Standardized Uptake Value Atlas: Characterization of Physiological 2-Deoxy-2-[<Superscript>18</Superscript>F]fluoro-<Emphasis Type="SmallCaps">d</Emphasis>-glucose Uptake in Normal Tissues

Purpose The purpose of this study was to map the distribution of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptake in organs of patients with no known abnormalities in those tissues. Procedures We measured maximum and mean standardized uptake values (SUV) from FDG-positron emission tomography (PET)/computed tomography (CT) obtained from 98 patients (48 males and 50 females). Results Significant uptake (mean SUV_mean > 2.5) was visualized in the cerebellum (8.0 ± 2.2), soft palate (2.92 ± 0.86), palatine tonsils (3.45 ± 1.4), lingual tonsils (3.08 ± 1.05), sublingual glands (3.3 ± 1.5), and testes (2.57 ± 0.56). Negative correlation for FDG uptake versus age was observed for the palatine tonsils, sublingual glands, and lungs (P < 0.001). Conclusion Better understanding of physiological uptake throughout the body is valuable for improved interpretive accuracy and should be useful for future semi-automated comparisons to a normal SUV database.     

2-Deoxy-2-[F-18]fluoro-<Emphasis Type="SmallCaps">d</Emphasis>-glucose Accumulation in Ovarian Carcinoma Cell Lines

Purpose To evaluate 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) accumulation in human ovarian carcinoma cell lines compared with control tumor cell lines known to accumulate FDG. Procedures FDG accumulation assays were performed in 15 different ovarian carcinoma cell lines at 1, 2, and 3 hours after incubation with 1 μCi of FDG. Results were compared with FDG accumulation in six different control tumor cell lines. 2-Deoxy-2-[F-18]fluoro-d-glucose accumulation was expressed as counts per minute (cpm) in cells and normalized to initial cpm in medium and total protein content of cell lysates. Results FDG accumulation in all 15 ovarian carcinoma cell lines was equal to or higher than 0.0005 ± 8.6 10⁻⁵ cpm in cells/cpm in medium/μg protein at all three different time points. In two ovarian carcinoma cell lines (ES-2, poorly differentiated clear cell carcinoma, and OVCAR-3, poorly differentiated papillary adenocarcinoma), FDG accumulation was not statistically, significantly different compared to the control cell line with the highest FDG accumulation (LS 174T human colorectal adenocarcinoma) at two or more time points (P ≥ 0.07). In 2 of 15 (13%) ovarian carcinoma cell lines (OVCAR5 epithelial carcinoma and SKOV3 clear cell carcinoma), FDG accumulation was lower than that in the control cell line with the lowest FDG accumulation (HT-29 human colorectal adenocarcinoma) at one or more time points (P < 0.05). Conclusions Most human ovarian carcinoma cell lines showed comparable FDG accumulations with control cell lines known to accumulate FDG. This study lays the foundations for further comparisons with other ovarian cancer cell lines and for other positron emission tomography tracers.     

Monitoring Response to Radiotherapy in Human Squamous Cell Cancer Bearing Nude Mice: Comparison of 2′-deoxy-2′-[<Superscript>18</Superscript>F]fluoro-<Emphasis Type="SmallCaps">d</Emphasis>-glucose (FDG) and 3′-[<Superscript>18</Superscript>F]fluoro-3′-deoxythymidine (FLT)

Objective The uptake of 3′-[¹⁸F]fluoro-3′-deoxythymidine (FLT), a proliferation marker, was measured before and during fractionated radiotherapy to evaluate the potential of FLT-positron emission tomography (PET) imaging as an indicator of tumor response compared to 2′-deoxy-2′-[¹⁸F]fluoro-d-glucose (FDG). Materials and Methods Nude mice bearing established human head and neck xenografts (HNX-OE; nu/nu mice) were locally irradiated (three fractions/week; 22 Gy) using a 150-kV_p unit. Multiple FDG- and FLT-PET scans were acquired during treatment. Tumor volume was determined regularly, and tissue was analyzed for biomarkers involved in tracer uptake. Results Both groups revealed a significant decline in tumor volume (P < 0.01) compared to untreated tumors. For FDG as well as for FLT, a significant decline in retention was observed at day 4. For FLT, most significant decline in retention was observed at day 12; whereas, for FDG, this was already noted at day 4. Maximum decline in tumor-to-nontumor ratios (T/NT) for FDG and FLT was 42 ± 18% and 49 ± 16% (mean ± SD), respectively. FLT uptake was higher then that of FDG. For FLT, statistical significant correlations were found for both tumor volume at baseline and at day 29 with T/NT and ΔT/NT. All tumors demonstrated expression of glucose transporter-1, thymidine kinase-1, and hexokinase II. No differences were found for amount of tumor cells and necrosis at the end of treatment. Conclusion This new experimental in vivo model supports the promise of using FLT-PET, as with FDG-PET, to monitor response to external radiotherapy. This warrants further clinical studies to compare these two tracers especially in cancers treated with radiotherapy.     

Optimization of Whole-Body Positron Emission Tomography Imaging by Using Delayed 2-Deoxy-2-[F-18]fluoro-d-glucose Injection Following I.V. Insulin in Diabetic Patients

Purpose High blood glucose levels may decrease the sensitivity of 2-deoxy-2-[F-18]fluoro-d-glucose (FDG)-positron emission tomography (PET). The goal of this study was to assess whether intravenous (i.v.) insulin followed by FDG injection 60 minutes later could decrease the blood glucose level of hyperglycemic patients without altering muscular, liver, or lung FDG uptake.Methods We evaluated 53 diabetic patients with a fasting glycemia higher than 7.0 mmol/l. The control group consisted of 53 nondiabetic patients with a normal fasting glycemia. Sixty minutes before FDG injection, all diabetic patients received up to two intravenous bolus of insulin. Regions of interest were drawn over the lungs, heart, liver, skeletal muscles, and over the most active lung nodule, if present, to calculate a standardized uptake value (SUV) normalized to the lean body weight.Results After one or two boluses of insulin (mean 3.4 units), 39 diabetic patients decreased their blood glucose level from 9.4 ± 1.8 to 6.1 ± 1.3 mmol/l. In 14 patients, two doses of insulin (mean 4.5 ± 2.3 units) were not sufficient, but managed to decrease the blood glucose level from 10.6 ± 2.1 to 9.1 ± 2.1 mmol/l. There was no significant difference for the SUV calculated on the lung, liver, heart, and skeletal muscles. No differences were noted in lung tumor uptake in patients who received insulin compared to the control group.Conclusions With a sufficient waiting period between the insulin and FDG injections, an i.v. bolus of insulin makes it possible to effectively decrease glycemia of diabetic patients without increasing muscular FDG uptake.     

NCI-Sponsored Trial for the Evaluation of Safety and Preliminary Efficacy of 3′-Deoxy-3′-[18F]fluorothymidine (FLT) as a Marker of Proliferation in Patients with Recurrent Gliomas: Preliminary Efficacy Studies

Purpose  3′-Deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) is being developed for imaging cellular proliferation. The goals were to explore the capacity of FLT-positron emission tomography (PET) to distinguish between recurrence and radionecrosis in gliomas and compare the results to those obtained with 2-fluoro-2-deoxy-d-glucose (FDG). Procedures  Fifteen patients with tumor recurrence and four with radionecrosis, determined by clinical course and magnetic resonance imaging results, were studied by dynamic [¹⁸F]FLT-PET with arterial blood sampling. A two-tissue compartment four-rate constant model was used to determine metabolic flux (K _FLT), blood to tissue transport (K ₁), and phosphorylation (k ₃). FDG-PET scans were obtained 75–90 min postinjection. Results   K _FLT and k ₃, but not K ₁ or k ₃/k ₂ + k ₃, reached significance for separating the recurrence from radionecrosis groups. Standardized uptake value and visual analyses of FLT or FDG images did not reach significance. Conclusions   K _FLT (flux) appears to distinguish recurrence from radionecrosis better than other parameters, FLT and FDG semiquantitative approaches, or visual analysis of images of either tracer.     

Time Sensitivity: A Parameter Reflecting Tumor Metabolic Kinetics by Variable Dual-Time F-18 FDG PET Imaging

Objectives  The aim of this study was to define and investigate the time sensitivity of tumors by variable dual-time fluorodeoxyglucose positron emission tomography (FDG PET). Methods  Variable dual-time (t) protocol (P) FDG PET–computed tomography (CT) scans from 40 patients with pathologically proven head and neck tumors without brain metastasis were analyzed. The first protocol (P.I) consisted of 26 patients with early (E) and delayed (D) PET–CT obtained at 106 ± 15 and 135 ± 16 min after injection of 16.3 ± 1.9 mCi FDG. The second protocol (P.II) recruited 14 patients with E- and D-PET performed at 54 ± 13 and 151 ± 28 min after injection of 9.6 ± 1.7 mCi FDG. The maximum standardized uptake values (SUVs) were measured in the primary tumor (CA1) and the cerebellum (CBL). The time sensitivity (S) was defined as d{ln(SUV)}/d{ln(t)} and its value was obtained by linear regression of ln(D-SUV/E-SUV) vs ln(t _D/t _E). Patients with cerebellar variations greater than 30% in SUV between E- and D-PET was excluded from the analysis. Results  Two patients from P.I were excluded due to wide cerebellar SUV variations. D-SUV were significantly higher than E-SUV in CA1 for both P.I (18.9 ± 6.9 vs 14.8 ± 5.6, p < 0.0005) and P.II (11.5 ± 7.9 vs 9.7 ± 6.9, p = 0.013). The S values for CA1 in P.I and P.II were 0.67 and 0.17, respectively. The D-SUV were also higher than E-SUV in CBL for both P.I (12.5 ± 1.6 vs 11.6 ± 1.6, p < 0.0005) and P.II (7.6 ± 1.6 vs 7.0 ± 1.6, p = 0.008). The S values for CBL in P.I and P.II were 0.47 and 0.04, respectively, which were over 1.4-fold smaller than that of CA1, suggesting fundamental kinetic differences between CA1 and CBL. Conclusions  The time sensitivity factor reflects another kinetic parameter of tumor metabolism besides SUV when using variable dual-time FDG PET. It offers another useful diagnostic tool in optimizing choices of dual-time protocols for oncologic PET–CT and in reducing SUV variations due to time interval differences with corrections using S.     

Increasing Uptake Time in FDG-PET: Standardized Uptake Values in Normal Tissues at 1 versus 3 h

Objective  Positron emission tomography (PET) imaging at more than 1 h after 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) administration may result in less blood pool activity and possibly decreased normal FDG uptake in tissues such as liver. Lower normal background activity could be an important component of improved image contrast on delayed imaging. Increasing FDG uptake in normal organs, however, may mitigate the beneficial effects of blood pool clearance. The purpose of this study is to determine the normal tissue and blood pool FDG uptake at 1 and 3 h after injection. Subjects and methods  Ninety-nine patients with known or suspected malignancy referred for FDG-PET–computed tomography (CT) were retrospectively evaluated. PET imaging was performed at either 1 h (60 ± 15 min; n = 50) or at 3 h (180 ± 15 min; n = 49) after FDG administration. Normal tissue FDG uptake without involvement by malignancy or influenced by artifact (misregistration, “brown fat,” focal muscle uptake, focal atherosclerotic disease) was confirmed by inspection of both the PET and CT scans. Aortic blood pool, adipose tissue, bone marrow, cerebellum, liver, lungs, muscle, and spleen were quantitatively evaluated by CT-guided region of interest analysis in three contiguous slices. Mean standardized uptake values (SUVs) were analyzed using one-way analysis of variance. Results  Mean SUVs on the 3- versus 1-h images were significantly lower for aortic blood pool 13% (p < 0.0001) and adipose tissue 20% (p < 0.008). FDG uptake showed significant increases at 3 h compared to 1-h imaging in the cerebellum 40% (p < 0.0001), bone marrow 25% (p = 0.003), muscle 21% (p = 0.0004), and spleen 13% (p = 0.01). The liver and lung showed no significant differences (1%, p = 0.85; −2%, p = 0.62, respectively). Conclusions  On FDG imaging at 3 h compared to 1 h, significant changes were apparent, but the magnitude of changes was modest overall. Three-hour delayed imaging demonstrated significantly lower aortic blood pool and adipose tissue activity and significantly higher cerebellum, muscle, spleen, and bone marrow activity. Hepatic and lung activities were not significantly different. These results suggest that previously reported improvements in tumor image contrast with delayed imaging may be primarily due to cumulative FDG uptake within the tumor rather than reduction in normal background activity.     

Assessment of the biodistribution of an [18F]FDG‐loaded perfluorocarbon double emulsion using dynamic micro‐PET in rats

Perfluorocarbon (PFC) double emulsions loaded with a water‐soluble, therapeutic agent can be triggered by ultrasound in a process known as acoustic droplet vaporization. Elucidating the stability and biodistribution of these sonosensitive vehicles and encapsulated agents is critical in developing targeted drug delivery strategies using ultrasound. [¹⁸F]fluorodeoxyglucose (FDG) was encapsulated in a PFC double emulsion and the in vitro diffusion of FDG was assessed using a Franz diffusion cell. Using dynamic micro‐positron emission tomography and direct tissue sampling, the biodistribution of FDG administered as a solution (i.e. non‐emulsified) or as an emulsion was studied in Fisher 344 rats (n = 6) bearing subcutaneous 9L gliosarcoma. Standardized uptake values (SUVs) and area under the curve of the SUV (AUC_SUV) of FDG were calculated for various tissues. The FDG flux from the emulsion decreased by up to a factor of 6.9 compared with the FDG solution. FDG uptake, calculated from the AUC_SUV, decreased by 36% and 44% for brain and tumor, respectively, when comparing FDG solution vs FDG emulsion (p < 0.01). Decreases in AUC_SUV in highly metabolic tissues such as brain and tumor demonstrated retention of FDG within the double emulsion. No statistically significant differences in lung AUC_SUV were observed, suggesting minimal accumulation of the emulsion in the pulmonary capillary bed. The liver AUC_SUV increased by 356% for the FDG emulsion, thus indicating significant hepatic retention of the emulsion. Copyright © 2013 John Wiley & Sons, Ltd.     

Age-Related Changes in the Metabolic Activity and Distribution of the Red Marrow as Demonstrated by 2-Deoxy-2-[<Emphasis Type="Italic">F</Emphasis>-18]fluoro-<Emphasis Type="SmallCaps">d</Emphasis>-glucose-Positron Emission Tomography

Objectives The objective of the study was to determine age-related changes occurring in red marrow with regard to its distribution and the degree of its metabolic activity by whole-body 2-deoxy-2-[F-18]fluoro-d-glucose (FDG)-positron emission tomography (PET). Methods This retrospective study included 112 patients (56 male, 56 female, mean age 40 years, range 2–85) who underwent whole-body FDG-PET scans for assessment of disorders that were determined not to affect red marrow activity. These patients were categorized into the following groups with equal gender distribution: 0–15 years (12 individuals), 16–25 years (20), 26–35 years (10), 36–45 years (20), 46–55 years (14), 56–65 years (16), 66–75 years (14), and 76–85 years (6). Whole-body FDG-PET images were performed at 60 min after the intravenous administration of 0.14 mCi/kg of FDG. By employing a dedicated whole-body PET scanner. Maximal standardized uptake value (SUV_max) was calculated from three consecutive transverse sections of the upper thirds of the humeri and femora, manubrium of the sternum, 12th thoracic and 5th lumbar vertebra and anterior superior iliac crests of the pelvis. All available results from other imaging examinations [magnetic resonance imaging (MRI), computed tomography (CT), and conventional radiolography], laboratory data, biopsies, and the clinical course of these subjects were reviewed to make certain that the bone marrow sites examined were free of any known pathologies. Results SUV_max in the extremities showed significant decline with aging (correlation coefficient of −0.60 to −0.67, p < 0.01). In contrast, a weak correlation was noted in the axial skeletal activity with advancing age (correlation coefficient of −0.28 to −0.48, p < 0.05). Conclusions These data suggest that FDG metabolic activity of the red marrow in the extremities decline significantly with normal aging, while that of the axial skeleton show minimal decrease related to this biologic phenomenon. These findings are of value in assessing the effects of hematological and other disorders in the distribution and the metabolic activity of this important tissue and testing therapeutic interventions that are employed for treating such maladies.     

The Synthesis of <Superscript>18</Superscript>F-FDS and Its Potential Application in Molecular Imaging

Purpose 2-Deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) is the most commonly used positron emission tomography (PET) tracer for oncological and neurological imaging, but it has limitations on detecting tumor or inflammation in brain gray matter. In this study, we describe the development of 2-deoxy-2-[¹⁸F]fluorosorbitol (¹⁸F-FDS) and its possible application in lesion detection around brain area. Procedures ¹⁸F-FDS was obtained by reduction of FDG using NaBH₄ (81 ± 4% yield in 30 min). Cell uptake/efflux experiments in cell culture and small animal PET imaging on tumor and inflammation models were performed. Results Despite the low accumulation in cell culture, ¹⁸F-FDS had good tumor uptake and contrast in the subcutaneous U87MG tumor model (4.54%ID/g at 30 min post-injection). Minimal uptake in the normal mouse brain facilitated good tumor contrast in both U87MG and GL-26 orthotopic tumor models. ¹⁸F-FDS also had increased uptake in the inflamed foci of the TPA-induced acute inflammation model. Conclusions Because of the ease of synthesis and favorable in vivo kinetics, ¹⁸F-FDS may have potential applications in certain cases where FDG is inadequate (e.g., brain tumor). Zi-Bo Li and Zhanhong Wu contributed equally to this work     

Variability and reproducibility of hepatic FDG uptake measured as SUV as well as tissue‐to‐blood background ratio using positron emission tomography in healthy humans

Introduction: To investigate variability and reproducibility of hepatic [¹⁸F]‐2‐fluoro‐2‐deoxy‐d ‐glucose (FDG) uptake in healthy individuals. Methods:  Static images were obtained 70 min after the injection of 160 MBq FDG in six healthy subjects at two occasions with 13 days’ interval. FDG uptake was adjusted for tissue‐to‐blood background ratio (T/B), or measured as standardized uptake value (SUV). Small regions of interest (ROIs) of 10 cm³ in two different hepatic regions were analysed as well as the total liver. Results: Mean SUV was 1·16 ± 0·15 and mean T/B corrected values was 1·87 ± 0·17. The maximal values were 2·70 (SUV) and 4·67 (T/B). Reproducibility was 6·7% for the mean SUV and 0·2% for the max SUV values. The corresponding figures for the T/B corrected mean values were 6·4% and for the max T/B values 13·0%. In general, the small ROIs had a comparable or even lower CV% for SUV values, but a higher CV% for T/B corrected values. Conclusions: In normal subjects hepatic FDG‐uptake is high and homogeneous with a low CV% between days. T/B corrected values are largely comparable to SUV values but not superior, probably due to the standardization of procedures and homogeneity of the subjects. The T/B corrected method is theoretically superior in a more inhomogeneous population or when using different scanners and is shown here to be easy to apply. Small ROIs of 10 cm³ are representative with respect to mean FDG uptake in the total liver and reproducibility, but do not identify the max FDG uptake.     

Metabolic Tumor Width Parameters as Determined on PET/CT Predict Disease-free Survival and Treatment Response in Squamous Cell Carcinoma of the Esophagus

Materials and Methods  We investigated the utility of metabolic tumor width parameters in predicting response to chemoradiotherapy and in predicting disease-free survival in patients with esophageal cancer. Furthermore, we evaluated the possible confounding effect of therapy-induced esophagitis on the evaluation of treatment response. Forty-nine patients with squamous cell carcinoma, who had undergone positron emission tomography/computed tomography (PET/CT) exams before and after neoadjuvant chemoradiotherapy, were included in the study. In the slice with the maximum 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) uptake of the tumor, the following metabolic tumor width parameters were measured: Area of the tumor, maximum diameter of the tumor, maximum and mean standardized uptake value (SUV). Furthermore, the “diameter-SUV index” was calculated by multiplying the tumor diameter by the mean SUV. Results  The decrease of the metabolic tumor diameter between pre- and post-treatment PET/CT scans was the single best predictor of treatment response and tumor-free survival. However, the accuracy of predicting response and survival was even higher when using the decrease of the “diameter-SUV index” as the metabolic criterion for treatment response. A decrease by more than 55% of the diameter-SUV index identified pathologic responders (n = 22) with a sensitivity of 91% and a specificity of 93%. Radiation esophagitis was found to have a significant impact on the assessment of treatment response when evaluating therapy response based on the maximum SUV, whereas no confounding effect of radiation esophagitis was seen when evaluating therapy response based on the tumor diameter or the diameter-SUV index. Conclusion  The present study shows that tumor width parameters, especially the tumor diameter or the combination of diameter and SUV in the “diameter-SUV index”, are valuable for predicting tumor-free survival and treatment response independent from the presence of radiation esophagitis.     

Implications of Standardized Uptake Value Measurements of the Primary Lesions in Proven Cases of Breast Carcinoma with Different Degree of Disease Burden at Diagnosis: Does 2-Deoxy-2-[F-18]fluoro-d-glucose-Positron Emission Tomography Predict Tumor Biology?

Objectives Tumor glycolytic activity as determined by 2-deoxy-2-[F-18]fluoro-d-glucose-positron emission tomography (FDG-PET) imaging is an important marker of tumor biology and provides critical information about the behavior of most malignancies at different stages of the disease. This study was undertaken to determine whether the degree of FDG uptake differs between the primary breast lesions with varying disease burden at diagnosis in proven cases of breast carcinoma. Materials and Methods Among 250 patients enrolled for this prospective study, 174 patients with newly diagnosed breast carcinoma at different disease stages who had undergone dual time point FDG-PET before any therapeutic or surgical interventions were considered for inclusion in this analysis. These patients prospectively underwent multimodality imaging techniques, such as magnetic resonance imaging (MRI), ultrasonography, digital mammography, computed tomography (CT), and dual time point FDG-PET, as a component of a National Institutes of Health-funded project for characterizing primary breast lesions and local–regional staging. The slice with maximum FDG uptake in the region of interest (ROI) was chosen for the first time point and the second time point images for quantitative measurement of the metabolic activity of the tracer (SUVmax1 and SUVmax2, respectively). Furthermore, the percent change in SUVmax (%ΔSUVmax) between SUVmax1 and SUVmax2 was calculated. Results The patient population (n = 174) were divided into three groups for the purposes of this study. Sixty-four patients with primary and metastatic axillary lymphadenopathy (designated as group I) and 18 patients with both axillary and distant metastases (designated as group II) met the inclusion criteria for this analysis. The third group (group III) comprised of a population of 92 patients without any metastasis either at the lymph nodes or at distant sites. The mean SUVmax1, SUVmax2, and the %ΔSUVmax in the early and delayed FDG-PET in group I (n = 64) patients were as follows: primary lesion 4.8 ± 3.9, 5.3 ± 4.5, and 9.4 ± 12.8%, respectively, and axillary lesions 3 ± 2.6, 3 ± 2.7, and 1.1 ± 21.3%, respectively. Among the group II patients (n = 18), the mean values of the primary lesion with regard to the SUVmax1, SUVmax2, and the %ΔSUVmax were 7.7 ± 6.2, 8.9 ± 7.1, and 15.7 ± 10.8%, respectively. The corresponding figures for the axillary lesions were 3.5 ± 3.1, 3.7 ± 3.1, and 6.3 ± 20.9%, respectively, and those for the distant metastatic lesions were 3 ± 1.4, 3.1 ± 1.2, and 8.5 ± 21.2%, respectively. The mean SUVmax1, SUVmax2, and the %ΔSUVmax of the primary lesion of group III patients (n = 92) without any metastasis were 2.9 ± 2.7, 3.4 ± 2.4, and 4.5 ± 4.2%, respectively. Unifactorial ANOVA of the three parameters among the primary lesions of these three groups were statistically significant with regard to the mean SUVmax1 (p = 0.01) and SUVmax2 (p = 0.01). These values in the primary lesions were highest in group II (those with both axillary and distant metastases), followed by group I (those with only metastatic axillary adenopathy) and group III (patients without any metastasis), and could be related to the more aggressive tumor biology in group II. Conclusion The findings provide evidence that among the lesions with varying disease burden at diagnosis, the FDG uptake is highest in cases with both axillary and distant metastasis, followed by those with axillary metastasis and then by those with no metastatic disease. These provide in vivo insight into tumor biology as FDG uptake is regarded as a surrogate marker of the same.     

Investigating the Existence of Quantum Metabolic Values in Non-Hodgkin’s Lymphoma by 2-Deoxy-2-[F-18]fluoro-d-glucose Positron Emission Tomography

Objectives To investigate the existence of quantum metabolic values in various subtypes of non-Hodgkin’s lymphoma (NHL). Methods Fifty-eight patients with newly diagnosed NHL and positron emission tomography (PET) performed within three months of biopsy were included. The standardized uptake value (SUV) from PET over the area of biopsy and serum glucose [Glc] were recorded. The group glucose sensitivity(G) for indolent and aggressive NHL was obtained by linear regression with ln(SUV) = G·ln[Glc] + C, where C is a constant for the group. Finally, the individual’s glucose sensitivity (g) was obtained by g = {ln(SUV)-C}/ln[Glc], along with their means in various subtypes of NHL. To further investigate the influence of extreme [Glc] conditions, the SUVs corrected by the individually calculated g at various glucose levels, [Glc′] using SUV′ =SUV·{[Glc′]/[Glc]} ^g , were compared to the original SUVs for both indolent and aggressive NHL. Results The averaged g (=G) for aggressive was significant different from that for indolent NHL (−0.94 ± 0.51 vs. +0.13 ± 0.10, respectively, p < 0.00005). There were significant differences in SUV for [Glc] < 80 or >110 mg/dl for both types of NHL. Unlike overlap among SUVs between NHL subtypes, the g value clearly categorized them into two distinct groups with positive (near-zero) and negative g values (around −1) for the indolent and aggressive NHLs, respectively. Conclusions Distinct quantum metabolic values of −1 and 0 were noted in NHL. Aggressive NHL has a more negative value (or higher glucose sensitivity) than that of indolent and, thus, is more susceptible to extreme glucose variation.     

胆管细胞癌与不同分化程度肝细胞癌CEUS特征的对比研究

目的 比较肝内胆管细胞癌（ICC）和不同分化程度肝细胞癌（HCC）CEUS表现对ICC和不同分化程度HCC的鉴别诊断价值。方法 回顾性分析经病理证实的34例ICC（ICC组）和136例不同分化程度的HCC患者高、中、低分化（HCC组）的常规超声及CEUS表现,并评价CEUS始退时间对ICC的诊断效能。结果 ICC组在门静脉早期开始消退的比例（24/34,70.59%）均高于各HCC组,在门静脉中期开始消退的比例（0/34）和在门静脉晚期/延迟期开始消退的比例（4/34,11.76%）均低于中、高分化HCC组,差异均有统计学意义（P均<0.008）。低分化HCC组在门静脉中期开始消退的比例（16/41,39.02%）高于高分化HCC组（P<0.008）。CEUS诊断ICC的敏感度、特异度、阳性预测值、阴性预测值、准确率、阳性似然比及阴性似然比分别为82.35%（28/34）、91.18%（124/136）、70.00%（28/40）、95.38%（124/130）、89.41%（152/170）、9.4、0.2。ICC及低、中、高分化HCC组病灶CEUS始增时间分别为（13.03±3.49）s、（13.80±3.04）s、（14.89±4.12）s、（16.00±3.38）s,差异有统计学意义（F=4.369,P<0.05）,ICC组始增时间早于高分化HCC组（P<0.05）。结论 不同分化程度HCC和ICC的CEUS表现存在差异,CEUS对其鉴别诊断有一定的参考价值。     

Effective Inhibition of Xenografts of Hepatocellular Carcinoma (HepG2) by Rapamycin and Bevacizumab in an Intrahepatic Model

Purpose  Hepatocellular carcinoma (HCC) displays a characteristic hypervascularity and depends on angiogenesis for tumor growth, which thus provides a potential target for therapeutic approaches to HCC. In this study, through the use of combined micro-positron emission tomography (PET)/computed tomography (CT), we investigate if such a combined targeting of vascular endothelial growth factor (VEGF) activity and expression might retard HCC growth in an orthotopic intrahepatic xenograft model. Procedures  Xenograft models were created by intraportal vein injection of HepG2 cell suspensions in severe combined immunodeficient mice. The mice were then treated with (1) rapamycin (RAPA), a mammalian target of rapamycin pathway inhibitor; (2) bevazicumab (BEV), a VEGF monoclonal antibody; and (3) a RAPA/BEV combination. Results  Assessment of HCC progression using CT with Omnipaque and PET with 2-deoxy-2-(F-18)-fluoro-d-glucose showed that mice treated with RAPA/BEV had the lowest standardized uptake values (SUVs). At week 2, mice treated with RAPA/BEV, RAPA, and BEV all showed a marked decrease in the SUV_max readings with the greatest drop being observed in the RAPA/BEV group (1.33 + 0.26, 1.81 + 0.2, 2.05 + 0.4 vs. vehicle control 2.11 + 0.53). Conclusions  Our results, supported by micro-PET/CT, suggest that RAPA/BEV represents a potential novel antiangiogenic therapy for the treatment of HCC.     

Reproducibility of Semi-quantitative Parameters in FDG-PET Using Two Different PET Scanners: Influence of Attenuation Correction Method and Examination Interval

Purpose The aim of this study is to evaluate the reproducibility of semi-quantitative parameters obtained from two 2-deoxy-2-[F-18]fluoro-d-glucose-positron emission tomography (FDG–PET) studies using two different PET scanners. Methods Forty-five patients underwent FDG–PET examination with two different PET scanners on separate days. Two PET images with different attenuation correction method were generated in each patient, and three regions of interest (ROIs) were placed on the lung tumor and normal organs (mediastinum and liver) in each image. Mean and maximum standardized uptake values (SUVs), tumor-to-mediastinum and tumor-to-liver ratios (T/M and T/L), and the percentage difference in parameters between two PET images (% Diff.) were compared. Results All measured values except maximum SUV in the liver and tumor-related parameters (SUV in lung tumor, T/M, T/L) showed no significant difference between two PET images. Conclusion The mean measured values showed high reproducibility and demonstrate that follow-up study or measurement of tumor response to anticancer drugs can be undertaken by FDG–PET examination without specifying the particular type of PET scanner.     

A Weight Index for the Standardized Uptake Value in 2-Deoxy-2-[F-18]fluoro-<Emphasis Type="SmallCaps">d</Emphasis>-glucose-Positron Emission Tomography

Introduction Known errors in the standardized uptake value (SUV) caused by variations in subject weights W encountered can be corrected by lean body mass or body surface area (bsa) algorithms replacing W in calculations. However this is infrequently done. The aims of the work here are: quantify sensitivity to W, encourage SUV correction with an approach minimally differing from tradition, and show what improvements in the SUV coefficient of variation (cv) for a population can be expected. Methods Selected for analyses were 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) SUV data from positron emission tomography (PET) and PET/computed tomography (CT) scans at the University of Tennessee as well as from the literature. A weight sensitivity index was defined as −n=slope of ln(SUV/W) vs. lnW. The portion of the SUV variability due to this trend is removed by using the defined , or a virtually equal SUV _m using , with Q and ID being tissue specific-activity and injected dose. measures performance. Adapting to animal studies’ tradition, is preferred over the conventional . Results For FDG in adults from averaging over most tissues. In children, however, . Tissues have the same index if their influx constants are independent of W. Suggested, therefore, is a very simplified , which is dimensionless and keeps the same population averages as traditional SUVs. It achieves . Hence, for cv’s of SUVs below ∼1/3 improvements over tradition are possible, leading to F’s<0.95. Accounting additionally for height, as in SUV_bsa, gives very little improvement over the simplified approach here and gives essentially the same F’s as SUV _m . Conclusions Introduced here is a weight index useful in reducing variability and further understanding the SUV. Addressing weight sensitivity is appropriate where the cv of the SUVs is below about 1/3. Proposed is the very simple approach of using an average of an adult patient’s weight and ∼70 kg for FDG SUV calculations. Unlike other approaches the dimensionless population average of SUV _m s is unchanged from tradition.     

Usefulness of 3′-[F-18]Fluoro-3′-deoxythymidine with Positron Emission Tomography in Predicting Breast Cancer Response to Therapy

Objective The usefulness of 2-deoxy-2-[F-18]fluoro-d-glucose (FDG)–positron emission tomography (PET) in monitoring breast cancer response to chemotherapy has previously been reported. Elevated uptake of FDG by treated tumors can persist however, particularly in the early period after treatment is initiated. 3′-[F-18]Fluoro-3′-deoxythymidine (FLT) has been developed as a marker for cellular proliferation and, in principle, could be a more accurate predictor of the long-term effect of chemotherapy on tumor viability. We examined side-by-side FDG and FLT imaging for monitoring and predicting tumor response to chemotherapy. Methods Fourteen patients with newly diagnosed primary or metastatic breast cancer, who were about to commence a new pharmacologic treatment regimen, were prospectively studied. Dynamic 3-D PET imaging of uptake into a field of view centered over tumor began immediately after administration of FDG or FLT (150 MBq). After 45 minutes of dynamic acquisition, a clinically standard whole-body PET scan was acquired. Patients were scanned with both tracers on two separate days within one week of each other (1) before beginning treatment, (2) two weeks following the end of the first cycle of the new regimen, and (3) following the final cycle of that regimen, or one year after the initial PET scans, whichever came first. (Median and mean times of early scans were 5.0 and 6.6 weeks after treatment initiation; median and mean times for late scans were 26.0 and 30.6 weeks after treatment initiation.) Scan data were analyzed on both tumor-by-tumor and patient-by-patient bases, and compared to each patient's clinical course. Results Mean change in FLT uptake in primary and metastatic tumors after the first course of chemotherapy showed a significant correlation with late (av. interval 5.8 months) changes in CA27.29 tumor marker levels (r = 0.79, P = 0.001). When comparing changes in tracer uptake after one chemotherapy course versus late changes in tumor size as measured by CT scans, FLT was again a good predictor of eventual tumor response (r = 0.74, P = 0.01). Tumor uptake of FLT was near-maximal by 10 minutes after injection. The time frame five to 10 minutes postinjection of FLT produced standardized uptake value (SUV) values highly correlated with SUV values obtained after 45-minute uptake (r = 0.83, P < 0.0001), and changes in these early SUVs after the first course of chemotherapy correlated with late changes in CA27.29 (r = 0.93, P = 0.003). Conclusion A 10-minute FLT-PET scan acquired two weeks after the end of the first course of chemotherapy is useful for predicting longer-term efficacy of chemotherapy regimens for women with breast cancer.     

Fusion of <Emphasis Type="Italic">Gaussia</Emphasis> Luciferase to an Engineered Anti-carcinoembryonic Antigen (CEA) Antibody for <Emphasis Type="Italic">In Vivo</Emphasis> Optical Imaging

The bioluminescent protein Gaussia luciferase (GLuc) was fused to an anti-carcinoembryonic antigen (CEA) antibody fragment, the diabody, for in vivo optical tumor imaging. A 15-amino acid N-terminal truncation (GLΔ15) resulted in a brighter protein. Fusions of the anti-CEA diabody to full-length GLuc and GLΔ15 retained high affinity for the antigen, emitted light, and exhibited excellent enzymatic stability. In vivo optical imaging of tumor-bearing mice demonstrated specific targeting of diabody-GLΔ15 to CEA-positive xenografts, with a tumor/background ratio of 3.8 ± 0.4 at four hours after tail-vein injection, compared to antigen-negative tumors at 1.3 ± 0.1 (p = 0.001). MicroPET imaging using ¹²⁴I-diabody-GLΔ15 demonstrated specific uptake in the CEA-positive tumor (2.6% ID [injected dose]/g) compared to the CEA-negative tumor (0.4% ID/g) at 21 hours. Although further optimization of this fusion protein may be needed to improve in vivo performance, the diabody-GLΔ15 is a promising optical imaging probe for tumor detection in vivo.