11C methionine positron emission tomography for glioma

MET PET appears to be useful in evaluating grade, type, and proliferative activity of astrocytic tumor (AT). CHO PET may be useful in evaluating the potential malignancy of oligodendroglial tumors (OTs). In terms of visual evaluation of tumor localization, MET PET is superior to FDG and CHO PET in all of the gliomas, due to its straightforward detection of “hot lesions” 1).

MET-PET is a helpful tool for pretreatment evaluation of non-contrast media enhancing, suggestive low-grade intracerebral lesions. MET-PET adds valuable information for the decision-making for surgery or stereotactic biopsy 2).

The aim of a study of Beppu et al., was to clarify whether arterial spin labeling (ASL) perfusion imaging can assess biological effects from bevacizumab (BEV) therapy as reliably as PET with 11C methionine positron emission tomography.

Twenty-four patients with recurrent glioblastoma were examined using both ASL and C-met-PET before and 4 and 8 weeks after starting BEV treatment. Tumor-to-normal brain (T/N) ratios, fluctuations in T/N ratio, and tumor volumes were compared between ASL and C-met-PET. Accuracy of predicting patient with long progression free survival (PFS) was assessed for T/N ratios and fluctuations for ASL and C-met-PET in each phase and in each period using receiver operating characteristic curves. Between 2 groups of patients assigned by cutoff values from receiver operating characteristic curves, PFS was compared in each phase or in each period.

T/N ratios, fluctuations in ratio, and tumor volumes correlated significantly between ASL and C-met-PET at all time points and all periods. Arterial spin labeling was eligible as a predictor for long PFS only in assessment of fluctuations in T/N ratio. However, the most accurate predictors for long PFS were T/N ratio from C-met-PET at 8 weeks and the fluctuation from baseline to 4 weeks in T/N ratio from C-met-PET.

Blood flows on ASL correlated with accumulations of C-met on PET in recurrent glioblastoma under BEV treatment. Although C-met-PET offered superior accuracy for predicting patients with long PFS from time points, ASL offered reliable prediction of long PFS, provided that fluctuations in T/N ratio between consecutive scans are assessed 3).

The metabolically active tumour volume observed in (11)C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in (11)C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas 4).

11C methionine positron emission tomography parameters are significantly correlated with histological grade and IDH1 mutation status in patients with glioma. Grade, pathological classification, molecular biomarkers, SUVmax and SUVratio were prognostic factors for PFS in a cohort of patients. The trial was registered with ClinicalTrials.gov (registration: NCT02518061) 5).



Kato T, Shinoda J, Nakayama N, Miwa K, Okumura A, Yano H, Yoshimura S, Maruyama T, Muragaki Y, Iwama T. Metabolic assessment of gliomas using 11C-methionine, [18F] fluorodeoxyglucose, and 11C-choline positron-emission tomography. AJNR Am J Neuroradiol. 2008 Jun;29(6):1176-82. doi: 10.3174/ajnr.A1008. Epub 2008 Apr 3. PubMed PMID: 18388218.

Gumprecht H, Grosu AL, Souvatsoglou M, Dzewas B, Weber WA, Lumenta CB. 11C-Methionine positron emission tomography for preoperative evaluation of suggestive low-grade gliomas. Zentralbl Neurochir. 2007 Feb;68(1):19-23. PubMed PMID: 17487804.

Beppu T, Sato Y, Sasaki T, Terasaki K, Yamashita F, Sasaki M, Ogasawara K. Comparisons Between PET With 11C-Methyl-L-Methionine and Arterial Spin Labeling Perfusion Imaging in Recurrent Glioblastomas Treated With Bevacizumab. Clin Nucl Med. 2018 Dec 17. doi: 10.1097/RLU.0000000000002417. [Epub ahead of print] PubMed PMID: 30562194.

Arbizu J, Tejada S, Marti-Climent JM, Diez-Valle R, Prieto E, Quincoces G, Vigil C, Idoate MA, Zubieta JL, Peñuelas I, Richter JA. Quantitative volumetric analysis of gliomas with sequential MRI and ¹¹C-methionine PET assessment: patterns of integration in therapy planning. Eur J Nucl Med Mol Imaging. 2012 May;39(5):771-81. doi: 10.1007/s00259-011-2049-9. Epub 2012 Jan 19. PubMed PMID: 22258713.

Lopci E, Riva M, Olivari L, Raneri F, Soffietti R, Piccardo A, Bizzi A, Navarria P, Ascolese AM, Rudà R, Fernandes B, Pessina F, Grimaldi M, Simonelli M, Rossi M, Alfieri T, Zucali PA, Scorsetti M, Bello L, Chiti A. Prognostic value of molecular and imaging biomarkers in patients with supratentorial glioma. Eur J Nucl Med Mol Imaging. 2017 Jan 21. doi: 10.1007/s00259-017-3618-3. [Epub ahead of print] PubMed PMID: 28110346.

Mini mental state examination for hydrocephalus

Matsuoka et al., analyzed their Mini Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Trail Making Test (TMT) scores on tests conducted before and 1 day and 1 week after the Cerebrospinal fluid tap test (CSFTT).

Changes in MMSE scores were negligible 1 day after the CSFTT but began to appear 1 week later. Changes in FAB scores were observed from 1 day to 1 week after the CSFTT. Although no statistically significant differences in TMT scores were observed at either time point, the execution time for the test tended to be shorter on the day after the CSFTT. Changes in cognitive function were not associated with demographic or morphological parameters. More severe impairments at baseline, however, were associated with greater changes in cognitive function.

Performing several reevaluations using each test may enable more accurate assessment of cognitive function in patients with suspected iNPH. The results highlight the need for long-term follow-up, regardless of the severity of cognitive impairment 1).

A significant difference between normal pressure hydrocephalus (NPH) and controls in the change between baseline and 1 day after spinal tap was only observed in MMSE. In the domains of visuoconstructive function and attention, controls performed slightly better at day one compared to baseline, which could be interpreted as a learning effect, but after adjusting for multiple testing none of the P values were significant. In contrast to other reports, the MMSE seems to provide a sensitive evaluation of the response to spinal tap in NPH patients and might therefore be included into the routine work up of NPH patients. All other neuropsychological (NPSY) tests showed less prominent changes within 1 day after spinal tap 2).



Matsuoka T, Akakabe M, Iida JI, Kawahara M, Uchiyama Y. Changes in Cognitive Function Scores After Cerebrospinal Fluid Tap Testing in Patients with Suspected Idiopathic Normal-Pressure Hydrocephalus. Cogn Behav Neurol. 2018 Dec;31(4):201-206. doi: 10.1097/WNN.0000000000000176. PubMed PMID: 30562229.

Schmidt H, Elster J, Eckert I, Wiefek J, Paulus W, von Steinbuechel N, Abatih EN, Blocher J. Cognitive functions after spinal tap in patients with normal pressure hydrocephalus. J Neurol. 2014 Sep 20. [Epub ahead of print] PubMed PMID: 25239390.


Tariquidar (INN/USAN) is a P-glycoprotein inhibitor undergoing research as an adjuvant against multidrug resistance in cancer.

Cyclin D1 (CCND1) is frequently overexpressed in malignant gliomas.

Zhang et al., have previously shown ectopic overexpression of CCND1 in human malignant gliomas cell lines.

Quantitative Reverse transcription polymerase chain reaction and Western Blot (WB) was performed to investigate the expression of CCND1 in glioma tissues and cell lines. The biological function of CCND1 was also investigated through knockdown and overexpression of BCYRN1 in vitro.

They reported that CCND1 expression was positively associated with the pathological grade and proliferative activity of astrocytomas, as the lowest expression was found in normal brain tissue (N = 3) whereas the highest expression was in high grade glioma tissue (N = 25). Additionally, they found that the expression level of CCND1 was associated with IC50 values in malignant glioma cell lines. Forced inhibition of CCND1 increased temozolomide efficacy in U251 and SHG-44 cells. After CCND1 overexpression, the temozolomide efficacy decreased in U251 and SHG-44 cells. Colony survival assay and apoptosis analysis confirmed that CCND1 inhibition renders cells more sensitive to temozolomide treatment and temozolomide-induced apoptosis in U251 and SHG-44 cells. Inhibition of P-gp (MDR1) by Tariquidar overcomes the effects of CCND1 overexpression on inhibiting temozolomide-induced apoptosis. Inhibition of CCND1 inhibited cell growth in vitro and in vivo significantly more effectively after temozolomide treatments than single temozolomide treatments. Finally, inhibition of CCND1 in glioma cells reduced tumor volume in a murine model.

Taken together, these data indicate that CCND1 overexpression upregulate P-gp and induces chemoresistance in human malignant gliomas cells and that inhibition of CCND1 may be an effective means of overcoming CCND1 associated chemoresistance in human malignant glioma cells 1).

Studies in rodents suggest that flumazenil is a P-glycoprotein substrate at the blood-brain barrier. This study aimed to assess whether [11C]flumazenil is a P-glycoprotein substrate in humans and to what extent increased P-glycoprotein function in epilepsy may confound interpretation of clinical [11C]flumazenil studies used to assess gamma-aminobutyric acid A receptors. Nine drug-resistant patients with epilepsy and mesial temporal sclerosis were scanned twice using [11C]flumazenil before and after partial P-glycoprotein blockade with tariquidar. Volume of distribution, nondisplaceable binding potential, and the ratio of rate constants of [11C]flumazenil transport across the blood-brain barrier (K1/k2) were derived for whole brain and several regions. All parameters were compared between pre- and post-tariquidar scans. Regional results were compared between mesial temporal sclerosis and contralateral sides. Tariquidar significantly increased global K1/k2 (+23%) and volume of distribution (+10%), but not nondisplaceable binding potential. At the mesial temporal sclerosis side volume of distribution and nondisplaceable binding potential were lower in hippocampus (both ∼-19%) and amygdala (both ∼-16%), but K1/k2 did not differ, suggesting that only regional gamma-aminobutyric acid A receptor density is altered in epilepsy. In conclusion, although [11C]flumazenil appears to be a (weak) P-glycoprotein substrate in humans, this does not seem to affect its role as a tracer for assessing gamma-aminobutyric acid A receptor density 2).

Brandt et al., selected a group of phenobarbital-resistant rats, which was subsequently treated by combinations of phenobarbital with the selective P-gp inhibitor tariquidar. Coadministration of tariquidar (15-20 mg/kg) fully restored the anticonvulsant activity of phenobarbital without altering plasma pharmacokinetics or neurotoxicity of the antiepileptic drug. These data demonstrate that inhibiting P-gp in epileptic rats with proven drug resistance counteracts resistance, providing the first proof-of-principle of the multidrug transporter hypothesis of medically refractory epilepsy 3).



Zhang D, Dai D, Zhou M, Li Z, Wang C, Lu Y, Li Y, Wang J. Inhibition of Cyclin D1 Expression in Human Glioblastoma Cells is Associated with Increased Temozolomide Chemosensitivity. Cell Physiol Biochem. 2018 Dec 11;51(6):2496-2508. doi: 10.1159/000495920. [Epub ahead of print] PubMed PMID: 30562739.

Froklage FE, Postnov A, Yaqub MM, Bakker E, Boellaard R, Hendrikse NH, Comans EF, Schuit RC, Schober P, Velis DN, Zwemmer J, Heimans JJ, Lammertsma AA, Voskuyl RA, Reijneveld JC. Altered GABAA receptor density and unaltered blood-brain barrier [11C]flumazenil transport in drug-resistant epilepsy patients with mesial temporal sclerosis. J Cereb Blood Flow Metab. 2017 Jan;37(1):97-105. Epub 2015 Nov 19. PubMed PMID: 26661244; PubMed Central PMCID: PMC5167109.

Brandt C, Bethmann K, Gastens AM, Löscher W. The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis. 2006 Oct;24(1):202-11. Epub 2006 Aug 22. PubMed PMID: 16928449.
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