Molecular Imaging and Biology最新文献

Purpose: Colony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([¹⁸F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([¹⁸F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation.

Procedures: A cell-based MSD assay was used to measure the IC₅₀ of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [¹⁸F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and App^SAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [¹⁸F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study.

Results: JNJ-CSF1R-1 is a 12 nM (IC₅₀) inhibitor of CSF1R. ​[¹⁸F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the App^SAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. ​[¹⁸F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, ​[¹⁸F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics.

Conclusion: ​[¹⁸F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.

Purpose: Peptide-based probes targeting integrin α_vβ₆ have shown promise in clinical trials for cancer imaging based on the high over-expression of this epithelial-specific cell surface receptor in many cancerous tissues. Recently, the α_vβ₆-targeting gallium-68 labeled DOTA-5G peptide, [⁶⁸Ga]Ga DOTA-5G, demonstrated diagnostic value in patients with metastatic pancreatic cancer. To facilitate adoption at sites without access to gallium-68 and take advantage of the characteristics of fluorine-18 through convenient [¹⁸F]fluoride chelation chemistry, this study evaluated the fluorine-18 labeled analog, [¹⁸F]AlF NOTA-5G, in vitro and in vivo in a tumor mouse model, and compared it to [⁶⁸Ga]Ga DOTA-5G.

Procedures: NOTA-5G was synthesized on solid phase and radiolabeled with aluminum [¹⁸F]fluoride to generate [¹⁸F]AlF NOTA-5G. Cell binding and internalization of [¹⁸F]AlF NOTA-5G were evaluated in paired DX3puroβ6 (α_vβ₆ +) and DX3puro (α_vβ₆ -), and pancreatic BxPC-3 (α_vβ₆ +) cells. Imaging (1-6 h) and biodistribution were performed in BxPC-3 tumor-bearing mice.

Results: [¹⁸F]AlF NOTA-5G was obtained in > 93% radiochemical purity. Cell binding was α_vβ₆-targeted (1 h: 66% bound to DX3puroβ6, vs 2% to DX3puro), and ≥ 50% of bound activity was internalized; analogous to [⁶⁸Ga]Ga DOTA-5G, PET imaging showed clearly delineated tumors. Excretion remained primarily renal (1 to 4 h: 18.6 to 12.5% ID/g). Tumor uptake remained relatively steady (1 to 4 h: 2.3 ± 0.4 to 1.8 ± 0.6% ID/g - closely matching [⁶⁸Ga]Ga DOTA-5G with 2.6 ± 0.8 and 2.0 ± 0.6% ID/g at 1 and 2 h), resulting in tumor/pancreas, tumor/liver, and tumor/blood ratios of 18/1, 24/1, and 162/1, respectively (4 h); by comparison, for [⁶⁸Ga]Ga DOTA-5G the values were 21/1, 20/1, and 22/1 (2 h).

Conclusions: [¹⁸F]AlF NOTA-5G demonstrated selective α_vβ₆-targeting and tumor uptake similar to [⁶⁸Ga]Ga DOTA-5G. The tumor-to-background ratio resulted high-contrast PET images, with an extended imaging window compared to [⁶⁸Ga]Ga DOTA-5G. The synthesis of [¹⁸F]AlF NOTA-5G is currently being optimized for clinical production.

Purpose: The goal of this study is to create a novel framework for identifying MSI status in colorectal cancer using advanced radiomics and deep learning strategies, aiming to enhance clinical decision-making and improve patient outcomes in oncology.

Procedures: The study utilizes histopathological slide images from the NCT-CRC-HE-100 K and PAIP 2020 databases. Key procedures include self-attentive adversarial stain normalization for data standardization, tumor delineation via a Slimmable Transformer, and radiomics feature extraction using a hybrid quantum-classical neural network.

Results: The proposed system reaches 99% accuracy when identifying colorectal cancer MSI status. It shows the model is good at telling the difference between MSI and MSS tumors and can be used in real medical care for cancer.

Conclusions: Our research shows that the new system improves colorectal cancer MSI status determination better than previous methods. Our optimized processing technology works better than other methods to divide and analyze tissue features making the system good for improving patient care decisions.

Purpose: ¹¹C-acetate PET is used to measure biventricular oxygen myocardial consumption rate (MVO₂) and myocardial blood flow (MBF) changes associated with right ventricular (RV) remodelling. We studied PET reproducibility and repeatability for such RV assessments.

Procedures: 10 pulmonary hypertension (PH) patients underwent ¹¹C-acetate PET. Five of these patients also had a repeat scan after 26 ± 2 weeks. A one-tissue compartment model was used to measure the myocardial tissue-activity washout rate (k2 [1/min] for MVO₂ estimation) and the blood-to-tissue activity flux (K1 [1/min] for MBF calculation). Values were measured by 2 blinded observers and analyzed by ANOVA and Bland-Altman tests. The interquartile ranges (IQR), within-subject coefficients of variation (wCV), and intraclass correlation coefficients (ICC) were reported.

Results: All patients had stable PH with the clinical assessments showed comparable biventricular function and size between baseline and follow-up. The k2-derived MVO₂ and K1-derived MBF values were consistently higher in the LV than RV. The high inter- and intra-observer reproducibility (for biventricular MVO₂ and MBF) was indicated by low IQR (≤ 7.6%) and wCV (≤ 8%) as well as high ICC (≥ 95%). The test-retest (baseline to follow-up) repeatability showed larger IQR (≤ 35.4%) and wCV (≤ 29%) but consistently high ICC (= 95%).

Conclusions: MVO₂ and MBF values measured in the RV of patients with PH were highly reproducible and repeatable. This can help inform the design of clinical research studies using serial ¹¹C-acetate PET imaging to evaluate RV metabolism.

Purpose: Lymphodepletion before tumor-infiltrating lymphocytes (TIL) infusion can activate the immune system, enhance the release of homeostatic cytokines, and decrease the number of immunosuppressive cells. This process is crucial for improving the therapeutic efficacy of TIL therapy. However, the challenge of in vivo assessing TILs targeting tumors limits the optimization of lymphodepleting conditioning regimen (LDC).

Procedures: This study aims to employ magnetic particle imaging (MPI) and fluorescence molecular imaging (FMI) to monitor TIL biodistribution in vivo and optimize LDC in triple-negative breast cancer TIL therapy. MPI provides quantitative imaging capabilities without depth limitations, effectively complementing the high sensitivity of FMI. The efficacy of different LDCs in enhancing TIL therapy was assessed using FMI, and MPI quantified the number of TILs accumulated in the 4T1 tumor.

Results: TILs preserved viability, phenotypes, and anti-tumor efficacy after being labeled with superparamagnetic iron oxide and fluorescence dye DiR. The dual-modality imaging system effectively discerned variations in LDC treatments that enhanced TIL therapy. Compared to TIL monotherapy, lymphodepletion with TIL therapy improves tumor dual-modality imaging signal intensity, increases the expression of monocyte chemotactic protein-1 in serum and tumor tissue, and enhances the therapeutic effect of TILs.

Conclusion: Our results confirm the utility of optical-magnetic dual-modality imaging for tracking the biodistribution of TILs in vivo. With the help of optical-magnetic dual-modality imaging, we successfully optimize TIL combination therapy. Optical-magnetic dual-modality imaging provides a new approach to develop personalized immunotherapy strategies and mine potential therapeutic mechanisms for TIL.

Purpose: Hepatic organic anion transporting polypeptides (OATPs) transport off-the-shelf, FDA-approved, hepatospecific Gd-based MRI contrast agents into cells that express the transporters enhancing signal on T1-weighted MRI. Studies have used MRI to identify OATP-overexpressing tumors and metastases transplanted in mice following the delivery of Gd-EOB-DTPA at 27-67-fold higher than clinical doses. With safety and regulatory concerns over Gd-based contrast agents, translating OATPs as an MRI reporter protein to humans for regenerative medicine will require substantially lower doses of agent.

Procedures: We engineered the MyC-CaP mouse tumor cell line to express rat OATP1B2, which influxes both Gd-EOB-DTPA and Gd-BOPTA, resulting in signal enhancement on T1-weighted MRI. We then inoculated mice with rat OATP1B2 and non-expressing cells bilaterally to generate tumors. 3-4 weeks after inoculation, when tumors had formed, in-vivo MRI imaging was performed with delivery of 0.025 mmol/kg or 0.25 mmol/kg of the Gd-based contrast agents. We complemented static T1-weighted MRI and T1-mapping with dynamic contrast enhanced (DCE)-MRI and performed area under the curve (AUC) analysis to discriminate the two tumor types.

Results: While all OATP1B2-expressing tumors were easily visible at the high dose of 0.25 mmol/kg on T1-weighted MRI and easy to distinguish from control tumors, OATP1B2-expressing tumors were hard to identify and distinguish from non-expressing tumors at the lower, clinical dose of 0.025 mmol/kg with standard T1-weighted MRI or T1-mapping. However, AUC analyses of the DCE-MRI curves could identify and distinguish these tumors, needing 30 (Gd-EOB-DTPA) or 45 (Gd-BOPTA) minutes acquisition time.

Conclusions: By performing AUC analyses of DCE-MRI curves following delivery of clinical concentration of MRI contrast agents, OATP1B2-expressing tumors could be identified and distinguished from control tumors, suggesting this imaging approach as a path to substantially reducing the amount of contrast agent needed to use OATPs as a clinically viable reporter protein for imaging regenerative medicine.

Purpose: To investigate the diagnostic efficacy of ⁶⁸Ga-pentixafor positron emission tomography/computed tomography (PET/CT) in primary aldosteronism (PA) subtyping and lateralization of aldosterone secretion in PA patients.

Procedures: 37 patients who were diagnosed with PA, were prospectively enrolled in the study, and underwent adrenal vein sampling (AVS) after ⁶⁸Ga-pentixafor PET/CT was conducted. Lateralization index (LI), defined as aldosterone/cortisol ratio in the dominant side to the contralateral adrenal vein when bilateral adrenal vein catheterization succeeded, and the aldosterone/cortisol ratio in the left adrenal vein to IVC (LAV/IVC) when the catheterization of right adrenal vein failed, were applied to determine lateralization side. Statistical analysis was performed using SPSS 21.0.

Results: The female proportion of all patients with PA was 32.4% (12/37), and the mean age was 51.3 ± 10.9 years. Patients with bilateral adrenal mass accounted for 54.1% (20/37), and 10 of them (27.0%) had adrenal hyperplasia or adrenal nodules ≤ 1.0 cm. In all 37 patients, the sensitivity, specificity and accuracy of ⁶⁸Ga-pentixafor PET/CT in distinguishing lateralization by visualization were 89.3%, 77.8% and 86.5%, respectively. The area under the ROC curve for detecting positive lateralization based on the value of ⁶⁸Ga-pentixafor SUV_max was 0.750 (95%CI 0.578-0.922, p = 0.026). The optimum SUV_max cut-off value was 6.86, with the sensitivity of 78.6%, specificity of 66.7%, and accuracy of 78.4%. Defining SUV ratio as SUV_max/SUV of contralateral adrenal gland, the area under the ROC curve for identifying lateralization based on the SUV ratio was 0.710 (95%CI 0.500-0.921, p = 0.061). The optimum SUV ratio cut-off was 2.40, with the sensitivity of 60.7%, specificity of 88.9%, and accuracy of 67.6%. The consistency of ⁶⁸Ga-pentixafor PET/CT with AVS was of no significant difference between patients with bilateral adrenal lesions (80.0%, 16/20) and unilateral lesion (94.1%, 16/17; p = 0.737), and no significance was revealed in the consistency between patients with adrenal hyperplasia or adrenal lesion of diameter ≤ 1 cm (81.8%, 9/11) and those with adrenal lesions > 1 cm (88.5%, 23/26; p = 0.884).

Conclusions: ⁶⁸Ga-pentixafor PET/CT showed at least 80% consistency for the lateralization in patients with PA compared with AVS, even in those presented with bilateral adrenal hyperplasia. Visual analysis exhibited better diagnostic efficacy compared with SUV_max or SUV_max/SUV of the contralateral adrenal gland.( ChiCTR2300073049. Registered 30 June 2023. Retrospectively registered).

Purpose: (2S,4R)-4-[¹⁸F]fluoroglutamine ([¹⁸F]FGln) is a promising metabolic imaging marker in cancer. Based on the fact that major inflammatory cells are heavily dependent on glutamine metabolism like cancer cells, we explored the potential utility of [¹⁸F]FGln as a metabolic imaging marker for inflammation in two rat models: carrageenan-induced paw edema (CIPE) and collagen-induced arthritis (CIA).

Procedures: The CIPE model (n = 4) was generated by injecting 200 µL of 3% carrageenan solution into the left hind paw three hours before the PET. The CIA model (n = 4) was generated by injecting 200 µg of collagen emulsion subcutaneously at the tail base 3-4 weeks before the PET. A qualitative scoring system was used to assess the severity of paw inflammation. After a CT scan, 15.7 ± 4.9 MBq of [¹⁸F]FGln was injected via the tail vein, followed by a dynamic micro-PET scan for 90 min under anesthesia with isoflurane. The standard uptake value of [¹⁸F]FGln was measured by placing a volume of interest in each paw. The non-injected right hind paws of the CIPE model rats served as controls for both models. The paws with CIA were pathologically examined after PET.

Results: The CIPE models showed a trend toward higher uptake in the injected paw compared to the non-injected paw (P = 0.068). In CIA models, uptake in the paws with severe inflammation was significantly higher than the controls (P = 0.011), while that with mild and no inflammation was slightly higher (33%) and lower (-7%), respectively. Combined overall, the [¹⁸F]FGln uptake in CIA showed a significant positive correlation with inflammation severity (r = 0.88, P = 0.009). The pathological findings confirmed profound inflammation in CIA.

Conclusions: [¹⁸F]FGln uptake was increased in both acute and chronic inflammation, and the uptake level was significantly correlated with the severity, suggesting its potential utility as a novel metabolic imaging marker for inflammation.

Significance: Selecting a nerve-specific lead fluorescent agent for translation in fluorescence-guided surgery is time-consuming and expensive. Preclinical fluorescent agent studies rely primarily on animal models, which are a critical component of preclinical testing, but these models may not predict fluorophore performance in human tissues.

Aim: The primary aim of this study was to evaluate and compare two preclinical models to test tissue-specific fluorophores based on discarded human tissues. The secondary aim was to use these models to determine the ability of a molecularly targeted fluorophore, LGW16-03, to label ex vivo human nerve tissues.

Approach: Patients undergoing standard-of-care transtibial or transfemoral amputation were consented and randomized to topical or systemic administration of LGW16-03 following amputation. After probe administration, nerves and background tissues were surgically resected and imaged to determine nerve fluorescence signal-to-background tissue ratio (SBR) and signal-to-noise ratio (SNR) metrics. Analysis of variance (ANOVA) determined statistical differences in metric means between administration cohorts and background tissue groups. Receiver operating characteristic (ROC) curve-derived statistics quantified the discriminatory performance of LGW16-03 fluorescence for labeling nerve tissues.

Results: Tissue samples from 18 patients were analyzed. Mean nerve-to-adipose SBR was greater than nerve-to-muscle SBR (p = 0.001), but mean nerve-to-adipose SNR was not statistically different from mean nerve-to-muscle SNR (p = 0.069). Neither SBR nor SNR means were statistically different between fluorophore administration cohorts (p ≥ 0.448). When administration cohorts were combined, nerve-to-adipose SBR was greater than nerve-to-muscle SBR (mean ± standard deviation; 4.2 ± 2.9 vs. 1.8 ± 1.9; p < 0.001), but SNRs for nerve-to-adipose and nerve-to-muscle were not significantly different (5.1 ± 4.0 vs. 3.1 ± 3.4; p = 0.055). ROC curve-derived statistics to quantify LGW16-03 nerve labeling performance varied widely between patients, with sensitivities and specificities ranging from 0.2-99.9% and 0.4-100.0%.

Conclusion: Systemic and topical administration of LGW16-03 yielded similar fluorescence labeling of nerve tissues. Both administration approaches provided nerve-specific contrast similar to that observed in preclinical animal models. Fluorescence contrast was generally higher for nerve-to-adipose versus nerve-to-muscle. Ex vivo human tissue models provide safe evaluation of fluorophores in the preclinical phase and can aid in the selection of lead agents prior to first-in-human trials.

Purpose: To develop a novel risk model incorporating ⁶⁸Ga-PSMA PET/CT parameters for prediction of perineural invasion (PNI) of prostate cancer (PCa).

Methods: The study retrospectively enrolled 192 PCa patients with preoperative multiparametric MRI, ⁶⁸Ga-PSMA PET/CT and radical specimen. Imaging parameters were derived from both mpMRI and PET/CT images. S100 immunohistochemistry staining was conducted to evaluate PNI of PCa. Significant predictors were derived with univariate and multivariate logistic regression analyses, and the PNI-risk nomogram was constructed with significant predictors. Internal discrimination validation was performed with receiver operating characteristic analysis. Calibration curves were plotted, decision curve and clinical impact curve analysis were performed for clinical benefit exploration.

Results: With the median peritumoral nerve density of 6, patients were stratified as low-PNI group (nerve density < 6, n = 78, 40.6%) and high-PNI group (nerve density ≥ 6, n = 114, 59.4%). Compared with low-PNI PCa, high-PNI PCa harbored significantly larger imaging lesion diameter (P < 0.001), higher PI-RADS score (P = 0.009), higher SUVmax (P < 0.001), larger tumor diameter (P = 0.024) and higher Gleason grade group (P < 0.001). Further, with univariate and multivariate analyses, imaging lesion diameter (OR 2.98, 95% CI 1.73-5.16, P = 0.004) and SUVmax (OR 3.59, 95%CI 2.32-5.55, P < 0.001) and were identified as independent predictors for PNI in PCa, and a PNI-risk nomogram incorporating these two predictors was constructed. The PNI-risk nomogram demonstrated considerable calibration (mean absolute error 0.026) and discrimination (area under the curve = 0.889, sensitivity 73.1%, specificity 97.4%) abilities, harboring net benefits with threshold probabilities range from 0 to 0.80.

Conclusion: ⁶⁸Ga-PSMA PET/CT-based model could effectively predict the perineural invasion of PCa. These results may help with the decision-making on active surveillance, focal therapy and surgery approach. Additionally, patients suspicious of high-density PNI PCa should receive more radical treatment than low-PNI PCa.