Gabriele Stoffels

Comparison of 18 F-FET PET and 5-ALA fluorescence in cerebral gliomas

PurposeThe aim of the study was to compare presurgical 18F-fluoroethyl-L-tyrosine (18F-FET) uptake and Gd-diethylenetriaminepentaacetic acid (DTPA) enhancement on MRI (Gd) with intraoperative 5-aminolevulinic acid (5-ALA) fluorescence in cerebral gliomas.Methods18F-FET positron emission tomography (PET) was performed in 30 patients with brain lesions suggestive of diffuse WHO grade II or III gliomas on MRI. PET and MRI data were coregistered to guide neuronavigated biopsies before resection. After oral application of 5-ALA, 38 neuronavigated biopsies were taken from predefined tumour areas that were positive or negative for 18F-FET or Gd and checked for 5-ALA fluorescence. 18F-FET uptake with a mean tumour to brain ratio ≥1.6 was rated as positive.ResultsOf 38 biopsies, 21 corresponded to high-grade glioma tissue (HGG) of WHO grade III (n = 19) or IV (n = 2) and 17 biopsies to low-grade glioma tissue (LGG) of WHO grade II. In biopsies corresponding to HGG, 18F-FET PET was positive in 86% (18/21), but 5-ALA and Gd in only 57% (12/21). A mismatch between Gd and 5-ALA was observed in 6 of 21 cases of HGG biopsy samples (3 Gd-positive/5-ALA-negative and 3 Gd-negative/5-ALA-positive). In biopsies corresponding to LGG, 18F-FET was positive in 41% (7/17), while 5-ALA and Gd were negative in all but one instance. All tumour areas with 5-ALA fluorescence were positive on 18F-FET PET.ConclusionThere are differences between 18F-FET and 5-ALA uptake in cerebral gliomas owing to a limited sensitivity of 5-ALA to detect tumour tissue especially in LGG. 18F-FET PET is more sensitive to detect glioma tissue than 5-ALA fluorescence and should be considered as an additional tool in resection planning.

Prognostic Value of O-(2-18F-Fluoroethyl)-l-Tyrosine PET and MRI in Low-Grade Glioma

In glioma of World Health Organization (WHO) grade II (low-grade glioma), the natural course of a particular patient is not predictable and the treatment strategy is controversial. We determined prognostic factors in adult patients with untreated, nonenhancing, supratentorial low-grade glioma with special regard to PET using the amino acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) and MRI. Methods: In a prospective study, baseline 18F-FET PET and MRI analyses were performed on 33 consecutive patients with histologically confirmed low-grade glioma. None of the patients had radiation or chemotherapy. Clinical, histologic, therapeutic (initial cytoreduction vs. biopsy), 18F-FET uptake, and MRI morphologic parameters were analyzed for their prognostic significance. Statistical endpoints were clinical or radiologic tumor progression, malignant transformation to glioma of WHO grade III or IV (high-grade glioma), and death. Results: Baseline 18F-FET uptake and a diffuse versus circumscribed tumor pattern on MRI were highly significant predictors of prognosis (P < 0.01). By the combination of these prognostically significant variables, 3 major prognostic subgroups of low-grade glioma patients could be identified. The first of these subgroups was patients with circumscribed low-grade glioma on MRI without 18F-FET uptake (n = 11 patients, progression in 18%, no malignant transformation and no death). The second subgroup was patients with circumscribed low-grade glioma with 18F-FET uptake (n = 13 patients, progression in 46%, malignant transformation to a high-grade glioma in 15%, and death in 8%). The third subgroup was patients with diffuse low-grade glioma with 18F-FET uptake (n = 9 patients, progression in 100%, malignant transformation to a high-grade glioma in 78%, and death in 56%). Conclusion: We conclude that baseline amino acid uptake on 18F-FET PET and a diffuse versus circumscribed tumor pattern on MRI are strong predictors for the outcome of patients with low-grade glioma.

Comparison of 18F-FET and 18F-FDG PET in brain tumors

UNLABELLED The purpose of this study was to compare the diagnostic value of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose ((18)F-FDG) and O-(2-[(18)F]fluoroethyl)-l-tyrosine ((18)F-FET) in patients with brain lesions suspicious of cerebral gliomas. METHODS Fifty-two patients with suspicion of cerebral glioma were included in this study. From 30 to 50 min after injection of 180 MBq (18)F-FET, a first PET scan ((18)F-FET scan) was performed. Thereafter, 240 MBq (18)F-FDG was injected and a second PET scan was acquired from 30 to 60 min after the second injection ((18)F-FET/(18)F-FDG scan). The cerebral accumulation of (18)F-FDG was calculated by decay corrected subtraction of the (18)F-FET scan from the (18)F-FET/(18)F-FDG scan. Tracer uptake was evaluated by visual scoring and by lesion-to-background (L/B) ratios. The imaging results were compared with the histological results and prognosis. RESULTS Histology revealed 24 low-grade gliomas (LGG) of World Health Organization (WHO) Grade II and 19 high-grade gliomas (HGG) of WHO Grade III or IV, as well as nine others, mainly benign histologies. The gliomas showed increased (18)F-FET uptake (>normal brain) in 86% and increased (18)F-FDG uptake (>white matter) in 35%. (18)F-FET PET provided diagnostically useful delineation of tumor extent while this was impractical with (18)F-FDG due to high tracer uptake in the gray matter. A local maximum in the tumor area for biopsy guidance could be identified with (18)F-FET in 76% and with (18)F-FDG in 28%. The L/B ratios showed significant differences between LGG and HGG for both tracers but considerable overlap so that reliable preoperative grading was not possible. A significant correlation of tracer uptake with overall survival was found with (18)F-FDG only. In some benign lesions like abscesses, increased uptake was observed for both tracers indicating a limited specificity of both techniques. CONCLUSIONS (18)F-FET PET is superior to (18)F-FDG for biopsy guidance and treatment planning of cerebral gliomas. The uptake of (18)F-FDG is associated with prognosis, but the predictive value is limited and a histological evaluation of tumor tissue remains necessary. Therefore, amino acids like (18)F-FET are the preferred PET tracers for the clinical management of cerebral gliomas.

Assessment of Treatment Response in Patients with Glioblastoma Using O-(2-18F-Fluoroethyl)-l-Tyrosine PET in Comparison to MRI

The assessment of treatment response in glioblastoma is difficult with MRI because reactive blood–brain barrier alterations with contrast enhancement can mimic tumor progression. In this study, we investigated the predictive value of PET using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET PET) during treatment. Methods: In a prospective study, 25 patients with glioblastoma were investigated by MRI and 18F-FET PET after surgery (MRI-/FET-1), early (7–10 d) after completion of radiochemotherapy with temozolomide (RCX) (MRI-/FET-2), and 6–8 wk later (MRI-/FET-3). Maximum and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively) were determined by region-of-interest analyses. Furthermore, gadolinium contrast-enhancement volumes on MRI (Gd-volume) and tumor volumes in 18F-FET PET images with a tumor-to-brain ratio greater than 1.6 (Tvol 1.6) were calculated using threshold-based volume-of-interest analyses. The patients were grouped into responders and nonresponders according to the changes of these parameters at different cutoffs, and the influence on progression-free survival and overall survival was tested using univariate and multivariate survival analyses and by receiver-operating-characteristic analyses. Results: Early after completion of RCX, a decrease of both TBRmax and TBRmean was a highly significant and independent statistical predictor for progression-free survival and overall survival. Receiver-operating-characteristic analysis showed that a decrease of the TBRmax between FET-1 and FET-2 of more than 20% predicted poor survival, with a sensitivity of 83% and a specificity of 67% (area under the curve, 0.75). Six to eight weeks later, the predictive value of TBRmax and TBRmean was less significant, but an association between a decrease of Tvol 1.6 and PFS was noted. In contrast, Gd-volume changes had no significant predictive value for survival. Conclusion: In contrast to Gd-volumes on MRI, changes in 18F-FET PET may be a valuable parameter to assess treatment response in glioblastoma and to predict survival time.

Role of O-(2-18 F-Fluoroethyl)-L-Tyrosine PET for differentiation of local recurrent brain metastasis from radiation necrosis

The aim of this study was to investigate the potential of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation necrosis after radiation therapy because the use of contrast-enhanced MRI for this issue is often difficult. Methods: Thirty-one patients (mean age ± SD, 53 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 40) on MRI after radiation therapy of brain metastases were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively; 20–40 min after injection) of 18F-FET uptake were determined. Time–activity curves were generated, and the time to peak (TTP) was calculated. Furthermore, time–activity curves of each lesion were assigned to one of the following curve patterns: (I) constantly increasing 18F-FET uptake, (II) 18F-FET uptake peaking early (TTP ≤ 20 min) followed by a plateau, and (III) 18F-FET uptake peaking early (TTP ≤ 20 min) followed by a constant descent. The diagnostic accuracy of the TBRmax and TBRmean of 18F-FET uptake and the curve patterns for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or Fisher exact test for 2 × 2 contingency tables using subsequent histologic analysis (11 lesions in 11 patients) or clinical course and MRI findings (29 lesions in 20 patients) as reference. Results: Both TBRmax and TBRmean were significantly higher in patients with recurrent metastasis (n = 19) than in patients with radiation necrosis (n = 21) (TBRmax, 3.2 ± 0.9 vs. 2.3 ± 0.5, P < 0.001; TBRmean, 2.1 ± 0.4 vs. 1.8 ± 0.2, P < 0.001). The diagnostic accuracy of 18F-FET PET for the correct identification of recurrent brain metastases reached 78% using TBRmax (area under the ROC curve [AUC], 0.822 ± 0.07; sensitivity, 79%; specificity, 76%; cutoff, 2.55; P = 0.001), 83% using TBRmean (AUC, 0.851 ± 0.07; sensitivity, 74%; specificity, 90%; cutoff, 1.95; P < 0.001), and 92% for curve patterns II and III versus curve pattern I (sensitivity, 84%; specificity, 100%; P < 0.0001). The highest accuracy (93%) to diagnose local recurrent metastasis was obtained when both a TBRmean greater than 1.9 and curve pattern II or III were present (AUC, 0.959 ± 0.03; sensitivity, 95%; specificity, 91%; P < 0.001). Conclusion: Our findings suggest that the combined evaluation of the TBRmean of 18F-FET uptake and the pattern of the time–activity curve can differentiate local brain metastasis recurrence from radionecrosis with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases.

Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence.

OBJECTIVE Diffuse gliomas may harbor anaplastic foci which affect prognosis and determine adjuvant therapies. Such foci are not always detected by contrast-enhancement on MRI. Recently, other modalities have been introduced, such as FET-PET for pre-diagnostic imaging and 5-aminolevulinic derived tumor fluorescence for intraoperative identification of malignant glioma tissue. The relationship between these modalities and their value for guiding biopsies during resection has not yet been elucidated in the group of diffuse gliomas. METHODS FET-PET was performed in 30 consecutive patients with intracerebral lesions suggestive of diffuse gliomas on MRI with or without areas of contrast-enhancement. Prior to surgery patients were given 5-ALA at a dose of 20mg/kg body weight. Areas of FET uptake with a lesion/brain ratio of 1.6 or more were considered indicators of tumor. FET-PET data were corregistered with MRI data before surgery in order to obtain neuronavigated biopsies during resection, which were collected from FET positive and negative areas, analyzed for tumor fluorescence and correlated to contrast-enhancement on MRI. RESULTS 13 of 30 tumors were diagnosed as gliomas WHO Grade II, 15 as gliomas WHO Grade III and 2 as gliomas WHO Grade IV. The mean lesion/brain tissue ratio of FET uptake was significantly greater for high-grade than for low-grade gliomas (averages SD 2.323±0.754 vs. 1.453±0.538 p=0.0014). A match of FET-pos/ALA-pos biopsies was found in 70.6% (12/17) of high-grade gliomas (WHO Grade III/IV) but only in 7.7% (1/13) of low grade gliomas. Gd-neg/FET-neg/ALA-neg biopsies yielded a low-grade tumor in 46.2% (6/13). A mismatch between FET uptake and 5-ALA (FET-pos/ALA-neg) was found in 46.2% (6/13) of the low-grade and in 17.6% (3/17) of the high-grade tumors. The combination of FET-PET- and 5-ALA-positivity yielded a sensitivity for identifying high-grade glioma foci of 70.5% and a specificity of 92.3%. CONCLUSIONS In low grade gliomas 5-ALA fluorescence is the exception and FET PET is more sensitive. High grade areas in diffuse gliomas with anaplastic foci usually fluoresce, if they are FET PET positive. As a result, FET PET appears valuable for pre-operative identification of anaplastic foci and hot spots are strongly predictive for ALA-derived fluorescence, which highlight anaplastic foci during resection.

Diagnostic Performance of 18F-FET PET in Newly Diagnosed Cerebral Lesions Suggestive of Glioma

The aim of this study was to assess the clinical value of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET in the initial diagnosis of cerebral lesions suggestive of glioma. Methods: In a retrospective study, we analyzed the clinical, radiologic, and neuropathologic data of 174 patients (77 women and 97 men; mean age, 45 ± 15 y) who had been referred for neurosurgical assessment of unclear brain lesions and had undergone 18F-FET PET. Initial histology (n = 168, confirmed after surgery or biopsy) and the clinical course and follow-up MR imaging in 2 patients revealed 66 high-grade gliomas (HGG), 77 low-grade gliomas (LGG), 2 lymphomas, and 25 nonneoplastic lesions (NNL). In a further 4 patients, initial histology was unspecific, but during the course of the disease all patients developed an HGG. The diagnostic value of maximum and mean tumor-to-brain ratios (TBRmax/TBRmean) of 18F-FET uptake was assessed using receiver-operating-characteristic (ROC) curve analyses to differentiate between neoplastic lesions and NNL, between HGG and LGG, and between high-grade tumor (HGG or lymphoma) and LGG or NNL. Results: Neoplastic lesions showed significantly higher 18F-FET uptake than NNL (TBRmax, 3.0 ± 1.3 vs. 1.8 ± 0.5; P < 0.001). ROC analysis yielded an optimal cutoff of 2.5 for TBRmax to differentiate between neoplastic lesions and NNLs (sensitivity, 57%; specificity, 92%; accuracy, 62%; area under the curve [AUC], 0.76; 95% confidence interval [CI], 0.68–0.84). The positive predictive value (PPV) was 98%, and the negative predictive value (NPV) was 27%. ROC analysis for differentiation between HGG and LGG (TBRmax, 3.6 ± 1.4 vs. 2.4 ± 1.0; P < 0.001) yielded an optimal cutoff of 2.5 for TBRmax (sensitivity, 80%; specificity, 65%; accuracy, 72%; AUC, 0.77; PPV, 66%; NPV, 79%; 95% CI, 0.68–0.84). Best differentiation between high-grade tumors (HGG or lymphoma) and both NNL and LGG was achieved with a TBRmax cutoff of 2.5 (sensitivity, 79%; specificity, 72%; accuracy, 75%; AUC, 0.79; PPV, 65%; NPV, 84%; 95% CI, 0.71–0.86). The results for TBRmean were similar with a cutoff of 1.9. Conclusion: 18F-FET uptake ratios provide valuable additional information for the differentiation of cerebral lesions and the grading of gliomas. TBRmax of 18F-FET uptake beyond the threshold of 2.5 has a high PPV for detection of a neoplastic lesion and supports the necessity of an invasive procedure, for example, biopsy or surgical resection. Low 18F-FET uptake (TBRmax < 2.5) excludes a high-grade tumor with high probability.

High resolution BrainPET combined with simultaneous MRI.

UNLABELLED After the successful clinical introduction of PET/CT, a novel hybrid imaging technology combining PET with the versatile attributes of MRI is emerging. At the Forschungszentrum Jülich, one of four prototypes available worldwide combining a commercial 3T MRI with a newly developed BrainPET insert has been installed, allowing simultaneous data acquisition with PET and MRI. The BrainPET is equipped with LSO crystals of 2.5 mm width and Avalanche photodiodes (APD) as readout electronics. Here we report on some performance characteristics obtained by phantom studies and also on the initial BrainPET studies on various patients as compared with a conventional HR+ PET-only scanner. MATERIAL, METHODS The radiotracers [18F]-fluoro-ethyl-tyrosine (FET), [11C]-flumazenil and [18F]-FP-CIT were applied. RESULTS Comparing the PET data obtained with the BrainPET to those of the HR+ scanner demonstrated the high image quality and the superior resolution capability of the BrainPET. Furthermore, it is shown that various MR images of excellent quality could be acquired simultaneously with BrainPET scans without any relevant artefacts. DISCUSSION, CONCLUSION Initial experiences with the hybrid MRI/BrainPET indicate a promising basis for further developments of this unique technique allowing simultaneous PET imaging combined with both anatomical and functional MRI.

Role of O-(2-18F-Fluoroethyl)-l-Tyrosine PET as a Diagnostic Tool for Detection of Malignant Progression in Patients with Low-Grade Glioma

In patients with low-grade glioma (LGG) of World Health Organization (WHO) grade II, early detection of progression to WHO grade III or IV is of high clinical importance because the initiation of a specific treatment depends mainly on the WHO grade. In a significant number of patients with LGG, however, information on tumor activity and malignant progression cannot be obtained on the basis of clinical or conventional MR imaging findings only. We here investigated the potential of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET to noninvasively detect malignant progression in patients with LGG. Methods: Twenty-seven patients (mean age ± SD, 44 ± 15 y) with histologically proven LGG (WHO grade II) were investigated longitudinally twice using dynamic 18F-FET PET and routine MR imaging. Initially, MR imaging and PET scans were performed, and diagnosis was confirmed on the basis of biopsy. Subsequently, PET scans were obtained when clinical findings or contrast-enhanced MR imaging suggested malignant progression. Maximum and mean tumor-to-brain ratios (20–40 min after injection) (TBRmax and TBRmean, respectively) of 18F-FET uptake as well as tracer uptake kinetics (i.e., time to peak [TTP] and patterns of the time–activity curves) were determined. The diagnostic accuracy of imaging parameters for the detection of malignant progression was evaluated by receiver-operating-characteristic analyses and by Fisher exact test for 2 × 2 contingency tables. Results: In patients with histologically proven malignant progression toward WHO grade III or IV (n = 18), TBRmax and TBRmean increased significantly, compared with baseline (TBRmax, 3.8 ± 1.0 vs. 2.4 ± 1.0; TBRmean, 2.2 ± 0.3 vs. 1.6 ± 0.6; both P < 0.001), whereas TTP decreased significantly (median TTP, 35 vs. 23 min; P < 0.001). Furthermore, time–activity curve patterns changed significantly in 10 of 18 patients (P < 0.001). The combined analysis of 18F-FET PET parameters (i.e., changes of TBRmax, TTP, or time–activity curve pattern) yielded a significantly higher diagnostic accuracy for the detection of malignant progression than changes of contrast enhancement in MR imaging (accuracy, 81% vs. 63%; P = 0.003). Conclusion: Both tumor-to-brain ratio and kinetic parameters of 18F-FET PET uptake provide valuable diagnostic information for the noninvasive detection of malignant progression of LGG. Thus, repeated 18F-FET PET may be helpful for further treatment decisions.

The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma

BACKGROUND We evaluated the diagnostic value of static and dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) PET parameters in patients with progressive or recurrent glioma. METHODS We retrospectively analyzed 132 dynamic (18)F-FET PET and conventional MRI scans of 124 glioma patients (primary World Health Organization grade II, n = 55; grade III, n = 19; grade IV, n = 50; mean age, 52 ± 14 y). Patients had been referred for PET assessment with clinical signs and/or MRI findings suggestive of tumor progression or recurrence based on Response Assessment in Neuro-Oncology criteria. Maximum and mean tumor/brain ratios of (18)F-FET uptake were determined (20-40 min post-injection) as well as tracer uptake kinetics (ie, time to peak and patterns of the time-activity curves). Diagnoses were confirmed histologically (95%) or by clinical follow-up (5%). Diagnostic accuracies of PET and MR parameters for the detection of tumor progression or recurrence were evaluated by receiver operating characteristic analyses/chi-square test. RESULTS Tumor progression or recurrence could be diagnosed in 121 of 132 cases (92%). MRI and (18)F-FET PET findings were concordant in 84% and discordant in 16%. Compared with the diagnostic accuracy of conventional MRI to diagnose tumor progression or recurrence (85%), a higher accuracy (93%) was achieved by (18)F-FET PET when a mean tumor/brain ratio ≥2.0 or time to peak <45 min was present (sensitivity, 93%; specificity, 100%; accuracy, 93%; positive predictive value, 100%; P < .001). CONCLUSION Static and dynamic (18)F-FET PET parameters differentiate progressive or recurrent glioma from treatment-related nonneoplastic changes with higher accuracy than conventional MRI.