Biological Tumor Volume Research Articles

18F-FET PET Uptake Characteristics of Long-Term IDH-Wildtype Diffuse Glioma Survivors

Simple SummaryIDH-wildtype (IDHwt) gliomas represent a tumor entity with poor overall survival. Only rare cases have an overall survival over several years. Dynamic and static 18F-FET PET is recommended as valuable complementary tool for glioma imaging in gliomas. This study shows that, besides molecular genetic prognosticators, long survival (≥36 months survival) in IDHwt gliomas is associated with a longer time-to-peak and smaller volume on 18F-FET PET at initial diagnosis compared to glioma patients with a short-term survival (≤15 months survival). 18F-FET uptake intensity and MRI-derived tumor size do not differ in patients with long-term survival compared to patient with a short-term survival.Background: IDHwt diffuse gliomas represent the tumor entity with one of the worst clinical outcomes. Only rare cases present with a long-term survival of several years. Here we aimed at comparing the uptake characteristics on dynamic 18F-FET PET, clinical and molecular genetic parameters of long-term survivors (LTS) versus short-term survivors (STS): Methods: Patients with de-novo IDHwt glioma (WHO grade III/IV) and 18F-FET PET prior to any therapy were stratified into LTS (≥36 months survival) and STS (≤15 months survival). Static and dynamic 18F-FET PET parameters (mean/maximal tumor-to-background ratio (TBRmean/max), biological tumor volume (BTV), minimal time-to-peak (TTPmin)), diameter and volume of contrast-enhancement on MRI, clinical parameters (age, sex, Karnofksy-performance-score), mode of surgery; initial treatment and molecular genetics were assessed and compared between LTS and STS. Results: Overall, 75 IDHwt glioma patients were included (26 LTS, 49 STS). LTS were significantly younger (p < 0.001), had a higher rate of WHO grade III glioma (p = 0.032), of O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter methylation (p < 0.001) and missing Telomerase reverse transcriptase promoter (TERTp) mutations (p = 0.004) compared to STS. On imaging, LTS showed a smaller median BTV (p = 0.017) and a significantly longer TTPmin (p = 0.008) on 18F-FET PET than STS, while uptake intensity (TBRmean/max) did not differ. In contrast to the tumor-volume on PET, MRI-derived parameters such as tumor size as well as all other above-mentioned parameters did not differ between LTS and STS (p > 0.05 each). Conclusion: Besides molecular genetic prognosticators, a long survival time in IDHwt glioma patients is associated with a longer TTPmin as well as a smaller BTV on 18F-FET PET at initial diagnosis. 18F-FET uptake intensity as well as the MRI-derived tumor size (volume and maximal diameter) do not differ in patients with long-term survival.

TERT-Promoter Mutational Status in Glioblastoma - Is There an Association With Amino Acid Uptake on Dynamic 18F-FET PET?

ObjectiveThe mutation of the ‘telomerase reverse transcriptase gene promoter’ (TERTp) has been identified as an important factor for individual prognostication and tumorigenesis and will be implemented in upcoming glioma classifications. Uptake characteristics on dynamic 18F-FET PET have been shown to serve as additional imaging biomarker for prognosis. However, data on the correlation of TERTp-mutational status and amino acid uptake on dynamic 18F-FET PET are missing. Therefore, we aimed to analyze whether static and dynamic 18F-FET PET parameters are associated with the TERTp-mutational status in de-novo IDH-wildtype glioblastoma and whether a TERTp-mutation can be predicted by dynamic 18F-FET PET.MethodsPatients with de-novo IDH-wildtype glioblastoma, WHO grade IV, available TERTp-mutational status and dynamic 18F-FET PET scan prior to any therapy were included. Here, established clinical parameters maximal and mean tumor-to-background-ratios (TBRmax/TBRmean), the biological-tumor-volume (BTV) and minimal-time-to-peak (TTPmin) on dynamic PET were analyzed and correlated with the TERTp-mutational status.ResultsOne hundred IDH-wildtype glioblastoma patients were evaluated; 85/100 of the analyzed tumors showed a TERTp-mutation (C228T or C250T), 15/100 were classified as TERTp-wildtype. None of the static PET parameters was associated with the TERTp-mutational status (median TBRmax 3.41 vs. 3.32 (p=0.362), TBRmean 2.09 vs. 2.02 (p=0.349) and BTV 26.1 vs. 22.4 ml (p=0.377)). Also, the dynamic PET parameter TTPmin did not differ in both groups (12.5 vs. 12.5 min, p=0.411). Within the TERTp-mutant subgroups (i.e., C228T (n=23) & C250T (n=62)), the median TBRmax (3.33 vs. 3.69, p=0.095), TBRmean (2.08 vs. 2.09, p=0.352), BTV (25.4 vs. 30.0 ml, p=0.130) and TTPmin (12.5 vs. 12.5 min, p=0.190) were comparable, too.ConclusionUptake characteristics on dynamic 18F-FET PET are not associated with the TERTp-mutational status in glioblastoma However, as both, dynamic 18F-FET PET parameters as well as the TERTp-mutation status are well-known prognostic biomarkers, future studies should investigate the complementary and independent prognostic value of both factors in order to further stratify patients into risk groups.

F18-FET PET in pediatric brain tumors: integrative analysis of image derived parameters and clinico-pathological data.

F18-FET PET has an established diagnostic role in adult brain gliomas. In this study we analyzed image derived static and dynamic parameters with available conventional MRI, histological, clinical and follow-up data in assessment of pediatric brain tumor patients at different stages of the disease. Forty-four pediatric patients with median age 7 years, diagnosed with brain tumors and underwent forty-seven 18F-FET PET scans either initially (20 scans) or post-therapy (27 scans) were enrolled. Standardized analysis of summed FET PET images early from 10-20 min and late from 30-40 min post-injection were used for static (mean and maximum tumor to brain ratio [TBR] and biological tumor volume [BTV]) parameters evaluation as well as the time activity curve [TAC]. Nineteen out of 20 initially assessed patients had pathologically and/or clinico-radiologically proven neoplastic lesions and one patient had pathologically proven abscess. Receiver operator curve (ROC) marked early TBR max 2.95, early TBR mean 1.76, late TBR max 2.5 and late TBR mean 1.74 as discriminator points with diagnostic accuracy reaching 90% when TBR max was combined with dynamic parameters. Significant association was found between initial FET scans, early and late BTV and event free survival (EFS) (P value=0.042 and 0.005 respectively). In post-therapy assessment, the diagnostic accuracy of conventional MRI was 81.48% when used alone and 96.30% when combined with F18-FET PET scan findings. A cutoff point of 3.2 cm3 for late BTV, in post-therapy scans, was successfully marked as a predictor for therapy response (P value 0.042) and was significantly associated with EFS (P value 0.002). In FET-avid / MRI non-enhancing lesions, early TBR max was able to detect highly malignant processes (high-grade tumors in initial scans and residue/recurrence in post-therapy scans) with 80% sensitivity and 100% specificity when cutoff value of 2.25 was used (P value=0.024). In patients with FET-avid brainstem lesions, whether enhancing or non-enhancing in MRI scans, 81.8% were associated with high risk diagnoses and 68.2% of them were associated with poor therapy outcome. The degree of FET uptake matched tumor-grading, but did not show significant association with OS or EFS (P value>0.05). F18-FET PET seems to be an evolving pediatric neuro-imaging technique with valuable diagnostic and prognostic information at initial and post-therapy evaluation.

Precision Radiotherapy: 18F-FDG PET-based radiotherapy planning in Head and Neck cancers.

Precision medicine is gaining importance in this era of molecular imaging where the molecular features of a disease can be noninvasively assessed and treated with personalized medicine. This is especially suited for head and neck cancers (HNCa). Early stage HNCa are ideally managed with radiotherapy (RT) or surgery. Head and neck (HN) is a complex region and its tumors respond to RT differently due to dissimilar structures and moving organs such as tongue. Radiation oncologists are always in the process of trying and investigating newer RT techniques in order to achieve precise and targetted therapy to tumour/s. One such innovation is Intensity modulated RT (IMRT) using 3 Dimensional conformal RT (3DCRT). This 3DCRT resizes the radiation beams to match the shape of the tumor. Such focused dose escalation may improve local control in HNCa. Image guided RT in conjunction with IMRT is the most advanced form of RT planning being used these days. Simulation computerized tomography (CT) images are usually incorporated into RT planning module. But limitations of CT such as poor soft tissue contrast than magnetic resonance imaging and inability to clearly define solid / cystic / necrotic areas and viable tumour exist. Functional imaging such as Positron Emission Tomography (PET) has established its superiority over CT in delineating the actual site and extent of HN tumors. A combination of IMRT with BTV (Biological Tumour Volume) may be the most ideal technique to deliver a homogeneous radiation boost to tumour. This review shall discuss PET based RT planning, challenges, practical tips, and how to optimize therapy with the least side effects to the normal surrounding tissues.

Margin reduction in radiotherapy for glioblastoma through 18F-fluoroethyltyrosine PET? – A recurrence pattern analysis

Background and purpose18F-fluoroethyltyrosine (18F-FET) PET is increasingly used in radiation treatment planning for the primary treatment of glioblastoma (GBM) patients additionally to contrast-enhanced MRI. To answer the question, whether a margin reduction in the primary treatment setting could be achieved through 18F-FET PET imaging, a recurrence pattern analysis was performed. Patients and methodsGBM patients undergoing 18F-FET PET examination before primary radiochemotherapy from 05/2009 to 11/2014 were included into the recurrence pattern analysis. Biological tumour volumes were semi-automatically created and fused with MR-based gross tumour volumes (MRGTVs). The pattern of recurrence was examined for MRGTVs and for PET-MRGTVs. The minimal margin including all recurrent tumour sites was assessed by gradual expansion of the PET-MRGTVs and MRGTVs until inclusion of all contrast-enhancing areas at recurrence. Results36 GBM patients were included to the analysis. The minimal margin including all contrast enhancing tumour at recurrence was significantly smaller for the PET-MRGTVs compared to the MRGTVs (median 12.5 mm vs. 16.5 mm; p < 0.001, Wilcoxon-Test). PET-MRGTVs with 15 mm CTV margins were significantly smaller than MRGTVs with 20 mm CTV margins (median volume 255.92 vs. 258.35 cm3; p = 0.020, Wilcoxon-Test; excluding 3 cases with large non-contrast enhancing tumours). The pattern of recurrence of PET-MRGTVs with 15 mm CTV margins was comparable to MRGTVs with 20 mm CTV margins (32 vs. 30 central, 2 vs. 4 in-field, 2 vs. 2 ex-field and no marginal recurrences). ConclusionTarget volume delineation of GBM patients can be improved through 18F-FET PET imaging prior to primary radiation treatment, since vital tumour can be detected more accurately. Furthermore, the results suggest that CTV margins could be reduced through 18F-FET PET imaging prior to primary RT of GBM.

Machine-learned target volume delineation of 18F-FDG PET images after one cycle of induction chemotherapy

Biological tumour volume (GTVPET) delineation on 18F-FDG PET acquired during induction chemotherapy (ICT) is challenging due to the reduced metabolic uptake and volume of the GTVPET. Automatic segmentation algorithms applied to 18F-FDG PET (PET-AS) imaging have been used for GTVPET delineation on 18F-FDG PET imaging acquired before ICT. However, their role has not been investigated in 18F-FDG PET imaging acquired after ICT. In this study we investigate PET-AS techniques, including ATLAAS a machine learned method, for accurate delineation of the GTVPET after ICT. Twenty patients were enrolled onto a prospective phase I study (FiGaRO). PET/CT imaging was acquired at baseline and 3 weeks following 1 cycle of induction chemotherapy. The GTVPET was manually delineated by a nuclear medicine physician and clinical oncologist. The resulting GTVPET was used as the reference contour. The ATLAAS original statistical model was expanded to include images of reduced metabolic activity and the ATLAAS algorithm was re-trained on the new reference dataset. Estimated GTVPET contours were derived using sixteen PET-AS methods and compared to the GTVPET using the Dice Similarity Coefficient (DSC). The mean DSC for ATLAAS, 60% Peak Thresholding (PT60), Adaptive Thresholding (AT) and Watershed Thresholding (WT) was 0.72, 0.61, 0.63 and 0.60 respectively. The GTVPET generated by ATLAAS compared favourably with manually delineated volumes and in comparison, to other PET-AS methods, was more accurate for GTVPET delineation after ICT. ATLAAS would be a feasible method to reduce inter-observer variability in multi-centre trials.

Gated 18F-FDG PET/CT of the Lung Using a Respiratory Spirometric Gating Device: A Feasibility Study.

Spirometric gating devices (SGDs) can measure the respiratory signal with high temporal resolution and accuracy. The primary objective of this study was to assess the feasibility and tolerance of a gated lung PET/CT acquisition using an SGD. The secondary objective was to compare the technical quality, accuracy, and interoperability of the SGD with that of a standard respiratory gating device, Real-Time Position Management (RPM), based on measurement of vertical thoracoabdominal displacement. Methods: A prospective phase I monocentric clinical study was performed on patients undergoing 18F-FDG PET/CT for assessment of a solitary lung nodule, staging of lung malignancy, or planning of radiotherapy. After whole-body PET/CT, a centered gated acquisition of both PET and CT was simultaneously obtained with the SGD and RPM during normal breathing. Results: Of the 46 patients who were included, 6 were prematurely excluded (1 because of hyperglycemia and 5 because of distant metastases revealed by whole-body PET/CT, leading to an unjustified extra gated acquisition). No serious adverse events were observed. Of the 40 remaining patients, the gated acquisition was prematurely stopped in 1 patient because of mask discomfort (2.5%; confidence interval [CI], 0.1%-13.2%). This event was considered patient tolerance failure. The SGD generated accurately gated PET/CT images, with more than 95% of the breathing cycle detected and high temporal resolution, in 34 of the 39 patients (87.2%; 95% CI, 60.0%-100.0%) and failed to generate a biologic tumor volume in 1 of 21 patients with increased 18F-FDG uptake (4.8%; 95% CI, 0.1%-26.5%). The quality and accuracy of respiratory signal detection and synchronization were significantly better than those obtained with RPM (P < 0.05). Conclusion: This trial supports the use of an SGD for gated lung PET/CT because of its high patient tolerance and accuracy. Although this technique seems to technically outperform RPM for gated PET/CT, further assessment of its superiority and the clinical benefit is warranted. We believe that this technique could be used as a gold standard to develop innovative approaches to eliminate respiration-induced blurring artifacts.

K-nearest neighbor driving active contours to delineate biological tumor volumes

An algorithm for tumor delineation in positron emission tomography (PET) is presented. Segmentation is achieved by a local active contour algorithm, integrated and optimized with the k-nearest neighbor (KNN) classification method, which takes advantage of the stratified k-fold cross-validation strategy. The proposed approach is evaluated considering the delineation of cancers located in different body districts (i.e. brain, head and neck, and lung), and considering different PET radioactive tracers. Data are pre-processed in order to be expressed in terms of standardized uptake value, the most widely used PET quantification index. The algorithm uses an initial, operator selected region containing the lesion, and automatically identifies an operator-independent optimal region of interest around the tumor. Successively, a slice-by-slice marching local active contour segmentation algorithm is used. The key novelty of the proposed approach consists of a novel form of the energy to be minimized during segmentation, which is enhanced by incorporating the information provided by a KNN classifier. The delineation process and its termination are fully automatic, so that intervention from the user is reduced to a minimum. Due to the high level of automation, the final segmented lesion is independent of inter-operator variation in the initial user input, making the entire process robust and the result completely repeatable.In order to assess the performance under different contrast ratio scenarios, we first evaluate the proposed method on five phantom datasets. Next, we assess the applicability of the method in the radiotherapy environment by investigating fifty clinical cases and two different PET radio-tracers. Our investigation shows that the proposed method can be applied in clinical settings and produces accurate and operator-independent segmentations, attaining good accuracy in realistic conditions.

Deep Learning Based Attenuation Correction of PET/MRI in Pediatric Brain Tumor Patients: Evaluation in a Clinical Setting.

Aim: Positron emission tomography (PET) imaging is a useful tool for assisting in correct differentiation of tumor progression from reactive changes. O-(2-18F-fluoroethyl)-L-tyrosine (FET)-PET in combination with MRI can add valuable information for clinical decision making. Acquiring FET-PET/MRI simultaneously allows for a one-stop-shop that limits the need for a second sedation or anesthesia as with PET and MRI in sequence. PET/MRI is challenged by lack of a direct measure of photon attenuation. Accepted solutions for attenuation correction (AC) might not be applicable to pediatrics. The aim of this study was to evaluate the use of the subject-specific MR-derived AC method RESOLUTE, modified to a pediatric cohort, against the performance of an MR-AC technique based on deep learning in a pediatric brain tumor cohort.Methods: The modifications to RESOLUTE and the implementation of a deep learning method were performed using 79 pediatric patient examinations. We analyzed the 36 of these with active brain tumor area above 1 mL. We measured background (B), tumor mean and maximal activity (TMEAN, TMAX), biological tumor volume (BTV), and calculated the clinical metrics TMEAN/B and TMAX/B.Results: Overall, we found both RESOLUTE and our DeepUTE methodologies to accurately reproduce the CT-AC clinical metrics. Regardless of age, both methods were able to obtain AC maps similar to the CT-AC, albeit with DeepUTE producing the most similar based on both quantitative metrics and visual inspection. In the patient-by-patient analysis DeepUTE was the only technique with all patients inside the predefined acceptable clinical limits. It also had a higher precision with relative %-difference to the reference CT-AC (TMAX/B mean: -0.1%, CI: [-0.8%, 0.5%], p = 0.54) compared to RESOLUTE (TMAX/B mean: 0.3%, CI: [-0.6%, 1.2%], p = 0.67) and DIXON-AC (TMAX/B mean: 5.9%, CI: [4.5%, 7.4%], p < 0.0001).Conclusion: Overall, we found DeepUTE to be the AC method that most robustly reproduced the CT-AC clinical metrics per se, closely followed by RESOLUTE modified to pediatric cohorts. The added accuracy due to better noise handling of DeepUTE, ease of use, as well as the improved runtime makes DeepUTE the method of choice for PET/MRI attenuation correction.

253. An accurate and operator independent method for biological tumour volume segmentation

Purpose The aim of this paper is to develop an operator independent method for biological tumour volume (BTV) delineation from Positron Emission Tomography (PET) images. BTV delineation is challenging because of the low spatial resolution and high noise level in PET images. In addition, BTV varies substantially depending on the method used to segment. Manual delineation is widely-used, but it is strongly user dependent. Methods The proposed method starts with the automatic identification of the PET slice with maximum Standardized Uptake Value (SUV). Then, a user- independent mask is obtained by a rough pre-segmentation step and it is used to perform the local active contour segmentation on the next slices. When the proposed method finds a slice where the mean SUV on the interior of the delineation contour is greater or equal than the mean SUV on the exterior of the delineation contour, the segmentation is automatically stopped. The algorithm is evaluated on four datasets of synthetic lesions considering different ratios between lesion and background radioactivity concentrations. In this way, the actual lesion volumes are known and the segmentation algorithm is evaluated under different contrast ratio scenarios. In addition, BTVs of 25 patient studies have been manually delineated and compared to the proposed method in order to assess its applicability in a clinical environment. Results In phantom experiments, dice similarity coefficient (DSC) rate and true positive volume fraction (TPVF) rate greater than 90% were observed in synthetic lesions with a diameter greater than 17 mm. In clinical cases, TPVF and DSC were 91.00 ± 7.33% and 85.98 ± 3.40%, respectively. Conclusion Our method produces accurate segmentation results in phantom studies. In addition, it is feasible in clinical context and shows good accuracy in realistic conditions, reducing any user interaction.

Characterization of Diffuse Gliomas With Histone H3-G34 Mutation by MRI and Dynamic 18F-FET PET.

Recent data suggest that diffuse gliomas carrying mutations in codon 34 of the H3 histone family 3A protein represent a very rare, distinct subgroup of IDH-wild type malignant astrocytic gliomas. However, characteristics detectable by MRI and F-FET PET in H3-G34-mutant gliomas are unknown. We report on MRI and F-FET PET findings in 8 patients from 4 German centers with H3-G34-mutant diffuse gliomas. MRI analyses included multifocality, contrast enhancement, necrosis, cysts, hemorrhages, calcification, and edema. F-FET PET characteristics were evaluated on the basis of static F-FET PET parameters, such as maximal tumor-to-background ratio (TBRmax) and biological tumor volume (BTV), as well as the minimal time-to-peak (TTPmin) obtained from dynamic F-FET PET data. MRI showed multifocal lesions in 2 of 8, contrast enhancement in 6 of 8, necrosis in 3 of 8, cysts in 3 of 8, hemorrhage in 1 of 8, and calcifications in 1 of 8 patients. None of the tumors showed marked peritumoral edema. However, all 8 H3-G34-mutant gliomas were characterized by a high uptake intensity on F-FET PET with a median TBRmax of 3.4 (range, 2.5-11.7) and a relatively diffuse uptake pattern leading to a large BTV (median, 41.9 mL; range, 7.5-115.6). Dynamic PET data revealed a short median TTPmin of 12.5 minutes. MRI features of diffuse gliomas with H3-G34 mutation may present very heterogeneously with some cases not even fulfilling the imaging criteria of high-grade glioma. In contrast, in F-FET PET, these tumors show an extensive and diffuse tracer uptake resulting in large BTV with a high TBRmax and a short TTPmin, thus resembling PET characteristics of aggressive high-grade gliomas, namely, glioblastomas.

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

BackgroundGlioma 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.ResultsAggressive 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.ConclusionsThe 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.

A smart and operator independent system to delineate tumours in Positron Emission Tomography scans

Positron Emission Tomography (PET) imaging has an enormous potential to improve radiation therapy treatment planning offering complementary functional information with respect to other anatomical imaging approaches.The aim of this study is to develop an operator independent, reliable, and clinically feasible system for biological tumour volume delineation from PET images. Under this design hypothesis, we combine several known approaches in an original way to deploy a system with a high level of automation.The proposed system automatically identifies the optimal region of interest around the tumour and performs a slice-by-slice marching local active contour segmentation. It automatically stops when a “cancer-free” slice is identified. User intervention is limited at drawing an initial rough contour around the cancer region. By design, the algorithm performs the segmentation minimizing any dependence from the initial input, so that the final result is extremely repeatable.To assess the performances under different conditions, our system is evaluated on a dataset comprising five synthetic experiments and fifty oncological lesions located in different anatomical regions (i.e. lung, head and neck, and brain) using PET studies with 18F-fluoro-2-deoxy-d-glucose and 11C-labeled Methionine radio-tracers.Results on synthetic lesions demonstrate enhanced performances when compared against the most common PET segmentation methods. In clinical cases, the proposed system produces accurate segmentations (average dice similarity coefficient: 85.36 ± 2.94%, 85.98 ± 3.40%, 88.02 ± 2.75% in the lung, head and neck, and brain district, respectively) with high agreement with the gold standard (determination coefficient R2 = 0.98). We believe that the proposed system could be efficiently used in the everyday clinical routine as a medical decision tool, and to provide the clinicians with additional information, derived from PET, which can be of use in radiation therapy, treatment, and planning.

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

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. 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. 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. 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.

Influence of Dexamethasone on O-(2-[18F]-Fluoroethyl)-L-Tyrosine Uptake in the Human Brain and Quantification of Tumor Uptake.

O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is an established positron emission tomography (PET) tracer for brain tumor imaging. This study explores the influence of dexamethasone therapy on [18F]FET uptake in the normal brain and its influence on the maximum and mean tumor-to-brain ratio (TBR). [18F]FET PET scans of 160 brain tumor patients were evaluated (80 dexamethasone treated, 80 untreated; each group with 40 men/40 women). The standardized uptake value of [18F]FET uptake in the normal brain (SUVbrain) in the different groups was compared. Nine patients were examined repeatedly with and without dexamethasone therapy. SUVbrain of [18F]FET uptake was significantly higher in dexamethasone-treated patients than in untreated patients (SUVbrain 1.33 ± 0.1 versus 1.06 ± 0.16 in male and 1.45 ± 0.25 versus 1.31 ± 0.28 in female patients). Similar results were observed in patients with serial PET scans. Furthermore, compared to men, a significantly higher SUVbrain was found in women, both with and without dexamethasone treatment. There were no significant differences between the different groups for TBRmax and TBRmean, which could have been masked by the high standard deviation. In a patient with a stable brain metastasis investigated twice with and without dexamethasone, the TBRmax and the biological tumor volume (BTV) decreased considerably after dexamethasone due to an increased SUVbrain. Dexamethasone treatment appears to increase the [18F]FET uptake in the normal brain. An effect on TBRmax, TBRmean, and BTV cannot be excluded which should be considered especially for treatment monitoring and the estimation of BTV using [18F]FET PET.

Correction to: Biological tumour volumes of gliomas in early and standard 20-40 min 18F-FET PET images differ according to IDH mutation status.

The name of M. Unterrainer was inadvertently presented as M. Unterrrainer in the original article.

Biological tumour volumes of gliomas in early and standard 20-40min 18F-FET PET images differ according to IDH mutation status.

For the clinical evaluation of O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET images, the use of standard summation imagesobtained 20-40min after injection is recommended. However, early summation imagesobtained 5-15min after injection have been reported to allow better differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) by capturing the early 18F-FET uptake peak specific for HGG. We compared early and standard summation images with regard to delineation of the PET-derived biological tumour volume (BTV) in correlation with the molecular genetic profile according the updated 2016 WHO classification. The analysis included 245 patients with newly diagnosed, histologically verified glioma and a positive 18F-FET PET scan prior to any further treatment. BTVs were delineated during the early 5-15min and standard 20-40min time frames using a threshold of 1.6 × background activity and were compared intraindividually. Volume differences between early and late summation images of >20% were considered significant and were correlated with WHO grade and the molecular genetic profile (IDH mutation and 1p/19q codeletion status). In 52.2% of the patients (128/245), a significant difference in BTV of >20% between early and standard summation images was found. While 44.3% of WHO grade II gliomas (31 of 70) showed a significantly smaller BTV in the early summation images, 35.0% of WHO grade III gliomas (28/80) and 37.9% of WHO grade IV gliomas (36/95) had a significantly larger BTVs. Among IDH-wildtype gliomas, an even higher portion (44.4%, 67/151) showed significantly larger BTVs in the early summation images, which was observed in 5.3% (5/94) of IDH-mutant gliomas only: most of the latter had significantly smaller BTVs in the early summation images, i.e. 51.2% of IDH-mutant gliomas without 1p/19q codeletion (21/41) and 39.6% with 1p/19q codeletion (21/53). BTVs delineated in early and standard summation images differed significantly in more than half of gliomas. While the standard summation images seem appropriate for delineation of LGG as well as IDH-mutant gliomas, a remarkably high percentage of HGG and, particularly, IDH-wildtype gliomas were depicted with significantly larger volumes in early summation images. This finding might be of interest for optimization of treatment planning (e.g. radiotherapy) in accordance with the individual IDH mutation status.

Utilizing 18F-fluoroethyltyrosine (FET) positron emission tomography (PET) to define suspected nonenhancing tumor for radiation therapy planning of glioblastoma

AimThe authors sought to evaluate the impact of 18F-fluoroethyltyrosine (FET) positron emission tomography (PET) on radiation therapy planning for patients diagnosed with glioblastoma (GBM) and the presence of suspected nonenhancing tumors compared with standard magnetic resonance imaging (MRI). Methods and materialsPatients with GBM and contrast-enhanced MRI scans showing regions suspicious of nonenhancing tumor underwent postoperative FET-PET before commencing radiation therapy. Two clinical target volumes (CTVs) were created using pre- and postoperative MRI: MRI fluid-attenuated inversion recovery (FLAIR) sequences (CTVFLAIR) and MRI contrast sequences with an expansion on the surgical cavity (CTVSx). FET-PET was used to create biological tumor volumes (BTVs) by encompassing FET-avid regions, forming BTVFLAIR and BTVSx. Volumetric analyses were conducted between CTVs and respective BTVs using Wilcoxon signed-rank tests. The volume increase with addition of FET was analyzed with respect to BTVFLAIR and BTVSx. Presence of focal gadolinium contrast enhancement within previously nonenhancing tumor or within the FET-avid region was noted on MRI scans at 1 and 3 months after radiation therapy. ResultsTwenty-six patients were identified retrospectively from our database, of whom 24 had demonstrable FET uptake. The median CTVFLAIR, CTVSx, BTVFLAIR, and BTVSx were 57.1 mL (range, 1.1-217.4), 83.6 mL (range, 27.2-275.8), 62.8 mL (range, 1.1-307.3), and 94.7 mL (range, 27.2-285.5), respectively. When FET-PET was used, there was a mean increase in volume of 26.8% from CTVFLAIR to BTVFLAIR and 20.6% from CTVSx to BTVSx. A statistically significant difference was noted on Wilcoxon signed-rank test when assessing volumetric change between CTVFLAIR and BTVFLAIR (P < .0001) and CTVSx and BTVSx (P < .0001). Six of 24 patients (25%) with FET avidity before radiation therapy showed focal gadolinium enhancement within the radiation therapy portal. ConclusionsFET-PET may help improve delineation of GBM in cases with a suspected nonenhancing component. This may result in improved radiation therapy target delineation and reduce the risk of potential geographical miss. SummaryWe investigated the impact of 18F-fluoroethyltyrosine (FET) positron emission tomography (PET) on radiation therapy planning for patients diagnosed with glioblastoma (GBM) and a suspected nonenhancing tumor compared with standard magnetic resonance imaging. We performed volumetric analyses between clinical target volumes and respective biological target volumes using Wilcoxon signed-rank tests. FET-PET may help improve delineation of GBM in cases with a suspected nonenhancing component and reduce the risk of potential geographical miss.

Use of FDG-PET/CT for Biological Target Volume Definition in Head and Neck Cancer

Most of patients with head and neck cancers (HNC) need curative radiotherapy either as radical treatment or in the postoperative adjuvant setting. Accurate target definition is paramount to ensure a good outcome of radiotherapy. Pretreatment Computed Tomography (CT) is regularly performed for radiation therapy planning, which both guides dose calculation and aids accurately contouring the tumor volume. Nevertheless, when using CT, the low resolution of soft- tissue and the dental artifacts may render the primary tumor identification difficult. The interobserver inconsistency on the definition of the radiation target volume is additionally a generally perceived issue. With the increase of the frequency of HNC treatment by Intensity-modulated radiotherapy (IMRT), the accurate target volume delineation performed by using Fluorodeoxy D-glucose positron emission tomography combined to CT (FDG-PET/CT) had become even more significant. Nevertheless, the ideal technique for precisely deciding the exact margins and form of the biologic tumor volume (BTV) remains challenging. FDG-PET/CT can define BTVs either for escalation of dose or alternative treatment strategies. Debatable issues still exist on the role of FDG PET/CT during radiotherapy treatment. Moreover, some new PET tracers, other than FDG, have been investigated for imaging specific biologic tumor characteristics in HNC. The purpose of this narrative review is to discuss the use of FDG-PET/CT for BTV definition before and during delivery of radiotherapy for HNC with attention to PET tracers other than FDG.

PET and MRI Guided Irradiation of a Glioblastoma Rat Model Using a Micro-irradiator.

For decades, small animal radiation research was mostly performed using fairly crude experimental setups applying simple single-beam techniques without the ability to target a specific or well-delineated tumor volume. The delivery of radiation was achieved using fixed radiation sources or linear accelerators producing megavoltage (MV) X-rays. These devices are unable to achieve sub-millimeter precision required for small animals. Furthermore, the high doses delivered to healthy surrounding tissue hamper response assessment. To increase the translation between small animal studies and humans, our goal was to mimic the treatment of human glioblastoma in a rat model. To enable a more accurate irradiation in a preclinical setting, recently, precision image-guided small animal radiation research platforms were developed. Similar to human planning systems, treatment planning on these micro-irradiators is based on computed tomography (CT). However, low soft-tissue contrast on CT makes it very challenging to localize targets in certain tissues, such as the brain. Therefore, incorporating magnetic resonance imaging (MRI), which has excellent soft-tissue contrast compared to CT, would enable a more precise delineation of the target for irradiation. In the last decade also biological imaging techniques, such as positron emission tomography (PET) gained interest for radiation therapy treatment guidance. PET enables the visualization of e.g., glucose consumption, amino-acid transport, or hypoxia, present in the tumor. Targeting those highly proliferative or radio-resistant parts of the tumor with a higher dose could give a survival benefit. This hypothesis led to the introduction of the biological tumor volume (BTV), besides the conventional gross target volume (GTV), clinical target volume (CTV), and planned target volume (PTV). At the preclinical imaging lab of Ghent University, a micro-irradiator, a small animal PET, and a 7 T small animal MRI are available. The goal was to incorporate MRI-guided irradiation and PET-guided sub-volume boosting in a glioblastoma rat model.