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Fluorescent semiconductor quantum dots hold great potential for molecular imaging in vivo 1 , 2 , 3 , 4 , 5 . However, the utility of existing quantum dots for in vivo imaging is limited because they require excitation from external illumination sources to fluoresce, which results in a strong autofluorescence background and a paucity of excitation light at nonsuperficial locations. Here we present quantum dot conjugates that luminesce by bioluminescence resonance energy transfer in the absence of external excitation. The conjugates are prepared by coupling carboxylate-presenting quantum dots to a mutant of the bioluminescent protein Renilla reniformis luciferase. We show that the conjugates emit long-wavelength (from red to near-infrared) bioluminescent light in cells and in animals, even in deep tissues, and are suitable for multiplexed in vivo imaging. Compared with existing quantum dots, self-illuminating quantum dot conjugates have greatly enhanced sensitivity in small animal imaging, with an in vivo signal-to-background ratio of > 10 3 for 5 pmol of conjugate.

Semiconductor quantum dots are inorganic fluorescent nanocrystals that, because of their unique optical properties compared with those of organic fluorophores, have become popular as fluorescent imaging probes. Although external light excitation is typically required for imaging with quantum dots, a new type of quantum dot conjugate has been reported that can luminesce with no need for external excitation. These self-illuminating quantum dot conjugates can be prepared by coupling of commercially available carboxylate-presenting quantum dots to the light-emitting protein Renilla luciferase. When the conjugates are exposed to the luciferase's substrate coelenterazine, the energy released by substrate catabolism is transferred to the quantum dots through bioluminescence resonance energy transfer, leading to quantum dot light emission. This protocol describes step-by-step procedures for the preparation and characterization of these self-illuminating quantum dot conjugates. The preparation process is relatively simple and can be done in less than 2 hours. The availability of self-illuminating quantum dot conjugates will provide many new possibilities for in vivo imaging and detection, such as monitoring of in vivo cell trafficking, multiplex bioluminescence imaging and new quantum dot-based biosensors.

PurposeTo evaluate acquisition time and clinical image quality of a variable refocusing flip angle (vrf) single-shot fast spin echo (SSFSE) sequence in comparison with a conventional SSFSE sequence for imaging of liver lesions in patients undergoing whole-body PET/MRI for oncologic staging.MethodsA vrfSSFSE sequence was acquired in 43 patients with known pancreatic neuroendocrine tumors undergoing 68Ga-DOTA-TOC PET on a simultaneous time-of-flight 3.0T PET/MRI. Liver lesions ≥1.5 cm with radionucleotide uptake were analyzed. Contrast-to-noise ratios (CNRs) were measured, and four blinded radiologists assessed overall image quality. Differences in repetition time and CNR were assessed using a paired Student’s t test with p < 0.05 considered statistically significant. Inter-reader variability was assessed with Fleiss’ kappa statistic.Results53 eligible lesions in 27 patients were included for analysis. vrfSSFSE demonstrated higher mean lesion CNR compared to SSFSE (9.9 ± 4.1 vs. 6.7 ± 4.1, p < 0.001). Mean repetition time (TR) was 679 ± 97 ms for the vrfSSFSE sequence compared to 1139 ± 106 ms for SSFSE (p < 0.0001), corresponding to a 1.7-fold decrease in acquisition time. Overall quality of liver lesion and common bile duct images with the vrfSSFSE sequence was graded as superior than or equivalent to the SSFSE sequence for 59% and 67% of patients, respectively.ConclusionsCompared to conventional SSFSE, vrfSSFSE resulted in improved lesion contrast on simultaneous PET/MRI in patients with liver metastases. Due to decreased SAR demands, vrfSSFSE significantly decreased TR, allowing coverage of the entire liver in a single twenty-second breath hold. This may have important clinical implications in the setting of PET/MRI, where scan time is limited by the necessity of whole-body image acquisition in addition to bed specific imaging.

National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical Ga-RM2 in patients with biochemical recurrence of prostate cancer. This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent Ga-RM2 PET-MRI. The primary outcome was the proportion of patients with PET-positive findings on Ga-RM2 PET-MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by Ga-RM2 PET-MRI and the detection by Ga-RM2 PET-MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete. Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7-59·2). The primary endpoint was met; Ga-RM2 PET-MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis Ga-RM2 PET-MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported. Ga-RM2 PET-MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients. The US Department of Defense.

National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer. This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET–MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET–MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET–MRI and the detection by 68Ga-RM2 PET–MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete. Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7–59·2). The primary endpoint was met; 68Ga-RM2 PET–MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET–MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported. 68Ga-RM2 PET–MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients. The US Department of Defense.

PurposeThe purpose of this study is to prospectively evaluate the performance of sodium 18F]fluoride (Na[18F]F)/2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) simultaneous time-of-flight enabled positron emission tomography (PET)/magnetic resonance imaging (MRI) for the detection of skeletal metastases in selected patients with advanced breast and prostate cancers.ProcedureThe institutional review board approved this HIPAA-compliant protocol. Written informed consent was obtained from each patient. A total of 74 patients (23 women and 51 men with breast and prostate cancer, respectively) referred for standard-of-care whole-body bone scintigraphy (WBBS) were enrolled in this prospective study. All patients underwent a [99mTc]methyldiphosphonate ([99mTc]MDP) WBBS followed by Na[18F]F/[18F]FDG PET/MRI. Lesions detected by each imaging modality were tabulated and a lesion-based and patient-based analysis was conducted.ResultsOn a patient-based analysis, [99mTc]MDP WBBS identified skeletal lesions in 37 patients and PET/MRI in 45 patients. On a lesion-based analysis, WBBS identified a total of 81 skeletal lesions, whereas PET/MRI identified 140 lesions. Additionally, PET/MRI showed extra-skeletal lesions in 19 patients, including lymph nodes (16), prostate (4) lung (3), and liver (2) lesions.ConclusionsThe ability of Na[18F]F/[18F]FDG PET/MRI to identify more skeletal lesions than 99mTc-MDP WBBS and to additionally identify extra-skeletal disease may be beneficial for patient care and represent an alternative to the single modalities performed separately. Na[18F]F/[18F]FDG PET/MRI is a promising approach for evaluation of skeletal and extra-skeletal lesions in a selected population of breast and prostate cancer patients.

Recent developments have established molecular imaging of mouse models with small-animal PET and bioluminescence imaging (BLI) as an important tool in cancer research. One of the disadvantages of these imaging modalities is the lack of anatomic information. We combined small-animal PET and BLI technology with small-animal CT to obtain fusion images with both molecular and anatomic information. We used small-animal PET/CT and BLI to detect xenografts of different cell lines and metastases of a melanoma cell line (A375M-3F) that had been transduced with a lentiviral vector containing a trimodality imaging reporter gene encoding a fusion protein with Renilla luciferase, monomeric red fluorescent protein, and a mutant herpes simplex virus type 1 thymidine kinase. Validation studies in mouse xenograft models showed a good coregistration of images from both PET and CT. Melanoma metastases were detected by 18F-FDG PET, 9-[4-(18)F-fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG) PET, CT, and BLI and confirmed by ex vivo assays of Renilla luciferase and mutant thymidine kinase expression. 18F-FHBG PET/CT allowed detection and localization of lesions that were not seen on CT because of poor contrast resolution and were not seen on 18F-FDG PET because of higher background uptake relative to 18F-FHBG. The combination of 18F-FHBG PET, small-animal CT, and BLI allows a sensitive and improved quantification of tumor burden in mice. This technique is potentially useful for the study of the biologic determinants of metastasis and for the evaluation of novel cancer treatments.

To evaluate the performance of computed high b value diffusion-weighted images (DWI) in prostate cancer detection. 97 consecutive patients who had undergone multiparametric MRI of the prostate followed by biopsy were reviewed. Five radiologists independently scored 138 lesions on native high b-value images (b = 1200 s/mm 2 ), apparent diffusion coefficient (ADC) maps, and computed high b-value images (contrast equivalent to b = 2000 s/mm 2 ) to compare their diagnostic accuracy. Receiver operating characteristic (ROC) analysis and McNemar’s test were performed to assess the relative performance of computed high b value DWI, native high b-value DWI and ADC maps. No significant difference existed in the area under the curve (AUC) for ROCs comparing B1200 (b = 1200 s/mm 2 ) to computed B2000 (c-B2000) in 5 readers. In 4 of 5 readers c-B2000 had significantly increased sensitivity and/or decreased specificity compared to B1200 (McNemar’s p < 0.05), at selected thresholds of interpretation. ADC maps were less accurate than B1200 or c-B2000 for 2 of 5 readers (P < 0.05). This study detected no consistent improvement in overall diagnostic accuracy using c-B2000, compared with B1200 images. Readers detected more cancer with c-B2000 images (increased sensitivity) but also more false positive findings (decreased specificity).

PurposeMagnetic resonance imaging (MRI) sequences with conical k-space trajectories are able to decrease motion artifacts while achieving ultrashort echo times (UTE). We assessed the performance of free-breathing conical UTE MRI in the evaluation of the pediatric pelvis for suspected appendicitis.MethodsOur retrospective review of 84 pediatric patients who underwent MRI for suspected appendicitis compared three contrast-enhanced sequences: free-breathing conical UTE, breath-hold three-dimensional (3D) spoiled gradient echo (BH-SPGR), and free-breathing high-resolution 3D SPGR (FB-SPGR). Two radiologists performed blinded and independent evaluations of each sequence for image quality (four point scale), anatomic delineation (four point scale), and diagnostic confidence (five point scale). Subsequently, the three sequences were directly compared for overall image quality (− 3 to + 3 scale). Scores were compared using Kruskal–Wallis and Wilcoxon signed-rank tests.ResultsUTE demonstrated significantly better perceived signal-to-noise ratio (SNR) and fewer artifacts than BH-SPGR and FB-SPGR (means of 3.6 and 3.4, 3.4 and 3.2, 3.1 and 2.7, respectively; p < 0.0006). BH-SPGR and FB-SPGR demonstrated significantly better contrast than UTE (means of 3.6, 3.4, and 3.2, respectively; p < 0.03). In the remaining categories, UTE performed significantly better than FB-SPGR (p < 0.00001), while there was no statistical difference between UTE and BH-SPGR. Direct paired comparisons of overall image quality demonstrated the readers significantly preferred UTE over both BH-SPGR (mean + 0.5, p < 0.00001) and FB-SPGR (mean + 1.2, p < 0.00001).ConclusionsIn the evaluation of suspected appendicitis, free-breathing conical UTE MRI performed better in the assessed metrics than FB-SPGR. When compared to BH-SPGR, UTE demonstrated superior perceived SNR and fewer artifacts.

Background Single-shot fast spin echo (SSFSE) is particularly appealing in pediatric patients because of its motion robustness. However radiofrequency energy deposition at 3 tesla forces long pauses between slices, leading to longer scans, longer breath-holds and more between-slice motion. Objective We sought to learn whether modulation of the SSFSE refocusing flip-angle train could reduce radiofrequency energy deposition without degrading image quality, thereby reducing inter-slice pauses and overall scan times. Materials and methods We modulated the refocusing flip-angle train for SSFSE to minimize energy deposition while minimizing blurring and motion-related signal loss. In a cohort of 50 consecutive patients (25 boys, mean age 5.5 years, range 1 month to 17 years) referred for abdominal MRI we obtained standard SSFSE and variable refocusing flip-angle (vrfSSFSE) images and recorded sequence scan times. Two readers independently scored the images in blinded, randomized order for noise, tissue contrast, sharpness, artifacts and left lobe hepatic signal uniformity on a four-point scale. The null hypothesis of no difference between SSFSE and vrfSSFSE image-quality was assessed with a Mann–Whitney U test, and the null hypothesis of no scan time difference was assessed with the paired t -test. Results SSFSE and vrfSSFSE mean acquisition times were 54.3 and 26.2 s, respectively ( P -value <0.0001). For each reader, SSFSE and vrfSSFSE noise, tissue contrast, sharpness and artifacts were not significantly different ( P -values 0.18–0.86). However, SSFSE had better left lobe hepatic signal uniformity ( P  < 0.01, both readers). Conclusion vrfSSFSE is twice as fast as SSFSE, with equivalent image quality with the exception of left hepatic lobe signal heterogeneity.