Fibroblast Activation Protein Inhibitor Research Articles

Comparison of [18F]FAPI-42 and [18F]FDG PET/CT in the evaluation of systemic vasculitis.

The role of fibroblast activation protein (FAP)-targeted imaging in systemic vasculitis is currently unclear. We aimed to evaluate the clinical value of fluorine-18-labeled FAP inhibitor 42 ([18F]FAPI-42) in patients with systemic vasculitis and to compare with [18F]fluorodeoxyglucose (FDG) imaging. Patients with systemic vasculitis who underwent dual-tracer PET/CT([18F]FDG and [18F]FAPI) imaging from September 2020 to March 2022 were retrospectively analyzed. Positive lesions are defined as vascular/extravascular lesions with increased tracer uptake above surrounding background, which cannot be attributed to the physiologic biodistribution of the radiotracer. The vascular/extravascular lesion detection rate and semiquantitative values (SUVmax, TBRblood and TBRliver) of [18F]FAPI and [18F]FDG were compared, and the correlation between the extent and range of tracer uptake and levels of inflammatory markers was investigated. Thirty patients (13 males and 17 females; mean age, 52.5 ± 17.2 years) with systemic vasculitis were included (17 large vessel vasculitis, 10 anti-neutrophil cytoplasmic antibody-associated vasculitis, 2 Behcet's disease and 1 polyarteritis nodosa). [18F]FDG PET/CT had positive findings in 93.3% (28/30) of patients, while [18F]FAPI PET/CT had positive findings in all patients (100%, P = 0.500). Compared with [18F]FDG PET/CT, [18F]FAPI PET/CT detected more lesions (161/168 vs. 145/168, P = 0.005), and more extensive vascular involvement in 60% (18/30) of patients. Although SUVmax did not differ significantly between [18F]FAPI and [18F]FDG (median, 5.94 vs. 5.46, P = 0.517), [18F]FAPI had higher TBRliver (median, 9.59 vs. 3.15, P < 0.001) and TBRblood (median, 5.45 vs. 4.20, P = 0.006). The total number of positive lesions in FAPI PET/CT show a moderate correlation with erythrocyte sedimentation rate (rs =0.478, P = 0.008) and C-reactive protein (rs =0.486, P = 0.006). After treatment, follow-up FAPI PET/CT of 6 patients showed decreased SUVmax, TBR and number of detected lesions, paralleling the clinical remission. [18F]FAPI PET/CT imaging is a promising imaging modality for the diagnosis and therapeutic monitoring of systemic vasculitis.

Recent advances in nuclear medicine and their role in inflammatory arthritis: focus on the emerging role of FAPI PET/CT

AbstractImaging molecular processes associated with inflammatory disease has been revolutionized by hybrid imaging using positron emission tomography/computed tomography (PET/CT). PET/CT visualizes metabolic activity as well as protein expression and provides a comprehensive whole-body evaluation. It has the potential to reveal inflammation prior to detection of structural changes in inflammatory joint diseases. FAP is a type II transmembrane glycoprotein overexpressed not only in the stroma of tumors but also in the fibrotic processes of certain immune-mediated disorders. The recent introduction of fibroblast activation protein inhibitors (FAPI) labeled by positron emitters and thus suitable for PET/CT allows to investigate FAP expression in vivo. This review will focus on the use of FAPI-PET/CT for the diagnosis and evaluation of treatment response in inflammatory joint diseases.

Unveiling the Tumor Microenvironment Through Fibroblast Activation Protein Targeting in Diagnostic Nuclear Medicine: A Didactic Review on Biological Rationales and Key Imaging Agents

The tumor microenvironment (TME) is a dynamic and complex medium that plays a central role in cancer progression, metastasis, and treatment resistance. Among the key elements of the TME, cancer-associated fibroblasts (CAFs) are particularly important for their ability to remodel the extracellular matrix, promote angiogenesis, and suppress anti-tumor immune responses. Fibroblast activation protein (FAP), predominantly expressed by CAFs, has emerged as a promising target in both cancer diagnostics and therapeutics. In nuclear medicine, targeting FAP offers new opportunities for non-invasive imaging using radiolabeled fibroblast activation protein inhibitors (FAPIs). These FAP-specific radiotracers have demonstrated excellent tumor detection properties compared to traditional radiopharmaceuticals such as [18F]FDG, especially in cancers with low metabolic activity, like liver and biliary tract tumors. The most recent FAPI derivatives not only enhance the accuracy of positron emission tomography (PET) imaging but also hold potential for theranostic applications by delivering targeted radionuclide therapies. This review examines the biological underpinnings of FAP in the TME, the design of FAPI-based imaging agents, and their evolving role in cancer diagnostics, highlighting the potential of FAP as a target for precision oncology.

Emerging Radiopharmaceuticals in Pet Imaging for Mesothelioma: A Review of [18F]FDG Alternatives.

Mesothelioma is a malignant tumor associated primarily with asbestos exposure, characterized by an aggressive nature and poor prognosis. Accurate diagnosis, staging, and monitoring of therapeutic response are crucial for effective patient management. Along with a computed tomography (CT) scan, fluorodeoxyglucose labeled with fluorine-18 ([18F]FDG) positron emission tomography (PET) is commonly used in mesothelioma evaluation. However, it has some limitations, including lower sensitivity after pleurodesis and poor accuracy for involved lymph node evaluation. Thus, there is the need to explore other agents. The aim of the present review is to analyze the current literature on the use of alternative radiopharmaceuticals for PET imaging in patients with mesothelioma. A comprehensive search of scientific databases (PubMed, Scopus, and Web of Science) for studies published in the last decade was performed by using the following keywords: "mesothelioma" AND "PET" AND "PET/CT" "radiopharmaceuticals", "[18F]FDG alternatives". Articles focused solely on [18F]FDG, non-English publications or preclinical studies, reviews, meeting abstracts, letters to the editors, and editorials were excluded. A qualitative assessment was made by using the Critical Appraisal Skills Programme (CASP) checklist for diagnostic test studies, when applicable. In total, 14 papers were selected; in seven articles more than five patients were enrolled, while the other seven were only clinical cases (enrolling up to two subjects). [18F]/gallium-68 ([68Ga])-labeled fibroblast activation protein inhibitor (FAPI) compounds, [18F]Fluorothymidine ([18F]FLT), methionine labeled with carbon-11 ([11C]MET), and fluoromisonidazole labeled with fluorine-18 ([18F]FMISO) PET/CT were the alternative agents used most often. In 12 articles, [18F]FDG PET/CT was used as a comparator imaging modality. Detection rate of [18F]FDG was similar to the other radiopharmaceuticals ([68Ga]/[18F]-labeled FAPI compounds, [18F]FLT, [18F]FMISO, [11C]MET, and [68Ga]-Pentaxifor), although radiolabeled FAPI seems to exhibit a higher diagnostic performance. [18F]FDG is still a valuable agent in patients with mesothelioma. However, radiolabeled FAPI appears to be promising and its theranostic properties should therefore be further assessed.

Exploring the FAP-Targeted Therapeutics for Adrenocortical Carcinoma: Choosing the Right Track.

Metastatic or recurrent adrenocortical carcinoma is a potentially lethal malignancy, presenting significant challenges in disease management owing to absence of effective systemic treatments. Significantly diminished survival rates necessitate rapid identification of specific molecules for the development of targeted therapeutics. Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts have been a major breakthrough causing a paradigm shift in targeted theranostics focusing on the tumor microenvironment. The effectiveness of various FAP inhibitors (FAPis) and FAP targeting peptide has been extensively documented in diverse clinical investigations. We have evaluated 3 molecules, that is, DOTA.SA.FAPi (SA.FAPi), FAPi46, and FAP2286, as potential theranostic probes for adrenocortical carcinoma.

Feasibility of Early 68Ga-FAP-2286 PET Imaging: A Case Study.

Fibroblast activation protein (FAP) has emerged as a promising molecular target for diagnostic and therapeutic strategies. Previous research, including our own study and other published reports, has highlighted the potential of FAP inhibitors labeled with 68Ga as effective diagnostic radiopharmaceuticals. In this study, we present a comparative analysis of early and late PET/CT scans, using 68Ga-FAP-2286, for the detection of tumor lesions in a patient with metastatic breast adenocarcinoma.

O09 Correlation between Fibroblast Activation Protein inhibitor (99mTc-FAPi/SPECT) and histology in patients submitted to Retroperitoneal Lymph Node Dissection (RPLND) with residual post-chemotherapy disease in Non-Seminomatous Germ Cell Tumors (NSGCT)

O09 Correlation between Fibroblast Activation Protein inhibitor (99mTc-FAPi/SPECT) and histology in patients submitted to Retroperitoneal Lymph Node Dissection (RPLND) with residual post-chemotherapy disease in Non-Seminomatous Germ Cell Tumors (NSGCT)

Assessing the Value of 68Ga-FAPI PET/CT in Gastric Mucinous Adenocarcinoma or Signet Ring Cell Carcinoma.

Purpose To investigate the clinical impact and prognostic value of gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) PET/CT in gastric mucinous adenocarcinoma (MAC) and signet ring cell carcinoma (SRCC). Materials and Methods Eighty-six participants with newly diagnosed or recurrent gastric MAC or SRCC were prospectively enrolled from April 2021 to October 2021 and underwent both fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT and 68Ga-FAPI PET/CT. The sensitivity, specificity, and accuracy of the two scans in primary and metastatic tumors were evaluated using the McNemar test. Changes of treatment strategies were recorded to compare the treatment management value of the two PET/CT scans. The maximum standardized uptake value (SUVmax) and peritoneal cancer index (PCI) were recorded for survival analysis. Progression-free survival (PFS) was defined as the time interval from the date of PET/CT scans to the date of disease progression. Results Eighty-six participants (median age, 62 years [IQR, 45-78 years]; 49 female) were evaluated. 68Ga-FAPI PET/CT showed higher diagnostic accuracy in detecting involved lymph nodes (87% [212 of 244] vs 71% [173 of 244], P < .001) and peritoneal metastases (96% [70 of 73] vs 55% [40 of 73], P < .001) than 18F-FDG PET/CT. Twenty-six participants (30% [26 of 86]) had treatment changes due to more accurate diagnosis with 68Ga-FAPI PET/CT. Additionally, the 68Ga-FAPI PCI was an independent predictor for PFS (hazard ratio, 6.9; 95% CI: 2.1, 23.1; P = .002). Conclusion 68Ga-FAPI PET/CT had higher accuracy in diagnosis of gastric MAC/SRCC compared with 18F-FDG PET/CT and demonstrated the potential to improve treatment strategies and predict prognosis. Keywords: PET/CT, Mucinous Adenocarcinoma, Signet Ring Cell Carcinoma, Oncology, Abdomen/GI, Molecular Imaging Supplemental material is available for this article. © RSNA, 2024.

Non-Fluorine 18 Fluorodeoxyglucose-Avid Bone Marrow Metastases at Gallium 68 Fibroblast Activation Protein Inhibitor PET/CT.

Non-Fluorine 18 Fluorodeoxyglucose-Avid Bone Marrow Metastases at Gallium 68 Fibroblast Activation Protein Inhibitor PET/CT.

Theranostics: Timing is Everything.

On stage, and in real life, timing is critical for success. Theranostic cancer care epitomizes the central role of timing in the evolution of efficacious molecular targeted radioligand therapy and its incorporation into routine clinical practice of oncology. Nuclear medicine has returned to its therapeutic roots, having been founded as a medical specialty, over three-quarters of a century ago, with radioiodine therapy of thyroid cancer. The very recent oncologist acceptance of 68Ga/177Lu/225Ac-PSMA effectiveness in treating prostate cancer has re-established the role of the physician in nuclear medicine. This article addresses various important issues in respect of timing related to this resurgence. Training of the required new workforce in technical -omics expertise and physicianly virtues is an urgent priority. Precision in radioligand therapy requires definition of individual radiation absorbed dose (Gy) to tumor and to critical normal organs, preferably prospectively. It is time to abandon one-size-fits-all administration of fixed activities (GBq) in arbitrary cycle intervals and duration. The time has also come to design combination sequenced theranostic-immuno-chemotherapeutic approaches to metastatic cancer to address unmet needs, particularly in pancreatic carcinoma; exploiting the potential of new fibroblast activation protein inhibitor radioligands targeting the tumor microenvironment. Public perception of all things "nuclear," including nuclear medicine, has recently recovered from the general opprobrium and radiophobia of the last half-century. Nuclear is the new green. At last, there have arisen propitious circumstances for the future development of theranostics: The timing is right, now.

Feasibility, Tolerability, and Preliminary Clinical Response of Fractionated Radiopharmaceutical Therapy with 213Bi-FAPI-46: Pilot Experience in Patients with End-Stage, Progressive Metastatic Tumors.

Radiopharmaceutical therapies (RPTs) based on fibroblast activation protein (FAP) and FAP inhibitors (FAPIs) are a new option for progressive metastatic cancer in patients pretreated multiple times. To date, published in-human data refer to initial experiences with β-emitting 90Y- and 177Lu-based RPT. However, the short tumor retention time of FAPI ligands is considered a major limitation of FAPI RPT. Therefore, fractionated FAPI RPT with 213Bi, an α-emitter with a half-life of 46 min, appears to be a promising FAPI RPT regimen. Here, we report on our initial experiences with regard to the feasibility, tolerability, and response of fractionated 213Bi-FAPI-46 RPT. Methods: Six patients (4 women and 2 men) with progressive metastatic solid tumors (3 colon cancer, 1 anal cancer, 1 breast cancer, and 1 prostate cancer) aged 16-77 y were treated with a mean of 1,609 MBq of 213Bi-FAPI-46, fractionated into 53 single applications (range, 5-12 RPT applications per patient; mean, 8.8 applications) over a period of up to 107 h per patient. Of the 6 patients, 4 patients received adjuvant treatment with pembrolizumab. 18F-FDG (4 patients) and 68Ga-FAPI-46 (5 patients) PET/CT scans were performed before and after RPT. PET images were assessed visually and by calculating total lesion glycolysis and total lesion FAPI. Results: RPT with 213Bi-FAPI-46 was well tolerated without adverse side effects. In terms of visual response assessment, there was 1 partial response (16.7%), 1 patient with stable disease (16.7%), and 4 patients with progressive disease (66.7%). Concordantly, total lesion glycolysis and total lesion FAPI were decreased in the responding patient (not applicable and -24.3%, respectively), slightly decreased in the patient with stable disease (-10.6% and -5.9%, respectively), and increased in the 4 patients with progression (mean, +104.4% and +321.3%, respectively). Conclusion: Fractionated FAPI RPT with the short-half-life α-emitter 213Bi-FAPI-46 is a promising approach that matches the pharmacokinetics of FAPI-46 better than the 177Lu- or 90Y-labeled compounds. In this pilot project, fractionated RPT with 213Bi-FAPI-46 showed good clinical tolerability and even led to regressive or stable disease in the short term in 2 of 6 patients. Further studies with larger patient cohorts are required to evaluate the actual efficacy and long-term effects of this variant of FAPI RPT.

Predicting Malignancy in Adnexal Tumors With FAPI PET/CT and FDG PET/CT: A Case Report on a Borderline Ovarian Tumor.

A 54-year-old woman presented with a 55 × 64-mm tumor in the ovary with high [18F]FDG uptake on [18F]FDG PET/CT highly suggestive of ovarian cancer. Prior to surgery, the patient underwent [68Ga]-Ga- fibroblast activation protein inhibitor (FAPI)-46 PET/CT, which revealed low [68Ga]-Ga-FAPI-46 tumor uptake. Histopathology revealed a borderline ovarian tumor, which has low malignant potential and a 10-year survival rate greater than 93%. High [18F]FDG uptake is considered a fair predictor of malignancy in adnexal tumors. The present case demonstrates the potential superiority of [68Ga]-Ga-FAPI-46 PET/CT over [18F]-FDG PET/CT in differentiating malignant adnexal tumors from borderline ovarian tumors.

FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study.

Prostate-specific membrane antigen (PSMA) is a theranostic target for metastatic prostate cancer (PCa). However, castration-resistant PCa (CRPC) may lose PSMA expression after systemic therapy. Fibroblast activation protein (FAP), expressed by carcinoma-associated fibroblasts in various cancer types, including PCa, has the potential to be an alternative target. In this study, we evaluated FAP expression in CRPC to assess its potential, using PSMA as a comparison. Methods: FAP expression was assessed using immunohistochemistry in 116 CRPC tumors: 78 adenocarcinomas, 11 small cell carcinomas, and 27 anaplastic carcinomas. Correlation analysis between manual scoring and automated scoring was performed on 54 whole-slide sections of metastatic CRPC. Paired FAP and PSMA stains were assessed in tissue microarray cores of CRPC (n = 62), consisting of locally advanced CRPC (n = 9) and metastatic CRPC (n = 53). FAP and PSMA positivity was defined by an immunohistochemistry score of at least 10. To explore the correlation of PSMA and FAP inhibitor (FAPi) PET imaging and immunohistochemistry, a preliminary analysis of 4 patients included in a [68Ga]-FAPi-46 imaging trial (NCT04457232) was conducted. Results: Manual and automated scoring of FAP yielded results with strong correlations. Overall, FAP expression in CRPC was notably lower than PSMA expression (median immunoscores, 14 vs. 72; P < 0.001). Different histologic subtypes of CRPC demonstrated distinct levels of PSMA expression, whereas their FAP expression levels were comparable. Among the 19 PSMA-negative tumors, 11 (58%) exhibited FAP positivity. FAP expression levels in lymph node metastases were significantly lower than those in nonnodal metastases (P = 0.021). Liver metastases showed significant enrichment of tumors with strong FAP expression compared with nonliver lesions (P = 0.016). In the 4 clinical trial patients, the biopsied metastatic lesions showed lower uptake on FAPi PET than on PSMA PET (median SUVmax, 9.6 vs. 14.5), consistent with FAP expression that was lower than PSMA expression in the corresponding tumor biopsy samples (median immunoscores, 30 vs. 160). Conclusion: Because of the low FAP expression levels in CRPC, the utility of FAPi PET imaging may be limited. Although FAPi PET imaging may be further tested in PSMA-negative CRPC, such as small cell carcinoma, other molecular imaging modalities should be evaluated as alternative choices.

CTR-FAPI PET enables precision management of medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but 29-60% patients failed to localize the disease in the current clinical practice. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]FDG PET-CT in 50 MTC patients. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, p=0.0002). This improved detection was attributed to increased tumor uptake (SUVmax 11.71±9.16 vs. 2.55±1.73, p<0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared to [18F]FDG (96.7% vs. 43.3%, p<0.0001). Notably, 32% patients altered management following [68Ga]Ga-CTR-FAPI PET-CT, and 66.7% patients changed their surgical plan. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared to [18F]FDG PET-CT, enabling precision management of MTC patients.

Recent Updates of PET in Lymphoma: FDG and Beyond.

Lymphoma is one of the most common cancers worldwide, categorized into Hodgkin lymphoma and non-Hodgkin lymphoma. 18F-fluorodeoxyglucose positron emission tomography (FDG PET) has become an essential imaging tool for evaluating patients with lymphoma in terms of initial diagnosis, staging, prognosis, and treatment response assessment. Recent advancements in imaging technology and methodologies, along with the development of artificial intelligence, have revolutionized the evaluation of complex imaging data, enhancing the diagnostic and predictive power of PET in lymphoma. However, FDG is not cancer-specific, but it primarily reflects glucose metabolism, which has prompted the investigation of alternative PET tracers to address this limitation. Novel PET radiotracers, such as fibroblast activation protein inhibitors targeting the tumor microenvironment, have recently shown promising results in evaluating various malignancies compared to FDG PET. Furthermore, with the rapid advancements in immunotherapy and the favorable imaging properties of 89Zr, immunoPET has emerged as a promising modality, offering insights into the functional and molecular status of the immune system. ImmunoPET can also facilitate the development of new antibody therapeutics and radioimmunotherapy by providing pharmacokinetic and pharmacodynamic data. This review provides comprehensive insights into the current clinical applications of FDG PET in lymphoma, while also exploring novel PET imaging radiotracers beyond FDG, discussing their mechanisms of action and potential impact on patient management.

Rational modifications on N-(4-quinolinoyl)-Gly-2-cyanopyrrolidine to develop fibroblast activation protein-targeted radioligands with improved affinity and tumor uptake

Fibroblast activation protein (FAP) has been an attractive target for cancer imaging and therapy. Radiolabeled FAP-targeting ligands have shown promising results for clinical applications. However, further improvements are ongoing in pursuit of increasing tumor uptake, prolonging tumor residence, and maintenance good tumor–to–background contrast for extensive theranostic application. Achieving a higher affinity of the precursor is one of the ways in research. In this study, we designed a series of FAP inhibitors based on N-(4-quinolinoyl)-Gly-2-cyanopyrrolidine and found compound QI-18 with an IC50 value of 0.50 nM, which is a 6.5-fold increase in potency over that of UAMC-1110 (IC50 of 3.25 nM). QI-18 was then functionalized with a DOTA chelator to obtain the ligand CY03 for further radiolabeling with 68Ga to obtain the radiotracer [68Ga]Ga-CY03. In BALB/c nude mice bearing U87MG tumor models, [68Ga]Ga-CY03 exhibited a high and specific uptake (10.30 ± 0.63 % ID/g at 1 h post-injection and 9.28 ± 1.60 % ID/g at 2 h post-injection), which represented 3.2- and 4.1-fold increases over those for [68Ga]Ga-FAPI-04 (3.24 ± 0.53 % ID/g and 2.25 ± 0.33 % ID/g, respectively). [68Ga]Ga-CY03 also showed higher tumor–to–blood and tumor–to–kidney ratios (7.62 ± 0.44 and 2.59 ± 0.27, respectively) than [68Ga]Ga-FAPI-04 (2.38 ± 0.47 and 0.98 ± 0.19, respectively). The results indicate that [68Ga]Ga-CY03 is a promising imaging agent to target FAP.

Evaluation of Targeted Alpha Therapy Using [211At]FAPI1 in Triple-Negative Breast Cancer Xenograft Models.

Triple-negative breast cancer (TNBC) presents limited therapeutic options and is associated with poor prognosis. Early detection and the development of novel therapeutic agents are therefore imperative. Fibroblast activation protein (FAP) is a membrane protein expressed on cancer-associated fibroblasts (CAFs) that plays an essential role in TNBC proliferation, migration, and invasion. Consequently, it is hypothesized that the Astatine (211At)-labeled FAP inhibitor (FAPI) selectively exerts anti-tumor effects through alpha-particle emission. In this study, we aimed to assess its theranostic capabilities by integrating [18F]FAPI-74 PET imaging with targeted alpha therapy using [211At]FAPI1 in TNBC models. Mice xenografts were established by transplanting MDA-MB-231 and HT1080 cells (control). As a parallel diagnostic method, [18F]FAPI-74 was administered for PET imaging to validate FAP expression. A single dose of [211At]FAPI1 (1.04 ± 0.10 MBq) was administered to evaluate the therapeutic efficacy. [18F]FAPI-74 exhibited high accumulation in MDA-MB-231 xenografts, and FAP expression was pathologically confirmed via immunostaining. The group that received [211At]FAPI1 (n = 11) demonstrated a significantly enhanced anti-tumor effect compared with the control group (n = 7) (p = 0.002). In conclusion, [18F]FAPI-74 PET imaging was successfully used to diagnose FAP expression, and as [211At]FAPI1 showed promising therapeutic efficacy in TNBC models, it is expected to be a viable therapeutic option.

Valvular and myocardial fibroblast activation in aortic stenosis: a prospective positron emission tomography study

Abstract Introduction In patients with aortic stenosis, fibrosis is a common pathophysiological feature of leaflet thickening as well as left ventricular decompensation as it transitions from hypertrophy to heart failure. Valvular fibrosis can be quantified by contrast-enhanced computed tomography, and myocardial fibrosis by late gadolinium enhancement on magnetic resonance imaging, but neither can detect the activity of fibrosis and extracellular matrix remodelling. Gallium-68 Fibroblast Activation Protein Inhibitor (68Ga-FAPI) binds to activated fibroblasts, the key effector cell of fibrogenesis, and provides a measure of fibroblast activation and fibrosis activity. We aimed to measure fibrosis activity in the aortic valve and left ventricular myocardium of patients with aortic stenosis using 68Ga-FAPI uptake. Methods In a prospective observational cohort, patients with aortic stenosis and control subjects with normal aortic valves underwent transthoracic echocardiography, 68Ga-FAPI positron emission tomography, computed tomography, and magnetic resonance imaging. Valvular and myocardial 68Ga-FAPI uptake was quantified using the target-to-background ratio (TBRmax). Valvular non-calcific volume was quantified on computed tomography and replacement myocardial fibrosis was quantified by late gadolinium enhancement on magnetic resonance imaging. Results Fifty patients with aortic valve disease (9 with aortic sclerosis, and 7 with mild, 23 with moderate and 11 with severe aortic stenosis; 72±8 years, 70% male) and 4 control subjects (66±7 years, 50% male) participated. Increased 68Ga-FAPI uptake was observed in the aortic valves of patients with aortic sclerosis and stenosis and peaked in those with moderate disease (Figure 1). TBRmax of 68Ga-FAPI uptake correlated with the aortic valve non-calcific volume (r=0.354, p&amp;lt;0.05) on computed tomography. Thirty-one patients (62%) had myocardial 68Ga-FAPI uptake, of whom half (n=17; 34%) also had late gadolinium enhancement corresponding to the region of 68Ga-FAPI uptake (Figure 2). Myocardial 68Ga-FAPI uptake correlated with increased indexed left ventricular mass (r=0.333, p&amp;lt;0.05) and left ventricular wall thickness (r=0.385, p&amp;lt;0.05). Conclusions For the first time, we have identified both valvular and myocardial fibrosis activity in patients with aortic stenosis. Valvular fibroblast activation is increased in patients with aortic sclerosis and stenosis, peaking in patients with moderate disease and correlating with leaflet thickening. Myocardial fibroblast activation is seen in the majority of patients with aortic stenosis both in areas with and without established fibrosis, and is associated with indices of adverse left ventricular remodelling. Activated fibroblasts are thus an important potential treatment target in the valve and myocardium, with 68Ga-FAPI positron emission tomography holding major promise in better understanding the pathophysiology, progression and consequences of aortic stenosis.

Same-Day Positron Emission Tomography/Computed Tomography with 68Ga-Radiolabeled Fibroblast Activation Protein Inhibitors and 18F-Fluorodeoxyglucose Imaging for Gastrointestinal Cancers.

Objective: We investigated the clinical practicability of same-day 68Ga-radiolabeled fibroblast activation protein inhibitors (68Ga-FAPI)-first and 18F-fluorodeoxyglucose (18F-FDG) imaging and compared it with same-day 18F-FDG-first or 2-day procedures in diagnosing gastrointestinal cancers. Materials and Methods: Sixty-five patients with confirmed gastrointestinal cancers were divided into same-day 68Ga-FAPI-first group (Group A), same-day 18F-FDG-first group (Group B), and 2-day group (Group C). Low-dose CT and low injection activity were performed on 68Ga-FAPI positron emission tomography/computed tomography (PET/CT). Interval times, radiation dose, diagnostic performance, and detectability were assessed among groups. Additionally, the uptake, tumor-to-liver ratio (TLR), diagnostic efficacy, and TNM stage were compared between the two modalities. Results: The total waiting time for Group C was significantly longer than that for Group A or B (both p < 0.001). The total dose-length product and effective dose decreased in all groups. There were comparable detectability and diagnostic performance among groups (all p > 0.05). The within-group analysis in Group B indicated that 68Ga-FAPI PET/CT had higher uptake in the primary and recurrent lesions than 18F-FDG without differences in TLR, due to higher liver background on 68Ga-FAPI PET than Group A or C (both p < 0.001).68Ga-FAPI PET/CT possessed higher accuracy than 18F-FDG and changed staging in 14 patients (14/65, 21.54%). Conclusions: The same-day 68Ga-FAPI-first and 18F-FDG imaging reduced examination waiting time without increased radiation dose, simultaneously achieving excellent diagnostic performance and improving clinical staging in diagnosing gastrointestinal cancers.

A Rare Case of Orbital Metastasis from Invasive Lobular Carcinoma: Challenges of 18F-FDG PET/CT and the Search for Consensus on Imaging.

Invasive lobular carcinoma (ILC) frequently underlies orbital metastasis. A 74-y-old woman, who was current with mammograms and had no cancer history, presented to her ophthalmologist with visual complaints and was found to have metastatic ILC. MRI was contraindicated, and an 18F-FDG PET/CT scan revealed a mildly hypermetabolic right orbital mass and low uptake in the left subareolar breast, suggestive of metastatic ILC. Small studies have found that in ILC, 16α-18F-fluoroestradiol and fibroblast activation protein inhibitors are more avid than 18F-FDG. There is currently no consensus regarding imaging for ILC. Many people have contraindications to MRI, and the higher rate of false-negative findings on mammography for ILC than for other breast cancers makes this patient population more vulnerable to inaccurate staging, incorrect assessment of tumor burden, and, consequently, insufficient treatment. We provide this interesting case to highlight the potential of 18F-fluoroestradiol PET/CT and fibroblast activation protein inhibitors over 18F-FDG in this breast cancer subtype.