Synthesis and evaluation of 2-(2'-((dimethylamino)methyl)-4'-(2-fluoroethoxy-substituted)phenylthio)benzenamine derivatives as potential positron emission tomography imaging agents for serotonin transporters.

A series of diphenylsulfide derivatives with various substitutions at the 4-position on phenyl ring A and different lengths of the 2-fluoroethoxy-substituted side-chain at the 4'-position on ring B were synthesized and evaluated as potential positron emission tomography (PET) imaging agents for serotonin transporters (SERT). These ligands exhibited high SERT binding affinities (Ki = 0.11-1.3 nM) and the 4-methyl-substituted (4-Me) compounds 7a and 8a displayed excellent selectivity for SERT versus norepinephrine transporters (NET) (392- and 700-fold, respectively). In the parallel artificial membrane permeability assay (PAMPA), these ligands demonstrated moderate to high brain penetration, and the 4-Me analogs showed higher BBB permeability than the corresponding 4-F analogs. The 2-fluoroethoxy-substituted ligands showed higher metabolic stability and lower lipophilicity than 4-F-ADAM. [18F]7a-c were readily prepared using an automatic synthesizer and exhibited significant uptake and slow washout in rat brains. At 120 min after iv injection, [18F]7a exhibited the highest uptake in the midbrain, whereas [18F]7b exhibited the highest uptake in the hypothalamus and midbrain. After treatment with citalopram, a SERT-selective ligand, the uptake of [18F]7a in the hypothalamus and striatum was significantly decreased. The potent and highly selective SERT binding and the selective and reversible accumulation in SERT-rich brain regions suggested that [18F]7a is a promising lead for the further development of novel [18F]-labeled PET imaging agents for SERT binding sites in the brain.

An one-pot two-step automated synthesis of [18F]T807 injection, its biodistribution in mice and monkeys, and a preliminary study in humans.

[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/µmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 µSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) µSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.

Evaluation of 5-[18F]fluoro-2'-deoxycytidine as a tumor imaging agent: A comparison of [18F]FdUrd, [18F]FLT and [18F]FDG.

One of the hallmarks of cancer is increased cell proliferation. Measurements of cell proliferation by estimation of DNA synthesis with several radiolabeled nucleosides have been tested to assess tumor growth. Deoxycytidine can be phosphorylated by deoxycytidine kinase (dCK) and is incorporated into DNA. This study evaluated a radiofluorinated deoxycytidine analog, 5-[18F]fluoro-2'-deoxycytidine ([18F]FdCyd), as a proliferation probe and compared it with 5-[18F]fluoro-2'-deoxyuridine ([18F]FdUrd), 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), and [18F]fluorodeoxyglucose ([18F]FDG) in a tumor-bearing mouse model. [18F]FdCyd was synthesized from two precursors by direct electrophilic substitution. The serum stability and partition coefficient of [18F]FdCyd were evaluated in vitro. Positron emission topography (PET) imaging of Lewis lung carcinoma (LLC)-bearing mice with [18F]FdCyd, [18F]FdUrd, [18F]FLT, and [18F]FDG were evaluated. [18F]FdCyd was stable in mouse serum and normal saline for up to 4 h. With all radiotracers except [18F]FLT, PET can clearly delineate the tumor lesion. [18F]FdCyd and [18F]FdUrd showed high accumulation in the liver and kidney. The SUV and tumor-to-muscle (T/M) ratios derived from PET imaging of the radiotracers were [18F]FDG > [18F]FdCyd > [18F]FdUrd > [18F]FLT. Selective retention in tumors with a favorable tumor/muscle ratio makes [18F]FdCyd a protential candidate for further investigation as a proliferation imaging agent.

Phase II study of metabolic response to one-cycle chemotherapy in patients with locally advanced esophageal squamous cell carcinoma.

BACKGROUND: In the treatment of esophageal squamous cell carcinoma (ESCC), the optimal use of 18fluorodeoxyglucose positron emission tomography (PET) in measuring metabolic tumor response is undetermined. We launched a phase II trial to evaluate early metabolic response to one-cycle induction chemotherapy in patients with locally advanced ESCC. METHODS: ESCC patients in stage classification T3N0, N1M0, or M1a (American Joint Committee on Cancer, 6th edition) received one-cycle chemotherapy comprising paclitaxel, cisplatin, and 24-h infusional 5-fluorouracil and leucovorin on days 1 and 8, followed by neoadjuvant chemoradiotherapy, 40 Gy, with paclitaxel/cisplatin and then esophagectomy. PET was performed at baseline and day 14 of chemotherapy. The primary endpoint was pathologic complete response (pCR). We hypothesized early metabolic responders with >35% reduction in maximum standardized uptake value (SUVmax), would have better pCR Results. RESULTS: Sixty-six patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 16 months (95% confidence interval [CI], 9-27) and 22 months (16-40), respectively. The early metabolic response rate was 55%; and the pCR rate was 34% in the esophagectomy population. The early metabolic response was not associated with pCR or survival. In an exploratory analysis, the postchemotherapy SUVmax was an independent prognostic factor for pCR, PFS, and OS. CONCLUSION: Our study failed to validate the predefined early metabolic response for pCR to neoadjuvant chemoradiotherapy in locally advanced ESCC patients. However, postchemotherapy SUVmax may be prognostic and predictive, and warrants further study.

The Relation Between Brain Amyloid Deposition, Cortical Atrophy, and Plasma Biomarkers in Amnesic Mild Cognitive Impairment and Alzheimer's Disease.

Background: Neuritic plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease (AD), while the role of brain amyloid deposition in the clinical manifestation or brain atrophy remains unresolved. We aimed to explore the relation between brain amyloid deposition, cortical thickness, and plasma biomarkers. Methods: We used 11C-Pittsburgh compound B-positron emission tomography to assay brain amyloid deposition, magnetic resonance imaging to estimate cortical thickness, and an immunomagnetic reduction assay to measure plasma biomarkers. We recruited 39 controls, 25 subjects with amnesic mild cognitive impairment (aMCI), and 16 subjects with AD. PiB positivity (PiB+) was defined by the upper limit of the 95% confidence interval of the mean cortical SUVR from six predefined regions (1.0511 in this study). Results: All plasma biomarkers showed significant between-group differences. The plasma Aß40 level was positively correlated with the mean cortical thickness of both the PiB+ and PiB- subjects. The plasma Aß40 level of the subjects who were PiB+ was negatively correlated with brain amyloid deposition. In addition, the plasma tau level was negatively correlated with cortical thickness in both the PiB+ and PiB- subjects. Moreover, cortical thickness was negatively correlated with brain amyloid deposition in the PiB+ subjects. In addition, the cut-off point of plasma tau for differentiating between controls and AD was higher in the PiB- group than in the PiB+ group (37.5 versus 25.6 pg/ml, respectively). Lastly, ApoE4 increased the PiB+ rate in the aMCI and control groups. Conclusion: The contributions of brain amyloid deposition to cortical atrophy are spatially distinct. Plasma Aß40 might be a protective indicator of less brain amyloid deposition and cortical atrophy. It takes more tau pathology to reach the same level of cognitive decline in subjects without brain amyloid deposition, and ApoE4 plays an early role in amyloid pathogenesis.

Single allele Lmbrd1 knockout results in cardiac hypertrophy.

BACKGROUND/PURPOSE: LMBD1 protein, a type IV-B plasma membrane protein possessing nine putative trans-membrane domains, was previously demonstrated at cellular level to play a critical part in the signaling cascade of insulin receptor through its involvement in regulating clathrin-mediated endocytosis. However, at physiological level, the significance of LMBD1 protein in cardiac development remains unclear. METHODS: To understand the role of Lmbrd1 gene involved in the cardiac function, heterozygous knockout mice were used as an animal model system. The pathological outcomes were analyzed by micro-positron emission tomography, ECG acquisition, cardiac ultrasound, and immunohistochemistry. RESULTS: By studying the heterozygous knockout of Lmbrd1 (Lmbrd1+/-), we discovered that lack of Lmbrd1 not only resulted in the increase of cardiac-glucose uptake, pathological consequences were also observed. Here, we have distinguished that Lmbrd1+/- is sufficient in causing cardiac diseases through a pathway independent of the recessive vitamin B12 cblF cobalamin transport defect. Lmbrd1+/- mice exhibited an increase in myocardial glucose uptake and insulin receptor signaling that is insensitive to the administration of additional insulin. Pathological symptoms such as cardiac hypertrophy, ventricular tissue fibrosis, along with the increase of heart rate and cardiac muscle contractility were observed. As Lmbrd1+/- mice aged, the decrease in ejection fraction and fraction shortening showed signs of ventricular function deterioration. CONCLUSION: The results suggested that Lmbrd1 gene not only plays a significant role in mediating the energy homeostasis in cardiac tissue, it may also be a key factor in the regulation of cardiac function in mice.

Targeting histone deacetylase 4/ubiquitin-conjugating enzyme 9 impairs DNA repair for radiosensitization of hepatocellular carcinoma cells in mice.

Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach is to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiation's effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or short hairpin RNA to knock down expression of HDAC4 and then irradiated (2.5-10.0 Gy). We evaluated cell survival by a clonogenic assay; apoptosis by Annexin V immunofluorescence; γH2AX, Rad51, and HDAC4 by immunofluorescence staining; HDAC4, Rad51, and ubiquitin-conjugating enzyme 9 (Ubc9) in HCC cell nuclei by cell fractionation and confocal microscopy; physical interaction between HDAC4/Rad51/Ubc9 by immunoprecipitation; and the downstream targets of HDAC4 knockdown by immunoblotting. Both HDAC4 knockdown and HDAC inhibitor enhanced radiation-induced cell death and reduced homologous recombination repair of DNA double-strand breaks and protein kinase B activation, leading to increased apoptosis. HDAC4 knockdown with or without an HDAC inhibitor significantly delayed tumor growth in a radiation-treated xenograft model. Radiation stimulated nuclear translocation of Rad51 in an HDAC4-dependent manner and the binding of Ubc9 directly to HDAC4, which led to Ubc9 acetylation. Moreover, these effects were accompanied by HDAC4/Ubc9/Rad51 complex dissociation through inhibiting nuclear translocation. Conclusion: HDAC4 signaling blockade enhances radiation-induced lethality in HCC cells and xenografts. These findings raise the possibility that HDAC4/Ubc9/Rad51 complex in DNA repair may be a target for radiosensitization of HCC. (Hepatology 2018;67:586-599).

High yield one-pot production of [18F]FCH via a modified TRACERlab FxFN module.

INTRODUCTION: [18F]Fluoromethylcholine ([18F]FCH) is a potent tumors imaging agent. In order to fulfill the demand of pre-clinical and clinical studies, we have developed an automated high yield one-pot synthesis of this potent tumors imaging agent. METHODS: [18F]FCH was synthesized using a modified TRACERlab FxFN module. Briefly, dibromomethane (10% in CH3CN) was fluorinated with K[18F]/K 2.2.2 in a glassy carbon reaction vessel at 120°C for about 5min to generate [18F]fluorobromomethane ([18F]FBM). The resulting [18F]FBM was then bubbling (He, 700mL/min) through four Sep-Pak® Silica Plus Long cartridges to react with dimethylaminoethanol (10% DMAE in 0.3mL DMSO) which was pre-loaded on Sep-Pak® C18 Plus Short cartridge. The [18F]FCH was purified by solid-phase extraction (SPE) using one Sep-Pak® C18 Plus Short and one Sep-Pak® CM Plus Short in series. The quality of [18F]FCH synthesized by this method was verified by HPLC and TLC as compared to authentic sample. RESULTS: Using this improved one-pot method, the RCY of [18F]FCH was 18.8 ± 2.1% (EOB, n = 27) in a synthesis time of 49 ± 5min from EOB. The radiochemical purity of [18F]FCH was greater than 90% and the residual DMAE concentration in the final product was less than 10ppm. CONCLUSIONS: This optimized method could fulfill the demand of [18F]FCH for both pre-clinical and clinical studies, especially for nearby study sites without a cyclotron.

Risk Stratification of Pediatric Patients With Neuroblastoma Using Volumetric Parameters of 18F-FDG and 18F-DOPA PET/CT.

PURPOSE: This study determined the prognostic value of volumetric parameters derived from pretreatment F-FDG and F-DOPA PET/CT of neuroblastoma and their correlation with clinical and histopathologic features. PATIENTS AND METHODS: A total of 25 children with neuroblastoma underwent pretreatment F-FDG and F-DOPA PET/CT within 4 weeks. The SUVmax of primary tumors on F-FDG and F-DOPA PET were recorded as SUVFDG and SUVDOPA, respectively. For volumetric parameters of primary tumors, 40% of SUVmax was used to generate volume of interest. If the 40% of SUVmax was below 2.5, an SUV threshold of 2.5 was used instead. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), dopaminergic tumor volume (DTV), and total lesion F-DOPA activity (TLDA) were recorded as F-FDG and F-DOPA volumetric parameters. All indices were compared between groups distinguished by survival status and clinical features, including bone marrow involvement, lymph node metastasis, amplification of the MYCN oncogene, invasive features on anatomic images, and risk categories. The Kaplan-Meier method and log-rank test were used to compare the survival curves between groups. RESULTS: The median follow-up period was 28.2 months. Nonsurvivors (20%) tended to have lower SUVDOPA, DTV, and TLDA (P ≤ 0.05), and higher SUVFDG, MTV, and TLG (all P < 0.05). Lower F-DOPA uptake is associated with bone marrow and lymph node metastases (all P < 0.05). Higher F-FDG uptake is associated with MYCN amplification (all P < 0.05) and anatomic invasive features of tumors such as vascular encasement or adjacent organ invasion (TLG, P = 0.05). Only volumetric indices (DTV, TLDA, MTV, and TLG) significantly differed among risk groups (all P < 0.05). CONCLUSIONS: Pretherapeutic F-DOPA and F-FDG PET provided complementary information, and both can be served for risk stratification. Volumetric indices of F-DOPA and F-FDG PET correlate more highly with risk grouping.

Performing Repeated Quantitative Small-Animal PET with an Arterial Input Function Is Routinely Feasible in Rats.

Performing quantitative small-animal PET with an arterial input function has been considered technically challenging. Here, we introduce a catheterization procedure that keeps a rat physiologically stable for 1.5 mo. We demonstrated the feasibility of quantitative small-animal 18F-FDG PET in rats by performing it repeatedly to monitor the time course of variations in the cerebral metabolic rate of glucose (CMRglc). Methods: Aseptic surgery was performed on 2 rats. Each rat underwent catheterization of the right femoral artery and left femoral vein. The catheters were sealed with microinjection ports and then implanted subcutaneously. Over the next 3 wk, each rat underwent 18F-FDG quantitative small-animal PET 6 times. The CMRglc of each brain region was calculated using a 3-compartment model and an operational equation that included a k*4Results: On 6 mornings, we completed 12 18F-FDG quantitative small-animal PET studies on 2 rats. The rats grew steadily before and after the 6 quantitative small-animal PET studies. The CMRglc of the conscious brain (e.g., right parietal region, 99.6 ± 10.2 µmol/100 g/min; n = 6) was comparable to that for 14C-deoxyglucose autoradiographic methods. Conclusion: Maintaining good blood patency in catheterized rats is not difficult. Longitudinal quantitative small-animal PET imaging with an arterial input function can be performed routinely.

A multidisciplinary team care approach improves outcomes in high-risk pediatric neuroblastoma patients.

We assessed the impact of a multidisciplinary team care program on treatment outcomes in neuroblastoma patients. Newly diagnosed neuroblastoma patients received treatment under the Taiwan Pediatric Oncology Group (TPOG) N2002 protocol at the National Taiwan University Hospital beginning in 2002. A multidisciplinary team care approach that included nurse-led case management for patients treated under this protocol began in January 2010. Fifty-eight neuroblastoma patients, including 29 treated between 2002 and 2009 (Group 1) and 29 treated between 2010 and 2014 (Group 2), were enrolled in the study. The 5-year overall survival (OS) and event-free survival (EFS) rates for all 58 patients were 59% and 54.7%, respectively. Group 2 patients, who were treated after implementation of the multidisciplinary team care program, had better 3-year EFS (P = 0.046), but not OS (P = 0.16), rates than Group 1 patients. In a multivariate analysis, implementation of the multidisciplinary team approach was the only significant independent prognostic factor for neuroblastoma patients. In further subgroup analyses, the multidisciplinary team approach improved EFS, but not OS, in patients with stage 4 disease, those in the high-risk group, and those with non-MYCN amplified tumors. These data indicate a multidisciplinary team care approach improved survival outcomes in high-risk neuroblastoma patients. However, further investigation will be required to evaluate the long-term effects of this approach over longer follow-up periods.

A Novel Potential Positron Emission Tomography Imaging Agent for Vesicular Monoamine Transporter Type 2.

In the early 1990s, 9-(+)-11C-dihydrotetrabenazine (9-(+)-11C-DTBZ) was shown to be a useful positron emission tomography (PET) imaging agent for various neurodegenerative disorders. Here, we described the radiosynthesis and evaluation of the 9-(+)-11C-DTBZ analog, 10-(+)-11C-DTBZ, as a vesicular monoamine transporter 2 (VMAT2) imaging agent and compare it with 9-(+)-11C-DTBZ. 10-(+)-11C-DTBZ was obtained by 11C-MeI methylation with its 10 hydroxy precursor in the presence of 5 M NaOH. It had a slightly better average radiochemical yield of 35.3 ± 3.6% (decay-corrected to end of synthesis (EOS)) than did 9-(+)-11C-DTBZ (30.5 ± 2.3%). MicroPET studies showed that 10-(+)-11C-DTBZ had a striatum-to-cerebellum ratio of 3.74 ± 0.21 at 40 min post-injection, while the ratio of 9-(+)-11C-DTBZ was 2.50 ± 0.33. This indicated that 10-(+)-11C-DTBZ has a higher specific uptake in VMAT2-rich brain regions, and 10-(+)-11C-DTBZ may be a potential VMAT2 radioligand. Our experiment is the first study of 10-(+)-11C-DTBZ to include dynamic brain distribution in rat brains.

Diagnostic Performance of Attenuation-Corrected Myocardial Perfusion Imaging for Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Myocardial perfusion imaging (MPI) with SPECT is a well-established tool for the diagnosis of coronary artery disease (CAD). However, soft-tissue attenuation is a common artifact that limits the diagnostic accuracy of MPI. The aim of this study was to determine whether attenuation correction (AC) improved the diagnostic performance of MPI, using coronary angiography as a reference standard. METHODS: MEDLINE and EMBASE were searched until March 2015 for studies evaluating AC MPI for the diagnosis of CAD. Methodologic quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. For each study, the sensitivity, specificity, and diagnostic odds ratio, along with 95% confidence intervals (CIs), were calculated to determine the diagnostic accuracy of AC versus non-attenuation-corrected (NAC) MPI. A bivariate mixed-effects model was applied for pooling the data. RESULTS: Of 201 articles, 17 studies (1,701 patients) were identified, including 5 studies that used CT AC, 12 studies that used radionuclide source AC (RAC), and 15 studies that reported NAC results. The pooled sensitivities across studies were 0.80 (95% CI, 0.64-0.91), 0.85 (95% CI, 0.81-0.88), 0.84 (95% CI, 0.79-0.88), and 0.80 (95% CI, 0.75-0.85) for CT AC, RAC, all AC, and NAC, respectively. The pooled specificities were 0.83 (95% CI, 0.71-0.91), 0.81 (95% CI, 0.73-0.86), 0.80 (95% CI, 0.74-0.85), and 0.68 (95% CI, 0.61-0.74). Both sensitivities and specificities resulted in a pooled diagnostic odds ratio of 20 (95% CI, 12-34), 24 (95% CI, 13-43), 22 (95% CI, 13-35), and 9 (7-11). Significant differences in specificity and diagnostic odds ratios were noted when AC (including CT AC, RAC, and all AC) was compared with NAC. CONCLUSION: The results from this study suggested that AC should be applied to MPI to improve the diagnosis of CAD, especially the specificity.

A two-center study for the quality control of [(18)F]FDG using FASTlab phosphate cassettes.

OBJECTIVE: The GE FASTlab radiosynthesis module is routinely used for the production of [(18)F]FDG, utilizing the commercially available phosphate cassettes. Because of the observation of a white precipitate in the product vial before the product expiry time, we re-examined the quality of the produced [(18)F]FDG solution. METHODS: Phosphate buffered [(18)F]FDG solution was synthesized on the FASTlab and analyzed at both National Taiwan University Hospital (NTUH) of Taiwan and Royal Brisbane and Women's Hospital (RBWH) of Australia. In addition to the standard product quality control (QC), the concentration of aluminum (Al(3+)) as probable cause of the precipitations in the [(18)F]FDG solution was analyzed by inductively coupled plasma mass spectrometry (ICP-MS at RBWH) and inductively coupled plasma optical emission spectrometry (ICP-OES at NTUH), and using three semi-quantitative methods at NTUH, Advantec(®) Alumi Check Test Strip, Quantofix(®) Aluminum Test Strip and MColortest™ Aluminum Test kit. RESULTS: The precipitates were observed in the [(18)F]FDG solution within 24 (NTUH) and 6 (RBWH) hours after the end of synthesis in 38-100 % of the batches, dependent on the batch of the FASTlab cassettes. Addition of metal-free HCl(aq) to aliquots of [(18)F]FDG containing precipitate, followed by ICP-MS analysis revealed Al(3+) concentrations of 70-80 ppm. Al(3+) concentrations of 10-12 ppm were detected in [(18)F]FDG batches that did not show any precipitation. In contrast, less than 5 ppm of the residual Al(3+) was detected by semi-quantitative methods in all batches. CONCLUSION: The US (USP), British (BP), European (EP) and Japanese (JP) pharmacopeias demand that [(18)F]FDG for injection should be clear and particulate free within the given shelf-life/expiration time. To avoid Al-phosphate precipitation within the product expiry time, FASTlab citrate cassettes, rather than phosphate cassettes, should be used for [(18)F]FDG production. Although testing for Al(3+) is not listed in the [(18)F]FDG monographs of the USP, BP and EP, residual Al(3+) levels should be considered in the interests of patient safety.

The Incremental Diagnostic Performance of Coronary Computed Tomography Angiography Added to Myocardial Perfusion Imaging in Patients with Intermediate-to-High Cardiovascular Risk.

PURPOSE: Several studies have suggested that a combined approach of stress myocardial perfusion imaging (MPI) and coronary computed tomography angiography (CCTA) can provide diagnostic results with excellent accuracy. We aimed to explore whether the addition of CCTA to stress MPI provides incremental diagnostic value in intermediate-to-high cardiovascular risk patients. METHODS: A total of 106 consecutive patients (93 male, 65 ± 10.4 years) underwent coronary artery calcium scoring (CACS), CCTA and (201)Thallium stress MPI before coronary angiography was reviewed. Thirty-seven patients (34.9%) had a history of proven coronary artery disease (CAD) or revascularization procedures, and four had documented non-significant CAD (3.8%). The remaining patients consisted of 17 (16.0%) classified as intermediate, and 48 (45.3%) as the high-risk groups. RESULTS: Obstructive CAD was diagnosed by invasive coronary angiography in 88 patients with 161 vessels. The sensitivity and specificity in a patient-based analysis for obstructive CAD were 99% and 17% for CCTA, 80% and 50% for MPI and 91% and 67% for the combined method, respectively. The per-vessel diagnostic sensitivity and specificity were 95% and 54% for CCTA, 59% and 75% for MPI and 84% and 76% for the combined method. There were significant differences (p < 0.05) when comparing the combined method with MPI or CCTA by areas under the curve in a patient- or vessel-based analysis. However, CACS of 400 or more could not further stratify the patients with obstructive CAD. CONCLUSIONS: CCTA, not CACS, provided additional diagnostic values to stress MPI in patients with intermediate-to-high cardiovascular risk. KEY WORDS: Coronary artery disease (CAD) • Coronary computed tomography angiography (CCTA) • Myocardial perfusion imaging (MPI) • Single-photon emission computed tomography (SPECT).

Clinical significance of right ventricular activity on treadmill thallium-201 myocardial single-photon emission computerized tomography using cadmium-zinc-telluride cameras.

OBJECTIVE: Identification of right ventricular (RV) abnormalities is important in patients with suspected coronary artery disease (CAD). RV activity can be better visualized on myocardial single-photon emission computerized tomography (SPECT) using a higher sensitivity cadmium-zinc-telluride (CZT) detector. The aim of this study was to investigate the clinical significance of RV/left ventricular (LV) uptake ratios during exercise thallium-201 SPECT using CZT detectors. PATIENTS AND METHODS: A total of 102 patients underwent treadmill ECG-gated SPECT, coronary angiography, and echocardiography. SPECT myocardial perfusion was interpreted using a 17-segment model and a 0-4-point scale. RV/LV uptake ratios were calculated on the basis of maximum counts per pixel within the entire RV and LV walls. The relationships between RV/LV uptake ratio and gated SPECT, presence of CAD (≥50% stenosis in the left main or ≥70% in the main branches), demographics, and echocardiographic parameters were analyzed. RESULTS: Stress RV/LV ratios correlated positively with the presence of left main or multivessel disease, and tricuspid regurgitation maximum pressure gradient. After multivariate regression, stress/rest RV/LV ratios correlated positively with mitral flow deceleration time, age, female sex, and use of ß-blockers. CONCLUSION: RV/LV uptake ratios on the basis of exercise myocardial perfusion SPECT imaging using CZT cameras are useful for the detection of severe CAD and could serve as an indicator of pulmonary hypertension and LV diastolic dysfunction.

Diagnostic FDG and FDOPA positron emission tomography scans distinguish the genomic type and treatment outcome of neuroblastoma.

Neuroblastoma (NB) is a heterogeneous childhood cancer that requires multiple imaging modalities for accurate staging and surveillances. This study aims to investigate the utility of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and 18F-fluoro-dihydroxyphenylalanine (FDOPA) in determining the prognosis of NB. During 2007-2014, forty-two NB patients (male:female, 28:14; median age, 2.0 years) undergoing paired FDG and FDOPA PET scans at diagnosis were evaluated for the maximum standardized uptake value (SUV(max)) of FDG or FDOPA by the primary tumor. Patients with older age, advanced stages, or MYCN amplification showed higher FDG and lower FDOPA SUV(max) (all P < 0.02). Receiver operating characteristics analysis identified FDG SUV(max) ≥ 3.31 and FDOPA SUV(max) < 4.12 as an ultra-high-risk feature (PET-UHR) that distinguished the most unfavorable genomic types, i.e. segmental chromosomal alterations and/or MYCN amplification, at a sensitivity of 81.3% (54.4%-96.0%) and a specificity of 93.3% (68.1%-99.8%). Considering with age, stage, MYCN status, and anatomical image-defined risk factor, PET-UHR was an independent predictor of inferior event-free survival (multivariate hazard ratio, 4.9 [1.9-30.1]; P = 0.012). Meanwhile, the ratio between FDG and FDOPA SUV(max) (G:D) correlated positively with HK2 (Spearman's ρ = 0.86, P < 0.0001) and negatively with DDC (ρ = -0.58, P = 0.02) gene expression levels, which might suggest higher glycolytic activity and less catecholaminergic differentiation in NB tumors taking up higher FDG and lower FDOPA. In conclusion, the intensity of FDG and FDOPA uptake on diagnostic PET scans may predict the tumor behavior and complement the current risk stratification systems of NB.

Search of Unknown Fever Focus Using PET in Critically Ill Children With Complicated Underlying Diseases.

OBJECTIVES: PET/CT with F-fluorodeoxyglucose can be used to image cellular metabolism and has been used for evaluating fever of unknown origin in adults. However, there are limited studies about the role of F-fluorodeoxyglucose PET/CT in evaluation of fever of unknown origin in critically ill children, especially those presenting with complicated underlying diseases under treatment. Here, we report our preliminary experience using F-fluorodeoxyglucose PET/CT in this specific group of patients. DESIGN: Retrospective observational study. SETTING: PICUs of a university hospital. PATIENTS: Nineteen critically ill children (mean age, 5.7 yr old) with complicated underlying diseases requiring intensive care support underwent F-fluorodeoxyglucose PET/CT to evaluate fever of unknown origin. The median hospitalized stay was 34 days (range, 15-235 d) and fever of at least 7 days (mean, 21.6 d; range, 7-52 d). The PET scan was advocated after all routine microbiology, and conventional imaging showed negative or inconclusive results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The F-fluorodeoxyglucose PET/CT findings (blinded to the final clinical diagnosis) were compared with final histopathology, culture, serology results, or follow-up imaging. A final diagnosis was made in 16 patients (84.2%). F-fluorodeoxyglucose PET/CT accurately localized the source of fever in 14 patients, confers to a sensitivity of 87.5% (14 of 16; 95% CI, 0.604-0.978). A false-positive scan in a patient led to subsequent unnecessary investigations. Two false-negative F-fluorodeoxyglucose PET/CT images were later attributed to relapse of underlying disease in the bone marrow and renal abscesses, respectively. In the other two patients where F-fluorodeoxyglucose PET/CT also showed negative findings, fever subsided shortly thereafter without treatment. CONCLUSIONS: Our preliminary experience suggests that F-fluorodeoxyglucose PET/CT may be clinically beneficial in evaluating fever of unknown origin in children with complicated underlying diseases mandating intensive support in ICUs if usual investigative methods are unsuccessful. Further large prospective studies are needed to validate these findings.

Incremental Diagnostic Performance of Combined Parameters in the Detection of Severe Coronary Artery Disease Using Exercise Gated Myocardial Perfusion Imaging.

PURPOSE: Myocardial perfusion imaging (MPI) using gated single-photon emission tomography (gSPECT) may underestimate the severity of coronary artery disease (CAD). This study aimed to evaluate the significance of combined parameters derived from gSPECT, as well as treadmill stress test parameters, in the detection of severe CAD. METHODS: A total of 211 consecutive patients referred for exercise MPI between June 2011 and June 2013 (who received invasive coronary angiography within six months after MPI) were retrospectively reviewed. Exercise MPI was performed with Bruce protocol and 201Tl injected at peak exercise. Gated SPECT was performed using a cadmium-zinc-telluride camera and processed by QPS/QGS software. Perfusion defect abnormalities such as sum stress score (SSS); sum difference score, algorithm-derived total perfusion deficits, transient ischemic dilatation ratios of end-diastolic volumes and end-systolic volumes, post-stress changes in ejection fraction, and lung/heart ratio (LHR) were calculated. Treadmill parameters, including ST depression (STD) at the 1st and 3rd minutes of recovery stage (1'STD and 3'STD), maximal STD corrected by heart rate increment (ST/HR), heart rate decline in 1st and 3rd minutes of recovery stage, recovery heart rate ratio (HR ratio), systolic and mean blood pressure ratios (SBP ratio and MAP ratio) during recovery phase were recorded. Diagnostic performances of these parameters were analyzed with receiver operating characteristic (ROC) analysis and logistic regression for detection of left main (≥ 50%) or 3-vessel disease (all ≥ 70% luminal stenosis) on invasive angiography. RESULTS: Among various MPI and treadmill parameters used for detection of severe CAD, SSS and ST/HR had the highest AUC (0.78, 0.73, p = NS) and best cut-off values (SSS > 6, ST/HR > 17.39 10-2mV/bpm), respectively. By univariate logistic regression, all parameters except 1'HRR, 3'HRR, SBP and MAP ratios increased the odds ratio of severe CAD. Only increased L/H ratio, 3'STD, and HR ratio remained significant after multivariate regression. The predicted values of combined MPI and treadmill parameters (LHR, 3'STD, and HR ratio) gave the best ROC (AUC: 0.91) than any individual parameter or parameter combination. CONCLUSIONS: Of all treadmill and gSPECT parameters, the combination of MPI and treadmill parameters can offer better diagnostic performance for severe CAD.

Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (Ddc(KI) mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old Ddc(KI) mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment.