Biodistribution and radiation dosimetry of multiple tracers on total-body positron emission tomography/computed tomography.

Background: [18F]F-FDG, [68Ga]Ga-PSMA-11, and [68Ga]Ga-FAPI-04 have achieved good results in multiple clinical trials and clinical practice, but the imaging of these tracers is limited to traditional short-axis positron emission tomography/computed tomography (PET/CT). Therefore, we aimed to use total-body PET/CT dynamic scanning to describe whole-body biodistribution of these three tracers and to calculate more precise radiation doses. Methods: Total-body PET/CT (uExplorer, United Imaging Healthcare) dynamic scanning was performed on 54 patients, including 30 patients with [18F]F-FDG, 10 patients with [68Ga]Ga-PSMA-11, and 14 patients with [68Ga]Ga-FAPI-04. A 60-minute dynamic scanning of whole body was performed simultaneously after bedside bolus injection of the corresponding tracers. The dynamic sequence of 92 frames was quantitatively analyzed by the Pmod4.0 software. Whole body biodistribution was calculated as time-activity curves (TACs) describing dynamic uptake patterns in the subject's major organs, followed by calculation of tracer kinetics and cumulative organ activity. Finally, combined with the OLINDA/EXM software, effective doses of the different tracers and individual organ doses were calculated. Results: In a systematic TAC analysis of three tracers, we identified distinct biodistribution patterns in major organs. [68Ga]Ga-PSMA-11 showed a trend of rapid increasing and slow decreasing in liver, spleen, muscle, and bone. In the heart, stomach, brain, and lung, tracer decreased rapidly after rapid increasing. Similarly, tracer uptake in the kidney and urinary bladder increased gradually. [68Ga]Ga-FAPI-04 showed a rapid increasing and rapid decreasing trend in brain, lung, liver, spleen, bone, heart, kidney, and stomach. The mean effective dose of [68Ga]Ga-PSMA-11 was 1.47E-02 mSv/MBq, and the mean effective doses of [18F]F-FDG and [68Ga]Ga-FAPI-04 were comparable (2.52E-02 mSv/MBq and 2.23E-02 mSv/MBq). The mean effective dose of [18F]F-FDG was lower than that reported in the literature measured by previous short-axis PET, while both [68Ga]Ga-PSMA-11 and [68Ga]Ga-FAPI-04 had higher value than previously reported value. Conclusions: [18F]F-FDG, [68Ga]Ga-PSMA-11 and [68Ga]Ga-FAPI-04 have good biodistribution in human organs. Real-time high-sensitivity dynamic scanning with total-body PET/CT is a very effective way to accurately calculate biodistribution and effective dose of positron-labeled radiopharmaceuticals.

Improved [68Ga]Ga-PSMA-11 image qualities reconstructed by total variation regularized expectation maximization on total-body PET/CT.

Background: Total variation regularized expectation maximization (TVREM) reconstruction algorithm on the image quality of gallium (68GA) prostate-specific membrane antigen-11 ([68Ga]Ga-PSMA-11) total-body positron emission tomography/computed tomography (PET/CT). Methods: Images of a phantom with small hot sphere inserts and the total-body PET/CT scans of 51 prostate cancer patients undergoing [68Ga]Ga-PSMA-11 were reconstructed using TVREM with 5 different penalization factors between 0.09 and 0.45 and for 20-, 40-, 60-, 120-, and 300-second acquisition, respectively. As a comparison, the same data were also reconstructed using the ordered subset expectation maximization (OSEM) with 3 iterations, 20 subsets, and 300 second acquisition. The contrast recovery coefficients (CRC) and background variability (BV) of the phantom, the tumor-to-background ratios (TBR), the contrast recovery (CR) ratio, the image noise of the liver, and maximum standard uptake value (SUVmax) of the lesions were calculated to evaluate the image quality. The clinical performance of the images was evaluated by 2 radiologists with a 5-point scale (1-poor, 5-excellent). Results: The TVREM reconstructions groups fwith 120 second acquisition and the penalization of 0.27 to 0.45 showed the best performance in terms of CR, TBR, image noise, and the gain of SUVmax compared to that obtained in the OSEM 300 second group. Even the image noise of the TVREM 120 second group with a penalization factor of 0.27 and 0.36 was comparable to the OSEM 300 second group; the lesions' SUVmax increased by 28% whereas the image noise decreased by 5% and 14%, respectively. The TVREM 120 second group with a penalization factor of 0.36 (5.00±0.00) had the highest qualitative score that equaled OSEM and TVREM for the 300 second (P>0.05) group. Conclusions: Our study has shown the potential of the TVREM reconstruction algorithm with optimized penalization factors to achieve comparable [68Ga]Ga-PSMA-11 total-body PET/CT image quality with a shorter acquisition time, compared with the conventional OSEM reconstruction algorithm.

Relationship between the expression of PD-L1 and 18F-FDG uptake in pancreatic ductal adenocarcinoma.

BACKGROUND: PD-L1 promotes glycolysis in tumour cells. We observed a correlation between high PD-L1 expression and high 18F-FDG uptake in patients with pancreatic ductal adenocarcinoma (PDAC) in a previous study. This study aims to determine the usefulness of 18F-FDG PET/CT for evaluating the PD-L1 status in PDAC and to elucidate its rationality by integrated analyses. METHODS: For bioinformatics analysis, WGCNA, GSEA and TIMER were applied to analyse the pathways and hub genes associated with PD-L1 and glucose uptake. 18F-FDG uptake assay was used to determine the glucose uptake rate of PDAC cells in vitro. Related genes expression were verified by RT-PCR and western blot. A retrospective analysis was performed on 47 patients with PDAC who had undergone 18F-FDG PET/CT. Maximum standardised uptake values (SUVmax) were determined. The usefulness of SUVmax for evaluating PD-L1 status was determined by receiver operating characteristic (ROC) curve analysis. RESULTS: Bioinformatics analysis showed that several signalling pathways are associated with both PD-L1 expression and tumour glucose uptake, among which JAK-STAT may be an important one. By in vitro experiments, the regulatory role of PD-L1 on glucose uptake was demonstrated, and its dependency on the JAK-STAT pathway was also verified by the rescue study. The SUVmax of PD-L1-positive patients was significantly higher than PD-L1-negative in tumour cells (TCs) (6.1 ± 2.3 vs. 11.1 ± 4.2; P < 0.001), and in tumour-infiltrating immune cells (TIICs) (6.4 ± 3.2 vs. 8.4 ± 3.5; P < 0.001). In a multivariate analysis, SUVmax was significantly associated with PD-L1 expression in TCs and TIICs (P < 0.001 and P = 0.018, respectively). Using SUVmax cut-off values of 8.15 and 7.75, PD-L1 status in TCs and TIICs could be predicted with accuracies of 91.5% and 74.5%, respectively. CONCLUSION: Higher 18F-FDG uptake by PDAC is associated with elevated PD-L1 expression. JAK-STAT is an important pathway that mediates PD-L1 to promote glucose uptake in PDAC.

Preparation and validation of cyclodextrin-based excipients for radioiodinated hypericin applied in a targeted cancer radiotherapy.

BACKGROUND: Iodine-131 labeled hypericin (131I-Hyp) has been utilized as a necrosis-avid theragnostic tracer in a dual targeting pan-anticancer strategy called OncoCiDia. Widespread use of previously-tested solvent dimethyl sulfoxide (DMSO) is limited by safety concerns. To tackle this, the present study was designed to explore a clinically feasible excipient for the formulation of the hydrophobic 131I-Hyp for intravenous administration. METHOD: Solubility of Hyp in serial solutions of already-approved hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was evaluated by UVspectrophotometry and 50% HP-ß-CD was chosen for further experiments. Two novel HP-ß-CD-based formulations of 131I-Hyp were compared with previous DMSO-based formulation, with regards to necrosis-targetability and biodistribution, by magnetic resonance imaging, single-photon emission computed tomography (SPECT), gamma counting, autoradiography, fluorescence microscopy and histopathology. RESULTS: Hyp solubility was enhanced with increasing HP-ß-CD concentrations. The radiochemical purity of 131I-Hyp was higher than 90% in all formulations. The necrosis-targetability of 131I-Hyp in the novel formulations was confirmed in vivo by SPECT and in vitro by autoradiography, fluorescence microscopy and histopathology. The plasma clearance of radioactivity was faster in the novel formulations. CONCLUSION: The novel 131I-Hyp formulations with HP-ß-CD could be a suitable pharmaceutical excipient for 131I-Hyp for intravenous administration.

ImmunoPET imaging of human CD8+ T cells with novel 68Ga-labeled nanobody companion diagnostic agents.

BACKGROUND: Although immunotherapy has revolutionized treatment strategies for some types of cancers, most patients failed to respond or obtain long-term benefit. Tumor-infiltrating CD8+ T lymphocytes are closely related to the treatment outcome and prognosis of patients. Therefore, noninvasive elucidation of both systemic and tumor-infiltrating CD8+ T lymphocytes is of extraordinary significance for patients during cancer immunotherapy. Herein, a panel of 68Ga-labeled Nanobodies were designed and investigated to track human CD8+ T cells in vivo through immuno-positron emission tomography (immunoPET). RESULTS: Among the screened Nanobodies, SNA006a showed the highest binding affinity and specificity to both human CD8 protein and CD8+ cells in vitro, with the equilibrium dissociation constant (KD) of 6.4 × 10-10 M and 4.6 × 10-10 M, respectively. 68Ga-NOTA-SNA006 was obtained with high radiochemical yield and purity, and stayed stable for at least 1 h both in vitro and in vivo. Biodistribution and Micro-PET/CT imaging studies revealed that all tracers specifically concentrated in the CD8+ tumors with low accumulation in CD8- tumors and normal organs except the kidneys, where the tracer was excreted and reabsorbed. Notably, the high uptake of 68Ga-NOTA-SNA006a in CD8+ tumors was rapid and persistent, which reached 24.41 ± 1.00% ID/g at 1.5 h after intravenous injection, resulting in excellent target-to-background ratios (TBRs). More specifically, the tumor-to-muscle, tumor-to-liver, and CD8+ to CD8- tumor was 28.10 ± 3.68, 5.26 ± 0.86, and 19.58 ± 2.70 at 1.5 h, respectively. Furthermore, in the humanized PBMC-NSG and HSC-NPG mouse models, 68Ga-NOTA-SNA006a accumulated in both CD8+ tumors and specific tissues such as liver, spleen and lung where human CD8 antigen was overexpressed or CD8+ T cells located during immunoPET imaging. CONCLUSIONS: 68Ga-NOTA-SNA006a, a novel Nanobody tracer targeting human CD8 antigen, was developed with high radiochemical purity and high affinity. Compared with other candidates, the long retention time, low background, excellent TBRs of 68Ga-NOTA-SNA006a make it precisely track the human CD8+ T cells in mice models, showing great potential for immunotherapy monitoring and efficacy evaluation.

Delayed 18F FDG PET/CT Imaging in the Assessment of Residual Tumors after Transurethral Resection of Bladder Cancer.

Background Delayed fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT is used to diagnose bladder cancer. However, it remains difficult to determine whether a lesion with abnormal 18F FDG uptake is tumor residue or recurrence or if it is an inflammatory reaction in patients with bladder cancer after oncologic treatment. Purpose To determine the diagnostic performance of delayed 18F FDG PET/CT in the differentiation of residual tumors from postoperative inflammatory reactions in patients with bladder cancer after initial transurethral resection of bladder tumor (TURBT). Materials and Methods A retrospective clinical study between January 2015 and April 2018 was performed in 79 patients with bladder cancer who had undergone 18F FDG PET/CT within 1 month after initial TURBT. After PET/CT, all patients underwent a second surgery within 2 weeks to confirm the histologic nature of the suspicious lesion and to remove residual tumors. Uni- and multivariable analysis were used to identify predictive factors for residual bladder tumors. Results A total of 79 patients (61 men, 18 women; mean age, 63 years ± 11 [standard deviation]) were enrolled in this study. A total of 98 lesions was studied, 64 (65.3%) of which were residual tumors after initial TURBT. When compared with inflammatory reactions, residual tumors had higher mean standardized uptake value (SUVmean) (mean, 5.8 ± 2.0 vs 9.3 ± 5.4; P < .001), higher maximum standardized uptake value (SUVmax) (mean, 15.5 ± 9.8 vs 22.2 ± 13.6, P = .01), and greater lesion thickness (mean, 9.6 mm ± 4.1 vs 17.9 mm ± 11.1, P < .001) at 18F FDG PET/CT. SUVmean (odds ratio [OR], 1.2; 95% confidence interval [CI]: 1.0, 1.5; P = .049) and lesion thickness (OR, 1.2; 95% CI: 1.0, 1.3; P = .006 or OR, 1.2; 95% CI: 1.1, 1.3; P = .001) were identified as independent predictors for residual tumors with multivariable logistic regression analysis. On the basis of the threshold values of SUVmean and lesion thickness, we revealed a prediction rate of 37.5% (17 of 47), 85.4% (26 of 29), and 98.3% (21 of 22) for residual tumors in low-, moderate-, and high-risk subgroups, respectively. Conclusion Use of fluorine 18 fluorodeoxyglucose PET/CT to differentiate lesions after transurethral resection of bladder tumor indicates that higher mean standardized uptake values and greater lesion thickness are predictive factors for residual tumors in patients with bladder cancer after oncologic treatment. Published under a CC BY 4.0 license.

Is there an impact of 18F-FDG PET/CT on the surveillance and clinical management of recurrent ovarian cancer? Research based on a large sample in a single PET/CT center.

OBJECTIVES: The aim of the study was to evaluate the use of F-fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (CT) in the follow-up and clinical management of ovarian cancer patients after therapy. MATERIALS AND METHODS: A total of 152 ovarian cancer patients who had undergone therapy were evaluated. Clinical information, CA-125 levels, and traditional imaging findings were analyzed. According to the indication for PET/CT the patients were divided into five groups for assessing the role of (18)F-FDG PET/CT in the clinical management of ovarian cancer patients after therapy. A comparison was made between the PET/CT findings and the results of clinical follow-up. RESULTS: Of the 152 patients, 137 had follow-up results and 15 were lost to follow-up. A total of 105 patients were found to have recurrent tumor and 32 were found to be disease-free after long-term follow-up. The diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 98.3, 91.2, 96.8, 97.5, and 93.9%, respectively. PET/CT was especially useful in patients when indications were to diagnose suspected recurrence, assess disease progression, and evaluate therapeutic response. CONCLUSION: PET/CT has been proven to be extremely valuable in the evaluation of patients with recurrent ovarian cancer and is particularly helpful in guiding treatment planning.

Comparison of the effect of positive and negative oral contrast agents on (18)F-FDG PET/CT scan.

UNLABELLED: Our aim was to compare the effect of orally taken 1% diatrizoate meglumine, 5% mannitol and water before positron emission tomography/computerized tomography (PET/CT) scan on gastrointestinal tract delineation and fluorine-18-fluorodeoxyglucose ((18)F-FDG) uptake. Our methods were as follows: Sixty-one patients referred for PET/CT scan without gastrointestinal diseases were divided into three groups. One thousand mL of 1% diatrizoate meglumine was orally taken 50 min before PET/CT scan in Group 1 (n=25), 1000 mL 2.5% mannitol was orally taken before scan in Group 2 (n=20) and 1000 mL water was orally taken before scan in Group 3 (n=16). Serum glucose and insulin were tested before and 45 min after taking mannitol in Group 2 patients. Paired t test was used to compare the glucose and insulin changes. The degree of gastrointestinal filling and (18)F-FDG uptake were evaluated by three nuclear medicine physicians using a 4 grade classification standard. Kruskal-Wallis and Mann- Whitney none parametric test was used to compare the filling condition and (18)F-FDG uptake difference among the three groups and between each group. RESULTS: the differences of serum glucose and insulin levels were not significant before and after contrast taken, in Group 2 patients. Group 2 patients had better gastrointestinal filling than patients of Group 1. Also, Group 2 patients' gastrointestinal filling was better than in Group 3 except in rectum. The jejunum, ascending, transverse and descending colon were better filled in Group 1 patients than in Group 3 patients. The degree of (18)FFDG uptake in stomach, jejunum and ileum, in Group 2 were significantly lower than those of Group 3 (P<0.05). (18)F-FDG uptake in jejunum, in Group 1 was also lower than in Group 3 (P<0.05). (18)F-FDG uptake in ascending colon in Group 1 was higher than in Group 3 (P<0.05). (18)F-FDG uptake in transverse and descending colon, in both Group 1 and Group 2 was significantly higher than in Group 3 (P<0.05). (18)F-FDG uptake in rectum, in Group 2 was significantly higher than in Group 3 (P<0.01). The average maximum CT values in stomach, jejunum, ileum and ascending colon in Group 1 patients were: 132+/-23, 191+/-31, 313+/-47 and 374+/-53 Hounsfield units respectively (Mean+/-SD, P<0.01 between every two groups). In conclusion, patients who take iso-osmia mannitol have good gastrointestinal filling, less physiological (18)F-FDG uptake and may thus have better (18)F-FDG images displaying gastrointestinal abnormalities and differentiating pathological from physiological lesions.

Efficacy and safety of (32)P-nanocolloid for treatment of distant lymph node metastasis in VX2 tumor-bearing rabbits.

BACKGROUND: Eradication of micrometastases present in lymph nodes of cancer patients improves their prognosis significantly. Radionuclide therapy possesses the potential to eliminate such metastases. OBJECTIVE: This study was performed to evaluate the efficacy and safety of (32)P-nanocolloid therapy in the treatment of distant carcinoma cell metastases in lymph nodes of VX2 tumor-bearing rabbits. METHODS: To obtain VX2 tumor micrometastases in right armpit lymph nodes of 12 male New Zealand white rabbits, VX2 tumors were implanted by hypodermal inoculation into the right anterior limb. Animals were randomly divided into therapy (n = 6) and control (n = 6) groups. (32)P-nanocolloid (0.5 mCi), 95% of which was >50 nm in diameter, was administered to the therapy group, and saline was administered to the control group. Injections were given once weekly for 4 weeks. RESULTS: 2-Deoxy-2[(18)F]-fluoro-D -glucose positron emission tomography revealed that the number of involved lymph nodes and the maximum standardized uptake value decreased in the (32)P-nanocolloid therapy group as compared with the baseline or saline control group (P < 0.05). The expression of the lymphangiogenesis factors vascular endothelial growth factors (VEGF)-C and VEGF-D by VX2 tumor cells present in lymph nodes was significantly lower in the therapy group as compared with the control group. Additionally, apoptotic VX2 tumor cell death was significantly greater in lymph nodes of the therapy as compared with the control group (P < 0.01). With the exception of a decrease in white blood cells of peripheral blood (P < 0.05), standard laboratory values were unaffected throughout the course of therapy with (32)P-nanocolloid. CONCLUSIONS: These findings support treatment with (32)P-nanocolloid as a safe and effective approach for eradication of lymph node micrometastases.