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.

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.

Unusual Achalasia Presentation Detected on 131 I SPECT/CT in a Papillary Thyroid Carcinoma Patient.

ABSTRACT: Various factors leading to unexpected false-positive 131 I uptake have been extensively studied in patients with differentiated thyroid carcinoma. In this case, we present a patient who underwent achalasia surgery and subsequently exhibited abnormal 131 I uptake on SPECT/CT imaging. The patient was a known case of papillary thyroid carcinoma that suggested to 131 I therapy. 131 I SPECT/CT showed linear increased activity in the distended esophagus.

[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.

Landscape of Nuclear Medicine in China and Its Progress on Theranostics.

Nuclear medicine in China started in 1956 and, with the rapid development of the economy and continuous breakthroughs in precision medicine, has made significant progress in recent years. Almost 13,000 staff members in nearly 1,200 hospitals serve more than 3.9 million patients each year. Over the past decade, the radiopharmaceutical industry has developed rapidly, with the initial formation of a complete industrial chain of production of various radiopharmaceuticals for both clinical use and basic research. Advanced equipment such as PET/CT scanners is being manufactured domestically and even installed abroad. Recently, research into screening and synthesizing new target probes and their translation into the clinic has gained more attention, with various new tracers with potential clinical value being thoroughly studied. Simultaneously, 68Ga- and 177Lu-labeled tumor-targeted probes and others have been implemented for theranostics in an increasing number of hospitals and would be helped by approval from the National Medical Products Administration. Over the next 10-20 y, with the launch of the Mid- and Long-Term Development Plan for Medical Isotopes (2021-2035) by the Chinese government, there is great potential for nuclear medicine in China. With the rise in independent innovation in manufacturing, the shortage of radiopharmaceuticals will be effectively curtailed. We anticipate that the scale of nuclear medicine will at least double by 2035, covering all high-grade hospitals and leading to the aim of "one county, one department" in China.

Fibroblast Activation Protein Inhibitor Tracers and Their Preclinical, Translational, and Clinical Status in China.

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors.

Melanin-Targeting Radiotracers and Their Preclinical, Translational, and Clinical Status: From Past to Future.

Melanin is one of the representative biomarkers of malignant melanoma and a potential target for diagnosis and therapy. With advancements in chemistry and radiolabeling technologies, promising strides have been made to synthesize radiolabeled melanin-binding molecules for various applications. We present an overview of melanin-targeted radiolabeled molecules and compare their features reported in preclinical studies. Clinical practice and trials are also discussed to elaborate on the safety and validity of the probes, and expanded applications beyond melanoma are reviewed. Melanin-targeted imaging holds potential value in the diagnosis, staging, and prognostic assessment of melanoma and other applications. Melanin-targeted radionuclide therapy possesses immense potential but requires more clinical validation. Furthermore, an intriguing avenue for future research involves expanding the application scope of melanin-targeted probes and exploring their value.

Development and evaluation of albumin binder-conjugated heterodimeric radiopharmaceuticals targeting integrin αvß3 and CD13 for cancer therapy.

PURPOSE: The advancement of heterodimeric tracers, renowned for their high sensitivity, marks a significant trend in the development of radiotracers for cancer diagnosis. Our prior work on [68Ga]Ga-HX01, a heterodimeric tracer targeting CD13 and integrin αvß3, led to its approval for phase I clinical trials by the China National Medical Production Administration (NMPA). However, its fast clearance and limited tumor retention pose challenges for broader clinical application in cancer treatment. This study aims to develop a new radiopharmaceutical with increased tumor uptake and prolonged retention, rendering it a potential therapeutic candidate. METHODS: New albumin binder-conjugated compounds were synthesized based on the structure of HX01. In vitro and in vivo evaluation of these new compounds were performed after labelling with 68Ga. Small-animal PET/CT imaging were conducted at different time points at 0.5-6 h post injection (p.i.) using BxPC-3 xenograft mice models. The one with the best imaging performance was further radiolabeled with 177Lu for small-animal SPECT/CT and ex vivo biodistribution investigation. RESULTS: We have synthesized novel albumin binder-conjugated compounds, building upon the structure of HX01. When radiolabeled with 68Ga, all compounds demonstrated improved pharmacokinetics (PK). Small-animal PET/CT studies revealed that these new albumin binder-conjugated compounds, particularly [68Ga]Ga-L6, exhibited significantly enhanced tumor accumulation and retention compared with [68Ga]Ga-L0 without an albumin binder. [68Ga]Ga-L6 outperformed [68Ga]Ga-L7, a compound developed using a previously reported albumin binder. Furthermore, [177Lu]Lu-L6 demonstrated rapid clearance from normal tissues, high tumor uptake, and prolonged retention in small-animal SPECT/CT and biodistribution studies, positioning it as an ideal candidate for radiotherapeutic applications. CONCLUSION: A new integrin αvß3 and CD13 targeting compound was screened out. This compound bears a novel albumin binder and exhibits increased tumor uptake and prolonged tumor retention in BxPC-3 tumors and low background in normal organs, making it a perfect candidate for radiotherapy when radiolabeled with 177Lu.

Voltage-gated potassium channel 1.3: A promising molecular target in multiple disease therapy.

Voltage-gated potassium channel 1.3 (Kv1.3) has emerged as a pivotal player in numerous biological processes and pathological conditions, sparking considerable interest as a potential therapeutic target across various diseases. In this review, we present a comprehensive examination of Kv1.3 channels, highlighting their fundamental characteristics and recent advancements in utilizing Kv1.3 inhibitors for treating autoimmune disorders, neuroinflammation, and cancers. Notably, Kv1.3 is prominently expressed in immune cells and implicated in immune responses and inflammation associated with autoimmune diseases and chronic inflammatory conditions. Moreover, its aberrant expression in certain tumors underscores its role in cancer progression. While preclinical studies have demonstrated the efficacy of Kv1.3 inhibitors, their clinical translation remains pending. Molecular imaging techniques offer promising avenues for tracking Kv1.3 inhibitors and assessing their therapeutic efficacy, thereby facilitating their development and clinical application. Challenges and future directions in Kv1.3 inhibitor research are also discussed, emphasizing the significant potential of targeting Kv1.3 as a promising therapeutic strategy across a spectrum of diseases.

[18F]FDG PET/CT for prognosis and toxicity prediction of diffuse large B-cell lymphoma patients with chimeric antigen receptor T-cell therapy.

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy has been confirmed to benefit patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL). It is important to provide precise and timely predictions of the efficacy and toxicity of CAR T-cell therapy. In this study, we evaluated the value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) combining with clinical indices and laboratory indicators in predicting outcomes and toxicity of anti-CD19 CAR T-cell therapy for DLBCL patients. METHODS: Thirty-eight DLBCL patients who received CAR T-cell therapy and underwent [18F]FDG PET/CT within 3 months before (pre-infusion) and 1 month after CAR T-cell infusion (M1) were retrospectively reviewed and regularly followed up. Maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), clinical indices, and laboratory indicators were recorded at pre-infusion and M1 time points, and changes in these indices were calculated. Progression-free survival (PFS) and overall survival (OS) were as endpoints. Based on the multivariate Cox regression analysis, two predictive models for PFS and OS were developed and evaluated the efficiency. Pre-infusion indices were subjected to predict the grade of cytokine release syndrome (CRS) resulting from toxic reactions. RESULTS: For survival analysis at a median follow-up time of 18.2 months, patients with values of international prognostic index (IPI), SUVmax at M1, and TLG at M1 above their optimal thresholds had a shorter PFS (median PFS: 8.1 months [IPI ≥ 2] vs. 26.2 months [IPI < 2], P = 0.025; 3.1 months [SUVmax ≥ 5.69] vs. 26.8 months [SUVmax < 5.69], P < 0.001; and 3.1 months [TLG ≥ 23.79] vs. 26.8 months [TLG < 23.79], P < 0.001). In addition, patients with values of SUVmax at M1 and ∆SUVmax% above their optimal thresholds had a shorter OS (median OS: 12.6 months [SUVmax ≥ 15.93] vs. 'not reached' [SUVmax < 15.93], P < 0.001; 32.5 months [∆SUVmax% ≥ -46.76] vs. 'not reached' [∆SUVmax% < -46.76], P = 0.012). Two novel predictive models for PFS and OS were visualized using nomogram. The calibration analysis and the decision curves demonstrated good performance of the models. Spearman's rank correlation (rs) analysis revealed that the CRS grade correlated strongly with the pre-infusion SUVmax (rs = 0.806, P < 0.001) and moderately with the pre-infusion TLG (rs = 0.534, P < 0.001). Multinomial logistic regression analysis revealed that the pre-infusion value of SUVmax correlated with the risk of developing a higher grade of CRS (P < 0.001). CONCLUSION: In this group of DLBCL patients who underwent CAR T-cell therapy, SUVmax at M1, TLG at M1, and IPI were independent risk factors for PFS, and SUVmax at M1 and ∆SUVmax% for OS. Based on these indicators, two novel predictive models were established and verified the efficiency for evaluating PFS and OS. Moreover, pre-infusion SUVmax correlated with the severity of any subsequent CRS. We conclude that metabolic parameters measured using [18F]FDG PET/CT can identify DLBCL patients who will benefit most from CAR T-cell therapy, and the value before CAR T-cell infusion may predict its toxicity in advance.

Tau induces inflammasome activation and microgliosis through acetylating NLRP3.

BACKGROUND: Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule-associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. METHODS: The levels of nucleotide-binding oligomerisation domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme-linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test-tube acetylation assay, co-immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau-overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno-associated virus injection. The cognitive functions of Tau-overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba-1 IF staining and [18F]-DPA-714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau-NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. RESULTS: Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg-AD mice, microtubule-associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of 'early' phosphorylated-Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau-K18 domain acetyltransferase activity-dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV-2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau-NLRP3-binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. CONCLUSIONS: In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies.

Different Ectopic Endocrine Tumors on Renal Hilum Detected by 68 Ga-DOTATATE PET.

ABSTRACT: Renal hilum is a very rare location for primary adrenocortical adenoma or pheochromocytoma. We report 68 Ga-DOTATATE PET/CT findings of primary renal hilar adrenocortical adenoma in one patient and 68 Ga-DOTATATE PET/MR findings of pheochromocytoma in another patient.

Case report: Exploring the utility of whole-body bone scintigraphy for pediatric Langerhans cell histiocytosis: insights from clinical practice.

Purpose: This mini-review delves into the realm of Langerhans cell histiocytosis (LCH) in children, focusing on its skeletal involvement. By synthesizing pertinent literature, we sought to provide a comprehensive understanding of LCH's clinical and radiographic spectrum. Our study then demonstrates the diagnostic prowess of whole-body 99mTc-methyl diphosphonate (MDP) scintigraphy in LCH cases, underscoring its value in tandem with existing knowledge. Methods: Our approach involved an extensive literature review that contextualized LCH within the current medical landscape. Subsequently, we presented a case series featuring five pediatric instances of skeletal LCH, one accompanied by soft tissue infiltration. The principal aim was to illuminate the diagnostic and staging potential of whole-body 99mTc-MDP scintigraphy, augmenting existing insights. Results: Through meticulous literature synthesis, we highlighted pediatric LCH's protean clinical manifestations and radiological variability. Aligning with this spectrum, our case series underscored the role of 99mTc-MDP scintigraphy in diagnosing and staging LCH. Among the five pediatric cases, one demonstrated concurrent soft tissue involvement. This aligns with the multifaceted nature of LCH presentations. Conclusion: Pediatric LCH can present with a wide range of clinical and radiologic features. By amalgamating our cases with extant literature, we stress the necessity of a multimodal strategy. 99mTc-MDP scintigraphy emerged as an indispensable tool for accurate staging and soft tissue detection. Our findings collectively advocate for a holistic approach to managing LCH, ensuring informed therapeutic decisions for optimal patient outcomes.

Surgical evidence-based comparison of [68Ga]Ga-FAPI-04 PET and MRI-DWI for assisting debulking surgery in ovarian cancer patients.

PURPOSE: Imaging assessment of abdominopelvic tumor burden is crucial for debulking surgery decision in ovarian cancer patients. This study aims to compare the efficiency of [68Ga]Ga-FAPI-04 FAPI PET and MRI-DWI in the preoperative evaluation and its potential impact to debulking surgery decision. METHODS: Thirty-six patients with suspected/confirmed ovarian cancer were enrolled and underwent integrated [68Ga]Ga-FAPI-04 PET/MRI. Nineteen patients (15 stage III-IV and 4 I-II stage) who underwent debulking surgery were involved in the diagnostic efficiency analysis. The images of [68Ga]Ga-FAPI-04 PET and MRI-DWI were visually analyzed respectively. Immunohistochemistry on FAP was performed in metastatic lesions to investigate the radiological missing of [68Ga]Ga-FAPI-04 PET as well as its different performance in primary debulking surgery (PDS) and interval debulking surgery (IDS) patients. Potential imaging impact on management was also studied in 35 confirmed ovarian cancer patients. RESULTS: [68Ga]Ga-FAPI-04 PET displayed higher sensitivity (76.8% vs.59.9%), higher accuracy (84.9% vs. 80.7%), and lower missing rate (23.2% vs. 40.1%) than MRI-DWI in detecting abdominopelvic metastasis. The diagnostic superiority of [68Ga]Ga-FAPI-04 PET is more obvious in PDS patients but diminished in IDS patients. [68Ga]Ga-FAPI-04 PET outperformed MRI-DWI in 70.8% abdominopelvic regions (17/24), which contained seven key regions that impact the resectability and surgical complexity. MRI-DWI hold advantage in the peritoneal surface of the bladder and the central tendon of the diaphragm. Of the contradictory judgments between the two modalities (14.9%), [68Ga]Ga-FAPI-04 PET correctly identified more lesions, particularly in PDS patients (73.8%). In addition, FAP expression was independent of lesion size and decreased in IDS patients. [68Ga]Ga-FAPI-04 PET changed 42% of surgical planning that was previously based on MRI-DWI. CONCLUSION: [68Ga]Ga-FAPI-04 PET is more efficient in assisting debulking surgery in ovarian cancer patients than MRI-DWI. Integrated [68Ga]Ga-FAPI-04 PET/MR imaging is a potential method for planning debulking surgery in ovarian cancer patients.

Congenital Mesoblastic Nephroma Mimic Wilms Tumor on 18 F-FDG PET/CT and PET/MR.

ABSTRACT: Congenital mesoblastic nephroma is an extremely rare, low-grade malignant renal tumor in children. A 10-month-old boy and a 4-month-old girl were admitted to our hospital with a huge abdominal mass. For staging of the mass, 18 F-FDG PET/CT and PET/MR were performed showing a huge heterogeneous abdominal mass accompanied by extensive heterogeneous aggregation. Both of them were highly suspected to be Wilms tumor, the most common renal malignant tumor in children. However, histopathological examination after surgery confirmed congenital mesodermal nephroma.

Noninvasive longitudinal PET/CT imaging of CAR T cells using PSMA reporter gene.

PURPOSE: Chimeric antigen receptor (CAR) T cell therapy has achieved great success in treating hematologic malignancies. However, it is yet to prove effective in the treatment of solid tumors. Thus, it is necessary to develop appropriate methodology for the long-term, accurate, and quantitative evaluation of the distribution and activities of CAR T cells in solid tumors. In the present study, we engineered TfR ΔPSMA CAR (CAR-ΔPSMA) T cells, which targeted the transferrin receptor (TfR) expressed by tumor cells and could be tracked in vivo via a reporter gene encoding the truncated prostate specific membrane antigen (ΔPSMA). We then quantitatively monitored these CAR T cells in vitro and in vivo using [68Ga]Ga-PSMA-617 positron emission tomography (PET)/computed tomography (CT). METHODS: The CAR-ΔPSMA T cells were genetically engineered by transducing T cells with a lentiviral vector encoding TfR41BBζ-T2A-ΔPSMA. Firstly, the target expression, activation, and cytotoxicity of CAR-ΔPSMA T cells were validated in vitro. Secondly, the minimum thresholds of CAR-ΔPSMA T cells detection for [68Ga]Ga-PSMA-617 PET/CT were also determined in vitro and in vivo respectively. Lastly, the feasibility of monitoring the biodistribution and infiltration of CAR-ΔPSMA T cells after systematic administration was evaluated in the breast cancer subcutaneous xenograft model. RESULTS: The CAR-ΔPSMA T cells retained activation and tumor killing capacity after transduction of the ΔPSMA-encoding reporter gene. Next, the CAR-ΔPSMA T cells could be reliably tracked by [68Ga]Ga-PSMA-617 PET/CT, the detection sensitivity of which was 250 cells/mm3 in vitro and 100 cells/mm3 in vivo. Next, the sequential imaging assays revealed that [68Ga]Ga-PSMA-617 PET/CT could be used to specifically visualize ΔPSMA+ CAR T cells at the tumor site. The increase in the [68Ga]Ga-PSMA-617 signal intensity over time allowed us to effectively detect CAR T cells in vivo. CONCLUSION: Our findings preliminarily confirmed that [68Ga]Ga-PSMA-617 PET/CT could reliably detect CAR-ΔPSMA T cells in vitro and in vivo in solid tumors, laying the foundation for the monitoring CAR T cell therapy in the future.