Visual Abstract
Abstract
Fibroblast activation protein α (FAPα) is expressed at high levels in several types of tumors. Here, we report the expression pattern of FAPα in solitary fibrous tumor (SFT) and its potential use as a radiotheranostic target. Methods: We analyzed FAPα messenger RNA and protein expression in biopsy samples from SFT patients using immunohistochemistry and multiplexed immunofluorescence. Tracer uptake and detection efficacy were assessed in patients undergoing clinical 68Ga-FAPα inhibitor (FAPI)–46 PET,18F-FDG PET, and contrast-enhanced CT. 90Y-FAPI-46 radioligand therapy was offered to eligible patients with progressive SFT. Results: Among 813 patients and 126 tumor entities analyzed from the prospective observational MASTER program of the German Cancer Consortium, SFT (n = 34) had the highest median FAPα messenger RNA expression. Protein expression was confirmed in tumor biopsies from 29 of 38 SFT patients (76%) in an independent cohort. Most cases showed intermediate to high FAPα expression by immunohistochemistry (24/38 samples, 63%), which was located primarily on the tumor cell surface. Nineteen patients who underwent 68Ga-FAPI-46 PET imaging demonstrated significantly increased tumor uptake, with an SUVmax of 13.2 (interquartile range [IQR], 10.2), and an improved mean detection efficacy of 94.5% (SEM, 4.2%), as compared with 18F-FDG PET (SUVmax, 3.2 [IQR, 3.1]; detection efficacy, 77.3% [SEM, 5.5%]). Eleven patients received a total of 34 cycles (median, 3 cycles [IQR, 2 cycles]) of 90Y-FAPI-46 radioligand therapy, which resulted in disease control in 9 patients (82%). Median progression-free survival was 227 d (IQR, 220 d). Conclusion: FAPα is highly expressed by SFT and may serve as a target for imaging and therapy. Further studies are warranted to define the role of FAPα-directed theranostics in the care of SFT patients.
Theranostics is an emerging approach in precision oncology using tumor-specific targets for diagnosis and treatment (1). A novel pan-tumor target is fibroblast activation protein α (FAPα), which is expressed in activated fibroblasts during stromal remodeling and in cancer-associated fibroblasts in most epithelial tumors but is absent in normal adult tissues (2). With a recently developed series of quinolone-based FAPα inhibitors (FAPIs), FAPα is a promising target for theranostic approaches in various tumor entities (3).
We recently demonstrated the safety and efficacy of 90Y-FAPI-46 radioligand therapy (RLT) in a cohort of 21 patients with advanced sarcoma and other cancer entities. Here, most subentities were attributable to sarcomas, particularly solitary fibrous tumor (SFT) (4). It was reported that sarcoma cancer cells themselves often aberrantly express high levels of FAPα (5–7) and that PET revealed high sarcoma uptake of the ligand 68Ga-FAPI (3,8–10). Indeed, the tumoral uptake intensity on 68Ga-FAPI-46 PET correlates with histopathologic FAPα expression in biopsy and surgical specimens (9).
SFT is a rare spindle cell tumor of mesenchymal origin with an incidence of about 3.5 per million each year (11). Although SFTs typically demonstrate benign behavior, with a 5-y disease-specific survival rate of 93%, high-risk groups present a considerable risk of recurrence and metastasis, with a 5-y survival rate of 60% (12). In advanced disease, the outcome is less satisfactory; there are no prospective data on the efficacy of chemotherapy for SFTs, and variable median progression-free survival (PFS) is reported to be between 3 and 11 mo (13). Retrospective case series and prospective phase II data on vascular endothelial growth factor receptor–targeted therapies using tyrosine kinase inhibitors, particularly pazopanib or sunitinib, or the combination of temozolomide and bevacizumab, found a median PFS of around 5–10 mo (13).
Therefore, better diagnosis and efficacious treatment are urgently needed. On the basis of our previous findings (4), here we systematically explore FAPα as a theranostic target in SFT.
MATERIALS AND METHODS
Study Design and Patient Cohorts
Details on ethics approval and consent to participate are reported in the supplemental methods (supplemental materials are available at http://jnm.snmjournals.org) (14–16). In 3 independent cohorts, with a minor overlap of patients, we were addressing ex vivo FAPα expression in tumor tissue, in vivo tumor uptake of the FAPα-targeting radioligand 68Ga-FAPI-46 on PET/CT, and efficacy of FAPα-targeting RLT using 90Y-FAPI-46 (Fig. 1). We assessed messenger RNA (mRNA) data from the National Center for Tumor Diseases/German Cancer Research Center/German Cancer Consortium Molecularly Aided Stratification for Tumor Eradication Research (MASTER) program of the National Center for Tumor Diseases, Heidelberg, Germany, a prospective, continuously recruiting, multicenter observational study for biology-driven stratification of adults with advanced cancer across various histologies (14). The cohort of 813 patients (the MASTER cohort) consists of 779 non-SFT and 15 SFT cases that were published previously (17). In addition, 19 other SFT cases, which had been analyzed until October 2021, were included and analyzed in the same way.
Patient flow diagram and overview of the 3 study cohorts: MASTER (A), tissue (B), and theranostic (C). Numbers of overlapping patients are indicated in gray. IHC = immunohistochemistry.
We analyzed FAPα expression with immunohistochemical staining in archived formalin-fixed, paraffin-embedded blocks of tumor tissue from an independent cohort of 38 SFT patients (the tissue cohort; Supplemental Table 1) treated at the West German Cancer Center of the University Hospital Essen, Germany. Moreover, we performed multiplexed immunofluorescence (mIF).
In 19 patients who underwent clinical 68Ga-FAPI-46 and 18F-FDG PET as well as contrast-enhanced CT (the theranostic cohort; Supplemental Table 2), we assessed imaging findings. Examinations took place during participation in a prospective observational trial at University Hospital Essen (NCT04571086) (8,9). Within the theranostic cohort, 11 of 19 patients (58%) received 90Y-FAPI-46 RLT on a compassionate-use basis. The patient flow diagram is shown in Figure 1C. Data on 9 of 11 patients have been shown previously in a report on our study on safety and efficacy in patients with advanced sarcoma and other cancer entities (4). Here, we performed a subgroup analysis and follow-up of these patients and present data on 2 additional patients.
Quantification of Gene Expression
Expression levels were determined per gene and sample as transcripts per million mapped reads. Extraction of RNA, RNA sequencing, and data processing were described previously (17). The difference in transcripts per million mapped reads in SFT versus non-SFT cases was evaluated using a Student t test.
Sequential mIF and Computer-Aided Quantification
mIF was performed using the Opal multiplex system (Akoya Biosciences) according to the manufacturer’s instructions. Details on the multiplexed staining conditions are reported in the supplemental methods.
Imaging
Clinical PET/CT scans with 18F-FDG and 68Ga-FAPI-46 as well as contrast-enhanced CT were performed in the craniocaudal orientation on a Biograph mCT or Biograph mCT Vision (Siemens Healthineers) as previously described (9). Details of the radiosynthesis are presented in the supplemental methods. The mean (±SD) injected activities were 244 ± 77 MBq for 18F-FDG and 116 ± 35 MBq for 68Ga-FAPI-46.
Detection Efficacy
Detection efficacy was assessed by an independent lesion-based evaluation of 68Ga-FAPI-46 PET, 18F-FDG PET, and contrast-enhanced CT by 2 masked nuclear medicine physicians and 1 masked radiologist. Disagreement was resolved by a joint consensus read. Across all imaging modalities, a total of 388 lesions was detected. On PET, areas with focal uptake above the surrounding background level, not attributable to physiologic findings, were rated positive. On CT, lymph nodes that were larger than 1 cm in short diameter and had suggestive features (contrast enhancement and a round shape, among others) were considered positive, as were organ lesions (including features such as morphologic delineation, necrosis, or hyperarterialization). Follow-up imaging (CT or PET/CT), clinical data, or histologic confirmation was used as the standard of truth.
90Y-FAPI-46 RLT
The 90Y-FAPI-46 administration protocol and eligibility criteria have been reported previously (4,18). Details on the radiosynthesis are shown in the supplemental methods. Ten patients received a scout dose of 3.7 ± 0.1 GBq of 90Y-FAPI-46 (except patient 3, who received a first-cycle high dose of 8.9 GBq) with PET-based dosimetry. Patients manifesting focal 90Y-FAPI-46 uptake in more than 50% of tumor lesions on posttherapy 90Y-FAPI-46 bremsstrahlung scintigraphy, and if otherwise clinically indicated, were eligible to receive 3 further cycles every 4–6 wk with 7.4 ± 0.5 GBq of 90Y-FAPI-46 (high dose), split into 2 intravenous applications administered 4 h apart (except for patients 4 and 11, who received a second-cycle single application of 90Y-FAPI-46 at a dose of 1.0 and 3.8 GBq, respectively). Bremsstrahlung scintigraphy was performed within 24 h of scout dosing. Details on the posttherapeutic dosimetry are presented in the supplemental methods.
Response Evaluation
18F-FDG PET with morphologic imaging follow-up was performed as per clinical routine at 2- to 3-mo intervals during and after 90Y-FAPI-46 treatment. The median follow-up time was 270 d. Imaging response was defined according to RECIST version 1.1 for CT and PERCIST version 1.0 for 18F-FDG PET/CT (19,20). Two nuclear medicine physicians analyzed the follow-up imaging through unmasked, independent rereadings. For calculating disease control rate, disease control was defined as a complete response or complete metabolic response, a partial response or partial metabolic response, and stable disease or stable metabolic disease. For calculating the overall response rate, response was defined as a complete response or complete metabolic response or as a partial response or partial metabolic response. PFS was defined from the first 90Y-FAPI-46 treatment to the time of progressive disease or death.
Statistical Considerations
Descriptive statistics, that is, the frequency of occurrence, percentage, median, and interquartile range (IQR), were calculated for each of the independent variables. An unpaired t test with Welch correction was used for statistical analysis. PFS was calculated using the Kaplan–Meier method. Statistical analyses were performed with SPSS Statistics version 27 (IBM) and Prism version 9 (GraphPad).
RESULTS
High Expression of Theranostic Target FAPα in SFT Tumor Tissue
We assessed FAPα mRNA pan-tumor expression levels in the MASTER cohort with available RNA sequencing data (17). Among the 813 patients with 126 different morphology codes (International Classification of Diseases for Oncology, third revision), we identified 34 patients with a diagnosis of SFT. Interestingly, SFT showed the highest median FAPα mRNA expression among all histologies (median transcripts per million mapped reads: 40.18 for SFT vs. 5.98 for non-SFT; P < 0.0001) (Fig. 2A). Next, we aimed to verify FAPα protein expression in the tissue cohort. By visual analysis of FAPα in immunohistochemistry, 8 of 38 (21%) SFT samples were rated negative and 30 (79%) were rated positive (Supplemental Fig. 1A, upper graph). Supplemental Figure 2 depicts representative hematoxylin and eosin and FAPα staining with negative, low, intermediate, and high expression. Semiquantitative assessment of FAPα staining in the entire tumor section, as percentage of FAPα-positive cells, indicated high expression in 32% of the patients, intermediate expression in 34%, and absent or low expression in only 34% (Supplemental Fig. 1A, lower graph).
RNA and protein expression of FAPα in SFT tissue. (A) mRNA expression of FAPα in MASTER cohort (813 patients; 126 different morphology codes [International Classification of Diseases for Oncology, third revision] categorized into subcohorts). (B) Representative mIF from tissue cohort demonstrating staining with FAPα, STAT6, and DAPI. mIF 1 shows FAPα-positive tumor cells (FAPα-positive/STAT6-positive; arrow), mIF 2 shows FAPα-positive stroma cells (FAPα-positive/STAT6-negative; arrow), and mIF 3 shows FAPα-negative tumor cells (FAPα-negative/STAT6-positive; arrow). GIST = gastrointestinal stromal tumor; NSCLC = non–small cell lung carcinoma; PNET = primitive neuroectodermal tumor; STAT6 = signal transducer and activator of transcription 6; TPM = transcripts per million mapped reads.
To address which cell type in SFT expresses FAPα, we performed mIF in 30 of the 38 tumor samples of the tissue cohort, using computer-aided analysis of signal transducer and activator of transcription 6 as a marker for tumor cells. Here, we distinguished tumor cells with expression of FAPα (mIF 1), stromal cells with expression of FAPα (mIF 2), and tumor cells without FAPα expression (mIF 3) (Fig. 2B). The overall median expression of FAPα was 34.6% (IQR, 38.5%) of all cells in the tumor tissue, with a median FAPα positivity of tumor cells of 27.3% (IQR, 33.1%), which significantly exceeded the FAPα positivity of stroma cells (12.7%; IQR, 11.2%; P < 0.001) (Supplemental Fig. 1B).
High In Vivo Uptake of FAPα-Directed Radioligand with Improved Detection Efficacy
We investigated the diagnostic value of 68Ga-FAPI-46 in the theranostic cohort. All patients underwent 68Ga-FAPI-46 PET/CT, 18F-FDG PET/CT, and diagnostic contrast-enhanced CT within a short interval of no more than 3 d (Fig. 3A; Supplemental Fig. 3). Tumor uptake was significantly higher for 68Ga-FAPI-46 than for 18F-FDG (respectively, 13.2 [IQR, 10.2] vs. 3.2 [IQR, 3.1] [P < 0.01] for median SUVmax and 7.6 [IQR, 6.4] vs. 2.0 [IQR, 2.0] [P < 0.01] for median SUVmean) (Fig. 3B). Also, the patient-based detection efficacy of tumor lesions was highest for 68Ga-FAPI-46 PET by detecting 367 of a total of 388 tumor lesion over all modalities (94.5%; SEM, 4.2%). This was higher than standard imaging with contrast-enhanced CT, which detected 338 lesions (87.8%; SEM, 4.3%), and significantly superior to 18F-FDG PET, which detected only 262 lesions (77.3%; SEM, 5.5%; P < 0.05) (Fig. 3C).
Comparison of 68Ga-FAPI-46 PET uptake intensity and detection efficacy in theranostic cohort (n = 19). (A) 85-y-old patient with metastatic SFT. Shown are representative maximum-intensity projection (top) and axial PET images (left, 68Ga-FAPI-46 PET; right, 18F-FDG PET), as well as axial CT image (bottom). Tumor lesions are indicated by arrows. (B) Column scatter graph comparing uptake intensity using mean SUVmax and mean SUVmean of 68Ga-FAPI-46 PET and 18F-FDG PET in patients with localized and metastatic SFT. (C) Truncated violin plots showing patient-based detected tumor lesion as percentage of maximum detected lesions for all modalities (total number of lesions, 388), for 68Ga-FAPI-46 PET, for 18F-FDG PET, and for CT. Statistical significance is defined as P < 0.05 with Welch t test. CE-CT = contrast-enhanced CT.
Efficacy of FAPα-Directed RLT
Eleven of the 19 patients (58%) in the theranostic cohort subsequently received 90Y-FAPI-46 RLT. The patients received a total of 34 cycles of 90Y-FAPI-46 RLT, with a median of 3 cycles (IQR, 2 cycles) per patient (Supplemental Table 3). The distribution of cycles and reasons for discontinuation in the 11 patients receiving RLT, as well as reasons for not receiving RLT in the other 8 patients, are displayed in Figure 1C. The median maximal absorbed radiation dose was 2.9 Gy/GBq (IQR, 3.9 Gy/GBq; range, 0.5–24.7 Gy/GBq) in tumor (Supplemental Table 3). Both RECIST and PERCIST response during or after therapy revealed a partial response in 3 patients (27%) and stable disease in 6 patients (55%), leading to a disease control rate of 82% (Supplemental Table 3). Representative images of 2 patients with a partial response are shown in Figure 4. A swimmer plot in Figure 5A displays the course of treatment: 3 patients were in follow-up without progression, 1 patient was still under RLT, 1 patient died because of relapse of concomitant breast cancer without progression of SFT, 1 patient was lost to follow-up after progression, and 5 patients received subsequent systemic treatment after progression. Kaplan–Meier plots illustrate PFS of the therapy before RLT (PFS1), of 90Y-FAPI-46 RLT (PFS2), and of the first subsequent therapy after RLT (PFS3) (Fig. 5B). The observed median PFS for 90Y-FAPI-46 RLT was 227 d (Supplemental Table 3).
Patients with partial response after 90Y-FAPI-46 RLT. At far left and right are maximum-intensity PET projections, and at center are axial 18F-FDG PET/CT (top rows) and CT (bottom rows) images, with SUVmax and tumor diameter, respectively, before therapy (left) and at time point of best response (right). (A) 67-y-old woman (patient 2) with metastatic SFT who progressed under 3 lines of systemic therapy, with RECIST partial response and PERCIST partial metabolic response under RLT. 90Y-FAPI-46 RLT was discontinued because of relapse of metastatic breast cancer in liver and lung. (B) 57-y-old woman (patient 5) with metastatic SFT who progressed under 2 lines of systemic therapy, with RECIST partial response and PERCIST stable metabolic disease under RLT.
Response and survival under 90Y-FAPI-46 RLT (n = 11). (A) Swimmer plot showing PFS for therapy before RLT (PFS1), for RLT (PFS2), and for subsequent therapies after RLT (PFS3–PFS5). Death of patient 2 was due to relapse of breast cancer. (B) Corresponding Kaplan–Meier plot for PFS. Arrows denote ongoing treatment or follow-up. †Death. Tx = treatment.
DISCUSSION
To our knowledge, this was the first study systematically investigating FAPα as a theragnostic target in SFT to report high expression level of FAPα on the tumor cell surface, enabling superior tumor detection by FAPα-directed PET. Moreover, we report on efficacy and survival after 90Y-FAPI-46 RLT in a patient subgroup.
Our analysis showed that SFT samples demonstrated the highest median mRNA expression of FAPα in the MASTER cohort. Likewise, we confirmed FAPα cell surface expression by immunohistochemistry and mIF in the tissue cohort. The high FAPα expression, particularly in tumor cells of SFT, is in contrast to previous reports on epithelial cancers, where FAPα expression was concentrated in cancer-associated fibroblasts, with low levels in the tumor cells (2,21,22).
In line with the observed high FAPα mRNA and protein expression, 18 of the 19 patients (95%) with SFT from the theranostic cohort showed high uptake of the FAPα-directed radioligand 68Ga-FAPI-46 in tumor lesions. Also, tumor detection efficacy was better for 68Ga-FAPI-46 PET than for contrast-enhanced CT and significantly better than for 18F-FDG PET. Our data are supported by recent studies showing similarly high 68Ga-FAPI PET uptake in 4 SFT patients and 2 studies reporting high FAPα protein expression in tumor tissue as well (23–26).
FAPα-associated RLT is an emerging approach for targeted systemic therapy against solid tumors (27). We recently demonstrated that 90Y-FAPI-46-RLT was safe and led to disease control in 8 of 16 (50%) evaluable patients, which was associated with improved overall survival (4). Noteworthy, 7 of 8 patients (88%) with disease control had metastatic sarcoma, including 5 patients with SFT (4). Here, we report expanded follow-up in 11 patients with SFT, including 9 patients (patients 1–9) of the previous study (4) and 2 new patients. We observed disease control in 9 patients (82%): partial response in 3 and stable disease in 6. When all other available therapeutic options fail, development of a novel therapy has a primary goal of achieving disease control.
This study was limited by its retrospective design, short follow-up for the theranostic cohort, and small sample size of treated patients due to low incidence. Moreover, the study lacked a direct correlation of RNA/protein expression, FAPI uptake, dosimetry, and treatment response. Another question, which should be addressed in future studies, is the mechanism regulating FAPα expression in SFT. Nevertheless, for such a rare disease our numbers are high and the data are consistent across 3 independent cohorts using different endpoints. In rare diseases, solid retrospective data are important since they are often the only available evidence-based data and form a basis for prospective research.
CONCLUSION
Screening of tissue mRNA and protein expression by immunohistochemistry identified FAPα as hallmark theranostic target for SFT. In line with this finding, 68Ga-FAPI-46 PET demonstrated SFT detection superior to that of 18F-FDG PET and contrast-enhanced CT. Finally, 90Y-FAPI-46 RLT of SFT led to disease control in more than 80% of cases. These data strongly support future prospective evaluation of FAPα-directed radioligand imaging and therapy in SFT and potentially other sarcomas.
DISCLOSURE
Rainer Hamacher was supported by the Clinician Scientist Program of the University Medicine Essen Clinician Scientist Academy (UMEA; Faculty of Medicine and Deutsche Forschungsgemeinschaft [DFG]); reports travel grants from Lilly, Novartis, and PharmaMar; and reports personal fees from Lilly and PharmaMar outside the submitted work. Kim Pabst has received a Junior Clinician Scientist Stipend from the University Medicine Essen Clinician Scientist Academy (UMEA; Faculty of Medicine and Deutsche Forschungsgemeinschaft [DFG]); reports travel fees from IPSEN; and reports research funding from Bayer. Phyllis Cheung is supported by the Deutsche Forschungsgemeinschaft (DFG) (CH 2320/2-3). Lukas Kessler is a consultant for AAA and BTG and received fees from Sanofi. Sabrina Borchert reports fees from Brystol Myers Squibb (research funding) outside the submitted work. Martin Schuler reports personal fees as a consultant from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, and Takeda; honoraria for continuing medical education presentations from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, MSD, and Novartis; and research funding (to the institution) from AstraZeneca and Bristol Myers Squibb—all outside the submitted work. Sebastian Bauer reports personal fees from Bayer, Eli Lilly, Novartis, Pfizer, and PharmaMar; serves in an advisory/consultancy role for ADC Therapeutics, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eli Lilly, Exelixis, Janssen-Cilag, Nanobiotix, Novartis, PharmaMar, Plexxikon, and Roche; reports research funding from Novartis; and serves as a member of the external advisory board of the Federal Ministry of Health for off-label use in oncology—all outside the submitted work. Stefan Fröhling reports personal fees from Amgen, Bayer, Eli Lilly, Illumina, PharmaMar, and Roche and research funding from AstraZeneca, Boehringer Ingelheim, Pfizer, PharmaMar, and Roche. Ken Herrmann reports personal fees from Bayer, SOFIE Biosciences, SIRTEX, Adacap, Curium, Endocyte, IPSEN, Siemens Healthineers, GE Healthcare, Amgen, Novartis, ymabs, Aktis, Oncology, and Pharma15; nonfinancial support from ABX; and grants and personal fees from BTG. Jens Siveke is supported by German Cancer Aid (grant 70112505, PIPAC; grant 70113834, PREDICT-PACA), the Wilhelm-Sander Foundation (grant 2019.008.1), the DFG through grant SI1549/3-1 (Clinical Research Unit KFO337) and SI1549/4-1, and the Federal Ministry of Education and Research (BMBF; SATURN3 consortium); receives honoraria as a consultant or for continuing medical education presentations from AstraZeneca, Bayer, Immunocore, Roche, and Servier; receives research funding (to the institution) from Bristol Myers Squibb, Celgene, and Roche; and holds ownership and serves on the board of directors of Pharma15—all outside the submitted work. Wolfgang Fendler reports fees from SOFIE Biosciences (research funding), Janssen (consultant, speaker), Calyx (consultant, image review), Bayer (consultant, speaker, research funding), Novartis (speaker, consultant), Telix (speaker), GE Healthcare (speaker), Eczacıbaşı Monrol (speaker), Abx (speaker), and Amgen (speaker)—all outside the submitted work. No other potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: Does FAPα serve as a suitable target for radiotheranostic applications in SFT?
PERTINENT FINDINGS: In this translational study, we demonstrated high expression of FAPα in SFT, particularly in tumor cells, with superiority of FAPα-targeting PET imaging and efficacy of FAPα-targeting RLT.
IMPLICATIONS FOR PATIENT CARE: These results form the basis and rationale for exploring SFT FAPα-directed radioligand imaging and therapy in future prospective trials.
ACKNOWLEDGMENTS
We thank Ulrike Winter and Katja Beck from the Department of Translational Medical Oncology at the National Center for Tumor Diseases Heidelberg for coordination and logistic support within the National Center for Tumor Diseases/German Cancer Research Center/German Cancer Consortium MASTER program. We thank Yvonne Krause and Sophia Berger from the Schildhaus Laboratory, as well as the technicians from the Institute of Pathology, for technical support. We thank all the nurses and technicians of the nuclear medicine team for ongoing logistic support.
Footnotes
↵* Contributed equally to this work.
Published online Jan. 4, 2024.
- © 2024 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication July 24, 2023.
- Revision received November 7, 2023.
