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Jansen et al. EJNMMI Research 2014, 4:8 18 F-FDG PET standard uptake values of thenormal pons in children: establishing a referencevalue for diffuse intrinsic pontine glioma Marc H A Jansen1*, Reina W Kloet2, Dannis G van Vuurden1,3, Sophie EM Veldhuijzen van Zanten1, Birgit I Witte4,Serge Goldman5, W Peter Vandertop6, Emile FI Comans2, Otto S Hoekstra2, Ronald Boellaard2and Gert-Jan JL Kaspers1 Background: Positron emission tomography (PET) scanning with [18 F]fluorodeoxyglucose (18 F-FDG) is a usefuldiagnostic and prediction tool in brain tumors, but its value in childhood diffuse intrinsic pontine glioma (DIPG) isstill unclear. For interpretation of 18 F-FDG PET results in DIPG, uptake values of the normal pons of children ofincreasing ages are mandatory. The aim of this study was to determine 18 F-FDG standard uptake value ratios (SUVr)of the normal pons and to compare these to those of DIPG.
Methods: We studied 36 subjects with a normal, non-affected pons (aged 5 to 23 years) and 6 patients with DIPG(aged 4 to 17 years) who underwent 18 F-FDG PET scanning. Magnetic resonance imaging (MRI) was co-registeredto define the regions of interest. SUVr and SUVrmax for the pons/cerebellum (SUVrp/c) and the pons/occipital lobe(SUVrp/o) were calculated. Independent-samples t tests and Mann–Whitney U tests were used to compare the meanSUVr and Pearson's test for correlations.
Results: For the normal pons, mean SUVrp/c and SUVrp/o were 0.65 (±0.054) and 0.51 (±0.056), respectively. Nosignificant correlations were found between the SUVr of the normal pons and sex, age, nor pontine volume. Amodest but statistically significant correlation was found between SUVr and post-injection time acquisition timing.
For DIPG, mean SUVrp/c and SUVrp/o were 0.74 (±0.20) and 0.65 (±0.30), respectively, while mean SUVrp(max)/c andSUVrp(max)/o were 1.95 (±0.48) and 1.81 (±0.20), respectively.
Conclusion: The SUVr of the unaffected pons are strikingly constant between children, irrespective of sex and age,and can therefore be well used as a reference value for 18 F-FDG PET studies in DIPG.
Keywords: Positron emission tomography; [18 F]fluorodeoxyglucose; Pontine glioma; Brain neoplasms;Reference values; Pons stereotactic brain biopsy In the past few years, 18 F- Positron emission tomography (PET) scanning with [18 F] FDG PET studies have been introduced in diffuse intrinsic fluorodeoxyglucose (18 F-FDG) provides information on pontine glioma (DIPG) a fatal disease that almost glucose metabolism. 18 F-FDG PET positively correlates exclusively occurs in children [Interestingly, 18 F-FDG with an increasing WHO grade in astrocytomas In metabolism in the majority of the DIPG was lower than high-grade glioma (HGG), 18 F-FDG PET is an indicator of that in the non-affected occipital lobe, but increased 18 F- response to therapy and is used for PET-guided planning of FDG uptake correlated with decreased overall survival However, reference values of 18 F-FDG uptake in the nor-mal pons of children of increasing age are mandatory to * Correspondence: 1 know what increased uptake is in the pons, and these data Division of Oncology and Hematology, Department of Pediatrics, VU University Medical Center, De Boelelaan 1118, Amsterdam 1007 MB, the are lacking. Therefore, the aim of this study was to calculate the standard uptake value ratios (SUVr) for the pons/ Full list of author information is available at the end of the article 2014 Jansen et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License which permits unrestricted use, distribution, and reproductionin any medium, provided the original work is properly cited.
Jansen et al. EJNMMI Research 2014, 4:8 cerebellum (SUVrp/c) and for the pons/occipital lobe Table 1 Baseline and PET characteristics of controls and patients with DIPG p/o) in subjects with a normal pons and to investigate the influence of age, pontine size, and post-injection inter- val on the SUVr. The SUVr of the normal pons were then Number of subjects compared to the SUVr and SUVrmax of DIPG.
Median age (years) SubjectsTo study the 18 F-FDG uptake of the normal pons, a retro- spective cohort was used. Thirty-six children and adoles- cents aged 6 to 23 years who underwent 18 F-FDG PET scans for epilepsy surgery planning in the period of 2002 until 2012 were included. All controls had focal epilepsy and were in a non-ictal state at the moment of scanning.
We inventoried the anti-epileptic agents used at the day Anti-epileptic drugs of scanning. We excluded scans that revealed space- occupying lesions anywhere in the brain or epilepsy- induced changes in the pons, occipital lobe, and cerebellum and scans that did not meet the criteria as described under ‘Scanning procedure'. The affected population consisted of six children with a newly diagnosed DIPG, based on criteria as described elsewhere from VU University Medical Center(VUmc), Amsterdam, the Netherlands, who underwent an 18 F-FDG PET scan at diagnosis [. The study was ap- Anaplastic astrocytoma proved by the institutional review board of VUmc.
Glioblastoma multiforme DIPG histology unknown Scanning procedure PET characteristics Scans of controls and DIPG patients were performed usingan ECAT EXACT HR + PET scanner (Siemens/CTI, Knox- Mean 18 F-FDG dose (MBq) ville, TN, USA), as previously described [Patients and Mean scan duration (min) controls fasted for at least 4 h before the PET scan. Fifteen minutes before injection, they were positioned in a quiet, darkened room, with their eyes closed and no noise. After 18 F-FDG uptake interval time injection of 185 MBq 18 F-FDG (mean 187.2 MBq ±5.6), subjects remained in the quiet, darkened room for 35 minfollowed by a 10-min 2D transmission scan, acquired using PET reconstruction parameters retractable rotating 68Ge sources, used for attenuation cor- rection purposes. Approximately 45 min post-injection, a static 3D emission scan of 15 min was acquired. All emis- sion scans were reconstructed using ordered subset expect- OSEM, ordered subset expectation maximization. aThe controls consisted of 6 ation maximization (OSEM, 4 iterations, 16 subsets) with a subjects with temporal lobe, 1 with parietal lobe, and 2 with frontal lobe Hanning filter with a cutoff at 0.5 times the Nyquist fre- epileptogenic foci; 5 with hypometabolism of the hippocampus; 5 with focalcortical dysplasia; 3 with mesial temporal sclerosis; and 14 without structural or 18F-FDG PET epileptogenic foci.
normalization, decay, dead time, attenuation, scatter, andrandoms During reconstruction, a zoom factor of Institute, Cologne, Germany) and subsequently used to 2.123 and a matrix of 256 × 256 were used, resulting in manually define the regions of interest (ROIs) of the pons, voxel sizes of 1.2 × 1.2 × 2.4 mm3. All subjects underwent occipital lobe, and cerebellum in normal subjects (Figure structural magnetic resonance imaging (MRI) T1-T2 for For DIPG, the ROI was defined as the hypointense pontine diagnostic purposes. PET characteristics are summarized in lesion on T1 MRI, independent of contrast enhancement.
The ROIs were projected on the PET, and the mean uptake(becquerel per cubic centimeter) was calculated for the en- tire defined ROI. Next, the SUV ratios were calculated by Each patient's T1-weighted MR image was co-registered to dividing the activity (becquerel per cubic centimeter) of the their 18 F-FDG PET using VINCI software (Max Planck pons by the reference regions. Control group reference

Jansen et al. EJNMMI Research 2014, 4:8 Figure 1 Co-registered T1-MR and FDG PET of a control. The ROI was defined on the co-registered T1-MR on sagittal, coronal, and axial slices.
The upper row shows the ROI of the pons, the second row of the occipital lobe, and the third row of the cerebellum. For the occipital lobe, fiveslices were taken as the ROI from the coronal angle. The lower row shows the PET scan after T1-MRI fusion.
regions were the occipital lobe (SUVrpons/occipital = SUVrp/o) are illustrated in histograms and boxplots. To determine and cerebellum (SUVrpons/cerebellum = SUVrp/c). Temporo- whether the observations followed a normal (Gaussian) parietal lobe was excluded as a reference region in this con- distribution, histograms and QQ plots were established.
trol group as FDG uptake may have been affected by The mean, standard deviation, and corresponding confi- epilepsy-induced changes in this region. For DIPG, the dence intervals were calculated accordingly. Based on a maximal SUV ratios (SUVrp(max)/c and SUVrp(max)/o) were Gaussian distribution in both groups, independent- calculated by dividing the hottest pixel of the pons (bec- samples t tests were used to compare the mean SUV ra- querel per cubic centimeter) by the mean uptake of the ref- tios of male versus female subjects. Non-parametric tests erence region (becquerel per cubic centimeter). Finally, (Mann–Whitney U tests) were used to compare the SUV ratios were correlated to post-injection time, age, sex, SUVr of DIPG versus the SUVr of controls. Pearson's and pontine volume (calculated on MRI) in the control correlation test was used to correlate parameters with SPSS 18.0 for Windows was used for statistical analyses.
Baseline characteristics The range and distribution of the SUVrp/c and SUVrp/c Baseline characteristics are summarized in Table Jansen et al. EJNMMI Research 2014, 4:8 Normal pons
Normal pons
Figure 2 Boxplots of SUVrp/c (a) and SUVrp/o (b) for the normal pons versus DIPG. The SUVr deviation between controls is limitedcompared to that between patients with DIPG. The mean SUVrp/c and SUVrp/o are both not significantly higher in DIPG compared to controls. Inthe majority of the DIPG patients, the SUVrp/c and SUVrp/o are less than 1.0. Some patients with DIPG even show SUVr at the lower end of theSUVr of controls.
SUV ratios of the normal pons Pontine SUV ratios in relation to pontine volume, sex, Controls showed consistent SUV ratios of the normal pons: a mean SUVrp/c of 0.65 (±0.054) and a mean The average volume of the normal pons was 10 cm3 SUVrp/o of 0.51 (±0.056). SUVrp/c and SUVrp/o showed (±1.4). The pontine volume linearly increased with age normal Gaussian distributions as confirmed by histo- (regression coefficient 0.17, r = 0.51, p = 0.001; Figure grams and QQ plots (Additional file Figure S1).
There was no significant correlation between SUVrp/o Figure shows the SUV ratios of the normal pons.
(r = 0.18, p = 0.28; Figure and pontine volume nor Pontine volume (ml) controls
Age (years)
Volume (ml)
Age (years)
Figure 3 Correlation between SUVr and pontine volume, sex, and age. Age is significantly correlated with the pontine volume of controls asmeasured on MRI (a). The line shown is the regression curve. The SUVrp/o of controls and DIPG is plotted against pontine volume (b) and age(c). No correlation was found between SUVrp/o and these parameters. This also applies to SUVrp/c (figures not shown).
Jansen et al. EJNMMI Research 2014, 4:8 p/c (r = −0.13, p = 0.45) and pontine volume. Fur- F-FDG uptake in the normal pons versus DIPG thermore, SUV ratios were found to be age independent, The average DIPG volume on MRI was 27 cm3 (±4.1).
with r values of −0.17 (p = 0.324) and 0.18 (p = 0.305) for The mean SUVrp/c in DIPG patients was 0.74 (±0.20), SUVrp/c and SUVrp/o (Figure respectively. We also whereas in controls a SUVrp/c of 0.65 (±0.054) was found no significant difference between male and female found (p = 0.64) (Figure The mean SUVrp/o in DIPG subjects for SUVrp/c (p = 0.86) nor SUVrp/o (p = 0.98).
patients was 0.65 (±0.30), which was 0.51 (±0.056) incontrols (p = 0.37). In only one out of six DIPGs, aSUVrp/o and SUVrp/c ≥1.0 was found. In three patients Pontine FDG SUV ratios as a function of post-injection with increased local 18 F-FDG tumor uptake, the SUVr- max was calculated. The mean SUVrp(max)/o was 1.81 To determine whether uptake time influenced the 18 F- (±0.20) and SUVrp(max)/c was 1.95 (±0.48) which was sig- FDG uptake, we investigated the correlation between the nificantly higher than the mean SUVr of the normal SUV ratios and the post-injection uptake time in the pons (p = 0.042 and p = 0.005).
control group (Figure A modest positive correlationwas found with both SUVrp/c (r = 0.37, p = 0.034) and SUVrp/o (r = 0.43, p = 0.012) and increasing post- In an era where numerous drug trials in DIPG are on- injection time. The regression coefficients were small going or will be initiated shortly, it is essential to develop (0.0011/min and 0.0015/min, respectively).
tools to predict disease evolution and to monitor re-sponse to therapy ]. 18 F-FDG PET has the potentialto be such a tool. However, the interpretation of 18 F-FDG PET results in DIPG is hampered by a lack of dataon normal pontine glucose metabolism in children. Weshow in this study that 18 F-FDG SUV ratios of the nor-mal pons versus those of the cerebellum and occipitallobe are very consistent in between controls, independ-ent of sex, age, and pontine volume, and are thereforesuitable as a reference value for 18 F-FDG PET studies inDIPG. Not only the pons of controls but also the ponsinfiltrated by tumor often showed lower 18 F-FDGuptake than the cerebellum and occipital lobe, aphenomenon that has been reported before More-over, the mean SUVr of DIPG were not significantlyhigher than those of the normal pons, but this is prob-ably due to the small DIPG sample size as the standarddeviations were high. One may therefore question therole of 18 F-FDG PET in DIPG; however, the meanSUVrmax clearly increased in DIPG compared to thenormal pons. Indeed, a recent study showed a significantcorrelation between increased 18 F-FDG tumor uptakeand decreased survival in patients with this disease This correlation might be even stronger when consider-ing that a SUVrp/o in DIPG between 0.5 and 1.0 alreadyreflects increased 18 F-FDG uptake in comparison withthe normal pons. This consideration is not taken into ac-count in studies using semi-quantitative measurementsthat lead to classification as ‘hypo/iso/hypermetabolic'compared to other brain areas [ An explanation for the limited 18 F-FDG uptake in DIPG compared to supratentorial HGG is that DIPGs are hetero- Figure 4 Correlation between SUVr and post-injection (PI) time.
geneous tumors with a mixed histologic tumor grade, as The SUVrp/o (a) and SUVrp/c (b) are plotted against the PI time. Both local uptake of the tracer is related to the presence of ana- SUV ratios slightly increase over time; in other words, the pons plastic features . Calculating the SUVrmax, shows a delayed uptake of 18 F-FDG compared to the cerebellum reflecting the highest local uptake in the tumor, is helpful in and occipital lobe. The line shown is the regression curve.
those tumors with heterogeneous 18 F-FDG uptake. Other Jansen et al. EJNMMI Research 2014, 4:8 explanations of the limited uptake are the frequently ob- way, the sensitivity and applicability of 18 F-FDG PET as a served integrity of the blood–brain barrier in DIPG and the predictive and response monitoring tool for patients with presence of white matter in the pontine region, which has DIPG can be increased.
low glucose metabolism We further investigated whether the time between injec- tion and PET scanning had an influence on the 18 F-FDG We established a reference SUVr for 18 F-FDG uptake in uptake in the pons of controls compared to other brain the normal pons. SUV ratios are very consistent in between areas. Indeed, SUVrp/c and SUVrp/o were positively corre- controls and independent of pontine volume, sex, or age.
lated with increasing post-injection time. This suggests a Not only was the 18 F-FDG uptake in the normal pons low delayed uptake of this tracer in the pons compared to the compared to that in the reference brain areas, but also the cerebellum and occipital lobe. However, the SUVr regres- uptake in DIPG was often lower than that in the occipital sion coefficients were small, and therefore, the influence of and cerebellar tissues. We encourage a study in controls to the uptake interval in clinical practice is negligible.
validate our results and propose that future 18 F-FDG PET The main advantage of SUV ratios is that the possible er- trials in DIPG calculate SUV and SUV(max) ratios in order rors in the measurement of weight or transcription and to relate these to the here reported mean SUV ratios of the dose administered are minimized by the ratio between the normal pons. Smaller changes in the tumor's glucose me- two SUV measurements [. This applies especially for tabolism can be detected in this way, which may have prog- pediatric cancer, with low patient numbers and therefore nostic relevance for the patient.
often multi-national multi-center trials. In this study, weshowed that SUV ratios of the normal pons are independ- ent of sex, pontine volume, and age, although we had anunder-representation of the youngest children (<5 years) in SUVrp/c and SUVrp/o distributions in the control group. Although SUV ratios may give useful in- normal controls. Normal Gaussian distributions of both SUVrs are formation in serial measurements, they have their limita- presented in histograms (a, d) and boxplots (b, e). The Gaussiandistribution was confirmed by QQ plots (c, f).
tions. In situations in which the 18 F-FDG uptake of thereference tissue varies, changes in SUV ratios can be mis- Competing interests leading. For example, this may be the case when patients The authors declare that they have no competing interests.
use steroids, which influence the glucose metabolism of thebrain A methodological issue in this study was the use Authors' contributions of epilepsy patients as controls, as 18 F-FDG PET data of MJ, RK, OH, RB, DV, GK, and WV contributed to the concept and studydesign. MJ, RK, OH, EC, SG, and SV collected the data. MJ and BW performed healthy children could not be obtained due to ethical rea- the statistical analysis. MJ, RK, OH, RB, GK, and BW were involved in the sons regarding radiation exposure. We, however, do not ex- interpretation of the data. All authors were involved in the writing process pect significant changes in glucose metabolism of the pons and all approved the manuscript before submission.
due to epilepsy as all our subjects were in an inter-ictal state, which is not associated with changed glucose DIPG research is funded by the Semmy and Egbers foundations. The metabolism Furthermore, several anti-epileptic drugs sponsors had no role in the preparation and execution of the study and/or including phenobarbital, phenytoin, benzodiazepines, and valproic acid have been associated with hypometabolism of the brain and especially the cerebellum and may therefore 1Division of Oncology and Hematology, Department of Pediatrics, VU overestimate the SUVr University Medical Center, De Boelelaan 1118, Amsterdam 1007 MB, the p/c. Of these drugs, only valproic acid Netherlands. 2Department of Radiology and Nuclear Medicine, VU University and clobazam were used in this study by, respectively, 3 Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands.
and 4 out of 37 controls The lack of variance in be- 3Neuro-oncology Research Group, Cancer Center Amsterdam, De Boelelaan tween controls of both SUVr 1117, Amsterdam 1081 HV, the Netherlands. 4Department of Epidemiology p/c and SUVrp/o presumes that and Biostatistics, VU University Medical Center, De Boelelaan 1118, the use of anti-epileptic drugs has not influenced our re- Amsterdam 1081 HV, the Netherlands. 5Department of Nuclear Medicine, U.L.
sults significantly. In addition, the use of the cerebellum as B.-Hôpital Erasme Brussels, 808 route de Lennik, Brussels 1070, Belgium.
6 a reference in epileptic patients in 18 F-FDG PET studies is Neurosurgical Center Amsterdam, VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands.
Future 18 F-FDG PET studies in DIPG may now compare Received: 20 September 2013 Accepted: 14 January 2014 SUVr and SUVrmax in DIPG to the here reported mean Published: 28 January 2014 SUV ratios of the normal pons. By comparing SUV ratios to the normal pons, smaller increases in glucose metabol- Di CG, Oldfield E, Bairamian D, Patronas NJ, Brooks RA, Mansi L, Smith BH, ism can be detected in comparison with semi-quantitative Kornblith PL, Margolin R: Metabolic imaging of the brain stem and spinalcord: studies with positron emission tomography using 18 F-2- measurements, as DIPGs often show lower glucose metab- deoxyglucose in normal and pathological cases. J Comput Assist Tomogr olism than the reference brain tissue (occipital lobe). In this 1983, 7:937–945.
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Gender differences and the medicalization of sexuality in the creation of sexual dysfunctions diagnosis CLAM. 2013. Sexuality, Culture and Politics - A South American Reader. Pp. 620-638. ISBN 978-85-89737-82-1 Sexuality, culture and politics A South American reader Although mature and vibrant, Latin American scholarship on sexuality still remains largely invisible to a global readership. In this collection of articles translated from Portuguese and Spanish, South American scholars explore the values, practices, knowledge, moralities and politics of sexuality in a variety of local contexts. While conventionally read as an intellectual legacy of Modernity, Latin American social thinking and research has in fact brought singular forms of engagement with, and new ways of looking at, political processes. Contributors to this reader have produced fresh and situated understandings of the relations between gender, sexuality, culture and society across the region. Topics in this volume include sexual politics and rights, sexual identities and communities, eroticism, pornography and sexual consumerism, sexual health and well-being, intersectional approaches to sexual cultures and behavior, sexual knowledge, and sexuality research methodologies in Latin America.