Christian la Fougère

Real versus imagined locomotion: A [18F]-FDG PET-fMRI comparison

The cortical, cerebellar and brainstem BOLD-signal changes have been identified with fMRI in humans during mental imagery of walking. In this study the whole brain activation and deactivation pattern during real locomotion was investigated by [(18)F]-FDG-PET and compared to BOLD-signal changes during imagined locomotion in the same subjects using fMRI. Sixteen healthy subjects were scanned at locomotion and rest with [(18)F]-FDG-PET. In the locomotion paradigm subjects walked at constant velocity for 10 min. Then [(18)F]-FDG was injected intravenously while subjects continued walking for another 10 min. For comparison fMRI was performed in the same subjects during imagined walking. During real and imagined locomotion a basic locomotion network including activations in the frontal cortex, cerebellum, pontomesencephalic tegmentum, parahippocampal, fusiform and occipital gyri, and deactivations in the multisensory vestibular cortices (esp. superior temporal gyrus, inferior parietal lobule) was shown. As a difference, the primary motor and somatosensory cortices were activated during real locomotion as distinct to the supplementary motor cortex and basal ganglia during imagined locomotion. Activations of the brainstem locomotor centers were more prominent in imagined locomotion. In conclusion, basic activation and deactivation patterns of real locomotion correspond to that of imagined locomotion. The differences may be due to distinct patterns of locomotion tested. Contrary to constant velocity real locomotion (10 min) in [(18)F]-FDG-PET, mental imagery of locomotion over repeated 20-s periods includes gait initiation and velocity changes. Real steady-state locomotion seems to use a direct pathway via the primary motor cortex, whereas imagined modulatory locomotion an indirect pathway via a supplementary motor cortex and basal ganglia loop.

The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder.

There is evidence that abnormalities within the dopamine system in the brain play a major role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). For instance, dopaminergic psychostimulants, the drugs of first choice in ADHD, interact directly with the dopamine transporter (DAT). Molecular genetic studies suggest involvement of a polymorphism of the DAT gene in ADHD. More recent imaging studies show abnormalities in various brain structures, but particularly in striatal regions. In the current paper we review recent studies in this area. First in vivo measurements of DAT with single photon emission computed tomography (SPECT) in ADHD patients revealed an elevation of striatal DAT density. No differences in DAT density between the left and right side and between putamen and caudate nucleus have been found in [99mTc]TRODAT-1 SPECT of ADHD patients. Patients with ADHD and with a history of nicotine abuse both displayed lower values of DAT density in [99mTc]TRODAT-1 SPECT than non-smokers with ADHD. DAT seem to be elevated in non-smoking ADHD patients suffering from the purely inattentive subtype of ADHD as well as in those with the combined or purely hyperactive/impulsive subtype.

Hepatic Yttrium-90 Radioembolization of Chemotherapy-refractory Colorectal Cancer Liver Metastases

PURPOSE To present data for radioembolization with yttrium-90 ((90)Y) resin microspheres in patients with colorectal cancer liver metastases in whom currently available therapies had failed. MATERIALS AND METHODS Retrospective review was conducted of case files of patients with colorectal cancer liver metastases in whom chemotherapy had failed, prompting hepatic (90)Y radioembolization administered as a single-session, whole-liver treatment. Imaging and laboratory follow-up results were available for 36 patients. Response and toxicity were assessed by computed tomography/magnetic resonance imaging with the Response Evaluation Criteria in Solid Tumors and the National Cancer Institutes Common Terminology Criteria for Adverse Events, version 3.0. RESULTS Forty-one patients (mean age, 61 years; 30 men) received hepatic (90)Y radioembolization with resin microspheres (mean activity, 1.9 GBq). At a median interval of 2.9 months after radioembolization, partial response, stable disease, and progressive disease were demonstrated in seven, 25, and four patients, respectively. Median overall survival was 10.5 months, with improved survival for patients with a decrease in carcinoembryonic antigen level (19.1 months vs 5.4 months) and imaging response (29.3 months vs 4.3 months; P = .0001). Except for one instance of treatment-associated cholecystitis (grade 4 toxicity) and two gastric ulcers (grade 2 toxicity), no severe toxicities were observed. CONCLUSIONS Hepatic (90)Y radioembolization can be performed with manageable toxicity in patients with colorectal cancer liver metastases whose disease is refractory to chemotherapy. The antitumoral effect is supported by imaging and tumor marker responses. Further investigation is warranted to determine the optimal use of this emerging therapeutic modality.

Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas.

This guideline provides recommendations for the use of PET imaging in gliomas. The review examines established clinical benefit in glioma patients of PET using glucose ((18)F-FDG) and amino acid tracers ((11)C-MET, (18)F-FET, and (18)F-FDOPA). An increasing number of studies have been published on PET imaging in the setting of diagnosis, biopsy, and resection as well radiotherapy planning, treatment monitoring, and response assessment. Recommendations are based on evidence generated from studies which validated PET findings by histology or clinical course. This guideline emphasizes the clinical value of PET imaging with superiority of amino acid PET over glucose PET and provides a framework for the use of PET to assist in the management of patients with gliomas.

In Vivo Imaging of Macrophage Activity in the Coronary Arteries Using 68Ga-DOTATATE PET/CT: Correlation with Coronary Calcium Burden and Risk Factors

We measured the uptake of the somatostatin receptor ligand 68Ga-[1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) in the left anterior descending coronary artery (LAD) in association with calcified plaques (CPs) and cardiovascular risk factors. Methods: Seventy consecutive tumor patients were examined by whole-body 68Ga-DOTATATE contrast-enhanced PET/CT. Blood-pool–corrected standardized uptake value (target-to-background ratio) was measured in the LAD, and CT images were used to detect CP. Cardiovascular risk factors and history of prior cardiovascular events were recorded. Results: 68Ga-DOTATATE uptake was detectable in the LAD of all patients. Target-to-background ratio in the LAD correlated significantly with the presence of CP (R = 0.34; P < 0.01), prior vascular events (R = 0.26; P < 0.05), and male sex (R = 0.29; P < 0.05), whereas CP correlated with these parameters but also with age (R = 0.34; P < 0.01) and hypertension (R = 0.25; P < 0.05). Conclusion: In a series of oncologic patients, those with prior cardiovascular events and calcified atherosclerotic plaques showed significantly increased 68Ga-DOTATATE uptake in the LAD, suggesting a potential role of this tracer for plaque imaging in the coronary arteries.

[18F]-fluoro-ethyl-l-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma

BACKGROUND To assess the sensitivity and specificity of [(18)F]-fluoro-ethyl-l-tyrosine ((18)F-FET) PET in brain tumors and various non-neoplastic neurologic diseases. METHODS We retrospectively evaluated (18)F-FET PET scans from 393 patients grouped into 6 disease categories according to histology (n = 299) or distinct MRI findings (n = 94) (low-grade/high-grade glial/nonglial brain tumors, inflammatory lesions, and other lesions). (18)F-FET PET was visually assessed as positive or negative. Maximum lesion-to-brain ratios (LBRs) were calculated and compared with MRI contrast enhancement (CE), which was graded visually on a 3-point scale (no/moderate/intense). RESULTS Sensitivity and specificity for the detection of brain tumor were 87% and 68%, respectively. Significant differences in LBRs were detected between high-grade brain tumors (LBR, 2.04 ± 0.72) and low-grade brain tumors (LBR, 1.52 ± 0.70; P < .001), as well as among inflammatory (LBR, 1.66 ± 0.33; P = .056) and other brain lesions (LBR, 1.10 ± 0.37; P < .001). Gliomas (n = 236) showed (18)F-FET uptake in 80% of World Health Organization (WHO) grade I, 79% of grade II, 92% of grade III, and 100% of grade IV tumors. Low-grade oligodendrogliomas, WHO grade II, had significantly higher (18)F-FET uptakes than astrocytomas grades II and III (P = .018 and P = .015, respectively). (18)F-FET uptake showed a strong association with CE on MRI (P < .001) and was also positive in 52% of 157 nonglial brain tumors and nonneoplastic brain lesions. CONCLUSIONS (18)F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood-brain barrier and (18)F-FET uptake in nonneoplastic brain lesions. Gliomas show specific tracer uptake in the absence of CE on MRI, which most likely reflects biologically active tumor.

Irradiation and Bevacizumab in High-Grade Glioma Retreatment Settings

PURPOSE Reirradiation is a treatment option for recurrent high-grade glioma with proven but limited effectiveness. Therapies directed against vascular endothelial growth factor have been shown to exert certain efficacy in combination with chemotherapy and have been safely tested in combination with radiotherapy in a small cohort of patients. To study the feasibility of reirradiation combined with bevacizumab treatment, the toxicity and treatment outcomes of this approach were analyzed retrospectively. PATIENTS AND METHODS After previous treatment with standard radiotherapy (with or without temozolomide) patients with recurrent malignant glioma received bevacizumab (10 mg/kg intravenous) on Day 1 and Day 15 during radiotherapy. Maintenance therapy was selected based on individual considerations, and mainly bevacizumab-containing regimens were chosen. Patients received 36 Gy in 18 fractions. RESULTS The data of the medical charts of the 30 patients were analyzed retrospectively. All were irradiated in a single institution and received either bevacizumab (n = 20), no additional substance (n = 7), or temozolomide (n = 3). Reirradiation was tolerated well, regardless of the added drug. In 1 patient treated with bevacizumab, a wound dehiscence occurred. Overall survival was significantly better in patients receiving bevacizumab (p = 0.03, log-rank test). In a multivariate proportional hazards Cox model, bevacizumab, Karnovsky performance status, and World Health Organization grade at relapse turned out to be the most important predictors for overall survival. CONCLUSION Reirradiation with bevacizumab is a feasible and effective treatment for patients with recurrent high-grade gliomas. A randomized trial is warranted to finally answer the question whether bevacizumab adds substantial benefit to a radiotherapeutic retreatment setting.

FET-PET for malignant glioma treatment planning.

BACKGROUND AND PURPOSE The aim of this study was to compare MRI-based morphological gross tumour volumes (GTVs) to biological tumour volumes (BTVs), defined by the pathological radiotracer uptake in positron emission tomography (PET) imaging with (18)F-fluoroethyltyrosine (FET), subsequently clinical target volumes (CTVs) and finally planning target volumes (PTVs) for radiotherapy planning of glioblastoma. PATIENTS AND METHODS Seventeen patients with glioblastoma were included into a retrospective protocol. Treatment-planning was performed using clinical target volume (CTV=BTV+20mm or CTV=GTV+20mm+inclusion of the edema) and planning target volume (PTV=CTV+5mm). Image fusion and target volume delineation were performed with OTP-Masterplan®. Initial gross tumour volume (GTV) definition was based on MRI data only or FET-PET data only (BTV), secondarily both data sets were used to define a common CTV. RESULTS FET based BTVs (median 43.9 cm(3)) were larger than corresponding GTVs (median 34.1cm(3), p=0.028), in 11 of 17 cases there were major differences between GTV/BTV. To evaluate the conformity of both planning methods, the index (CTV(MRT)∩CTV(FET))/(CTV(MRT)∪CTV(FET)) was quantified which was significantly different from 1 (0.73 ± 0.03, p<0.001). CONCLUSION With FET-PET-CT planning, the size and geometrical location of GTVs/BTVs differed in a majority of patients. It remains open whether FET-PET-based target definition has a relevant clinical impact for treatment planning.

Radioembolization in Patients with Hepatic Metastases from Breast Cancer

PURPOSE To determine the safety of and survival outcomes associated with single-session, whole-liver radioembolization with Yttrium-90 (90Y)-labelled resin microspheres in patients with nonresectable liver metastases from breast cancer that were refractory to other treatments. MATERIALS AND METHODS Thirty patients underwent radioembolization with 90Y-labeled resin microspheres infusion in a single-session, whole-liver treatment. All patients had undergone polychemotherapy regimens including at least anthracyclines and taxanes, hormonal therapy, and trastuzumab where applicable. Follow-up data were available for 23 patients. After treatment, the authors assessed tumor response with computed tomography and/or magnetic resonance imaging by using Response Evaluation Criteria in Solid Tumors (RECIST), laboratory and clinical toxicities, and survival. RESULTS A mean activity of 1.9 GBq of 90Y was delivered. Follow-up at a median of 4.2 months demonstrated partial response, stable disease, and progressive disease in 61%, 35%, and 4% of patients, respectively. With respect to tumor diameters, imaging revealed a maximum and minimum response of -64.8% to +23.6%, respectively (mean, 29.2%; median, 39.7%). The median follow-up time was 14.2 months. The median overall survival was 11.7 months. The median survival of responders and nonresponders was 23.6 and 5.7 months, respectively, and the median survival of patients with and patients without extrahepatic disease was 9.6 and 16 months. Clinically significant toxicities with the appearance of increasing transaminase level, increasing bilirubin level, nausea and vomiting, gastric ulcers, and ascites occurred in eight of 30 patients. One patients death was attributed to treatment-related hepatic toxicity. CONCLUSIONS Single-session, whole-liver 90Y radioembolization can be performed with an acceptable toxicity profile in patients with liver metastases from breast cancer. Response to radioembolization in these patients is supported by the decrease in tumor size. Further investigation is warranted to prove survival benefit.

Prognostic Significance of Dynamic 18F-FET-PET in Newly Diagnosed Astrocytic High Grade Glioma

Despite advances in diagnosis and the use of different therapeutic regimens in astrocytic high-grade glioma (HGG), the prognosis for patients remains grim. Additional pretherapeutic information is needed to tailor management. To gain additional prognostic information at primary diagnosis, we investigated the value of dynamic O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET. Methods: We retrospectively evaluated 121 patients who had a primary diagnosis of astrocytic HGG (51 World Health Organization [WHO] grade III; 70 WHO IV) and underwent dynamic 18F-FET PET before histopathologic assessment. We assessed static parameters (maximal and mean tumoral standardized uptake value corrected for mean background activity in the contralateral hemisphere [SUVmax/BG and SUVmean/BG, respectively], biologic tumor volume) and dynamic time–activity curves, including minimal time to peak (TTPmin). The prognostic influence of PET parameters and other clinical parameters on progression-free and overall survival was evaluated using uni- and multivariate Cox regression and Kaplan–Meier survival estimates. Results: In the group overall, median progression-free survival and overall survival were 12.2 and 21.9 mo. SUVmax/BG, SUVmean/BG, and biologic tumor volume were significantly higher in WHO IV than in WHO III gliomas; median TTPmin was 12.5 min in both groups. On univariate analysis, the factors age, WHO grade, O6-methylguanine-DNA methyltransferase promoter methylation status, contrast enhancement, initial treatment, and TTPmin showed prognostic significance, with WHO grade, O6-methylguanine-DNA methyltransferase status, age, and TTPmin remaining significant in the multivariate analysis. WHO grade and TTPmin reached a similar fit for the prognostic evaluation. The prognosis of WHO III astrocytoma with an early TTPmin of 12.5 min or less did not differ significantly from that of glioblastoma. Conclusion: Early TTPmin is associated with worse outcome in patients with newly diagnosed astrocytic HGG. In the preoperative setting, TTPmin can be a valuable noninvasive prognostic marker with comparable significance to WHO grade. Additionally, TTPmin can help identify highly aggressive WHO III astrocytoma tumors and may help in adjusting standard treatment toward an individualized, risk-adapted therapy regime.