Fibroblast Activation Protein Inhibitor Research Articles

State of the Art in 2022 PET/CT in Breast Cancer: A Review.

Molecular imaging with positron emission tomography is a powerful and well-established tool in breast cancer management. In this review, we aim to address the current place of the main PET radiopharmaceuticals in breast cancer care and offer perspectives on potential future radiopharmaceutical and technological advancements. A special focus is given to the following: the role of 18F-fluorodeoxyglucose positron emission tomography in the clinical management of breast cancer patients, especially during staging; detection of recurrence and evaluation of treatment response; the role of 16α-18Ffluoro-17β-oestradiol positron emission tomography in oestrogen receptors positive breast cancer; the promising radiopharmaceuticals, such as 89Zr-trastuzumab and 68Ga- or 18F-labeled fibroblast activation protein inhibitor; and the application of artificial intelligence.

Interesting Findings in 68 Ga-FAPI-46 PET/CT Imaging in a Patient With Glioblastoma Multiforme.

A 55-year-old disabled man with glioblastoma multiforme was referred to us for fibroblast activation protein inhibitor (FAPI) PET/CT imaging. 68 Ga-DOTA-FAPI-46 scan revealed uptake in the primary tumor and unexpected uptakes in soft tissue, especially in periarticular regions. These latter foci were compatible with calcifications on the CT. One in the breast was compatible with fibrotic tissue, but 2 other foci, in the rectus abdominis and gallbladder wall, could not be correlated with the CT findings. In Neurogenic heterotopic ossification, hypoxia-associated oxidative stress results in the metaplastic transformation of fibroblasts. Abnormal differentiation of fibroblasts in neurogenic heterotopic ossification before ossification could explain radiolabeled FAPI avidity in the mentioned areas.

First Total-Body Kinetic Modeling and Parametric Imaging of Dynamic 68Ga-FAPI-04 PET in Pancreatic and Gastric Cancer.

Fibroblast activation protein inhibitor (FAPI) is an ideal diagnostic and therapeutic target in malignant tumors. However, the knowledge of kinetic modeling and parametric imaging of 68Ga-FAPI is limited. Purpose: The purpose of this study was to explore the pharmacokinetics of 68Ga-FAPI-04 PET/CT in pancreatic cancer and gastric cancer and to conduct parametric imaging of dynamic total-body data compared with SUV imaging. Methods: Dynamic total-body 68Ga-FAPI-04 PET/CT was performed on 13 patients. The lesion time-activity curves were fitted by 3-compartment models and multigraphical models. The kinetics parameters derived from the 2-tissue reversible compartment model (2T4K) and multigraphical models were analyzed. Parametric [Formula: see text] imaging was generated using the 2T4K and Logan models, and their performances were evaluated compared with SUV images. Results: 2T4K had the lowest Akaike information criterion value, and its fitting curves matched excellently with the origin time-activity curves. Visual assessment revealed that the [Formula: see text](2T4K) images and [Formula: see text](Logan with spatial constraint [SC]) images both showed less image noise and higher lesion conspicuity compared with SUV images. Objective image quality assessment demonstrated that parametric [Formula: see text](2T4K) images and parametric [Formula: see text](Logan with SC) images had a 5.0-fold and 5.0-fold higher average signal-to-noise ratio and 3.6-fold and 4.1-fold higher average contrast-to-noise ratio compared with conventional SUV images, respectively. In addition, no significant differences in signal-to-noise ratio and contrast-to-noise of pathologic lesions were observed between parametric [Formula: see text](2T4K) images and parametric [Formula: see text](Logan with SC) images (all P > 0.05). Conclusions: The 2T4K model was the preferred compartment model. Total-body parametric imaging of 68Ga-FAPI-04 PET yielded superior quantification beyond SUV with enhanced lesion contrast, which may serve as a promising imaging method to make an early diagnosis, to better reflect tumor characterization, or to allow evaluation of treatment response. [Formula: see text](2T4K) images are comparable in image quality and consistent to [Formula: see text](Logan with SC) images in lesions conspicuity; however, [Formula: see text](Logan with SC) images presented an appealing alternative to [Formula: see text](2T4K) images because of their simplicity.

FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease.

Gallium 68 (68Ga)-labeled fibroblast activation protein (FAP) inhibitor (FAPI) PET is based on the molecular targeting of the FAP, which is known to be highly expressed in the major cell population in tumor stroma, termed cancer-associated fibroblasts. Among many FAP-targeted radiopharmaceuticals developed so far, 68Ga-FAPI exhibits rapid tracer accumulation in target lesions and low background signal, which results in excellent imaging features. FAPI PET can be integrated in the clinical workflow and enables the detection of small primary or metastatic lesions, especially in the brain, liver, pancreas, and gastrointestinal tract due to the low tracer accumulation in these organs. Moreover, the DOTA (1,4,7,10-tetraazacylclododecane-1,4,7,10-tetrayl tetraacetic acid) chelator in the molecular structure allows coupling of the FAPI molecules with therapeutic emitters such as yttrium 90 for theranostic applications. This review provides an overview of the state of the art in FAP imaging, summarizes the current knowledge of relevant cancer biology, and highlights the latest findings in the clinical use of 68Ga-FAPI PET and other current FAPI tracers. Published under a CC BY 4.0 license.

RADIOPHARMACEUTICALS BASED ON FIBROBLAST ACTIVATION PROTEIN INHIBITORS IN ONCOLOGICAL PRACTICE.

The review is devoted to the application of the new perspective class of radionuclide tracers, based on inhibitors of the fibroblast activation protein (FAP), which is a marker of cancer-associated fibroblasts of microenvironment of most malignant tumors. FAP inhibitors (FAPI) can be labeled by a wide spectrum of radionuclides, which can provide both radionuclide diagnostics and radionuclide therapy. It was showed, that the diagnostic efficacy of FAPI positron emission tomography/computed tomography (PET/CT) in various cancers is similar to 18F-fluorodesoxyglu-cose-PET/CT or superior. The FAPI radiopharmaceuticals (RP) have some advantage compared to 18F-fluorodesoxy-glucose (FDG): no need for special preparation and diet, fast imaging with high contrast, and increased sensitivity in region with high glucose metabolism. FAPI-PET/CT may be an important addition to conventional methods in all stages of diagnostic process in oncology, especially when 18F-FDG cannot be used. It is need to further wide prospective investigations for assessing of diagnostic efficacy of FAPI-RP and determination of indications for its using.

Localization of Pyelonephritis by 68Ga-FAPI PET CT.

Fibroblast activation protein inhibitor (FAPI) is a quinoline-based membrane-bound glycoprotein enzyme that is not usually expressed in normal adult tissues, except for the myometrium and sometimes the pancreas. Its expression increases in inflammation and cancer-associated fibroblasts (CAF). As FAPI is a new molecule with a promising future, presented here is a case report of uncontrolled diabetes with abdominal pain that showed features of inflammation in the kidneys. The patient had been previously diagnosed with maxillary sinusitis with Aspergillus niger and was receiving antibiotic treatment. The urine culture performed later was negative, and the patient was referred for 18F-fluorodeoxyglucose (18F-FDG) PET Computed Tomography (CT) to look for the focus of infection. However, as blood sugar was 500 mg/dL, 18F-FDG PET CT could not be performed. Therefore, 68Ga-FAPI PET CT was run instead after taking the patient's written informed consent. The 99mTc-dimercaptosuccinic acid scan performed on another day confirmed the presence of pyelonephritis bilaterally. In situations where FDG cannot be used because of hyperglycemia, 68Ga-FAPI PET CT scan may be considered an alternative in the detection of occult infection or inflammation, as demonstrated in this case report.

Transformable prodrug nanoplatform via tumor microenvironment modulation and immune checkpoint blockade potentiates immunogenic cell death mediated cancer immunotherapy.

Rationale: Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance. Methods: Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist (DPPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core (DPPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part. Results: DPPA-TRPP/Tab reassembled into a micellar structure in vivo with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by DPPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. In vivo results indicated that DPPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response. Conclusion: The study offers potential in tumor eradication via exploiting an "all-in-one" smart polymeric nanoplatform.

Development and Characterization of Novel FAP-Targeted Theranostic Pairs: A Bench-to-Bedside Study.

Fibroblast activation protein (FAP) is among the most popular targets in nuclear medicine imaging and cancer theranostics. Several small-molecule moieties (FAPI-04, FAPI-46, etc.) are used for developing FAP-targeted theranostic agents. Nonetheless, the circulation time of FAP inhibitors is relatively short, resulting in rapid clearance via kidneys, low tumor uptake, and associated unsatisfactory treatment efficacy. To address the existing drawbacks, we engineered 3 peptides named FD1, FD2, and FD3 with different circulation times through solid-phase peptide synthesis. All the 3 reported peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance. The diagnostic and therapeutic potential of the agents labeled with 68Ga and 177Lu was assessed in several tumor models exhibiting different levels of FAP expression. While radiolabeled FD1 was rapidly excreted from kidneys, radiolabeled FD2/FD3 have significantly prolonged circulation, increased tumor uptake, and decreased kidney accumulation. Our findings indicated that [68Ga]Ga-DOTA-FD1 positron emission tomography (PET) effectively detected FAP dynamics, whereas [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing tumor models, including pancreatic cancer cell models characterized by abundant stroma. Moreover, a pilot translational investigation demonstrated that [68Ga]Ga-DOTA-FD1 had the capability to identify both primary and metastatic tumors with precision and distinction. In summary, we developed [68Ga]Ga-DOTA-FD1 for same-day PET imaging of FAP dynamics and [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 for effective radioligand therapy of FAP-overexpressing tumors.

Emerging molecular imaging targets and tools for myocardial fibrosis detection.

Myocardial fibrosis is the heart's common healing response to injury. While initially seeking to optimize the strength of diseased tissue, fibrosis can become maladaptive, producing stiff poorly functioning and pro-arrhythmic myocardium. Different patterns of fibrosis are associated with different myocardial disease states, but the presence and quantity of fibrosis largely confer adverse prognosis. Current imaging techniques can assess the extent and pattern of myocardial scarring, but lack specificity and detect the presence of established fibrosis when the window to modify this process may have ended. For the first time, novel molecular imaging methods, including gallium-68 (68Ga)-fibroblast activation protein inhibitor positron emission tomography (68Ga-FAPI PET), may permit highly specific imaging of fibrosis activity. These approaches may facilitate earlier fibrosis detection, differentiation of active vs. end-stage disease, and assessment of both disease progression and treatment-response thereby improving patient care and clinical outcomes.

Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis

Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis invivo and invitro. FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. Invitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

Prospective comparison of 68Ga-FAPI-04 and 18F-FDG PET/CT for tumor staging in nasopharyngeal carcinoma.

To explore the difference in the effectiveness of gallium-68 fibroblast activation protein inhibitor (68Ga-FAPI-04) PET/CT and fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT for the initial staging of patients with nasopharyngeal carcinoma (NPC). The Affiliated Hospital of Southwest Medical University hosted this single-center prospective investigation (Clinical Trials registration No.ChiCTR2100044131) between March 2020 and September 2021. Within a week, all subjects underwent MR scans, 68Ga-FAPI-04 PET/CT, and 18F-FDG PET/CT in order. The effectiveness of medical staging employing 68Ga-FAPI-04 and 18F-FDG PET/CT was compared. Twenty-eight patients with primary NPC were evaluated (mean age53 ± 11 years). 68Ga-FAPI-04 PET/CT indicated an elevated recognition rate for diagnosing primary tumors (28/28 [100%] vs. 27/28 [96%]) and lymph node metastases (263/285 [92%] vs. 228/285 [80%]), but a lower detection rate for distant metastases (5/7 [71%] vs. 7/7 [100%]) compared with 18F-FDG PET/CT. A significant association between the maximum standard uptake value (SUVmax) of 18F-FDG PET and 68Ga-FAPI-04 PET was found in the primary cancers (r = 0.691, p < 0.001). In comparison to 18F-FDG PET/CT, 68Ga-FAPI-04 PET/CT upstaged the T stage in five patients while downstaging the N stage in seven patients. 68Ga-FAPI-04 PET/CT corrected the overall staging of five patients on18F-FDG PET/CT. 68Ga-FAPI-04 PET/CT is preferable to 18F-FDG PET/CT for NPC staging in terms of the detection efficiency for primary tumors and lymph node metastasis. This is especially true when evaluating the primary cancer and any spread to contiguous tissues. It is possible to improve the staging assessment of NPCby using 68Ga-FAPI-04 PET/CT in conjunction with 18F-FDG PET/CT.

Comparison of 68 Ga-FAPI-04 and fluorine-18-fluorodeoxyglucose PET/computed tomography in the detection of ovarian malignancies.

Currently, fluorine-18-fluorodeoxyglucose ( 18 F-FDG) is the most frequently used diagnostical radiotracer for PET/computed tomography (PET/CT) in ovarian malignancies. However, 18 F-FDG has some limitations. The fibroblast activation protein inhibitor (FAPI) previously demonstrated highly promising results in studies on various tumor entities and 68 Ga-labeled FAPI presents a promising alternative to 18 F-FDG. This study aimed to compare the performance of 68 Ga-FAPI and 18 F-FDG PET/CT for imaging of ovarian malignancies. A total of 27 patients were included in this retrospective study conducted at the Affiliated Hospital of Southwest Medical University between June 2020 and February 2022. The 18 F-FDG and 68 Ga-FAPI uptakes of tumors, lymph nodes, and distant metastases were quantified using the maximum standardized uptake values, and the tumor-to-background ratios were also evaluated and calculated by using the Wilcoxon signed-rank test. Twenty-one patients with suspected ( n = 11) and previously treated ovarian malignancies ( n = 10) were in statistical analysis finally. For detecting tumors, 68 Ga-FAPI PET/CT was more sensitive than 18 F-FDG PET/CT [14 of 14 (100%) vs. 11 of 14 (78%)], lymph node metastases [75 of 75 (100%) vs. 60 of 75 (80%)] and superior to 18 F-FDG PET/CT in terms of the peritoneal and pleural metastases [9 of 9 (100%) vs. 5 of 9 (56%)]. For four of the newly diagnosed patients ( n = 11), 68 Ga-FAPI PET/CT upstaged the clinical stage compared to 18 F-FDG PET/CT. 68 Ga-FAPI PET/CT has superior potential in the detection of ovarian cancers, especially in peritoneal carcinomatosis. 68 Ga-FAPI PET/CT may be a promising supplement for staging and follow-up of ovarian malignancies.

Current research topics in FAPI theranostics: a bibliometric analysis.

The study aimed to provide a comprehensive bibliometric overview of the current scientific publications on fibroblast activation protein inhibitor (FAPI) positron emission tomography imaging and radionuclide therapy. A PubMed search was performed to identify all MEDLINE-indexed publications on FAPI imaging and radionuclide therapy. The last update was performed on 31 May 2022. An online database of this literature was created, and hierarchical topic-related tags were subsequently assigned to all relevant studies. Frequency analysis was used to evaluate the distribution of the following characteristics: first author's country of origin, journal of publication, study design, imaging techniques and radiopharmaceutical used, histopathological correlation, the type of cancer, and benign disease/uptake types evaluated. A total of 294 relevant publications on original studies were identified, consisting of 209 (71%) case reports/series and 85 cohort studies (29%). The majority of studies focused on imaging topics, predominantly comparing uptake on FAPI-PET/CT with 2-[18F]FDG-PET/CT, anatomical imaging, and/or histopathology results. 68% of studies focused on malignancies, with gastro-intestinal cancer, hepato-pancreato-biliary cancer, mixed cancers/metastases, lung cancer, sarcoma, head and neck cancer, and breast cancer being the most frequently reported. 42% of studies focused on benign disease categories, with cardiovascular, musculoskeletal, HPB, head and neck, and IgG4-related disease as most common categories. 16/294 (5%) studies focused on radionuclide therapy, with preliminary reports of acceptable toxicity profiles, tumour activity retention, and suggestion of disease control. FAPI research is rapidly expanding from diagnostic studies in malignancies and benign diseases to the first reports of salvage radionuclide therapy. The research activity needs to shift now from low-level-of-evidence case reports and series to prospectively designed studies in homogenous patient groups to provide evidence on how and in which clinical situations FAPI theranostics can be of added value to clinical care. We have provided an overview of current research topics to build upon.

Toxicity Assessment of [177Lu]Lu-iFAP/iPSMA Nanoparticles Prepared under GMP-Compliant Radiopharmaceutical Processes.

The fibroblast activation protein (FAP) is heavily expressed in fibroblasts associated with the tumor microenvironment, while the prostate-specific membrane antigen (PSMA) is expressed in the neovasculature of malignant angiogenic processes. Previously, we reported that [177Lu]lutetium sesquioxide-iFAP/iPSMA nanoparticles ([177Lu]Lu-iFAP/iPSMA) inhibit HCT116 tumor progression in mice. Understanding the toxicity of [177Lu]Lu-iFAP/iPSMA in healthy tissues, as well as at the tissue and cellular level in pathological settings, is essential to demonstrate the nanosystem safety for treating patients. It is equally important to demonstrate that [177Lu]Lu-iFAP/iPSMA can be prepared under good manufacturing practices (GMP) with reproducible pharmaceutical-grade quality characteristics. This research aimed to prepare [177Lu]Lu-iFAP/iPSMA under GMP-compliant radiopharmaceutical processes and evaluate its toxicity in cell cultures and murine biological systems under pathological environments. [177Lu]Lu2O3 nanoparticles were formulated as radiocolloidal solutions with FAP and PSMA inhibitor ligands (iFAP and iPSMA), sodium citrate, and gelatin, followed by heating at 121 °C (103-kPa pressure) for 15 min. Three consecutive batches were manufactured. The final product was analyzed according to conventional pharmacopeial methods. The Lu content in the formulations was determined by X-ray fluorescence. [177Lu]Lu-iFAP/iPSMA performance in cancer cells was evaluated in vitro by immunofluorescence. Histopathological toxicity in healthy and tumor tissues was assessed in HCT116 tumor-bearing mice. Immunohistochemical assays were performed to corroborate FAP and PSMA tumor expression. Acute genotoxicity was evaluated using the micronuclei assay. The results showed that the batches manufactured under GMP conditions were reproducible. Radiocolloidal solutions were sterile and free of bacterial endotoxins, with radionuclidic and radiochemical purity greater than 99%. The lutetium content was 0.10 ± 0.02 mg/mL (0.9 GBq/mg). Significant inhibition of cell proliferation in vitro and in tumors was observed due to the accumulation of nanoparticles in the fibroblasts (FAP+) and neovasculature (PSMA+) of the tumor microenvironment. No histopathological damage was detected in healthy tissues. The data obtained in this research provide new evidence on the selective toxicity to malignant tumors and the absence of histological changes in healthy tissues after intravenous injection of [177Lu]Lu-iFAP/iPSMA in mammalian hosts. The easy preparation under GMP conditions and the toxicity features provide the added value needed for [177Lu]Lu-iFAP/iPSMA clinical translation.

Usefulness of [68Ga]FAPI-04 and [18F]FDG PET/CT for the detection of primary tumour and metastatic lesions in gastrointestinal carcinoma: a comparative study.

To assess and compare the diagnostic performance of gallium-68-labelled fibroblast activation protein inhibitor ([68Ga]FAPI-04) and fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in gastrointestinal cancer. Fifty-one patients who underwent both [18F]FDG and [68Ga]FAPI-04 PET/CT for initial staging or restaging were enrolled. Histopathological findings, typical radiological appearances, and clinical imaging follow-up were used as the reference standard. The diagnostic performance of the two tracers was calculated and compared. The maximum standardised uptake value (SUVmax), mean SUV (SUVmean), tumour-to-mediastinal blood pool ratio (TBR), and tumour-to-liver ratio (TLR) of primary and metastatic lesions were measured and compared between two imaging modalities. In patient-based analysis, [68Ga]FAPI-04 showed much better diagnostic sensitivity than [18F]FDG in detecting primary tumour (94.44% [17/18] vs. 61.11% [11/18]), postoperative recurrence and metastases (95.65% [22/23] vs. 69.57% [16/23]), and peritoneal carcinomatosis (100% [28/28] vs. 60.71% [17/28]) (all p < 0.05). In lesion-based analysis, [68Ga]FAPI-04 showed higher sensitivity than [18F]FDG for detecting lymph node metastases. In peritoneal carcinomatosis, the median SUVmax (12.12 vs. 7.18) and SUVmean (6.84 vs. 4.11) with [68Ga]FAPI-04 were significantly higher than those with [18F]FDG (all p < 0.005). The TBR and TLR of [68Ga]FAPI-04 were significantly higher than those of [18F]FDG for detecting primary tumour, lymph node, liver, and peritoneal metastases (all p < 0.005). Therapeutic management changed in 13 patients according to [68Ga]FAPI-04 PET/CT compared with conventional imaging. [68Ga]FAPI-04 is superior to [18F]FDG PET/CT for detecting primary tumour, postoperative recurrence and metastasis, and peritoneal carcinomatosis in gastrointestinal cancer. • [68Ga]FAPI-04 PET/CT showed significantly higher sensitivity than [18F]FDG PET/CT in the detection of primary tumour and postoperative recurrence and metastasis in patients with gastrointestinal carcinoma. • [68Ga]FAPI-04 PET/CT had obvious advantages over [18F]FDG PET/CT in the detection of peritoneal carcinomatosis from gastrointestinal carcinoma with a much higher FAPI uptake value, TBR, and TLR. • Although the median SUVmax and SUVmean of [68Ga]FAPI-04 were similar to those of [18F]FDG for the primary tumour, lymph node metastases, and liver metastases in gastrointestinal carcinoma, the TBR and TLR of the SUVmax and SUVmean were significantly higher on [68Ga]FAPI-04 PET/CT, causing the lesions to be displayed more clearly.

Initial Results of 68Ga-FAPI-46 PET/MRI to Assess Response to Neoadjuvant Chemotherapy in Breast Cancer.

Improving imaging-based response after neoadjuvant chemotherapy (NAC) in breast cancer assessment could obviate histologic confirmation of pathologic complete response (pCR) and facilitate deescalation of chemotherapy or surgery. Fibroblast activation protein inhibitor (FAPI) PET/MRI is a promising novel molecular imaging agent for the tumor microenvironment with intense uptake in breast cancer. We assessed the diagnostic performance of follow-up breast 68Ga-FAPI-46 (68Ga-FAPI) PET/MRI in classifying the response status of local breast cancer and lymph node metastases after completion of NAC and validated this approach immunohistochemically. Methods: In women who completed NAC for invasive breast cancer, follow-up 68Ga-FAPI PET/MRI and corresponding fibroblast activation protein (FAP) immunostainings were retrospectively analyzed. Metrics of 68Ga-FAPI uptake and FAP immunoreactivity in women with or without pCR were compared using the Mann-Whitney U test. Diagnostic performance to detect remnant invasive cancer was calculated for tracer uptake metrics using receiver-operating-characteristic curves and for masked readers' visual assessment categories of PET/MRI and MRI alone. Results: Thirteen women (mean age ± SD, 47 ± 9 y) were evaluated. Seven of the 13 achieved pCR in the breast and 6 in the axilla. FAP immunoreactivity was significantly associated with response status. The 68Ga-FAPI PET/MRI mean breast tumor-to-background ratio was 0.9 (range, 0.6-1.2) for pCR and 2.1 (range, 1.4-3.1) for no pCR (P = 0.001). Integrated PET/MRI could classify breast response correctly in all 13 women based on readers' visual assessment or tumor-to-background ratio. Evaluation of MRI alone resulted in at least 2 false-positives. For lymph nodes, PET/MRI readers had at least 2 false-negative classifications, whereas MRI alone resulted in 2 false-negatives and 1 false-positive. Conclusion: To our knowledge, this was the first analysis of 68Ga-FAPI PET/MRI for response assessment after NAC for breast cancer. The diagnostic performance of PET/MRI in a small study sample trended toward a gain over MRI alone, clearly supporting future prospective studies.

18F]FAPI PET/CT in the evaluation of focal liver lesions with [18F]FDG non-avidity.

This prospective study was aimed to investigate the potential utility of [18F]fibroblast activation protein inhibitor (FAPI) PET/CT for evaluating focal liver lesions (FLLs) with [18F]FDG non-avidity. From January 2021 to March 2022, this prospective study included 80 FLLs that were not avid on [18F]FDG PET/CT from 37 patients, then underwent [18F]FAPI PET/CT. All patients with FLL(s) with biopsy-proof or follow-up confirmation were categorized into four subgroups (20 hepatocellular carcinomas [HCCs]/5 non-HCC malignancies/4 inflammatory FLLs/8 benign noninflammatory FLLs). The diagnostic value of [18F]FAPI for detecting liver malignancy was determined by visual evaluation. Differences in the maximum standardized uptake value (SUVmax) and lesion-to-background ratio (LBR) obtained from [18F]FAPI PET/CT among the four subgroups were analyzed by semiquantitative analysis. Among the thirty-seven enrolled participants (34 males; median age 57years, range 48-67years), on visual evaluation, the sensitivity, specificity, and accuracy of [18F]FAPI PET for detecting liver malignancy in the patient-based analysis were 96.0% (24/25), 58.3% (7/12), and 83.8% (31/37), respectively. On semiquantitative analysis, the SUVmax and LBR of [18F]FAPI PET in liver malignancy (33 HCC lesions; 19 non-HCC malignant lesions) were significantly higher than those in 11 benign noninflammatory FLLs [HCC: SUVmax: 6.4 vs. 4.5, P = 0.017; LBR: 5.1 vs. 1.5, P = 0.003; non-HCC: SUVmax: 5.5 vs. 4.5, P = 0.008; LBR: 4.4 vs. 1.5, P = 0.042]. Notably, there was no significant difference in the SUVmax of [18F]FAPI PET between 33 HCC lesions and 17 inflammatory FLLs (6.4 vs. 8.2, P = 0.37), but the LBR of [18F]FAPI PET in HCC were significantly lower than that in inflammatory FLLs (5.1 vs. 9.1, P = 0.003). [18F]FAPI PET/CT shows high sensitivity in detecting HCC and non-HCC malignancy with [18F]FDG non-avidity. [18F]FAPI might be a promising radiopharmaceutical for the differential diagnosis of benign noninflammatory FLLs and liver malignancy with [18F]FDG non-avidity.

Abstract 14533: Molecular Imaging of Fibroblast Activity in Pressure Overload Heart Failure

Introduction: Cardiac fibrosis, mediated by the activation of cardiac fibroblasts, is critical in pressure overload-induced heart failure. Fibroblast activation protein (FAP), specifically expressed by activated fibroblasts, can be visualized by radiolabeled FAP inhibitors (FAPI) PET/CT. Hypothesis: To evaluate whether 68Ga-FAPI-04 could characterize the early stages of cardiac fibrosis in pressure overload heart failure. Methods: Sprague-Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with 68 Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. Cardiac function was measured by echocardiography. The expression of FAP in the myocardium was detected by immunohistochemistry. Results: Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p &lt; 0.01). The AAC group showed higher 68 Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, respectively (all p &lt; 0.001), and FAPI increased significantly from 2 to 8 weeks. Immunohistochemistry confirmed the higher density of the FAP + area in the AAC group. The intensity of the 68 Ga-FAPI-04 PET signal correlated with the density of the FAP + area on histology (p &lt; 0.001). The expression of the 68 Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = -0.87; FS: R = -0.72; LVIDd: R = 0.77; LVIDs: R= 0.79; all p &lt; 0.001). The AAC group also showed an increased 68 Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals directly correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010). A combination of the FAPI intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks. Conclusion: The activated fibroblasts in the heart and liver after pressure overload can be monitored by 68 Ga-FAPI-04 PET/CT. This imaging technique reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis.

Selective tumor targeting enabled by picomolar fibroblast activation protein inhibitors isolated from a DNA-encoded affinity maturation library

<h2>Summary</h2> The availability of ultra-high-affinity small organic ligands, which are specific to accessible cancer antigens, is crucially important to enable efficient and selective tumor targeting applications. In this article, we describe the isolation of highly potent inhibitors of fibroblast activation protein (FAP), an enzyme that is abundantly and selectively expressed in the stroma of most of aggressive human solid malignancies. Affinity-maturation DNA-encoded chemical libraries, based on three series of 50,730 propargylglycine derivatives, enabled the identification of picomolar FAP inhibitors. A ¹⁷⁷Lu-DOTAGA conjugate of the most potent novel ligand (named "<b>OncoFAP-11</b>") localized to tumors implanted in mice, with tumor-to-blood ratios of ∼220:1 17 h after intravenous administration. A dimeric derivative (named "<b>BiOncoFAP-11</b>") further enhanced tumor residence time with a low uptake in healthy organs.

Impact of 68 Ga-FAPI-04 PET/CT on Staging and Therapeutic Management in Patients With Digestive System Tumors.

We aimed to determine the impact of fibroblast activation protein inhibitor (FAPI)-directed molecular imaging on staging and therapeutic management in patients affected with digestive system tumors when compared with guideline-compatible imaging (GCI). Thirty-two patients with tumors of the digestive system were included: colon adenocarcinoma, 2/32 (6.3%); hepatocellular carcinoma (HCC), 6/32 (18.8%); pancreatic duct adenocarcinoma (PDAC), 6/32 (18.8%), and gastroenteropancreatic neuroendocrine neoplasms, 18/32 (56.3%). All patients underwent GCI and 68 Ga-FAPI-04 PET/CT within median 4 days. Staging outcomes and subsequent treatment decisions were compared between GCI and 68 Ga-FAPI-04 PET/CT. Compared with GCI, 68 Ga-FAPI-04 PET/CT led to staging changes in 15/32 patients (46.9%). Among those, downstaging was recorded in 3/15 cases (20.0%) and upstaging in the remaining 12/15 patients (HCC, 4/12 [33.3%]; PDAC, 4/12 [33.3%]; neuroendocrine neoplasms, 3/12 [25%]; colon adenocarcinoma, 1/12 [8.3%]). Therapeutic management was impacted in 8/32 patients (25.0%), including 4 instances of major and 4 instances of minor therapeutic changes. The highest proportion of treatment modifications was observed in patients diagnosed with PDAC and HCC in 6/8 (75%). In patients affected with digestive system tumors, 68 Ga-FAPI-04 PET/CT resulted in staging changes in more than 46% and therapeutic modifications in 25% of the cases, in particular in patients with HCC and PDAC. In clinical routine, such findings may favor a more widespread adoption of FAP-directed imaging in those tumor types.