Extended stereotactic brain biopsy in suspected primary central nervous system angiitis: good diagnostic accuracy and high safety.

OBJECTIVE: To evaluate the diagnostic accuracy and safety of extended stereotactic brain biopsy (ESBB) in a single center cohort with suspected primary angiitis of the central nervous system (PACNS). METHODS: A standardized stereotactic biopsy targeting MRI-positive lesions and collecting samples from the meninges and the cortex as well as from the white matter was performed in 23 patients with clinically suspected PACNS between 2010 and 2017. The relationship between biopsy yield and clinical characteristics, cerebrospinal fluid parameters, MR-imaging, time point of biopsy and exact localization of biopsy as well as number of tissue samples were examined. RESULTS: PACNS was confirmed in 7 of 23 patients (30.4%). Alternative diagnoses were identified in 7 patients (30%). A shorter time period between the onset or worsening of symptoms (p = 0.018) and ESBB significantly increased the diagnostic yield. We observed only minor and transient postoperative complications in 3 patients (13.0%). ESBB led to a direct change of the therapeutic regime in 13 of 23 patients (56.5%). Careful neuropathological analysis furthermore revealed that cortical samples were crucial in obtaining a diagnosis. CONCLUSION: ESBB is a safe approach with good feasibility, even in critically ill patients, and high diagnostic accuracy in patients with suspected PACNS changing future therapies in 13 of 23 patients (56.5%). Early biopsy after symptom onset/worsening is crucial and (sub)acute MRI-lesions should be targeted with a particular need for biopsy samples from the cortical layer.

MicroRNA-93 acts as an "anti-inflammatory tumor suppressor" in glioblastoma.

BACKGROUND: Inflammation is an important driver of malignant glioma disease. Inflammatory mediators are not only produced by immune cells in the tumor microenvironment, but also by glioblastoma (GBM) cells themselves creating a mutually reinforcing loop. We here aimed at identifying an "anti-inflammatory switch" that allows to dampen inflammation in GBM. METHODS: We used human GBM specimens, primary cultures, and cell lines. The response of GBM cells toward inflammatory stimuli was tested by incubation with supernatant of stimulated human immune cells. Expression levels were measured by whole transcriptome microarrays and qRT-PCR, and protein was quantified by LUMINEX and SDS-PAGE. MicroRNA binding to 3'UTRs was analyzed by luciferase assays. Proliferation rates were determined by flow cytometry, and invasion and angiogenesis were studied using migration and endothelial tube formation assays. RESULTS: We demonstrated GBM cells to secrete high amounts of proinflammatory mediators in an inflammatory microenvironment. We found miR-93 as a potential "anti-inflammatory tumor suppressor" dramatically downregulated in GBM. Concordantly, cytokine secretion dropped after miR-93 re-expression. Transfection of miR-93 in GBM cells led to down-regulation of hubs of the inflammatory networks, namely, HIF-1α and MAP3K2 as well as IL-6, G-CSF, IL-8, LIF, IL-1ß, COX2, and CXCL5. We showed only COX2 and CXCL5 to be indirectly regulated by miR-93 while all other genes are true targets. Phenotypically, re-expression of miR-93 in GBM cells substantially suppressed proliferation, migration, and angiogenesis. CONCLUSIONS: Alleviating GBM-derived inflammation by re-expression of miR-93 may be a powerful tool to mitigate these tumors' aggressiveness and holds promise for new clinical approaches.

The IL-1 Antagonist Anakinra Attenuates Glioblastoma Aggressiveness by Dampening Tumor-Associated Inflammation.

BACKGROUND: The recombinant IL-1 receptor antagonist anakinra-currently approved for the treatment of autoinflammatory diseases-blocks IL-1ß-mediated inflammatory signaling. As inflammation is a major driver of cancer, we hypothesized that anakinra might be able to mitigate glioblastoma (GBM) aggressiveness. METHODS: Primary GBM or T98G cells were incubated alone or with peripheral blood mononuclear cells (PBMCs) and were subsequently treated with IL-1ß and/or anakinra. T cells were obtained by magnetic bead isolation. Protein and mRNA expression were quantified by SDS-PAGE, qRT-PCR, and ELISA, respectively. Cell proliferation and apoptosis were analyzed via flow cytometry. Chemotaxis was studied via time-lapse microscopy. RESULTS: Upon IL-1ß stimulation, anakinra attenuated proinflammatory gene expression in both GBM cells and PBMCs, and mitigated tumor migration and proliferation. In a more lifelike model replacing IL-1ß stimulation by GBM-PBMC co-culture, sole presence of PBMCs proved sufficient to induce a proinflammatory phenotype in GBM cells with enhanced proliferation and migration rates and attenuated apoptosis. Anakinra antagonized these pro-tumorigenic effects and, moreover, reduced inflammatory signaling in T cells without compromising anti-tumor effector molecules. CONCLUSION: By dampening the inflammatory crosstalk between GBM and immune cells, anakinra mitigated GBM aggressiveness. Hence, counteracting IL-1ß-mediated inflammation might be a promising strategy to pursue.

Non-invasive prediction of IDH-wildtype genotype in gliomas using dynamic 18F-FET PET.

PURPOSE: According to the updated WHO classification of gliomas with its emphasis on molecular parameters, tumours with an IDH-wildtype status have a dismal prognosis. To ensure timely adjustment of treatment, demand for non-invasive prediction methods is high. 18F-FET PET has been shown to be an important diagnostic tool for glioma management. The aim of this study was to assess the value of dynamic 18F-FET PET for the non-invasive prediction of the IDH-mutation status. METHODS: Newly diagnosed WHO grade II-IV glioma patients with MRI and dynamic 18F-FET PET were included. The 18F-FET PET parameters mean and maximal tumour-to-background ratio (TBRmean, TBRmax) and minimal time-to-peak (TTPmin) were evaluated. The diagnostic power for the prediction of the IDH genotype (positive/negative predictive value) was tested in the overall study group and in the subgroup of non-contrast enhancing gliomas. RESULTS: Three hundred forty-one patients were evaluated. Molecular analyses revealed 178 IDH-mutant and 163 IDH-wildtype tumours. Overall, 270/341 gliomas were classified as 18F-FET-positive (TBRmax > 1.6), 90.2% of the IDH-wildtype and 69.1% of IDH-mutant gliomas. Median TBRmax was significantly higher in IDH-wildtype compared with IDH-mutant gliomas (2.9 vs. 2.3, p < 0.001); however, ROC-analyses revealed no reliable cutoff due to a high overlap (range 1.0-7.1 vs. 1.1-7.9). Dynamic analysis revealed a significantly shorter TTPmin in IDH-wildtype gliomas; using TTPmin ≤ 12.5 min as indicator for IDH-wildtype gliomas, a positive predictive value of 87% was reached (negative predictive value 72%, AUC = 0.796, p ≤ 0.001). A total of 161/341 gliomas did not show contrast enhancement on MRI; even within this subgroup, TTPmin ≤ 12.5 min remained a good predictor of IDH-wildtype glioma (positive predictive value 83%, negative predictive value 90%; AUC = 0.868, p < 0.001). CONCLUSION: A short TTPmin in dynamic 18F-FET PET serves as good predictor of highly aggressive IDH-wildtype status in gliomas. In particular, a high diagnostic power was observed in the subgroup of non-contrast enhancing gliomas, which helps to identify patients with worse prognosis.

Bevacizumab reduces toxicity of reirradiation in recurrent high-grade glioma.

PURPOSE: The role of bevacizumab (BEV) in the setting of reirradiation (reRT) of malignant glioma recurrences is poorly defined. At our institution, reRT plus BEV was routinely used until its disapproval for glioma treatment by the European Medical Agency. Accordingly, reRT was applied without the addition of BEV since 2017. Here we present for the first time outcome and toxicity profiles of reRT plus BEV and reRT alone for malignant glioma recurrences. PATIENTS AND METHODS: All adult patients consecutively undergoing reRT of a recurrent malignant glioma (37 anaplastic astrocytoma, WHO III; 124 glioblastoma, WHO IV) between 2007 and 2017 were included. In one group of patients, BEV (10 mg/kg bodyweight) was applied concomitantly on days 1 and 15 of reRT. Radiation toxicity referred to clinically significant toxicities of proven symptomatic radionecrosis (RN) and symptomatic oedema (SE) requiring steroid treatment for more than six weeks after reRT. Post-recurrence survival (PRS) and freedom from RN/SE were estimated with the Kaplan-Meier method. Prognostic factors were obtained from proportional hazards models. RESULTS: BEV plus reRT was applied in 124 and reRT alone in 37 patients. Both groups were comparable in terms of their patient-, tumour-, and RT/reRT-related variables. PRS was independent from the applied reRT protocols. RN/SE was less frequently seen after reRT plus BEV absolutely (27/124 (21.8%) vs. 14/37 (37.8%) patients; p = 0.025) and over time (1-year RN/SE rate: 23.9% vs. 54.1%; p = 0.013). The unadjusted and adjusted hazard ratio for RN/SE was doubled in case of reRT alone. Absence of BEV remained the only risk factor for RN/SE in multivariate models (p = 0.026). CONCLUSION: Concomitant BEV effectively reduces treatment toxicity of reRT and should be reconsidered in future reRT protocols.

The surgical perspective in precision treatment of diffuse gliomas.

Over the last decade, advances in molecular and imaging-based biomarkers have induced a more versatile diagnostic classification and prognostic evaluation of glioma patients. This, in combination with a growing therapeutic armamentarium, enables increasingly individualized, risk-benefit-optimized treatment strategies. This path to precision medicine in glioma patients requires surgical procedures to be reassessed within multidimensional management considerations. This article attempts to integrate the surgical intervention into a dynamic network of versatile diagnostic characterization, prognostic assessment, and multimodal treatment options in the light of the latest 2016 World Health Organization (WHO) classification of diffuse brain tumors, WHO grade II, III, and IV. Special focus is set on surgical aspects such as resectability, extent of resection, and targeted surgical strategies including minimal invasive stereotactic biopsy procedures, convection enhanced delivery, and photodynamic therapy. Moreover, the influence of recent advances in radiomics/radiogenimics on the process of surgical decision-making will be touched.

Outcome after individualized stereoelectroencephalography (sEEG) implantation and navigated resection in patients with lesional and non-lesional focal epilepsy.

BACKGROUND: Refined localization of the epileptogenic zone (EZ) in patients with pharmacoresistant focal epilepsy proceeding to resective surgery might improve postoperative outcome. We here report seizure outcome after stereo EEG (sEEG) evaluation with individually planned stereotactically implanted depth electrodes and subsequent tailored resection. METHODS: A cohort of consecutive patients with pharmacoresistant focal epilepsy, evaluated with a non-invasive evaluation protocol and invasive monitoring with personalized, stereotactically implanted depth electrodes for sEEG was analyzed. Co-registration of post-implantation CT scan to presurgical MRI data was used for 3D reconstructions of the patients' brain surface and mapping of neurophysiology data. Individual multimodal 3D maps of the EZ were used to guide subsequent tailored resections. The outcome was rated according to the Engel classification. RESULTS: Out of 914 patients who underwent non-invasive presurgical evaluation, 85 underwent sEEG, and 70 were included in the outcome analysis. Median follow-up was 31.5 months. Seizure-free outcome (Engel class I A-C, ILAE class 1-2) was achieved in 83% of the study cohort. Patients exhibiting lesional and non-lesional (n = 42, 86% vs. n = 28, 79%), temporal and extratemporal (n = 45, 80% vs. n = 25, 84%), and right- and left-hemispheric epilepsy (n = 44, 82% vs. n = 26, 85%) did similarly well. This remains also true for those with an EZ adjacent to or distant from eloquent cortex (n = 21, 86% vs. n = 49, 82%). Surgical outcome was independent of resected tissue volume. CONCLUSION: Favourable post-surgical outcome can be achieved in patients with resistant focal epilepsy, using individualized sEEG evaluation and tailored navigated resection, even in patients with non-lesional or extratemporal focal epilepsy.

Radiation dose and image quality in intraoperative CT (iCT) angiography of the brain with stereotactic head frames.

OBJECTIVES: Intraoperative CT (iCT) angiography of the brain with stereotactic frames is an integral part of navigated neurosurgery. Validated data regarding radiation dose and image quality in these special examinations are not available. We therefore investigated two iCT protocols in this IRB-approved study. METHODS: Retrospective analysis of patients, who received a cerebral stereotactic iCT angiography on a 128 slice CT scanner between February 2016 and December 2017. In group A, automated tube current modulation (ATCM; reference value 410 mAs) and automated tube voltage selection (reference value 120 kV) were enabled, and only examinations with a selected voltage of 120 kV were included. In group B, fixed parameters were applied (300 mAs, 120 kV). Radiation dose was measured by assessing the volumetric CT dose index (CTDIvol), dose length product (DLP) and effective dose (ED). Signal-to-noise ratio (SNR) and image noise were assessed for objective image quality, visibility of arteries and grey-white differentiation for subjective image quality. RESULTS: Two hundred patients (n = 100 in each group) were included. In group A, median selected tube current was 643 mAs (group B, 300 mAs; p < 0.001). Median values of CTDIvol, DLP and ED were 91.54 mGy, 1561 mGy cm and 2.97 mSv in group A, and 43.15 mGy, 769 mGy cm and 1.46 mSv in group B (p < 0.001). Image quality did not significantly differ between groups (p > 0.05). CONCLUSIONS: ATCM yielded disproportionally high radiation dose due to substantial tube current increase at the frame level, while image quality did not improve. Thus, ATCM should preferentially be disabled. KEY POINTS: • Automated tube current modulation (ATCM) yields disproportionally high radiation dose in intraoperative CT angiography of the brain with stereotactic head frames. • ATCM does not improve overall image quality in these special examinations. • ATCM is not yet optimised for CT angiography of the brain with major extracorporeal foreign materials within the scan range.

Dynamic 18F-FET PET is a powerful imaging biomarker in gadolinium-negative gliomas.

BACKGROUND: We aimed to elucidate the place of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) PET in prognostic models of gadolinium (Gd)-negative gliomas. METHODS: In 98 patients with Gd-negative gliomas undergoing 18F-FET PET guided biopsy, time activity curves (TACs) of each tumor were qualitatively categorized as either increasing or decreasing. Additionally, post-hoc quantitative analyses were done using minimal time-to-peak (TTPmin) measurements. Prognostic factors were obtained from multivariate hazards models. The fit of the biospecimen- and imaging-derived models was compared. RESULTS: A homogeneous increasing, mixed, and homogeneous decreasing TAC pattern was seen in 51, 19, and 28 tumors, respectively. Mixed TAC tumors exhibited both increasing and decreasing TACs. Corresponding adjusted 5-year survival was 85%, 47%, and 19%, respectively (P < 0.001). Qualitative and quantitative TAC measurements were highly intercorrelated (P < 0.0001). TTPmin was longest (shortest) in the homogeneous increasing (decreasing) TAC group and in between in the mixed TAC group. TTPmin was longer in isocitrate dehydrogenase (IDH)-mutant tumors (P < 0.001). Outcome was similarly precisely predicted by biospecimen- and imaging-derived models. In the biospecimen model, World Health Organization (WHO) grade (P < 0.0001) and IDH status (P < 0.001) were predictors for survival. Outcome of homogeneous increasing (homogeneous decreasing) TAC tumors was nearly identical, with both TTPmin > 25 min (TTPmin ≤ 12.5 min) tumors and IDH-mutant grade II (IDH-wildtype) gliomas. Outcome of mixed TAC tumors matched that of both intermediate TTPmin (>12.5 min and ≤25 min) and IDH-mutant, grade III gliomas. Each of the 3 prognostic clusters differed significantly from the other ones of the respective models (P < 0.001). CONCLUSION: TAC measurements constitute a powerful biomarker independent from tumor grade and IDH status.

Dual-room CT with a sliding gantry for intraoperative imaging: feasibility and workflow analysis of an interdisciplinary concept.

PURPOSE: Currently, intraoperative computed tomography (iCT) is a scarcely used technique in neurosurgery. It remains unclear whether this phenomenon is explained by unfavorable iCT-related workflows and/or a limited number of indications. We here analyzed workflows of an installed dual-room iCT (DR-iCT) as compared to surgical procedures lacking iCT. We compared infection rates, utilizations rates, and the spectrum of indications of DR-iCT with that of a previously used single-room iCT. METHODS: The study refers to a consecutive series of patients undergoing either single-room iCT (January 2014-August 2014) or DR-iCT (September 2014-July 2016). A further group undergoing surgery without iCT in the interconnected operating rooms represents the reference group. Workflow measurements and infection rates were calculated. Indications for iCT and utilization rates were compared for each of the devices. CT image quality was rated. RESULTS: Application of DR-iCT led to a broader use of this technique as compared to the single-room device, which concerned in particular stereotactic neurosurgery. Accordingly, iCT utilization rates significantly increased (up to 50.8 ± 4.6 surgeries per month, p < 0.001). Workflow was slightly prolonged in case of DR-iCT imaging; the difference, however, was not statistically significant. Infections rates were low (range 0.0-0.17 infections per month) and not influenced by the utilization rate. Image quality of the DR-iCT was classified as very good in 34/43 evaluated microsurgical patients. CONCLUSIONS: The use of DR-iCT enhances utilization rates with a broader field of indications for intraoperative imaging. Workflow measurements are not significantly prolonged. The technology is safe, and the imaging quality of modern devices can be expected to be good.

Contrast enhancement is a prognostic factor in IDH1/2 mutant, but not in wild-type WHO grade II/III glioma as confirmed by machine learning.

BACKGROUND: Mutation of the isocitrate dehydrogenase (IDH) gene and co-deletion on chromosome 1p/19q is becoming increasingly relevant for the evaluation of clinical outcome in glioma. Among the imaging parameters, contrast enhancement (CE) in WHO II/III glioma has been reported to indicate poor outcome in the past. We aimed at reassessing the prognostic value of CE in these tumours within the framework of molecular markers using a machine learning approach (random survival forests [RSF]) as well as conventional Cox regression modelling. METHODS: 301 patients with WHO grade II (n = 181) or grade III glioma (n = 120) were stratified according to their molecular profile. Pre-operative magnetic resonance imaging (MRI) was reviewed and volumetric analyses of CE and T2 volumes were performed followed by conventional univariate and multivariate Cox analyses. Furthermore, the dataset was split into discovery and validation datasets, and RSFs were trained on the discovery dataset to predict the individual risk of each patient. Concordance indices for Cox and RSF models were determined and the variable importance of explanatory variables was assessed using the minimal-depth concept. RESULTS: In IDH mut tumours only, both conventional Cox regression modelling and RSF analyses showed that CE on initial MRI is a prognostic factor for survival with dependence on volume (p < 0.05). In contrast, presence of CE on initial MRI was not associated with outcome in IDH wt tumours. CONCLUSIONS: In patients with diffuse IDH wt gliomas WHO grade II/III, CE is not associated with survival, whereas in tumours with an IDH mutation, presence of CE on initial MRI is linked to inferior survival.

Stereotactic Internal Shunt Placement in Congenital Intracranial Cysts.

INTRODUCTION: Treatment of symptomatic intracranial cysts remains a controversial issue. We present a risk/benefit profile of a minimally invasive, not yet described, stereotactic internal shunt implantation technique. The provided data might serve as a reference against which other treatment modalities could be compared. METHODS: From our prospective database, we identified a consecutive series of patients with symptomatic, untreated cysts who had undergone internal shunting from 2009 to 2017. We estimated the rates of clinical symptom improvement (RCSI), cyst reduction, total complications, and long-term complications. A minimal follow-up of 6 months was required. The prognostic factors were obtained from logistic regression models. Cyst recurrence-free survival was calculated using the Kaplan-Meier method. The outcomes data were compared with those from reported alternative treatment strategies using χ2 statistics. RESULTS: We included 38 patients. The cyst locations differed greatly and included the cerebellum (n = 2), brainstem (n = 5), and pineal area (n = 4). Cyst-associated hydrocephalus (n = 6) resolved after treatment. The 2-year cyst recurrence-free survival rate was 97%. The RCSI and rate of cyst reduction, total complications, and long-term complications was 91%, 97%, 11%, and 2.6%, respectively. We did not find any risk factors associated with the rate of total complications. The RCSI and rate of total and long-term complications compared favorably (P < 0.01) with the corresponding estimates of alternative treatments (P < 0.01). CONCLUSIONS: The described stereotactic internal shunt implantation technique is safe and can be successfully applied for treatment of cystic formations in any location in the brain.

Intronic miR-744 Inhibits Glioblastoma Migration by Functionally Antagonizing Its Host Gene MAP2K4.

BACKGROUND: The second intron of Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4), an important hub in the pro-invasive MAPK pathway, harbors miR-744. There is accumulating evidence that intronic micro-RNAs (miRNAs) are capable of either supporting or restraining functional pathways of their host genes, thereby creating intricate regulative networks. We thus hypothesized that miR-744 regulates glioma migration by interacting with its host's pathways. METHODS: Patients' tumor specimens were obtained stereotactically. MiR-744 was overexpressed in U87, T98G, and primary glioblastoma (GBM) cell lines. Cell mobility was studied using migration and Boyden chamber assays. Protein and mRNA expression was quantified by SDS-PAGE and qRT-PCR. Interactions of miR-744 and 3'UTRs were analyzed by luciferase reporter assays, and SMAD2/3, p38, and beta-Catenin activities by TOP/FOPflash reporter gene assays. RESULTS: As compared to a normal brain, miR-744 levels were dramatically decreased in GBM samples and in primary GBM cell lines. Astrocytoma WHO grade II/III exhibited intermediate expression levels. Re-expression of miR-744 in U87, T98G, and primary GBM cell lines induced focal growth and impaired cell mobility. Luciferase activity of 3'UTR reporter constructs revealed the pro-invasive factors TGFB1 and DVL2 as direct targets of miR-744. Re-expression of miR-744 reduced levels of TGFB1, DVL2, and the host MAP2K4, and mitigated activity of TGFB1 and DVL2 downstream targets SMAD2/3 and beta-Catenin. TGFB1 knock-down repressed MAP2K4 expression. CONCLUSION: MiR-744 acts as an intrinsic brake on its host. It impedes MAP2K4 functional pathways through simultaneously targeting SMAD-, beta-Catenin, and MAPK signaling networks, thereby strongly mitigating pro-migratory effects of MAP2K4. MiR-744 is strongly repressed in glioma, and its re-expression might attenuate tumor invasiveness.

Voxel-wise analysis of dynamic 18F-FET PET: a novel approach for non-invasive glioma characterisation.

BACKGROUND: Glioma grading with dynamic 18F-FET PET (0-40 min p.i.) is typically performed by analysing the mean time-activity curve of the entire tumour or a suspicious area within a heterogeneous tumour. This work aimed to ensure a reader-independent glioma characterisation and identification of aggressive sub-volumes by performing a voxel-based analysis with diagnostically relevant kinetic and static 18F-FET PET parameters. One hundred sixty-two patients with a newly diagnosed glioma classified according to histologic and molecular genetic properties were evaluated. The biological tumour volume (BTV) was segmented in static 20-40 min p.i. 18F-FET PET images using the established threshold of 1.6 × background activity. For each enclosed voxel, the time-to-peak (TTP), the late slope (Slope15-40), and the tumour-to-background ratios (TBR5-15, TBR20-40) obtained from 5 to 15 min p.i. and 20 to 40 min p.i. images were determined. The percentage portion of these values within the BTV was evaluated with percentage volume fractions (PVFs) and cumulated percentage volume histograms (PVHs). The ability to differentiate histologic and molecular genetic classes was assessed and compared to volume-of-interest (VOI)-based parameters. RESULTS: Aggressive WHO grades III and IV and IDH-wildtype gliomas were dominated by a high proportion of voxels with an early peak, negative slope, and high TBR, whereby the PVHs with TTP < 20 min p.i., Slope15-40 < 0 SUV/h, and TBR5-15 and TBR20-40 > 2 yielded the most significant differences between glioma grades. We found significant differences of the parameters between WHO grades and IDH mutation status, where the effect size was predominantly higher for voxel-based PVHs compared to the corresponding VOI-based parameters. A low overlap of BTV sub-volumes defined by TTP < 20 min p.i. and negative Slope15-40 with TBR5-15 > 2- and TBR20-40 > 2-defined hotspots was observed. CONCLUSIONS: The presented approach applying voxel-wise analysis of dynamic 18F-FET PET enables an enhanced characterisation of gliomas and might potentially provide a fast identification of aggressive sub-volumes within the BTV. Parametric 3D 18F-FET PET information as investigated in this study has the potential to guide individual therapy instrumentation and may be included in future biopsy studies.

18F-FET-PET as a biomarker for therapy response in non-contrast enhancing glioma following chemotherapy.

BACKGROUND: Monitoring treatment response after chemotherapy of gadolinium-(Gd)-negative gliomas is challenging as conventional MRI often indicates no radiological changes. We hypothesize that 18F-FET-PET can be used as a biomarker for response assessment in Gd-negative gliomas undergoing chemotherapy. METHODS: Sixty-one patients harboring Gd-negative WHO grade II or III glioma receiving alkylating agents (temozolomide or CCNU/procarbacine) were included. All patients underwent MRI and 18F-FET-PET before chemotherapy and 6 months later. We calculated T2-volume, 18F-FET-PET based biological tumour volume (BTV) and maximal tumour-to-brain ratio (TBRmax). Moreover, dynamic PET acquisition was performed using time-activity-curves (TACs) analysis. For MRI-based response assessment, RANO criteria for low-grade glioma were used. For 18F-FET-PET, following classification scheme was tested: responsive disease (RD) when a decrease in either BTV ≥ 25% and/or TBRmax ≥ 10% occurred, an increase in BTV ≥ 25% and/or TBRmax increase > 10% characterized progressive disease (PD), minor changes ± 25% for BTV and ± 10% for TBRmax were regarded as stable disease (SD). Post-chemotherapy survival (PCS) and time-to-treatment failure (TTF) were calculated using the Kaplan-Meier method. RESULTS: 18F-FET-PET based response has shown patients with RD to have the longest TTF time (78.5 vs 24.6 vs 24.1 months, p = 0.001), while there was no significant difference between patients with a SD and PD. A comparable pattern was observed for PCS (p < 0.001). T2-volume based assessment was not associated with outcome. CONCLUSION: 18F-FET-PET is a promising biomarker for early response assessment in Gd-negative gliomas undergoing chemotherapy. It might be helpful for a timely adjustment of potentially ineffective treatment concepts and overcomes limitations of conventional structural imaging.

Brachytherapy of Intracranial Gliomas.

Interstitial implantation of radioactive materials (brachytherapy [BT]) has been designed to protractedly deliver a high radiation dose to a well-defined target volume, while minimizing irradiation of the adjacent normal tissues. Even though promising results have been reported over time, the role of this treatment modality in the management of brain tumors is still poorly defined, and only a few centers worldwide apply it in clinical practice. Nevertheless, temporary or permanent interstitial implantation of low activity (<20 mCi) and low dose rate (≤10 cGy/h) iodine-125 (125I) seeds as possible therapy of intracranial gliomas is currently undergoing a definite revival, and several indications for its use have been identified. Generally, 125I-BT may be considered a reasonable option in cases of unresectable, well-circumscribed, either newly diagnosed or recurrent tumors with a diameter of ≤4 cm, virtually in any location within the brain. Importantly, this treatment does not narrow down the spectrum of the possible subsequent salvage therapeutic options, since neither repeated interstitial nor additional external beam irradiation at the time of tumor progression after BT is associated with a significantly increased risk of radiogenic complications. Using correct patient selection criteria, appropriate surgical technique, and established treatment parameters, would make BT a truly minimally invasive procedure with a low risk of complications and reasonable efficacy.

The role of surgery for brain metastases from solid tumors.

Surgery, stereotactic radiosurgery, radiotherapy, and chemotherapy including novel targeted therapy strategies and any combination thereof as well as supportive care are the key elements for treatment of brain metastases. Goals of microsurgery are to obtain tissue samples for histologic diagnosis (particularly in case of uncertainty about the unknown primary tumor but also in the context of future targeted therapies), to relieve burden from space-occupying effects, to improve local tumor control, and to prolong overall survival. Complete surgical resection improves local tumor control and may even affect overall survival. Stereotactic radiosurgery is an equal effective alternative for metastases up to 3 cm in diameter, especially in highly eloquent or deep seated location. Gross total resection (as defined by immediate postoperative MRI) does not necessarily have to be combined with whole brain radiotherapy (WBRT), at least for patients with good performance status and controlled systemic disease. Particularly in cases of incomplete resections, focal irradiation or radiosurgery of the resection cavity or tumor remnant rather than WBRT may be attempted.

Outcome in unresectable glioblastoma: MGMT promoter methylation makes the difference.

In 2011, we reported a predominant prognostic/predictive role of MGMT promoter methylation status on progression-free survival (PFS) in unresectable glioblastoma patients undergoing upfront radiotherapy plus concomitant and maintenance temozolomide (RTX/TMZ â†’ TMZ). We, here, present the final results of this prospective study focussing on the prognostic/predictive value of MGMT promoter methylation status for death risk stratification. Overall, 56 adult patients with unresectable, biopsy proven glioblastoma were prospectively assigned to upfront RTX/TMZ â†’ TMZ treatment between March 2006 and August 2008. Last follow-up was performed in June 2016. MGMT promoter methylation was determined using methylation-specific PCR (MSP) and sodium bisulfite sequencing. Analyses were done by intention to treat. Prognostic factors were obtained from proportional hazard models. At the time of the final analysis 55 patients showed progressive disease and 53 patients had died. MGMT promoter was methylated (unmethylated) in 30 (26) patients. Methylation of the MGMT promoter was the strongest favorable predictor for overall survival (OS, median: 20.3 vs. 7.3 months, p < 0.001, HR 0.30, 95% CI 0.16-0.55), and PFS (median: 15.0 vs. 6.1 months, p < 0.001, HR 0.31, 95% CI 0.17-0.57) and was also associated with higher frequencies of treatment response and prolonged post-recurrence survival (PRS, median: 4.5 vs. 1.4 months, p < 0.002, HR 0.39, 95% CI 0.21-0.71). Knowledge of MGMT promoter methylation status is essential for patients' counseling, prognostic evaluation, and for the design of future trials dealing with unresectable glioblastomas.

Cystic Craniopharyngiomas: Microsurgical or Stereotactic Treatment?

BACKGROUND: Prognosis and treatment of cystic craniopharyngiomas are poorly defined. OBJECTIVE: To analyze progression-free survival (PFS) and safety profile of cystic craniopharyngiomas undergoing resection or minimally invasive drainage procedures. We compared further outcome measurements for cystic and solid tumors undergoing resection to elucidate the impact of the initial tumor composition on both PFS and the toxicity profile. METHODS: All patients with craniopharyngiomas consecutively treated between 1999 and 2014 were included. A treatment decision in favor of microsurgery or stereotactic treatment was made interdisciplinarily. For stereotactic drainage, a catheter was implanted, allowing both permanent upstream (into ventricular spaces) and downstream (into prepontine cistern) drainage. Study endpoints were tumor progression, functional outcome, and treatment toxicity. Functional endocrinological and visual outcome analyses referred to data obtained preoperatively and 6 weeks after treatment. The Kaplan-Meier method was used for survival analysis. Prognostic factors were obtained from proportional hazard models. RESULTS: Seventy-nine patients were included. The distribution of clinical and tumor-related data was well balanced among patients with solid (n = 35) and cystic (n = 44) tumors and those undergoing microsurgical or stereotactic treatment. Cystic tumors had shorter PFS (5-year PFS: 53.6% vs 66.8%, P = .10) and needed significantly more therapeutic interventions, which was independent of the initial treatment mode. The endocrinological deterioration rate was high for both solid and cystic tumors after microsurgery (59.4% and 85.7%, respectively), whereas it was significantly lower for cystic tumors undergoing stereotactic treatment (23.1%, P < .001). CONCLUSION: Stereotactic bidirectional drainage of cystic craniopharyngiomas is effective and provides a better endocrinological outcome than conventional microsurgery.

Suspected recurrence of brain metastases after focused high dose radiotherapy: can [18F]FET- PET overcome diagnostic uncertainties?

BACKGROUND: After focused high dose radiotherapy of brain metastases, differentiation between tumor recurrence and radiation-induced lesions by conventional MRI is challenging. This study investigates the usefulness of dynamic O-(2-18F-Fluoroethyl)-L-Tyrosine positron emission tomography (18F-FET PET) in patients with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy of brain metastases. METHODS: Twenty-two patients with 34 brain metastases (median age 61.9 years) were included. Due to follow-up scan evaluations after repeated treatment in a subset of patients, a total of 50 lesions with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy could be evaluated. 18F-FET PET analysis included the assessment of maximum and mean tumor-to-background ratio (TBRmax and TBRmean) and analysis of time-activity-curves (TAC; increasing vs. decreasing) including minimal time-to-peak (TTPmin). PET parameters were correlated with histological findings and radiological-clinical follow-up evaluation. RESULTS: Tumor recurrence was found in 21/50 cases (15/21 verified by histology, 6/21 by radiological-clinical follow-up) and radiation-induced changes in 29/50 cases (5/29 verified by histology, 24/29 by radiological-clinical follow-up). Median clinical-radiological follow-up was 28.3 months (range 4.2-99.1 months). 18F-FET uptake was higher in tumor recurrence compared to radiation-induced changes (TBRmax 2.9 vs. 2.0, p < 0.001; TBRmean 2.2 vs. 1.7, p < 0.001). Receiver-operating-characteristic (ROC) curve analysis revealed optimal cut-off values of 2.15 for TBRmax and 1.95 for TBRmean (sensitivity 86 %, specificity 79 %). Increasing TACs and long TTPmin were associated with radiation-induced changes, decreasing TACs with tumor recurrence (p = 0.01). By combination of TBR and TACs, sensitivity and specificity could be increased to 93 and 84 %. CONCLUSIONS: In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions.