Clinical utility and limitations of FDG PET in detecting recurrent hepatocellular carcinoma in postoperative patients.

BACKGROUND: The clinical usefulness of positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) for the detection of recurrent hepatocellular carcinoma (HCC) is controversial because HCC displays varying FDG avidity. The purposes of this study were to re-evaluate the utility of FDG PET for the detection of recurrent HCC, and to assess its prognostic value in a large series of postoperative patients. METHODS: We retrospectively reviewed 113 scans in 86 patients undergoing FDG PET after curative surgery for HCC. These scans were performed for suspected recurrence on radiologic imaging (group A: n = 44) because of an elevated tumor marker level with negative prior imaging results (group B: n = 32) or with no suspicion of recurrence (group C: n = 37). FDG PET's accuracy for recurrence detection and its value as a predictor of survival were assessed. RESULTS: The sensitivity, specificity, and diagnostic accuracy were 53, 100, and 55 % for group A; 34, 100, and 41 % for group B; and 11, 100, and 78 % for group C, respectively. A change in therapy resulted from the scan results in 7, 9, and 8 % in groups A, B, and C, respectively. The combined sensitivities for intra- and extrahepatic recurrence were 30 and 42 %, respectively. Histopathological features at initial surgery did not affect the sensitivity. The overall survival of patients with positive scans was significantly poorer than that of patients with negative scans (P = 0.008). CONCLUSIONS: The sensitivity of FDG PET for recurrent HCC was low, with little change in treatment resulting. However, it can predict prognosis in postoperative patients.

Association between diffuse renal uptake of 18F-FDG and acute kidney injury.

OBJECTIVE: The aim of this study was to investigate the clinical characteristics of patients with diffuse renal uptake (DRU) of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG), with particular focus on renal function. METHODS: We retrospectively analyzed 40 patients who showed DRU on FDG PET/CT and the same number of matched controls. The clinical features, imaging parameters (the mean SUVmax of the kidneys and the kidney size), and laboratory data including renal function parameters (Cr, the serum creatinine level; estimated glomerular filtration ratio (eGFR); Cr-ratio, Cr divided by the baseline; max-Cr-ratio, the maximum serum creatinine level within 30 days divided by the baseline) and C-reactive protein (CRP) were compared between the two groups. In the DRU group, follow-up FDG PET/CT scans were additionally evaluated to determine the presence of DRU. RESULTS: No significant differences were observed in the clinical features except for antibiotic administration, Cr, and eGFR. Significantly more patients underwent antibiotic administration within 30 days in the DRU group (p = 0.002). The mean SUVmax of the kidneys was significantly higher (p < 0.001) and the kidney size was significantly larger in the DRU group (p = 0.003). Cr-ratio and max-Cr-ratio were significantly higher in the DRU group (p = 0.005 and p < 0.001, respectively). CRP was significantly higher in the DRU group (p < 0.001). Eighteen of the 40 patients in the DRU group underwent a second FDG PET/CT scan, and 16 of them did not show DRU. Six of the 18 patients showed acute kidney injury (AKI, i.e., Cr-ratio ≥ 1.5) at the time of the initial scan and recovered before the second scan. None of the six patients showed DRU on the second scan. CONCLUSION: DRU indicates the presence of AKI, could be a reversible finding, and may disappear as renal function improves.

Diagnostic performance of 68Ga-DOTATOC PET/CT in tumor-induced osteomalacia.

OBJECTIVE: Tumor-induced osteomalacia (TIO) is caused by typically small tumors that secrete fibroblast growth factor 23 (FGF23). As tumor resection is the only effective treatment for TIO, it is important to detect the culprit tumor. We aimed to assess the utility of 68Gallium-DOTA-D-Phe(1)-Tyr(3)-octreotide (68Ga-DOTATOC) PET/CT in TIO and the correlation between biochemical parameters and the PET/CT results. METHODS: Thirty-five patients with clinically suspected TIO who had undergone 68Ga-DOTATOC PET/CT were retrospectively analyzed. 68Ga-DOTATOC PET/CT results were compared with biochemical parameters and the final diagnosis, including histopathology. RESULTS: 68Ga-DOTATOC PET/CT detected focal uptake consistent with TIO in 21/35 patients, one of which was considered false positive. In 16 patients, the cause of osteomalacia was confirmed histologically as phosphaturic mesenchymal tumor (n = 15) or fibrous dysplasia (n = 1). The other four patients were judged clinically as true positive by subsequent MRI and the clinical course. Overall, the detection rate of 68Ga-DOTATOC PET/CT was 57% (20/35). Median tumor maximum standardized uptake value (SUVmax) was 6.9 (range 1.5-37.7). There was no significant difference in serum intact FGF23 level between DOTATOC-positive and DOTATOC-negative cases, and no significant correlation was observed between intact FGF23 level and tumor SUVmax. CONCLUSIONS: 68Ga-DOTATOC PET/CT was clinically useful in detecting culprit tumors and subsequent patient management in TIO.

Ventricular Distribution Pattern of the Novel Sympathetic Nerve PET Radiotracer 18F-LMI1195 in Rabbit Hearts.

We aimed to determine a detailed regional ventricular distribution pattern of the novel cardiac nerve PET radiotracer 18F-LMI1195 in healthy rabbits. Ex-vivo high resolution autoradiographic imaging was conducted to identify accurate ventricular distribution of 18F-LMI1195. In healthy rabbits, 18F-LMI1195 was administered followed by the reference perfusion marker 201Tl for a dual-radiotracer analysis. After 20 min of 18F-LMI1195 distribution time, the rabbits were euthanized, the hearts were extracted, frozen, and cut into 20-µm short axis slices. Subsequently, the short axis sections were exposed to a phosphor imaging plate to determine 18F-LMI1195 distribution (exposure for 3 h). After complete 18F decay, sections were re-exposed to determine 201Tl distribution (exposure for 7 days). For quantitative analysis, segmental regions of Interest (ROIs) were divided into four left ventricular (LV) and a right ventricular (RV) segment on mid-ventricular short axis sections. Subendocardial, mid-portion, and subepicardial ROIs were placed on the LV lateral wall. 18F-LMI1195 distribution was almost homogeneous throughout the LV wall without any significant differences in all four LV ROIs (anterior, posterior, septal and lateral wall, 99 ± 2, 94 ± 5, 94 ± 4 and 97 ± 3%LV, respectively, n.s.). Subepicardial 201Tl uptake was significantly lower compared to the subendocardial portion (subendocardial, mid-portion, and subepicardial activity: 90 ± 3, 96 ± 2 and *80 ± 5%LV, respectively, *p < 0.01 vs. mid-portion). This was in contradistinction to the transmural wall profile of 18F-LMI1195 (90 ± 4, 96 ± 5 and 84 ± 4%LV, n.s.). A slight but significant discrepant transmural radiotracer distribution pattern of 201Tl in comparison to 18F-LMI1195 may be a reflection of physiological sympathetic innervation and perfusion in rabbit hearts.

Longitudinal 18F-FDG PET imaging in a rat model of autoimmune myocarditis.

AIMS: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-18F-fluoro-D-glucose (18F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis. METHODS AND RESULTS: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund's adjuvant. Time course of disease was assessed by longitudinal 18F-FDG PET imaging. A correlative analysis between in- and ex vivo18F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal 18F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo18F-FDG PET signalling (R2 = 0.92) as well as with ex vivo18F-FDG autoradiography (R2 = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at 18F-FDG decrease). CONCLUSION: 18F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis.

Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated 18F-FDG PET.

In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated 18F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n = 6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, 18F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5 ± 4.2 vs. 59.4 ± 4.5%; HR: 331 ± 35 vs. 309 ± 24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1 ± 0.8 vs. 10.2 ± 1 Enddiastolic Volume/sec, P < 0.01). Investigating a diabetic rat model, ECG-gated 18F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.

Whitening and Impaired Glucose Utilization of Brown Adipose Tissue in a Rat Model of Type 2 Diabetes Mellitus.

Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by 18F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic 18F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. 18F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased 18F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.

Impact of tissue photon attenuation in small animal cardiac PET imaging.

OBJECTIVES: Tissue photon attenuation is one of the essential artifacts requiring correction in clinical cardiac positron emission tomography (PET) imaging. However, due to small body size its impact on diagnostic accuracy in small rodents is considered to be limited or even ignorable. The present cardiac PET study compares lean and obese rats to determine the influence of tissue attenuation on quantitative assessment as well as regional tracer distribution. METHODS: A dedicated small animal PET system equipped with a 57Co rotating source for transmission was used. To assess the impact of tissue attenuation in rats with different body sizes, cardiac 18F-FDG -PET studies for Zucker diabetic fatty rats (obese rats) and Zucker lean rats (lean rats) were performed. The radiotracer activity reduction by attenuation was compared between the two groups. Regional tracer distribution calculated with and without attenuation correction was also assessed. RESULTS: The chest diameter was significantly longer in obese than in lean rats (5.6±0.3cm in obese and 4.5±0.2cm in lean rats, p<0.0001). Whereas the activity reduction by attenuation was significantly greater in obese than in lean rats (44.1±2.5% and 5.1±3.1%, p<0.0001), the regional variation of tissue attenuation among the ventricular walls was minimal in both lean (p=0.73) and obese rats (p=0.65). CONCLUSION: Attenuation correction is indispensable for accurate comparison of cardiac tracer activity between animals with different body size, whereas it can be omitted for evaluation of regional tracer distribution.

Gastric motility and emptying assessment by magnetic resonance imaging after lung transplantation: correlation with gastric emptying scintigraphy.

PURPOSE: Gastroparesis is a frequent gastrointestinal complication after lung transplantation. Although gastric emptying scintigraphy (GES) is the standard technique to evaluate gastroparesis, magnetic resonance imaging (MRI) can also assess gastric motility and emptying. This study compared the results obtained by these two modalities. METHODS: Twenty-two lung transplant recipients underwent MRI and GES after ingesting a small pancake as a test meal. Parameters assessed on MRI included antral peristaltic wave velocity and frequency, and the ratios of gastric content volume at 15 and 35 min. GES parameters included retention rates (RR) in the stomach at 30, 60, and 120 min (RR30, RR60, and RR120) and half-time of emptying (T1/2) calculated by exponential curve fitting. Correlations between MRI and GES results were evaluated. RESULTS: Peristaltic wave velocity showed significant moderate negative correlations with RR120 (r = - 0.58, p < 0.05) and T1/2 (r = - 0.60, p < 0.05), indicating an association between reduced velocity and prolonged gastric emptying. Gastric content volume ratios on MRI showed significant moderate positive correlations with RR30 (r = 0.46, p < 0.05), RR60 (r = 0.60, p < 0.01), and T1/2 (r = 0.60, p < 0.01). There were no significant correlations between peristaltic wave frequency and GES parameters. MRI and GES parameters did not differ significantly between the six patients with and the 16 without upper gastrointestinal symptoms. CONCLUSIONS: MRI-based determinations of gastric motility and gastric emptying correlate with GES-based gastric emptying in lung transplant recipients, suggesting that MRI is useful for evaluating patients with gastroparesis.

Initial Preclinical Evaluation of 18F-Fluorodeoxysorbitol PET as a Novel Functional Renal Imaging Agent.

Accurate assessment of kidney function plays an essential role for optimal clinical decision making in a variety of diseases. The major intrinsic advantages of PET are superior spatial and temporal resolutions for quantitative tomographic renal imaging. 2-deoxy-2-18F-fluorodeoxysorbitol (18F-FDS) is an analog of sorbitol that is reported to be freely filtered at the renal glomerulus without reabsorption at the tubule. Furthermore, it can be synthesized via simple reduction of widely available 18F-FDG. We tested the feasibility of 18F-FDS renal PET imaging in rats. METHODS: The systemic and renal distribution of 18F-FDS were determined by dynamic 35-min PET imaging (15 frames × 8 s, 26 frames × 30 s, 20 frames × 60 s) with a dedicated small-animal PET system and postmortem tissue counting in healthy rats. Distribution of coinjected 99mTc-diethylenetriaminepentaacetic acid (DTPA) was also estimated as a reference. Plasma binding and in vivo stability of 18F-FDS were determined. RESULTS: In vivo PET imaging visualized rapid excretion of the administrated 18F-FDS from both kidneys, with minimal tracer accumulation in other organs. Initial cortical tracer uptake followed by visualization of the collecting system could be observed with high contrast. Split-function renography curves were successfully obtained in healthy rats (the time of maximal concentration [Tmax] right [R] = 2.8 ± 1.2 min, Tmax left [L] = 2.9 ± 1.5 min, the time of half maximal concentration [T1/2max] R = 8.8 ± 3.7 min, T1/2max L = 11.1 ± 4.9 min). Postmortem tissue counting of 18F-FDS confirmed the high kidney extraction (kidney activities at 10, 30, and 60 min after tracer injection [percentage injected dose per gram]: 1.8 ± 0.7, 1.2 ± 0.1, and 0.5 ± 0.2, respectively) in a degree comparable to 99mTc-DTPA (2.5 ± 1.0, 1.5 ± 0.2, and 0.8 ± 0.3, respectively). Plasma protein binding of 18F-FDS was low (<0.1%), and metabolic transformation was not detected in serum and urine. CONCLUSION: In rat experiments, 18F-FDS demonstrated high kidney extraction and excretion, low plasma protein binding, and high metabolic stability as preferable properties for renal imaging. These preliminary results warrant further confirmatory studies in large animal models and clinical studies as a novel functional renal imaging agent, given the advantages of PET technology and broad tracer availability.

A comparison between 11C-methionine PET/CT and MIBI SPECT/CT for localization of parathyroid adenomas/hyperplasia.

OBJECTIVE: The purpose of this study was to compare the sensitivity of single-photon emission computed tomography/computed tomography (SPECT/CT) using 99mTc-sestamibi (MIBI) with that of PET/CT using 11C-methionine (MET) for localization of parathyroid adenomas/hyperplasia in primary hyperparathyroidism. MATERIALS AND METHODS: Twenty-three patients with primary hyperparathyroidism were analyzed. Fifteen patients underwent surgery, and the remaining eight did not, but these patients were clinically diagnosed as having primary hyperparathyroidism. Patients underwent both MET PET/CT and MIBI SPECT/CT scanning. The sensitivities of both modalities were evaluated on a per-patient basis, and on a per-lesion basis for parathyroid lesions detected by surgery. The size of the parathyroid adenoma/hyperplasia and serum intact parathyroid hormone levels were compared with the results of each of the two modalities. RESULTS: Per-patient sensitivities of MET PET/CT and MIBI SPECT/CT were 65 and 61%, respectively. Per-lesion sensitivities of MET PET/CT and MIBI SPECT/CT were 91 and 73% for histologically confirmed adenomas and 30 and 30% for hyperplastic glands, respectively. No significant differences were observed between the two modalities. The size of uptake-positive lesions was significantly larger than that of uptake-negative lesions in both modalities. Intact parathyroid hormone levels showed no significant difference between uptake-positive and uptake-negative patients in both modalities. CONCLUSION: The sensitivities of MET PET/CT and MIBI SPECT/CT were comparable. MET PET/CT has a complementary role in localizing parathyroid adenomas/hyperplasia when MIBI SPECT/CT is inconclusive.

Diffuse homogeneous bone marrow uptake of FDG in patients with acute lymphoblastic leukemia.

PET (positron emission tomography) using FDG (¹8F-fluorodeoxyglucose) has been widely used in the evaluation of various malignancies, but its clinical application to leukemia remains limited. We report a case of leukemia in which diffuse bone marrow uptake of FDG was observed, and bone marrow aspiration subsequently revealed acute lymphoblastic leukemia. It is not easy to differentiate between physiological and pathologic uptake when diffuse homogeneous uptake in bone marrow is observed.