Journal of nuclear medicine : official publication, Society of Nuclear Medicine最新文献

Immuno-PET/CT imaging, a branch of molecular imaging, can noninvasively and specifically visualize biomarker expression across the body. Trophoblast cell surface antigen 2 (Trop2) is a pan-cancer biomarker and plays a crucial role in tumorigenesis through multiple signaling pathways. The study aims to develop and translate novel Trop2 single-domain antibody (sdAb) tracers for clinical use. Methods: Two sdAbs (i.e., His-tagged T4 and His-tag-free RT4) are recombinantly expressed in Chinese hamster ovary cells. The purities and binding kinetics are determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis, high-performance liquid chromatography, and surface plasmon resonance assays. The AlF restrained complexing agent (RESCA) method is applied to develop ¹⁸F-labeled sdAb tracers ([¹⁸F]AlF-RESCA-T4 and [¹⁸F]AlF-RESCA-RT4), followed by thorough preclinical imaging and blocking studies on tumor-bearing mice and a pilot clinical trial evaluating the clinical imaging safety and feasibility of [¹⁸F]AlF-RESCA-T4 immuno-PET/CT. Results: [¹⁸F]AlF-RESCA-T4 and [¹⁸F]AlF-RESCA-RT4 possess high radiochemical purities. Preclinical imaging in the T3M-4 tumor model revealed prominent uptake (percentage injected dose/g) of [¹⁸F]AlF-RESCA-T4 (11.13 ± 1.53, n = 4) and [¹⁸F]AlF-RESCA-RT4 (8.83 ± 1.22, n = 4), which were significantly reduced by coinjection of unlabeled T4 and RT4 in blocking studies. The His-tag removal strategy further optimized the probe's in vivo pharmacokinetics and reduced renal radioactivity accumulation without significantly decreasing tumor uptake. In a pilot clinical trial, [¹⁸F]AlF-RESCA-T4 immuno-PET/CT showed promising potency in annotating Trop2 expression and differentiating tumors from inflammatory diseases such as tuberculosis. Conclusion: [¹⁸F]AlF-RESCA-T4 and [¹⁸F]AlF-RESCA-RT4 can specifically annotate Trop2 expression. Clinical [¹⁸F]AlF-RESCA-T4 immuno-PET/CT imaging can screen patients for Trop2-targeted therapies and differentiate lung inflammation from cancer.

Several studies have demonstrated strong agreement between routine clinical visual assessment and quantification, suggesting that quantification approaches could support assessment by less experienced readers or in challenging cases. However, all studies to date have implemented a retrospective case collection, and challenging cases were generally underrepresented. Methods: We included all participants (n = 741) from the AMYPAD diagnostic and patient management study with available baseline amyloid PET quantification. Quantification was done with the PET-only AmyPype pipeline, providing global Centiloid and regional z scores. Visual assessment was performed by local readers for the entire cohort. From the total cohort, we selected a subsample of 85 cases for which the amyloid status based on the local reader's visual assessment and the Centiloid classification (cutoff = 21) was discordant or that were assessed with low confidence (i.e., ≤3 on a 5-point scale) by the local reader. In addition, concordant negative (n = 8) and positive (n = 8) scans across tracers were selected. In this sample (n = 101 cases; [¹⁸F]flutemetamol, n = 48; [¹⁸F]florbetaben, n = 53), the visual assessments and corresponding confidence by 5 certified independent central readers were captured before and after disclosure of the quantification results. Results: For the whole AMYPAD diagnostic and patient management study cohort, overall assessment by local readers highly agreed with Centiloid status (κ = 0.85, 92.3% agreement). This was consistently observed within disease stages (subjective cognitive decline-plus, κ = 0.82, 92.3% agreement; mild cognitive impairment, κ = 0.80, 89.8% agreement; dementia, κ = 0.87, 94.6% agreement). Across all central reader assessments in the challenging subsample, quantification of global Centiloid and regional z scores was considered supportive of visual reads in 70.3% and 49.3% of assessments, respectively. After disclosure of the quantitative results, we observed improvement in concordance across the 5 readers (baseline κ = 0.65, 65.3% agreement; κ after disclosure = 0.74, 73.3% agreement) and a significant increase in reader confidence (baseline mean (M) = 4.0 vs. M after disclosure = 4.34, Wilcoxon statistic (W) = 101,056, P < 0.001). Conclusion: In this clinical study enriched for challenging amyloid PET cases, we demonstrate the value of quantification to support visual assessment. After disclosure, both interreader agreement and confidence showed significant improvement. These results are important considering the arrival of antiamyloid therapies, which used the Centiloid metric for trial inclusion and target engagement. Moreover, quantification could support determination of amyloid-β status with high certainty, an important factor for treatment initiation.

The VISION and TheraP trials introduced different PET-based criteria for patient selection for treatment with ¹⁷⁷Lu-PSMA-617 (LuPSMA). TheraP used a higher prostate-specific membrane antigen (PSMA) uptake threshold than VISION and required ¹⁸F-FDG PET to exclude patients with discordant findings. Although the screen-failed patients had shorter overall survival (OS) than those treated with LuPSMA, it remains unclear whether their outcomes might have been modified if they had been exposed to LuPSMA. In this study, we evaluated associations between the TheraP eligibility criteria and subgroups and the treatment outcomes of patients who were deemed suitable and treated on the basis of VISION criteria. Methods: Consecutive patients who were treated with LuPSMA and who underwent pretreatment PSMA and ¹⁸F-FDG PET were classified as TheraP-eligible (TheraP-E) and TheraP-ineligible (TheraP-I), the latter of which were subclassified as low PSMA or discordant. Odds ratios for an at least 50% decline in prostate-specific antigen (PSA50) were computed using logistic regression, and hazard ratios (HRs) for PSA progression-free survival (PSA-PFS) and OS were computed using Cox regressions. Multivariable analyses were adjusted for baseline imaging and clinical parameters. Results: Of 75 patients, 31 (41%) were deemed TheraP-I; of those, 24 were subclassified as having discordant disease. TheraP-I patients had a lower PSA50 rate than that of TheraP-E patients (28% vs. 67%; odds ratio, 0.19; 95% CI, 0.06-0.52; P = 0.002) and a higher risk of PSA progression (HR, 2.0; 95% CI, 1.2-3.3; P = 0.007). OS in the TheraP-I group was numerically shorter than in the TheraP-E group, but the comparison was only marginally significant (10.4 mo vs. not reached; HR, 1.9; 95% CI, 1.0-3.7; P = 0.054). TheraP-I patients with low PSMA had no significantly different risk of death (P = 0.9) from that of TheraP-E patients, but those with discordant findings had higher risk of death (HR, 2.3; 95% CI, 1.1-4.6; P = 0.02). Discordant disease remained prognostic for OS after adjusting for baseline imaging and clinical parameters (HR, 3.0; 95% CI, 1.3-6.8; P = 0.01). Conclusion: In VISION-eligible patients who were treated with LuPSMA, TheraP-I patients with discordant findings had lower PSA50, PSA-PFS, and OS. Our study suggests that the shorter OS of TheraP-I patients is mainly driven by the presence of discordant disease.

This study aimed to investigate the diagnostic efficacy of [⁶⁸Ga]Ga-NYM046 PET/CT in animal models and patients with clear cell renal cell carcinoma (ccRCC) and to compare its performance with that of ¹⁸F-FDG PET/CT. Methods: The in vivo biodistribution of [⁶⁸Ga]Ga-NYM046 was evaluated in mice bearing OS-RC-2 xenografts. Twelve patients with ccRCC were included in the study; all completed paired [⁶⁸Ga]Ga-NYM046 PET/CT and ¹⁸F-FDG PET/CT. The diagnostic efficacies of these 2 PET tracers were compared. Moreover, the positive rate of carbonic anhydrase IX in the pathologic tissue sections was compared with the SUV_max obtained by PET/CT. Results: The tumor accumulation of [⁶⁸Ga]Ga-NYM046 at 1 h after injection in OS-RC-2 xenograft tumor models was 7.21 ± 2.39 injected dose per gram of tissue. Apart from tumors, the kidney and stomach showed high-uptake distributions. In total, 9 primary tumors, 96 involved lymph nodes, and 147 distant metastases in 12 patients were evaluated using [⁶⁸Ga]Ga-NYM046 and ¹⁸F-FDG PET/CT. Compared with ¹⁸F-FDG PET/CT, [⁶⁸Ga]Ga-NYM046 PET/CT detected more primary tumors (9 vs. 1), involved lymph nodes (95 vs. 92), and distant metastases (137 vs. 127). In quantitative analysis, the primary tumors' SUV_max (median, 13.5 vs. 2.4; z = -2.668, P = 0.008) was significantly higher in [⁶⁸Ga]Ga-NYM046 PET/CT. Conversely, the involved lymph nodes' SUV_max (median, 5.9 vs. 7.6; z = -3.236, P = 0.001) was higher in ¹⁸F-FDG PET/CT. No significant differences were found for distant metastases (median SUV_max, 5.0 vs. 5.0; z = -0.381, P = 0.703). Higher [⁶⁸Ga]Ga-NYM046 uptake in primary tumors corresponded to higher expression of carbonic anhydrase IX, with an R ² value of 0.8274. Conclusion: [⁶⁸Ga]Ga-NYM046 PET/CT offers a viable strategy for detecting primary tumors, involved lymph nodes, and distant metastases in patients with ccRCC.

Our laboratory recently developed [¹¹C]PS13 as a PET radioligand to selectively measure cyclooxygenase-1 (COX-1). The cyclooxygenase enzyme family converts arachidonic acid into prostaglandins and thromboxanes, which mediate inflammation. The total brain uptake of [¹¹C]PS13, which is composed of both specific binding and background uptake, can be accurately quantified with gold standard methods of compartmental modeling. This study sought to quantify the specific binding of [¹¹C]PS13 to COX-1 in healthy human brain using scans performed with arterial input function at baseline and after blockade by the COX-1-selective inhibitor ketoprofen. Methods: Eight healthy volunteers underwent two 90-min [¹¹C]PS13 PET scans with radiometabolite-corrected arterial input function, at baseline and about 2 h after oral administration of ketoprofen (75 mg). Results: Two-tissue compartment modeling effectively identified the total uptake of radioactivity in the brain (as distribution volume), showing the highest densities in the hippocampus, the occipital cortex, and the banks of the central sulcus. All brain regions exhibited displaceable and specific binding, and thus none could be used as a reference region. Ketoprofen blocked approximately 84% of the binding sites on COX-1 in the whole brain. After full occupancy was extrapolated, the average whole-brain values of [¹¹C]PS13 were 1.6 ± 0.8 mL·cm^-3 for specific uptake, 1.7 ± 0.6 mL·cm^-3 for background uptake, and 1.1 ± 0.5 for the specific-to-background ratio. The hippocampus had the highest specific-to-background ratio value of 2.7 ± 0.9. Conclusion: [¹¹C]PS13 exhibited high specific binding to COX-1 in the human brain, but its quantification requires arterial blood sampling.

¹⁷⁷Lu-vipivotide tetraxetan prostate-specific membrane antigen (¹⁷⁷Lu-PSMA) therapy is under current scientific investigation and aims to become established in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, real-world evidence in treatment comparison is scant. Methods: We relied on the FRAMCAP database and compared cabazitaxel versus ¹⁷⁷Lu-PSMA therapy in mCRPC patients regarding progression-free survival (PFS) and overall survival (OS). Sensitivity analyses addressed second- to fourth-line mCRPC treatment to approximate current phase III patient selection criteria. Results: Of 373 patients, 14% received cabazitaxel, 65% received ¹⁷⁷Lu-PSMA, and 21% received both. Patients undergoing ¹⁷⁷Lu-PSMA therapy were significantly older than cabazitaxel patients (median, 72 y vs. 66 y; P < 0.01), and a higher proportion had an Eastern Cooperative Oncology Group score of 2 or more (12% vs. 5.0%, P = 0.1). Rates of a prostate-specific antigen decline of at least 50% were 32% versus 0% for ¹⁷⁷Lu-PSMA versus cabazitaxel. In outcome analyses, significant superior median PFS was observed for ¹⁷⁷Lu-PSMA versus cabazitaxel (13.4 mo vs. 7.1 mo, P < 0.001), even after multivariable adjustment (hazard ratio, 0.38; P < 0.001). Regarding OS, rates also significantly differed, with median OS of 14.7 mo versus 16.5 mo versus 29.6 mo for cabazitaxel versus ¹⁷⁷Lu-PSMA versus both treatments (P < 0.01). In sensitivity analyses of second- to fourth-line mCRPC treatment, PFS rates and median OS rates for cabazitaxel versus ¹⁷⁷Lu-PSMA versus both therapies qualitatively remained the same as for the entire cohort. Conclusion: In a real-world setting, ¹⁷⁷Lu-PSMA provides significantly better PFS and qualitatively better OS rates than does cabazitaxel chemotherapy and should therefore be considered a valuable treatment option for advanced mCRPC patients according to the European Medicines Agency approval.

Over the last 2 decades, significant progress has been made in our understanding of the genomics, tumor immune microenvironment, and immunogenicity of malignant melanoma. Historically, the prognosis for metastatic melanoma was poor because of limited treatment options. However, after multiple landmark clinical trials displaying the efficacy of combined BRAF/MEK inhibition for BRAF-mutant melanoma and the application of immune checkpoint inhibitors targeting the programmed death-1, cytotoxic T-lymphocyte antigen-4, and lymphocyte activation gene-3 molecules, overall survival rates have dramatically improved. The role of immune checkpoint inhibition has since expanded to the neoadjuvant and adjuvant settings with multiple regimens in routine use. Personalized therapies, including tumor-infiltrating lymphocytes that are extracted from a patient's melanoma and eventually reinfused into the patient, and messenger RNA vaccines used to target neoantigens unique to a patient's tumor, show promise. Improvements in accompanying imaging modalities, particularly within the field of nuclear medicine, have allowed for more accurate staging of disease and assessment of treatment response. Continued growth in the role of nuclear medicine in the evaluation of melanoma, including the incorporation of artificial intelligence into image interpretation and use of radiolabeled tracers allowing for intricate imaging of the tumor immune microenvironment, is expected in the coming years.