Cyrill Burger

Radiation treatment planning with an integrated positron emission and computer tomography (PET/CT): A feasibility study

PURPOSE To investigate the usefulness of hardware coregistered PET/CT images for target volume definition. METHODS AND MATERIALS Thirty-nine patients presenting with various solid tumors were investigated. CT and a FDG-PET were obtained in treatment position in an integrated PET/CT scanner, and coregistered images were used for treatment planning. First, volume delineation was performed on the CT data. In a second step, the corresponding PET data were used as an overlay to the CT data to define the target volume. Delineation was done independently by two investigators. RESULTS Coregistered PET/CT showed good fusion accuracy. The GTV increased by 25% or more because of PET in 17% of cases with head-and-neck (2/12) and lung cancer (1/6), and in 33% (7/21) in cancer of the pelvis. The GTV was reduced > or =25% in 33% of patients with head-and-neck cancer (4/12), in 67% with lung cancer (4/6), and 19% with cancer of the pelvis (4/21). Overall, in 56% (22/39) of cases, GTV delineation was changed significantly if information from metabolic imaging was used in the planning process. The modification of the GTV translated into altered PTV changes exceeding >20% in 46% (18/39) of cases. With PET, volume delineation variability between two independent oncologists decreased from a mean volume difference of 25.7 cm(3) to 9.2 cm(3) associated with a reduction of the standard deviation from 38.3 cm(3) to 13.3 cm(3) (p = 0.02). In 16% of cases, PET/CT revealed distant metastasies, changing the treatment strategy from curative to palliative. CONCLUSION Integrated PET/CT for treatment planning for three-dimensional conformal radiation therapy improves the standardization of volume delineation compared with that of CT alone. PET/CT has the potential for reducing the risk for geographic misses, to minimize the dose of ionizing radiation applied to non-target organs, and to change the current practice to three-dimensional conformal radiation therapy planning by taking into account the metabolic and biologic features of cancer. The impact on treatment outcome remains to be demonstrated.

Reduced Metabotropic Glutamate Receptor 5 Density in Major Depression Determined by [11C]ABP688 PET and Postmortem Study

OBJECTIVE Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects. METHOD Images of mGluR5 receptor binding were acquired using PET with [(11)C]ABP688, which binds to an allosteric site with high specificity, in 11 unmedicated individuals with major depression and 11 matched healthy comparison subjects. The amount of mGluR5 protein was investigated using Western blot in postmortem brain samples of 15 depressed individuals and 15 matched comparison subjects. RESULTS The PET study revealed lower levels of regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus, and the hippocampus in the depression group relative to the comparison group. Severity of depression was negatively correlated with mGluR5 binding in the hippocampus. The postmortem study showed lower levels of mGluR5 protein expression in the prefrontal cortex (Brodmanns area 10) in the depression group relative to the comparison group, while prefrontal mGluR1 protein expression did not differ between groups. CONCLUSIONS The lower levels of mGluR5 binding observed in the depression group are consonant with the lower levels of protein expression in brain tissue in the postmortem depression group. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression.

Absolute quantification of cerebral blood flow with magnetic resonance, reproducibility of the method, and comparison with H215O positron emission tomography

While H215O positron emission tomography (PET) is still the gold standard in the quantitative assessment of cerebral perfusion (rCBF), its technical challenge, limited availability, and radiation exposure are disadvantages of the method. Recent work demonstrated the feasibility of magnetic resonance (MR) for quantitative cerebral perfusion imaging. There remain open questions, however, especially regarding reproducibility. The main purpose of this study was to assess the accuracy and reproducibility of MR-derived flow values to those derived from H215O PET. Positron emission tomography and MR perfusion imaging was performed in 20 healthy male volunteers, who were chronic smokers, on day 1 and day 3 of a 4-day hospitalization. Subjects were randomly assigned to one of two groups, each with 10 subjects. One group was allowed to smoke as usual during the hospitalization, while the other group stopped smoking from day 2. Positron emission tomography and MR images were coregistered and rCBF was determined in two regions of interest, defined over gray matter (gm) and white matter (wm), yielding rCBFPETgm, rCBFMRgm, rCBFPETwm, and rCBFMRwm. Bland-Altman analysis was used to investigate reproducibility by assessing the difference rCBFday3 - rCBFday1 in eight continual-smoker volunteers. The analysis showed a good reproducibility for PET, but not for MR. Mean ± SD of the difference rCBFday3 - rCBFday1 in gray matter was 6.35 ± 21.06 and 0.49 ± 5.27 mL · min−1 · 100 g−1 for MR and PET, respectively; the corresponding values in white matter were 2.60 ± 15.64 and −1.14 ± 4.16 mL · min−1 · 100 g−1. The Bland-Altman analysis was also used to assess MRI and PET agreement comparing rCBF measured on day 1. The analysis demonstrated a reasonably good agreement of MR and PET in white matter (rCBFPETwm - rCBFMRwm; −0.09 ± 7.23 mL · min−1 · 100 g−1), while in gray matter a reasonable agreement was only achieved after removing vascular artifacts in the MR perfusion maps (rCBFPETgm - rCBFMRgm; −11.73 ± 14.52 mL · min−1 · 100 g−1). In line with prior work, these results demonstrate that reproducibility was overall considerably better for PET than for MR. Until reproducibility is improved and vascular artifacts are efficiently removed, MR is not suitable for reliable quantitative perfusion measurements.

Optical imaging of the spatiotemporal dynamics of cerebral blood flow and oxidative metabolism in the rat barrel cortex

Oxidative metabolism and cerebral blood flow (CBF) are two of the most important measures in neuroimaging. However, results from concurrent imaging of the two with high spatial and temporal resolution have never been published. We used flavoprotein autofluorescence (AF) and laser speckle imaging (LSI) in the anaesthetized rat to map oxidative metabolism and CBF in response to single vibrissa stimulation. Autofluorescence responses reflecting oxidative metabolism demonstrated a fast increase with a delay of 0.1 s. The sign‐reversed speckle contrast reflecting CBF started to rise with a delay of 0.6 s and reached its maximum 1.4 s after the stimulation offset. The fractional signal changes were 2.0% in AF and 9.7% in LSI. Pixelwise modelling revealed that CBF maps spread over an area up to 2.5‐times larger than metabolic maps. The results provide evidence that the increase in cerebral oxidative metabolism in response to sensory stimulation is considerably faster and more localized than the CBF response. This suggests that future developments in functional imaging concentrating on the metabolic response promise an increased spatial resolution.

Use of coronary calcium score scans from stand-alone multislice computed tomography for attenuation correction of myocardial perfusion SPECT

PurposeTo evaluate the use of CT attenuation maps, generated from coronary calcium scoring (CCS) scans at in- and expiration with a 64-slice CT scanner, for attenuation correction (AC) of myocardial perfusion SPECT images.MethodsThirty-two consecutive patients underwent 99mTc-tetrofosmin gated adenosine stress/rest SPECT scan on an Infinia Hawkeye SPECT-CT device (GE Medical Systems) followed by CCS and CT angiography on a 64-slice CT. AC of the iteratively reconstructed images was performed with AC maps obtained: (a) from the “Hawkeye” low-resolution X-ray CT facility attached to the Infinia camera (IRAC); (b) from the CCS scan acquired on a 64-slice CT scanner during maximal inspiration (ACINSP) and (c) during normal expiration (ACEXP). Automatically determined uptake values of stress scans (QPS, Cedars Medical Sinai) from ACINSP and ACEXP were compared with IRAC. Agatston score (AS) values using ACINSPversus ACEXP were also compared.ResultsACINSP and ACEXP resulted in identical findings versus IRAC by visual analysis. A good correlation for uptake values between IRAC and ACINSP was found (apex, r=0.92; anterior, r=0.85; septal, r=0.91; lateral, r=0.86; inferior, r=0.90; all p<0.0001). The correlation was even closer between IRAC and ACEXP (apex, r=0.97; anterior, r=0.91; septal, r=0.94; lateral, r=0.92; inferior, r=0.97; all p<0.0001). The mean AS during inspiration (319±737) and expiration(317±778) was comparable (p=NS).ConclusionAttenuation maps from CCS allow accurate AC of SPECT MPI images. ACEXP proved superior to ACINSP, suggesting that in hybrid scans CCS may be performed during normal expiration to allow its additional use for AC of SPECT MPI.

Characterization of Focal Bone Lesions in the Axial Skeleton: Performance of Planar Bone Scintigraphy Compared with SPECT and SPECT Fused with CT

OBJECTIVE The purpose of this study was to evaluate the diagnostic performance of planar 99mTc methylene diphosphonate bone scintigraphy compared with SPECT and SPECT fused with CT in patients with focal bone lesions of the axial skeleton. SUBJECTS AND METHODS Thirty-seven patients with 42 focal lesions of the axial skeleton were included in this prospective study. All patients underwent planar scintigraphy, SPECT through the focal lesions, and SPECT-guided CT. SPECT and CT images then were fused digitally. The three types of images were evaluated separately from one another by two experienced reviewers working to consensus. Visibility of the lesions, diagnostic performance, and certainty in diagnosis were evaluated. Performance for specific diagnoses also was evaluated. Histologic, MRI, and clinical follow-up findings were used as the reference standard. RESULTS Visibility of the lesions was significantly better with SPECT than with planar scintigraphy (p < 0.0001). Sensitivity and specificity for differentiation of benign and malignant bone lesions were 82% and 94% for planar scintigraphy, 91% and 94% for SPECT, and 100% and 100% for SPECT fused with CT. Differences between the three methods of differentiating benign and malignant lesions did not reach statistical significance. Certainty in diagnosis was significantly higher for SPECT fused with CT than for planar scintigraphy (p = 0.004) and SPECT (p = 0.004). A specific diagnosis was made with planar scintigraphy in 64% of cases, with SPECT in 86%, and with SPECT fused with CT in all cases. CONCLUSION Planar scintigraphy may suffice for differentiating benign and malignant lesions of the axial skeleton, but SPECT fused with CT significantly increases certainty in diagnosis and is the best tool for making a specific diagnosis.

Changes of Cerebral Blood Flow during Short-Term Exposure to Normobaric Hypoxia

Decreased arterial partial oxygen pressure (PaO2) below a certain level presents a strong stimulus for increasing cerebral blood flow. Although several field studies examined the time course of global cerebral blood flow (gCBF) changes during hypoxia at high altitude, little was known about the regional differences in the flow pattern. Positron emission tomography (PET) with [15O]H2O was used on eight healthy volunteers to assess regional cerebral blood flow (rCBF) during short-term exposure to hypoxia corresponding to simulated altitudes of 3,000 and 4,500 m. Scans at the simulated altitudes were preceded and followed by baseline scans at the altitude of Zurich (450 m, baseline-1 and baseline-2). Each altitude stage lasted 20 minutes. From baseline to 4,500 m, gCBF increased from 34.4 ± 5.9 to 41.6 ± 9.0 mL · minute−1 · 100 g−1 (mean ± SD), whereas no significant change was noted at 3,000 m. During baseline-2 the flow values returned to those of baseline-1. Statistical parametric mapping identified the hypothalamus as the only region with excessively increased blood flow at 4,500 m (+32.8% ± 21.9% relative to baseline-1). The corresponding value for the thalamus, the structure with the second largest increase, was 19.2% ± 16.3%. Compared with the rest of the brain, an excessive increase of blood flow during acute exposure to hypoxia is found in the hypothalamus. The functional implications are at present unclear. Further studies of this finding should elucidate its meaning and especially focus on a potential association with the symptoms of acute mountain sickness.

Evaluation of Serotonergic Transporters using PET and [11C](+)McN-5652: Assessment of Methods

[11C](+)McN-5652 is an established positron emission tomography tracer used to assess serotonergic transporter density. Several methods have been used to analyze [11C](+)McN-5652 data; however, no evaluation of candidate methods has been published in detail yet. In this study, compartmental modeling using a one-tissue compartment model (K1, k″2), a two-tissue compartment model (K1 to k4), and a noncompartmental method that relies on a reference region devoid of specific binding sites were assessed. Because of its low density of serotonergic transporters, white matter was chosen as reference. Parameters related to transporter density were the total distribution volume DV″ (=K1/k″2, one tissue compartment), DVtot (=K1/k′1 (1 + k3/k4), two tissue compartments), and Rv (=k′3/k4, noncompartmental method). The DV″, DVtot, and Rv values extended over a similar range and reflected the known pattern of serotonergic transporters. However, all parameters related to transporter density were markedly confounded by nonspecific binding. With regard to K1, the one-tissue compartment model yielded markedly lower values, which were, however, more stable. The minimal study duration needed to determine stable values for the distribution volume was ∼60 minutes. The choice of the method to analyze [11C](+)McN-5652 data depends on the situation. Parametric maps of Rv are useful if no information on K1 is needed. If compartmental modeling is chosen, both the one- and the two-tissue compartment models have advantages. The one-tissue compartment model underestimates K1 but yields more robust values. The distribution volumes calculated with both models contain a similar amount of information. None of the parameters reflected serotonergic transporter density in a true quantitative manner, as all were confounded by nonspecific binding.

Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography

Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [11C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.

PET with 18fluorodeoxyglucose and hexamethylpropylene amine oxime SPECT in late whiplash syndrome

Background: Many patients have cognitive abnormalities and psychological problems after whiplash injury to the cervical spine. To our knowledge, neuroradiologic imaging has not depicted brain damage that explains the symptoms. Parietotemporo-occipital perfusion deficits on hexamethylpropylene amine oxime (HMPAO) SPECT studies have been described among patients who have sustained whiplash injury. Methods: We examined 13 patients with typical late whiplash syndrome (study group) using HMPAO SPECT, 18fluorodeoxyglucose (FDG) PET, and MRI of the brain and compared the findings with those for 16 control subjects who underwent FDG PET. Results: In the study group, statistical parametric mapping revealed significantly decreased FDG uptake in the frontopolar and lateral temporal cortex and in the putamen. The frontopolar hypometabolism correlated significantly with scores of the Beck Depression Inventory. However, in individual cases, reliability in the depiction of hypometabolic areas was relatively low. No alterations were found in the parietotemporo-occipital area. In these areas, decreased uptake of HMPAO and FDG correlated with cortical mass. Conclusion: FDG PET did not allow reliable diagnosis of metabolic disturbances for individual patients. Therefore, we do not recommend FDG PET or HMPAO SPECT as a diagnostic tool in routine examinations of patients with late whiplash syndrome.