Personalized PET Imaging in Gastric Cancer: An Umbrella Review of Meta-Analyses to Guide Radiopharmaceutical Selection and Clinical Indication.

Objective The urokinase-type plasminogen activator receptor (uPAR) is a well-established prognostic biomarker in many cancer types including breast cancer (BC). Numerous studies using immunohistochemically evaluation of uPAR expression in tissue samples from BC patients have shown that not only is uPAR consistently overexpressed, but also carries strong prognostic value and is associates with overall survival. Accordingly, uPAR is an obvious target for identifying BC and for phenotyping aggressiveness in BC. Using whole body Positron Emission Tomography (PET) imaging rather than tissue specimens circumvents possible sampling error and allows for staging. Our objective was therefore to perform first-in-humans studies of uPAR-specific PET imaging in BC using either 64Cu-DOTA-AE105 or 68Ga-NOTA-AE105 Methods Six patients with BC and scheduled for surgery were included. Prior to operation, patients were either PET/CT scanned 1, 3 and 24 h after injection of the uPAR PET ligand 64Cu-DOTA-AE105 (n=3; half life of 64Cu: 13 h) or PET/CT scanned 10 min, 1 h or 2 h after injection of 68Ga-NOTA-AE105 (n=3; half life of 68Ga: 1 h). PET Images were visually analyzed for visible tumor uptake of 64Cu-DOTA-AE105 or 68Ga-NOTA-AE105 and Standardized Uptake Values (SUV) were obtained by manually drawing volumes of interest (VOIs) around the primary tumor as well as identified metastases. Results are given as SUVmax. Tumor-to-background ratios relative to liver, kidney, blood and muscle were also calculated. Surgical tumor specimens were obtained from all patients during subsequent surgery. In addition to routine pathological examination, tissue was analyzed for ex vivo uPAR expression as target validation. Results Both primary tumors and metastases were visually detectable. For 64Cu-DOTA-AE105 SUVmax values were 2.9–4.0., and 2.9-4.0 after 1 and 3 h, respectively. Tumor-to-background ratios after 1 h were 0.91 (tumor-liver), 1.65 (tumor-kidney), 0.96 (tumor-blood) and 8.9 (tumor-muscle), respectively. Tumor-to-background ratios after 3 h were 0.50 (tumor-liver), 0.96 (tumor-kidney), 4.2 (tumor-blood) and 11.4 (tumor-muscle), respectively. Ex vivo analysis by immunohistochemistry confirmed uPAR expression in all primary cancer lesions. For 68Ga-NOTA-AE105, SUVmax was 5.0, 3.8 and 4.2 after 10 min, 1 h and 3 h, respectively (first patient analyzed). Tumor-to-background ratios after 10 min were 2.8 (tumor-liver), 0.4 (tumor-kidney), 1.6 (tumor-blood) and 8.4 (tumor-muscle), respectively. Tumor-to-background ratios after 1 h were 3.2 (tumor-liver), 0.6 (tumor-kidney), 1.7 (tumor-blood) and 7.1 (tumor-muscle), respectively. Conclusion This is the first study in humans using PET imaging of uPAR in BC. Both primary tumors and metastases were clearly visible with robust PET tracer uptake and a high and sufficient contrast between tumors and background. Our data supports continuation into phase II clinical studies using uPAR PET for staging and risk stratification, which potentially may be used for selection of treatment strategy in BC. Citation Format: Kjaer A, Persson M, Skovgaard D, Brandt-Larsen M, Christensen C, Madsen J, Nielsen CH, Loft A, Berthelsen AK, Kroman N, Højgaard L. uPAR PET imaging in breast cancer: First-in-humans studies using 64Cu-DOTA-AE105 and 68Ga-NOTA-AE105. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-01-04.

The role and clinical value of EUS in a multimodality esophageal carcinoma staging program with CT and positron emission tomography

The overexpression of integrin αvβ6 in pancreatic cancer makes it a promising target for noninvasive PET imaging. However, currently, most integrin αvβ6-targeting radiotracers are based on linear peptides, which are quickly degraded in the serum by proteinases. Herein, we aimed to develop and assess a 68Ga-labeled integrin αvβ6-targeting cyclic peptide (68Ga-cycratide) for PET imaging of pancreatic cancer. Methods:68Ga-cycratide was prepared, and its PET imaging profile was compared with that of the linear peptide (68Ga-linear-pep) in an integrin αvβ6-positive BxPC-3 human pancreatic cancer mouse model. Five healthy volunteers (2 women and 3 men) underwent whole-body PET/CT imaging after injection of 68Ga-cycratide, and biodistribution and dosimetry were calculated. PET/CT imaging of 2 patients was performed to investigate the potential role of 68Ga-cycratide in pancreatic cancer diagnosis and treatment monitoring. Results:68Ga-cycratide exhibited significantly higher tumor uptake than did 68Ga-linear-pep in BxPC-3 tumor-bearing mice, owing-at least in part-to markedly improved in vivo stability. 68Ga-cycratide could sensitively detect the pancreatic cancer lesions in an orthotopic mouse model and was well tolerated in all healthy volunteers. Preliminary PET/CT imaging in patients with pancreatic cancer demonstrated that 68Ga-cycratide was comparable to 18F-FDG for diagnostic imaging and postsurgery tumor relapse monitoring. Conclusion:68Ga-cycratide is an integrin αvβ6-specific PET radiotracer with favorable pharmacokinetics and a favorable dosimetry profile. 68Ga-cycratide is expected to provide an effective noninvasive PET strategy for pancreatic cancer lesion detection and therapy response monitoring.

The use of fibroblast activation protein inhibitors (FAPis) for positron emission tomography (PET) imaging in cancer has garnered significant interest in recent years, yielding promising results in preclinical and clinical settings. FAP is predominantly expressed in pathological conditions such as fibrosis and cancer, making it a compelling target. An optimized approach involves using FAPi homodimers as PET tracers, which enhance tumor uptake and retention, making them more effective candidates for therapy. Here, a UAMC-1110 inhibitor-based homodimer, DOTAGA-Glu(FAPi)2, was synthesized and radiolabeled with gallium-68, and its efficacy was evaluated in vivo for PET imaging in an endogenously FAP-expressing xenografted mouse model, U87MG. Notably, 45 min post-injection, the mean uptake of [68Ga]Ga-DOTAGA-Glu(FAPi)2 was 4.7 ± 0.5% ID/g in the tumor with low off-target accumulation. The ex vivo analysis of the FAP expression in the tumors confirmed the in vivo results. These findings highlight and confirm the tracer's potential for diagnostic imaging of cancer and as a theranostic companion.

Positron Emission Tomography Imaging of Adenoviral-Mediated Transgene Expression in Liver Cancer Patients

Respiratory motion is known to deteriorate positron emission tomography (PET) images and may lead to potential diagnostic errors when a standardized uptake value (SUV) cut-off threshold is used to discriminate between benign and malignant lesions. To evaluate and compare ungated and respiratory-gated 18F-fluorodeoxyglucose PET/computed tomography (CT) methods for the characterization of pulmonary nodules. The list-mode acquisition during respiratory-gated PET was combined with a short breath-hold CT scan to form the CT-based images. We studied 48 lesions in 43 patients. PET images were analyzed in terms of the maximum SUV (SUV(max)) and the lesion location. Using receiver-operating characteristic (ROC) curves, the optimal SUV cut-off thresholds for the ungated and CT-based methods were calculated to be 2.0 and 2.2, respectively. The corresponding sensitivity values were 83% and 92%, respectively, with a specificity of 67% for both methods. The two methods gave equivalent performance levels for the upper and middle lobes (sensitivity 93%, specificity 62%). They differed for the lower lobes, where the CT-based method outperformed the ungated method (sensitivity values of 90% and 70%, respectively, and a specificity of 73% with both methods) - especially for lesions smaller than 15 mm. The CT-based method increased sensitivity and did not diminish specificity, compared with the ungated method. It was more efficient than the ungated method for imaging the lower lobes and smallest lesions, which are most affected by respiratory motion.

2-[18F]Fluoropropionic acid (RS-[18F]FPA) has shown potential value as a short-chain fatty acid positron emission tomography (PET) tracer for the detection of liver cancer. However, RS-[18F]FPA is a mixture of 2-R-[18F]fluoropropionic acid (R-[18F]FPA) and 2-S-[18F]fluoropropionic acid (S-[18F]FPA). The aim of this study is to validate the feasibility of R-[18F]FPA in preclinical PET imaging of liver cancer and to compare the use of R-[18F]FPA with that of RS-[18F]FPA and S-[18F]FPA. A comparative study of R-[18F]FPA, RS-[18F]FPA, S-[18F]FPA, and [18F]FDG micro-PET imaging was performed in HepG2 and SK-Hep-1 tumor-bearing mice. A comparison of R-[18F]FPA uptake with that of S-[18F]FPA by HepG2 and SK-Hep-1 cells was made at different time points. Additionally, in vivo blocking experiments in HepG2 and SK-Hep-1 tumor models were conducted with orlistat and 3-nitropropionic acid (3-NP). In vitro blocking experiments with orlistat or 3-NP were performed with HepG2 and SK-Hep-1 cells. The radioactivity uptake values of R-[18F]FPA were comparable to those of RS-[18F]FPA but were higher than those of S-[18F]FPA and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in HepG2 tumors. The radioactivity uptake values of R-[18F]FPA in large HepG2 tumors were lower than those of [18F]FDG (P < 0.05), while R-[18F]FPA PET was significantly superior to [18F]FDG PET in detecting small tumors (both SK-Hep-1 and HepG2 tumors). The in vivo PET imaging experiments showed that R-[18F]FPA uptake in HepG2 tumor-bearing mice was blocked by 19.3% and 31.8% after treatment with orlistat and 3-NP, respectively. The radioactivity uptake values of R-[18F]FPA in SK-Hep-1 tumor-bearing mice was blocked by 39.5% with orlistat. R-[18F]FPA seems to be more potential than S-[18F]FPA as an optically pure PET probe, with effective compensation for the deficiencies of [18F]FDG, particularly in PET imaging of small liver cancer. The uptake mechanism of [18F]FPA in liver cancer may be related to fatty acid synthesis and the tricarboxylic acid cycle. However, compared with the racemic RS-[18F]FPA, the possible advantages of R-enantiomer R-[18F]FPA still needs further research.

Positron emission tomography (PET) has shown an increase in both sensitivity and specificity over computed tomography (CT) in lung cancer. However, motion artifacts in the 18F fluorodioxydoglucose (FDG) PET images caused by respiration persists to be an important factor in degrading PET image quality and quantification. Motion artifacts lead to two major effects: First, it affects the accuracy of quantitation, producing a reduction of the measured standard uptake value (SUV). Second, the apparent lesion volume is overestimated. Both impact upon the usage of PET images for radiation treatment planning. The first affects the visibility, or contrast, of the lesion. The second results in an increase in the planning target volume, and consequently a greater radiation dose to the normal tissues. One way to compensate for this effect is by applying a multiple-frame capture technique. The PET data are then acquired in synchronization with the respiratory motion. Reduction in smearing due to gating was investigated in both phantoms and patient studies. Phantom studies showed a dependence of the reduction in smearing on the lesion size, the motion amplitude, and the number of bins used for data acquisition. These studies also showed an improvement in the target-to-background ratio, and a more accurate measurement of the SUV. When applied to one patient, respiratory gating showed a 28% reduction in the total lesion volume, and a 56.5% increase in the SUV. This study was conducted as a proof of principle that a gating technique can effectively reduce motion artifacts in PET image acquisition.

Recently carbon-11 acetate (AC) positron emission tomography (PET) has been reported to be of clinical value for the diagnosis of cancer that is negative on fluorine-18 fluorodeoxyglucoce (FDG) PET. We investigated the uptake of AC in lung cancer to determine whether this tracer is of potential value for tumour detection and characterisation, and to compare AC PET imaging with FDG PET and technetium-99m sestamibi (MIBI) single-photon emission tomography (SPET). Twenty-three patients with 25 lung cancers underwent AC and FDG PET. Twenty of 23 patients were also investigated with MIBI SPET. Dynamic images were acquired for 26 min after the injection of 555 MBq of AC. Standardised uptake values (SUVs) and/or tumour to non-tumour activity ratios (T/N) for each tumour were investigated at 10-20 min after AC administration, 40-60 min after administration of 185 MBq FDG and 15-45 min after administration of 555 MBq MIBI. Twenty lung cancers were resected surgically, and the degree of tracer uptake in the primary lesion was correlated with histopathological features (cell dedifferentiation and aggressiveness) and prognosis. Rapid uptake of AC followed by extremely slow clearance was observed. For the purpose of tumour identification, AC PET was inferior to FDG PET in 8 of 25 (32%) lung cancers, and the T/N of AC was lower than that of FDG. However, AC PET was superior to FDG PET in the identification of a slow-growing tumour (bronchiolo-alveolar carcinoma). There was a positive correlation between AC uptake (T/N) and MIBI uptake (T/N) (r=0.799, P<0.0001). A positive correlation was not observed between either AC or MIBI uptake and the degree of cell dedifferentiation in lung adenocarcinomas, whereas FDG uptake did correlate with the degree of cell dedifferentiation. In lung adenocarcinoma, there was a weak correlation between aggressiveness and FDG uptake, but no correlation was evident for AC and MIBI. In addition, a positive correlation was not observed between AC or MIBI uptake and postoperative recurrence in lung adenocarcinoma, whereas FDG uptake did correlate with postoperative recurrence. Thus, the greater the FDG uptake, the higher the malignant grade. In conclusion, for the purpose of tumour identification, AC PET was inferior to FDG PET but superior to MIBI SPET. Neither AC nor MIBI uptake reflects the malignant grade in lung adenocarcinoma, whereas FDG uptake does. AC PET is less diagnostically informative than FDG PET in patients with lung cancer. However, AC PET may play a complementary role in the identification of low-grade malignancies that are not FDG avid.

Positron Emission Tomography—the Promise of Metabolic Imaging

Human copper transporter 1 (CTR1) has been proven to be overexpressed in many types of cancer cells, and copper (II)-64 chloride (64CuCl2) has been used as an effective tracer for positron emission tomography (PET) imaging in tumor-bearing animal models. Thus, this study aimed to investigate the potential application of 64CuCl2 in PET imaging of lung cancer through targeting CTR1. The expression of CTR1 in a series of lung cancer cell lines was identified by quantitative real-time polymerase chain reaction (Q-PCR), western blot, enzyme-linked immunosorbnent assay (ELISA), and immunofluorescent staining. Then in vitro cell uptake assay of 64CuCl2 was investigated in human lung cancer cell lines with different levels of CTR1 expression. Small animal PET imaging and quantitative analysis were performed in human lung cancer tumor-bearing mice after intravenous injection of 64CuCl2, respectively. The CTR1 expression in multiple human lung cancer cells was identified and confirmed, and H1299 cell lines with high CTR1 expression, H460 with moderate CTR1, and H1703 with low CTR1 were selected for further experiments. In vitro cellular uptake assay displayed that the 64CuCl2 uptake by these three kinds of cells was positively correlated with their CTR1 expressed levels. The blocking experiments testified the specificity of 64CuCl2 to target CTR1. Moreover, small animal PET imaging and quantitative results showed that 64CuCl2 accumulation in H1299, H460, and H1703 tumor-bearing mice were consistent with CTR1 levels and cell uptake experiments. The expression of CTR1 in human lung cancer xenograft model could be successfully visualized by 64CuCl2 PET examination. With the expected growth of PET/CT examination to be an essential strategy in clinical lung cancer management, 64CuCl2 has the potential to be a promising PET imaging agent of lung cancer.

About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[18F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER+) breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three 18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by 18F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER+ MCF-7 tumor cells was highest for the less hydrophilic derivative (18F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER+ MCF-7 and T47D versus ER- MDA-MB-231), 18F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of 18F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60-90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of 18F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of 18F-TA-Glyco-EE to ER+ tumor slices. We conclude that 18F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer.

The axial field of view (AFOV) of a positron emission tomography (PET) scanner greatly affects the quality of PET images. Although a total-body PET scanner (uEXPLORER) with a large AFOV is more sensitive, it is more expensive and difficult to widely use. Therefore, we attempt to utilize high-quality images generated by uEXPLORER to optimize the quality of images from short-axis PET scanners through deep learning technology while controlling costs. The experiments were conducted using PET images of three anatomical locations (brain, lung, and abdomen) from 335 patients. To simulate PET images from different axes, two protocols were used to obtain PET image pairs (each patient was scanned once). For low-quality PET (LQ-PET) images with a 320-mm AFOV, we applied a 300-mm FOV for brain reconstruction and a 500-mm FOV for lung and abdomen reconstruction. For high-quality PET (HQ-PET) images, we applied a 1940-mm AFOV during the reconstruction process. A 3D Unet was utilized to learn the mapping relationship between LQ-PET and HQ-PET images. In addition, the peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM) were employed to evaluate the model performance. Furthermore, two nuclear medicine doctors evaluated the image quality based on clinical readings. The generated PET images of the brain, lung, and abdomen were quantitatively and qualitatively compatible with the HQ-PET images. In particular, our method achieved PSNR values of 35.41 ± 5.45dB (p < 0.05), 33.77 ± 6.18dB (p < 0.05), and 38.58 ± 7.28dB (p < 0.05) for the three beds. The overall mean SSIM was greater than 0.94 for all patients who underwent testing. Moreover, the total subjective quality levels of the generated PET images for three beds were 3.74 ± 0.74, 3.69 ± 0.81, and 3.42 ± 0.99 (the highest possible score was 5, and the minimum score was 1) from two experienced nuclear medicine experts. Additionally, we evaluated the distribution of quantitative standard uptake values (SUV) in the region of interest (ROI). Both the SUV distribution and the peaks of the profile show that our results are consistent with the HQ-PET images, proving the superiority of our approach. The findings demonstrate the potential of the proposed technique for improving the image quality of a PET scanner with a 320mm or even shorter AFOV. Furthermore, this study explored the potential of utilizing uEXPLORER to achieve improved short-axis PET image quality at a limited economic cost, and computer-aided diagnosis systems that are related can help patients and radiologists.

Positron emission tomography (PET) imaging has transformed diagnostic nuclear medicine and become an essential strategy in cancer management. With the expected growth of this molecular imaging modality, there is a recognized need for new PET probes to address the clinical challenges in the early diagnosis and staging of various types of cancers. In this endeavor, the prospect of using 64Cu in the form of simple Cu2+ ions as PET probe is not only a cost-effective proposition but also seems poised to broaden the palette of molecular imaging probes in the foreseeable future. The usefulness of 64Cu2+ ions as PET probe is based on the fact that Cu is an essential element that plays an important role in cell proliferation and angiogenesis. Over the past few years, there has been continuous flow of evidences based on studies in animal models on the uptake of 64Cu2+ ions in different types of tumors, including, hepatoma, colorectal cancer, prostate cancer, lung cancer, breast cancer, head and neck cancer, fibrosarcoma, melanoma, glioblastoma, and ovarian cancer. The widespread preclinical success of 64Cu2+ ions as PET probe has recently resulted in translation of this radiotracer to clinical settings for noninvasive imaging and staging of prostate cancer in human patients. In this concise review, we have focused on the latest developments in PET imaging of cancer in preclinical and clinical settings using 64Cu2+ ion as a probe and discussed the challenges and opportunities for future development.

Recently, deep learning-based methods have been established to denoise the low-count positron emission tomography (PET) images and predict their standard-count image counterparts, which could achieve reduction of injected dosage and scan time, and improve image quality for equivalent lesion detectability and clinical diagnosis. In clinical settings, the majority scans are still acquired using standard injection dose with standard scan time. In this work, we applied a 3D U-Net network to reduce the noise of standard-count PET images to obtain the virtual-high-count (VHC) PET images for identifying the potential benefits of the obtained VHC PETimages. The training datasets, including down-sampled standard-count PET images as the network input and high-count images as the desired network output, were derived from 27 whole-body PET datasets, which were acquired using 90-min dynamic scan. The down-sampled standard-count PET images were rebinned with matched noise level of 195 clinical static PET datasets, by matching the normalized standard derivation (NSTD) inside 3D liver region of interests (ROIs). Cross-validation was performed on 27 PET datasets. Normalized mean square error (NMSE), peak signal to noise ratio (PSNR), structural similarity index (SSIM), and standard uptake value (SUV) bias of lesions were used for evaluation on standard-count and VHC PET images, with real-high-count PET image of 90 min as the gold standard. In addition, the network trained with 27 dynamic PET datasets was applied to 195 clinical static datasets to obtain VHC PET images. The NSTD and mean/max SUV of hypermetabolic lesions in standard-count and VHC PET images were evaluated. Three experienced nuclear medicine physicians evaluated the overall image quality of randomly selected 50 out of 195 patients' standard-count and VHC images and conducted 5-score ranking. A Wilcoxon signed-rank test was used to compare differences in the grading of standard-count and VHCimages. The cross-validation results showed that VHC PET images had improved quantitative metrics scores than the standard-count PET images. The mean/max SUVs of 35 lesions in the standard-count and true-high-count PET images did not show significantly statistical difference. Similarly, the mean/max SUVs of VHC and true-high-count PET images did not show significantly statistical difference. For the 195 clinical data, the VHC PET images had a significantly lower NSTD than the standard-count images. The mean/max SUVs of 215 hypermetabolic lesions in the VHC and standard-count images showed no statistically significant difference. In the image quality evaluation by three experienced nuclear medicine physicians, standard-count images and VHC images received scores with mean and standard deviation of 3.34±0.80 and 4.26 ± 0.72 from Physician 1, 3.02 ± 0.87 and 3.96 ± 0.73 from Physician 2, and 3.74 ± 1.10 and 4.58 ± 0.57 from Physician 3, respectively. The VHC images were consistently ranked higher than the standard-count images. The Wilcoxon signed-rank test also indicated that the image quality evaluation between standard-count and VHC images had significantdifference. A DL method was proposed to convert the standard-count images to the VHC images. The VHC images had reduced noise level. No significant difference in mean/max SUV to the standard-count images was observed. VHC images improved image quality for better lesion detectability and clinicaldiagnosis.