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Autoradiographic Quantification of ¹⁸F-FDG Uptake in Experimental Soft-Tissue Abscesses in Rats¹

¹ From the Division of Nuclear Medicine (A.H.K., B.W., G.K.v.S., A.B.), Department of Pathology (M.O.K.), and Institute of Medical Microbiology (J.G.), University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. From the 2001 RSNA scientific assembly. Received May 11, 2001; revision requested June 11; revision received August 24; accepted September 20. Supported by Novartis-Stiftung, Basel, Switzerland; EMDO-Stiftung, Zurich, Switzerland; and Freie Akademische Gesellschaft, Basel, Switzerland. Address correspondence to A.H.K. (e-mail: achim.kaim@dmr.usz.ch).

	ABSTRACT

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PURPOSE: To use semiquantitative autoradiography to investigate fluorodeoxyglucose (FDG) uptake, distribution, and cellular localization in acute, early chronic, and late chronic soft-tissue infections.

MATERIALS AND METHODS: Unilateral calf-muscle abscesses were induced in 12 Sprague-Dawley rats by means of intramuscular inoculation of 0.1 mL of bacterial suspension (Staphylococcus aureus, 1.2 x 10⁹ CFU/mL). Following injection of 130–180 MBq of fluorine 18 FDG, autoradiography of the abscess and contralateral muscle was performed (10-µm section thickness) on days 2, 5, and 9 after infection. Detailed spatial correlation of autoradiographs and histopathologic samples was performed by means of image fusion. Regions of interest were placed in the abscess wall, and measured gray values were converted to kilobecquerels per cubic centimeter according to kilobecquerels of injected activity per gram of body weight, which yielded standardized uptake values (SUVs).

RESULTS: Acute abscess formation was characterized by central necrosis predominantly surrounded by neutrophils and a second necrotic tissue layer that bordered neutrophil infiltrates peripherally. Areas with increased FDG uptake corresponded to cellular inflammatory infiltrates, mainly granulocytes. The corresponding SUV was calculated to be 4.08 ± 0.65 (mean ± SD). Early chronic phase showed mixed cellular infiltrate of granulocytes and macrophages that surrounded central necrosis with interspersed fibroblasts and only residual muscle necrosis layer within the abscess wall. FDG uptake was located where granulocytes and macrophages were present, as in acute infection (SUV = 5.32 ± 2.30). Late chronic infection was characterized by a prominent layer of macrophages around residual central necrosis and fibroblast-enriched granulation tissue delineating the infection from muscle tissue. FDG uptake clearly coincided with the macrophages, and no substantial increase of FDG uptake was detected within fibroblast-enriched granulation tissue. The SUV was calculated as 7.97 ± 0.21. Results of Kruskal-Wallis ANOVA demonstrated that the change in SUV with time was statistically significant (² = 7.42, P < .05).

CONCLUSION: The highest FDG uptake coincides with areas of inflammatory cell infiltrates, predominantly in neutrophils in the acute phase and in macrophages in the chronic phase of soft-tissue infection.

© RSNA, 2002

Index terms: Inflammation, radionuclide studies, 456.1216 • Radionuclide imaging, experimental studies, 456.1216 • Soft tissues, infection, 456.2012 • Soft tissues, radionuclide studies, 456.1216

	INTRODUCTION

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It has been reported that fluorine 18 (¹⁸F) fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful in the imaging of musculoskeletal infections (1–5). Results of various studies on rodents (6–9) have shown that there is an increased FDG uptake in activated inflammatory cells, such as granulocytes, macrophages, and lymphocytes. With an aseptic, turpentine-induced abscess model, Yamada et al (7) showed that the grade of FDG uptake depends on the age of the inflammation and that its maximum appears in an early phase of chronic inflammation. Results of qualitative macroautoradiography suggested that uptake was due to increased glycolytic activity of young fibroblasts and macrophages. The purpose of this study was to investigate FDG uptake, distribution, and cellular localization in acute, early chronic, and late chronic soft-tissue infections by means of semiquantitative autoradiography.

	MATERIALS AND METHODS

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Abscess Models
The study was performed according to the guidelines of the National Institutes of Health and the recommendations of the committee on animal research at our institution. The protocol was fully approved by the local institutional review committee on animal care. The study included 12 male Sprague-Dawley rats (stock IcoIbm: OFA, Fullinsdorf, Switzerland) (weight, 250–300 g; age, 7 weeks). All animals were kept in cages with standardized conditions of light and free access to water and food. With the use of general inhalation anesthesia (Metoxyfluranum; Pitman-Moore GmbH, Burgwedel, Germany), a left-sided, unilateral, deep calf-muscle abscess was induced with intramuscular inoculation (with a 25-gauge needle) of 0.1 mL of a bacterial suspension (Staphylococcus aureus, clinical strain 10B; Novartis Pharma, Basel, Switzerland). One author (J.G.) measured bacterial concentration (1.2 x 10⁹ CFU/mL) by means of optical density (McFarland Standard; bioMerieux, Marcy-l’Etoile, France). A similar infection model was previously described by several investigators (9–11), with the difference that those groups used Escherichia coli as opposed to S aureus. We chose the latter because it is a typical and frequent cause of bacterial abscesses in humans (12).

The animals were divided into three groups of four animals and investigated 2 (acute), 5 (early chronic), and 9 (late chronic) days after infection. All animals developed a palpable fluctuating mass in the left calf muscle within 36 hours after bacterial inoculation. No systemic infection occurred.

Autoradiography
A dose of 130–180 MBq of ¹⁸F FDG was injected intraperitoneally, and the animals were sacrificed 45 minutes later with an intracardial overdose of pentobarbital (Nembutal; Abbott Laboratories, North Chicago, Ill). Infected calf muscle, contralateral normal calf muscle, and the brain were dissected immediately (A.H.K., B.W.) and frozen in isopentane (Isopentan; Fluka Chemie GmbH, Buchs, Switzerland) cooled to -50°C. The frozen samples were cut to a 10-µm thickness and mounted on glass slides. Film (Biomax MR; Eastman Kodak, Rochester, NY) was subsequently exposed for 24 hours together with carbon 14 (¹⁴C) standards for later quantification of gray values. The slices were then stained with hematoxylin-eosin (H-E) for histologic examination.

Quantitative Analysis
In a calibration experiment, each ¹⁴C standard was assigned a value (in kilobecquerels per cubic centimeter) of ¹⁸F activity. For this purpose, 10-µm-thick slices of a brain paste that contained defined amounts of ¹⁸F activity (in kilobecquerels per milligram) were exposed on film together with the ¹⁴C standard for 24 hours.

Autoradiographs were digitized, and the gray values were converted to kilobecquerels per milligram by using the calibrated ¹⁴C standards. The activities were then decay corrected according to the time of injection. Dividing these values by the amount of injected activity per gram of body weight yielded standardized uptake values (SUVs). Regions of interest were placed on the abscess wall, contralateral muscle, and white (corpus callosum) and gray (frontal cortex) matter (A.H.K.). The sizes of the regions of interest were adjusted to the individual abscess configuration (range, 0.011–0.056 cm²). Contralateral muscle and white and gray matter served as internal standards assuming relative stability of FDG uptake. The time course of the SUV in the abscess wall and the ratios FDG_{abscess wall}/FDG_{gray matter} and FDG_{abscess wall}/FDG_{white matter} were statistically analyzed by using Kruskal-Wallis analysis of variance and exact tests for small sample sizes (13) with time as the independent variable.

Qualitative Analysis
Detailed histomorphologic comparison between histologic samples and autoradiographs was performed (A.H.K., M.O.K.). Both autoradiographs and histologic specimens were digitized, and image fusion allowed optimal spatial correlation. Differences in relative ¹⁸F-FDG uptake in the abscess and surrounding tissue were correlated to histologic characteristics and assigned to inflammatory cell infiltration, tissue necrosis, granulation tissue, and muscle. The cells of the inflammatory infiltration were histologically characterized to granulocytes, macrophages, and lymphocytes (M.O.K.).

	RESULTS

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Acute abscess formation (at 2 days after inoculation) was histologically characterized by central necrosis predominantly surrounded by neutrophils. A second necrotic tissue layer was located between the inner neutrophil layer and a more peripherally localized cellular infiltration that consisted mainly of granulocytes and some interspersed macrophages. The areas with increased ¹⁸F-FDG uptake corresponded to cellular inflammatory infiltrates mainly consisting of granulocytes. The necrotic abscess center and the second necrotic tissue layer were characterized by a decreased FDG uptake. The SUVs of the inner and outer cellular zones were 4.08 ± 0.65 (mean ± SD) and 3.11 ± 0.52, respectively. Figure 1 shows a typical autoradiograph with correlating histologic sample in the acute phase of the abscess.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x5 and x40, respectively) from an acute intramuscular abscess (obtained 2 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The abscess is characterized by central necrosis (CN), an inner layer (IL) of inflammatory cells mainly consisting of granulocytes (arrowheads in d), a second necrotic muscle layer (nml), and an outer layer (OL) of predominantly granulocytes. Areas with increased 18F-FDG accumulation are correlated to cellular infiltrates. The central necrosis appears more extended at autoradiography than at histologic examination, and the FDG accumulation of the inner layer at autoradiography coincides with the outer border of the inner layer at histologic examination. This means that the inner portion of the inner layer at histologic examination mainly consists of dead granulocytes.

View larger version (101K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x5 and x40, respectively) from an acute intramuscular abscess (obtained 2 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The abscess is characterized by central necrosis (CN), an inner layer (IL) of inflammatory cells mainly consisting of granulocytes (arrowheads in d), a second necrotic muscle layer (nml), and an outer layer (OL) of predominantly granulocytes. Areas with increased 18F-FDG accumulation are correlated to cellular infiltrates. The central necrosis appears more extended at autoradiography than at histologic examination, and the FDG accumulation of the inner layer at autoradiography coincides with the outer border of the inner layer at histologic examination. This means that the inner portion of the inner layer at histologic examination mainly consists of dead granulocytes.

View larger version (165K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x5 and x40, respectively) from an acute intramuscular abscess (obtained 2 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The abscess is characterized by central necrosis (CN), an inner layer (IL) of inflammatory cells mainly consisting of granulocytes (arrowheads in d), a second necrotic muscle layer (nml), and an outer layer (OL) of predominantly granulocytes. Areas with increased 18F-FDG accumulation are correlated to cellular infiltrates. The central necrosis appears more extended at autoradiography than at histologic examination, and the FDG accumulation of the inner layer at autoradiography coincides with the outer border of the inner layer at histologic examination. This means that the inner portion of the inner layer at histologic examination mainly consists of dead granulocytes.

View larger version (121K): [in this window] [in a new window] [Download PPT slide]   Figure 1d. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x5 and x40, respectively) from an acute intramuscular abscess (obtained 2 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The abscess is characterized by central necrosis (CN), an inner layer (IL) of inflammatory cells mainly consisting of granulocytes (arrowheads in d), a second necrotic muscle layer (nml), and an outer layer (OL) of predominantly granulocytes. Areas with increased 18F-FDG accumulation are correlated to cellular infiltrates. The central necrosis appears more extended at autoradiography than at histologic examination, and the FDG accumulation of the inner layer at autoradiography coincides with the outer border of the inner layer at histologic examination. This means that the inner portion of the inner layer at histologic examination mainly consists of dead granulocytes.

View larger version (163K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x5 and x40, respectively) from an early chronic intramuscular abscess (obtained 5 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The abscess wall consists of an inner cellular zone (ICZ, *), residues of necrotic muscle layer (nml, ) and granulation tissue (GT). Areas with increased 18F-FDG accumulation are correlated to the inner cellular zone and granulation tissue. The small photopenic areas within the abscess wall at autoradiography correspond to the necrotic muscle layer. The inner cellular zone and granulation tissue consist of a mixed cellular pattern of granulocytes and macrophages. (d) Interspersed fibroblasts can be delineated in the granulation tissue.

View larger version (129K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x5 and x40, respectively) from an early chronic intramuscular abscess (obtained 5 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The abscess wall consists of an inner cellular zone (ICZ, *), residues of necrotic muscle layer (nml, ) and granulation tissue (GT). Areas with increased 18F-FDG accumulation are correlated to the inner cellular zone and granulation tissue. The small photopenic areas within the abscess wall at autoradiography correspond to the necrotic muscle layer. The inner cellular zone and granulation tissue consist of a mixed cellular pattern of granulocytes and macrophages. (d) Interspersed fibroblasts can be delineated in the granulation tissue.

View larger version (167K): [in this window] [in a new window] [Download PPT slide]   Figure 2c. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x5 and x40, respectively) from an early chronic intramuscular abscess (obtained 5 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The abscess wall consists of an inner cellular zone (ICZ, *), residues of necrotic muscle layer (nml, ) and granulation tissue (GT). Areas with increased 18F-FDG accumulation are correlated to the inner cellular zone and granulation tissue. The small photopenic areas within the abscess wall at autoradiography correspond to the necrotic muscle layer. The inner cellular zone and granulation tissue consist of a mixed cellular pattern of granulocytes and macrophages. (d) Interspersed fibroblasts can be delineated in the granulation tissue.

View larger version (151K): [in this window] [in a new window] [Download PPT slide]   Figure 2d. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x5 and x40, respectively) from an early chronic intramuscular abscess (obtained 5 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The abscess wall consists of an inner cellular zone (ICZ, *), residues of necrotic muscle layer (nml, ) and granulation tissue (GT). Areas with increased 18F-FDG accumulation are correlated to the inner cellular zone and granulation tissue. The small photopenic areas within the abscess wall at autoradiography correspond to the necrotic muscle layer. The inner cellular zone and granulation tissue consist of a mixed cellular pattern of granulocytes and macrophages. (d) Interspersed fibroblasts can be delineated in the granulation tissue.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 3. SUVs of the abscess wall and contralateral muscle in acute, early chronic, and late chronic stages. Indicated are the mean (bars) and individual values. The value for granulation tissue is plotted only at day 9. = abscess wall, = contralateral muscle, + = granulation tissue.

View larger version (158K): [in this window] [in a new window] [Download PPT slide]   Figure 4a. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x10 and x40, respectively) from a late chronic intramuscular abscess (obtained 9 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The FDG uptake is clearly correlated to the prominent layer of macrophages (ML) surrounding the residual central necrosis (CN). There is no substantial FDG accumulation in the granulation tissue (GT), which mainly consists of fibroblasts.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 4b. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x10 and x40, respectively) from a late chronic intramuscular abscess (obtained 9 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The FDG uptake is clearly correlated to the prominent layer of macrophages (ML) surrounding the residual central necrosis (CN). There is no substantial FDG accumulation in the granulation tissue (GT), which mainly consists of fibroblasts.

View larger version (158K): [in this window] [in a new window] [Download PPT slide]   Figure 4c. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x10 and x40, respectively) from a late chronic intramuscular abscess (obtained 9 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The FDG uptake is clearly correlated to the prominent layer of macrophages (ML) surrounding the residual central necrosis (CN). There is no substantial FDG accumulation in the granulation tissue (GT), which mainly consists of fibroblasts.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 4d. (a) Autoradiograph, (b) corresponding slice stained with H-E, and (c, d) histologic sample stained with H-E (original magnifications, x10 and x40, respectively) from a late chronic intramuscular abscess (obtained 9 days after bacterial inoculation). Histologic magnification of c corresponds to the areas in the rectangles on a and b. The FDG uptake is clearly correlated to the prominent layer of macrophages (ML) surrounding the residual central necrosis (CN). There is no substantial FDG accumulation in the granulation tissue (GT), which mainly consists of fibroblasts.

	DISCUSSION

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When exposed to certain stimuli, phagocytes (ie, neutrophils, eosinophils, and mononuclear phagocytes) start metabolizing large quantities of glucose by way of the hexose monophosphate shunt, and their rates of oxygen uptake increase greatly, sometimes more than 50-fold (14). This change from resting cell to activated phagocyte is known as "respiratory burst." Energy-dependent, interrelated cellular defense mechanisms include migration, generation, release of microbicidal agents, and phagocytosis (15,16). The activation of phagocytes leads to elevated ¹⁸F-FDG uptake and glucose transporter activity. ¹⁸F-FDG PET has proven to be a clinically promising method in infection imaging, but few data are available regarding the uptake observed at PET and histopathologic examination. Specifically, it is not known how FDG uptake changes with the changing phase of the infection and whether the FDG uptake occurs only in white blood cells or also in fibroblasts.

Performing basic studies for the purpose of defining the relative contribution of ¹⁸F-FDG uptake of different cell groups in an infection should aid in the more accurate interpretation of clinical PET scans. Yamada et al (7) failed to produce a stable animal abscess model and therefore used an aseptic turpentine oil-induced inflammatory tissue model in an early chronic stage to show the cellular distribution of radionuclide activity with autoradiography. They demonstrated increased ¹⁸F-FDG uptake in areas with macrophages, neutrophils, and fibroblasts. In humans, many infections are caused by bacteria or fungi, and abscess formation is more common in infections with pyogenic organisms. Therefore, a bacterial model is physiologically relevant and is likely more applicable to clinical conditions. We established a stable bacterial abscess model in the rat, which allowed us to study the time course of a soft-tissue infection by means of autoradiography with histomorphologic correlation. Moreover, the semiquantitative autoradiographic technique enabled us to calculate the SUV in different abscess zones. The amount of FDG uptake depends on the type, activation status, and number of cells involved, the biologic state of the animal (eg, plasma glucose concentration and amount of physical activity), and the number and growth phase of bacteria. Nevertheless, by using a standardized experimental setup, the applied autoradiographic technique allowed comparison of quantitative FDG uptake at different time points and in different histomorphologic areas.

The early abscess formation in the acute phase could be divided into a zone of central necrosis, an inner neutrophil layer with an intense ¹⁸F-FDG uptake, a second necrosis zone, and an outer neutrophil layer. Increased SUVs were detected in zones with polymorphonuclear infiltrates, and the lower number of granulocytes in the outer neutrophil zone explained why the SUV was smaller than that of the inner neutrophil layer. The unusual histologic finding of a second ring with necrotic muscle and an outer ring of granulocytes was consistently found in all acute abscesses, and, to a lesser extent, in early chronic abscesses, although the reason remains unclear, and a similar appearance has not been described in studies by other investigators. The abscess wall in the early chronic phase was characterized by a mixed infiltrate of neutrophils, macrophages, and granulation tissue with fibroblasts. The areas with visually increased ¹⁸F-FDG uptake could be correlated with the inflammatory cells, even though a clear distinction from interspersed fibroblasts was not possible. The outer zones of the granulation tissue were characterized by young fibroblasts but were less infiltrated by macrophages and neutrophils, and these zones showed low activity at autoradiography, thus confirming that the predominant FDG uptake resides with the white blood cells. The macroscopic reduction in abscess size in the late chronic phase was due to an advanced organization of the infectious focus. The residual central necrosis was surrounded by a dense layer that predominantly contained macrophages and showed a high ¹⁸F-FDG uptake. The SUV of this area was the highest over the time course of abscess development and showed a 16-fold increase when compared with that of the contralateral muscle. The outer zone consisted of fibroblast-enriched granulation tissue with only a twofold increase of SUV when compared with contralateral muscle. Fibroblasts are known to metabolize glucose for proliferation (17), but our results suggest that their glucose usage does not substantially contribute to radioactive uptake in infection imaging.

We did not perform a quantitative differential assessment of the number of inflammatory cells at histopathologic examination, and, therefore, it remains partly hypothetical whether granulocytes or macrophages have a higher FDG uptake. However, the temporal course of the SUV suggested a higher uptake of FDG in activated macrophages than in granulocytes. One reason may be that macrophages have a high capacity for phagocytosis and a highly developed system for digesting engulfed material (15,16). They are much more resistant than granulocytes, which die in the tissues in the process of killing phagocytosed bacteria. A second reason may be that, with macrophages, the energy need for phagocytosis, migration, and synthesis exclusively derives from extracellular glucose by intrinsic activation of glucose transporter molecules (18,19), while neutrophils mobilize stored glycogen to fuel the respiratory burst in addition to using exogenous glucose (20,21).

The bacterial consumption of ¹⁸F FDG could not be discriminated from cellular uptake, although it is known that abscess-forming bacteria use glucose as an energy source (22). The problems were the mixed pattern of inflammatory cells and bacteria and the small bacterial size, which could not be resolved with the applied technique. To quantify the microbial fraction of FDG accumulation, one would have to apply advanced autoradiographic techniques to allow visualization of structures at the cellular level.

The results of this study show that ¹⁸F-FDG uptake in septic soft-tissue lesions varies according to the age of the abscess. The visualization of activated white blood cell infiltrates with ¹⁸F FDG in acute and chronic bacterial abscesses and the fact that fibroblasts did not substantially contribute to FDG accumulation mean that ¹⁸F-FDG PET may discriminate granulation tissue from activated cellular infiltrates. The inflammatory activity in suspected chronic infection may potentially be assessed with high specificity.

In conclusion, autoradiography demonstrated the highest FDG uptake in areas of inflammatory cell infiltrates in experimental bacterial abscesses in rats. The FDG uptake was predominantly associated with neutrophils in the acute phase and with macrophages in the chronic phase of soft-tissue infection. The increasing FDG uptake of the cellular infiltrates with time suggests a higher rate of glucose usage in macrophages than in neutrophils. Fibroblasts did not substantially contribute to FDG uptake.

	ACKNOWLEDGMENTS

 
The authors thank Valerie Treyer, MS, for important help.

	FOOTNOTES

 
Abbreviations: FDG = fluorodeoxyglucose, H-E = hematoxylin-eosin, SUV = standardized uptake value

Author contributions: Guarantor of integrity of entire study, A.H.K.; study concepts, A.H.K., G.K.v.S.; study design, A.H.K., A.B.; literature research, A.H.K.; clinical studies, A.H.K., J.G., M.O.K.; experimental studies, B.W., A.H.K.; data acquisition, A.H.K., A.B.; data analysis/interpretation, M.O.K., A.H.K., A.B.; statistical analysis, A.B.; manuscript preparation and definition of intellectual content, A.H.K.; manuscript editing, A.H.K., G.K.v.S., A.B.; manuscript revision/review and final version approval, A.H.K., A.B.

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