further supports the value of high-resolution TCR-Seq analyses to characterize the TCR repertoire in patients.

Early and Accurate Detection of Radiation-induced Heart Damage by Cardiodynamicsgram.

Cardiodynamicsgram (CDG) has emerged recently as a noninvasive spatiotemporal electrocardiographic method for subtle cardiac dynamics information analysis within electrocardiogram (ECG). This study explored the feasibility of CDG for detecting radiation-induced heart damage (RIHD) in a rat model. A single radiation dose of 40 Gy was delivered to the cardiac apex of female Wistar rats. First, CDG was generated through dynamic modeling of ECG signals using the deterministic learning algorithm. Furthermore, CDG indexes were calculated using the wavelet transform and entropy. In this model, CDG entropy indexes decreased significantly after radiotherapy. The shape of CDG changed significantly after radiotherapy (irregular shape) compared with controls (regular shape). Macrophage and fibrosis in myocardium of rats increased significantly after radiotherapy. CDG changes after radiotherapy were significantly correlated with histopathological changes and occurred significantly earlier than histopathological changes. This study provides an experimental basis for the clinical application of CDG for the early detection of RIHD.

FAPI Compared with FDG PET/CT for Diagnosis of Primary and Metastatic Lung Cancer.

Background The radiotracer fluorine 18 (18F)-labeled fibroblast activation protein inhibitor (FAPI) has shown promise for visualizing several types of cancer, but the accuracy of 18F-FAPI compared with 18F-fluorodeoxyglucose (FDG) for the detection of lung cancer remains uncertain. Purpose To evaluate the effectiveness of 18F-FAPI-based PET/CT imaging for the diagnosis of primary and metastatic lung cancer lesions as compared with 18F-FDG PET/CT. Materials and Methods In this secondary analysis of a prospective trial, consecutively recruited patients from a single center with pathologically confirmed lung cancer were prospectively enrolled from December 2020 to April 2022 and underwent paired 18F-FAPI and 18F-FDG PET/CT examinations at intervals of more than 20 hours and within 7 days of each other. Histopathologic and clinical follow-up results were used as reference standards for final diagnoses. 18F-FAPI and 18F-FDG uptake were compared using the McNemar test or paired Student t test. Diagnostic accuracy was compared between the two techniques by using the McNemar χ2 test. Results Sixty-eight participants (median age, 63 years [IQR, 58-68 years; range, 42-79 years]; 46 male [68%]) were evaluated. Compared with the mean tumor-to-background ratio (TBR) for FDG uptake, TBR for FAPI uptake was lower in primary lung tumors (25.3 ± 14.0 [SD] vs 32.1 ± 21.1; P < .001) but higher in metastatic lymph nodes (7.5 ± 6.6 vs 5.9 ± 8.6; P < .001) and bone metastases (8.6 ± 5.4 vs 4.3 ± 2.3; P < .001). For diagnostic accuracy in a total of 548 lesions in 68 participants, compared with 18F-FDG PET/CT, 18F-FAPI PET/CT demonstrated a higher sensitivity (99% [392 of 397 lesions] vs 87% [346 of 397]; P < .001), specificity (93% [141 of 151 lesions] vs 79% [120 of 151]; P = .004), accuracy (97% [533 of 548 lesions] vs 85% [466 of 548]; P < .001), and negative predictive value (97% [141 of 146 lesions] vs 70% [120 of 171 lesions]; P < .001), but there was no evidence of a difference for positive predictive value (98% [392 of 402 lesions] vs 92% [346 of 377 lesions]; P = .57). Conclusion 18F-FAPI PET/CT may be superior to 18F-FDG PET/CT for detecting lung cancer. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Zukotynski and Gerbaudo in this issue.

Increased 18F-FAPI uptake in bones and joints of lung cancer patients: characteristics and distributions.

OBJECTIVE: This study investigated the distribution and characteristics of various bone and joint lesions on 18F-FAPI PET/CT in lung cancer patients. METHODS: Seventy-four lung cancer patients who underwent 18F-FAPI PET/CT were reviewed. Bone and joint lesions with elevated 18F-FAPI uptake were recorded and analyzed. The distribution and maximum uptake value (SUVmax) of different benign lesions or bone metastases were presented. In addition, the SUVmax of bone metastases on 18F-FDG and 18F-FAPI-04 PET/CT were also compared. RESULTS: In 53 patients, a total of 262 lesions presented 18F-FAPI accumulation. Bone metastases were mainly in vertebrae, pelvis, and ribs, while benign lesions were in vertebral margins, alveolar bone, and shoulder joints. The SUVmax of bone metastases was significantly higher than that of benign lesions ([Formula: see text] vs. [Formula: see text], [Formula: see text]), with NSCLC cases having higher SUVmax values than SCLC cases ([Formula: see text] vs. [Formula: see text], [Formula: see text]). Among benign lesions, arthritis and periodontitis demonstrated higher SUVmax than degenerative lesions (arthritis: [Formula: see text]; periodontitis: [Formula: see text]; degenerative diseases: [Formula: see text]; [Formula: see text] and [Formula: see text], respectively). The SUVmax of bone metastases was comparable between 18F-FDG and 18F-FAPI PET/CT. However, 18F-FAPI PET/CT was found to be superior in identifying cranial metastases compared to 18F-FDG PET/CT (TBRmet/brain: [Formula: see text] vs. [Formula: see text], [Formula: see text]). CONCLUSION: This study demonstrated that 18F-FAPI PET/CT is a valuable imaging modality for detecting bone and joint lesions in lung cancer patients. The SUVmax of malignant lesions was higher than that of benign lesions, but cannot accurately distinguish benign and malignant lesions. The uptake of FAPI differs among lesions with different pathological types.

Plasma Markers for Early Prediction of Radiation-Induced Myocardial Damage.

There is no sensitive and effective method to predict radiation-induced myocardial damage (RIMD). The aim of this study was to explore effective plasma biomarkers for early prediction of RIMD after radiotherapy (RT) in lung cancer patients and in a rat model. Biomarker levels were measured in plasma samples collected before and after thoracic RT from 17 lung cancer patients. For the animal model, a single radiation dose of 40 Gy was delivered to the cardiac apex of female Wistar rats. Control rats received sham irradiation (0 Gy). Dynamic plasma biomarker detection and histopathological analysis to confirm RIMD were performed in rats up to 6 months after RT. In lung cancer patients, the plasma caspase-3 concentration was significantly increased after thoracic RT (P = 0.0479), with increasing but nonsignificant trends observed for caspase-1, CCL2, vascular endothelial growth factor (VEGF), interleukin-1ß, and IL-6 (P > 0.05). Changes in caspase-3, VEGF, and IL-6 correlated significantly with mean heart dose (P < 0.05). In the RIMD rat model, caspase-1, caspase-3, CCl-2, VEGF, CCl-5, and TGF-ß1 levels were significantly elevated in the first week post-RT (P < 0.05), which was earlier than pathological changes. Myocardial tissue of the RIMD rats also showed significant macrophage infiltration at 1 month (P < 0.01) and fibrosis at 6 months postradiation (P < 0.0001). Macrophage infiltration correlated significantly with plasma caspase-3, CCL2, CCL5, VEGF, and TGF-ß1 levels from 3 weeks to 2 months post-RT. Increased plasma caspase-1, caspase-3, CCl-2, and VEGF levels were detected before RIMD-related pathological changes, indicating their clinical potential as biomarkers for early prediction of RIMD.

Correlation of Mean Heart Dose and Cardiac Biomarkers with Electrocardiographic Changes in Patients Receiving Thoracic Radiation Therapy.

Cardiotoxicity is a well-recognized, serious adverse effect of thoracic radiation therapy. This study aimed to evaluate longitudinal electrocardiogram (ECG) changes in patients receiving thoracic radiation therapy and identify correlating factors that can predict the risk of cardiotoxicity. This retrospective study included 202 patients treated with thoracic radiation therapy, and chemotherapy and targeted therapy were allowed. Mean heart dose (MHD) was evaluated on dose-volume histograms. ECG, high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal B-type natriuretic peptide (NT-proBNP) analyses were conducted before irradiation and during the follow-up period of 6-12 months (average 8 months). Chi square test and logistic regression analysis were applied to identify risk factors associated with ECG changes. At a median time of 3 months postirradiation, 46.5% of patients showed ECG changes, and 33.0% of patients achieved baseline ECG levels during the follow-up period at a median of 5 months postirradiation. Logistic regression analysis identified MHD, hs-cTnT and NT-pro BNP as significant factors associated with ECG changes (P < 0.05). Hs-cTnT and NT-proBNP were increased significantly after radiation therapy compared with baseline levels (P < 0.05), and these increases were observed as a median time of 2 months postirradiation, which was earlier than ECG changes. Higher MHD and elevated hs-cTnT and NT-proBNP levels correlated with an increased risk of ECG changes in patients receiving thoracic radiation therapy. Early identification of patients at high risk of cardiotoxicity and timely intervention might reduce the incidence of radiation-induced cardiac toxicity.

Response Prediction Using 18F-FAPI-04 PET/CT in Patients with Esophageal Squamous Cell Carcinoma Treated with Concurrent Chemoradiotherapy.

This prospective study examined whether imaging results obtained using the tracer 18F-AlF-NOTA-fibroblast activation protein inhibitor (FAPI)-04 (denoted as 18F-FAPI-04) in PET/CT can predict the short-term outcome in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) treated with concurrent chemoradiotherapy (CCRT). Methods: The 18 enrolled LA-ESCC patients underwent 18F-FAPI-04 PET/CT scanning before CCRT. The SUVmax, SUVmean, SUVpeak, metabolic tumor volume, and total lesion fibroblast activation protein expression of the primary tumor were recorded. Additionally, the SUVmax of the primary tumor and SUVmean of normal tissue (muscle and blood) were measured, and their ratios were denoted as target-to-background ratios (TBRmuscle and TBRblood). Patients were classified as responders or nonresponders according to RECIST (version 1.1), and variables were compared between the 2 groups. Results: The TBRblood, TBRmuscle, and SUVmean were significantly higher in nonresponders than in responders (all P < 0.05). Receiver-operating-characteristic curve analysis identified TBRblood (area under the curve [AUC], 0.883; P = 0.008), TBRmuscle (AUC, 0.896; P = 0.006) and SUVmean (AUC, 0.870; P = 0.010) as significant predictors of the response to CCRT, with cutoffs of 10.68, 10.95, and 6.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were also determined for TBRblood (100.0%, 72.7%, 66.7%, 88.9%, and 77.8%, respectively), TBRmuscle (100.0%, 72.7%, 66.7%, 88.9%, and 77.8%, respectively), and SUVmean (85.7%, 81.8%, 75.0%, 90.0%, and 83.3%, respectively). On univariate logistic regression analysis, TBRblood (P = 0.026), TBRmuscle (P = 0.036), SUVmean (P = 0.045), and tumor site (P = 0.032) were significantly correlated with the short-term outcome. On multivariable logistic regression analysis, TBRblood (P = 0.046) was an independent prognostic factor for short-term outcome. Conclusion: A higher baseline TBRblood on 18F-FAPI-04 PET/CT scans was associated with a poor response to CCRT in LA-ESCC patients, and thus, TBRblood may be useful for screening LA-ESCC patients before CCRT treatment.

Early detection of radiation-induced myocardial damage by [18F]AlF-NOTA-FAPI-04 PET/CT imaging.

PURPOSE: Retrospective analysis revealed increased [18F]AlF-NOTA-FAPI-04 uptake in the myocardium of patients with esophageal squamous cell cancer (ESCC) treated with concurrent chemoradiotherapy (CCRT). This study investigated and verified the feasibility of [18F]AlF-NOTA-FAPI-04 PET/CT for detecting radiation-induced myocardial damage (RIMD). METHODS: Myocardial FAPI uptake was analyzed before and during radiotherapy in thirteen ESCC patients treated with CCRT. In the animal study, a single dose of 50 Gy was delivered to the cardiac apex of Wistar rats (24 rats, including 16 RIMD model rats and 8 control model rats). RIMD model rats were scanned with [18F]AlF-NOTA-FAPI-04 PET/CT weekly for 12 weeks, and left ventricular ejection fraction (LVEF) was measured by magnetic resonance imaging. Dynamic, blocking, and [18F]FDG PET/CT studies (4 rats/group) were performed on RIMD rats at 5 weeks post-radiation, and histopathological analyses were conducted. RESULTS: Increased FAPI uptake in the myocardium was found after CCRT (1.53 ± 0.53 vs 1.88 ± 0.70, P = 0.015). In RIMD rats, significantly increased FAPI uptake in the damaged myocardium was observed from the 2nd week post-radiation exposure and peaked in the 5th week. Significantly more intense tracer accumulation was observed in the damaged myocardium than in the remote myocardium, as identified by decreased [18F]FDG uptake and confirmed by autoradiography, hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining. The LVEF remained unchanged at the 3rd week post-radiation exposure but was remarkably decreased compared with that in the control group at the 8th week. CONCLUSION: Through clinical phenomena and animal experimental studies, this study indicated that [18F]AlF-NOTA-FAPI-04 PET/CT imaging can detect RIMD noninvasively and before a decrease in LVEF, indicating the clinical potential of [18F]AlF-NOTA-FAPI-04 as a PET/CT tracer for early monitoring of RIMD.

Diagnostic Value of 18F-NOTA-FAPI PET/CT in a Rat Model of Radiation-Induced Lung Damage.

In this study, we explore the diagnostic value of a novel PET/CT imaging tracer that specifically targets fibroblast activation protein (FAP), 18F-NOTA-FAPI, in a radiation induced lung damage (RILD) rat model. High focal radiation (40, 60, or 90 Gy) was administered to a 5-mm diameter area of the right lung in Wistar rats for evaluation of RILD induction. Lung tissues exposed to 90 Gy radiation were scanned with 18F-NOTA-FAPI PET/CT and with 18F-FDG. Dynamic 18F-NOTA-FAPI PET/CT scanning was performed on day 42 post-irradiation. After in vivo scanning, lung cryosections were prepared for autoradiography, hematoxylin and eosin (HE) and immunohistochemical (IHC) staining. An animal model of RILD was established and validated by histopathological analysis. On 18F-NOTA-FAPI PET/CT, RILD was first observed on days 42, 35 and 7 in the 40, 60 and 90 Gy groups, respectively. After treatment with 90 Gy, 18F-NOTA-FAPI uptake in an area of RILD emerged on day 7 (0.65 ± 0.05%ID/ml) and reappeared on day 28 (0.81 ± 0.09%ID/ml), remaining stable for 4-6 weeks. Autoradiography and HE staining IHC staining revealed that 18F-NOTA-FAPI accumulated mainly in the center of the irradiated area. IHC staining confirmed the presence of FAP+ macrophages in the RILD area, while FAP+ fibroblasts were observed in the peripheral area of irradiated lung tissue. 18F-NOTA-FAPI represents a promising radiotracer for in vivo imaging of RILD in a dose- and time-dependent manner. Noninvasive imaging of FAP may potentially aiding in the clinical management of radiotherapy patients.

Preclinical evaluation and pilot clinical study of [18F]AlF-NOTA-FAPI-04 for PET imaging of rheumatoid arthritis.

PURPOSE: Fibroblast-like synoviocytes (FLSs) are key effector cells in the inflamed joints of patients with rheumatoid arthritis (RA). Previous studies have suggested that fibroblast activation protein (FAP) is highly expressed in RA-derived FLSs and is a specific marker of activated RA FLSs. In this study, we developed aluminum-[18F]-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid-conjugated FAP inhibitor 04 ([18F]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients. METHODS: RA FLSs and NIH3T3 cells transfected with FAP were used to perform in vitro-binding studies. Biodistribution was conducted in normal DBA1 mice. Collagen-induced arthritis (CIA) models with different arthritis scores were subjected to [18F]AlF-NOTA-FAPI-04 and 18F-FDG PET imaging. Histological examinations were performed to evaluate FAP expression and Cy3 dye-labeled FAPI-04(Cy3-FAPI-04) uptake. Blocking studies with excess unlabeled FAPI-04 in CIA mice and NIH3T3 xenografts in immunocompromised mice were used to evaluate the binding specificity of [18F]AlF-NOTA-FAPI-04. Additionally, [18F]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients. RESULTS: The binding of [18F]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (FAP-GFP-NIH3T3 vs. GFP-NIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/105 cells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/105 cells). Compared to 18F-FDG imaging, [18F]AlF-NOTA-FAPI-04 showed high uptake in inflamed joints in the early stage of arthritis, which was positively correlated with the arthritic scores (Pearson r=0.834, P<0.001). In addition, the binding of [18F]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [18F]AlF-NOTA-FAPI-04 in arthritic joints both could be blocked by excessive unlabeled FAPI-04. Fluorescent staining showed that the intensity of Cy3-FAPI-04 binding to FAP increased accordingly as the expression of FAP protein increased in cells and tissue sections. Furthermore, the uptake of [18F]AlF-NOTA-FAPI-04 in FAP-GFP-NIH3T3 xenografts was significantly higher than that in GFP-NIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [18F]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints. CONCLUSION: [18F]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters.

[18F]AlF-NOTA-FAPI-04: FAP-targeting specificity, biodistribution, and PET/CT imaging of various cancers.

PURPOSE: In this pilot study, we developed a new tracer, [18F]AlF-labeled FAPI-04 chelated with NOTA, denoted as [18F]AlF-NOTA-FAPI-04, and tested the specificity, biodistribution, and clinical application for PET/computed tomography (CT) imaging of various types of cancers in patients. METHODS: In vitro binding specificity of FAPI-04 to FAP was verified in U87 cells confocal of a fluorescence-labeled variant. In vivo imaging, competition, and dynamic scanning analyses were conducted to evaluate [18F]AlF-NOTA-FAPI-04 imaging in xenograft mouse model using small-animal PET/CT. The application of [18F]AlF-NOTA-FAPI-04 was analyzed by imaging different types of cancers in patients. RESULTS: Both in vitro and in vivo results showed high binding specificity of FAPI-04 to FAP. High intratumoral uptake and fast body clearance of the tracer were observed in the xenograft mouse model and cancer patients. High-contrast images and negligible radiation exposure to normal tissue were observed on [18F]AlF-NOTA-FAPI-04 PET/CT in 28 patients with 8 different types of cancers. Five of 28 patients underwent PET/CT scanning at 1 h, 2 h, and 4 h after intravenous injection of [18F]AlF-NOTA-FAPI-04. Seven patients with advanced lung cancer underwent dual-tracer imaging, and 44 and 37 metastatic lesions were detected by [18F]AlF-NOTA-FAPI-04 PET/CT and [18F]F-FDG PET/CT, respectively. Overall, 80.0% of metastatic lesions was identified by both [18F]AlF-NOTA-FAPI-04 and 18F-FDG, 17.8% by [18F]AlF-NOTA-FAPI-04 PET/CT only, and 2.2% by [18F]FDG PET/CT only. CONCLUSION: [18F]AlF-NOTA-FAPI-04 offers high specificity as a tracer for FAP imaging and allows fast imaging with high contrast in tumors. [18F]AlF-NOTA-FAPI-04 is better at identifying metastatic lesions in patients with advanced lung cancer than [18F]FDG, and its use may facilitate tumor staging.

Tumor angiogenesis at baseline identified by 18F-Alfatide II PET/CT may predict survival among patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy.

BACKGROUND: The study investigated the predictive value of tumor angiogenesis observed by 18F-ALF-NOTA-PRGD2 II (denoted as 18F-Alfatide II) positron emission tomography (PET)/computed tomography (CT) before concurrent chemoradiotherapy (CCRT) for treatment response and survival among patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Patients with unresectable stage IIIA or IIIB NSCLC (AJCC Cancer Staging 7th Edition) who received CCRT were included in this prospective study. All patients had undergone 18F-Alfatide PET/CT scanning before CCRT, and analyzed parameters included maximum uptake values (SUVmax) of primary tumor (SUVP) and metastatic lymph nodes (SUVLN) and mean uptake value of blood pool (SUVblood). Tumor-to-background ratios (TBRs) and changes in tumor diameter before and after CCRT (ΔD) were calculated. The ratios of SUVP to SUVblood, SUVLN to SUVblood, and SUVP to SUVLN were denoted as TBRP, TBRLN, and T/LN. Short-term treatment response, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: Of 38 enrolled patients, 28 completed CCRT. SUVP, SUVLN, TBRP, TBRLN and T/LN showed significant correlation with PFS (all P < 0.05). SUVP was negatively correlated with OS (P = 0.005). SUVP and TBRP were higher in non-responders than in responders (6.55 ± 2.74 vs. 4.61 ± 1.94, P = 0.039; 10.49 ± 7.58 vs. 7.73 ± 6.09, P = 0.023). ΔD was significantly greater in responders (2.78 ± 1.37) than in non-responders (-0.16 ± 1.33, P < 0.001). Exploratory receiver operating characteristic curve analysis identified TBRP (area under the curve [AUC] = 0.764, P = 0.018), with a cutoff value of 6.52, as the only parameter significantly predictive of the response to CCRT, with sensitivity, specificity, and accuracy values of 71.43%, 78.57%, and 75.00%, respectively. ROC curve analysis also identified SUVP (AUC = 0.942, P < 0.001, cutoff value 4.64) and TBRP (AUC = 0.895, P = 0.001, cutoff value 4.95) as predictive of OS with high sensitivity (84.21%, 93.75%), specificity (100.00%, 66.67%), and accuracy (89.29%, 82.14%). CONCLUSIONS: Evaluation of tumor angiogenesis by 18F-Alfatide II at baseline may be useful in predicting the short-term response to CCRT as well as PFS and OS in patients with LA-NSCLC.

Genomic Correlates of Unfavorable Outcome in Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemoradiation.

PURPOSE: Neoadjuvant therapy modality can increase the operability rate and mitigate pathological risks in locally advanced cervical cancer, but treatment response varies widely. It remains unclear whether genetic alterations correlate with the response to neoadjuvant therapy and disease-free survival (DFS) in locally advanced cervical cancer. MATERIALS AND METHODS: A total of 62 locally advanced cervical cancer (stage IB-IIA) patients who received neoadjuvant chemoradiation plus radical hysterectomy were retrospectively analyzed. Patients' tumor biopsy samples were comprehensively profiled using targeted next generation sequencing. Pathologic response to neoadjuvant treatment and DFS were evaluated against the association with genomic traits. RESULTS: Genetic alterations of PIK3CA were most frequent (37%), comparable to that of Caucasian populations from The Cancer Genome Atlas. The mutation frequency of genes including TERT, POLD1, NOS2, and FGFR3 was significantly higher in Chinese patients whereas RPTOR, EGFR, and TP53 were underrepresented in comparison to Caucasians. Germline mutations were identified in 21% (13/62) of the cohort and more than half (57%) had mutations in DNA damage repair genes, including BRCA1/2, TP53 and PALB2. Importantly, high tumor mutation burden, TP53 polymorphism (rs1042522), and KEAP1 mutations were found to be associated with poor pathologic response to neoadjuvant chemoradiation treatment. KEAP1 mutations, PIK3CA-SOX2 co-amplification, TERC copy number gain, and TYMS polymorphism correlated with an increased risk of disease relapse. CONCLUSION: We report the genomic profile of locally advanced cervical cancer patients and the distinction between Asian and Caucasian cohorts. Our findings highlight genomic traits associated with unfavorable neoadjuvant chemoradiation response and a higher risk of early disease recurrence.

[18F]AlF-NOTA-FAPI-04 PET/CT uptake in metastatic lesions on PET/CT imaging might distinguish different pathological types of lung cancer.

PURPOSE: Heterogeneity is found in the tumor microenvironment among different pathological types of tumors. Radionuclide-labeled fibroblast-activation-protein inhibitor (FAPI), as an important tracer for non-invasive imaging of the tumor microenvironment, can be used to evaluate the expression of FAP in cancer-associated fibroblasts, macrophages, and tumor cells. Our aim was to explore the ability of [18F]AlF-NOTA-FAPI-04 positron emission tomography (PET)/computed tomography (CT) to distinguish different types of lung cancer by evaluating the uptake of this tracer in primary and metastatic lesions. METHODS: We prospectively enrolled 61 patients with histopathologically proven primary lung cancer with metastases. PET/CT scanning was performed before any antitumor therapy and 1 h after injection of 235.10 ± 3.89 MBq of [18F]AlF-NOTA-FAPI-04. Maximum standard uptake values (SUVmax) were calculated for comparison among primary and metastatic lesions. Immunohistochemical staining for FAP was performed on tumor specimens. RESULTS: Sixty-one patients with adenocarcinoma (ADC, n = 30), squamous cell carcinoma (SCC, n = 17), and small cell lung cancer (SCLC, n = 14) were enrolled in this study, and 61 primary tumors and 199 metastases were evaluated. No difference in [18F]AlF-NOTA-FAPI-04 uptake was observed among primary ADC, SCC, and SCLC tumors (P = 0.198). Additionally, no difference in uptake was found between primary and metastatic lesions of lung cancer with the same pathological type (P > 0.05). However, uptake did differ among metastases of differing pathological types (P < 0.001). The SUVmax of metastatic lymph nodes was highest for SCC, followed by ADC and then SCLC (P < 0.001). The SUVmax of bone metastases also was highest for SCC, followed by ADC and SCLC (P < 0.05), but no difference was observed between ADC and SCLC. The SUVmax of metastases in other organs was higher in SCC cases than in ADC cases but did not differ between SCC and SCLC or ADC and SCLC. Bone metastases exhibited higher uptake than those of lymph nodes and other organs in SCC and ADC (P < 0.05) but not in SCLC. Positive correlations were found between FAPI uptake and FAP expression in surgical plus biopsy specimens (r = 0.439, P = 0.012) and surgical specimens (r = 0.938, P = 0.005). CONCLUSION: [18F]AlF-NOTA-FAPI-04 PET/CT imaging revealed differences in FAP expression in metastases of lung cancer, with the highest expression specifically in bone metastases, and thus, may be valuable for distinguishing different pathological types of lung cancer.

Validating METCAM/MUC18 as a Novel Biomarker to Predict the Malignant Potential of Prostate Cancer at an Early Stage by Using a Modified Gold Nanoparticles-Based Lateral Flow Immunoassay.

(1) Background: To further validate METCAM/MUC18 as a diagnostic biomarker for prostate cancer, a modified Lateral Flow Immune Assay (LFIA) with increased sensitivity and specificity was designed by taking advantage of the extremely high affinity between biotin and streptavidin and used. (2) Methods: The combination of a commercial biotinylated rabbit antibody (EPP11278), or the home-made biotinylated chicken antibody, and the nano-gold conjugated home-made chicken antibody or a commercial rabbit antibody (EPP11278), had the higher sensitivity and specificity in this modified LFIA to establish calibration curves from the two recombinant METCAM/MUC18 proteins and were used for determining METCAM/MUC18 concentrations in serum specimens from normal individuals, benign prostatic hyperplasia (BPH) patients, prostatic intraepithelial neoplasia (PIN) patients, prostate cancer patients with various Gleason scores, and treated patients. (3) Results: Data obtained by this modified LFIA were statistically better than traditional LFIA and prostate-specific antigen (PSA) test. Interestingly, serum METCAM/MUC18 concentrations were higher in pre-malignant PIN patients than prostate cancer patients and both were higher than normal individuals, BPH patients, and treated patients. Serum METCAM/MUC18 concentrations were directly proportional to most serum PSA. (4) Conclusions: Elevated serum METCAM/MUC18 concentrations may be used for predicting the malignant potential of prostate cancer at an early premalignant (PIN) stage, which is not achievable by the current PSA test.

Assessing the response of vegetation change to drought during 2009-2018 in Yunnan Province, China.

Yunnan Province in southwest China is characterized by a vast area, diverse climate types, rich ecosystem types, and unique biodiversity resources. With consideration of global climate change, there is an urgent need to evaluate the response of vegetation to drought in Yunnan. This study utilized the MOD13A3, MOD17A2, and Tropical Rainfall Measuring Mission (TRMM) 3B43 remote sensing products. The TRMM 3B43 downscaled monthly precipitation data were used to calculate the tropical rainfall condition index (TRCI) for Yunnan. The TRCI was used as a drought index, and the temporal and spatial changes in TRCI, gross primary productivity (GPP), and vegetation condition index (VCI) from 2009 to 2018 were explored. The response of vegetation to drought was evaluated under different time scales and varying land-use types. The results showed that during 2009-2018, (1) at an annual scale, the drought in Yunnan showed a weakening trend, and at a spatial scale, the drought showed a weakening trend from northwest to southeast. This weakening trend was more noticeable for cultivated land than for forest, grassland, and other land-use types. (2) GPP and VCI showed overall increasing trends at an annual scale, indicating gradual improvements in the GPP of vegetation and vegetation status, whereas the summer vegetation index showed a decreasing trend. (3) Although both the GPP and the growth state of vegetation were affected by drought, the responses of GPP and VCI to drought differed under different temporal scales and different land-use types. The responses of GPP and VCI to drought during spring were greater than those over other seasons, and the response of VCI to drought was more sensitive than that of GPP. Drought had a high impact on the GPP and vegetation growth of cultivated land and grassland with shallow root systems, whereas the impact of drought on forest was relatively stable.

Remote sensing estimation of chlorophyll-a concentration in Taihu Lake considering spatial and temporal variations.

The estimation of chlorophyll-a concentrations (Chla) in lakes using remote sensing is convenient, but its use remains challenging in large eutrophic water bodies due to the great spatial and temporal variations of its optical properties. Combining the sampling location and date information with Chla data, this study divided the lake water into three types, I, II and III, and then built an optimal Chla estimation model for each type based on 11 datasets collected from 2004 to 2012 in Taihu Lake, China. The resultant model expression is Chla = exp (ax2 + bx + c), where x is R701/R677, (1/R686-1/R695) × R710 and (R690/R550-R675/R700) / (R690/R550 + R675/R700). For the Chla ranging from 2 to 192 mg/m3, the root-mean-square error (RMSE) of the new model decreased up to 5.1 mg/m3 compared to that of previous band combination models, such as band ratio, three-band and four-band models when directly validated. The RMSE of the re-parametrization model (the lowest RMSE < 12 mg/m3) is also lower than for those models (the lowest RMSE > 16 mg/m3), indicating that the Chla estimation model that considers the spatial and temporal variations has a better performance and validation accuracy and therefore is more effective for remote sensing monitoring of water quality.

Relationship Between Clinicopathological Characteristics and PET/CT Uptake in Esophageal Squamous Cell Carcinoma: [18F]Alfatide versus [18F]FDG.

PURPOSE: To assess a novel radiotracer aluminum [18F]fluoride-1,4,7-triazacyclononane-triacetic acid-pegylated dimeric RGD ([18F]ALF-NOTA-PRGD2, denoted as [18F]Alfatide) for positron emission tomography (PET)/X-ray computed tomography (CT) and explore the relationships between clinicopathological characteristics and maximum standard uptake values in primary (SUVP) and metastatic lymph nodes (SUVLN) of patients with esophageal squamous cell carcinoma (ESCC), as verified by pathologic examination and compared with those obtained with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]DG) PET. PROCEDURES: We prospectively enrolled patients with newly diagnosed ESCC who agreed to undergo [18F]Alfatide PET/CT or [18F]FDG PET/CT scans before surgery at Shandong Cancer Hospital from May 2011 to July 2017. SUVs and the pathological tumor-node-metastasis (pTNM) stages of primary tumors and metastatic lymph nodes (LNs) were measured and confirmed pathologically. Immunohistochemical (IHC) staining for integrin αvß3 was performed on tumor samples (both primary tumors and metastatic LNs) collected from nine patients. RESULTS: Of 61 patients who underwent PET/CT scans, 46 then underwent curative surgery and were included in our analysis (n = 21 for [18F]Alfatide PET/CT and n = 25 for [18F]FDG PET/CT). No significant differences in the SUVP on [18F]Alfatide PET/CT or [18F]FDG PET/CT were observed among the cohorts according to gender, pathological stage, T stage, status of LNs, and differentiation (all P > 0.05). The SUVLN differed significantly between the pathological stages and status of LNs both on [18F]Alfatide PET/CT (P = 0.03, 0.003) and [18F]FDG PET/CT (P = 0.001. < 0.001), but not according to gender (P = 0.128, 0.129), T stage (P = 0.791, 0.727), or tumor differentiation (P = 0.049, 0.053). Significant positive correlations were observed between the SUVLN on [18F]Alfatide PET/CT and [18F]FDG PET/CT, and pathological stage (r = 0.52, P = 0.016; r = 0.503, P = 0.01), LN status (r = 0.73, P < 0.001; r = 0.649, P < 0.001), and differentiation (r = 0.509, P < 0.019; r = 0.459, P = 0.021) were observed. No significant differences were found between the relationships of SUVP with SUVLN, length, age, gender, pathological stage, T stage, status of LN, or differentiation, or of SUVLN with length, age, gender, or T stage both on [18F]Alfatide PET/CT and [18F]FDG PET/CT (all P > 0.05). The quantitated expression levels of αvß3 in primary tumors and metastatic LNs were 1.67 ± 1.12 and 3.42 ± 2.93, respectively (P = 0.031). CONCLUSIONS: Our results suggest that SUVLN is influenced by pathological stage, LN status, and differentiation. SUVLN may therefore serve as a new parameter for risk stratification of with ESCC patients. Moreover, [18F]Alfatide PET can provide complementary molecular information about ESCC metastasis.