European Journal of Nuclear Medicine and Molecular Imaging最新文献

Purpose

The T cell immunoglobulin and ITIM domain (TIGIT) blockade immunotherapy response is directly associated with individual differences of TIGIT expression on tumour-infiltrating lymphocytes (TILs) in tumour immune microenvironment (TIME) of non-small cell lung cancer (NSCLC). Here, we developed a TIGIT-targeted PET tracer to evaluate its feasibility in predicting immunotherapy efficacy, aiming to manage NSCLC patients accurately.

Methods

We synthesised a ¹⁸F-labeled TIGIT-targeted D-peptide, [¹⁸F]TTDP, and investigated the specificity of [¹⁸F]TTDP both to murine TIGIT and human TIGIT by a series of in vitro and in vivo assays. [¹⁸F]TTDP PET imaging was performed in humanised immune system (HIS) mice models bearing NSCLC patient-derived xenografts (PDXs) to evaluate the predictive value of FDA-approved combination immunotherapy of atezolizumab plus tiragolumab. Lastly, rhesus macaque was applied for [¹⁸F] TTDP PET to explore the tracer's in vivo distribution and translational potential in non-human primates.

Results

[¹⁸F]TTDP showed high specificity for both murine TIGIT and human TIGIT in vitro and in vivo. The HIS NSCLC PDX platform was successfully established for [¹⁸F]TTDP PET imaging, and tumour uptake of [¹⁸F]TTDP was significantly correlated with the TIGIT expression of TILs in the TIME. [¹⁸F]TTDP PET imaging, in predicting treatment response to the combination immunotherapy in NSCLC HIS-PDX models, showed a sensitivity of 83.33% and a specificity of 100%. In addition, [¹⁸F]TTDP PET also showed cross-species consistency of the tracer biodistribution between non-human primate and murine animals, and no adverse events were observed.

Conclusion

The combined implementation of the [¹⁸F]TTDP and HIS-PDX model creates a state-of-the-art preclinical platform that will impact the identification and validation of TIGIT-targeted PET image-guided diagnosis, treatment response prediction, beneficial patient screening, novel immunotherapies, and ultimately the outcome of NSCLC patients. We first provided in vivo biodistribution of [¹⁸F]TTDP PET imaging in rhesus macaque, indicating its excellent translational potential in the clinic.

Graphical Abstract

Purpose

Sodium[¹⁸F]fluoride (Na[¹⁸F]F) used in positron emission tomography (PET) binds to active calcification and correlates consistently with higher cardiovascular risk. This study aims to investigate the feasibility of aortic Na[¹⁸F]F-PET in hybrid combination with low-dose computed tomography (CT) as a risk model for major adverse cardiovascular events (MACE).

Methods

Patient data and Na[¹⁸F]F-PET/CT scans from January 2019 to February 2022 were retrospectively collected at the University Medical Center Groningen (UMCG), the Netherlands. MACE-outcome was a composite of time to first documented myocardial infarction, cerebral vascular accident (CVA), acute heart failure hospitalization, and aortic aneurysms. MACE dates were recorded from the day of the scan until follow-up in December 2023. The aorta was manually segmented in all low-dose CT scans. To minimize spill-over effects from the vertebrae, the vertebrae were automatically segmented using an open-source model, dilated with 10 mm, and subtracted from the aortic mask. The total aortic Na[¹⁸F]F corrected maximum standardized uptake value (cSUV_max) and total aortic Agatston score were automatically calculated using SEQUOIA. Kaplan–Meier and Cox regression survival analysis were performed, stratifying patients into high, medium, and low cSUV_max and Agatston categories. Cox regression models were adjusted for age.

Results

Out of 280 identified scans, 216 scans of unique patients were included. During a median follow-up of 3.9 years, 12 MACE occurred. Kaplan–Meier survival analysis demonstrated a significant difference in MACE-free survival among the high cSUV_max group compared to the medium and low groups (p = 0.03 and p < 0.01, respectively). Similarly, patients with high Agatston scores had a significantly lower MACE-free survival probability compared to those with medium and low scores (both p < 0.01).

Conclusion

This study highlights the potential clinical utility of Na[¹⁸F]F-PET/CT as an imaging tool to predict the risk of MACE. Clinical validation of this novel proof-of-concept method is needed to confirm these results and expand the clinical context.

Purpose

The stimulator of interferon genes (STING) is a critical component of the innate immune system and plays a pivotal role in tumor immunotherapy. Developing non-invasive in vivo diagnostic methods for visualizing STING is highly valuable for STING-related immunotherapy. This work aimed to build a noninvasive imaging platform that can dynamically and quantitatively monitor tumor STING expression.

Methods

We investigated the in vivo positron emission tomography (PET) imaging of STING-expressing tumors (B16F10, MC38, and Panc02) with STING-targeted radioprobe ([¹⁸F]F-CRI₁). The expression of STING in tumors was quantified, and correlation analysis was performed between these results and the outcomes of PET imaging. Furthermore, we optimized the structure of [¹⁸F]F-CRI_n with polyethylene glycol (PEG) to improve the pharmacokinetic characteristics in vivo. A comprehensive comparison of the imaging and biodistribution results obtained with the optimized probes was conducted in the B16F10 tumors.

Results

The PET imaging results showed that the uptake of [¹⁸F]F-CRI₁ in tumors was positively correlated with the expression of STING in tumors (r = 0.9184, P < 0.001 at 0.5 h). The lipophilicity of the optimized probes was significantly reduced. As a result of employing optimized probes, B16F10 tumor-bearing mice exhibited significantly improved tumor visualization in PET imaging, along with a marked reduction in retention within non-target areas such as the gallbladder and intestines. Biodistribution experiments further validated the efficacy of probe optimization in reducing uptake in non-target areas.

Conclusion

In summary, this work demonstrated a promising pathway for the development of STING-targeted radioprobes, advancing in vivo PET imaging capabilities.

Graphical Abstract

Abstract

Although peptide radionuclide therapy (PRRT) using a somatostatin analog (SSA) radiolabeled with a beta- emitter: [¹⁷⁷Lu]Lu-DOTATATE has shown a good clinical efficacy in neuroendocrine tumors (NETs), most of the patients only achieved tumoral stabilization and rare but severe long-term hematological toxicities have been reported. One of the promising options to improve PRRT is targeted alpha therapy. It is therefore essential to propose animal models that can mimic systemic spread disease, especially microscopic disease such as early stage of NET liver metastases to explore targeted alpha therapy. Herein, we report the evaluation of efficacy and toxicity of [²²⁵Ac]Ac-DOTATOC in an original preclinical murine model simulating the development of well-characterized liver metastases of pancreatic NETs with SSTR overexpression.

Methods

A mouse model of liver metastases of pancreatic NETs was developed by intraportal injection of AR42J cells and explored using [⁶⁸ Ga]Ga-DOTATOC and [¹⁸F]F-FDG PET/MRI. Biodistribution study and radiation dosimetry of [²²⁵Ac]Ac-DOTATOC were determined in subcutaneous tumor-bearing NMRI-nude mice. Efficacy and toxicity were determined by intravenous injection of increasing activities of [²²⁵Ac]Ac-DOTATOC 10 days after intraportal graft.

Results

Liver tumors showed a high uptake of [⁶⁸ Ga]Ga-DOTATOC and no uptake of [¹⁸F]F-FDG confirming the well-differentiated phenotype. All groups treated with [²²⁵Ac]Ac-DOTATOC showed a significant increase in overall survival compared with DOTATOC-treated mice, especially those treated with the highest activities: 53 days with 240 kBq (p = 0.0001), and 58 days with 2 × 120 kBq (p < 0.0001) vs 28 days with non-radiolabeled DOTATOC. On blood tests, a transient and moderate decreased in white blood cells count after treatment and no severe hepatic or renal toxicity were observed after treatment which was consistent with pathological and radiation dosimetry findings.

Conclusion

[²²⁵Ac]Ac-DOTATOC exhibit a favorable efficacy and toxicity profile in a mouse model of liver micrometastatic pancreatic NET.

Purpose

Quantification of PSMA expression via PSMA PET is well-established, however quantification of PSMA via immunohistochemistry (IHC) is not standardized. Our aim was to determine the most optimal PSMA IHC scoring system to quantify PSMA expression with PSMA PET as reference standard.

Methods

Primary intermediate- and high-risk prostate cancer patients received an [¹⁸F]PSMA-1007 PET/MRI followed by radical prostatectomy. SUV_max, SUV_mean and K_i of the prostate tumor was determined. Prostate tumors were stained with anti-PSMA antibodies and scored by 2 readers via 10 IHC scoring systems: histochemical score (H-score), immunoreactivity score_{predominant intensity} (IRS_{predominant intensity}), IRS classification_{predominant intensity}, IRS_{mean intensity}, IRS classification_{mean intensity}, Allred score, predominant expression pattern, Shannon diversity index (SDI), percentage negatively stained cells and total percentage positively stained cells. Spearman’s rank correlation coefficients (ρ) were calculated between PET parameters and IHC scoring systems. Interreader agreement for the IHC scoring systems was measured by the intraclass correlation coefficient (ICC).

Results

Fifty tumors in 46 patients were analysed. H-score had the best correlation with SUV_max (ρ 0.615 p < 0.0001) and SUV_mean (ρ 0.570, p < 0.0001) and the second best correlation with K_i (ρ 0.411, p = 0.0030). SDI had the best correlation with K_i (ρ -0.440, p = 0.0014) and the second best correlation with SUV_max (ρ -0.516, p = 0.0001) and SUV_mean (ρ -0.490, p = 0.0003). A moderate interreader agreement was observed for H-score (ICC 0.663, 95% CI 0.495–0.797) and SDI (ICC 0.546, 95% CI 0.354–0.725).

Conclusion

H-score had the best correlation with PSMA PET quantification and an acceptable interreader agreement. Therefore, we deem H-score the most optimal PSMA IHC scoring system.

Purpose

An MRI-based risk calculator (RC) has been recommended for diagnosing clinically significant prostate cancer (csPCa). PSMA PET/CT can detect lesions that are not visible on MRI, and the addition of PSMA PET/CT to MRI may improve diagnostic performance. The aim of this study was to incorporate the PRIMARY score or SUVmax derived from [⁶⁸Ga]Ga-PSMA-11 PET/CT into the RC and compare these models with MRI-based RC to assess whether this can further reduce unnecessary biopsies.

Methods

A total of 683 consecutive biopsy-naïve men who underwent both [⁶⁸Ga]Ga-PSMA-11 PET/CT and MRI before biopsy were temporally divided into a development cohort (n = 552) and a temporal validation cohort (n = 131). Three logistic regression RCs were developed and compared: MRI-RC, MRI-SUVmax-RC and MRI-PRIMARY-RC. Discrimination, calibration, and clinical utility were evaluated. The primary outcome was the clinical utility of the risk calculators for detecting csPCa and reducing the number of negative biopsies.

Results

The prevalence of csPCa was 47.5% (262/552) in the development cohort and 41.9% (55/131) in the temporal validation cohort. In the development cohort, the AUC of MRI-PRIMARY-RC was significantly higher than that of MRI-RC (0.924 vs. 0.868, p < 0.001) and MRI-SUVmax-RC (0.924 vs. 0.904, p = 0.002). In the temporal validation cohort, MRI-PRIMARY-RC also showed the best discriminative ability with an AUC of 0.921 (95% CI: 0.873–0.969). Bootstrapped calibration curves revealed that the model fit was acceptable. MRI-PRIMARY-RC exhibited near-perfect calibration within the range of 0–40%. DCA showed that MRI-PRIMARY-RC had the greatest net benefit for detecting csPCa compared with MRI-RC and MRI-SUVmax-RC at a risk threshold of 5–40% for csPCa in both the development and validation cohorts.

Conclusion

The addition of the PRIMARY score to MRI-based multivariable model improved the accuracy of risk stratification prior to biopsy. Our novel MRI-PRIMARY prediction model is a promising approach for reducing unnecessary biopsies and improving the early detection of csPCa.

Purpose

For several years, oncological positron emission tomography (PET) has developed beyond 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG). This umbrella review of meta-analyses aims to provide up-to-date, comprehensive, high-level evidence to support appropriate referral for a specific radiopharmaceutical PET/computed tomography (CT) or PET/magnetic resonance (MR) in the diagnosis and staging of solid cancers other than brain malignancies.

Methods

We performed a systematic literature search on the PubMed/MEDLINE and EMBASE databases for meta-analyses assessing the accuracy of PET/CT and/or PET/MRI with [¹⁸F]FDG, somatostatin- receptor-targeting ⁶⁸Ga-DOTA-peptides, ¹⁸F-labelled dihydroxyphenylalanine ([¹⁸F]DOPA), prostate-specific membrane antigen (PSMA)-targeted radioligands, and fibroblast activation protein inhibitors (FAPI) in the diagnosis/disease characterisation and staging of solid cancers other than brain tumours.

Results

The literature search yielded 449 scientific articles. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 173 meta-analyses to assess the strength of evidence. One article was selected from references. Sixty-four meta-analyses were finally considered. The current evidence corroborates the role of [¹⁸F]FDG as the main player in molecular imaging; PSMA tracers are useful in staging and re-staging prostate cancer; somatostatin-targeting peptides (e.g. [⁶⁸Ga]Ga- DOTA-TOC and -TATE) or [¹⁸F]DOPA are valuable in neuroendocrine tumours (NETs). FAPI has emerged in gastric cancer assessment. According to search and selection criteria, no satisfactory meta-analysis was selected for the diagnosis/detection of oesophageal cancer, the diagnosis/detection and N staging of small cell lung cancer and hepatic cell carcinoma, the diagnosis/detection and M staging of melanoma and Merkel cell carcinoma, cervical, vulvar and penis cancers, the N and M staging of lung and gastroenteropancreatic NET, testicular cancer, and chondrosarcoma, and the M staging of differentiated thyroid, bladder and anal cancers.

Conclusion

The comprehensive high-level evidence synthesised in the present umbrella review serves as a guiding compass for clinicians and imagers, aiding them in navigating the increasingly intricate seascape of PET examinations.