Frontiers in nuclear medicine (Lausanne, Switzerland)最新文献

Imaging biomarkers have changed the way we study Alzheimer's disease and related dementias, develop new therapeutics to treat the disease, and stratify patient populations in clinical trials. With respect to protein aggregates comprised of amyloid-β plaques and tau neurofibrillary tangles, Positron Emission Tomography (PET) has become the gold standard imaging modality for quantitative visualization. Due to high infrastructural costs, the availability of PET remains limited to large urban areas within high income nations. This limits access to leading edge medical imaging, and potentially access to new treatments, by millions of rural and remote residents in those regions as well as billions of people in middle- and low-income countries. Single Photon Emission Computed Tomography (SPECT) is a more widely available imaging alternative with lower infrastructural costs and decades of familiarity amongst nuclear medicine professionals. Recent technological advances have closed the gap in spatial resolution and quantitation between SPECT and PET. If effective SPECT radiotracers were available to visualize amyloid-β plaques, geographic barriers to imaging could be circumvented. In this review, we will discuss past efforts to develop SPECT radiotracers targeting amyloid-β plaques which incorporate the most used radionuclide in nuclear medicine: technetium-99m (^99mTc; t _1/2 = 6.01 h; γ = 140 keV). While reviewing the various chemical scaffolds and chelates employed, the focus will be upon the impact to the pharmacological properties of putative ^99mTc-based amyloid-targeting radiotracers.

Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade, including antibody therapeutics, has transformed cancer treatment. However, a major challenge in the field relates to selecting patients who are likely to respond to immune checkpoint inhibitors. Indeed, biopsy-based diagnostic tests to determine immune checkpoint protein levels do not accurately capture the inherent spatial and temporal heterogeneity of PD-L1 tumor expression. As a result, not all PD-L1-positive tumors respond to immunotherapies, and some patients with PD-L1-negative tumors have shown clinical benefits. In 2018, a first-in-human study of the clinically-approved anti-PD-L1 antibody Atezolizumab labeled with the positron emitter zirconium-89 validated the ability of positron emission tomography (PET) to visualize PD-L1 expression in vivo and predict tumor response to immunotherapy. These studies have triggered the expansion of PD-L1-targeted immunoPET to assess PD-L1 protein levels and PD-L1 expression heterogeneity in real time and across the whole tumor. First, this mini-review introduces new PD-L1 PET imaging studies of the last 4 years, focusing on the expansion of preclinical tumor models and anti-PD-L1 antibodies/antibody fragments in development. Then, the review discusses how these preclinical models and targeting agents can be utilized to study spatial and temporal heterogeneity of PD-L1 expression.

Introduction and aim: Diagnosis of hepatocellular carcinoma (HCC) often occurs when the disease is unresectable and therapeutic options are limited. The extent of disease and liver function according to Child-Pugh (C-P) classification are the main prognostic factors guiding clinicians in the management of HCC. The integration of albumin-bilirubin (ALBI) grade is emerging to assess liver function on account of its objectivity and reproducibility. Our aim was to investigate the value of the ALBI grade in predicting the outcome in patients treated with transarterial radioembolization (TARE).

Methods: We retrospectively enrolled patients with advanced and unresectable HCC treated with TARE in our institution. All patients underwent a preliminary dosimetric study before Yttrium-90 resin microsphere TARE. Barcelona Clinic Liver Cancer (BCLC), C-P, and ALBI scores were established at the time of TARE. Overall survival (OS), progression-free survival (PFS), and survival after TARE were assessed with the Kaplan-Meier method. Survival analyses were stratified according to ALBI grade, C-P, and BCLC classification. Univariate and multivariate Cox proportional regression models determined the association between prognostic factors and clinical outcomes.

Results: In total, 72 patients were included in the study, showing an OS of 51 months. The ALBI grade identified groups of patients with different prognoses both in the whole cohort and within the C-P classes, especially between ALBI 1 and ALBI 2. This result is confirmed also within BCLC classes. In treatment naïve patients, the ALBI grade was not able to predict outcomes, whereas the presence and degree of portal vein thrombosis (PVT) significantly affected prognosis.

Conclusions: The ALBI grade provided a more accurate prognostic stratification than the C-P classification in patients with intermediate and advanced HCC treated with TARE. However, the outcome of HCC is affected not only by liver function but also by disease-related characteristics, such as disease burden and degree of PVT. Including the ALBI grade in clinical guidelines may improve the management of patients affected by HCC.

Identifying risk factors for cardiovascular diseases in patients is key to reducing their resulting morbidity and mortality. Currently, risk factors are assessed using parameters that include and emphasize the role of the level of cholesterol carried by lipoproteins. Most providers focus on targeting cholesterol levels in patient management. However, recent research shows that lipoprotein particle number is more predictive of cardiovascular risk than cholesterol levels. The Nuclear Magnetic Resonance (NMR) LipoProfile test assesses the number of lipoprotein particles, sizes of lipoproteins, levels of cholesterol, and patient risk categories. Furthermore, it enables the identification of patients with underestimated cardiovascular risks-those with a discordant high number of low-density lipoprotein (LDL) particles (LDL-P) despite low cholesterol levels. While the NMR LipoProfile test requires a higher cost and longer waiting time for results in comparison to the lipid panel test, its advantages cannot be ignored. This review article focuses on exploring the routine use of NMR LipoProfile in clinical practice.

Background: To assess single-photon emission computed tomography cadmium-zinc-telluride (SPECT CZT)-derived myocardial blood flow (MBF) flow reserve (MFR) and flow difference (FD) in patients with acute myocardial infarction (AMI) and to compare this data with serum cardiac troponin and cardiac magnetic resonance (CMR) findings.

Methods: A total of 31 patients with AMI underwent invasive coronary angiography (ICA), serial high-sensitivity serum cardiac troponin I (cTnI) measurement, and CZT SPECT with visual and quantitative (MBF, MFR, and FD) perfusion parameters, and contrast-enhanced CMR. All patients with AMI were divided into two groups: (1) with non-obstructive coronary arteries (MINOCA), n = 10; (2) with obstructive coronary artery disease (MICAD), n = 21.

Results: The values of SSS and SRS were significantly (p < 0.01) higher whereas global stress MBF, MFR significantly lower in patients with MICAD as compared to MINOCA - 5.0 (3.0; 5.0) vs. 9.0 (5.0; 13.0); 2.0 (1.0; 3.0) vs. 6.0 (3.0; 11.0); 2.02 (1.71; 2.37) vs. 0.86 (0.72; 1.02) ml/min/g; and 2.61 (2.23; 3.14) vs. 1.67 (1.1; 1.9), respectively. Stress MBF correlated with cTnI at 24 h and day 4: ρ = -0.39; p = 0.03 and ρ = -0.47; p = 0.007, respectively. FD correlated with cTnI at 24 h and day 4: ρ = -0.39; p = 0.03 and ρ = -0.46; p = 0.009. CMR analysis showed that infarct size, MVO and myocardial edema in patients with MICAD were significantly (< 0.05) higher as compared to MINOCA: 19.4 (10.4; 29.7) vs. 1.8 (0.0; 6.9); 0.1 (0.0; 0.7) vs. 0.0 (0.0; 0.0) and 19.5 (12.0;30.0) vs. 3.0 (0.0; 12.0), respectively. According to vessel-based analysis of CMR data, acute myocardial injury (defined as late gadolinium enhancement and myocardial edema) was observed more frequently in patients with MICAD compared to MINOCA: 34(37%) vs. 5(5%) p = 0.005, respectively. The values of regional stress MBF, MFR and FD were significantly decreased in LV territories characterized by myocardial injury compared to those without: 0.98 (0.73; 1.79) vs. 1.33 (0.94; 2.08) p < 0.01, 1.64 (1.0; 2.36) vs. 2.0 (1.53; 2.89) p < 0.01 and 0.33 (0.05; 0.57) vs. 0.56 (0.36; 1.32) p> 0.01, respectively.

Conclusion: In patients with AMI, SPECT CZT-derived flow measures were associated with the high-sensitivity troponin I as well as the extent of edema, microvascular obstruction, and infarct size detected by CMR. On the regional level, quantitative SPECT CZT measures were significantly lower in vessel territories characterized by myocardial injury.

Prostate cancer (PCa) is one of the most common cancer types worldwide. 90% of men with late stage PCa will develop bone metastases. Since the expression level of PSMA (prostate-specific membrane antigen) in bone metastases can vary significantly, a compound is being searched for which accumulates in bone metastases independently of PSMA level. With DOTA-L-Lys(SA.Pam)-PSMA-617, we present a compound that, in addition to a PSMA inhibitor as a target vector, also contains a bisphosphonate that is established as a bone tracer and thus combines the advantages of PSMA targeting and bone targeting. This is a class of small molecules combining targeting of two different targets with the potential advantages for treatment of biologically heterogeneous bone metastasis from prostate cancer. The molecule can be labeled with lutetium-177 and used for the therapy of PCa-related bone metastases. DOTA-L-Lys(SA.Pam)-PSMA-617 was synthesized and radiolabelled in 1 M ammonium acetate buffer pH 5.5 at 95°C. Different amounts of precursor were evaluated. Complex stability was evaluated in three different media. LogD_7.4 value was evaluated via the determination of the equilibrium distribution in a PBS/n-octanol mixture. A hydroxyapatite binding assay was used to evaluate the potential binding to bone metastases. In vitro affinity was determined and K_i value was evaluated. To evaluate the binding potential in mice, ex vivo biodistribution studies were carried out in LNCaP tumor-bearing Balb/c mice. [¹⁷⁷Lu]Lu-labeling of DOTA-L-Lys(SA.Pam)-PSMA-617 showed quantitative RCY within 10 min and high complex stability over 14 days. The lipophilicity of the labeled compound was similar to the lipophilicity of the reference compound [¹⁷⁷Lu]Lu-PSMA-617 and showed an excellent and selective HAP binding of 98.2 ± 0.11%. With a K_i of 42.3 ± 7.7 nM PSMA binding affinity is lower in comparison to [¹⁷⁷Lu]Lu-PSMA-617. First ex vivo biodistribution studies with LNCaP tumor-bearing Balb/c mice showed a PSMA dependent tumor accumulation of 4.2 ± 0.7%ID/g and a femur accumulation of 3.4 ± 0.4%ID/g. [¹⁷⁷Lu]Lu-DOTA-L-Lys(SA.Pam)-PSMA-617 is a promising compound for therapy of PCa related bone and tissue metastases. Accumulation on the bone metastases via two mechanisms also enables the treatment of bone metastases that show little or no PSMA expression.

Bisphosponates are an interesting molecular class and in recent years their application has found its way into radiopharmaceutical research and thus into molecular imaging. In addition to great imaging of bone metastases, bisphospnate-based tracers for imaging also have some significant drawbacks. For example, their synthesis is often difficult. Additionally, this can lead to complex and almost impossible purification and quality control. This has limited the production and labeling of suitable molecular and their widespread use to a few facilities. Our squaric acid-based approach provides a way to overcome these problems and makes the synthesis as well as the purification of the compounds much easier. In addition, we were able to demonstrate that labeling with ⁶⁸Ga is possible under the typical conditions.