Tumor suppressor FRMD3 controls mammary epithelial cell fate determination via notch signaling pathway.

The luminal-to-basal transition in mammary epithelial cells (MECs) is accompanied by changes in epithelial cell lineage plasticity; however, the underlying mechanism remains elusive. Here, we report that deficiency of Frmd3 inhibits mammary gland lineage development and induces stemness of MECs, subsequently leading to the occurrence of triple-negative breast cancer. Loss of Frmd3 in PyMT mice results in a luminal-to-basal transition phenotype. Single-cell RNA sequencing of MECs indicated that knockout of Frmd3 inhibits the Notch signaling pathway. Mechanistically, FERM domain-containing protein 3 (FRMD3) promotes the degradation of Disheveled-2 by disrupting its interaction with deubiquitinase USP9x. FRMD3 also interrupts the interaction of Disheveled-2 with CK1, FOXK1/2, and NICD and decreases Disheveled-2 phosphorylation and nuclear localization, thereby impairing Notch-dependent luminal epithelial lineage plasticity in MECs. A low level of FRMD3 predicts poor outcomes for breast cancer patients. Together, we demonstrated that FRMD3 is a tumor suppressor that functions as an endogenous activator of the Notch signaling pathway, facilitating the basal-to-luminal transformation in MECs.

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade.

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.

Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome.

In glucose transporter 1 deficiency syndrome (Glut1DS), glucose transport into brain is reduced due to impaired Glut1 function in endothelial cells at the blood-brain barrier. This can lead to shortages of glucose in brain and is thought to contribute to seizures. Ketogenic diets are the first-line treatment and, among many beneficial effects, provide auxiliary fuel in the form of ketone bodies that are largely metabolized by neurons. However, Glut1 is also the main glucose transporter in astrocytes. Here, we review data indicating that glucose shortage may also impact astrocytes in addition to neurons and discuss the expected negative biochemical consequences of compromised astrocytic glucose transport for neurons. Based on these effects, auxiliary fuels are needed for both cell types and adding medium chain triglycerides (MCTs) to ketogenic diets is a biochemically superior treatment for Glut1DS compared to classical ketogenic diets. MCTs provide medium chain fatty acids (MCFAs), which are largely metabolized by astrocytes and not neurons. MCFAs supply energy and contribute carbons for glutamine and γ-aminobutyric acid synthesis, and decanoic acid can also block α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. MCTs do not compete with metabolism of ketone bodies mostly occurring in neurons. Triheptanoin, an anaplerotic but also gluconeogenic uneven MCT, may be another potential addition to ketogenic diets, although maintenance of "ketosis" can be difficult. Gene therapy has also targeted both endothelial cells and astrocytes. Other approaches to increase fuel delivery to the brain currently investigated include exchange of Glut1DS erythrocytes with healthy cells, infusion of lactate, and pharmacological improvement of glucose transport. In conclusion, although it remains difficult to assess impaired astrocytic energy metabolism in vivo, astrocytic energy needs are most likely not met by ketogenic diets in Glut1DS. Thus, we propose prospective studies including monitoring of blood MCFA levels to find optimal doses for add-on MCT to ketogenic diets and assessing of short- and long-term outcomes.

Occult SMARCA4-Deficient Undifferentiated Carcinoma Unmasked by 68 Ga-FAPI-46 PET/CT.

ABSTRACT: SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) are rare and aggressive neoplasms commonly found in male smokers and portend a poor prognosis. In this case, we reported 18 F-FDG and 68 Ga-FAPI-46 PET/CT findings in an occult SMARCA4-dUT located in the left pulmonary hilum along with mediastinal lymph node metastases. 68 Ga-FAPI-46 PET/CT showed superiority over 18 F-FDG for detecting SMARCA4-dUT lesions. This case highlighted that 68 Ga-FAPI-46 PET/CT may be a promising imaging modality in the evaluation of SMARCA4-dUT, particularly for detecting the occult SMARCA4-dUT arising in uncommon sites.

Performance of Fluxgate Magnetometer with Cu-Doped CoFeSiB Amorphous Microwire Core.

In this study, we investigated the effects of Cu doping on the performance of CoFeSiB amorphous microwires as the core of a fluxgate magnetometer. The noise performance of fluxgate sensors primarily depends on the crystal structure of constituent materials. CoFeSiB amorphous microwires with varying Cu doping ratios were prepared using melt-extraction technology. The microstructure of microwire configurations was observed using transmission electron microscopy, and the growth of nanocrystalline was examined. Additionally, the magnetic performance of the microwire and the noise of the magnetic fluxgate sensors were tested to establish the relationship between Cu-doped CoFeSiB amorphous wires and sensor noise performance. The results indicated that Cu doping triggers a positive mixing enthalpy and the reduced difference in the atomic radius that enhances the degree of nanocrystalline formation within the system; differential scanning calorimetry analysis indicates that this is due to Cu doping reducing the glass formation capacity of the system. In addition, Cu doping affects the soft magnetic properties of amorphous microwires, with 1% low-doping samples exhibiting better soft magnetic properties. This phenomenon is likely the result of the interaction between nanocrystalline organization and magnetic domains. Furthermore, a Cu doping ratio of 1% yields the best noise performance, aligning with the trend observed in the material's magnetic properties. Therefore, to reduce the noise of the CoFeSiB amorphous wire sensor, the primary goal should be to reduce microscopic defects in amorphous alloys and enhance soft magnetic properties. Cu doping is a superior preparation method which facilitates control over preparation conditions, ensuring the formation of stable amorphous wires with consistent performance.

Transient anticonvulsant effects of time-restricted feeding in the 6-Hz mouse model.

INTRODUCTION: Intermittent fasting enhances neural bioenergetics, is neuroprotective, and elicits antioxidant effects in various animal models. There are conflicting findings on seizure protection, where intermittent fasting regimens often cause severe weight loss resembling starvation which is unsustainable long-term. Therefore, we tested whether a less intensive intermittent fasting regimen such as time-restricted feeding (TRF) may confer seizure protection. METHODS: Male CD1 mice were assigned to either ad libitum-fed control, continuous 8 h TRF, or 8 h TRF with weekend ad libitum food access (2:5 TRF) for one month. Body weight, food intake, and blood glucose levels were measured. Seizure thresholds were determined at various time points using 6-Hz and maximal electroshock seizure threshold (MEST) tests. Protein levels and mRNA expression of genes, enzyme activity related to glucose metabolism, as well as mitochondrial dynamics were assessed in the cortex and hippocampus. Markers of antioxidant defence were evaluated in the plasma, cortex, and liver. RESULTS: Body weight gain was similar in the ad libitum-fed and TRF mouse groups. In both TRF regimens, blood glucose levels did not change between the fed and fasted state and were higher during fasting than in the ad libitum-fed groups. Mice in the TRF group had increased seizure thresholds in the 6-Hz test on day 15 and on day 19 in a second cohort of 2:5 TRF mice, but similar seizure thresholds at other time points compared to ad libitum-fed mice. Continuous TRF did not alter MEST seizure thresholds on day 28. Mice in the TRF group showed increased maximal activity of pyruvate dehydrogenase in the cortex, which was accompanied by increased protein levels of mitochondrial pyruvate carrier 1 in the cortex and hippocampus. There were no other major changes in protein or mRNA levels associated with energy metabolism and mitochondrial dynamics in the brain, nor markers of antioxidant defence in the brain, liver, or plasma. CONCLUSIONS: Both continuous and 2:5 TRF regimens transiently increased seizure thresholds in the 6-Hz model at around 2 weeks, which coincided with stability of blood glucose levels during the fed and fasted periods. Our findings suggest that the lack of prolonged anticonvulsant effects in the acute electrical seizure models employed may be attributed to only modest metabolic and antioxidant adaptations found in the brain and liver. Our findings underscore the potential therapeutic value of TRF in managing seizure-related conditions.

Fibroblast Activation Protein-Targeted PET/CT with 18F-Fibroblast Activation Protein Inhibitor-74 for Evaluation of Gastrointestinal Cancer: Comparison with 18F-FDG PET/CT.

Fibroblast activation protein is overexpressed in the stroma of several cancer types. 18F-fibroblast activation protein inhibitor (FAPI)-74 is a PET tracer with high selectivity for fibroblast activation protein and has shown high accumulation in human tumors in clinical studies. However, the use of 18F-FAPI-74 for PET imaging of gastrointestinal cancer has not been systematically investigated. Herein, we investigated the diagnostic accuracy of 18F-FAPI-74 (18F-LNC1005) PET/CT in gastric, liver, and pancreatic cancers and compared the results with those of 18F-FDG PET/CT. Methods: This prospective study analyzed patients with confirmed gastric, liver, or pancreatic malignancies who underwent concurrent 18F-FDG and 18F-FAPI-74 PET/CT between June 2022 and December 2022. PET/CT findings were confirmed by histopathology or radiographic follow-up. 18F-FDG and 18F-FAPI-74 uptake and tumor-to-background ratios were compared using the Wilcoxon signed-rank test. The McNemar test was used to compare the diagnostic accuracy of the 2 scans. Results: Our cohort consisted of 112 patients: 49 with gastric cancer, 39 with liver cancer, and 24 with pancreatic cancer. Among them, 69 patients underwent PET/CT for initial staging and 43 for recurrence detection. Regarding lesion-based diagnostic accuracy, 18F-FAPI-74 PET/CT showed higher sensitivity than did 18F-FDG in the detection of primary tumors (gastric cancer, 88% [22/25] vs. 60% [15/25], P = 0.016; liver cancer, 100% [22/22] vs. 82% [18/22], P = 0.125; pancreatic cancer, 100% [22/22] vs. 86% [19/22], P = 0.250), local recurrence (92% [23/25] vs. 56% [14/25]; P = 0.021), involved lymph nodes (71% [41/58] vs. 40% [23/58]; P < 0.001), and bone and visceral metastases (98% [350/358] vs. 47% [168/358]; P < 0.001). Compared with 18F-FDG, 18F-FAPI-74 PET/CT upstaged 17 patients' TNM staging among all treatment-naïve patients (17/69, 25%) and changed the clinical management of 4 patients (4/43, 9%) in whom recurrence or metastases were detected. Conclusion: 18F-FAPI-74 PET/CT is superior to 18F-FDG PET/CT in detecting primary tumors, local recurrence, lymph node involvement, and bone and visceral metastases in gastric, pancreatic, and liver cancers, with higher uptake in most primary and metastatic lesions.

Acute Appendicitis Complicated by Septic Thrombophlebitis of the Portal Vein Shown by 18 F-FDG and 68 Ga-FAPI-46 PET/CT.

ABSTRACT: Septic thrombophlebitis of the portal vein is a serious infectious disorder and is difficult to be diagnosed at an early stage. In this case, we presented 18 F-FDG and 68 Ga-FAPI-46 PET/CT findings in a 45-year-old man with acute appendicitis complicated by septic thrombophlebitis of the portal vein. 68 Ga-FAPI-46 PET/CT showed intense radiotracer uptake in the thrombosis of the portal vein, with higher SUV max and larger disease extent than 18 F-FDG PET/CT. This case demonstrated that 68 Ga-FAPI PET/CT may be a useful imaging modality for the diagnosis of this infectious condition.

Tell me your position: Distantly supervised biomedical entity relation extraction using entity position marker.

A significant amount of textual data has been produced in the biomedical area recently as a result of the advancement of biomedical technologies. Large-scale biomedical data can be automatically obtained with the help of distant supervision. However, the noisy data brought by distant supervision methods makes relation extraction tasks more difficult. Previous work has focused more on how to restore mislabeled relationships, but little attention has been paid to the importance of labeled entity locations for relationship extraction tasks. In this paper, we present a "four-stage" model based on BioBERT and Multi-Instance Learning by using entity position markers. Firstly, the sentence is marked with position. Secondly, BioBERT, a biomedical pre-trained language model, is used in the final sentence feature vector representation not only with the global position marker but also with the start and end marker of both the head and tail entity. Thirdly, the aggregation of sentence vectors in the bag is used as the vector feature of the bag by three aggregation methods, and the performance of different sentence feature vectors combined with different bag encoding methods is discussed. At last, relation classification is performed at the bag level. According to experimental results, the presented model significantly outperforms all baseline models and contributes to noise reduction. In addition, different bag encoding methods need to match corresponding sentence encoding representation to achieve the best performance.

Fibroblast Activation Protein-Targeted Radioligand Therapy with 177Lu-EB-FAPI for Metastatic Radioiodine-Refractory Thyroid Cancer: First-in-Human, Dose-Escalation Study.

PURPOSE: Fibroblast activation protein (FAP) is a promising target for tumor treatment. In this study, we aimed to investigate the safety and efficacy of the albumin binder-conjugated FAP-targeted radiopharmaceutical, 177Lu-EB-FAPI (177Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC). PATIENTS AND METHODS: This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week 177Lu-LNC1004 treatment cycle in patients with mRAIR-TC at 2.22 GBq initially, with subsequent cohorts receiving an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed. RESULTS: 177Lu-LNC1004 administration was well tolerated, with no life-threatening adverse events observed. No patients experienced DLT in Group A (2.22 GBq/cycle). One patient experienced grade 4 thrombocytopenia in Group B (3.33 GBq/cycle); hence, another three patients were enrolled, none of whom experienced DLT. Two patients experienced grade 3 and 4 hematotoxicity in Group C (4.99 GBq/cycle). The mean whole-body effective dose was 0.17 ± 0.04 mSv/MBq. Intense 177Lu-LNC1004 uptake and prolonged tumor retention resulted in high mean absorbed tumor doses (8.50 ± 12.36 Gy/GBq). The mean effective half-lives for the whole-body and tumor lesions were 90.20 ± 7.68 and 92.46 ± 9.66 hours, respectively. According to RECIST, partial response, stable disease, and progressive disease were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively. The objective response and disease control rates were 25% and 83%, respectively. CONCLUSIONS: FAP-targeted radioligand therapy with 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated in patients with advanced mRAIR-TC, with high radiation dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects.

Morphological connectivity differences in Alzheimer's disease correlate with gene transcription and cell-type.

Alzheimer's disease (AD) is one of the most prevalent forms of dementia in older individuals. Convergent evidence suggests structural connectome abnormalities in specific brain regions are linked to AD progression. The biological basis underpinnings of these connectome changes, however, have remained elusive. We utilized an individual regional mean connectivity strength (RMCS) derived from a regional radiomics similarity network to capture altered morphological connectivity in 1654 participants (605 normal controls, 766 mild cognitive impairment [MCI], and 283 AD). Then, we also explored the biological basis behind these morphological changes through gene enrichment analysis and cell-specific analysis. We found that RMCS probes of the hippocampus and medial temporal lobe were significantly altered in AD and MCI, with these differences being spatially related to the expression of AD-risk genes. In addition, gene enrichment analysis revealed that the modulation of chemical synaptic transmission is the most relevant biological process associated with the altered RMCS in AD. Notably, neuronal cells were found to be the most pertinent cells in the altered RMCS. Our findings shed light on understanding the biological basis of structural connectome changes in AD, which may ultimately lead to more effective diagnostic and therapeutic strategies for this devastating disease.

Predicting brain age gap with radiomics and automl: A Promising approach for age-Related brain degeneration biomarkers.

The Brain Age Gap (BAG), which refers to the difference between chronological age and predicted neuroimaging age, is proposed as a potential biomarker for age-related brain degeneration. However, existing brain age prediction models usually rely on a single marker and can not discover meaningful hidden information in radiographic images. This study focuses on the application of radiomics, an advanced imaging analysis technique, combined with automated machine learning to predict BAG. Our methods achieve a promising result with a mean absolute error of 1.509 using the Alzheimer's Disease Neuroimaging Initiative dataset. Furthermore, we find that the hippocampus and parahippocampal gyrus play a significant role in predicting age with interpretable method called SHapley Additive exPlanations. Additionally, our investigation of age prediction discrepancies between patients with Alzheimer's disease (AD) and those with mild cognitive impairment (MCI) reveals a notable correlation with clinical cognitive assessment scale scores. This suggests that BAG has the potential to serve as a biomarker to support the diagnosis of AD and MCI. Overall, this study presents valuable insights into the application of neuroimaging models in the diagnosis of neurodegenerative diseases.

Superior Identification of Metastatic Lesions by 68 Ga-FAPI-46 to 18 F-FDG PET/CT in a Case of SMARCA4-Deficient Undifferentiated Carcinoma of Stomach.

ABSTRACT: SMARCA4-deficient undifferentiated carcinoma is a new clinical entity characterized by SMARCA4 inactivation and has a dismal prognosis because of rapid growth. In this case, we reported 18 F-FDG and 68 Ga-FAPI-46 PET/CT imaging findings in a patient with SMARCA4-deficient undifferentiated carcinoma of stomach. 68 Ga-FAPI-46 PET/CT showed much higher tumor-to-background contrast of primary tumor and revealed more metastatic lesions than 18 F-FDG PET/CT. This case demonstrated the superiority of 68 Ga-FAPI PET/CT over 18 F-FDG for identifying both primary and metastatic lesions in SMARCA4-deficient undifferentiated carcinoma. This observation may add the information on the benefit of FAPI PET in oncology imaging.

Metabolic aspects of genetic ion channel epilepsies.

Nowadays, particularly in countries with high incomes, individual mutations in people affected by genetic epilepsies are identified, and genetic therapies are being developed. In addition, drugs are being screened to directly target specific mutations, and personalised medicine is possible. However, people with epilepsy do not yet benefit from these advances, and many types of epilepsies are medication-resistant, including Dravet syndrome. Thus, in the meantime, alternative and effective treatment options are needed. There is increasing evidence that metabolic deficits contribute to epileptic seizures and that such metabolic impairments may be amenable to treatment, with metabolic treatment options like the ketogenic diet being employed with some success. However, the brain metabolic alterations that occur in ion channel epilepsies are not well-understood, nor how these may differ from epilepsies that are of acquired and unknown origins. Here, we provide an overview of studies investigating metabolic alterations in epilepsies caused by mutations in the SCN1A and KCNA1 genes, which are currently the most studied ion channel epilepsies in animal models. The metabolic changes found in these models are likely to contribute to seizures. A metabolic basis of these ion channel epilepsies is supported by human and/or animal studies that show beneficial effects of the ketogenic diet, which may be mediated by the provision of auxiliary brain fuel in the form of ketone bodies. Other potentially more preferred dietary therapies including medium-chain triglycerides and triheptanoin have also been tested in a limited number of studies, but their efficacies remain to be clearly established. The extent to which brain metabolism is affected in people with Dravet syndrome, KCNA1 epilepsy and the models thereof still requires clarification. This requires more experiments that yield functional insight into metabolism.

Evaluation of FAPI PET imaging in gastric cancer: a systematic review and meta-analysis.

Purpose: Recent studies suggest that 68Ga-FAPI PET/CT demonstrated superiority over 18F-FDG PET/CT in the evaluation of various cancer types, especially in gastric cancer (GC). By comprehensively reviewing and analysing the differences between 68Ga-FAPI and 18F-FDG in GC, some evidence is provided to foster the broader clinical application of FAPI PET imaging. Methods: In this review, studies published up to July 3, 2023, that employed radionuclide labelled FAPI as a diagnostic radiotracer for PET in GC were analysed. These studies were sourced from both the PubMed and Web of Science databases. Our statistical analysis involved a bivariate meta-analysis of the diagnostic data and a meta-analysis of the quantitative metrics. These were performed using R language. Results: The meta-analysis included 14 studies, with 527 patients, of which 358 were diagnosed with GC. Overall, 68Ga-FAPI showed higher pooled sensitivity (0.84 [95% CI 0.67-0.94] vs. 0.46 [95% CI 0.32-0.60]), specificity (0.91 [95% CI 0.76-0.98] vs. 0.88 [95% CI 0.74-0.96]) and area under the curve (AUC) (0.92 [95% CI 0.77-0.98] vs. 0.52 [95% CI 0.38-0.86]) than 18F-FDG. The evidence showed superior pooled sensitivities of 68Ga-FAPI PET over 18F-FDG for primary tumours, local recurrence, lymph node metastases, distant metastases, and peritoneal metastases. Furthermore, 68Ga-FAPI PET provided higher maximum standardized uptake value (SUVmax) and tumour-to-background ratios (TBR). For bone metastases, while 68Ga-FAPI PET demonstrated slightly lower patient-based pooled sensitivity (0.93 vs. 1.00), it significantly outperformed 18F-FDG in the lesion-based analysis (0.95 vs. 0.65). However, SUVmax (mean difference [MD] 1.79 [95% CI -3.87-7.45]) and TBR (MD 5.01 [95% CI -0.78-10.80]) of bone metastases showed no significant difference between 68Ga-FAPI PET/CT and 18F-FDG PET/CT. Conclusion: Compared with 18F-FDG, 68Ga-FAPI PET imaging showed improved diagnostic accuracy in the evaluation of GC. It can be effectively applied to the early diagnosis, initial staging, and detection of recurrence/metastases of GC. 68Ga-FAPI may have the potential of replacing 18F-FDG in GC in future applications.

Visualization of Intermetastatic Heterogeneity in Mixed Neuroendocrine Carcinoma-Acinar Adenocarcinoma of the Prostate by 68 Ga-PSMA, 68 Ga-FAPI, and 18 F-FDG PET/CT.

ABSTRACT: Mixed neuroendocrine carcinoma-acinar carcinoma is an uncommon histological type of neuroendocrine prostate cancer. It has been rarely reported in de novo prostate malignancies. In this case, we present 68 Ga-PSMA (prostate-specific membrane antigen), 68 Ga-FAPI, and 18 F-FDG PET/CT findings in the de novo form of mixed large-cell neuroendocrine carcinoma-acinar adenocarcinoma of the prostate. Different levels of radiotracer uptake were observed in different metastatic sites on 68 Ga-PSMA, 68 Ga-FAPI, and 18 F-FDG PET/CT. This case demonstrates that the multitracer PET/CT strategy may be used for the noninvasive detection of the intermetastatic heterogeneity in metastatic neuroendocrine prostate cancer.

Clinical Evaluation of 68Ga-FAPI-RGD for Imaging of Fibroblast Activation Protein and Integrin αvß3 in Various Cancer Types.

Radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and Arg-Gly-Asp (RGD) peptides have been extensively investigated for imaging of FAP- and integrin αvß3-positive tumors. In this study, a FAPI-RGD heterodimer was radiolabeled with 68Ga and evaluated in patients with cancer. We hypothesized that the heterodimer, recognizing both FAP and integrin αvß3, would be advantageous because of its dual-receptor-targeting property. Methods: The effective dose of 68Ga-FAPI-RGD was evaluated in 3 healthy volunteers. The clinical feasibility of 68Ga-FAPI-RGD PET/CT was evaluated in 22 patients with various types of cancer, and the results were compared with those of 18F-FDG and 68Ga-FAPI-46. Results: 68Ga-FAPI-RGD was tolerated well, with no adverse events in any of the healthy volunteers or patients. The effective dose from 68Ga-FAPI-RGD PET/CT was 1.01 × 10-2 mSv/MBq. In clinical investigations with different types of cancer, the radiotracer uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in 68Ga-FAPI-RGD PET/CT were significantly higher than those in 18F-FDG PET/CT (primary tumors: SUVmax, 18.0 vs. 9.1 [P < 0.001], and TBR, 15.2 vs. 5.5 [P < 0.001]; lymph node metastases: SUVmax, 12.1 vs. 6.1 [P < 0.001], and TBR, 13.3 vs. 4.1 [P < 0.001]), resulting in an improved lesion detection rate and tumor delineation, particularly for the diagnosis of lymph node (99% vs. 91%) and bone (100% vs. 80%) metastases. 68Ga-FAPI-RGD PET/CT also yielded a higher radiotracer uptake and TBR than 68Ga-FAPI-46 PET/CT did. Conclusion: 68Ga-FAPI-RGD exhibited improved tumor uptake and TBR compared with 18F-FDG and 68Ga-FAPI PET/CT. This study demonstrated the safety and clinical feasibility of 68Ga-FAPI-RGD PET/CT for imaging of various types of cancer.

68 Ga-FAPI Versus 18 F-FDG PET/CT in the Evaluation of Epithelioid Hemangioendothelioma of Bone.

ABSTRACT: Epithelioid hemangioendothelioma (EHE) is a rare type of vascular tumor that may arise in bone. Here we presented a 62-year-old man with suspected bone metastases who underwent PET/CT to detect the primary tumor. He underwent 18 F-FDG and 68 Ga-FAPI PET/CT under the prospective trial NCT04416165. Radiotracer uptake was much higher with 68 Ga-FAPI PET/CT than with 18 F-FDG PET/CT in most of bone lesions. No intense uptake likely presenting the primary tumor was observed. Subsequent bone biopsy confirmed the diagnosis of EHE of bone. This case suggested that 68 Ga-FAPI PET/CT might be a useful tool for evaluation of EHE.