Identifying G6PC3 as a Potential Key Molecule in Hypoxic Glucose Metabolism of Glioblastoma Derived from the Depiction of 18F-Fluoromisonidazole and 18F-Fluorodeoxyglucose Positron Emission Tomography.

Purpose: Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using fluorine-18-fluoromisonidazole (18F-FMISO) and fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) could depict the degree of glucose metabolism with hypoxic condition. However, molecular mechanism of glucose metabolism under hypoxia in glioblastoma has been unclear. The aim of this study was to identify the key molecules of hypoxic glucose metabolism. Methods: Using surgically obtained specimens, gene expressions associated with glucose metabolism were analyzed in patients with glioblastoma (n = 33) who underwent preoperative 18F-FMISO and 18F-FDG PET to identify affected molecules according to hypoxic condition. Tumor in vivo metabolic activities were semiquantitatively evaluated by lesion-normal tissue ratio (LNR). Protein expression was confirmed by immunofluorescence staining. To evaluate prognostic value, relationship between gene expression and overall survival was explored in another independent nonoverlapping clinical cohort (n = 17) and validated by The Cancer Genome Atlas (TCGA) database (n = 167). Results: Among the genes involving glucose metabolic pathway, mRNA expression of glucose-6-phosphatase 3 (G6PC3) correlated with 18F-FDG LNR (P = 0.03). In addition, G6PC3 mRNA expression in 18F-FMISO high-accumulated glioblastomas was significantly higher than that in 18F-FMISO low-accumulated glioblastomas (P < 0.01). Protein expression of G6PC3 was consistent with mRNA expression, which was confirmed by immunofluorescence analysis. These findings indicated that the G6PC3 expression might be facilitated by hypoxic condition in glioblastomas. Next, we investigated the clinical relevance of G6PC3 in terms of prognosis. Among the glioblastoma patients who received gross total resection, mRNA expressions of G6PC3 in the patients with poor prognosis (less than 1-year survival) were significantly higher than that in the patients who survive more than 3 years. Moreover, high mRNA expression of G6PC3 was associated with poor overall survival in glioblastoma, as validated by TCGA database. Conclusion: G6PC3 was affluently expressed in glioblastoma tissues with coincidentally high 18F-FDG and 18F-FMISO accumulation. Further, it might work as a prognostic biomarker of glioblastoma. Therefore, G6PC3 is a potential key molecule of glucose metabolism under hypoxia in glioblastoma.

Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates.

PURPOSE: Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. METHODS: We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions. RESULTS: [11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3 mL/cm3) in the monkey brain. CONCLUSION: [11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.

Deep learning-based attenuation map generation with simultaneously reconstructed PET activity and attenuation and low-dose application.

Objective. In PET/CT imaging, CT is used for positron emission tomography (PET) attenuation correction (AC). CT artifacts or misalignment between PET and CT can cause AC artifacts and quantification errors in PET. Simultaneous reconstruction (MLAA) of PET activity (λ-MLAA) and attenuation (µ-MLAA) maps was proposed to solve those issues using the time-of-flight PET raw data only. However,λ-MLAA still suffers from quantification error as compared to reconstruction using the gold-standard CT-based attenuation map (µ-CT). Recently, a deep learning (DL)-based framework was proposed to improve MLAA by predictingµ-DL fromλ-MLAA andµ-MLAA using an image domain loss function (IM-loss). However, IM-loss does not directly measure the AC errors according to the PET attenuation physics. Our preliminary studies showed that an additional physics-based loss function can lead to more accurate PET AC. The main objective of this study is to optimize the attenuation map generation framework for clinical full-dose18F-FDG studies. We also investigate the effectiveness of the optimized network on predicting attenuation maps for synthetic low-dose oncological PET studies.Approach. We optimized the proposed DL framework by applying different preprocessing steps and hyperparameter optimization, including patch size, weights of the loss terms and number of angles in the projection-domain loss term. The optimization was performed based on 100 skull-to-toe18F-FDG PET/CT scans with minimal misalignment. The optimized framework was further evaluated on 85 clinical full-dose neck-to-thigh18F-FDG cancer datasets as well as synthetic low-dose studies with only 10% of the full-dose raw data.Main results. Clinical evaluation of tumor quantification as well as physics-based figure-of-merit metric evaluation validated the promising performance of our proposed method. For both full-dose and low-dose studies, the proposed framework achieved <1% error in tumor standardized uptake value measures.Significance. It is of great clinical interest to achieve CT-less PET reconstruction, especially for low-dose PET studies.

Identification of patients with Graves' disease who benefit from high-dose radioactive iodine therapy.

OBJECTIVE: Radioactive iodine (RAI) therapy is a useful treatment for Graves' disease (GD). Most RAI sessions administer ≤ 500 MBq of iodine (I)-131. Sometimes patients require repeated RAI, often for longer periods of remission. We investigated the characteristics of patients for whom high dose (mostly 1110 MBq of I-131) RAI was effective as RAI therapy for GD. METHODS: We retrospectively analyzed the cases of 79 patients who underwent RAI for GD in a multicenter setting. We divided the patients into two groups based on the I-131 dose administered: the low dose (LD) group who received ≤ 500 MBq (n = 44) and the high dose (HD) group who received > 500 MBq (n = 35). The therapeutic effect was defined as achieving remission and reaching the point of participating in thyroid hormone replacement therapy within 1 year after RAI. We compared the LD and HD groups' remission rates and conducted a multivariate logistic regression analysis of predictive factors for remission. In a simulation, using the formula for predicting the probability of remission obtained from the analysis results, we estimated how much the remission rate would change if the I-131 dose is increased from 500 to 1110 MBq. RESULTS: The mean ± standard deviation I-131 dose administered in the LD group was 480 ± 6 MBq, and that of the HD group was 1054 ± 265 MBq. Thirty-five patients (80%) in the LD group and 26 patients (74%) in the HD group achieved remission; this difference in the remission rate was not significant. The multivariate analysis results demonstrated that the absorbed dose and thyroid-stimulating antibody (TSAb) were independent predictors of remission. Seven patients (8.9%) showed an increased probability of remission from < 50% to > 50% when the higher RAI dose was applied (1110 MBq instead of 500 MBq). The thyroid volume and TSAb values in these patients were relatively large at 54.7 ± 34.2 mL and 1378.4 ± 586.3%, respectively. CONCLUSION: Although the overall remission rate was not significantly different between the patients who received high- or low-dose I-131, treatment with high-dose RAI may improve the probability of remission in patients with a massive thyroid volume and/or high-TSAb Graves' disease.

Feasibility of imaging synaptic density in the human spinal cord using [11C]UCB-J PET.

PURPOSE: Neuronal damage and synapse loss in the spinal cord (SC) have been implicated in spinal cord injury (SCI) and neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS). Current standards of diagnosis for SCI include CT or MRI imaging to evaluate injury severity. The current study explores the use of PET imaging with [11C]UCB-J, which targets the synaptic vesicle protein 2A (SV2A), in the human spinal cord, as a way to visualize synaptic density and integrity in vivo. RESULTS: First, simulations of baseline and blocking [11C]UCB-J HRRT scans were performed, based on SC dimensions and SV2A distribution to predict VT, VND, and VS values. Next, human baseline and blocking [11C]UCB-J HRRT images were used to estimate these values in the cervical SC (cSC). Simulation results had excellent agreement with observed values of VT, VND, and VS from the real human data, with baseline VT, VND, and VS of 3.07, 2.15, and 0.92 mL/cm3, respectively, with a BPND of 0.43. Lastly, we explored full SC imaging with whole-body images. Using automated SC regions of interest (ROIs) for the full SC, cSC, and thoracic SC (tSC), the distribution volume ratio (DVR) was estimated using the brain gray matter as a reference region to evaluate SC SV2A density relative to the brain. In full body imaging, DVR values of full SC, cSC, and tSC were 0.115, 0.145, and 0.112, respectively. Therefore, measured [11C]UCB-J uptake, and thus SV2A density, is much lower in the SC than in the brain. CONCLUSIONS: The results presented here provide evidence for the feasibility of SV2A PET imaging in the human SC, however, specific binding of [11C]UCB-J is low. Ongoing and future work include further classification of SV2A distribution in the SC as well as exploring higher-affinity PET radioligands for SC imaging.

Deep learning-based attenuation correction for whole-body PET - a multi-tracer study with 18F-FDG, 68 Ga-DOTATATE, and 18F-Fluciclovine.

A novel deep learning (DL)-based attenuation correction (AC) framework was applied to clinical whole-body oncology studies using 18F-FDG, 68 Ga-DOTATATE, and 18F-Fluciclovine. The framework used activity (λ-MLAA) and attenuation (µ-MLAA) maps estimated by the maximum likelihood reconstruction of activity and attenuation (MLAA) algorithm as inputs to a modified U-net neural network with a novel imaging physics-based loss function to learn a CT-derived attenuation map (µ-CT). METHODS: Clinical whole-body PET/CT datasets of 18F-FDG (N = 113), 68 Ga-DOTATATE (N = 76), and 18F-Fluciclovine (N = 90) were used to train and test tracer-specific neural networks. For each tracer, forty subjects were used to train the neural network to predict attenuation maps (µ-DL). µ-DL and µ-MLAA were compared to the gold-standard µ-CT. PET images reconstructed using the OSEM algorithm with µ-DL (OSEMDL) and µ-MLAA (OSEMMLAA) were compared to the CT-based reconstruction (OSEMCT). Tumor regions of interest were segmented by two radiologists and tumor SUV and volume measures were reported, as well as evaluation using conventional image analysis metrics. RESULTS: µ-DL yielded high resolution and fine detail recovery of the attenuation map, which was superior in quality as compared to µ-MLAA in all metrics for all tracers. Using OSEMCT as the gold-standard, OSEMDL provided more accurate tumor quantification than OSEMMLAA for all three tracers, e.g., error in SUVmax for OSEMMLAA vs. OSEMDL: - 3.6 ± 4.4% vs. - 1.7 ± 4.5% for 18F-FDG (N = 152), - 4.3 ± 5.1% vs. 0.4 ± 2.8% for 68 Ga-DOTATATE (N = 70), and - 7.3 ± 2.9% vs. - 2.8 ± 2.3% for 18F-Fluciclovine (N = 44). OSEMDL also yielded more accurate tumor volume measures than OSEMMLAA, i.e., - 8.4 ± 14.5% (OSEMMLAA) vs. - 3.0 ± 15.0% for 18F-FDG, - 14.1 ± 19.7% vs. 1.8 ± 11.6% for 68 Ga-DOTATATE, and - 15.9 ± 9.1% vs. - 6.4 ± 6.4% for 18F-Fluciclovine. CONCLUSIONS: The proposed framework provides accurate and robust attenuation correction for whole-body 18F-FDG, 68 Ga-DOTATATE and 18F-Fluciclovine in tumor SUV measures as well as tumor volume estimation. The proposed method provides clinically equivalent quality as compared to CT in attenuation correction for the three tracers.

Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11 C]UCB-J.

INTRODUCTION: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. METHODS: We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD. RESULTS: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume. CONCLUSION: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.

Artificial intelligence for nuclear medicine in oncology.

As in all other medical fields, artificial intelligence (AI) is increasingly being used in nuclear medicine for oncology. There are many articles that discuss AI from the viewpoint of nuclear medicine, but few focus on nuclear medicine from the viewpoint of AI. Nuclear medicine images are characterized by their low spatial resolution and high quantitativeness. It is noted that AI has been used since before the emergence of deep learning. AI can be divided into three categories by its purpose: (1) assisted interpretation, i.e., computer-aided detection (CADe) or computer-aided diagnosis (CADx). (2) Additional insight, i.e., AI provides information beyond the radiologist's eye, such as predicting genes and prognosis from images. It is also related to the field called radiomics/radiogenomics. (3) Augmented image, i.e., image generation tasks. To apply AI to practical use, harmonization between facilities and the possibility of black box explanations need to be resolved.

Preliminary In Vivo Evidence of Reduced Synaptic Density in Human Immunodeficiency Virus (HIV) Despite Antiretroviral Therapy.

BACKGROUND: Synaptic injury is a pathological hallmark of neurological impairment in people living with human immunodeficiency virus (HIV, PLWH), a common complication despite viral suppression with antiretroviral therapy (ART). Measurement of synaptic density in living humans may allow better understanding of HIV neuropathogenesis and provide a dynamic biomarker for therapeutic studies. We applied novel synaptic vesical protein 2A (SV2A) positron emission tomographic (PET) imaging to investigate synaptic density in the frontostriatalthalamic region in PLWH and HIV-uninfected participants. METHODS: In this cross-sectional pilot study,13 older male PLWH on ART underwent magnetic resonance imaging (MRI) and PET scanning with the SV2A ligand [11C]UCB-J with partial volume correction and had neurocognitive assessments. SV2A binding potential (BPND) in the frontostriatalthalamic circuit was compared to 13 age-matched HIV-uninfected participants and assessed with respect to neurocognitive performance in PLWH. RESULTS: PLWH had 14% lower frontostriatalthalamic SV2A synaptic density compared to HIV-uninfected (PLWH: mean [SD], 3.93 [0.80]; HIV-uninfected: 4.59 [0.43]; P = .02, effect size 1.02). Differences were observed in widespread additional regions in exploratory analyses. Higher frontostriatalthalamic SV2A BPND associated with better grooved pegboard performance, a measure of motor coordination, in PLWH (r = 0.61, P = .03). CONCLUSIONS: In a pilot study, SV2A PET imaging reveals reduced synaptic density in older male PLWH on ART compared to HIV-uninfected in the frontostriatalthalamic circuit and other cortical areas. Larger studies controlling for factors in addition to age are needed to determine whether differences are attributable to HIV or comorbidities in PLWH. SV2A imaging is a promising biomarker for studies of neuropathogenesis and therapeutic interventions in HIV.

Preoperative Texture Analysis Using 11C-Methionine Positron Emission Tomography Predicts Survival after Surgery for Glioma.

BACKGROUND: Positron emission tomography with 11C-methionine (MET) is well established in the diagnostic work-up of malignant brain tumors. Texture analysis is a novel technique for extracting information regarding relationships among surrounding voxels, in order to quantify their inhomogeneity. This study evaluated whether the texture analysis of MET uptake has prognostic value for patients with glioma. METHODS: We retrospectively analyzed adults with glioma who had undergone preoperative metabolic imaging at a single center. Tumors were delineated using a threshold of 1.3-fold of the mean standardized uptake value for the contralateral cortex, and then processed to calculate the texture features in glioma. RESULTS: The study included 42 patients (median age: 56 years). The World Health Organization classifications were grade II (7 patients), grade III (17 patients), and grade IV (18 patients). Sixteen (16.1%) all-cause deaths were recorded during the median follow-up of 18.8 months. The univariate analyses revealed that overall survival (OS) was associated with age (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.01-1.08, p = 0.0093), tumor grade (HR 3.64, 95% CI 1.63-9.63, p = 0.0010), genetic status (p < 0.0001), low gray-level run emphasis (LGRE, calculated from the gray-level run-length matrix) (HR 2.30 × 1011, 95% CI 737.11-4.23 × 1019, p = 0.0096), and correlation (calculated from the gray-level co-occurrence matrix) (HR 5.17, 95% CI 1.07-20.93, p = 0.041). The multivariate analyses revealed OS was independently associated with LGRE and correlation. The survival curves were also significantly different (both log-rank p < 0.05). CONCLUSION: Textural features obtained using preoperative MET positron emission tomography may compliment the semi-quantitative assessment for prognostication in glioma cases.

Biodistribution and internal radiation dosimetry of a novel probe for thymidine phosphorylase imaging, [123I]IIMU, in healthy volunteers.

OBJECTIVE: We evaluated the radiation dosage, biodistribution, human safety, and tolerability of the injection of a single dose of [123I] 5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil (IIMU), a new radiotracer targeting thymidine phosphorylase (TP), in healthy volunteers. METHODS: Potential participants were tested at our hospital to confirm their eligibility. Two healthy male adults passed the screening tests. They were injected with 56 and 111 MBq of [123I]IIMU, respectively. Safety assessments were performed before and at 1, 3, 6, 9, 24, 48 h, and 1-week post-injection. Whole-body emission scans were conducted at 1, 3, 6, 24, and 48 h post-injection. Regions of interest were manually drawn to enclose the entire body at each time point, identifying high-uptake organs to obtain the time-activity curves. Urine and blood samples were collected at 1, 2, 3, 4, 5, 6, 9, 24, and 48 h post-injection. The radiation dose for each organ and the effective doses were estimated using OLINDA/EXM 1.1 software. RESULTS: No adverse events were observed as of the follow-up visit > 1-week post-injection. In both subjects, the highest uptake of [123I]IIMU occurred in the liver, with peak injected activity (%IA) values of 17.7% and 15.1%, respectively. The second highest uptake was in the thyroid (0.35% and 0.66% IA). The %IA decreased gradually toward the end of the study (48 h) in all organs except the liver and thyroid. By the end of the study, 52.5% and 51.5% of the injected activity of [123I]IIMU had been excreted via the subjects' renal systems. The estimated mean effective doses of [123I]IIMU were 9.19 µSv/MBq and 10.1 µSv/MBq, respectively. CONCLUSION: In this preliminary study, [123I]IIMU was safely administered to healthy adults, and its potential clinical use in TP imaging was revealed.

Prediction of Hypoxia in Brain Tumors Using a Multivariate Model Built from MR Imaging and 18F-Fluorodeoxyglucose Accumulation Data.

PURPOSE: The aim of this study was to generate a multivariate model using various MRI markers of blood flow and vascular permeability and accumulation of 18F-fluorodeoxyglucose (FDG) to predict the extent of hypoxia in an 18F-fluoromisonidazole (FMISO)-positive region. METHODS: Fifteen patients aged 27-74 years with brain tumors (glioma, n = 13; lymphoma, n = 1; germinoma, n = 1) were included. MRI scans were performed using a 3T scanner, and dynamic contrast-enhanced (DCE) perfusion and arterial spin labeling images were obtained. Ktrans and Vp maps were generated using the DCE images. FDG and FMISO positron emission tomography scans were also obtained. A model for predicting FMISO positivity was generated on a voxel-by-voxel basis by a multivariate logistic regression model using all the MRI parameters with and without FDG. Receiver-operating characteristic curve analysis was used to detect FMISO positivity with multivariate and univariate analysis of each parameter. Cross-validation was performed using the leave-one-out method. RESULTS: The area under the curve (AUC) was highest for the multivariate prediction model with FDG (0.892) followed by the multivariate model without FDG and univariate analysis with FDG and Ktrans (0.844 for all). In cross-validation, the multivariate model with FDG had the highest AUC (0.857 ± 0.08) followed by the multivariate model without FDG (0.834 ± 0.119). CONCLUSION: A multivariate prediction model created using blood flow, vascular permeability, and glycometabolism parameters can predict the extent of hypoxia in FMISO-positive areas in patients with brain tumors.

Influence of the scan time point when assessing hypoxia in 18F-fluoromisonidazole PET: 2 vs. 4 h.

PURPOSE: 18F-fluoromisonidazole (18F-FMISO) is the most widely used positron emission tomography (PET) tracer for imaging tumor hypoxia. Previous reports suggested that the time from injection to the scan may affect the assessment of 18F-FMISO uptake. Herein, we directly compared the images at 2 h and 4 h after a single injection of 18F-FMISO. METHODS: Twenty-three patients with or suspected of having a brain tumor were scanned twice at 2 and 4 h following an intravenous injection of 18F-FMISO. We estimated the mean standardized uptake value (SUV) of the gray matter and white matter and the gray-to-white matter ratio in the background brain tissue from the two scans. We also performed a semi-quantitative analysis using the SUVmax and maximum tumor-to-normal ratio (TNR) for the tumor. RESULTS: At 2 h, the SUVmean of gray matter was significantly higher than that of white matter (median 1.23, interquartile range (IQR) 1.10-1.32 vs. 1.04, IQR 0.95-1.16, p < 0.0001), whereas at 4 h, it significantly decreased to approach that of the white matter (1.10, IQR 1.00-1.23 vs. 1.02, IQR 0.93-1.13, p = NS). The gray-to-white matter ratio thus significantly declined from 1.17 (IQR 1.14-1.19) to 1.09 (IQR 1.07-1.10) (p < 0.0001). All 7 patients with glioblastoma showed significant increases in the SUVmax (2.20, IQR 1.67-3.32 at 2 h vs. 2.65, IQR 1.74-4.41 at 4 h, p = 0.016) and the TNR (1.75, IQR 1.40-2.38 at 2 h vs. 2.34, IQR 1.67-3.60 at 4 h, p = 0.016). CONCLUSION: In the assessment of hypoxic tumors, 18F-FMISO PET for hypoxia imaging should be obtained at 4 h rather than 2 h after the injection.

Combination of FDG-PET and FMISO-PET as a treatment strategy for patients undergoing early-stage NSCLC stereotactic radiotherapy.

BACKGROUND: We investigated the prognostic predictive value of the combination of fluorodeoxyglucose (FDG)- and fluoromisonidazole (FMISO)-PET in patients with non-small cell lung carcinoma (NSCLC) treated with stereotactic body radiation therapy (SBRT). PATIENTS AND METHODS: We prospectively examined patients with pathologically proven NSCLC; all underwent FDG and FMISO PET/CT scans before SBRT. PET images were acquired using a whole-body time-of-flight PET-CT scanner with respiratory gating. We classified them into recurrent and non-recurrent groups based on their clinical follow-ups and compared the groups' tumor diameters and PET parameters (i.e., maximum of the standardized uptake value (SUVmax), metabolic tumor volume, tumor-to-muscle ratio, and tumor-to-blood ratio). We performed univariate analysis to evaluate the impact of the PET variables on the patients' progression-free survival (PFS). We divided the patients by thresholds of FDG SUVmax and FMISO SUVmax obtained from receiver operating characteristic analysis for assessment of recurrence rate and PFS. RESULTS: Thirty-two NSCLC patients (19 male and 13 females; median age, 83 years) were enrolled. All received SBRT. At the study endpoint, 23 patients (71.9%) were non-recurrent and nine patients (28.1%) had recurrent disease. Significant between-group differences were observed in tumor diameter and all the PET parameters, demonstrating that those were significant predictors of the recurrence in all patients. In the 22 patients with tumors > 2 cm, tumor diameter and FDG SUVmax were not significant predictors. Thirty-two patients were divided into three patterns from the thresholds of FDG SUVmax (6.81) and FMISO SUVmax (1.89); A, low FDG and low FMISO (n = 14); B, high FDG and low FMISO (n = 8); C, high FDG and high FMISO (n = 10). No pattern A patient experienced tumor recurrence, whereas two pattern B patients (25%) and seven pattern C patients (70%) exhibited recurrence. A Kaplan-Meier analysis of all patients revealed a significant difference in PFS between patterns A and B (p = 0.013) and between patterns A and C (p < 0.001). In the tumors > 2 cm patients, significant differences in PFS were demonstrated between pattern A and C patients (p = 0.002). CONCLUSION: The combination of FDG- and FMISO-PET can identify patients with a baseline risk of recurrence and indicate whether additional therapy might be performed to improve survival.

Biodistribution and radiation dosimetry of the novel hypoxia PET probe [18F]DiFA and comparison with [18F]FMISO.

BACKGROUND: To facilitate hypoxia imaging in a clinical setting, we developed 1-(2,2-dihydroxymethyl-3-[18F]-fluoropropyl)-2-nitroimidazole ([18F]DiFA) as a new tracer that targets tumor hypoxia with its lower lipophilicity and efficient radiosynthesis. Here, we evaluated the radiation dosage, biodistribution, human safety, tolerability, and early elimination after the injection of [18F]DiFA in healthy subjects, and we performed a preliminary clinical study of patients with malignant tumors in a comparison with [18F]fluoromisonidazole ([18F]FMISO). RESULTS: The single administration of [18F]DiFA in 8 healthy male adults caused neither adverse events nor abnormal clinical findings. Dynamic and sequential whole-body scans showed that [18F]DiFA was rapidly cleared from all of the organs via the hepatobiliary and urinary systems. The whole-body mean effective dose of [18F]DiFA estimated by using the medical internal radiation dose (MIRD) schema with organ level internal dose assessment/exponential modeling (OLINDA/EXM) computer software 1.1 was 14.4 ± 0.7 µSv/MBq. Among the organs, the urinary bladder received the largest absorbed dose (94.7 ± 13.6 µSv/MBq). The mean absorbed doses of the other organs were equal to or less than those from other hypoxia tracers. The excretion of radioactivity via the urinary system was very rapid, reaching 86.4 ± 7.1% of the administered dose. For the preliminary clinical study, seven patients were subjected to [18F]FMISO and [18F]DiFA positron emission tomography (PET) at 48-h intervals to compare the two tracers' diagnostic ability for tumor hypoxia. The results of the tumor hypoxia evaluation by [18F]DiFA PET at 1 h and 2 h were not significantly different from those obtained with [18F]FMISO PET at 4 h ([18F]DiFA at 1 h, p = 0.32; [18F]DiFA at 2 h, p = 0.08). Moreover, [18F]DiFA PET at both 1 h (k = 0.68) and 2 h (k = 1.00) showed better inter-observer reproducibility than [18F]FMISO PET at 4 h (k = 0.59). CONCLUSION: [18F]DiFA is well tolerated, and its radiation dose is comparable to those of other hypoxia tracers. [18F]DiFA is very rapidly cleared via the urinary system. [18F]DiFA PET generated comparable images to [18F]FMISO PET in hypoxia imaging with shorter waiting time, demonstrating the promising potential of [18F]DiFA PET for hypoxia imaging and for a multicenter trial.

Dual Isotope SPECT Study With Epilepsy Patients Using Semiconductor SPECT System.

PURPOSE: We developed a prototype CdTe SPECT system with 4-pixel matched collimator for brain study. This system provides high-energy-resolution (6.6%), high-sensitivity (220 cps/MBq/head), and high-spatial-resolution images. The aim of this study was to evaluate dual-isotope study of CBF and central benzodiazepine receptor (BZR) images using Tc-ECD and I-IMZ with the new SPECT system in patients with epilepsy comparing with single-isotope study using the conventional scintillation gamma camera. METHODS: This study included 13 patients with partial epilepsy. The BZR images were acquired at 3 hours after I-IMZ injection for 20 minutes. The images of IMZ were acquired with a conventional 3-head scintillation gamma camera. After BZR image acquisition with the conventional camera, Tc-ECD was injected, and CBF and BZR images were acquired simultaneously 5 minutes after ECD injection with the new SPECT system. The CBF images were also acquired with the conventional camera on separate days. The findings were visually analyzed, and 3D-SSP maximum Z scores of lesions were compared between the 2 studies. RESULTS: There were 47 abnormal lesions on BZR images and 60 abnormal lesions on CBF images in the single-isotope study with the conventional camera. Dual-isotope study with the new system showed concordant abnormal findings of 46 of 47 lesions on BZR and 54 of 60 lesions on CBF images with the single-isotope study with the conventional camera. There was high agreement between the 2 studies in both BZR and CBF findings (Cohen κ values = 0.96 for BZR and 0.78 for CBF). In semiquantitative analysis, maximum Z scores of dual-isotope study with the new system strongly correlated with those of single-isotope study with the conventional camera (BZR: r = 0.82, P < 0.05, CBF: r = 0.87, P < 0.05). CONCLUSIONS: Our new SPECT system permits dual-isotope study for pixel-by-pixel analysis of CBF and BZR information with the same pathophysiological condition in patients with epilepsy.

Scatter Correction with Combined Single-Scatter Simulation and Monte Carlo Simulation Scaling Improved the Visual Artifacts and Quantification in 3-Dimensional Brain PET/CT Imaging with 15O-Gas Inhalation.

In 3-dimensional PET/CT imaging of the brain with 15O-gas inhalation, high radioactivity in the face mask creates cold artifacts and affects the quantitative accuracy when scatter is corrected by conventional methods (e.g., single-scatter simulation [SSS] with tail-fitting scaling [TFS-SSS]). Here we examined the validity of a newly developed scatter-correction method that combines SSS with a scaling factor calculated by Monte Carlo simulation (MCS-SSS). Methods: We performed phantom experiments and patient studies. In the phantom experiments, a plastic bottle simulating a face mask was attached to a cylindric phantom simulating the brain. The cylindric phantom was filled with 18F-FDG solution (3.8-7.0 kBq/mL). The bottle was filled with nonradioactive air or various levels of 18F-FDG (0-170 kBq/mL). Images were corrected either by TFS-SSS or MCS-SSS using the CT data of the bottle filled with nonradioactive air. We compared the image activity concentration in the cylindric phantom with the true activity concentration. We also performed 15O-gas brain PET based on the steady-state method on patients with cerebrovascular disease to obtain quantitative images of cerebral blood flow and oxygen metabolism. Results: In the phantom experiments, a cold artifact was observed immediately next to the bottle on TFS-SSS images, where the image activity concentrations in the cylindric phantom were underestimated by 18%, 36%, and 70% at the bottle radioactivity levels of 2.4, 5.1, and 9.7 kBq/mL, respectively. At higher bottle radioactivity, the image activity concentrations in the cylindric phantom were greater than 98% underestimated. For the MCS-SSS, in contrast, the error was within 5% at each bottle radioactivity level, although the image generated slight high-activity artifacts around the bottle when the bottle contained significantly high radioactivity. In the patient imaging with 15O2 and C15O2 inhalation, cold artifacts were observed on TFS-SSS images, whereas no artifacts were observed on any of the MCS-SSS images. Conclusion: MCS-SSS accurately corrected the scatters in 15O-gas brain PET when the 3-dimensional acquisition mode was used, preventing the generation of cold artifacts, which were observed immediately next to a face mask on TFS-SSS images. The MCS-SSS method will contribute to accurate quantitative assessments.

Hypoxic glucose metabolism in glioblastoma as a potential prognostic factor.

PURPOSE: Metabolic activity and hypoxia are both important factors characterizing tumor aggressiveness. Here, we used F-18 fluoromisonidazole (FMISO) and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) to define metabolically active hypoxic volume, and investigate its clinical significance in relation to progression free survival (PFS) and overall survival (OS) in glioblastoma patients. EXPERIMENTAL DESIGN: Glioblastoma patients (n = 32) underwent FMISO PET, FDG PET, and magnetic resonance imaging (MRI) before surgical intervention. FDG and FMISO PET images were coregistered with gadolinium-enhanced T1-weighted MR images. Volume of interest (VOI) of gross tumor volume (GTV) was manually created to enclose the entire gadolinium-positive areas. The FMISO tumor-to-normal region ratio (TNR) and FDG TNR were calculated in a voxel-by-voxel manner. For calculating TNR, standardized uptake value (SUV) was divided by averaged SUV of normal references. Contralateral frontal and parietal cortices were used as the reference region for FDG, whereas the cerebellar cortex was used as the reference region for FMISO. FDG-positive was defined as the FDG TNR ≥1.0, and FMISO-positive was defined as FMISO TNR ≥1.3. Hypoxia volume (HV) was defined as the volume of FMISO-positive and metabolic tumor volume in hypoxia (hMTV) was the volume of FMISO/FDG double-positive. The total lesion glycolysis in hypoxia (hTLG) was hMTV × FDG SUVmean. The extent of resection (EOR) involving cytoreduction surgery was volumetric change based on planimetry methods using MRI. These factors were tested for correlation with patient prognosis. RESULTS: All tumor lesions were FMISO-positive and FDG-positive. Univariate analysis indicated that hMTV, hTLG, and EOR were significantly correlated with PFS (p = 0.007, p = 0.04, and p = 0.01, respectively) and that hMTV, hTLG, and EOR were also significantly correlated with OS (p = 0.0028, p = 0.037, and p = 0.014, respectively). In contrast, none of FDG TNR, FMISO TNR, GTV, HV, patients' age, or Karnofsky performance scale (KPS) was significantly correlated with PSF or OS. The hMTV and hTLG were found to be independent factors affecting PFS and OS on multivariate analysis. CONCLUSIONS: We introduced hMTV and hTLG using FDG and FMISO PET to define metabolically active hypoxic volume. Univariate and multivariate analyses demonstrated that both hMTV and hTLG are significant predictors for PFS and OS in glioblastoma patients.

Change in 18F-Fluoromisonidazole PET Is an Early Predictor of the Prognosis in the Patients with Recurrent High-Grade Glioma Receiving Bevacizumab Treatment.

BACKGROUND: Bevacizumab (BEV), a humanized monoclonal antibody, become a currently important chemotherapeutic option for the patients with recurrent glioma. The aim of this retrospective study is to investigate whether 18F-Fluoromisonidazole (FMISO) PET have the potential to detect BEV-resistant gliomas in the early-stage. METHODS: We reviewed the FMISO PET and MRI appearances before and 3 to 4 courses after BEV treatment on 18 recurrent glioma patients. FMISO accumulation was assessed by visual inspection and semi-quantitative values which were tumor-to-normal (T/N) ratio and hypoxic volume. MRI responses were evaluated based on RANO (Response Assessment in Neuro-Oncology) criteria. The prognostic analysis was performed in relation to the response assessment by FMISO PET and MRI using overall survival (OS) after BEV application. RESULTS: After BEV application, MRI revealed partial response in 14 of 18 patients (78%), of which 9 patients also demonstrated decreased FMISO accumulation. These 9 patients (50%) were classified as "MRI-FMISO double responder". As for the other 5 patients (28%), FMISO accumulation volumes increased or remained stable after BEV treatment although partial responses were achieved on MRI. Therefore, these cases were classified as "MRI-only responder". The remaining 4 patients (22%) did not show treatment response on FMISO PET or MRI ("non-responder"). MRI-FMISO double responders showed significantly longer OS than that in other groups (median 12.4 vs 5.7 months; P < 0.001), whereas there were no overall survival difference between MRI-only responders and non-responders (median OS, 5.7 and 4.8 months; P = 0.58). Among the pre-treatment clinical factors, high FMISO T/N ratio was a significant prognostic factor of overall survival in these patients under the assessment of Cox proportional hazard model. CONCLUSIONS: Recurrent gliomas with decreasing FMISO accumulation after short-term BEV application could derive a survival benefit from BEV treatment. Change in FMISO PET appearance can identify BEV-resistant gliomas in early-stage regardless of MRI findings in a comprehensible way.