Liver-specific delivery of spherical DNA frameworks for alleviation of hepatic ischemic reperfusion injury.

DNA nanostructures have long been developed for biomedical purposes, but their controlled delivery in vivo proposes a major challenge for disease theranostics. We previously reported that DNA nanostructures on the scales of tens and hundreds nanometers showed preferential renal excretion or kidney retention, allowing for sensitive evaluation and effective protection of kidney function, in response to events such as unilateral ureter obstruction or acute kidney injury. Encouraged by the positive results, we redirected our focus to the liver, specifically targeting organs noticeably lacking DNA materials, to explore the interaction between DNA nanostructures and the liver. Through PET imaging, we identified SDF and M13 as DNA nanostructures exhibiting significant accumulation in the liver among numerous candidates. Initially, we investigated and assessed their biodistribution, toxicity, and immunogenicity in healthy mice, establishing the structure-function relationship of DNA nanostructures in the normal murine. Subsequently, we employed a mouse model of liver ischemia-reperfusion injury (IRI) to validate the nano-bio interactions of SDF and M13 under more challenging pathological conditions. M13 not only exacerbated hepatic oxidative injury but also elevated local apoptosis levels. In contrast, SDF demonstrated remarkable ability to scavenge oxidative responses in the liver, thereby mitigating hepatocyte injury. These compelling results underscore the potential of SDF as a promising therapeutic agent for liver-related conditions. This aimed to elucidate their roles and mechanisms in liver injury, providing a new perspective for the biomedical applications of DNA nanostructures.

Lymphoid organ-targeted nanomaterials for immunomodulation of cancer, inflammation, and beyond.

Nanomaterials exhibit significant potential for stimulating immune responses, offering both local and systemic modulation across a variety of diseases. The lymphoid organs, such as the spleen and lymph nodes, are home to various immune cells, including monocytes and dendritic cells, which contribute to both the progression and prevention/treatment of diseases. Consequently, many nanomaterial formulations are being rationally designed to target these organs and engage with specific cell types, thereby inducing therapeutic and protective effects. In this review, we explore crucial cellular interactions and processes involved in immune regulation and highlight innovative nano-based immunomodulatory approaches. We outline essential considerations in nanomaterial design with an emphasis on their impact on biological interactions, targeting capabilities, and treatment efficacy. Through selected examples, we illustrate the strategic targeting of therapeutically active nanomaterials to lymphoid organs and the subsequent immunomodulation for infection resistance, inflammation suppression, self-antigen tolerance, and cancer immunotherapy. Additionally, we address current challenges, discuss emerging topics, and share our outlook on future developments in the field.

[68Ga]FAPI PET for Imaging and Treatment Monitoring in a Preclinical Model of Pulmonary Fibrosis: Comparison to [18F]FDG PET and CT.

PURPOSE: This study aimed to evaluate the feasibility of using [68Ga]-fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET) imaging for diagnosing pulmonary fibrosis in a mouse model. We also examined its value in monitoring treatment response and compared it with traditional [18F]-fluorodeoxyglucose (FDG) PET and computed tomography (CT) imaging. METHODS: A model of idiopathic pulmonary fibrosis was established using intratracheal injection of bleomycin (BLM, 2 mg/kg) into C57BL/6 male mice. For the treatment of IPF, a daily oral dose of 400 mg/kg/day of pirfenidone was administered from 9 to 28 days after the establishment of the model. Disease progression and treatment efficacy were assessed at different stages of the disease every week for four weeks using CT, [18F]FDG PET, and [68Ga]FAPI PET (baseline imaging performed at week 0). Mice were sacrificed and lung tissues were harvested for hematoxylin-eosin staining, picrosirius red staining, and immunohistochemical staining for glucose transporter 1 (GLUT1) and FAP. Expression levels of GLUT1 and FAP in pathological sections were quantified. Correlations between imaging parameters and pathological quantitative values were analyzed. RESULTS: CT, [18F]FDG PET and [68Ga]FAPI PET revealed anatomical and functional changes in the lung that reflected progression of pulmonary fibrosis. In untreated mice with pulmonary fibrosis, lung uptake of [18F]FDG peaked on day 14, while [68Ga]FAPI uptake and mean lung density peaked on day 21. In mice treated with pirfenidone, mean lung density and lung uptake of both PET tracers decreased. Mean lung density, [18F]FDG uptake, and [68Ga]FAPI uptake correlated well with quantitative values of picrosirius red staining, GLUT1 expression, and FAP expression, respectively. Conclusions: Although traditional CT and [18F]FDG PET reflect anatomical and metabolic status in fibrotic lung, [68Ga]FAPI PET provides a means of evaluating fibrosis progression and monitoring treatment response.

Non-invasive visualization of liver fibrosis with [68Ga]Ga-DOTA-FAPI-04 PET from preclinical insights to clinical translation.

PURPOSE: The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([68Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. METHODS: The preclinical study employed [68Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [68Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [68Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). RESULTS: [68Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [68Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). CONCLUSION: [68Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. TRIAL REGISTRATION: NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939.

Theranostics - a sure cure for cancer after 100 years?

Cancer has remained a formidable challenge in medicine and has claimed an enormous number of lives worldwide. Theranostics, combining diagnostic methods with personalized therapeutic approaches, shows huge potential to advance the battle against cancer. This review aims to provide an overview of theranostics in oncology: exploring its history, current advances, challenges, and prospects. We present the fundamental evolution of theranostics from radiotherapeutics, cellular therapeutics, and nanotherapeutics, showcasing critical milestones in the last decade. From the early concept of targeted drug delivery to the emergence of personalized medicine, theranostics has benefited from advances in imaging technologies, molecular biology, and nanomedicine. Furthermore, we emphasize pertinent illustrations showcasing that revolutionary strategies in cancer management enhance diagnostic accuracy and provide targeted therapies customized for individual patients, thereby facilitating the implementation of personalized medicine. Finally, we describe future perspectives on current challenges, emerging topics, and advances in the field.

Aggregation-induced emission photosensitizer/bacteria biohybrids enhance Cerenkov radiation-induced photodynamic therapy by activating anti-tumor immunity for synergistic tumor treatment.

Cerenkov radiation-induced photodynamic therapy (CR-PDT) gets rid of the limited tissue penetration depth of the external light source and provides a feasible scheme for the PDT excited by the internal light. However, due to the low luminescence intensity of Cerenkov radiation, CR-PDT alone cannot effectively inhibit tumor growth, curbing the potential clinical translation of CR-PDT. Herein, we reported an AIE-PS/bacteria biohybrid (EcN@TTVP) composed of Escherichia coli Nissle 1917 (EcN) loaded with aggregation-induced emission photosensitizer (AIE-PS) termed TTVP, which enhanced CR-PDT by activating anti-tumor immunity for synergistic tumor treatment. The preferential tumor-colonized EcN@TTVP and radiopharmaceutical 18F-fluorodeoxyglucose (18F-FDG) were administered sequentially to enable them to co-enrich in the tumor site, thereby triggering CR-PDT and promoting immunogenic tumor cell death. Most importantly, EcN acting as immunoadjuvants enhanced the maturation of dendritic cells (DCs) and priming of cytotoxic T cells (CTLs). Therefore, under the synergistic treatment of CR-PDT and immunotherapy, AIE-PS/bacteria biohybrids resulted in either efficient tumor remission or a survival prolongation in tumor-bearing mice, which presented significant advantages over single CR-PDT. Remarkably, no obvious toxic effects were observed during the treatment. In this study, we proposed a synergistic therapeutic strategy based on EcN@TTVP for combined CR-PDT and immunotherapy against tumors. Moreover, this strategy may have great potential in clinical translation and provide references for deep-seated tumor treatment. STATEMENT OF SIGNIFICANCE: PDT is restricted due to the shallow penetration depth of light into tumor tissues. Using CR as the excitation light source for PDT can overcome the aforementioned issue and greatly expand the application of PDT. However, the low efficacy of single CR-PDT limits further its applications. Therefore, the design and development of feasible strategies to improve the efficacy of CR-PDT are of immediate importance. Introducing probiotics to our study can be used not only as tumor-targeting carriers of photosensitizers but also as immunoadjuvants. Under co-stimulation by immunogenic tumor cell death triggered by CR-PDT and probiotics acting as immunoadjuvants, anti-tumor immune responses were effectively activated, thus remarkably enhancing the efficacy of CR-PDT.

Berberin sustained-release nanoparticles were enriched in infarcted rat myocardium and resolved inflammation.

Inflammatory regulation induced by macrophage polarization is essential for cardiac repair after myocardial infarction (MI). Berberin (BBR) is an isoquinoline tetrasystemic alkaloid extracted from plants. This study analyzes the most likely mechanism of BBR in MI treatment determined via network pharmacology, showing that BBR acts mainly through inflammatory responses. Because platelets (PLTs) can be enriched in the infarcted myocardium, PLT membrane-coated polylactic-co-glycolic acid (PLGA) nanoparticles (BBR@PLGA@PLT NPs) are used, which show enrichment in the infarcted myocardium to deliver BBR sustainably. Compared with PLGA nanoparticles, BBR@PLGA@PLT NPs are more enriched in the infarcted myocardium and exhibit less uptake in the liver. On day three after MI, BBR@PLGA@PLT NPs administration significantly increases the number of repaired macrophages and decreases the number of inflammatory macrophages and apoptotic cells in infarcted rat myocardium. On the 28th day after MI, the BBR@PLGA@PLT group exhibits a protective effect on cardiac function, reduced cardiac collagen deposition, improved scar tissue stiffness, and an excellent angiogenesis effect. In addition, BBR@PLGA@PLT group has no significant impact on major organs either histologically or enzymologically. In summary, the therapeutic effect of BBR@PLGA@PLT NPs on MI is presented in detail from the perspective of the resolution of inflammation, and a new solution for MI treatment is proposed.

Enhancing Photothermal Therapy Efficacy by In Situ Self-Assembly in Glioma.

The residence time of some small molecular imaging and therapeutic agents in tumor tissue is short and the molecules can be easily dispersed, which decreases treatment efficacy. Therefore, methods that enhance oncotherapy performance are of significant importance. Here, we report an in situ self-assembly strategy aimed at enhancing the photothermal therapy of glioblastomas. The probe, ICG-PEP-c(RGD)fk, consisted of a glutathione-reactive self-assembling polypeptide as the skeleton, indocyanine green (ICG) as a theranostic agent, and cyclic Arg-Gly-Asp [c(RGD)fk] peptides as the targeting group. ICG-PEP-c(RGD)fk was synthesized and found to be assembled in the glutathione environment at 9.446 µM in vitro. Human glioblastoma cell line U87MG-luc with high integrin αvß3 expression was applied to invivo experiments. ICG-PEP-c(RGD)fk provided clearer tumor imaging and had a tumor retention time of 6.12 times longer than that of ICG-c(RGD)fk. In therapeutic experiments, ICG-PEP-c(RGD)fk significantly suppressed glioblastoma growth and the tumor volume was 2.61 times smaller than in the ICG-c(RGD)fk group at the end of the observation period. Moreover, the median survival time of ICG-PEP-c(RGD)fk group was significantly improved by 2.78 times compared with that of the control group. In conclusion, glutathione-reactive self-assembling peptides are capable of increasing the tumor retention time and improving the photothermal therapeutic effect. The in situ self-assembly strategy is a potential and feasible method to enhance oncotherapy.

Noninvasive Monitoring of Reparative Fibrosis after Myocardial Infarction in Rats Using 68Ga-FAPI-04 PET/CT.

Noninvasively monitoring activated fibroblasts is of great value for understanding the dynamic process of myocardial fibrosis after myocardial infarction (MI). This study aimed to evaluate the feasibility of 68Ga-labeled fibroblast activation protein inhibitor 04 (68Ga-FAPI-04) for monitoring reparative fibrosis and reactive fibrosis after MI. MI models were prepared by ligation of the left anterior descending (LAD) coronary artery and validated by electrocardiogram and 18F-FDG PET/CT 1 day after MI and hematoxylin and eosin (HE) staining. 68Ga-FAPI-04 PET/CT scans (1, 3, 6, 9, 12, 15, 18, 21, 28, and 35 days after MI) were carried out in MI rats and sham-operated rats without ligation of LAD. Blocking experiments were carried out on MI rats on day 7 after MI with 68Ga-FAPI-04 and excessive FAPI-04. Autoradiography, HE staining, Masson's trichrome staining, and immunofluorescence staining were carried out for ex vivo validation. The infarcted area with decreased or defective myocardial metabolic activity in 18F-FDG PET/CT correspondingly showed high 68Ga-FAPI-04 uptake in the MI rats. The myocardial tracer uptake was significantly different between MI and sham-operated rats from day 1 to 28 after MI and reached peak value 6 days after MI (0.806 ± 0.257%ID/cc vs 0.199 ± 0.012%ID/cc, P < 0.05). Tracer uptake at the infarcted myocardium and normal tissues in MI rats decreased significantly after blocking. Obvious tracer uptake was confirmed by autoradiography, and immunofluorescence staining showed FAP+ cells in the infarcted myocardium and border zone. Masson's trichrome staining of the heart sections of MI rats at different times suggested the presence of myocardial fibrosis. 68Ga-FAPI-04 uptake was not observed in the distal uninjured myocardium throughout the observation period. In conclusion, 68Ga-FAPI-04 PET could noninvasively monitor the activated fibroblasts in the early stage post acute MI and may be helpful for evaluating the degree of reparative fibrosis, while reactive fibrosis monitoring still needs further study.

Gallium-68-labeled fibroblast activation protein inhibitor PET in gastrointestinal cancer: insights into diagnosis and management.

PURPOSE: Gallium-68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) is an emerging promising tumor tracer. This study aims to evaluate the diagnostic efficiency of 68Ga-FAPI PET in gastrointestinal cancer, and to determine its potential impact on clinical management. METHODS: Patients with malignancies were prospectively enrolled in a clinical trial to evaluate the diagnostic value of 68Ga-FAPI PET. One hundred twenty patients with gastrointestinal malignancies (121 68Ga-FAPI PET scans) between June 2020 and May 2021 were retrospectively analyzed. Initial staging of untreated patients and restaging of treated patients were evaluated. The treatment scheme promoted by imaging was determined according to NCCN guidelines. Final diagnosis and treatment reference standards were determined by a dedicated multidisciplinary team. The diagnostic performance and treatment guidance of 68Ga-FAPI PET were compared with those of conventional imaging (CI) and 18F-FDG PET. RESULTS: The diagnostic accuracy of 68Ga-FAPI PET was much higher than that of CI and 18F-FDG PET (95.0% vs. 65.1% and 69.0%, respectively, both p < 0.001). 68Ga-FAPI PET revised diagnosis in 30.3% and 26.2% of patients compared with CI and 18F-FDG PET. The accordance rate of 68Ga-FAPI PET-guided treatment in comparison with the reference standard was significantly higher than that of CI and 18F-FDG PET (96.7% vs. 75.2% and 76.2%, respectively, both p < 0.001). 68Ga-FAPI PET changed treatment in 22.9% and 23.8% of patients compared with CI and 18F-FDG PET. CONCLUSIONS: 68Ga-FAPI PET showed remarkable diagnostic performance in gastrointestinal cancer, resulting in more accurate staging and guidance for timely treatment revision, thereby having a critical impact on clinical management. TRIAL REGISTRATION: NCT04554719. Registered September 8, 2020-retrospectively registered, http://clinicaltrails.gov/show/NCT04554719.

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. METHODS: Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. RESULTS: Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. CONCLUSION: mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

Advances in aptamer-based nuclear imaging.

Aptamers are short oligonucleotides that bind to specific target molecules. They have been extensively explored in biomedical applications, including biosensing, medical imaging, and disease treatment. Their adjustable affinity for specific biomarkers stimulates more translational efforts, such as nuclear imaging of tumors in preclinical and clinical settings. In this review, we present recent advances of aptamer-based nuclear imaging and compare aptamer tracers with other biogenic probes in forms of peptides, nanobodies, monoclonal antibodies, and antibody fragments. Fundamental properties of aptamer-based radiotracers are highlighted and potential directions to improve aptamer's imaging performance are discussed. Despite many translational obstacles to overcome, we envision aptamers to be a versatile tool for cancer nuclear imaging in the near future.

Spherical nucleic acids: Organized nucleotide aggregates as versatile nanomedicine.

Spherical nucleic acids (SNAs) are composed of a nanoparticle core and a layer of densely arranged oligonucleotide shells. After the first report of SNA by Mirkin and coworkers in 1996, it has created a significant interest by offering new possibilities in the field of gene and drug delivery. The controlled aggregation of oligonucleotides on the surface of organic/inorganic nanoparticles improves the delivery of genes and nucleic acid-based drugs and alters and regulates the biological profiles of the nanoparticle core within living organisms. Here in this review, we present an overview of the recent progress of SNAs that has speeded up their biomedical application and their potential transition to clinical use. We start with introducing the concept and characteristics of SNAs as drug/gene delivery systems and highlight recent efforts of bioengineering SNA by imaging and treatmenting various diseases. Finally, we discuss potential challenges and opportunities of SNAs, their ongoing clinical trials, and future translation, and how they may affect the current landscape of clinical practices. We hope that this review will update our current understanding of SNA, organized oligonucleotide aggregates, for disease diagnosis and treatment.

Targeting regulated cell death in tumor nanomedicines.

Nanomedicines hold great potential in anticancer therapy by modulating the biodistribution of nanomaterials and initiating targeted oxidative stress damage, but they are also limited by the inherent self-protection mechanism and the evolutionary treatment resistance of cancer cells. New emerging explorations of regulated cell death (RCD), including processes related to autophagy, ferroptosis, pyroptosis, and necroptosis, substantially contribute to the augmented therapeutic efficiency of tumors by increasing the sensitivity of cancer cells to apoptosis. Herein, paradigmatic studies of RCD-mediated synergistic tumor nanotherapeutics are introduced, such as regulating autophagy-enhanced photodynamic therapy (PDT), targeting ferroptosis-sensitized sonodynamic therapy (SDT), inducing necroptosis-augmented photothermal therapy (PTT), and initiating pyroptosis-collaborative chemodynamic therapy (CDT), and the coordination mechanisms are discussed in detail. Multiangle analyses addressing the present challenges and upcoming prospects of RCD-based nanomedicines have also been highlighted and prospected for their further strengthening and the broadening of their application scope. It is believed that up-and-coming coadjutant therapeutic methodologies based on RCDs will considerably impact precision nanomedicine for cancer.

Increased uptake of 68Ga-DOTA-FAPI-04 in bones and joints: metastases and beyond.

PURPOSE: To describe the uptake of 68Gallium-labelled fibroblast activation protein inhibitor (68Ga-FAPI) in the bones and joints for better understanding of the role of 68Ga-FAPI PET in benign and malignant bone lesions and joint diseases. METHODS: All 129 68Ga-FAPI PET/MR or PET/CT scans from June 1, 2020, to February 20, 2021, performed at our PET center were retrospectively reviewed. Foci of elevated 68Ga-FAPI uptake in the bones and joints were identified. All lesions were divided into malignant and benign diseases. Benign lesions included osteofibrous dysplasia, periodontitis, degenerative bone diseases, arthritis, and other inflammatory or trauma-related abnormalities. The number, locations, and SUVmax of all lesions were recorded and analyzed. The detectability of 68Ga-FAPI PET and 18F-FDG PET in patients who had two scans was also compared. RESULTS: Elevated uptake of 68Ga-FAPI in/around the bones and joints was found in 82 cases (63.57%). A total of 295 lesions were identified, including 94 (31.9%) malignant lesions (all were metastases) and 201 (68.1%) benign lesions. The benign lesions consisted of 13 osteofibrous dysplasia, 48 degenerative bone disease, 33 periodontitis, 56 arthritis, and 51 other inflammatory or trauma-related abnormalities. The spine, shoulder joint, alveolar ridge, and pelvis were the most commonly involved locations. Bone metastases were mainly distributed in the spine, pelvis, and ribs. Among benign diseases, periodontitis and arthritis are site-specific. The mean SUVmax of bone metastases was significantly higher than that of benign diseases (7.14 ± 4.33 vs. 3.57 ± 1.60, p < 0.001), but overlap existed. The differences in SUVmax among subgroups of benign diseases were statistically significant (p < 0.001), with much higher uptake in periodontitis (4.45 ± 1.17). 68Ga-FAPI PET identified much more lesions than 18F-FDG PET (104 vs. 48) with higher uptake value. CONCLUSION: 68Ga-FAPI accumulated in both bone metastases and some benign diseases of the bones and joints. Although the uptake of 68Ga-FAPI was often higher in bone metastases, this finding cannot be used to distinguish between benign and malignant lesions. 68Ga-FAPI PET also has the potential to locate and evaluate the extent of both malignant tumor and benign diseases in bones and joints. TRIAL REGISTRATION: NCT04554719, NCT04605939. Registered September 8, 2020 and October 25, 2020-retrospectively registered, http://clinicaltrails.gov/show/NCT04554719 ; http://clinicaltrails.gov/show/NCT04605939.

Uterine Uptake of 68Ga-FAPI-04 in Uterine Pathology and Physiology.

PURPOSE: 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI-04) has been useful in the imaging of desmoplastic reaction in different tumors. As we have found that most female patients showed avid uterine uptake of 68Ga-FAPI-04, we sought to further investigate the pathological and physiological uptake of 68Ga-FAPI-04 characteristics in the uterus. PATIENTS AND METHODS: We reviewed the image data of female patients who had undergone 68Ga-FAPI-04 PET/MRI at our institute between May 22, 2020, and June 21, 2021. The characteristics of uterine uptake and clinical information were collected. The uterus with and without malignancy were compared. We further analyzed the relationship of age, uterus size, gynecological history, and 18F-FDG uptake (if performed) with 68Ga-FAPI-04 uptake. RESULTS: Seventy-seven patients were included in this study. Much higher cervical 68Ga-FAPI-04 accumulation was noticed in cervical cancer patients than in normal cases, and 37 more metastases were found in 68Ga-FAPI-04 PET than that in 18F-FDG. Uterine body malignancies displayed different uptake features. Two cases with the metastases to uterine body showed relative lower 68Ga-FAPI-04 activity compared with their normal uteri. Of 67 patients without malignancy, lower 68Ga-FAPI-04 uptake was noted in postmenopausal women than in reproductive and perimenopausal patients. The invasive operation or hysteromyoma may increase 68Ga-FAPI-04 uptake. CONCLUSIONS: 68Ga-FAPI-04 PET might be a promising method in cervical cancers. However, physiological uptake may limit its diagnostic value in uterine body malignancy. It should be noticed that the metastatic lesion in the uterus may show relative lower uptake of 68Ga-FAPI-04 compared with the rest of the uterus. Age, fibroids, and uterine volume may influence 68Ga-FAPI-04 uptake in the uterus. More patients with various uterine diseases could be involved to provide more differential diagnostic information.

Head-to-Head Comparison of Neck 18F-FDG PET/MR and PET/CT in the Diagnosis of Differentiated Thyroid Carcinoma Patients after Comprehensive Treatment.

We explored the clinical value of 18F-FDG PET/MR in a head-to-head comparison with PET/CT in loco-regional recurrent and metastatic cervical lymph nodes of differentiated thyroid carcinoma (DTC) patients after comprehensive treatment. 18F-FDG PET/CT and neck PET/MR scans that were performed in DTC patients with suspected recurrence or cervical lymph node metastasis after comprehensive treatment were retrospectively analyzed. Detection rates, diagnostic efficacy, image conspicuity, and measured parameters were compared between 18F-FDG PET/CT and PET/MR. The gold standard was histopathological diagnosis or clinical and imaging follow-up results for more than 6 months. Among the 37 patients enrolled, no suspicious signs of tumor were found in 10 patients, 24 patients had lymph node metastasis, and 3 patients had both recurrence and lymph node metastases. A total of 130 lesions were analyzed, including 3 malignant and 6 benign thyroid nodules, as well as 74 malignant and 47 benign cervical lymph nodes. Compared with PET/CT, PET/MR presented better detection rates (91.5% vs. 80.8%), image conspicuity (2.74 ± 0.60 vs. 1.9 ± 0.50, p < 0.001, especially in complex level II), and sensitivity (80.5% vs. 61.0%). SUVmax differed in benign and malignant lymph nodes in both imaging modalities (p < 0.05). For the same lesion, the SUVmax, SUVmean, and diameters measured by PET/MR and PET/CT were consistent and had significant correlation. In conclusion, compared with 18F-FDG PET/CT, PET/MR was more accurate in determining recurrent and metastatic lesions, both from a patient-based and from a lesion-based perspective. Adding local PET/MR after whole-body PET/CT may be recommended to provide more precise diagnostic information and scope of surgical resection without additional ionizing radiation. Further scaling-up prospective studies and economic benefit analysis are expected.