Integrating and optimizing tonabersat in standard glioblastoma therapy: A preclinical study.

Glioblastoma (GB), a highly aggressive primary brain tumor, presents a poor prognosis despite the current standard therapy, including radiotherapy and temozolomide (TMZ) chemotherapy. Tumor microtubes involving connexin 43 (Cx43) contribute to glioma progression and therapy resistance, suggesting Cx43 inhibition as a potential treatment strategy. This research aims to explore the adjuvant potential of tonabersat, a Cx43 gap junction modulator and blood-brain barrier-penetrating compound, in combination with the standard of care for GB. In addition, different administration schedules and timings to optimize tonabersat's therapeutic window are investigated. The F98 Fischer rat model will be utilized to investigate tonabersat's impact in a clinically relevant setting, by incorporating fractionated radiotherapy (three fractions of 9 Gy) and TMZ chemotherapy (29 mg/kg). This study will evaluate tonabersat's impact on tumor growth, survival, and treatment response through advanced imaging (CE T1-w MRI) and histological analysis. Results show extended survival in rats receiving tonabersat with standard care, highlighting its adjuvant potential. Daily tonabersat administration, both preceding and following radiotherapy, emerges as a promising approach for maximizing survival outcomes. The study suggests tonabersat's potential to reduce tumor invasiveness, providing a new avenue for GB treatment. In conclusion, this preclinical investigation highlights tonabersat's potential as an effective adjuvant treatment for GB, and its established safety profile from clinical trials in migraine treatment presents a promising foundation for further exploration.

An improved F98 glioblastoma rat model to evaluate novel treatment strategies incorporating the standard of care.

Glioblastoma (GB) is the most common and malignant primary brain tumor in adults with a median survival of 12-15 months. The F98 Fischer rat model is one of the most frequently used animal models for GB studies. However, suboptimal inoculation leads to extra-axial and extracranial tumor formations, affecting its translational value. We aim to improve the F98 rat model by incorporating MRI-guided (hypo)fractionated radiotherapy (3 x 9 Gy) and concomitant temozolomide chemotherapy, mimicking the current standard of care. To minimize undesired tumor growth, we reduced the number of inoculated cells (starting from 20 000 to 500 F98 cells), slowed the withdrawal of the syringe post-inoculation, and irradiated the inoculation track separately. Our results reveal that reducing the number of F98 GB cells correlates with a diminished risk of extra-axial and extracranial tumor growth. However, this introduces higher variability in days until GB confirmation and uniformity in GB growth. To strike a balance, the model inoculated with 5000 F98 cells displayed the best results and was chosen as the most favorable. In conclusion, our improved model offers enhanced translational potential, paving the way for more accurate and reliable assessments of novel adjuvant therapeutic approaches for GB.

Assessment of the effect of therapy in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI.

OBJECTIVE: We investigated the potential of [18F]fluorodeoxyglucose ([18F]FDG) and [18F]Fluoromethylcholine ([18F]FCho) PET, compared to contrast-enhanced MRI, for the early detection of treatment response in F98 glioblastoma (GB) rats. METHODS: When GB was confirmed on T2- and contrast-enhanced T1-weighted MRI, animals were randomized into a treatment group (n = 5) receiving MRI-guided 3D conformal arc micro-irradiation (20 Gy) with concomitant temozolomide, and a sham group (n = 5). Effect of treatment was evaluated by MRI and [18F]FDG PET on day 2, 5, 9 and 12 post-treatment and [18F]FCho PET on day 1, 6, 8 and 13 post-treatment. The metabolic tumor volume (MTV) was calculated using a semi-automatic thresholding method and the average tracer uptake within the MTV was converted to a standard uptake value (SUV). RESULTS: To detect treatment response, we found that for [18F]FDG PET (SUVmean x MTV) is superior to MTV only. Using (SUVmean x MTV), [18F]FDG PET detects treatment effect starting as soon as day 5 post-therapy, comparable to contrast-enhanced MRI. Importantly, [18F]FDG PET at delayed time intervals (240 min p.i.) was able to detect the treatment effect earlier, starting at day 2 post-irradiation. No significant differences were found at any time point for both the MTV and (SUVmean x MTV) of [18F]FCho PET. CONCLUSIONS: Both MRI and particularly delayed [18F]FDG PET were able to detect early treatment responses in GB rats, whereas, in this study this was not possible using [18F]FCho PET. Further comparative studies should corroborate these results and should also include (different) amino acid PET tracers.

Automated MRI based pipeline for segmentation and prediction of grade, IDH mutation and 1p19q co-deletion in glioma.

In the WHO glioma classification guidelines grade (glioblastoma versus lower-grade glioma), IDH mutation and 1p/19q co-deletion status play a central role as they are important markers for prognosis and optimal therapy planning. Currently, diagnosis requires invasive surgical procedures. Therefore, we propose an automatic segmentation and classification pipeline based on routinely acquired pre-operative MRI (T1, T1 postcontrast, T2 and/or FLAIR). A 3D U-Net was designed for segmentation and trained on the BraTS 2019 training dataset. After segmentation, the 3D tumor region of interest is extracted from the MRI and fed into a CNN to simultaneously predict grade, IDH mutation and 1p19q co-deletion. Multi-task learning allowed to handle missing labels and train one network on a large dataset of 628 patients, collected from The Cancer Imaging Archive and BraTS databases. Additionally, the network was validated on an independent dataset of 110 patients retrospectively acquired at the Ghent University Hospital (GUH). Segmentation performance calculated on the BraTS validation set shows an average whole tumor dice score of 90% and increased robustness to missing image modalities by randomly excluding input MRI during training. Classification area under the curve scores are 93%, 94% and 82% on the TCIA test data and 94%, 86% and 87% on the GUH data for grade, IDH and 1p19q status respectively. We developed a fast, automatic pipeline to segment glioma and accurately predict important (molecular) markers based on pre-therapy MRI.

In vivo selection of the MDA-MB-231br/eGFP cancer cell line to obtain a clinically relevant rat model for triple negative breast cancer brain metastasis.

Young triple negative breast cancer (TNBC) patients are at high risk for developing very aggressive brain metastases associated with a poor prognosis and a high mortality rate. Preclinical models that allow follow-up by magnetic resonance imaging (MRI) can contribute to the development of new therapeutic approaches for brain metastasis. To date, preclinical brain tumor research has almost exclusively relied on xenograft mouse models. Yet, rats are an ideal model for imaging of brain metastasis as their larger brain offers better relative spatial resolution compared to a mouse brain. For the development of a clinically relevant rat model for TNBC brain metastasis, the MDA-MB-231br/eGFP cancer cell line can be used. However, as a result of species-dependent extracranial features, the propensity of the MDA-MB-231br/eGFP cancer cell line to metastasize exclusively to the brain needs to be enhanced by in vivo selection. In this study, repeated sequential passages of metastatic cancer cells obtained from brain metastases in nude rats were performed. Brain metastasis formation was evaluated using preclinical MRI, while bone metastasis formation was assessed using high-resolution computed tomography (CT) and 2-deoxy-2-[18F] fluoro-D-glucose ([18F] FDG) positron emission tomography (PET) imaging. Our results demonstrated that the metastatic tumor burden in the rat brain (number and volume) significantly increased with increasing passage, while the metastatic tumor burden in the skeleton (i.e., number of metastasis-affected bones) significantly decreased with increasing passage. However, bone metastasis development was not reduced to a negligible amount. Consequently, despite in vivo selection, our rat model is not recommended for investigating brain metastasis as a single disease. Our findings highlight the importance of well-reasoned selection of both the preclinical model and the cancer cell line in order to obtain reliable and reproducible scientific results.

Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma: A preclinical F98 glioblastoma rat model study.

PURPOSE: Even with an optimal treatment protocol, the median survival of glioblastoma (GB) patients is only 12-15 months. Hence, there is need for novel effective therapies that improve survival outcomes. Recent evidence suggests an important role for connexin (Cx) proteins (especially Cx43) in the microenvironment of malignant glioma. Cx43-mediated gap junctional communication has been observed between tumor cells, between astrocytes and between tumor cells and astrocytes. Therefore, gap junction directed therapy using a pharmacological suppressor or modulator, such as tonabersat, could be a promising target in the treatment of GB. In this preclinical study, we evaluated the possible therapeutic potential of tonabersat in the F98 model. PROCEDURES: Female Fischer rats were inoculated with ± 25.000 F98 tumor cells in the right frontal lobe. Eight days post-inoculation contrast-enhanced T1-weighted (CE-T1w) magnetic resonance (MR) images were acquired to confirm tumor growth in the brain. After tumor confirmation, rats were randomized into a Control Group, a Connexin Modulation Group (CM), a Standard Medical Treatment Group (ST), and a Standard Medical Treatment with adjuvant Connexin Modulation Group (STCM). To evaluate therapy response, T2-weighted (T2w) and CE-T1w sequences were acquired at several time points. Tumor volume analysis was performed on CE-T1w images and statistical analysis was performed using a linear mixed model. RESULTS: Significant differences in estimated geometric mean tumor volumes were found between the ST Group and the Control Group and also between the STCM Group and the Control Group. In addition, significant differences in estimated geometric mean tumor volumes between the ST Group and the STCM Group were demonstrated. No significant differences in estimated geometric mean tumor volumes were found between the Control Group and the CM Group. CONCLUSION: Our results demonstrate a therapeutic potential of tonabersat for the treatment of GB when used in combination with radiotherapy and temozolomide chemotherapy.

Technical feasibility of [18F]FET and [18F]FAZA PET guided radiotherapy in a F98 glioblastoma rat model.

BACKGROUND: Glioblastoma (GB) is the most common primary malignant brain tumor. Standard medical treatment consists of a maximal safe surgical resection, subsequently radiation therapy (RT) and chemotherapy with temozolomide (TMZ). An accurate definition of the tumor volume is of utmost importance for guiding RT. In this project we investigated the feasibility and treatment response of subvolume boosting to a PET-defined tumor part. METHOD: F98 GB cells inoculated in the rat brain were imaged using T2- and contrast-enhanced T1-weighted (T1w) MRI. A dose of 20 Gy (5 × 5 mm2) was delivered to the target volume delineated based on T1w MRI for three treatment groups. Two of those treatment groups received an additional radiation boost of 5 Gy (1 × 1 mm2) delivered to the region either with maximum [18F]FET or [18F]FAZA PET tracer uptake, respectively. All therapy groups received intraperitoneal (IP) injections of TMZ. Finally, a control group received no RT and only control IP injections. The average, minimum and maximum dose, as well as the D90-, D50- and D2- values were calculated for nine rats using both RT plans. To evaluate response to therapy, follow-up tumor volumes were delineated based on T1w MRI. RESULTS: When comparing the dose volume histograms, a significant difference was found exclusively between the D2-values. A significant difference in tumor growth was only found between active therapy and sham therapy respectively, while no significant differences were found when comparing the three treatment groups. CONCLUSION: In this study we showed the feasibility of PET guided subvolume boosting of F98 glioblastoma in rats. No evidence was found for a beneficial effect regarding tumor response. However, improvements for dose targeting in rodents and studies investigating new targeted drugs for GB treatment are mandatory.

New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma.

The use of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro Ki determination, the most promising compound, 2-[18F]-2-fluoroethyl-L-phenylalanine (2-[18F]FELP), was selected for further evaluation and in vitro comparison with [18F]FET. Subsequently, 2-[18F]FELP was assessed in vivo and compared with [18F]FET and [18F]FDG in a F98 glioblastoma rat model. 2-[18F]FELP showed improved in vitro characteristics over [18F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[18F]FELP is a promising new PET tracer for brain tumor imaging.

The Path Toward PET-Guided Radiation Therapy for Glioblastoma in Laboratory Animals: A Mini Review.

Glioblastoma is the most aggressive and malignant primary brain tumor in adults. Despite the current state-of-the-art treatment, which consists of maximal surgical resection followed by radiation therapy, concomitant, and adjuvant chemotherapy, progression remains rapid due to aggressive tumor characteristics. Several new therapeutic targets have been investigated using chemotherapeutics and targeted molecular drugs, however, the intrinsic resistance to induced cell death of brain cells impede the effectiveness of systemic therapies. Also, the unique immune environment of the central nervous system imposes challenges for immune-based therapeutics. Therefore, it is important to consider other approaches to treat these tumors. There is a well-known dose-response relationship for glioblastoma with increased survival with increasing doses, but this effect seems to cap around 60 Gy, due to increased toxicity to the normal brain. Currently, radiation treatment planning of glioblastoma patients relies on CT and MRI that does not visualize the heterogeneous nature of the tumor, and consequently, a homogenous dose is delivered to the entire tumor. Metabolic imaging, such as positron-emission tomography, allows to visualize the heterogeneous tumor environment. Using these metabolic imaging techniques, an approach called dose painting can be used to deliver a higher dose to the tumor regions with high malignancy and/or radiation resistance. Preclinical studies are required for evaluating the benefits of novel radiation treatment strategies, such as PET-based dose painting. The aim of this review is to give a brief overview of promising PET tracers that can be evaluated in laboratory animals to bridge the gap between PET-based dose painting in glioblastoma patients.

Species-dependent extracranial manifestations of a brain seeking breast cancer cell line.

PURPOSE: Metastatic brain tumors pose a severe problem in the treatment of patients with breast carcinoma. Preclinical models have been shown to play an important role in unraveling the underlying mechanisms behind the metastatic process and evaluation of new therapeutic approaches. As the size of the rat brain allows improved in vivo imaging, we attempted to establish a rat model for breast cancer brain metastasis that allows follow-up by 7 tesla (7T) preclinical Magnetic Resonance Imaging (MRI). PROCEDURES: Green fluorescent protein-transduced (eGFP) MDA-MB-231br breast cancer cells were labeled with micron-sized particles of iron oxide (MPIOs) and intracardially injected in the left ventricle of female nude rats and mice. 7T preclinical MRI was performed to show the initial distribution of MPIO-labeled cancer cells and to visualize metastasis in the brain. Occurrence of potential metastasis outside the brain was evaluated by 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/computed tomography (CT) and potential bone lesions were assessed using [18F]sodium fluoride ([18F]NaF) PET/CT. RESULTS: The first signs of brain metastasis development were visible as hyperintensities on T2-weighted (T2w) MR images acquired 3 weeks after intracardiac injection in rats and mice. Early formation of unexpected bone metastasis in rats was clinically observed and assessed using PET/CT. Almost no bone metastasis development was observed in mice after PET/CT evaluation. CONCLUSIONS: Our results suggest that the metastatic propensity of the MDA-MB-231br/eGFP cancer cell line outside the brain is species-dependent. Because of early and abundant formation of bone metastasis with the MDA-MB-231br/eGFP cancer cell line, this rat model is currently not suitable for investigating brain metastasis as a single disease model nor for evaluation of novel brain metastasis treatment strategies.

In Vivo DCE-MRI for the Discrimination Between Glioblastoma and Radiation Necrosis in Rats.

PURPOSE: In this study, the potential of semiquantitative and quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) was investigated to differentiate glioblastoma (GB) from radiation necrosis (RN) in rats. PROCEDURES: F98 GB growth was seen on MRI 8-23 days post-inoculation (n = 15). RN lesions developed 6-8 months post-irradiation (n = 10). DCE-MRI was acquired using a fast low-angle shot (FLASH) sequence. Regions of interest (ROIs) encompassed peripheral contrast enhancement in GB (n = 15) and RN (n = 10) as well as central necrosis within these lesions (GB (n = 4), RN (n = 3)). Dynamic contrast-enhanced time series, obtained from the DCE-MRI data, were fitted to determine four function variables (amplitude A, offset from zero C, wash-in rate k, and wash-out rate D) as well as maximal intensity (ImaxF) and time to peak (TTPF). Secondly, maps of semiquantitative and quantitative parameters (extended Tofts model) were created using Olea Sphere (O). Semiquantitative DCE-MRI parameters included wash-inO, wash-outO, area under the curve (AUCO), maximal intensity (ImaxO), and time to peak (TTPO). Quantitative parameters included the rate constant plasma to extravascular-extracellular space (EES) (K trans), the rate constant EES to plasma (K ep), plasma volume (V p), and EES volume (V e). All (semi)quantitative parameters were compared between GB and RN using the Mann-Whitney U test. ROC analysis was performed. RESULTS: Wash-in rate (k) and wash-out rate (D) were significantly higher in GB compared to RN using curve fitting (p = 0.016 and p = 0.014). TTPF and TTPO were significantly lower in GB compared to RN (p = 0.001 and p = 0.005, respectively). The highest sensitivity (87 %) and specificity (80 %) were obtained for TTPF by applying a threshold of 581 s. K trans, K ep, and V e were not significantly different between GB and RN. A trend towards higher V p values was found in GB compared to RN, indicating angiogenesis in GB (p = 0.075). CONCLUSIONS: Based on our results, in a rat model of GB and RN, wash-in rate, wash-out rate, and the time to peak extracted from DCE-MRI time series data may be useful to discriminate GB from RN.

"Unforgettable" - a pictorial essay on anatomy and pathology of the hippocampus.

The hippocampus is a small but complex anatomical structure that plays an important role in spatial and episodic memory. The hippocampus can be affected by a wide range of congenital variants and degenerative, inflammatory, vascular, tumoral and toxic-metabolic pathologies. Magnetic resonance imaging is the preferred imaging technique for evaluating the hippocampus. The main indications requiring tailored imaging sequences of the hippocampus are medically refractory epilepsy and dementia. The purpose of this pictorial review is threefold: (1) to review the normal anatomy of the hippocampus on MRI; (2) to discuss the optimal imaging strategy for the evaluation of the hippocampus; and (3) to present a pictorial overview of the most common anatomic variants and pathologic conditions affecting the hippocampus. TEACHING POINTS: • Knowledge of normal hippocampal anatomy helps recognize anatomic variants and hippocampal pathology. • Refractory epilepsy and dementia are the main indications requiring dedicated hippocampal imaging. • Pathologic conditions centered in and around the hippocampus often have similar imaging features. • Clinical information is often necessary to come to a correct diagnosis or an apt differential.

18F-FCho PET and MRI for the prediction of response in glioblastoma patients according to the RANO criteria.

PURPOSE: In this study, we investigated fluorine-18 fluoromethylcholine (F-FCho) PET and contrast-enhanced MRI for predicting therapy response in glioblastoma (GB) patients according to the Response Assessment in Neuro-Oncology criteria. Our second aim was to investigate which imaging modality enabled prediction of treatment response first. MATERIALS AND METHODS: Eleven GB patients who underwent no surgery or debulking only and received concomitant radiation therapy (RT) and temozolomide were included. The gold standard Response Assessment in Neuro-Oncology criteria were applied 6 months after RT to define responders and nonresponders. F-FCho PET and MRI were performed before RT, during RT (week 2, 4, and 6), and 1 month after RT. The contrast-enhancing tumor volume on T1-weighted MRI (GdTV) and the metabolic tumor volume (MTV) were calculated. GdTV, standardized uptake value (SUV)mean, SUVmax, MTV, MTV×SUVmean, and percentage change of these variables between all time-points were assessed to differentiate responders from nonresponders. RESULTS: Absolute SUV values did not predict response. MTV must be taken into account. F-FCho PET could predict response with a 100% sensitivity and specificity using MTV×SUVmean 1 month after RT. A decrease in GdTV between week 2 and 6, week 4 and 6 during RT and week 2 during RT, and 1 month after RT of at least 31%, at least 18%, and at least 53% predicted response with a sensitivity and specificity of 100%. As such, the parameter that predicts therapy response first is MR derived, namely, GdTV. CONCLUSION: Our data indicate that both F-FCho PET and contrast-enhanced T1-weighted MRI can predict response early in GB patients treated with RT and temozolomide.

Correction: Kinetic Modeling and Graphical Analysis of 18F-Fluoromethylcholine (FCho), 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET for the Fiscrimination between High-Grade Glioma and Radiation Necrosis in Rats.

[This corrects the article DOI: 10.1371/journal.pone.0161845.].

Kinetic Modeling and Graphical Analysis of 18F-Fluoromethylcholine (FCho), 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET for the Fiscrimination between High-Grade Glioma and Radiation Necrosis in Rats.

BACKGROUND: Discrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains challenging but has a large impact on further treatment and prognosis. In this study, the uptake mechanisms of 18F-fluorodeoxyglucose (18F-FDG), 18F-fluoroethyltyrosine (18F-FET) and 18F-fluoromethylcholine (18F-FCho) positron emission tomography (PET) tracers were investigated in a F98 GB and RN rat model applying kinetic modeling (KM) and graphical analysis (GA) to clarify our previous results. METHODS: Dynamic 18F-FDG (GB n = 6 and RN n = 5), 18F-FET (GB n = 5 and RN n = 5) and 18F-FCho PET (GB n = 5 and RN n = 5) were acquired with continuous arterial blood sampling. Arterial input function (AIF) corrections, KM and GA were performed. RESULTS: The influx rate (Ki) of 18F-FDG uptake described by a 2-compartmental model (CM) or using Patlak GA, showed more trapping (k3) in GB (0.07 min-1) compared to RN (0.04 min-1) (p = 0.017). K1 of 18F-FET was significantly higher in GB (0.06 ml/ccm/min) compared to RN (0.02 ml/ccm/min), quantified using a 1-CM and Logan GA (p = 0.036). 18F-FCho was rapidly oxidized complicating data interpretation. Using a 1-CM and Logan GA no clear differences were found to discriminate GB from RN. CONCLUSIONS: Based on our results we concluded that using KM and GA both 18F-FDG and 18F-FET were able to discriminate GB from RN. Using a 2-CM model more trapping of 18F-FDG was found in GB compared to RN. Secondly, the influx of 18F-FET was higher in GB compared to RN using a 1-CM model. Important correlations were found between SUV and kinetic or graphical measures for 18F-FDG and 18F-FET. 18F-FCho PET did not allow discrimination between GB and RN.

(18)F-fluoromethylcholine (FCho), (18)F-fluoroethyltyrosine (FET), and (18)F-fluorodeoxyglucose (FDG) for the discrimination between high-grade glioma and radiation necrosis in rats: a PET study.

INTRODUCTION: Discrimination between (high-grade) brain tumor recurrence and radiation necrosis (RN) remains a diagnostic challenge because both entities have similar imaging characteristics on conventional magnetic resonance imaging (MRI). Metabolic imaging, such as positron emission tomography (PET) could overcome this diagnostic dilemma. In this study, we investigated the potential of 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG), O-(2-[(18)F]-fluoroethyl)-L-tyrosine ((18)F-FET), and [(18)F]-Fluoromethyl-dimethyl-2-hydroxyethylammonium ((18)F-fluoromethylcholine, (18)F-FCho) PET in discriminating high-grade tumor from RN. METHODS: We developed a glioblastoma (GB) rat model by inoculating F98 GB cells into the right frontal region. Induction of RN was achieved by irradiating the right frontal region with 60 Gy using three arcs with a beam aperture of 3×3 mm (n=3). Dynamic PET imaging with (18)F-FDG, (18)F-FET, and (18)F-FCho, as well as (18)F-FDG PET at a delayed time interval (240 min postinjection), was acquired. RESULTS: MRI revealed contrast-enhancing tumors at 15 days after inoculation (n=4) and contrast-enhancing RN lesions 5-6 months postirradiation (n=3). On (18)F-FDG PET, the mean lesion-to-normal ratio (LNRmean) was significantly higher in GB than in RN (p=0.034). The difference in the LNRmean between tumors and RN was higher on the late (18)F-FDG PET images than on the PET images reconstructed from the last time frame of the dynamic acquisition (this is at a conventional time interval). LNRs obtained from (18)F-FCho PET were not significantly different between GB and RN (p=1.000). On (18)F-FET PET, the LNRmean was significantly higher in GB compared to RN (p=0.034). CONCLUSIONS: Unlike (18)F-FCho, (18)F-FDG and (18)F-FET PET were effective in discriminating GB from RN. Interestingly, in the case of (18)F-FDG, delayed PET seems particularly useful. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Our results suggest that (delayed) (18)F-FDG and (18)F-FET PET can be used to discriminate GB (recurrence) from RN. Confirmation of these results in clinical studies is needed.

MRI-guided 3D conformal arc micro-irradiation of a F98 glioblastoma rat model using the Small Animal Radiation Research Platform (SARRP).

Current glioblastoma (GB) small animal models for cranial radiation therapy (RT) use simple single beam technologies, which differ from the advanced conformal image-guided radiation techniques used in clinical practice. This technological disparity presents a major disadvantage for the development of new therapeutic approaches. Hence, we established a F98 GB rat model using magnetic resonance imaging (MRI)-guided three-dimensional (3D)-conformal arc RT with the Small Animal Radiation Research Platform (SARRP). Ten Fischer rats were inoculated with F98 tumor cells. When the tumor reached a volume of approximately 27 mm(3) on T2-weighted MR images, the animals were randomized into a treatment group (n = 5) receiving RT and concomitant temozolomide, and a sham group (n = 5) receiving control injections. For the treated animals, contrast-enhanced T1-weighted MR images were acquired followed by a cone-beam computed tomography (CBCT) on the SARRP system. Both scans were co-registered; MRI was used to define the target whereas CBCT was used for calculating a dose plan (20 Gy, three non-coplanar arc beams, 3 × 3 mm collimator). Tumor volumes were evaluated on follow-up contrast-enhanced T1-weighted MR images. Verification of treatment accuracy with γH2AX immunohistochemical staining was performed. Tumors in the control animals showed rapid proliferation during follow-up, encompassing almost the entire right cerebral hemisphere at day 12-15. Treated animals showed no significant tumor growth from 2 to 9 days post RT. γH2AX results confirmed the accuracy of dose delivery. This model, which is quite similar to the approach in the clinic, is valid for combined RT and chemotherapy of GB in rats.

Estimating blur at the brain gray-white matter boundary for FCD detection in MRI.

Focal cortical dysplasia (FCD) is a frequent cause of epilepsy and can be detected using brain magnetic resonance imaging (MRI). One important MRI feature of FCD lesions is the blurring of the gray-white matter boundary (GWB), previously modelled by the gradient strength. However, in the absence of additional FCD descriptors, current gradient-based methods may yield false positives. Moreover, they do not explicitly quantify the level of blur which prevents from using them directly in the process of automated FCD detection. To improve the detection of FCD lesions displaying blur, we develop a novel algorithm called iterating local searches on neighborhood (ILSN). The novelty is that it measures the width of the blurry region rather than the gradient strength. The performance of our method is compared with the gradient magnitude method using precision and recall measures. The experimental results, tested on MRI data of 8 real FCD patients, indicate that our method has higher ability to correctly identify the FCD blurring than the gradient method.

Spontaneous delayed brain herniation through a subdural membrane after tumor surgery.

BACKGROUND AND IMPORTANCE: We report on a rare case of spontaneous cerebral herniation through a subdural membrane in a 54-year-old patient. Brain herniation in adults as a complication of chronic subdural hematomas shortly after a neurosurgical intervention is rare. We are the first to report a case of delayed local herniation in an adult patient more than 1 year after a neurosurgical procedure. CLINICAL PRESENTATION: The patient suffered from a low-grade oligodendroglioma since 1993. Radiotherapy was then applied, followed by resective surgery and chemotherapy in 2008 because of tumor progression. Subsequently, he developed a symptomatic subdural hygroma treated with a subduro-atrial cerebrospinal fluid shunt. In January 2010, the shunt was occluded. Follow-up brain imaging showed a stable situation after tumor resection, with a cyst in the temporal resection cavity and a stable subdural hygroma. In February 2011, the patient visited the emergency department because of an acute right hemiparesis and progressive motor aphasia. Urgent magnetic resonance imaging was suspicious of a herniation of brain parenchyma in the left middle cranial fossa. Explorative surgery showed a locally incarcerated brain herniation through a membrane with a ring-like aperture. Resection of this membrane led to normalization of the position of the brain tissue and to clinical improvement. CONCLUSION: Brain herniation through a subdural membrane is an extremely rare complication, but must be a differential diagnosis in patients with a known chronic subdural hematoma or hygroma and clinical deterioration, even in the absence of recent surgery. Urgent surgical intervention of the herniated brain is recommended to reduce the risk of permanent neurological damage.

The optimal timing for imaging brain tumours and other brain lesions with 18F-labelled fluoromethylcholine: a dynamic positron emission tomography study.

PURPOSE: To determine the optimal timing for imaging brain tumours and other brain lesions with 18F-labelled fluoromethylcholine (18F-FCho) PET. MATERIALS AND METHODS: Dynamic PET imaging with 18F-FCho (acquisition time of 28 min) was performed in 24 patients with space-occupying lesions in the brain. On the coregistered PET and MRI, lesion-to-normal tissue uptake ratios (LNRs) were calculated. Time-activity curves (TACs) were generated on the basis of the LNRs. Changes in LNR over time were calculated on the basis of the linear part of the TAC (last 22 min of the acquisition). RESULTS: TACs for 18F-FCho in gliomas of different grading showed that, after a rapid uptake phase, the mean increase in LNR was 1.07 ± 0.93 for glioblastomas, -0.52 ± 1.56 for anaplastic astrocytomas, 0.04 ± 0.13 for grade 2 oligoastrocytomas and 0.37 in a case of a pilocytic astrocytoma. The average increase in LNR was 0.46 for a brain metastasis, 0.41 ± 0.69 for radiation-induced mass lesions and 1.07 for a tumefactive demyelinating lesion. In contrast, TACs for 18F-FCho in meningiomas showed that, after a rapid uptake phase, the average change in LNR was -5.25 ± 4.19 for typical meningiomas and -3.04 in a case of a mixed angiomatous and clear cell meningioma. CONCLUSION: On the basis of the TACs, PET imaging with 18F-FCho starting within minutes after the administration of the tracer is preferred for the detection of brain tumours and other brain lesions. If discrimination between meningioma and other brain tumours is of concern, both 'early' and 'late' PET imaging could be helpful.