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Purpose To investigate the potential of radiomics applied to static clinical PET data using the tracer O-(2-[18F]fluoroethyl)-l-tyrosine (FET) to differentiate treatment-related changes (TRC) from tumor progression (TP) in patients with gliomas. Patients and Methods One hundred fifty-one (151) patients with histologically confirmed gliomas and post-therapeutic progressive MRI findings according to the response assessment in neuro-oncology criteria underwent a dynamic amino acid PET scan using the tracer O-(2-[18F]fluoroethyl)-l-tyrosine (FET). Thereof, 124 patients were investigated on a stand-alone PET scanner (data used for model development and validation), and 27 patients on a hybrid PET/MRI scanner (data used for model testing). Mean and maximum tumor to brain ratios (TBRmean, TBRmax) were calculated using the PET data from 20 to 40 min after tracer injection. Logistic regression models were evaluated for the FET PET parameters TBRmean, TBRmax, and for radiomics features of the tumor areas as well as combinations thereof to differentiate between TP and TRC. The best performing models in the validation dataset were finally applied to the test dataset. The diagnostic performance was assessed by receiver operating characteristic analysis. Results Thirty-seven patients (25%) were diagnosed with TRC, and 114 (75%) with TP. The logistic regression model comprising the conventional FET PET parameters TBRmean and TBRmax resulted in an AUC of 0.78 in both the validation (sensitivity, 64%; specificity, 80%) and the test dataset (sensitivity, 64%; specificity, 80%). The model combining the conventional FET PET parameters and two radiomics features yielded the best diagnostic performance in the validation dataset (AUC, 0.92; sensitivity, 91%; specificity, 80%) and demonstrated its generalizability in the independent test dataset (AUC, 0.85; sensitivity, 81%; specificity, 70%). Conclusion The developed radiomics classifier allows the differentiation between TRC and TP in pretreated gliomas based on routinely acquired static FET PET scans with a high diagnostic accuracy.

Purpose Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study. Methods We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS. Results IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p p Conclusion This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.

Purpose We aimed to re-evaluate the relationship between thalamic infarct (TI) localization and clinical symptoms using a vascular (VTM) and a novel functional territorial thalamic map (FTM). Methods Magnetic resonance imaging (MRI) and clinical data of 65 patients with isolated TI were evaluated (female n = 23, male n = 42, right n = 23, left n = 42). A VTM depicted the known seven thalamic vascular territories (VT: inferolateral, anterolateral, inferomedial, posterior, central, anteromedian, posterolateral). An FTM was generated from a probabilistic thalamic nuclei atlas to determine six functionally defined territories (FT: anterior: memory/emotions; ventral: motor/somatosensory/language; medial: behavior/emotions/nociception, oculomotor; intralaminar: arousal/pain; lateral: visuospatial/somatosensory/conceptual and analytic thinking; posterior: audiovisual/somatosensory). Four neuroradiologists independently assigned diffusion-weighted imaging (DWI) lesions to the territories mapped by the VTM and FTM. Findings were correlated with clinical features. Results The most frequent symptom was a hemisensory syndrome (58%), which was not specific for any territory. A co-occurrence of hemisensory syndrome and hemiparesis had positive predictive values (PPV) of 76% and 82% for the involvement of the inferolateral VT and ventral FT, respectively. Thalamic aphasia had a PPV of 63% each for involvement of the anterolateral VT and ventral FT. Neglect was associated with involvement of the inferolateral VT/ventral FT. Interrater reliability for the assignment of DWI lesions to the VTM was fair (κ = 0.36), but good (κ = 0.73) for the FTM. Conclusion The FTM revealed a greater reproducibility for the topographical assignment of TI than the VTM. Sensorimotor hemiparesis and neglect are predictive for a TI in the inferolateral VT/ventral FT. The hemisensory syndrome alone does not allow any topographical assignment.

Superficial siderosis is a consequence of repetitive bleeding into the subarachnoid space, leading to toxic iron and hemosiderin deposits on the surface of the brain and spine. The clinical and radiological phenotypes of superficial siderosis are known to manifest over long time intervals. In contrast, this study defines the “acute superficial siderosis syndrome” and illustrates typical imaging and histopathological findings of this entity. We describe the case of a 61-year-old male patient who was diagnosed with a melanoma metastasis in the right frontal cortex in February 2019. Within a few weeks he developed a progressive syndrome characterized by cerebellar ataxia, gait disturbance, signs of myelopathy, and radiculopathy. MRI revealed ongoing hemorrhage from the metastasis into the lateral ventricle and the subarachnoid space. A semiquantitative assessment of three subsequent MRI within an 8-week period documented the rapid development of superficial siderosis along the surface of the cerebellum, the brain stem, and the lower parts of the supratentorial regions on T2*-weighted sequences. The diagnosis of a superficial siderosis was histopathologically confirmed by identifying iron and hemosiderin deposits on the cortex along with astrogliosis. The recognition of this “acute superficial siderosis syndrome” triggered surgical removal of the hemorrhagic metastasis. Based on a single case presentation, we define the “acute superficial siderosis syndrome” as a clinical entity and describe the radiological and histopathological characteristics of this entity. Early recognition of this syndrome may allow timely elimination of the bleeding source, in order to prevent further clinical deterioration.

European journal of nuclear medicine and molecular imaging 48(6), 1956-1965 (2020). doi:10.1007/s00259-020-05114-0, Published by Springer-Verl., Heidelberg [u.a.]

Dynamic susceptibility contrast (DSC) MR-perfusion is becoming a standard of care for the monitoring of glioblastoma. Yet, technical standards are lacking and measurements without leakage correction are still common. Also, data on leakage corrected measurements during stable disease is scarce. In this study we hypothesized that basic leakage correction would significantly enhance data quality during stable disease and improve progress detection. We furthermore investigated whether longitudinal data could increase diagnostic performance. Patients with histologically proven glioblastoma undergoing first-line therapy were prospectively recruited. We conducted DSC perfusion measurements without prebolus administration in 6-week intervals from the end of radiotherapy until progression. Maximum relative cerebral volume values (rCBVmax) with and without leakage correction were calculated using Philips IntelliSpace®. We recruited 16 patients and conducted 82 MRI scans with a mean follow up of 7.2 month. During stable disease, corrected rCBVmax was significantly more stable than uncorrected rCBVmax. Detection of progression with a rCBVmax cutoff was better for corrected (specificity 86%) than for uncorrected rCBVmax (specificity 41%). Interestingly, the increase of corrected rCBVmax upon progression also had a good diagnostic performance with a combination of both cutoffs delivering the best result (sensitivity/specificity 89%/93%). Corrected rCBVmax supports the imaging finding of a stable disease and large increases during longitudinal observation support the diagnosis of tumor progression. rCBV values without prebolus or leakage correction are not reliable to monitor glioblastomas. Further studies to investigate the value of longitudinal rCBV dynamics for the differentiation of real tumor progression from pseudoprogression are warranted.

Background: In brain tumor surgery, injury to cerebellar connectivity pathways can induce a neurodegenerative disease called hypertrophic olivary degeneration (HOD), along with a disabling clinical syndrome. In children, cerebellar mutism syndrome (CMS) is another consequence of damage to cerebello&ndash, thalamo&ndash, cortical networks. The goal of this study was to compare paravermal trans-cerebellar to other more midline or lateral operative approaches in their risk of causing HOD on MR-imaging and CMS. Methods: We scanned our neurosurgical database for patients with surgical removal of pilocytic astrocytoma, ependymoma and medulloblastoma in the posterior fossa. Fifty patients with a mean age of 22.7 (&plusmn, 16.9) years were identified and analyzed. Results: HOD occurred in n = 10/50 (20%) patients within four months (median), always associated with contralateral dentate nucleus (DN)-lesions (p &lt, 0.001). Patients with paravermal trans-cerebellar approach significantly more often developed HOD (7/11, 63.6%) when compared to other approaches (3/39, 7.7%, p &lt, 0.001). Injury to the DN occurred more frequently after a paravermal approach (8/11 vs. 13/39 patients, 0.05). CMS was described for n = 12/50 patients (24%). Data indicated no correlation of radiological HOD and CMS development. Conclusions: A paravermal trans-cerebellar approach more likely causes HOD due to DN-injury when compared to more midline or lateral approaches. HOD is a radiological indicator for surgical disruption of cerebellar pathways involving the DN. Neurosurgeons should consider trajectories and approaches in the planning of posterior fossa surgery that spare the DN, whenever feasible.

Introduction: Gliomatosis cerebri (GC) is defined by diffuse, widespread glial tumor growth affecting three or more cerebral lobes. Previous studies in gliomas found no distinct histological or molecular GC subtype, yet the presence of GC is associated with worse median overall survival (OS). Here, we explored whether differing therapeutic strategies in first-line treatment could account for this. Methods: From our University Cancer Center database, 47 patients with histological diagnosis of WHO grade II or III glioma and GC imaging pattern were identified. GC criteria were confirmed by independent review. Patients with WHO grade II or III glioma with non-GC pattern served as control cohort (n = 343). Results: Within the GC patient cohort, lower WHO grade, mutated isocitrate dehydrogenase 1 (IDH1) status, and absence of contrast enhancement were associated with better OS. Compared to the control cohort, patients with GC had significantly shorter OS independent of histological diagnosis or IDH1 mutation status. Patients with GC preferentially received chemotherapy alone (62 vs. 18%), and less frequently radiochemotherapy (21 vs. 27%). OS was significantly shorter in the GC cohort compared to the non-GC cohort both for chemotherapy (3.9 vs. 7.6 years, p = 0.0085) and for combined radiochemotherapy (1.1 vs. 8.4 years, p < 0.0001). However, when only patients who received biopsy plus chemotherapy were analyzed, the differences lost statistical significance (3.5 vs. 6.6 years, p = 0.196). Conclusion: We found major differences in the selection of first-line therapies of GC versus non-GC patients. Our results suggest that these differences may partly account for the worse prognosis of GC patients.

(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas. (2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients’ serum and CSF. (3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003). Diffusion restrictions were observed in 13 patients. (4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor.

BACKGROUND The term gliomatosis cerebri (GC) refers to glial brain tumors with widespread tumor expansion affecting three or more cerebral lobes. Formerly considered a distinct tumor entity, recent studies found no difference in the mutational profile of glial tumors with GC growth pattern compared to non-GC gliomas. Thus, in the new WHO classification of brain tumors, GC is no longer included as a separate diagnosis. While the presence of gliomas with GC growth pattern is associated with worse overall survival (OS), the underlying factors remain to be identified. Here, we asked whether differing therapeutic strategies in first line treatment could account for the worse outcome of patients with GC growth pattern and grade II and III histology. MATERIAL AND METHODS From the patient data bank of the University Cancer Center (UCT) Frankfurt, 47 patients with histological diagnosis of WHO grade II or III glioma, and with record of GC imaging pattern were identified. GC tumor expansion was confirmed by review of MRI scans prior to treatment initiation. Patients with WHO grade II or III glioma without GC growth pattern served as control cohort (n=379). IDH mutational status was available for 75% of GC tumors (IDH R132H mutated 32%; non-mutated 43%) and 69% of non-GC tumors (IDH R132H mutated 57%; non-mutated 12%). RESULTS Within the GC patient cohort, patients with tumors without contrast enhancement, lower WHO grade and mutated IDH status showed better OS. Compared to the control cohort, patients with GC had significantly shorter OS. This was independent of histological diagnosis or IDH mutation status. Patients with GC more frequently underwent radiochemotherapy (17% vs. 9% in the non-GC cohort), and drastically more often received chemotherapy alone (51% vs. 5%). We then analyzed OS in GC and non-GC patients that had received the same first line treatments. For radiochemotherapy in GC versus non-GC patients, OS was 1.1 years vs. 12.7 years (p =0.0075, log-rank test). For upfront chemotherapy alone, OS was significantly shorter in the GC cohort than in the non-GC cohort (3,6 years vs. undefined, p =0.0016, log-rank test). CONCLUSION Differences in first-line treatment cannot account for the worse prognosis of patients with GC imaging pattern. Further studies are needed to pinpoint biological or clinical factors that might influence responsiveness to therapy and prognosis of GC tumors.

CNS germinoma is a malignant germ cell tumor with a high potential for curative treatment. In MRI it mainly appears as contrast enhancing mass in the midline structures of the brain but it can also occur atypically located in the basal ganglia. We present the case of a 21-year-old patient suffering from psychiatric symptoms and a mild, right-sided hemiparesis. A MRI scan solely showed diffuse T2/FLAIR hyperintensity and mild atrophy around the left basal ganglia. As excessive diagnostics remained insignificant, 1H-MR-spectroscopy was performed. Considering the previous diagnostics, increased choline, decreased NAA and increased Myoinositol suggested a malignant disease. Consequently, brain biopsy was performed, revealing a germinoma. In comparable, published cases a lack of evidence for a neoplastic disease usually leads to a severely delayed diagnosis. Our report shows for the first time, that this evidence can be obtained early with MR-spectroscopy and discusses the possibility of specific metabolic patterns.

INTRODUCTION: Classification as well as treatment of patients with lower grade gliomas (°II+°III) have changed fundamentally during the last years. Molecular markers have augmented diagnostic workup and combined radiochemotherapy was established for most of the subgroups. However, molecular markers have not been part of the inclusion criteria of most of the relevant clinical trials. Larger analyses outside of clinical trials are rare. MATERIALS AND METHODS: We screened our clinical cancer database for patients with lower grade glioma newly diagnosed from 1995 to 2015. We identified 774 patients of whom 345 had to be excluded, resulting in an evaluable cohort of 423 patients. We evaluated general characteristics, morphological diagnosis, molecular markers, treatment, time-to-treatment-failure (TTF; initiation of a new treatment or death) and overall survival (OS). RESULTS: According to the 2007 WHO classification our cohort included 145 (34.3%) Astrocytoma WHO °II, 56 (13.3%) Oligoastrocytoma/Oligodendroglioma WHO °II, 129 (52.5%) Astrocytoma WHO °III and 93 (22.0%) Oligoastrocytoma/Oligodendroglioma WHO °III. In 235 patients we were able to molecularly classify the tumors based on the 2017 WHO classification using IDH status and 1p/19q or ATRX status. Patients with a molecularly defined Oligodendroglioma showed a median TTF of 5.2, 4.2 and 7.8 years for radiotherapy, chemotherapy and radiochemotherapy, respectively. Patients with a molecularly defined Astrocytoma showed a median TTF of 1.6, 2.9 and 6.7 years for radiotherapy, chemotherapy and radiochemotherapy, respectively. In IDH wildtype tumors TTF was below 12 months without relevant differences. Treatment with combined radiochemotherapy resulted in markedly improve TTF in molecular defined oligodendroglioma and astrocytoma compared with either radiotherapy or chemotherapy alone. Due to the short follow-up of 5.3 years (mean) median OS has not been reached for any of the IDH mutant subgroups. CONCLUSIONS: Combined treatment with radiotherapy and chemotherapy resulted in markedly improved TTF in patients with molecularly defined oligodendroglioma and astrocytoma.

Background: Antiangiogenic treatment of glioblastomas with Bevacizumab lacks predictive markers. Myoinositol (MI) is an organic osmolyte, with intracellular concentration changes depending on the extracellular osmolality. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy. Methods: We used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8–12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control. We performed a survival analysis to evaluate MI as a predictive biomarker for Bevacizumab therapy. Results: MI concentrations increased significantly during Bevacizumab therapy in tumor (p < .001) and control tissue (p = .001), but not during CCNU/VM26 treatment. For the Bevacizumab cohort, higher MI concentrations in the control tissue at baseline (p = .021) and higher differences between control and tumor tissue (delta MI, p = .011) were associated with longer survival. A Kaplan-Meier analysis showed a median OS of 164 days for patients with a deltaMI < 1,817 mmol/l and 275 days for patients with a deltaMI > 1,817 mmol/l. No differences were observed for the relative changes or the post treatment concentrations. Additionally calculated creatine concentrations showed no differences in between subgroups or between pre and post treatment measurements. Conclusion: Our data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab. Further, our results support the hypothesis that MI might be a marker for early tumor cell invasion. Pre-therapeutic MI concentrations are predictive of overall survival in patients with recurrent glioblastoma treated with Bevacizumab.

BACKGROUND: Classification as well as treatment of patients with lower grade gliomas (°II+°III) have changed fundamentally during the last years. Molecular markers have augmented diagnostic workup and combined radiochemotherapy was established for most of the subgroups. However, molecular markers have not been part of the inclusion criteria of most of the relevant clinical trials. Larger analyses outside of clinical trials are rare. MATERIAL AND METHODS: We screened our clinical cancer database for patients with lower grade glioma newly diagnosed from 1995 to 2015. We identified 774 patients of whom 345 had to be excluded, resulting in an evaluable cohort of 423 patients. We evaluated general characteristics, morphological diagnosis, molecular markers, treatment, time-to-treatment-failure (TTF; initiation of a new treatment or death) and overall survival (OS). RESULTS: According to the 2007 WHO classification our cohort included 145 (34.3%) Astrocytoma WHO °II, 56 (13.3%) Oligoastrocytoma/Oligodendroglioma WHO °II, 129 (52.5%) Astrocytoma WHO °III and 93 (22.0%) Oligoastrocytoma/Oligodendroglioma WHO °III. In 235 patients we were able to molecularly classify the tumors based on the 2017 WHO classification using IDH status and 1p/19q or ATRX status. Patients with a molecularly defined Oligodendroglioma showed a median TTF of 5.2, 4.2 and 7.8 years for radiotherapy, chemotherapy and radiochemotherapy, respectively. Patients with a molecularly defined Astrocytoma showed a median TTF of 1.6, 2.9 and 6.7 years for radiotherapy, chemotherapy and radiochemotherapy, respectively. In IDH wildtype tumors TTF was below 12 months without relevant differences. Treatment with combined radiochemotherapy resulted in markedly improve TTF in molecular defined oligodendroglioma and astrocytoma compared with either radiotherapy or chemotherapy alone. Due to the short follow-up of 5.3 years (mean) median OS has not been reached for any of the IDH mutant subgroups. CONCLUSION: Combined treatment with radiotherapy and chemotherapy resulted in markedly improved TTF in patients with molecularly defined oligodendroglioma and astrocytoma.