Brain Uptake Ratio Research Articles

Development of an automated region-of-interest-setting method based on a deep neural network for brain perfusion single photon emission computed tomography quantification methods.

A simple noninvasive microsphere (SIMS) method using 123I-IMP and an improved brain uptake ratio (IBUR) method using 99mTc-ECD for the quantitative measurement of regional cerebral blood flow have been recently reported. The input functions of these methods were determined using the administered dose, which was obtained by analyzing the time activity curve of the pulmonary artery (PA) for SIMS and the ascending aorta (AAo) for the IBUR methods for dynamic chest images. If the PA and AAo regions of interest (ROIs) can be determined using deep convolutional neural networks (DCNN) for segmentation, the accuracy of these ROI-setting methods can be improved through simple analytical operations to ensure repeatability and reproducibility. The purpose of this study was to develop new PA and AAo-ROI setting methods using a DCNN (DCNN-ROI method). A U-Net architecture based on convolutional neural networks was used to determine the PA and AAo candidate regions. Images of 290 patients who underwent 123I-IMP RI-angiography and 108 patients who underwent 99mTc-ECD RI-angiography were used. The PA and AAo-ROI results for the DCNN-ROI method were compared to those obtained using manual methods. The counts for the input function on the PA and AAo-ROI were determined by integrating the area under the curve (AUC) counts of the time-activity curve of PA and AAo-ROI, respectively. The effectiveness of the DCNN-ROI method was elucidated through a comparison with the integrated AUC counts of the DCNN-ROI and the manual ROI. The coincidence ratio for the locations of the PA and AAo-ROI obtained using the DCNN method and that for the manual method was 100%. Strong correlations were observed between the AUC counts using the DCNN and manual methods. New ROI- setting programs were developed using a deep convolution neural network DCNN to determine the input functions for the SIMS and IBUR methods. The accuracy of these methods is comparable to that of the manual method.

Synthesis and Bioevaluation of 2-Styrylquinoxaline Derivatives as Tau-PET Tracers.

This study focused on designing and evaluating Tau-PET tracers for noninvasive positron emission computed tomography (PET) imaging of neurofibrillary tangles (NFTs), a hallmark pathology of Alzheimer's disease (AD). The tracers were synthesized with a 2-styrylquinoxaline scaffold and varying lengths of FPEG chains. The compound [18F]15, which had two ethoxy units, showed high affinity for recombinant K18-Tau aggregates (Ki = 41.48 nM) and the highest selectivity versus Aβ1-42 aggregates (8.83-fold). In vitro autoradiography and fluorescent staining profiles further validated the binding of [18F]15 or 15 toward NFTs in brain sections from AD patients and Tau-transgenic mice. In normal ICR mice, [18F]15 exhibited an ideal initial brain uptake (11.21% ID/g at 2 min) and moderate washout ratio (2.29), and micro-PET studies in rats confirmed its ability to penetrate the blood-brain barrier with the peak SUV value of 1.94 in the cortex. These results suggest that [18F]15 has the potential to be developed into a useful Tau-PET tracer for early AD diagnosis and evaluation of anti-Tau therapeutics.

18 F-Fluorodeoxy Glucose and 11 C-Methionine Accumulation in Demyelinating Lesions.

Background Few studies have evaluated the accumulation of 18 F-fluorodeoxyglucose (FDG), 11 C-methionine (MET), and other positron emission tomography (PET) tracers in patients with demyelinating disease. Purpose This study aimed to investigate the accumulation of FDG-PET/computed tomography (CT) and MET-PET/CT in demyelinating lesions. Material and Methods A retrospective search of the patient database in our hospital identified five patients with demyelinating disease in whom PET studies performed in the past 10 years revealed accumulation of FDG or MET. The clinical diagnoses were multiple sclerosis ( n =1), myelitis ( n =1), limbic encephalitis ( n =1), chronic inflammatory demyelinating polyneuropathy (CIDP; n =1), and acute demyelinating encephalomyelitis (ADEM; n =1). Two patients received FDG-PET/CT alone and three patients received both FDG-PET/CT and MET-PET/CT on the same day. Images were visually and conjointly reviewed by two radiologists. In semiquantitative evaluation, the maximum standardized uptake value (SUV max ) of the lesion was measured. The lesion-to-normal brain uptake ratio (L/N ratio) was calculated. Results FDG and/or MET accumulated to a part of the lesions seen on MRI. SUV max on FDG-PET/CT ranged from 3.8 to 10.3, and L/N ratio on MET-PET/CT ranged from 16.6 to 2.4. Conclusion It has been established that neoplastic and demyelinating lesions can be differentiated on the basis of FDG or MET uptake. However, as accumulation of FDG and MET can also occur in demyelinating lesions; knowledge of this possibility is of clinical importance.

18F] Fluorothymidine Positron Emission Tomography Imaging in Primary Brain Tumours: A Systematic Review.

This review aimed to summarize the available literature on the clinical application of [18F] FLT PET imaging in primary brain tumours. A comprehensive search strategy based on Pubmed/Medline, Scopus, Web of Science, Cochrane Library, Google Scholar, and the Embase databases was carried on using the following search string: ('3` Fluorothymidine'/exp OR 'FLT' OR '[81F]-FLT' OR '[18F] Fluorothymidine') AND ('pet'/exp OR 'pet' OR 'positron emission tomography') AND ('glioma'/exp OR 'glioma' OR 'brain tumour'/exp OR 'brain tumour'). The search was updated till March 2021 and only articles in English and studies investigating the clinical applications of [18F] FLT PET and PET/CT in primary brain tumours were considered eligible for inclusion. The literature search ultimately yielded 52 studies included in the systematic review, with main results as follows: a) the uptake of [18F] FLT may guide stereotactic biopsy but does not discriminate between grade II and III glioma. b) [18F] FLT uptake and texture parameters correlate with overall survival (OS) in newly diagnosed gliomas. c) In patients with recurrent glioma, proliferative volume (PV) and tumour-to-normal brain (T/N) uptake ratio are independent predictors of survival. d) Patients demonstrating response to therapy at [18F] FLT PET scan show longer OS compared to non-responders. e) [18F] FLT PET demonstrated good performance in discriminating tumour recurrence from radionecrosis. However, controversial results exist in comparative literature examining the performance of [18F] FLT vs. other radiotracers in the assessment of recurrence. [18F] FLT PET imaging has demonstrated potential benefits for grading, diagnostic and prognostic purposes, despite the small sample size studies due to the relatively low availability of the radiotracer.

Correlation of <sup>11</sup>C-Methionine Combined Positron Emission and Computed Tomography and Ki-67 Proliferation Index in Pretreatment Assessment of Cerebral Gliomas

The purpose of the study was to explore the correlation between 11С-methionine (Met) uptake measured by combined positron emission and computed tomography (PET/CT) in newly diagnosed cerebral gliomas and tumor proliferative activity as measured by Ki-67 labeling index (Ki-67 LI).The results of PET/CT with 11С-methionine (PET-Met) of 236 adult patients with pretreated glial brain tumors were included in retrospective analysis. The final diagnosis of glioma according to WHO classification of CNS tumors (2007) was based on both histology and immunohistochemistry using Ki-67 antibodies. On PET-Met tumor-to normal brain uptake ratio (TBR) was calculated by dividing maximum Met uptake in the tumor (hot spot 10 mm in diameter) to activity concentration in the contralateral cortex. The Spearmen rank correlation test was used to analyze the relationships between TBR and Ki-67 LI.PET-Met analysis showed that TBR increases with an increase in the aggressiveness of the glial tumor. The differences of TBR values between gliomas grade II vs III and grade III vs IV were significant (p < 0,001). Among grades II-III gliomas Met uptake was significantly higher in oligodendroglial and mixed gliomas than in astrocytomas (p < 0,001), but the differences did not depend on Ki-67 LI.Correlation analysis demonstrated significant correlation between Ki-67 LI and TBR values (r = 0,49, p < 0,05, Spearman rank test). With analyzing glioma subgroups TBR values correlated with Ki-67 LI in diffuse astrocytomas (r = 0,52, p < 0,05), oligodendrogliomas (r = 0,40, p < 0,05), oligoastrocytomas (r = 0,47, p < 0,05) and in high-grade gliomas (r = 0,45, p < 0,05) but not in low-grade gliomas. Comparison between TBR value and Ki-67 LI in each glioma showed a lack of coincidence in 22 % of cases (high Met uptake but low Ki-67 LI and vice versa). The main reasons for such discrepancies were tumor molecular biology or incorrect biopsy target.Met uptake in diffuse gliomas correlates with proliferative activity which justifies the use of PET-Met for glioma grading. In case of mismatch between two biomarkers one should rely on the indicator that implies a higher aggressiveness of the glioma.

18F]-FDHT PET/CT as a tool for imaging androgen receptor expression in high-grade glioma.

BackgroundG lioblastoma (GBM) is associated with poor overall survival. Recently, we showed that androgen receptor (AR) protein is overexpressed in 56% of GBM specimens and AR antagonists induced dose-dependent death in several GBM cell lines and significantly reduced tumor growth and prolonged the lifespan of mice implanted with human GBM. 16β-18F-fluoro-5α-dihydrotestosterone ([18F]-FDHT) is a positron emission tomography (PET) tracer used to detect AR expression in prostate and breast cancers. This study was aimed at exploring the ability of [18F]-FDHT-PET to detect AR expression in high-grade gliomas.MethodsTwelve patients with suspected high-grade glioma underwent a regular workup and additional dynamic and static [18F]-FDHT-PET/CT. Visual and quantitative analyses of [18 F]-FDHT kinetics in the tumor and normal brain were performed. Mean and maximum (max) standardized uptake values (SUVs) were determined in selected volumes of interest. The patients had surgery or biopsy after PET/CT. AR protein was analyzed in the tumor samples by western blot. Fold change in AR expression was calculated by densitometry analysis. Correlation between imaging and AR protein samples was determined.ResultsIn six of the 12 patients, [18 F]-FDHT uptake was significantly higher in the tumor than in the normal brain. These patients also had increased AR protein expression within the tumor. Pearson correlation coefficient analysis for the tumor-to-control normal brain uptake ratio in terms of SUVmean versus AR protein expression was positive and significant (R = 0.84; P = .002).Conclusion[18 F]-FDHT-PET/CT could identify increased AR expression in high-grade glioma.

Radiosynthesis and Preliminary Biological Evaluation of 18F-Fluoropropionyl-Chlorotoxin as a Potential PET Tracer for Glioma Imaging

Purposes Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of [18F]-fluoropropionyl-chlorotoxin ([18F]-FP-chlorotoxin) as a novel PET tracer was investigated, and biodistribution in vivo and PET imaging were performed in the C6 glioma model. Procedures [18F]-FP-chlorotoxin was prepared from the reaction of chlorotoxin with [18F]-NFB (4-nitrophenyl 2-[18F]-fluoropropionate), which was synthesized from multistep reactions. Biodistribution was determined in 20 normal Kunming mice. Small-animal PET imaging with [18F]-FP-chlorotoxin was performed on the same rats bearing orthotopic C6 glioma at different time points (60 min, 90 min, and 120 min) after injection and compared with 2-deoxy-2-[18F] fluoro-D-glucose ([18F]-FDG). Results [18F]-FP-Chlorotoxin was successfully synthesized in the radiochemical yield of 41% and the radiochemical purity of more than 98%. Among all the organs, the brain had the lowest and stable uptake of [18F]-FP-chlorotoxin, while the kidney showed the highest uptake. Compared with [18F]-FDG, a low uptake of [18F]-FP-chlorotoxin was detected in normal brain parenchyma and a high accumulation of [18F]-FP-chlorotoxin was found in the gliomas tissue. The glioma to normal brain uptake ratio of [18F]-FP-chlorotoxin was higher than that of [18F]-FDG. Furthermore, the uptake of [18F]-FP-chlorotoxin at 90 min after injection was better than that at 60 min after injection. Conclusions Compared with [18F]-FDG, [18F]-FP-chlorotoxin has a low and stable uptake in normal brain parenchyma. [18F]-FP-Chlorotoxin seems to be a potential PET tracer with a good performance in diagnosis of the glioma.

Clinical usefulness of 99mTc-HYNIC-TOC, 99mTc(V)-DMSA, and 99mTc-MIBI SPECT in the evaluation of pituitary adenomas

BackgroundThe aim of this study was to evaluate the behavioral uptake and ability to diagnose pituitary adenoma (PA) using tumor-seeking radiopharmaceuticals, and to provide a semiquantitative analysis of tracer uptake in the pituitary region.Patients and methodsThe study included 33 (13 hormonally active and 20 nonfunctioning) patients with PA and 45 control participants without pituitary involvement. All patients (n=78) underwent single photon emission computed tomography (SPECT) imaging with technetium-99m-labeled hydrazinonicotinyl-tyr3-octreotide (99mTc-HYNIC-TOC), dimercaptosuccinic acid (99mTc(V)-DMSA) and hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI). A semiquantitative analysis of abnormal uptake was carried out by drawing identical regions of interest over the pituitary area and the normal brain on one transverse section that shows the lesion most clearly. The pituitary uptake to normal brain uptake (P/B) ratio was calculated in all cases.ResultsThe result of this study confirms that the SPECT semiquantitative method, with all three tracers, showed statistically significant differences between the PA group and the controls. However, 99mTc-HYNIC-TOC scintigraphy could have the highest diagnostic yield because of the smallest overlap between the P/B ratios between adenoma versus nonadenoma participants (the receiver operating characteristic curve P/B ratio cut-off value was 13.08). In addition, only 99mTc-MIBI SPECT have the diagnostic potential to detect secreting PAs, with statistically significant differences between groups (P<0.001), with an receiver operating characteristic curve P/B ratio cut-off value of 16.72.ConclusionA semiquantitative analysis of increased focal tracer uptake in the sellar area showed that 99mTc-HYNIC-TOC is a highly sensitive and reliable tumor-seeking agent for detecting PA, whereas 99mTc-MIBI SPECT is a highly sensitive and specific method in differentiating hormone-secreting pituitary tumor.

The prognostic value of [123I]-vascular endothelial growth factor ([123I]-VEGF) in glioma

PurposeRecent studies have shown that tumor vascular endothelial cells and various tumor cells overexpress receptors for vascular endothelial growth factor (VEGF). The aim of this study was to investigate the prognostic value of [123I]-VEGF scintigraphy in patients with histologically verified brain tumors.Methods23 consecutive patients (9 women and 14 men aged 30–83 years, mean age 56.6 ± 14.4 years) with histopathologically-verified primary brain tumors were included in the study. All patients had undergone [123I]-VEGF scintigraphy. SPECT examinations of brain were performed 30 min and 18 h after injection. Additional [11C]-methionine PET ([11C]-MET PET) was performed in eight of the 23 patients. Both [123I]-VEGF and [11C]-MET PET were evaluated visually and semiquantitatively by tumor-to-normal brain uptake ratio (T/N ratio). Thresholds of the T/N ratio were evaluated by analysis of receiver operating characteristics (ROC). Overall survival (OS) was estimated using the Kaplan-Meier method.ResultsWorld Health Organization (WHO) grade IV glioma lesions showed [123I]-VEGF uptake 18 h after the injection, whereas other brain tumors of grade II or III showed negative results. There was no significant difference in the tumor size between VEGF positive and VEGF negative tumors. Patients with [123I]-VEGF T/N ratio threshold <1.32 showed significantly longer survival than patients with T/N ratio ≥ 1.32 (2680 days vs 295 days; P < 0.05). In the subgroup of 16 grade IV glioma patients, significant OS differences were found using a T/N ratio of 1.75 as threshold (T/N ratio < 1.75: 720 days; T/N ≥ 1.75: 183 days; P < 0.05). Significant difference (P < 0.05) was also found in [11C]-MET PET T/N ratios between the grade IV glioma (mean T/N ratio: 3.71) and the grade II or III glioma (mean T/N ratio: 1.74).ConclusionOur results suggest that [123I]-VEGF scintigraphy may be useful for visualization of tumor angiogenesis. In addition, [123I]-VEGF may provide relevant prognostic information in patients with glioma.

Basic Investigation of a Cerebral Blood Flow Quantification Method without Blood Sampling Method (Improved Brain Uptake Ratio (IBUR)) Using a Fan-beam Collimator

We performed a basic evaluation for measuring the input function using a fan-beam collimator. Furthermore, we examined the validity of the brain blood flow quantitative measurement from the input function. Using the fanbeam collimator, we imaged syringes of various diameters containing 99 mTc as well as a virtual aorta inside a thoracic phantom. We changed the collimator distance and angle in relation to the sources, and the syringe was placed in vertical and horizontal positions as well. For evaluation, we used region of interest (ROI) of various sizes and positions. Furthermore, we conducted clinical evaluation for 19 subjects and calculated whole-brain mean cerebral blood flow using improved brain uptake ratio method by examination of 99 mTc-ECD cerebral blood flow. For ROIs smaller in size than diameter of the syringes and virtual ascending aorta, amount of change in the ROI counts by fan-beam collimator became smaller as distance to the source became closer, with less than 5% at 175 mm. Also, change with respect to angle of the collimator was less than 5% at 20°. In a clinical study, aortas could be imaged without truncation and input-functions could be measured in all 19 patients. By using ROIs smaller than the aorta diameter and placing the collimator close to the source, it was suggested that fan-beam collimator can be used to determine the input function.

Deuterated 18F-9-O-hexadeutero-3-fluoropropoxyl-(+)-dihydrotetrabenazine (D6-FP-(+)-DTBZ): A vesicular monoamine transporter 2 (VMAT2) imaging agent

IntroductionVesicular monoamine transporters 2 (VMAT2) in the brain serve as transporter for packaging monoamine in vesicles for normal CNS neurotransmission. Several VMAT2 imaging agents, [11C]-(+)-DTBZ, dihydrotetrabenazine and [18F]FP-(+)-DTBZ (9-O-fluoropropyl-(+)-dihydro tetrabenazine, a.k.a. [18F]AV-133), are useful for studying the changes in brain function related to monoamine transmission by in vivo imaging. Deuterated analogs have been reported targeting VMAT2 binding sites. MethodsA novel deuterated [18F]9-O-hexaduterofluoropropyl-(+)-dihydrotetrabenazine, [18F]D6-FP-(+)-DTBZ, [18F]1, was prepared as a VMAT2 imaging agent. This 18F agent which targeted VMAT2 was evaluated by in vitro binding, in vivo biodistribution and microPET imaging studies in rodents. ResultsThe one step radiolabeling reaction led to the desired [18F]D6-FP-(+)-DTBZ, [18F]1, which showed excellent binding affinity to VMAT2 (Ki=0.32±0.07nM) comparable to that of FP-(+)-DTBZ (Ki=0.33±0.02nM) using [18F]FP-(+)-DTBZ and rat striatum membrane homogenates. In vivo biodistribution in normal rats showed that 1, exhibited excellent brain uptake and comparable high ratio of striatum to cerebellum (target/background) ratio at 1h after injection (ratio of 6.05±0.43 vs 5.66±0.72 for [18F]FP-(+)-DTBZ vs [18F]1, respectively). MicroPET imaging studies in rats further confirm that the striatum with high VMAT2 concentration was clearly delineated in normal rat brain after iv injection of [18F]1. We observed minor changes of metabolism in rat plasma between these two agents; however, the changes showed little effect on regional brain uptake and retention. ConclusionsThe results reported here lend support for using [18F]D6-FP-(+)-DTBZ, [18F]1, as in vivo PET imaging agent for VMAT2 binding in the brain.

18F-FDG PET/CT in primary brain lymphoma.

The actual role of 18F-FDG PET/CT in evaluating primary brain lymphoma is still an open issue. Brain lymphoma usually show elevated 18F-FDG uptake, often higher than other brain tumors or inflammatory processes, but the metabolic behavior of this lymphoma is not still understood. Our aim was to investigate the particular metabolic behavior of this lymphoma. Forty six patients (21 female, 25 male) with histologically-confirmed brain lymphoma who underwent 18F-FDG PET/CT from vertex to the mid-thigh for initial staging were retrospectively evaluated. The PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value (SUVmax), lesion-to-liver SUVmax ratio, lesion-to-blood pool SUVmax ratio and the tumor to normal brain uptake ratio (T/N ratio) and compared with epidemiological (age, sex, HIV infection) and morphological (tumor size, MRI appearance) characteristics. Thirty-eight patients (83%) had positive 18F-FDG PET/CT (average SUVmax was 15.6 ± 9.2; lesion-to-liver SUVmax ratio 5.8 ± 2.8; lesion-to-blood pool SUVmax ratio 7.1 ± 3.8, T/N ratio 3.1 ± 1.7) at the corresponding brain lesion; the remaining 8 (17%) were not 18F-FDG avid. 18F-FDG avidity was significantly associated with morphological appearance and tumor size and not correlated with other features. 18F-FDG PET/CT detected extracranial disease in two cases (4%) with negative bone marrow biopsies and CT. In conclusion, brain lymphomas are 18F-FDG avid in 83% of cases showing high 18F-FDG uptake and 18F-FDG avidity is correlated with tumor size and morphological appearance of the lesion. PET/CT helped to recognize extracranial disease in two patients.

Usefulness of ¹¹C-methionine positron emission tomography for treatment-decision making in cases of non-enhancing glioma-like brain lesions.

The present study evaluated usefulness of the positron emission tomography with (11)C-methionine for prediction of the clinical course and treatment decision-making in adult patients with newly diagnosed non-enhancing brain lesions mimicking low-grade gliomas. Retrospective analysis was done in 163 cases. In overall, 131 tumors underwent surgical resection, which in 34 cases was done after initial period of observation. Among the latter 5 patients were operated on after significant clinical deterioration. In overall, 3 resected neoplasms corresponded to WHO histopathological grade I, 87 to grade II, 39 to grade III, and 2 to grade IV. In all 163 cases the tumor/normal brain uptake ratio (T/N ratio) of (11)C-methionine ranged from 0.68 to 8.02 (mean 2.21 ± 1.16, median 1.81). Mean T/N ratios of non-operated lesions, low-grade and high-grade tumors were 1.60 ± 0.85, 2.27 ± 1.22, and 2.54 ± 1.09, respectively (P < 0.0001), but overlap between 3 groups was prominent. In patients who had clinical deterioration during the period of observation T/N ratios of the lesion varied from 1.49 to 3.38 (mean 2.23 ± 0.70, median 2.15). Comparison of the deterioration-free survival of patients with T/N ratios of the lesion above and below 1.90 revealed statistically significant difference (P < 0.0001). In conclusion, "wait-and-scan" strategy with delay of surgical treatment does not seem reasonable option if T/N ratio of (11)C-methionine in the non-enhancing glioma-like brain lesion constitutes ≥1.90, since it may be associated with significant risk of tumor progression and clinical deterioration during follow-up.

Reproducibility Between Brain Uptake Ratio Using Anatomic Standardization and Patlak-Plot Methods.

The Patlak-plot and conventional methods of determining brain uptake ratio (BUR) have some problems with reproducibility. We formulated a method of determining BUR using anatomic standardization (BUR-AS) in a statistical parametric mapping algorithm to improve reproducibility. The objective of this study was to demonstrate the inter- and intraoperator reproducibility of mean cerebral blood flow as determined using BUR-AS in comparison to the conventional-BUR (BUR-C) and Patlak-plot methods. The images of 30 patients who underwent brain perfusion SPECT were retrospectively used in this study. The images were reconstructed using ordered-subset expectation maximization and processed using an automatic quantitative analysis for cerebral blood flow of ECD tool. The mean SPECT count was calculated from axial basal ganglia slices of the normal side (slices 31-40) drawn using a 3-dimensional stereotactic region-of-interest template after anatomic standardization. The mean cerebral blood flow was calculated from the mean SPECT count. Reproducibility was evaluated using coefficient of variation and Bland-Altman plotting. For both inter- and intraoperator reproducibility, the BUR-AS method had the lowest coefficient of variation and smallest error range about the Bland-Altman plot. Mean CBF obtained using the BUR-AS method had the highest reproducibility. Compared with the Patlak-plot and BUR-C methods, the BUR-AS method provides greater inter- and intraoperator reproducibility of cerebral blood flow measurement.

Usefulness of an Automatic Quantitative Method for Measuring Regional Cerebral Blood Flow Using (99m)Tc Ethyl Cysteinate Dimer Brain Uptake Ratio.

Improved brain uptake ratio (IBUR), employing (99m)Tc-ethyl cysteinate dimer ((99m)Tc-ECD), is an automatic non-invasive method for quantitatively measuring regional cerebral blood flow (rCBF). This method was developed by the reconstruction of the theory and linear regression equation, based on rCBF measurement by H2 (15)O positron emission tomography. Clarification of differences in rCBF values obtained by Patlak plot (PP) and IBUR method is important for clinical diagnosis during the transition period between these methods. Our purpose in this study was to demonstrate the relationship between rCBF values obtained by IBUR and PP methods and to evaluate the clinical applicability of IBUR method. The mean CBF (mCBF) and rCBF values in 15 patients were obtained using the IBUR method and compared with PP method values. Overall, mCBF and rCBF values, obtained using these independent techniques, were found to be correlated (r=0.68). The mCBF values obtained by the IBUR method ranged from 18.9 to 44.9 ml/100g/min, whereas those obtained by the PP method ranged from 34.7 to 48.1 ml/100g/min. The rCBF values obtained by the IBUR method ranged from 16.3 to 60.2 ml/100g/min, whereas those obtained by the PP method were within the range of 26.7-58.8 ml/100g/min. The ranges of mCBF and rCBF values, obtained by the IBUR method, were approximately 60% lower than those obtained by the PP method; therefore, this method can be useful for diagnosing lower flow area. Re-analysis of prior PP data, using the IBUR method, could be potentially useful for the clinical follow-up of rCBF.

Brain tumor magnetic targeting and biodistribution of superparamagnetic iron oxide nanoparticles linked with 70-kDa heat shock protein study by nonlinear longitudinal response

Brain tumor targeting efficiency and biodistribution of the superparamagnetic nanoparticles conjugated with heat shock protein Hsp70 (SPION–Hsp70) were evaluated in experimental glioma model. Synthesized conjugates were characterized using the method of longitudinal nonlinear response of magnetic nanoparticles to a weak ac magnetic field with measurements of second harmonic of magnetization (NLR-M2). Cellular interaction of magnetic conjugates was analyzed in 9L glioma cell culture. The biodistribution of the nanoparticles and their accumulation in tumors was assessed by the latter approach as well. The efficacy of Hsp70-conjugates for contrast enhancement in the orthotopic model of 9L glioma was assessed by MR imaging (11T). Magnetic nanoparticles conjugated with Hsp70 had the relaxivity properties of the MR-negative contrast agents. Morphological observation and cell viability test demonstrated good biocompatibility of Hsp70-conjugates. Analysis of the T2-weighted MR scans in tumor-bearing rats demonstrated the high efficacy of Hsp70-conjugates in contrast enhancement of the glioma in comparison to non-conjugated nanoparticles. High contrast enhancement of the glioma was provided by the accumulation of the SPION–Hsp70 particles in the glioma tissue (as shown by the histological assay). Biodistribution analysis by NLR-M2 measurements evidenced the many-fold increase (~40) in the tumor-to-normal brain uptake ratio in the Hsp70-conjugates treated animals. Biodistribution pattern of Hsp70-decorated nanoparticles differed from that of non-conjugated SPIONs. Coating of the magnetic nanoparticles with Hsp70 protein enhances the tumor-targeting ability of the conjugates that could be applied in the MR imaging of the malignant brain tumors.

Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION-cmHsp70.1).

The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. Herein, we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific targeting before and after ionizing irradiation. In vitro experiments demonstrated the selectivity of SPION-cmHsp70.1 conjugates to free and mHsp70 in different tumor cell types (C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI (11 T) on T(2)-weighted images showed the retention of the conjugates in the C6 glioma model. Accumulation of SPION-cmHsp70.1 nanoparticles in the glioma resulted in a nearly 2-fold drop of T*(2) values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M(2) measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of SPION-cmHsp70.1 conjugates in glioma-bearing rats in comparison to SPIONs. This accumulation within Hsp70-positive glioma was further enhanced after a single dose (10 Gy) of ionizing radiation. Elevated accumulation of the magnetic conjugates in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors.

Development of an automatic ROI setting program for input function determination in 99mTc-ECD non-invasive cerebral blood flow quantification

Non-invasive quantitative measurements are useful for clinical study as these are simple and pain-free procedures. A new non-invasive semi-automatic quantitative measurement method, the improved brain uptake ratio (IBUR) method using 99mTc-ECD SPECT, has recently been reported. If an automatic ROI setting algorithm could be developed to determine the input function for the IBUR method, analysis of regional cerebral blood flow (rCBF) can be completed within a few min without recourse to complex techniques, through a fully automatic rCBF analysis program. The purpose of this study was to develop an automatic input function determination program for 99mTc-ECD non-invasive cerebral blood flow quantification and to confirm the feasibility of use of this program.The images of 15 consecutive patients who underwent both 99mTc-ECD chest RI angiography and SPECT examinations were used for development of the automatic arterial input function program. The images of 69 consecutive patients were used for validation of the program.The coincidence ratio between the ROI automatic method and the manual setting method was 98%. The mean difference in the ROI location was ±6.4 mm in the X direction and ±8.6 mm in the Y direction. Individual rCBF values obtained using these independent techniques were also reasonably well correlated (r = 0.95). The total time for the IBUR analysis using the automatic method is 2–3 min as compared to 20–30 min for the current analysis method. This technique improves the throughput of nuclear medical examinations.

Comparison of &lt;sup&gt;11&lt;/sup&gt;C-Methionine, &lt;sup&gt;11&lt;/sup&gt;C-Choline, and &lt;sup&gt;18&lt;/sup&gt;F-Fluorodeoxyglucose-PET for Distinguishing Glioma Recurrence from Radiation Necrosis

The aim of this study is to assess the different metabolic activities characteristic of glioma recurrence and radiation necrosis (RN) and to explore the diagnostic accuracy for differentiation of the two conditions using 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). Fifty patients with lesions suggestive of recurrent glioma by magnetic resonance imaging (MRI) underwent MET, CHO, and FDG-PET. All patients who had previously been treated with radiotherapy for malignant glioma were subjected to open surgery and pathological diagnosis (17 recurrent grade 3- gliomas (Gr.3s) comprising 7 anaplastic astrocytomas (AAs) and 10 anaplastic oligodendrogliomas (AOs), 17 recurrent glioblastomas (Gr.4s), and 16 RNs). We measured the PET/Gd volume ratio, the PET/Gd overlap ratio, and the lesion/normal brain uptake ratio (L/N ratio) and determined the optimal index of each PET scan. The PET/Gd volume ratio and the PET/Gd overlap ratio for RN were significantly lower than those of glioma recurrence only with MET-PET (P < 0.05). The L/N ratio of RN was significantly lower than that of Gr.4 with all PET imaging (P < 0.001) and was significantly lower than that of Gr.3, especially for AO, only with MET-PET images (P < 0.005). Receiver operating characteristic (ROC) analysis showed that the area under the curve of MET, CHO, and FDG was 92.5, 81.4, and 77.4, respectively. MET L/N ratio of greater than 2.51 provided the best sensitivity and specificity for establishing glioma recurrence (91.2% and 87.5%, respectively). These results demonstrated that MET-PET was superior to both CHO and FDG-PET for diagnostic accuracy in distinguishing glioma recurrence from RN.

Improvement of the 99mTc-ECD brain uptake ratio (BUR) method for measurement of cerebral blood flow

The brain uptake ratio (BUR) method for the (99m)Tc-ECD SPECT, a non-invasive measurement method of rCBF, has been used in clinical practice in Japan, because it is simple to use. However, the accuracy of this method is limited, as it has problems in the determination of input function and the regression equation. The purpose of this study is to improve the BUR method by reconstructing the determination process of the input function and regression equation based on measurement of the rCBF by H (2) (15) O PET. The input function was obtained by setting the region of interest on the ascending aorta instead of the aortic arch. The 3DSRT algorithm was used to obtain the anatomically standardized rCBF, and developed a semi-automatic analyzing software using C++ in order to stabilize the repeatability of the improved BUR (IBUR) method. The regression equation for the IBUR method was obtained by the H (2) (15) O PET rCBFs in 15 patients with the arterial blood sampling method. All the measurements in this study were performed with the patient in the resting state. A good correlation was observed between the rCBF values measured by H (2) (15) O PET and the regional BURs measured by the IBUR method (r=0.86, p<0.0001). The rCBF values were calculated for only 5min using a semi-automatic analyzing software. The BUR method was improved by changing the location of the input function from the aortic arch to the ascending aorta based on arterial blood flow dynamics, and reconstructing regression equation based on the rCBF values obtained using H (2) (15) O PET. This finding indicates the potential clinical usefulness of this method.