Marco Skardelly

In vivo visualization of prostate-specific membrane antigen in glioblastoma

The expansion of nutrient vessels is an important factor in the growth of glioblastomas (GBM), which is one of the most vascularized tumours [1]. Therefore, new treatment concepts that include tumour vasculature targets are currently under investigation. Prostate-specific membrane antigen (PSMA) is overexpressed in the tumour vasculature of GBM, which therefore might be considered as a potential endothelial target for treatment with PSMA-based agents [2, 3]. However, according to the limited data so far available, PSMA expression in brain tumours varies with glioma grade [4]. PSMAexpressionwas evaluated in a patient suffering fromGBM prior to surgery by simultaneous PET/MR with [Ga]

Correlative assessment of tumor microcirculation using contrast‐enhanced perfusion MRI and intravoxel incoherent motion diffusion‐weighted MRI: is there a link between them?

The purpose of this study was to correlate intravoxel incoherent motion (IVIM) imaging with classical perfusion‐weighted MRI metrics in human gliomas. Parametric images for slow diffusion coefficient (D), fast diffusion coefficient (D*), and fractional perfusion‐related volume (f) in patients with high‐grade gliomas were generated. Maps of Fp (plasma flow), vp (vascular plasma volume), PS (permeability surface–area product), ve (extravascular, extracellular volume), E (extraction ratio), ke (influx ratio into the interstitium), and tc (vascular transit time) from dynamic contrast‐enhanced (DCE) and dynamic susceptibility contrast‐enhanced (DSC) MRI were also generated. A region‐of‐interest analysis on the contralateral healthy white matter and on the tumor areas was performed and the extracted parameter values were tested for any significant differences among tumor grades or any correlations. Only f could be significantly correlated to DSC‐derived vp and tc in healthy brain tissue. Concerning the tumor regions, Fp was significantly positively correlated with D* and inversely correlated with f in DSC measurements. The D*, f, and f × D* values in the WHO grade III gliomas were non‐significantly different from those in the grade IV gliomas. There was a trend to significant negative correlations between f and PS as well as between f × D* and ke in DCE experiments. Presumably due to different theoretical background, tracer properties and modeling of the tumor vasculature in the IVIM theory, there is no clearly evident link between D*, f and DSC‐ and DCE‐derived metrics. Copyright

Comparison of Three Different MR Perfusion Techniques and MR Spectroscopy for Multiparametric Assessment in Distinguishing Recurrent High-Grade Gliomas from Stable Disease

RATIONALE AND OBJECTIVES Magnetic resonance (MR) perfusion techniques and MR spectroscopy (MRS) provide specific physiological information that may allow distinction between recurrent glioma and progression from stable disease. MATERIALS AND METHODS Forty patients underwent conventional MR imaging, dynamic contrast-enhanced T1-weighted perfusion imaging, dynamic susceptibility contrast-enhanced perfusion imaging (DSC), and multivoxel MRS. Arterial spin labeling was available in 26 of these patients. Quantitative parameters were calculated in tumor recurrences and stable disease, which were retrospectively verified on clinical and radiological follow-up. Receiver operating characteristic curves for each parameter were generated for the differentiation between recurrent glioma and stable disease. A forward discriminant analysis was undertaken to assess the power of the conjunction of MR perfusion techniques and MRS. RESULTS Of the 40 patients, 23 were determined to have recurrent gliomas. Differences in arterial spin labeling between the two groups were not statistically significant (P = .063). Sensitivities and specificities for the detection of recurrent lesions in dynamic contrast-enhanced T1-weighted perfusion imaging and DSC were 61.9% and 80% transfer constant k(trans), 77.3% and 84.6% for cerebral blood flow, and 81% and 76.9% for cerebral blood volume, respectively. Among the parameters in MRS, the ratio of choline to normalized creatine showed the best diagnostic accuracy (P = .014; sensitivity 70%, specificity 78.6%). When considering all perfusion modalities, diagnostic accuracy could be increased to 82.5%, adding MRS to the multiparametric approach resulted in a diagnostic accuracy of 90.0%. CONCLUSIONS MR perfusion techniques and MRS are useful tools that enable improved differentiation between recurrent glioma and stable disease. Among the single parameters, DSC showed the best diagnostic performance. Multiparametric assessment substantially improved the ability to differentiate the two entities.

In vivo molecular profiling of human glioma using diffusion kurtosis imaging

The purpose of this study is to assess the diagnostic performance of diffusion kurtosis imaging (DKI) for in vivo molecular profiling of human glioma. Normalized mean kurtosis (MKn) and mean diffusivity (MDn) metrics from DKI were assessed in 50 patients with histopathologically confirmed glioma. The results were compared in regard to the WHO-based histological findings and molecular characteristics leading to integrated diagnosis (Haarlem Consensus): isocitrate-dehydrogenase (IDH1/2) mutation status, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression, chromosome 1p/19q loss of heterozygosity (LOH), and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. MKn was significantly lower in tumors with IDH1/2 mutation (0.43 ± 0.09) and ATRX loss of expression (0.41 ± 0.11) than in those with IDH1/2 wild type (0.57 ± 0.09, p < 0.001) and ATRX maintained expression (0.51 ± 0.10, p = 0.004), respectively. Regarding the integrated molecular diagnosis, MKn was significantly higher in primary glioblastoma (0.57 ± 0.10) than in astrocytoma (0.39 ± 0.11, p < 0.001) and oligodendroglioma (0.47 ± 0.05, p = 0.003). MK may be used to provide insight into the human glioma molecular profile regarding IDH1/2 mutation status and ATRX expression. Considering the diagnostic and prognostic significance of these molecular markers, MK appears to be a promising in vivo biomarker for glioma. The diagnostic performance of MK seems to fit more with the integrated molecular approach than the conventional histological findings of the current WHO 2007 classification.

Predictors of preoperative and early postoperative seizures in patients with intra‐axial primary and metastatic brain tumors: A retrospective observational single center study

Antiepileptic treatment of brain tumor patients mainly depends on the individual physicians choice rather than on well‐defined predictive factors. We investigated the predictive value of defined clinical parameters to formulate a model of risk estimations for subpopulations of brain tumor patients.

Prognostic Value of Blood Flow Measurements Using Arterial Spin Labeling in Gliomas

The period of event-free survival (EFS) within the same histopathological glioma grades may have high variability, mainly without a known cause. The purpose of this study was to reveal the prognostic value of quantified tumor blood flow (TBF) values obtained by arterial spin labeling (ASL) for EFS in patients with histopathologically proven astrocytomas independent of WHO (World Health Organization) grade. Twenty-four patients with untreated gliomas underwent tumor perfusion quantification by means of pulsed ASL in 3T. The clinical history of the patients was retrospectively extracted from the local database. Six patients had to be excluded due to insufficent follow-up data for further evaluation or histopathologically verified oligodendroglioma tumor components. Receiver operating characteristic (ROC) curves were used to define an optimal cut-off value of maximum TBF (mTBF) values for subgrouping in low-perfused and high-perfused gliomas. Kaplan-Meier curves and Cox proportional hazard regression model were used to determine the prognostic value of mTBF for EFS. An optimal mTBF cut-off value of 182 ml/100 g/min (sensitivity  = 83%, specificity  = 100%) was determined. Patients with low-perfused gliomas had significantly longer EFS compared to patients with high-perfused gliomas (p = 0.0012) independent of the WHO glioma grade. Quantified mTBF values obtained by ASL offer a new and totally non-invasive marker to prognosticate the EFS, independently on histopathological tumor grading, in patients with gliomas.

Spectroscopy imaging in intraoperative MR suite: tissue characterization and optimization of tumor resection

BackgroundMR spectroscopy (MRS) measurements are common practice in the preoperative diagnostic regimen, but no evidence exists concerning their value in intraoperative MRI (iMRI) setting. We sought to examine the feasibility of intraoperative MRS and to assess the clinical value of the method in optimizing the gliomas resection.MethodsForty-five patients with low- and high-grade gliomas underwent iMRI-assisted surgery, including pre- and intraoperative MRS measurements. During the intraoperative control scan, MRS was performed at the resection margin. Peak areas under the major metabolites (N-acetyl-aspartate: NAA; choline: Cho; and creatine: Cr) resonances were estimated, and their ratios entered in the statistical analysis.ResultsConcerning preoperative MRS imaging, mean Cho/NAA and Cho/Cr ratios in low-grade gliomas were 2.3 and 1.2, respectively. The average Cho/NAA and Cho/Cr ratios in the high-grade gliomas were 3.9 and 2.3, respectively. In 12 out of 20 cases with low-grade gliomas, intraoperative conventional MR imaging showed suspected tumor remnant and MRS diagnosed correctly the tissue signal alterations in 10 out of those 12 cases. MRS could characterize gadolinium-enhancing or non-enhancing tumor remnants in all cases with high-grade tumors. Thus, it could help achieve total tumor resection unless the latter was contraindicated due to increased risk of neurological complications.ConclusionsMR spectroscopy (MRS) in an iMRI setting is feasible, facilitating preoperative glioma staging as well as satisfactory characterization of suspected tumor remnants. Thus, it may be helpful tool for an extended tumor resection.

MR spectroscopy for in vivo assessment of the oncometabolite 2-hydroxyglutarate and its effects on cellular metabolism in human brain gliomas at 9.4T.

To examine in vivo metabolic alterations in the isocitrate dehydrogenase (IDH) mutated gliomas using magnetic resonance spectroscopy (MRS) at magnetic field 9.4T.

Prognostic value of blood flow estimated by arterial spin labeling and dynamic susceptibility contrast-enhanced MR imaging in high-grade gliomas

Several studies evaluated the predictive value of dynamic susceptibility contrast enhanced (DSC) imaging and arterial spin labeling (ASL) with regard to histological grade. Yet still less is known about their significance in terms of patients prognosis. Our purpose was to evaluate the agreement between them and the prognostic value of ASL- and DSC-CBF measurements for time-to-recurrence (TTR). Sixty nine cases of WHO Grade 3–4 gliomas underwent both DSC- and ASL-MRI. Normalized ASL and DSC-based cerebral blood flow (CBF) maps as well as DSC-derived cerebral blood volume maps (CBV) were analyzed. Wilcoxon test and Bland–Altman plot analysis were applied in order to compare DSC-rCBF and ASL-rCBF. Spearman’s rank correlation coefficients were determined for all perfusion parameters. Receiver operating characteristic (ROC) curve and survival curve analyses were performed. The median values of ASL-rCBF, DSC-rCBF, and DSC-rCBV were 5.3, 6.9, and 8.0, respectively. There was neither significant correlation nor difference between ASL-rCBF and DSC-rCBF. Slight proportional bias was demonstrated in the Bland–Altman plot analysis of ASL-rCBF and DSC-rCBF values. Unlikely to DSC-rCBV, DSC- and ASL-based rCBF parameters demonstrated moderate sensitivity and specifitity for tumor recurrence but no statistical significance regarding their prognostic values for TTR in the Kaplan–Meier analysis. There were neither correlation nor interchangeability between the DSC-rCBF and ASL-rCBF estimations, which demonstrated comparable, though not significant prognostic value for the prediction of TTR. rCBV measurements seem to provide the best sensitivity and specificity to predict tumor recurrence and survival time in these patients.

Primary cerebral low-grade B-cell lymphoma, monoclonal immunoglobulin deposition disease, cerebral light chain deposition disease and “aggregoma”: an update on classification and diagnosis

BackgroundThis work aims to add evidence and provide an update on the classification and diagnosis of monoclonal immunoglobulin deposition disease (MIDD) and primary central nervous system low-grade lymphomas. MIDD is characterized by the deposition of light and heavy chain proteins. Depending on the spatial arrangement of the secreted proteins, light chain-derived amyloidosis (AL) can be distinguished from non-amyloid light chain deposition disease (LCDD). We present a case of an extremely rare tumoral presentation of LCDD (aggregoma) and review the 3 previously published LCDD cases and discuss their presentation with respect to AL.Case presentationA 61-year-old woman presented with a 3½-year history of neurologic symptoms due to a progressive white matter lesion of the left subcortical parieto-insular lobe and basal ganglia. 2 former stereotactic biopsies conducted at different hospitals revealed no evidence of malignancy or inflammation; thus, no therapy had been initiated. After performing physiological and functional magnetic resonance imaging (MRI), the tumor was removed under intraoperative monitoring at our department. Histological analysis revealed large amorphous deposits and small islands of lymphoid cells.ConclusionLCCD is a very rare and obscure manifestation of primary central nervous system low-grade lymphomas that can be easily misdiagnosed by stereotactic biopsy sampling. If stereotactic biopsy does not reveal a definite result, a “wait-and-see” strategy can delay possible therapy for this disease. The impact of surgical removal, radiotherapy and chemotherapy in LCDD obviously remains controversial because of the low number of relevant cases.