Fibroblast Activation Protein Inhibitor Research Articles

Comparison of 68GA-FAPI-04 PET/CT and 18F-FDG PET/CT findings in peritonitis carcinomatosa cases.

This study was conducted to compare the diagnostic accuracy of gallium-68-radiolabeled fibroblast activation protein inhibitor (68Ga-FAPI-04), positron emission tomography/computed tomography (PET/CT), and fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT based on the peritoneal carcinomatosis (PC) index for detecting peritoneal metastases of various cancer types, and to evaluate the potential benefits of FAPI PET/CT in patients with peritoneal metastases. This retrospective study included 57 patients with peritoneal metastases between November 2020 and December 2021. All patients underwent 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT scans within 7 days. Among the 57 patients included, 32 (56.1%) were male and the median age was 54 years (22-86 years). In the visual evaluation made from a total of 13 quadrants on the abdominopelvic peritoneal surfaces, positive findings were observed in 111 quadrants in 39 patients by 18F-FDG PET/CT and in 280 quadrants in 57 patients by 68Ga-FAPI-04 PET/CT (P<0.001). The maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) values of 68Ga-FAPI-04 PET/CT for the PC lesions were significantly higher than the SUVmax and TBR values of 18F-FDG PET/CT in all patients and in all quadrants (SUVmax 6.45 vs 4.1; P<0.001; TBR 14.9 vs 6.8; P<0.001). Gallium-68-FAPI-04 PET/CT showed superior sensitivity compared to 18F-FDG PET/CT in both quantitative and visual evaluations of PC. Considering the low background activity and higher specific activity uptake values, 68Ga-FAPI-04 PET/CT helped improve diagnostic accuracy.

Synthesis and Preclinical Evaluation of a Novel FAPI-04 Dimer for Cancer Theranostics.

Overexpression of fibroblast activation protein (FAP) in cancer-associated fibroblasts in a wide variety of tumors enables a highly selective targeting strategy using FAP inhibitors (FAPIs). Quinoline-based FAPIs labeled with radionuclides have been widely developed for tumor-targeted nuclear medicine imaging. However, the short retention time of FAPIs at the tumor site limits their application in radionuclide therapy. In this study, a novel FAPI-04 dimer was synthesized and labeled with radionuclides to prolong the retention time in tumors for imaging and therapy. To prepare the FAPI-04 dimer complex, DOTA-Suc-Lys-(FAPI-04)2, we used Fmoc-Lys(Boc)-OH as the linker to conjugate two FAPI-04 structures by an amide reaction. The resulting product was further modified by DOTA groups to allow for conjugation with radioactive metals. Both [68Ga]Ga-(FAPI-04)2 and [177Lu]Lu-(FAPI-04)2 showed a radiochemical purity of >99% and remained stable in vitro. In vivo, micro-PET images of SKOV3, A431, and H1299 xenografts revealed that the tumor uptake of [68Ga]Ga-(FAPI-04)2 was about twice that of [68Ga]Ga-FAPI-04 and that the accumulation of [68Ga]Ga-(FAPI-04)2 at the tumor site did not significantly decrease even 3h after injection. The tumor-abdomen ratio of [68Ga]Ga-(FAPI-04)2 images was significantly higher than that of [18F]F-FDG images. For radionuclide therapy, [177Lu]Lu-(FAPI-04)2 effectively retarded tumor growth and displayed good tolerance. In conclusion, the DOTA-Suc-Lys-(FAPI-04)2 design enhanced its uptake in FAP-expressing tumors, improved its retention time at the tumor site, and produced high-contrast imaging in xenografts after radionuclide labeling. Furthermore, it showed a noticeable antitumor effect. DOTA-Suc-Lys-(FAPI-04)2 provides a new approach for applying FAPI derivatives in tumor theranostics.

Abstract 1989: DNA-encoded affinity maturation libraries enable the discovery of low picomolar fibroblast activation protein inhibitors suitable for radioligand therapy of solid tumors

Abstract The discovery of potent ligands highly specific to accessible cancer-associated antigens is essential for the development of small molecule therapeutics with broad therapeutic index. DNA-encoded chemical libraries (DELs) can be used to discover novel binders and to improve binding affinity of existing small organic ligands by affinity maturation procedures. OncoFAP is a 680 pM inhibitor of the stromal pan-tumoral antigen Fibroblast Activation Protein (FAP). OncoFAP displays best-in-class tumor targeting performance in patients, although its relatively short half-life limits the applicability as radioligand therapeutic against solid malignancies. We designed three focused affinity maturation DELs, containing 50,730 compounds bearing two sets of building blocks coupled to a propargylglycine central scaffold. Library selections against FAP from multiple species enabled the discovery of novel FAP inhibitors with potencies in the low picomolar range. 177Lu-DOTAGA conjugates of the most potent novel ligands (named “OncoFAP-11” and “BiOncoFAP-11”) localized to tumors implanted in mice, with excellent tumor-to-blood and tumor-to-kidney ratios at late time-points after systemic administration. The high affinity FAP ligands described here enable the efficient delivery of therapeutic radionuclides to tumors with long residence time and with low uptake in normal tissues. The results presented here show that DEL-based affinity maturation procedures can lead to the improvement of the targeting performance of FAP binders, without compromising their tumor selectivity. Citation Format: Sara Puglioli, Luca Prati, Sebastian Oehler, Andrea Galbiati, Dario Neri, Samuele Cazzamalli, Gabriele Bassi, Nicholas Favalli. DNA-encoded affinity maturation libraries enable the discovery of low picomolar fibroblast activation protein inhibitors suitable for radioligand therapy of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1989.

One-stop [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 total-body PET/CT examination with dual-low activity: a feasibility study.

Positron emission tomography/computed tomography (PET/CT) based on fibroblast activation protein inhibitors (FAPI) has shown complementary values to 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) in cancer imaging. This study aimed to investigate the feasibility of a one-stop FDG-FAPI dual-tracer imaging protocol with dual-low activity for oncological imaging. Nineteen patients with malignancies underwent one-stop [18F]FDG (0.37MBq/kg) PET (PETFDG) and dual-tracer PET 30-40 and 50-60min (hereafter, PETD30-40 and PETD50-60, respectively) after additional injection of [68Ga]Ga-DOTA-FAPI-04 (0.925MBq/kg), with a single diagnostic CT to generate the PET/CT. The lesion detection rate and tumor-to-normal ratios (TNRs) of tracer uptake were compared between PETFDG/CT and PETD50-60/CT and between PETD50-60/CT and PETD30-40/CT. In addition, a visual scoring system was established to compare the lesion detectability. The dual-tracer PETD50-60 and PETD30-40/CT showed similar performance in detecting primary tumors but presented significantly higher lesion TNRs than PETFDG. Significantly, more metastases with higher TNRs were identified on PETD50-60 than PETFDG (491 vs. 261, P < 0.001). The dual-tracer PETD50-60 received significantly higher visual scores than single PETFDG (111 vs. 10) in demonstrating both primary tumors (12 vs. 2) and metastases (99 vs. 8). However, these differences were not significant between PETD50-60 and PETD30-40. These resulted in tumor upstaging in 44.4% patients taking PET/CT for initial assessment, and more recurrences (68 vs. 7) were identified in patients taking PET/CT for restaging, both on PETD50-60 and PETD30-40, compared to PETFDG. The reduced effective dosimetry per patient (26.2 ± 2.57mSv) was equal to that of a single standard whole-body PET/CT. The one-stop dual-tracer dual-low-activity PET imaging protocol combines the strengths of [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 with shorter duration and lesser radiation and is thus clinically applicable.

Synthesis and Evaluation of 99mTc-Labeled FAP Inhibitors with Different Linkers for Imaging of Fibroblast Activation Proteins in Tumors.

Fibroblast activation protein (FAP) is a potential target for tumor diagnosis and treatment due to its selective expression on cancer-associated fibroblasts (CAFs) in most solid tumor stroma. Two FAP inhibitor (FAPI) derived ligands (L1 and L2) containing different lengths of DPro-Gly (PG) repeat units as linkers were designed and synthesized with high affinity for FAP. Two stable hydrophilic 99mTc-labeled complexes ([99mTc]Tc-L1 and [99mTc]Tc-L2) were obtained. In vitro cellular studies show that the uptake mechanism is correlated with FAP uptake, and [99mTc]Tc-L1 shows a higher cell uptake and specific binding to FAP. A nanomolar Kd value for [99mTc]Tc-L1 indicates its significantly high target affinity for FAP. The biodistribution and microSPECT/CT images obtained for U87MG tumor mice show that [99mTc]Tc-L1 has high tumor uptake with specificity to FAP and high tumor-to-nontarget ratios. As an inexpensive, easily made, and widely available tracer, [99mTc]Tc-L1 holds great promise for clinical applications.

68Ga]Ga-HBED-CC-FAPI Derivatives with Improved Radiolabeling and Specific Tumor Uptake.

Fibroblast activation protein (FAP) is selectively expressed in tumors and highly important for maintaining the microenvironment in malignant tumors. Radioisotope-labeled FAP inhibitors (FAPIs) were proven to be useful for diagnosis and radionuclide therapy of cancer and are under active clinical investigations. Ga-HBED complex displays a higher in vivo stability constant (log KGaL: 38.5), compared to that of Ga-DOTA (log KGaL: 21.3). Such advantage in stability constant suggests that it may be useful for development of alternative FAPI imaging agents. In this study, previously reported [68Ga]Ga-DOTA-FAPI-02 and -04 were converted to the corresponding [68Ga]Ga-HBED-CC-FAPI-02 and -04 derivatives ([68Ga]Ga-4, [68Ga]Ga-5, [68Ga]Ga-6, and [68Ga]Ga-7). It was found that substituting the DOTA chelating group with HBED-CC led to several unique and desirable tumor-targeting properties: (1) robust, fast, and high yield labeling─readily adaptable to a kit formulation; (2) high stabilities in vitro; (3) excellent FAP binding affinities (IC50 ranging between 4 and 7 nM) and improved cell uptake and retention (in HT1080 (FAP+) cells); and (4) excellent selective in vivo tumor uptake in nude mice bearing U87MG tumor. It appeared that Ga(III) chelation with HBED-CC improved the in vivo kinetics favoring higher tumor uptake and retention compared to the corresponding Ga-DOTA complex. Out of the four tested ligands the new [68Ga]Ga-HBED-CC-FAPI dimer, [68Ga]Ga-6, displayed the best tumor localization properties, and further studies are warranted to demonstrate that it is an alternative FAP imaging agent for cancer patients.

Preliminary Findings of the Role of FAPi in Prostate Cancer Theranostics

Prostate cancer (PCa) is the most frequently diagnosed cancer worldwide and the second most common cause of cancer-related deaths among men. Progress in molecular imaging has magnified its clinical management; however, an unmet clinical need involves the identification of new imaging biomarkers that complement the gold standard of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) in cases of clinically significant PCa that do not express PSMA. Fibroblast activation protein (FAP) is a type II transmembrane serine overexpressed in many solid cancers that can be imaged through quinoline-based PET tracers derived from an FAP inhibitor (FAPi). Preliminary results of FAPi application in PCa (in PSMA-negative lesions, and in comparison with fluorodeoxyglucose-FDG) are now available in the literature. FAP-targeting ligands for PCa are not limited to detection, but could also include therapeutic applications. In this preliminary review, we provide an overview of the clinical applications of FAPi ligands in PCa, summarising the main results and highlighting contemporary strengths and limitations.

68 Ga-FAPI04 Versus 68 Ga-DOTATATE PET/CT in a Patient With Multiple Meningioma.

We present the 68 Ga-DOTATATE and 68 Ga-FAPI (fibroblast activation protein inhibitor) PET/CT findings of a 61-year-old man diagnosed with atypical World Health Organization grade II multiple meningiomas. The patient has been stable for 2 years following multiple surgeries and external radiotherapy because of recurring disease until he recently described frequent headaches, and a follow-up examination confirmed new meningioma lesions on MRI. However, the patient was inoperable and was referred for 68 Ga-DOTATATE PET/CT to determine eligibility for salvage peptide receptor radionuclide therapy. He also underwent fibroblast activation protein-targeted imaging using 68 Ga-FAPI04 PET/CT, which revealed heterogeneous, low to mild fibroblast activation protein expression across multiple meningioma lesions.

A novel molecular imaging probe [99mTc]Tc-HYNIC-FAPI targeting cancer-associated fibroblasts

Fibroblast activation protein (FAP) is higher expressed on cancer-associated fibroblasts (CAFs) in most malignant epithelial neoplasms, which is lower expressed in normal tissues. As a promising small molecular probe, FAP inhibitor (FAPI) shows the specific binding to FAP. This study aimed to explore a novel molecular probe [99mTc]Tc-HYNIC-FAPI targeting CAFs. The in vitro characteristics of the probe were also evaluated. The FAPI targeting FAP was designed, synthesized and conjugated with the chelator 6-hydrazinylnicotinic acid (HYNIC) for radiolabeling with 99mTc. The radiolabeling yield, radiochemical purity and stability were evaluated by Instant thin-layer chromatography (ITLC) and High performance liquid chromatography (HPLC). Lipophilicity was performed by the distribution coefficient test. The binding and migration ability of the probe was assessed using the FAP transfected tumor cell line. The radiolabeling yield of [99mTc]Tc-HYNIC-FAPI was (97.29 ± 0.46) %. The radiochemical purity was more than 90% and kept stable until 6 h. The radioligand was shown as lower lipophilicity, of which logD7.4 value was − 2.38 pm 0.13. In vitro experiments, the results indicated that the probe showed binding properties, and inhibited the migration of tumor cells. The novel [99mTc]Tc-HYNIC-FAPI probe was successfully radiosynthesized and exhibited good radiochemical purity, stability and in vitro binding ability to tumor cells. The [99mTc]Tc-HYNIC-FAPI will be a promising SPECT/CT imaging probe.

Imaging Recommendations for Diagnosis, Staging, and Management of Carcinoma of Unknown Origin (Lymph Node, Pulmonary, Liver, Skeletal, and Brain) with Emphasis on the Current Position of PET-CT in Carcinoma of Unknown Origin (CUP)

AbstractMost of the established guidelines mention and recommend the use of FDG-PET/CT (fluorodeoxyglucose positron emission tomography/computed tomography) in carcinoma of unknown primary (CUP) especially in head–neck squamous cell carcinoma; as described in this article, this forms a powerful one-stop shop in diagnosing and staging modality and has multiple applications in difficult situations of CUPs. Although not used as a screening modality, FDG-PET/CT is recommended as the primary imaging modality in the evaluation of primary, staging, and response evaluation for CUP with histology known to demonstrate FDG avidity, especially patients presenting with lymph nodal disease. It should be remembered that many histological types do not concentrate on FDG and FDG also shows false-positive results in many other conditions like infection-inflammation; however, at the same time, it delivers high negative predictive values, an important consideration when employing FDG-PET/CT in the CUP scenario. SSTR-based PET/CT plays a pivotal role in primary diagnosis, staging, therapy planning, and response assessment in CUPs with neuroendocrine tumor or neuroendocrine neoplasm histology. The last two decades has witnessed great advancement in PET instrumentation and radiopharmaceuticals: particularly techniques like PET/magnetic resonance imaging and radiopharmaceuticals like FAPI (fibroblast-activation protein inhibitor)-based PET tracers. Hence, the role of PET/CT is expected to expand its reach in the coming years in line with accruing literature evidence, thereby upgrading its role and reliability in oncological practice strategies.

Evaluation of Intestinal Fibrosis with 68Ga-FAPI PET/MR Enterography in Crohn Disease.

Background In Crohn disease, differentiation between active intestinal inflammation and fibrosis has implications for treatment, but current imaging modalities are not reliably accurate. Purpose To evaluate the predictive value of gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) PET/MR enterography for the assessment of bowel wall fibrosis in Crohn disease. Materials and Methods In this prospective single-center study, consecutive participants with Crohn disease and obstructive symptoms underwent preoperative 68Ga-FAPI PET/MR enterography from May 2021 to January 2022. Histopathologic analysis of resected bowel segments was performed to grade active inflammation (A0-A2) and fibrosis (F0-F2), which served as the reference standard. The fibroblast activation protein (FAP) expression in bowel wall layers was analyzed immunohistochemically for each layer. 68Ga-FAPI-derived maximum standardized uptake value (SUVmax) was compared with histopathologic results by using mixed-model analysis of variance and Bonferroni-corrected post hoc tests. Results In 14 participants (mean age, 45 years ± 9 [SD]; 10 men), fibrosis was diagnosed histopathologically in 28 of 51 bowel segments (grade F1, n = 14; grade F2, n = 14). Mean SUVmax was higher in segments with fibrosis than without (7.6 vs 2.0; P < .001). In severe fibrosis, mean SUVmax was higher than in mild to moderate fibrosis (8.9 ± 0.9 vs 6.2 ± 0.9; P = .045). Bowel segments with isolated active inflammation had lower mean 68Ga-FAPI uptake than segments with combined active inflammation and fibrosis (SUVmax, 3.2 ± 0.4 vs 8.1 ± 0.1; P = .005). With an SUVmax cutoff value of 3.5, the area under the receiver operating characteristic curve for the prediction of fibrosis was 0.94 (95% CI: 0.9, 1.0), with sensitivity of 26 of 28 segments (93%) and specificity of five of six segments (83%). 68Ga-FAPI-derived SUVmax correlated with FAP expression across all bowel layers (R2 = 0.50, P < .001). Conclusion Higher gallium 68 fibroblast activation protein inhibitor uptake at PET/MR enterography was associated with histopathologically assessed bowel wall fibrosis in participants with Crohn disease, suggesting diagnostic potential for treatment decisions. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by O'Shea in this issue.

68Ga-FAPI PET/CT for Rheumatoid Arthritis: A Prospective Study.

Background In rheumatoid arthritis (RA), fibroblast-like synoviocyte cells, which are involved in inflammation of the articular cartilage and bone, overexpress fibroblast activation protein (FAP). This is a feature that could be leveraged to improve imaging assessment of disease. Purpose To determine the performance of gallium 68 (68Ga)-labeled FAP inhibitor (FAPI) in assessing joint disease activity of RA and to compare with fluorine 18 (18F) fluorodeoxyglucose (FDG) imaging. Materials and Methods Twenty participants with RA (15 women; mean age, 55 years ± 10 [SD]) were prospectively enrolled from September 2020 to December 2021 and underwent clinical and laboratory assessment of disease activity and dual-tracer PET/CT (68Ga-FAPI and 18F-FDG) imaging. Imaging-derived variables of PET joint count (the number of joints positive for RA at PET) and PET articular index (a sum of the points of the joints using a three-point scale) were correlated to clinical and laboratory variables of disease activity. Results The combined output of both PET/CT techniques helped detect 244 affected joints, all of which showed positive results at 68Ga-FAPI PET/CT. However, fifteen of 244 (6.1%) FAPI-avid joints in six of 20 (30%) participants were not detected at 18F-FDG PET/CT. The maximum standardized uptake value of the most affected joint in each participant was higher in 68Ga-FAPI than in 18F-FDG PET/CT (9.54 ± 4.92 vs 5.85 ± 2.81, respectively; P = .001). The maximum standardized uptake values of the joints at both 68Ga-FAPI and 18F-FDG PET/CT were positively correlated with laboratory evaluation of C-reactive protein levels (r = 0.49 [P = .03] and 0.54 [P = .01], respectively). The PET joint count and PET articular index scores at 68Ga-FAPI PET/CT were also positively correlated with most clinical disease activity variables and radiographic progression of joint damage (P < .05). Conclusion In participants with rheumatoid arthritis who underwent gallium 68 fibroblast activation protein inhibitor PET/CT, the extent of joint involvement correlated with clinical and laboratory variables of disease activity and showed a greater amount and degree of affected joints than at fluorine 18 fluorodeoxyglucose PET/CT. Clinical trial registration no. NCT04514614 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Williams and Ahlman in this issue.

Q.Clear reconstruction for reducing the scanning time for 68Ga-DOTA-FAPI-04 PET/MR imaging.

This study aims to determine whether Q.Clear positron emission tomography (PET) reconstruction may reduce tracer injection dose or shorten scanning time in 68Gallium-labelled fibroblast activation protein inhibitor (68Ga-FAPI) PET/magnetic resonance (MR) imaging. We retrospectively collected cases of 68Ga-FAPI whole-body imaging performed on integrated PET/MR. PET images were reconstructed using three different methods: ordered subset expectation maximization (OSEM) reconstruction with full scanning time, OSEM reconstruction with half scanning time, and Q.Clear reconstruction with half scanning time. We then measured standardized uptake values (SUVs) within and around lesions, alongside their volumes. We also evaluated image quality using lesion-to-background (L/B) ratio and signal-to-noise ratio (SNR). We then compared these metrics across the three reconstruction techniques using statistical methods. Q.Clear reconstruction significantly increased SUVmax and SUVmean within lesions (more than 30%) and reduced their volumes in comparison with OSEM reconstruction. Background SUVmax also increased significantly, while background SUVmean showed no difference. Average L/B values for Q.Clear reconstruction were only marginally higher than those from OSME reconstruction with half-time. SNR decreased significantly in Q.Clear reconstruction compared with OSEM reconstruction with full time (but not half time). Differences between Q.Clear and OSEM reconstructions in SUVmax and SUVmean values within lesions were significantly correlated with SUVs within lesions. Q.Clear reconstruction was useful for reducing PET injection dose or scanning time while maintaining the image quality. Q.Clear may affect PET quantification, and it is necessary to establish diagnostic recommendations based on Q.Clear results for Q.Clear application.

Clinical prospective study of Gallium 68 (68Ga)-labeled fibroblast-activation protein inhibitor PET/CT in the diagnosis of biliary tract carcinoma.

This study is to investigate the [68Ga]Ga-DOTA-FAPI PET/CT diagnosis performance in biliary tract carcinoma (BTC) and analyze the association between [68Ga]Ga-DOTA-FAPI PET/CT and clinical indexes. A prospective study (NCT05264688) was performed between January 2022 and July 2022. Fifty participants were scanned using [68Ga]Ga-DOTA-FAPI and [18F]FDG PET/CT and acquired pathological tissue. We employed the Wilcoxon signed-rank test to compare the uptake of [68Ga]Ga-DOTA-FAPI and [18F]FDG, and the McNemar test was used to compare the diagnostic efficacy between the two tracers. Spearman or Pearson correlation was used to assess the association between [68Ga]Ga-DOTA-FAPI PET/CT and clinical indexes. In total, 47 participants (mean age 59.09 ± 10.98 [range 33-80years]) were evaluated. The [68Ga]Ga-DOTA-FAPI detection rate was greater than [18F]FDG in primary tumors (97.62% vs. 85.71%), nodal metastases (90.05% vs. 87.06%), and distant metastases (100% vs. 83.67%). The uptake of [68Ga]Ga-DOTA-FAPI was higher than [18F]FDG in primary lesions (intrahepatic cholangiocarcinoma, 18.95 ± 7.47 vs. 11.86 ± 0.70, p = 0.001; extrahepatic cholangiocarcinoma, 14.57 ± 6.16 vs. 8.80 ± 4.74, p = 0.004), abdomen and pelvic cavity nodal metastases (6.91 ± 6.56 vs. 3.94 ± 2.83, p < 0.001), and distant metastases (pleural, peritoneum, omentum, and mesentery, 6.37 ± 4.21 vs. 4.50 ± 1.96, p = 0.01; bone, 12.15 ± 6.43 vs. 7.51 ± 4.54, p = 0.008). There was a significant correlation between [68Ga]Ga-DOTA-FAPI uptake and fibroblast-activation protein (FAP) expression (Spearman r = 0.432, p = 0.009), carcinoembryonic antigen (CEA) (Pearson r = 0.364, p = 0.012), and platelet (PLT) (Pearson r = 0.35, p = 0.016). Meanwhile, a significant relationship between [68Ga]Ga-DOTA-FAPI metabolic tumor volume and carbohydrate antigen199 (CA199) (Pearson r = 0.436, p = 0.002) was confirmed. [68Ga]Ga-DOTA-FAPI had a higher uptake and sensitivity than [18F]FDG in the diagnosis of BTC primary and metastatic lesions. The correlation between [68Ga]Ga-DOTA-FAPI PET/CT indexes and FAP expression, CEA, PLT, and CA199 were confirmed. clinicaltrials.gov: NCT 05,264,688.

Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics—Where We Are at and Where We Are Heading: A Systematic Review

Cancer is the leading cause of death around the globe, followed by heart disease and stroke, with the highest mortality to this day. We have reached great levels of understanding of how these various types of cancer operate at a cellular level and this has brought us to what we call "precision medicine" where every diagnostic examination and the therapeutic procedure is tailored to the patient. FAPI is among the new tracers that can be used to assess and treat many types of cancer. The aim of this review was to gather all the known literature on FAPI theranostics. A MEDLINE search was conducted on four web libraries, PUBMED, Cochrane, Scopus, and Web of Sciences. All of the available articles that included both diagnoses and therapy with FAPI tracers were collected and put through the CASP (Critical Appraisal Skills Programme) questionnaire for systematic reviewing. A total of 8 records were deemed suitable for CASP review, ranging from 2018 to November 2022. These studies were put through the CASP diagnostic checklist, in order to assess the goal of the study, diagnostic and reference tests, results, descriptions of the patient sample, and future applications. Sample sizes were heterogeneous, both for size as well as for tumor type. Only one author studied a single type of cancer with FAPI tracers. Progression of disease was the most common outcome, and no relevant collateral effects were noted. Although FAPI theranostics is still in its infancy and lacks solid grounds to be brought into clinical practice, it does not show any collateral effects that prohibit administration to patients, thus far, and has good tolerability profiles.

Head-To-Head Comparison of 68Ga-FAPI PET/CT and FDG PET/CT for the Detection of Peritoneal Metastases: Systematic Review and Meta-Analysis.

BACKGROUND. FDG PET/CT has limited diagnostic performance in the detection of peritoneal metastasis (PM). Gallium-68-labeled fibroblast activation protein inhibitor (FAPI) targets tumor stroma, leading to high accumulation across cancer types. OBJECTIVE. The purpose of this study was to conduct a meta-analysis to compare the diagnostic performances of 68Ga-FAPI PET/CT and FDG PET/CT in detecting PM on the basis of studies providing head-to-head comparisons between the two tests. EVIDENCE ACQUISITION. PubMed, Embase, and Cochrane Library databases were searched through July 2022 to identify studies reporting head-to-head comparison of 68Ga-FAPI PET/CT and FDG PET/CT for detection of PM. The reference standard was classified as histopathology for all patients or as a combination of histopathologic, clinical, imaging, laboratory, and follow-up information (multidisciplinary reference standard). A random-effects statistical model was applied to conduct a meta-analysis of the diagnostic performances of the tests in patient-based and lesion-based analyses. The QUADAS-2 and QUADAS Comparative tools were used to assess study quality. EVIDENCE SYNTHESIS. Eleven studies were included. Patient-based analysis was reported in nine studies including 340 patients, and lesion-based analysis was reported in four studies including 222 lesions. The pooled sensitivity of 68Ga-FAPI PET/CT was significantly higher than that of FDG PET/CT in patient-based analysis (98.2% [95% CI, 96.1-100.0%] vs 55.9% [95% CI, 33.9-77.9%]) and lesion-based analysis (99.9% [95% CI, 99.5-100.0%] vs 27.3% [95% CI, 11.2-43.4%]). Eight studies were rated at high risk of bias in the reference standard domain because the multidisciplinary reference standard was not sufficiently explained and may have included one of the two index tests, which would have artificially increased sensitivity. In three studies specificity was reported as 100.0% for both tests; these studies were considered at uncertain risk of bias in the patient selection domain because patients with benign peritoneal conditions may have been excluded, resulting in underestimation of potential false-positive results. CONCLUSION. The current evidence suggests excellent sensitivity of 68Ga-FAPI PET/CT for the detection of PM in comparison with poorer sensitivity of FDG PET/CT. However, most included studies had high risk of bias. Further studies are needed to more convincingly characterize true- and false-positive results. CLINICAL IMPACT. The sensitivity of 68Ga-FAPI PET/CT may be substantially greater than that of FDG PET/CT for the evaluation of PM, facilitating surgical planning and candidate selection.

The Superiority of Fibroblast Activation Protein Inhibitor (FAPI) PET/CT Versus FDG PET/CT in the Diagnosis of Various Malignancies.

Cancer represents a major cause of death worldwide and is characterized by the uncontrolled proliferation of abnormal cells that escape immune regulation. It is now understood that cancer-associated fibroblasts (CAFs), which express specific fibroblast activation protein (FAP), are critical participants in tumor development and metastasis. Researchers have developed various FAP-targeted probes for imaging of different tumors from antibodies to boronic acid-based inhibitor molecules and determined that quinoline-based FAP inhibitors (FAPIs) are the most appropriate candidate as the radiopharmaceutical for FAPI PET/CT imaging. When applied clinically, FAPI PET/CT yielded satisfactory results. Over the past few years, the utility and effectiveness of tumor detection and staging of FAPI PET/CT have been compared with FDG PET/CT in various aspects, including standardized uptake values (SUVs), rate of absorbance and clearance. This review summarizes the development and clinical application of FAPI PET/CT, emphasizing the diagnosis and management of various tumor types and the future prospects of FAPI imaging.

Diagnostic performance of Ga-68 FAPI 04 PET/CT in colorectal malignancies.

To evaluate the role of Ga-68 fibroblast activation protein inhibitor 04 PET/computed tomography (FAPI) in colorectal cancers (CRCs) in terms of diagnostic accuracy and impact on clinical management. FAPI is compared with FDG PET/CT and conventional imaging in staging, restaging, recurrence detection, and response evaluation of CRC. Twenty-nine consecutive patients of histopathologically confirmed primary or relapsed CRC were included in the study. Patients who underwent FAPI PET/CT along with either FDG PET/CT or conventional imaging were included. Primary lesions, recurrence sites, lymph nodes, and metastatic lesions were recorded on all the scans. Maximum standardized uptake value (SUVmax) was measured from both primary and metastatic lesions. The sensitivity of FAPI in primary and recurrence detection is 100% compared to 88% for FDG/conventional imaging. The overall sensitivity of FAPI stands at 98% with accuracy at 95% whereas for FDG/conventional imaging the sensitivity and accuracy are 78% and 77%, respectively, with P < 0.002. Significant difference was noted in the detection of peritoneal metastasis (96% vs. 66%). FAPI PET/CT shows better sensitivity and accuracy in the evaluation of CRCs, especially in peritoneal disease compared to FDG PET/CT and conventional imaging. FAPI has the potential to replace FDG in CRCs.

Comparison of 68Ga-FAPI-04 and 18F-FDG PET/CT for diagnosis of metastatic lesions in patients with recurrent papillary thyroid carcinoma.

We aimed to evaluate the gallium-68-labeled fibroblast-activation protein inhibitor (68Ga-FAPI) positron emission tomography/computed tomography (PET/CT) in localizing papillary thyroid carcinoma (PTC) foci in patients with biochemical relapse. Papillary thyroid carcinoma has achieved biochemical recovery after appropriate treatment and had biochemical relapse in the last follow-up were included in this retrospective study. Gallium-68-FAPI and fluorine-18-fluorodeoxyglucose (68F-FDG) PET/CT were performed to detect recurrence foci. Biochemically relapsed patients who underwent total thyroidectomy and were diagnosed with pathologically differentiated thyroid cancer were included in our study. Gallium-68-FAPI and 18F-FDG PET/CT imaging methods were used to determine the focus of metastasis or recurrence in all patients. Among 29 patients enrolled to the study, pathological subgroups were papillary (n=26) and poorly differentiated (n=3) PTC. Anti-thyroglobulin (TG) antibody positivity were noted in 5 of the patients, while all 29 of them were TG positive and had been consist of three groups as follows: 2-10ng/mL (n=4), 11-300ng/mL (n=14), 301ng/mL and above (n=11). Recurrence was detected in 72.4% (n=21) and 86% (n=25) of the patients via 18F-FDG and 68Ga-FAPI, respectively. Accuracy of detection noted as 100% (5/5), 75% (3/4), and 92.9% (13/14) in groups with the anti-TG antibody positivity, TG levels of 2-10ng/mL and 11-300ng/mL, respectively, when the two imaging modalities were utilized together. Furthermore, accuracy of 68Ga-FAPI was 100% (11/11) in the group with TG levels of 301ng/mL and above, whereas accuracy of 18F-FDG was 81.8% (9/11). Lastly, median maximum standardized uptake value (SUVmax) of recurrent lesions detected by the 68Ga-FAPI (median SUVmax: 6.0) were statistically higher than the ones detected by the 18F-FDG (median SUVmax: 3.7) (P=0.002). In recurrent PTC especially in case of higher TG levels, 68Ga-FAPI can be used in patients with inconclusive 18F-FDG findings.

PET/CT with Fibroblast Activation Protein Inhibitors in Breast Cancer: Diagnostic and Theranostic Application-A Literature Review.

Growing studies have recently reported on the promising application of radiolabeled-fibroblast activation protein inhibitors (FAPIs) as diagnostic and therapeutic agents in various oncological populations. To exclusively evaluate the current evidence on the diagnostic and therapeutic role of FAPI radiotracers in patients with breast cancer (BC), a narrative review of the available literature was performed. A search algorithm from PubMed/MEDLINE, based on the combination of "PET" OR "positron emission tomography" and "FAPI" and "cancer", with a last update in February 2022, was applied. From 233 identified articles, 33 studies conducted in BC patients and with available data on PET imaging or radiolabeled-FAPI therapy were finally considered, for a total of 191 patients. Despite some clinical and methodological heterogeneity among the reviewed articles, 68Ga-FAPI PET/CT emerges as a valuable diagnostic tool in BC patients both at staging and restaging, also demonstrating several technical advantages and an overall better performance than 18F-FDG, especially in histotypes with well-known low 18F-FDG avidity. Moreover, although with still limited clinical evidence in BC, radiolabeled FAPIs emerge as promising therapeutic agents in a theranostic perspective, increasing the possibility of more personalized treatments. From these results, future research directions on FAPI radiotracers application in BC patients are suggested.