From permeability to prediction: evolving strategies for evaluating oral drug absorption.

C ardiac computed tomography (CT) and positron emis- sion tomography (PET) are emerging as powerful noninvasive imaging tools for the evaluation of atherosclerosis in patients with known or suspected coronary artery disease (CAD).Unlike invasive coronary angiography, CT coronary angiography (CTA) not only assesses disease within the coronary lumen but can also provide direct qualitative and quantitative information about nonobstructive atherosclerotic plaque burden within the vessel wall.Thus, it is possible that CTA-based patient evaluation may provide more clinically relevant information on which to base risk assessments compared with conventional "lumenography."On the other hand, PET is rapidly growing as a powerful and efficient alternative to conventional single-photon emission CT (SPECT) imaging to evaluate regional myocardial perfusion and metabolism in patients with CAD.In addition, PET scanners are now being converted to hybrid PET/CT devices, which, in the setting of CAD, offer the potential for a comprehensive noninvasive cardiac evaluation of anatomy and function.This review will discuss current and potential future applications of cardiovascular CT, PET, and hybrid PET/CT, with a particular focus on ischemic heart disease.

Traditionally, the pilot bioequivalence study is a generalpractice for generic drug development. However, due to its difficulty in differentiating the variation between subject and drug formulation for bioequivalence results. A new instrument called PAMPA Dissolution is proposed in this study to improve the correlation between in vitro and in vivo absorption forbioequivalence study. PAMPA Dissolution allows for the simultaneous measurement of drug dissolution (Cb) and permeation (Pe), two key parameters in oral drug absorption according to the validated equation F (drug absorbed) = Cb*Pe*Area. The use of Parallel Artificial Membrane Permeability Assay (PAMPA) eliminates the concern of subject variation. Biorelevant media further allows this device to simulate in vivo conditions closely. Brand and generic formulations of 40 mg telmisartan tablets were used in various studies to demonstrate the potential of PAMPA Dissolution in generic drug development. Bioequivalence predictions between brand and generic telmisartan from PAMPA Dissolution produced avalue（test/reference）for Cmax of 86.3% and a value for AUC of 91.4%, indicating that PAMPA Dissolution predictions conform with bioequivalence requirements. Other parameters such as stirring at different speeds and phospholipids concentrations for PAMPA are also included for optimal performance of the system. Based on these data, the PAMPA Dissolution system is reproducible, precise, and can therefore be applied in predicting bioequivalence study.

Focus issue: Artificial intelligence in medical physics.

Blood Flow Imaging of the Brain: 50 Years Experience

There are many ways to perform noninvasive testing in patients with coronary artery disease (CAD), including myocardial perfusion imaging with single-photon emission computed tomography (SPECT), positron-emission tomography (PET), and coronary computed tomography angiography (CTA). Results from series of patients evaluated with single modalities have already been published by many researchers [1–3], but there are few head-to-head comparisons of the outcomes of alternative test strategies [4, 5]. Consequently, the comparative effectiveness of different noninvasive cardiac testing strategies has been difficult to assess. The recently published SPARC registry (Study of Myocardial Perfusion and Coronary Anatomy Imaging Roles in Coronary Artery Disease) in JACC by the group of DiCarli et al. (Stanford, CA, USA) was a multicentre study designed to collect standardised clinical data on patients undergoing CTA, PET, or SPECT [6]. The primary purpose of the SPARC study was to evaluate the economic outcomes of using CTA, PET, or SPECT to evaluate patients with suspected CAD. The authors used an observational registry of 1703 patients: 590 patients underwent CTA, 548 patients had PET and 565 patients SPECT for diagnosis of suspected CAD. Patients were followed for 2 years; documented resource use, medical costs for CAD, and clinical outcomes were assessed. The main findings were that costs were significantly lower for SPECT compared with CTA or PET in the evaluation of suspected CAD. SPECT was economically attractive compared with PET, whereas CTA was associated with higher costs and no significant difference in mortality compared with SPECT. More specifically, the authors observed that patients who underwent coronary CTA and PET experienced higher rates of subsequent invasive coronary arteriography (16 % and 15 %, respectively) as compared with patients who underwent SPECT (7 %). The mean total radiation was significantly higher for CTA (15.1 mSV) compared with SPECT (11.7 mSV), both for the initial tests (13 mSV vs. 11 mSV) and for follow-up tests and procedures (2.1 mSV vs. 0.7 mSV). Exposure from follow-up tests and procedures was higher after PET (2.0 mSV) than after SPECT (0.6 mSV). The findings in favour of SPECT are in line with a decision model by Garber and Solomon [7], who compared exercise treadmill testing, stress echocardiography, planar thallium imaging, SPECT, and PET imaging with a strategy of immediate invasive angiography. They found SPECT to be much more cost-effective than PET for noninvasive diagnosis, and SPECT to be a better option than immediate invasive coronary angiography. In terms of outcomes, Shaw et al. [1] found that patients who underwent initial SPECT with selective cardiac catheterisation had lower costs than patients who underwent routine coronary angiography (END study). In the EMPIRE study by Underwood et al. [2] it was demonstrated that strategies using myocardial perfusion imaging were cheaper and equally effective when compared with strategies that did not use myocardial perfusion imaging, both for the cost of diagnosis and for overall 2-year management costs; the 2-year patient outcome was the same. Sharples et al. [8] randomised 898 patients to SPECT, stress echocardiography, magnetic resonance imaging (MRI), or direct invasive coronary angiography, and found SPECT to be as useful as immediate invasive angiography with similar costs. A limitation of the SPARC study is the fact that MRI was not included in the comparative strategies. In addition, as the study started in 2006, in recent years many technological revolutions have taken place for all imaging modalities indicating that studies such as SPARC should be repeated and extended every 5–10 years [9]. Analysis of the current SPARC registry at least suggests that SPECT is the noninvasive imaging procedure of choice to evaluate patients with suspected CAD in terms of subsequent medical costs. SPECT offered the lowest costs over 2 years of follow-up among patients with suspected CAD. The significantly higher costs among patients undergoing CTA or PET were primarily due to higher rates of subsequent invasive cardiac procedures, because there was little difference in initial costs of testing. To conclude, the use of SPECT myocardial perfusion imaging was associated with lower costs over 2 years of follow-up than the use of CTA or PET, primarily because of fewer subsequent invasive procedures. Consequently, SPECT imaging seems to be the preferred imaging strategy in patients with suspected CAD. The value of SPECT imaging has been underscored by several recent reports [10–13]. However, larger and more definitive studies, such as the ongoing PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial (NCT01174550), are needed to assess the value and cost effectiveness of the various noninvasive imaging strategies.

CLINICAL PERFORMANCE OF RB82 MYOCARDIAL PERFUSION PET AND TC-99M SPECT IN PATIENTS WITH EXTREME OBESITY (BMI ≥ 40)

BackgroundPositron emission tomography (PET) imaging with fluorine-18 (18F) Fluorodeoxyglucose (FDG) and flow tracer such as Rubidium-82 (82Rb) is an established method for evaluating an ischemic but viable myocardium. However, the high cost of PET imaging restricts its wider clinical use. Therefore, less expensive 18F FDG single photon emission computed tomography (SPECT) imaging has been considered as an alternative to 18F FDG PET imaging. The purpose of the work is to compare SPECT with PET in myocardial perfusion/viability imaging.MethodsA nonuniform RH-2 thorax-heart phantom was used in the SPECT and PET acquisitions. Three inserts, 3 cm, 2 cm and 1 cm in diameter, were placed in the left ventricular (LV) wall to simulate infarcts. The phantom acquisition was performed sequentially with 7.4 MBq of 18F and 22.2 MBq of Technetium-99m (99mTc) in the SPECT study and with 7.4 MBq of 18F and 370 MBq of 82Rb in the PET study. SPECT and PET data were processed using standard reconstruction software provided by vendors. Circumferential profiles of the short-axis slices, the contrast and viability of the inserts were used to evaluate the SPECT and PET images.ResultsThe contrast for 3 cm, 2 cm and 1 cm inserts were for 18F PET data, 1.0 ± 0.01, 0.67 ± 0.02 and 0.25 ± 0.01, respectively. For 82Rb PET data, the corresponding contrast values were 0.61 ± 0.02, 0.37 ± 0.02 and 0.19 ± 0.01, respectively. For 18F SPECT the contrast values were, 0.31 ± 0.03 and 0.20 ± 0.05 for 3 cm and 2 cm inserts, respectively. For 99mTc SPECT the contrast values were, 0.63 ± 0.04 and 0.24 ± 0.05 for 3 cm and 2 cm inserts respectively. In SPECT, the 1 cm insert was not detectable. In the SPECT study, all three inserts were falsely diagnosed as "viable", while in the PET study, only the 1 cm insert was diagnosed falsely "viable".ConclusionFor smaller defects the 99mTc/18F SPECT imaging cannot entirely replace the more expensive 82Rb/18F PET for myocardial perfusion/viability imaging, due to poorer image spatial resolution and poorer defect contrast.

Optical Molecular Imaging Approaches in Colorectal Cancer

As bone metastases might be present in lung cancer despite a normal bone scan, we examined various alternatives prospectively. Positron emission tomography using F-18 sodium fluoride (PET) and single photon emission tomography (SPECT) were more sensitive than a planar bone scan. PET was more accurate with a shorter examination time than SPECT but had higher incremental costs. Previous studies have shown that vertebral bone metastases not seen on planar bone scans may be present on F-18 fluoride positron emission tomography (PET) scan or single photon emission computed tomography (SPECT). The purpose of this study was to measure the accuracy, clinical value and cost-effectiveness of tomographic bone imaging. A total of 103 patients with initial diagnosis of lung cancer was prospectively examined with planar bone scintigraphy (BS), SPECT of the vertebral column and PET using F-18 sodium fluoride (F-18 PET). Receiver operating characteristic (ROC) curve analysis was used for determination of the diagnostic accuracy. A decision-analysis model and the national charge schedule of the German Hospital Association were used for determination of the cost-effectiveness. Thirteen of 33 patients with bone metastases were false negative on BS, 4 on SPECT, and 2 on F-18 PET. The area under the ROC curve was 0.771 for BS, 0.875 for SPECT, and 0.989 for F-18 PET (p < 0.05). As a result of SPECT and F-18 PET imaging, clinical management was changed in 8 (7.8%) and 10 (9.7%) patients. Compared with BS, the costs per additional correctly diagnosed patient were 1272 Euro with SPECT and 2861 Euro with F-18 PET. The threshold for the costs of F-18 PET being more cost-effective than SPECT was 345 EUR. Routine performance of tomographic bone imaging improves the therapeutic strategy because of detection of otherwise missed metastases. F-18 PET is more effective than SPECT but is associated with higher incremental costs.

Purpose: Several noniiivasive imaging methods can detect epileptic ioci. We compared tnagnetic source imaging (MSI) of epilcptic spikes with the results of other imaging mcthoda, including positron emission tomography (PET), single photon emission CT (SPECT), and MRI, in order to determine characteristics of each. Methods: We studied 9 patients, age ranging from 1–23 years. Etiologies included acute encephalopathy, tubcrous sclerosis, pcrisylvian syndrome, and cerebral infarct in I patient each, unknown in the rest. Eight exhibited bca/ization‐related epilepsy (LRE) and the remaining iut syndrome (LGS). Informed cnsent was obtained from the patients or their parents. Thc magnctocncephalograins (MEG) were measured in 21 magnetically shielded room using a layingtype whole‐cortex MEG with 160‐channel first‐order gradiometers. We estimated the equivalent current dipoles (ECD) of spikes in the simultaneously recorded EEG. MRI scanning was performed at 5 m m thickness in 3 directions including the markers for superimposition with MEG. IXF‐FDG PET was performed with a Headtome IV in 4 paticnts and 123Tc ECD SPECT with a Toshiba GCA9300 in 8 patients. We visually evaluated these images. Results: We could estimate the ECD in 8 patients as having I or multiple locations. All 4 patients examined by PET cxhibitcd 1 or more hypometabolic arcas on PET. SPECT studies revealed hypoperfusion areas in 3 patients m d hyperperfusion areas in 2 patients. One id the patients with hypcrpcrfusion was on ictal study. Structural ahnormalities were presented on MRI in 3 patients. Casc I had advcrsivc seizures with turning to the lcft and exhibited a broad right frontotemporal hypometabolic area on PET. Her ECDs wcrc cstimatcd to originate from the right prcmotor area, in agreement with a hypoperfusion spot on ictal SPECT. Case 2 had epilepsy as a residuum of past cnccphalopathy and had complcx partial seizures (CPS) with rapid generalim tion. The foci detected on MSI, PET, and SPECT did not agree. Casc3 had CPS and anterotemporal hypomctabolism on PET. ECDs were focused in the lateral mterotemporal area. Case 4 had tuberous xlc‐ rosis and a past history of status cpilcpticus. MRI revealed cortical tubers and white matter lesions. Cortical tubers exhibited hypoperlu‐ sion on SPECT. However, ECDs werc cstimatcd to originate from the right occipital hypoperfusion area and not thc cortical tubcrs. C was suspected to have idiopathic LRE and exhibited no focus on PET and SPECT. ECDs were estimated to originate from the left frontal cortex. Case 6 had pcrisylvian syndrome with LGS. Bilaterally abnormal cortex exhibited hyperperfusion on SPECT, and ECDs wcrc citimated to originate lrom this cortex. Casc 7 had CPS and left temporal sporadic spikes on previous EEGs. The findings of SPECT and PET studies were normal, and ECDs could not be estimated because there was no spike in the MEG study. Case 8 had right leg pain and frontal slow wave bursts on the EEG. PET rcvcaled right frontal and left parietal hypometabolism, and ECDs were estimated to originate from the left parietal area. Case 9 had an old inraretion in the lcft occipital lobe and CPS. SPECT revealed perfusion defect in the infarction and right frontal hypoperfusion. ECDs were estimated to originatc from the margin of the infrarction. Conclusions: Interictal MEG studics can dctcct irritable zones of epileptic foci, hut their findings sometimes do not accurately reveal the epileptogcnic zone. However the majority of our cstimatcd ECDs agreed with the ictal symptomatology and the foci detected by PET and SPECT. The estimated area of ECDs was usually smaller than hypometabolic areas on PET and hypoperfusion area on SPECT. Multimodal interictal studies with noninvasive technologics will enablc more enable detection of epileptic foci.

BackgroundTraumatic brain injury (TBI) causes brain dysfunction in many patients. Using C-11 flumazenil (FMZ) positron emission tomography (PET), we have detected and reported the loss of neuronal integrity, leading to brain dysfunction in TBI patients. Similarly to FMZ PET, I-123 iomazenil (IMZ) single photon emission computed tomography (SPECT) is widely used to determine the distribution of the benzodiazepine receptor (BZR) in the brain cortex. The purpose of this study is to examine whether IMZ SPECT is as useful as FMZ PET for evaluating the loss of neuronal integrity in TBI patients.The subjects of this study were seven patients who suffered from neurobehavioral disability. They underwent IMZ SPECT and FMZ PET. Nondisplaceable binding potential (BPND) was calculated from FMZ PET images. The uptake of IMZ was evaluated on the basis of lesion-to-pons ratio (LPR). The locations of low uptake levels were visually evaluated both in IMZ SPECT and FMZ PET images. We compared FMZ BPND and (LPR-1) of IMZ SPECT.ResultsIn the visual assessment, FMZ BPND decreased in 11 regions. In IMZ SPECT, low uptake levels were observed in eight of the 11 regions. The rate of concordance between FMZ PET and IMZ SPECT was 72.7%. The mean values IMZ (LPR-1) (1.95 ± 1.01) was significantly lower than that of FMZ BPND (2.95 ± 0.80 mL/mL). There was good correlation between FMZ BPND and IMZ (LPR-1) (r = 0.80).ConclusionsIMZ SPECT findings were almost the same as FMZ PET findings in TBI patients. The results indicated that IMZ SPECT is useful for evaluating the loss of neuronal integrity. Because IMZ SPECT can be performed in various facilities, IMZ SPECT may become widely adopted for evaluating the loss of neuronal integrity.

Single photon emission computed tomography (SPECT) using ultra-high energy collimators permits wide clinical application of (18)F-fluorodeoxyglucose (FDG) imaging without the use of expensive positron emission tomography (PET) cameras. This study was designed to evaluate the value of FDG SPECT using ultra-high energy collimators in assessing myocardial viability compared with FDG PET on a regional basis. We prospectively studied 33 patients with ischaemic heart disease. The patients were injected with 555 MBq of FDG under a hyperinsulinaemic glucose clamp, and FDG PET was performed 40 min later. FDG SPECT using ultra-high energy collimators was performed immediately after FDG PET. The images of the left ventricular myocardium were divided into nine segments and the regional defect score was assessed visually using a four-point scale (0=normal to 3=defect). Regional FDG uptake (%uptake) was quantitatively analysed using polar maps. In 297 segments of all the 33 patients, agreement between the defect scores based on FDG SPECT images and those based on FDG PET images was 70%, and agreement within one rank was 96% (kappa value=0.52). The %uptake based on FDG SPECT images significantly correlated with that based on FDG PET images (r=0.77, P<0.01). However, the defect scores in the inferior wall based on FDG SPECT images were higher (1.41+/-1.14) than those based on FDG PET images (1.06+/-1.12, P<0.01). When the viable region is defined as %uptake > or =50% in FDG PET studies, the optimal cut-off level of %uptake based on FDG SPECT images was 60% in the anterior wall, apex, septum and lateral wall (accuracies, 97%, 93%, 96% and 99%, respectively), and 45% in the inferior wall (accuracy, 99%). It is concluded that FDG SPECT using ultra-high energy collimators can be used for the assessment of myocardial viability as accurately as FDG PET. However, a slight difference was observed in the defect scores mainly due to attenuation in the inferior wall. Therefore, a slightly different cut-off level for assessing myocardial viability should be applied to the inferior wall when using FDG SPECT.

Objective The aim of this study was to evaluate left ventricular systolic asynchronization in patients with heart failure by gated myocardial perfusion imaging(GMPI)using Cadmium-Zinc-Telluride(CZT)single photon emission computed tomography(SPECT), and compare with conventional SPECT myocardial perfusion imaging(MRI) and positron emission tomography(PET)assessment. Methods Thirty-five consecutive patients with heart failure were recruited from July to October 2016 in Fuwai hospital.All patients underwent CZT SPECT GMPI, conventional SPECT GMPI, PET and cardiac MRI within 7 days.Bind width(BW)and standard deviation(SD)were calculated by three nuclear medicine imaging modalities. Results CZT SPECT GMPI showed good correlation respectively for BW(r=0.833, P<0.001)and SD(r=0.795, P<0.001)with conventional SPECT GMPI.CZT SPECT GMPI also showed a good correlation respectively for BW(r=0.914, P<0.001)and SD(r=0.804, P<0.001)with PET.Bland-Altman analysis revealed good agreement of BW and SD between CZT SPECT and PET.Bland-Altman analysis showed systematic underestimation of BW and SD with conventional SPECT GMPI compared with CZT SPECT and PET. Conclusion CZT SPECT GMPI with minimal acquisition time provides the left ventricular dyssynchrony parameters that correlated well and had good agreement with PET, and has the high value of clinical application in patients with heart failure. Key words: Heart failure; Cadmium-Zinc-Telluride; Single photon emission computed tomography; Dyssynchrony

PAMPA--a drug absorption in vitro model 11. Matching the in vivo unstirred water layer thickness by individual-well stirring in microtitre plates.

03:27 PM Abstract No. 434 Comparison of tumor and liver enhancement on preinterventional MDCT, CBCT, SPECT, and postinterventional PET in patients with HCC undergoing SIRT