Hybrid MR-PET of brain tumours using amino acid PET and chemical exchange saturation transfer MRI

Purpose

PET using radiolabelled amino acids has become a promising tool in the diagnostics of gliomas and brain metastasis. Current research is focused on the evaluation of amide proton transfer (APT) chemical exchange saturation transfer (CEST) MR imaging for brain tumour imaging. In this hybrid MR-PET study, brain tumours were compared using 3D data derived from APT-CEST MRI and amino acid PET using O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET).

Methods

Eight patients with gliomas were investigated simultaneously with ¹⁸F-FET PET and APT-CEST MRI using a 3-T MR-BrainPET scanner. CEST imaging was based on a steady-state approach using a B₁ average power of 1μT. B₀ field inhomogeneities were corrected a Prametric images of magnetisation transfer ratio asymmetry (MTR_asym) and differences to the extrapolated semi-solid magnetisation transfer reference method, APT# and nuclear Overhauser effect (NOE#), were calculated. Statistical analysis of the tumour-to-brain ratio of the CEST data was performed against PET data using the non-parametric Wilcoxon test.

Results

A tumour-to-brain ratio derived from APT# and ¹⁸F-FET presented no significant differences, and no correlation was found between APT# and ¹⁸F-FET PET data. The distance between local hot spot APT# and ¹⁸F-FET were different (average 20?±?13 mm, range 4–45 mm).

Conclusion

For the first time, CEST images were compared with ¹⁸F-FET in a simultaneous MR-PET measurement. Imaging findings derived from¹⁸F-FET PET and APT CEST MRI seem to provide different biological information. The validation of these imaging findings by histological confirmation is necessary, ideally using stereotactic biopsy.

     

Influence of blood-brain barrier permeability on O-(2-<Superscript>18</Superscript>F-fluoroethyl)-L-tyrosine uptake in rat gliomas

Purpose

O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET) is an established tracer for the diagnosis of brain tumors with PET. This study investigates the influence of blood-brain barrier (BBB) permeability on ¹⁸F-FET uptake in two rat glioma models and one human xenograft model.

Methods

F98 glioma, 9L gliosarcoma or human U87 glioblastoma cells were implanted into the striatum of 56 Fischer or RNU rats. Thereafter, animals were divided into a control group and a group receiving injections of the glucocorticoid dexamethasone (Dex). After 12-13 days of tumor growth animals received injection of Evans blue dye (EBD) to visualize BBB disturbance and underwent ¹⁸F-FET PET followed by autoradiography. Time activity curves, standardized uptake values (SUV) and Tumor-to-brain ratios (TBR) of ¹⁸F-FET uptake [18-61 min post injection (p.i.)] were evaluated using a volume-of-Interest (VOI) analysis. BBB disturbance was quantitatively evaluated by EBD fluorescence. The membrane gaps of blood vessel endothelial tight junctions were measured using electron microscopy to visualize ultrastructural BBB alterations in one untreated and one Dex treated F98 glioma. Data were analyzed by two-way ANOVAs.

Results

In Dex treated animals EBD extravasation was significantly reduced in 9L (P?<?0.001) and U87 (P?=?0.008) models and showed a trend in F98 models (P?=?0.053). In contrast, no significant differences of ¹⁸F-FET uptake were observed between Dex treated animals and control group except a decrease of the TBR in the 9L tumor model in PET (P?<?0.01). Ultrastructural evaluation of tumor blood vessel endothelia revealed significant reduction of the cleft diameter between endothelial cells after Dex treatment in F98 model (P?=?0.010).

Conclusion

Despite a considerable reduction of BBB permeability in rat gliomas after Dex treatment, no relevant changes of ¹⁸F-FET uptake were noted in this experimental study. Thus, ¹⁸F-FET uptake in gliomas appears to be widely independent of the permeability of the BBB.

     

Reproducibility of O-(2-<Superscript>18</Superscript>F-fluoroethyl)-L-tyrosine uptake kinetics in brain tumors and influence of corticoid therapy: an experimental study in rat gliomas

Purpose

Positron emission tomography (PET) using O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET) is a well-established method for the diagnostics of brain tumors. This study investigates reproducibility of ¹⁸F-FET uptake kinetics in rat gliomas and the influence of the frequently used dexamethasone (Dex) therapy.

Methods

F98 glioma or 9L gliosarcoma cells were implanted into the striatum of 31 Fischer rats. After 10–11 days of tumor growth, the animals underwent dynamic PET after injection of ¹⁸F-FET (baseline). Thereafter, animals were divided into a control group and a group receiving Dex injections, and all animals were reinvestigated 2 days later. Tumor-to-brain ratios (TBR) of ¹⁸F-FET uptake (18–61 min p.i.) and the slope of the time-activity-curves (TAC) (18–61 min p.i.) were evaluated using a Volume-of-Interest (VOI) analysis. Data were analyzed by two-way repeated measures ANOVA and reproducibility by the intraclass correlation coefficient (ICC).

Results

The slope of the tumor TACs showed high reproducibility with an ICC of 0.93. A systematic increase of the TBR in the repeated scans was noted (3.7?±?2.8 %; p?<?0.01), and appeared to be related to tumor growth as indicated by a significant correlation of TBR and tumor volume (r?=?0.77; p?<?0.0001). After correction for tumor growth TBR showed high longitudinal stability with an ICC of 0.84. Dex treatment induced a significant decrease of the TBR (?8.2?±?6.1 %; p?<?0.03), but did not influence the slope of the tumor TAC.

Conclusion

TBR of ¹⁸F-FET uptake and tracer kinetics in brain tumors showed high longitudinal stability. Dex therapy may induce a minor decrease of the TBR; this needs further investigation.

     

Biological tumour volumes of gliomas in early and standard 20–40 min <Superscript>18</Superscript>F-FET PET images differ according to <Emphasis Type="Italic">IDH</Emphasis> mutation status

Purpose

For the clinical evaluation of O-(2-¹⁸F-fluoroethyl)-l-tyrosine (¹⁸F-FET) PET images, the use of standard summation images obtained 20–40 min after injection is recommended. However, early summation images obtained 5–15 min after injection have been reported to allow better differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) by capturing the early ¹⁸F-FET uptake peak specific for HGG. We compared early and standard summation images with regard to delineation of the PET-derived biological tumour volume (BTV) in correlation with the molecular genetic profile according the updated 2016 WHO classification.

Methods

The analysis included 245 patients with newly diagnosed, histologically verified glioma and a positive ¹⁸F-FET PET scan prior to any further treatment. BTVs were delineated during the early 5–15 min and standard 20–40 min time frames using a threshold of 1.6?×?background activity and were compared intraindividually. Volume differences between early and late summation images of >20% were considered significant and were correlated with WHO grade and the molecular genetic profile (IDH mutation and 1p/19q codeletion status).

Results

In 52.2% of the patients (128/245), a significant difference in BTV of >20% between early and standard summation images was found. While 44.3% of WHO grade II gliomas (31 of 70) showed a significantly smaller BTV in the early summation images, 35.0% of WHO grade III gliomas (28/80) and 37.9% of WHO grade IV gliomas (36/95) had a significantly larger BTVs. Among IDH-wildtype gliomas, an even higher portion (44.4%, 67/151) showed significantly larger BTVs in the early summation images, which was observed in 5.3% (5/94) of IDH-mutant gliomas only: most of the latter had significantly smaller BTVs in the early summation images, i.e. 51.2% of IDH-mutant gliomas without 1p/19q codeletion (21/41) and 39.6% with 1p/19q codeletion (21/53).

Conclusion

BTVs delineated in early and standard summation images differed significantly in more than half of gliomas. While the standard summation images seem appropriate for delineation of LGG as well as IDH-mutant gliomas, a remarkably high percentage of HGG and, particularly, IDH-wildtype gliomas were depicted with significantly larger volumes in early summation images. This finding might be of interest for optimization of treatment planning (e.g. radiotherapy) in accordance with the individual IDH mutation status.

     

<Emphasis Type="Italic">IDH</Emphasis> mutation is paradoxically associated with higher <Superscript>18</Superscript>F-FDOPA PET uptake in diffuse grade II and grade III gliomas

Purpose

The World Health Organization Classification of Tumors of the Central Nervous System has recently been updated by the integration of diagnostic and prognostic molecular parameters, giving pivotal attention to IDH mutation as a favourable factor. Amino acid PET is increasingly used in the management of gliomas, but its prognostic value is a matter of debate. The aim of this study was to assess the relationship between IDH mutation and ¹⁸F-FDOPA uptake on PET in newly diagnosed gliomas.

Methods

A total of 43 patients, presenting with diffuse astrocytic and oligodendroglial grade II and III gliomas, reclassified according to the 2016 WHO classification of tumours of the CNS, were retrospectively included. They had all undergone ¹⁸F-FDOPA PET at an initial stage before surgery and histological diagnosis. ¹⁸F-FDOPA uptake values were compared between patients with and without IDH mutation in terms of maximum standardized uptake value (SUVmax) ratios between tumour and normal contralateral brain (T/N), and between tumour and striatum (T/S).

Results

Patients with IDH mutation showed higher ¹⁸F-FDOPA T/N SUVmax ratios (1.6 vs. 1.2) and T/S SUVmax ratios (0.9 vs. 0.6) than patients without IDH mutation (p?<?0.05).

Conclusion

This study showed paradoxically higher ¹⁸F-FDOPA uptake in diffuse grade II and III gliomas with IDH mutation. Despite evident interest in the management of gliomas, and especially in relation to posttherapy evaluation, our findings raise the question of the prognostic value of ¹⁸F-FDOPA uptake on PET uptake in this group of patients. This may be related to differences in amino acid integration, metabolism, or cell differentiation.

     

Comparison of <Superscript>18</Superscript>F-FET PET and perfusion-weighted MRI for glioma grading: a hybrid PET/MR study

Purpose

Both perfusion-weighted MR imaging (PWI) and O-(2-¹⁸F-fluoroethyl)-L-tyrosine PET (¹⁸F–FET) provide grading information in cerebral gliomas. The aim of this study was to compare the diagnostic value of ¹⁸F–FET PET and PWI for tumor grading in a series of patients with newly diagnosed, untreated gliomas using an integrated PET/MR scanner.

Methods

Seventy-two patients with untreated gliomas [22 low-grade gliomas (LGG), and 50 high-grade gliomas (HGG)] were investigated with ¹⁸F–FET PET and PWI using a hybrid PET/MR scanner. After visual inspection of PET and PWI maps (rCBV, rCBF, MTT), volumes of interest (VOIs) with a diameter of 16 mm were centered upon the maximum of abnormality in the tumor area in each modality and the contralateral unaffected hemisphere. Mean and maximum tumor-to-brain ratios (TBR_mean, TBR_max) were calculated. In addition, Time-to-Peak (TTP) and slopes of time–activity curves were calculated for ¹⁸F–FET PET. Diagnostic accuracies of ¹⁸F–FET PET and PWI for differentiating low-grade glioma (LGG) from high-grade glioma (HGG) were evaluated by receiver operating characteristic analyses (area under the curve; AUC).

Results

The diagnostic accuracy of ¹⁸F–FET PET and PWI to discriminate LGG from HGG was similar with highest AUC values for TBR_mean and TBR_max of ¹⁸F–FET PET uptake (0.80, 0.83) and for TBR_mean and TBR_max of rCBV (0.80, 0.81). In case of increased signal in the tumor area with both methods (n = 32), local hot-spots were incongruent in 25 patients (78%) with a mean distance of 10.6 ± 9.5 mm. Dynamic FET PET and combination of different parameters did not further improve diagnostic accuracy.

Conclusions

Both ¹⁸F–FET PET and PWI discriminate LGG from HGG with similar diagnostic performance. Regional abnormalities in the tumor area are usually not congruent indicating that tumor grading by ¹⁸F–FET PET and PWI is based on different pathophysiological phenomena.

     

Prognostic implications of <Superscript>62</Superscript>Cu-diacetyl-bis (<Emphasis Type="Italic">N</Emphasis><Superscript>4</Superscript>-methylthiosemicarbazone) PET/CT in patients with glioma

Objective

The potential of positron emission tomography/computed tomography using ⁶²Cu-diacetyl-bis (N⁴-methylthiosemicarbazone) (⁶²Cu-ATSM PET/CT), which was originally developed as a hypoxic tracer, to predict therapeutic resistance and prognosis has been reported in various cancers. Our purpose was to investigate prognostic value of ⁶²Cu-ATSM PET/CT in patients with glioma, compared to PET/CT using 2-deoxy-2-[¹⁸F]fluoro-d-glucose (¹⁸F-FDG).

Method

56 patients with glioma of World Health Organization grade 2–4 were enrolled. All participants had undergone both ⁶²Cu-ATSM PET/CT and ¹⁸F-FDG PET/CT within mean 33.5 days prior to treatment. Maximum standardized uptake value and tumor/background ratio were calculated within areas of increased radiotracer uptake. The prognostic significance for progression-free survival and overall survival were assessed by log-rank test and Cox’s proportional hazards model.

Results

Disease progression and death were confirmed in 37 and 27 patients in follow-up periods, respectively. In univariate analysis, there was significant difference of both progression-free survival and overall survival in age, tumor grade, history of chemoradiotherapy, maximum standardized uptake value and tumor/background ratio calculated using ⁶²Cu-ATSM PET/CT. Multivariate analysis revealed that maximum standardized uptake value calculated using ⁶²Cu-ATSM PET/CT was an independent predictor of both progression-free survival and overall survival (p?<?0.05). In a subgroup analysis including patients of grade 4 glioma, only the maximum standardized uptake values calculated using ⁶²Cu-ATSM PET/CT showed significant difference of progression-free survival (p?<?0.05).

Conclusions

⁶²Cu-ATSM PET/CT is a more promising imaging method to predict prognosis of patients with glioma compared to ¹⁸F-FDG PET/CT.

     

The roles of <Superscript>11</Superscript>C-acetate PET/CT in predicting tumor differentiation and survival in patients with cerebral glioma

Purpose

This prospective study aimed to evaluate the clinical values of ¹¹C–acetate positron emission tomography/computed tomography (PET/CT) in predicting histologic grades and survival in patients with cerebral glioma.

Methods

Seventy-three patients with surgically confirmed cerebral gliomas (19 grade II, 21 grade III, and 33 grade IV) who underwent ¹¹C–acetate PET/CT before surgery were included. Tumor-to-choroid plexus ratio (TCR), which was defined as the maximum standardized uptake value (SUV) of tumors to the mean SUV of choroid plexus, was compared between three World Health Organization (WHO) grade groups. Moreover, metabolic tumor volumes (MTV) were calculated. Progression-free survival (PFS) and overall survival (OS) curves were plotted using the Kaplan–Meier method, and differences in survival between groups were assessed using the log-rank test.

Results

Median TCR was 1.20 (interquartile range [IQR], 1.14 to 1.4) in grade II, 1.65 (IQR, 1.26 to 1.79) in grade III, and 2.53 (IQR, 1.93 to 3.30) in grade IV gliomas. Significant differences in TCR were seen among the three WHO grade groups (P?<?0.001). In Cox regression analysis including TCR, MTV, molecular markers, and other clinical factors, TCR was prognostic for PFS (P?=?0.016) and TCR and MTV were prognostic for OS (P?=?0.024 [TCR], P?=?0.030 [MTV]). PFS and OS were significantly shorter in patients with a TCR?≥?1.6 than in those with a TCR?<?1.6. OS were significantly shorter in patients with a MTV?≥?1 than in those with a TCR?<?1.

Conclusions

TCR on ¹¹C–acetate PET/CT significantly differed between low- and high-grade cerebral gliomas, and it showed the capability to further differentiate grade III from grade IV tumors. TCR and MTV were independent prognostic factors and predicted survival better than did the WHO grade.

     

[18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis

Purpose

Hypoxia in gliomas is associated with tumor resistance to radio- and chemotherapy. However, positron emission tomography (PET) imaging of hypoxia remains challenging, and the validation of biological markers is, therefore, of great importance. We investigated the relationship between uptake of the PET hypoxia tracer [18F]-FMISO and other markers of hypoxia and angiogenesis and with patient survival.

Patients and methods

In this prospective single center clinical study, 33 glioma patients (grade IV: n?=?24, III: n?=?3, and II: n?=?6) underwent [18F]-FMISO PET and MRI including relative cerebral blood volume (rCBV) maps before surgery. Maximum standardized uptake values (SUVmax) and hypoxic volume were calculated, defining two groups of patients based on the presence or absence of [18F]-FMISO uptake. After surgery, molecular quantification of CAIX, VEGF, Ang2 (rt-qPCR), and HIF-1α (immunohistochemistry) were performed on tumor specimens.

Results

[18F]-FMISO PET uptake was closely linked to tumor grade, with high uptake in glioblastomas (GB, grade IV). Expression of biomarkers of hypoxia (CAIX, HIF-1α), and angiogenesis markers (VEGF, Ang2, rCBV) were significantly higher in the [18F]-FMISO uptake group. We found correlations between the degree of hypoxia (hypoxic volume and SUVmax) and expression of HIF-1α, CAIX, VEGF, Ang2, and rCBV (p?<?0.01). Patients without [18F]-FMISO uptake had a longer survival time than uptake positive patients (log-rank, p?<?0.005).

Conclusions

Tumor hypoxia as evaluated by [18F]-FMISO PET is associated with the expression of hypoxia markers on a molecular level and is related to angiogenesis. [18F]-FMISO uptake is a mark of an aggressive tumor, almost always a glioblastoma. Our results underline that [18F]-FMISO PET could be useful to guide glioma treatment, and in particular radiotherapy, since hypoxia is a well-known factor of resistance.

     

Early static <Superscript>18</Superscript>F-FET-PET scans have a higher accuracy for glioma grading than the standard 20–40 min scans

Purpose

Current guidelines for glioma imaging by positron emission tomography (PET) using the amino acid analogue O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (¹⁸F-FET) recommend image acquisition from 20–40 min post injection (p.i.). The maximal tumour-to-background evaluation (TBR_max) obtained in these summation images does not enable reliable differentiation between low and high grade glioma (LGG and HGG), which, however, can be achieved by dynamic ¹⁸F-FET-PET. We investigated the accuracy of tumour grading using TBR_max values at different earlier time points after tracer injection.

Methods

Three hundred and fourteen patients with histologically proven primary diagnosis of glioma (131 LGG, 183 HGG) who had undergone 40-min dynamic ¹⁸F-FET-PET scans were retrospectively evaluated. TBR_max was assessed in the standard 20–40 min summation images, as well as in summation images from 0–10 min, 5–15 min, 5–20 min, and 15–30 min p.i., and kinetic analysis was performed. TBR_max values and kinetic analysis were correlated with histological classification. ROC analyses were performed for each time frame and sensitivity, specificity, and accuracy were assessed.

Results

TBR_max values in the earlier summation images were significantly better for tumour grading (P?<?0.001) when compared to standard 20–40 min scans, with best results for the early 5–15 min scan. This was due to higher TBR_max in the HGG (3.9 vs. 3.3; p?<?0.001), while TBR_max remained nearly stable in the LGG (2.2 vs. 2.1). Overall, accuracy increased from 70 % in the 20–40 min analysis to 77 % in the 5–15 min images, but did not reach the accuracy of dynamic analysis (80 %).

Conclusions

Early TBR_max assessment (5–15 min p.i.) is more accurate for the differentiation between LGG and HGG than the standard static scan (20–40 min p.i.) mainly caused by the characteristic high ¹⁸F-FET uptake of HGG in the initial phase. Therefore, when dynamic ¹⁸F-FET-PET cannot be performed, early TBR_max assessment can be considered as an alternative for tumour grading.

     

TSPO PET for glioma imaging using the novel ligand <Superscript>18</Superscript>F-GE-180: first results in patients with glioblastoma

Objective

The 18-kDa mitochondrial translocator protein (TSPO) was reported to be upregulated in gliomas. ¹⁸F-GE-180 is a novel 3rd generation TSPO receptor ligand with improved target-to-background contrast compared to previous tracers. In this pilot study, we compared PET imaging with ¹⁸F-GE-180 and MRI of patients with untreated and recurrent pretreated glioblastoma.

Methods

Eleven patients with histologically confirmed IDH wildtype gliomas (10 glioblastomas, 1 anaplastic astrocytoma) underwent ¹⁸F-GE-180 PET at initial diagnosis or recurrence. The PET parameters mean background uptake (SUV_BG), maximal tumour-to-background ratio (TBR_max) and PET volume using different thresholds (SUV_BG × 1.6, 1.8 and 2.0) were evaluated in the 60-80 min p.i. summation images. The different PET volumes were compared to the contrast-enhancing tumour volume on MRI.

Results

All gliomas were positive on ¹⁸F-GE-180 PET and were depicted with extraordinarily high tumour-to-background contrast (median SUV_BG 0.47 (0.37-0.93), TBR_max 6.61 (3.88-9.07)). ¹⁸F-GE-180 uptake could be found even in areas without contrast enhancement on MRI, leading to significantly larger PET volumes than MRI-based volumes (median 90.5, 74.5, and 63.8 mL vs. 31.0 mL; p = 0.003, 0.004, 0.013). In percentage difference, the PET volumes were on average 179%, 135%, and 90% larger than the respective MRI volumes. The median spatial volumetric correlation (Sørensen-Dice coefficient) of PET volumes and MRI volumes prior to radiotherapy was 0.48, 0.54, and 0.58.

Conclusion

¹⁸F-GE-180 PET provides a remarkably high tumour-to-background contrast in untreated and pretreated glioblastoma and shows tracer uptake even beyond contrast enhancement on MRI. To what extent ¹⁸F-GE-180 uptake reflects the tumour extent of human gliomas and inflammatory cells remains to be evaluated in future prospective studies with guided stereotactic biopsies and correlation of histopathological results.

     

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

The purpose of this study was to compare the diagnostic value of positron emission tomography (PET) using [¹⁸F]-fluorodeoxyglucose (¹⁸F-FDG) and O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (¹⁸F-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 ¹⁸F-FET, a first PET scan (¹⁸F-FET scan) was performed. Thereafter, 240 MBq ¹⁸F-FDG was injected and a second PET scan was acquired from 30 to 60 min after the second injection (¹⁸F-FET/¹⁸F-FDG scan). The cerebral accumulation of ¹⁸F-FDG was calculated by decay corrected subtraction of the ¹⁸F-FET scan from the ¹⁸F-FET/¹⁸F-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 ¹⁸F-FET uptake (>normal brain) in 86% and increased ¹⁸F-FDG uptake (>white matter) in 35%. ¹⁸F-FET PET provided diagnostically useful delineation of tumor extent while this was impractical with ¹⁸F-FDG due to high tracer uptake in the gray matter. A local maximum in the tumor area for biopsy guidance could be identified with ¹⁸F-FET in 76% and with ¹⁸F-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 ¹⁸F-FDG only. In some benign lesions like abscesses, increased uptake was observed for both tracers indicating a limited specificity of both techniques.

Conclusions

¹⁸F-FET PET is superior to ¹⁸F-FDG for biopsy guidance and treatment planning of cerebral gliomas. The uptake of ¹⁸F-FDG is associated with prognosis, but the predictive value is limited and a histological evaluation of tumor tissue remains necessary. Therefore, amino acids like ¹⁸F-FET are the preferred PET tracers for the clinical management of cerebral gliomas.     

Pathological factors contributing to crossed cerebellar diaschisis in cerebral gliomas: a study combining perfusion,diffusion, and structural MR imaging

Purpose

To investigate imaging features of crossed cerebellar diaschisis (CCD) in cerebral gliomas, and its underlying pathophysiological mechanisms.

Methods

Thirty-three pre-surgical patients with cerebral gliomas and 33 healthy controls underwent arterial spin-labeling, diffusion tensor imaging, and high-resolution T1-weighted imaging using MRI, in order to estimate cerebral blood flow (CBF), white matter integrity, and lesion volume, respectively. Asymmetry indices of CBF in the cerebellum were used for evaluating the level of CCD in the patients. These indices were correlated with clinical variables (lesion size and position, tumor histological grade, and CBF asymmetry) and diffusion tensor imaging parameters (fractional anisotropy and number of fibers in the cortico-ponto-cerebellar pathway and across the cerebral hemispheres), respectively.

Results

The patients showed decreased CBF in the cerebellar hemisphere contralateral to the supratentorial tumor, and increased CBF asymmetry in the cerebellum (both P?<?0.05). CCD levels in high-grade gliomas were higher than those of low-grade gliomas (P?<?0.05). CCD levels were negatively correlated with the size of the supratentorial lesions, and positively correlated with FA asymmetry in the cerebral fibers (both P?<?0.05).

Conclusions

CCD in cerebral gliomas was specifically associated with tumor histological grade, lesion size, and white matter impairments in the hemisphere ipsilateral to the tumor. The findings implicated that observing CCD might have potential for assisting grading diagnosis of cerebral gliomas.

     

Whole-tumor histogram analysis of the cerebral blood volume map: tumor volume defined by 11C-methionine positron emission tomography image improves the diagnostic accuracy of cerebral glioma grading

Purpose

This study aimed to compare the tumor volume definition using conventional magnetic resonance (MR) and 11C-methionine positron emission tomography (MET/PET) images in the differentiation of the pre-operative glioma grade by using whole-tumor histogram analysis of normalized cerebral blood volume (nCBV) maps.

Materials and methods

Thirty-four patients with histopathologically proven primary brain low-grade gliomas (n = 15) and high-grade gliomas (n = 19) underwent pre-operative or pre-biopsy MET/PET, fluid-attenuated inversion recovery, dynamic susceptibility contrast perfusion-weighted magnetic resonance imaging, and contrast-enhanced T1-weighted at 3.0 T. The histogram distribution derived from the nCBV maps was obtained by co-registering the whole tumor volume delineated on conventional MR or MET/PET images, and eight histogram parameters were assessed.

Results

The mean nCBV value had the highest AUC value (0.906) based on MET/PET images. Diagnostic accuracy significantly improved when the tumor volume was measured from MET/PET images compared with conventional MR images for the parameters of mean, 50th, and 75th percentile nCBV value (p = 0.0246, 0.0223, and 0.0150, respectively).

Conclusion

Whole-tumor histogram analysis of CBV map provides more valuable histogram parameters and increases diagnostic accuracy in the differentiation of pre-operative cerebral gliomas when the tumor volume is derived from MET/PET images.

     

Correlation of 4′-[methyl-<Superscript>11</Superscript>C]-thiothymidine uptake with human equilibrative nucleoside transporter-1 and thymidine kinase-1 expressions in patients with newly diagnosed gliomas

Objective

We examined expressions of human equilibrative nucleoside transporter-1 (hENT1) and thymidine kinase-1 (TK1), the key enzyme in 4′-[methyl-¹¹C]-thiothymidine (4DST) phosphorylation, to elucidate the mechanism of 4DST uptake in patients with newly diagnosed gliomas.

Methods

A total of 19 patients with newly diagnosed gliomas were examined with 4DST PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of normal brain background. For semi-quantitative analysis, tumor-to-contralateral normal brain tissue (T/N) ratio was determined by dividing the maximal standardized uptake value (SUV) for tumor by that of the mean SUV for reference tissue. The expressions of hENT1, TK1 and Ki-67 in tumor specimens were examined by immunohistochemistry and compared with 4DST T/N ratio.

Results

All but two gliomas showed focally increased 4DST uptake. All gliomas showed hENT1 staining, except one grade II glioma, which was also not visualized on 4DST PET. A significant correlation was observed between T/N ratio and hENT1 score (ρ?=?0.90, p?<?0.001). All gliomas showed TK1 staining, except two gliomas which were also not visualized on 4DST PET. There was a significant correlation between T/N ratio and TK1 score (ρ?=?0.92, p?<?0.001). There was a significant correlation between T/N ratio and Ki-67 index (ρ?=?0.50, p?<?0.03).

Conclusion

Results of this preliminary study indicate that expressions of hENT1 and TK1 appear to be important determinants of 4DST uptake in newly diagnosed gliomas.

     

Use of FET PET in glioblastoma patients undergoing neurooncological treatment including tumour-treating fields: initial experience

Purpose

We present our first clinical experience with O-(2-¹⁸F-fluoroethyl)-l-tyrosine (FET) PET in patients with high-grade glioma treated with various neurooncological therapies including tumour-treating fields (TTFields) for the differentiation of tumour progression from treatment-related changes.

Methods

We retrospectively assessed 12 patients (mean age 51?±?12 years, range 33–72 years) with high-grade glioma (11 glioblastomas, 1 gliosarcoma) in whom the treatment regimen included TTFields and who had undergone FET PET scans for differentiation of tumour progression from treatment-related changes. Mean and maximum tumour-to-brain ratios (TBR_mean, TBR_max) were calculated. The definitive diagnosis (tumour progression or posttherapeutic changes) was confirmed either by histopathology (4 of 12 patients) or on clinical follow-up.

Results

In all nine patients with confirmed tumour progression, the corresponding FET PET showed increased uptake (TBR_max 3.5?±?0.6, TBR_mean 2.7?±?0.7). In one of these nine patients, FET PET was consistent with treatment-related changes, whereas standard MRI showed a newly diagnosed contrast-enhancing lesion. In two patients treated solely with TTFields without any other concurrent neurooncological therapy, serial FET PET revealed a decrease in metabolic activity over a follow-up of 6 months or no FET uptake without any signs of tumour progression or residual tumour on conventional MRI.

Conclusion

FET PET may add valuable information in monitoring therapy in individual patients with high-grade glioma undergoing neurooncological treatment including TTFields.

     

Static and dynamic <Superscript>18</Superscript>F–FET PET for the characterization of gliomas defined by IDH and 1p/19q status

Purpose

The molecular features isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion have gained major importance for both glioma typing and prognosis and have, therefore, been integrated in the World Health Organization (WHO) classification in 2016. The aim of this study was to characterize static and dynamic O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F–FET) PET parameters in gliomas with or without IDH mutation or 1p/19q co-deletion.

Methods

Ninety patients with newly diagnosed and untreated gliomas with a static and dynamic ¹⁸F–FET PET scan prior to evaluation of tumor tissue according to the 2016 WHO classification were identified retrospectively. Mean and maximum tumor-to-brain ratios (TBR_mean/max), as well as dynamic parameters (time-to-peak and slope) of ¹⁸F–FET uptake were calculated.

Results

Sixteen (18%) oligodendrogliomas (IDH mutated, 1p/19q co-deleted), 27 (30%) astrocytomas (IDH mutated only), and 47 (52%) glioblastomas (IDH wild type only) were identified. TBR_mean, TBR_max, TTP and slope discriminated between IDH mutated astrocytomas and IDH wild type glioblastomas (P < 0.01). TBR_mean showed the best diagnostic performance (cut-off 1.95; sensitivity, 89%; specificity, 67%; accuracy, 81%). None of the parameters discriminated between oligodendrogliomas (IDH mutated, 1p/19q co-deleted) and glioblastomas or astrocytomas. Furthermore, TBR_mean, TBR_max, TTP, and slope discriminated between gliomas with and without IDH mutation (p < 0.01). The best diagnostic performance was obtained for the combination of TTP with TBR_max or slope (accuracy, 73%).

Conclusion

Data suggest that static and dynamic ¹⁸F–FET PET parameters may allow determining non-invasively the IDH mutation status. However, IDH mutated and 1p/19q co-deleted oligodendrogliomas cannot be differentiated from glioblastomas and astrocytomas by ¹⁸F–FET PET.

     

Phase IIa clinical study of [<Superscript>18</Superscript>F]fluciclovine: efficacy and safety of a new PET tracer for brain tumors

Objective

[¹⁸F]Fluciclovine (anti-[¹⁸F]FACBC) has demonstrated diagnostic efficacy for cancers of the brain where [¹⁸F]fludeoxyglucose has limitations. We conducted a phase IIa study of anti-[¹⁸F]FACBC to assess its accumulation pattern and safety in patients with malignant glioma.

Methods

Five patients with glioma scheduled for brain tumor resection received anti-[¹⁸F]FACBC. Brain positron emission tomography (PET) was performed following intravenous administration of anti-[¹⁸F]FACBC, and subsequently, preoperative gadolinium contrast-enhanced T1-weighted (CE-T1W) magnetic resonance imaging (MRI) was performed for surgery. Specimens for histopathological evaluation were collected during surgery, and their location was precisely determined on CE-T1W MRI and anti-[¹⁸F]FACBC PET/CT images. In addition, tumor extent defined on the MRI and PET/CT images was compared. To determine time–activity curves for anti-[¹⁸F]FACBC uptake in brain tumor and normal tissues, regions of interest were set in the brain tumor, contralateral normal tissue and the cerebellum, and their standardized uptake values (SUV) were calculated. The safety of anti-[¹⁸F]FACBC was assessed based on subjective symptoms and objective findings, electrocardiograms, vital signs, laboratory results, and the incidence of adverse events.

Results

Anti-[¹⁸F]FACBC accumulated in the malignant gliomas of all patients. CE-T1W MRI detected gliomas in all patients, but anti-[¹⁸F]FACBC PET/CT generally delineated wider regions of tumor extent than CE-T1W MRI. Two of the histopathologically confirmed tumors were located in regions that were defined using anti-[¹⁸F]FACBC PET/CT, but not using CE-T1W MRI. Two patients experienced three mild adverse events: one complained of a dull headache and later a mild headache, and the other showed general malaise. These symptoms resolved spontaneously without treatment. Only the mild headache could not be ruled out from having a causal relationship with anti-[¹⁸F]FACBC. Favorable T/N ratios regarding anti-[¹⁸F]FACBC uptake between tumors and normal control tissues were demonstrated in this trial.

Conclusions

It is suggested that anti-[¹⁸F]FACBC PET/CT has the ability to delineate glioma spread that is undetectable using CE-T1W MRI. Anti-[¹⁸F]FACBC is safe in patients with malignant glioma.This study was registered in the Japan Pharmaceutical Information Center Clinical Trials Information, which is one of the World Health Organization registries (registration number: JapicCTI-111387).

     

Ability of <Superscript>18</Superscript>F-DOPA PET/CT and fused <Superscript>18</Superscript>F-DOPA PET/MRI to assess striatal involvement in paediatric glioma

Purpose

To assess the diagnostic performance of ¹⁸F-DOPA PET/CT and fused ¹⁸F-DOPA PET/MRI in detecting striatal involvement in children with gliomas.

Methods

This retrospective study included 28 paediatric patients referred to our institution for the presence of primary, residual or recurrent glioma (12 boys, 16 girls; mean age 10.7 years) and investigated with ¹⁸F-DOPA PET/CT and brain MRI. Fused ¹⁸F-DOPA PET/MR images were obtained and compared with PET/CT and MRI images. Accuracy, sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for striatal involvement were calculated for each diagnostic tool. Univariate and multivariate logistic analyses were applied to evaluate the associations between ¹⁸F-DOPA PET/CT and fused ¹⁸F-DOPA PET/MRI diagnostic results and tumour uptake outside the striatum, grade, dimension and site of striatal involvement (ventral and/or dorsal).

Results

Accuracy, sensitivity, specificity, PPV, and NPV were 100 % for MRI, 93 %, 89 %, 100 %, 100 % and 82 % for ¹⁸F-DOPA PET/MRI, and 75 %, 74 %, 78 %, 88 % and 58 % for ¹⁸F-DOPA PET/CT, respectively. ¹⁸F-DOPA PET/MRI showed a trend towards higher accuracy compared with ¹⁸F-DOPA PET/CT (p?=?0.06). MRI showed significantly higher accuracy compared with ¹⁸F-DOPA PET/CT (p?=?0.01), but there was no significant difference between MRI and ¹⁸F-DOPA PET/MRI. Both univariate and multivariate logistic analyses showed a significant association (OR 8.0 and 7.7, respectively) between the tumour-to-normal striatal uptake (T/S) ratio and the diagnostic ability of ¹⁸F-DOPA PET/CT (p?=?0.03). A strong significant association was also found between involvement of the dorsal striatum and the ¹⁸F-DOPA PET/CT results (p?=?0.001), with a perfect prediction of involvement of the dorsal striatum by ¹⁸F-DOPA PET/MRI.

Conclusion

Physiological striatal ¹⁸F-DOPA uptake does not appear to be a main limitation in the evaluation of basal ganglia involvement.¹⁸F-DOPA PET/CT correctly detected involvement of the dorsal striatum in lesions with a T/S ratio >1, but appeared to be less suitable for evaluation of the ventral striatum. The use of fused ¹⁸F-DOPA PET/MRI further improves the accuracy and is essential for evaluation of the ventral striatum.

     

<Superscript>18</Superscript>F-DOPA PET/CT in the diagnosis and localization of persistent medullary thyroid carcinoma

Purpose

To evaluate the performance of ¹⁸F-l-dihydroxyphenylalanine (¹⁸F-DOPA) PET/CT in the detection of locoregional and distant medullary thyroid carcinoma (MTC) metastases and to compare imaging findings with histological data.

Methods

We retrospectively evaluated 86 MTC patients with persistently high serum calcitonin levels after initial surgery who had undergone ¹⁸F-DOPA PET/CT between January 2007 and December 2014 in two referral centres. They were followed up for at least 6 months after the PET/CT assessment. The results were compared with histological data or with the findings obtained during follow-up using a complementary imaging modality.

Results

¹⁸F-DOPA PET/CT was positive in 65 of the 86 patients, corresponding to a patient-based sensitivity of 75.6 %. Distant metastatic disease (M1) was seen in 29 patients including 11 with previously unknown metastases revealed only by PET/CT. Among the 36 patients without distant metastatic spread, 25 had nodal involvement limited to the neck, and 10 of these 25 patients underwent reoperation. The lymph node compartment-based sensitivity of ¹⁸F-DOPA PET/CT was 100 % in the two institutions but lesion-based sensitivity was only 24 %. Preoperative and postoperative median calcitonin levels were 405 pg/mL (range 128 – 1,960 pg/mL) and 259 pg/mL (range 33 – 1,516 pg/mL), respectively. None of the patients achieved normalization of serum calcitonin after reoperation.

Conclusion

¹⁸F-DOPA PET/CT enables early diagnosis of a significant number of patients with distant metastasis. It has a limited sensitivity in the detection of residual disease but provides high performance for regional analysis. A surgical compartment-oriented approach could be the approach of choice whatever the number of nodes revealed by ¹⁸F-DOPA PET/CT.