Can Radiomics Provide Additional Information in [F-18]FET-Negative Gliomas?

Simple Summary Amino acid positron emission tomography (PET) complements standard magnetic resonance imaging (MRI) since it directly visualizes the increased amino acid transport into tumor cells. Amino acid PET using O-(2-[F-18]fluoroethyl)-L-tyrosine ([F-18]FET) has proven to be relevant, for example, for glioma classification, identification of tumor progression or recurrence, or for the delineation of tumor extent. Nevertheless, a relevant proportion of low-grade gliomas (30%) and few high-grade gliomas (5%) were found to show no or even decreased amino acid uptake by conventional visual analysis of PET images. Advanced image analysis with the extraction of radiomic features is known to provide more detailed information on tumor characteristics than conventional analyses. Hence, this study aimed to investigate whether radiomic features derived from dynamic [F-18]FET PET data differ between [F-18]FET-negative glioma and healthy background and thus provide information that cannot be extracted by visual read. The purpose of this study was to evaluate the possibility of extracting relevant information from radiomic features even in apparently [F-18]FET-negative gliomas. A total of 46 patients with a newly diagnosed, histologically verified glioma that was visually classified as [F-18]FET-negative were included. Tumor volumes were defined using routine T2/FLAIR MRI data and applied to extract information from dynamic [F-18]FET PET data, i.e., early and late tumor-to-background (TBR5-15, TBR20-40) and time-to-peak (TTP) images. Radiomic features of healthy background were calculated from the tumor volume of interest mirrored in the contralateral hemisphere. The ability to distinguish tumors from healthy tissue was assessed using the Wilcoxon test and logistic regression. A total of 5, 15, and 69% of features derived from TBR20-40, TBR5-15, and TTP images, respectively, were significantly different. A high number of significantly different TTP features was even found in isometabolic gliomas (after exclusion of photopenic gliomas) with visually normal [F-18]FET uptake in static images. However, the differences did not reach satisfactory predictability for machine-learning-based identification of tumor tissue. In conclusion, radiomic features derived from dynamic [F-18]FET PET data may extract additional information even in [F-18]FET-negative gliomas, which should be investigated in larger cohorts and correlated with histological and outcome features in future studies

Detection of Splenic Tissue Using Tc-99m-Labelled Denatured Red Blood Cells Scintigraphy-A Quantitative Single Center Analysis

Background: Red blood cells (RBC) scintigraphy can be used not only for detection of bleeding sites, but also of spleen tissue. However, there is no established quantitative readout. Therefore, we investigated uptake in suspected splenic lesions in direct quantitative correlation to sites of physiologic uptake in order to objectify the readout. Methods: 20 patients with Tc-99m-labelled RBC scintigraphy and SPECT/low-dose CT for assessment of suspected splenic tissue were included. Lesions were rated as vital splenic or non-splenic tissue, and uptake and physiologic uptake of bone marrow, pancreas, and spleen were then quantified using a volume-of-interest based approach. Hepatic uptake served as a reference. Results: The median uptake ratio was significantly higher in splenic (2.82 (range, 0.58-24.10), n = 47) compared to other lesions (0.49 (0.01-0.83), n = 7), p < 0.001, and 5 lesions were newly discovered. The median pancreatic uptake was 0.09 (range 0.03-0.67), bone marrow 0.17 (0.03-0.45), and orthotopic spleen 14.45 (3.04-29.82). Compared to orthotopic spleens, the pancreas showed lowest uptake (0.09 vs. 14.45, p = 0.004). Based on pancreatic uptake we defined a cutoff (0.75) to distinguish splenic from other tissues. Conclusion: As the uptake in extra-splenic regions is invariably low compared to splenules, it can be used as comparator for evaluating suspected splenic tissues

Longitudinal [F-18]GE-180 PET Imaging Facilitates In Vivo Monitoring of TSPO Expression in the GL261 Glioblastoma Mouse Model

The 18 kDa translocator protein (TSPO) is increasingly recognized as an interesting target for the imaging of glioblastoma (GBM). Here, we investigated TSPO PET imaging and autoradiography in the frequently used GL261 glioblastoma mouse model and aimed to generate insights into the temporal evolution of TSPO radioligand uptake in glioblastoma in a preclinical setting. We performed a longitudinal [F-18]GE-180 PET imaging study from day 4 to 14 post inoculation in the orthotopic syngeneic GL261 GBM mouse model (n = 21 GBM mice, n = 3 sham mice). Contrast-enhanced computed tomography (CT) was performed at the day of the final PET scan (+/- 1 day). [F-18] GE-180 autoradiography was performed on day 7, 11 and 14 (ex vivo: n = 13 GBM mice, n = 1 sham mouse;in vitro: n = 21 GBM mice;n = 2 sham mice). Brain sections were also used for hematoxylin and eosin (H&E) staining and TSPO immunohistochemistry. [F-18]GE-180 uptake in PET was elevated at the site of inoculation in GBM mice as compared to sham mice at day 11 and later (at day 14, TBRmax +27% compared to sham mice, p = 0.001). In GBM mice, [F-18]GE-180 uptake continuously increased over time, e.g., at day 11, mean TBRmax +16% compared to day 4, p = 0.011. [(18) F]GE-180 uptake as depicted by PET was in all mice co-localized with contrast-enhancement in CT and tissue-based findings. [F-18]GE-180 ex vivo and in vitro autoradiography showed highly congruent tracer distribution (r = 0.99, n = 13, p < 0.001). In conclusion, [F-18]GE-180 PET imaging facilitates non-invasive in vivo monitoring of TSPO expression in the GL261 GBM mouse model. [F-18]GE-180 in vitro autoradiography is a convenient surrogate for ex vivo autoradiography, allowing for straightforward identification of suitable models and scan time-points on previously generated tissue sections

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH-Wild-Type Glioblastoma

The 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients. Methods: Patients were included who had newly diagnosed, histologically confirmed isocitrate dehydrogenase (IDH)-wild-type glioblastoma with available TSPO PET before either normofractionated radiotherapy combined with temozolomide or hypofractionated radiotherapy. SUVmax on TSPO PET, TSPO binding affinity status, tumor volumes on MRI, and further clinical data, such as O (6)-alkylguanine DNA methyltransferase (MGMT) and telomerase reverse transcriptase (TERT) gene promoter mutation status, were correlated with patient survival. Results: Forty-five patients (median age, 63.3 y) were included. Median SUVmax was 2.2 (range, 1.0-4.7). A TSPO PET signal was associated with survival: High uptake intensity (SUVmax > 2.2) was related to significantly shorter overall survival (OS;8.3 vs. 17.8 mo, P = 0.037). Besides SUVmax, prognostic factors for OS were age (P = 0.046), MGMT promoter methylation status (P = 0.032), and T2-weighted MRI volume (P = 0.031). In the multivariate survival analysis, SUVmax in TSPO PET remained an independent prognostic factor for OS (P = 0.023), with a hazard ratio of 2.212 (95% CI, 1.115-4.386) for death in cases with a high TSPO PET signal (SUVmax > 2.2). Conclusion: A high TSPO PET signal before radiotherapy is associated with significantly shorter survival in patients with newly diagnosed IDH-wild-type glioblastoma. TSPO PET seems to add prognostic insights beyond established clinical parameters and might serve as an informative tool as clinicians make survival predictions for patients with glioblastoma

The Traumatic Inoculation Process Affects TSPO Radioligand Uptake in Experimental Orthotopic Glioblastoma

Background: The translocator protein (TSPO) has been proven to have great potential as a target for the positron emission tomography (PET) imaging of glioblastoma. However, there is an ongoing debate about the potential various sources of the TSPO PET signal. This work investigates the impact of the inoculation-driven immune response on the PET signal in experimental orthotopic glioblastoma. Methods: Serial [F-18]GE-180 and O-(2-[F-18]fluoroethyl)-L-tyrosine ([F-18]FET) PET scans were performed at day 7/8 and day 14/15 after the inoculation of GL261 mouse glioblastoma cells (n = 24) or saline (sham, n = 6) into the right striatum of immunocompetent C57BL/6 mice. An additional n = 25 sham mice underwent [F-18]GE-180 PET and/or autoradiography (ARG) at days 7, 14, 21, 28, 35, 50 and 90 in order to monitor potential reactive processes that were solely related to the inoculation procedure. In vivo imaging results were directly compared to tissue-based analyses including ARG and immunohistochemistry. Results: We found that the inoculation process represents an immunogenic event, which significantly contributes to TSPO radioligand uptake. [F-18]GE-180 uptake in GL261-bearing mice surpassed [F-18]FET uptake both in the extent and the intensity, e.g., mean target-to-background ratio (TBRmean) in PET at day 7/8: 1.22 for [F-18]GE-180 vs. 1.04 for [F-18]FET, p < 0.001. Sham mice showed increased [F-18]GE-180 uptake at the inoculation channel, which, however, continuously decreased over time (e.g., TBRmean in PET: 1.20 at day 7 vs. 1.09 at day 35, p = 0.04). At the inoculation channel, the percentage of TSPO/IBA1 co-staining decreased, whereas TSPO/GFAP (glial fibrillary acidic protein) co-staining increased over time (p < 0.001). Conclusion: We identify the inoculation-driven immune response to be a relevant contributor to the PET signal and add a new aspect to consider for planning PET imaging studies in orthotopic glioblastoma models

Prediction of TERTp-mutation status in IDH-wildtype high-grade gliomas using pre-treatment dynamic 18FFET PET radiomics

PURPOSE To evaluate radiomic features extracted from standard static images (20-40~min p.i.), early summation images (5-15~min p.i.), and dynamic 18FFET PET images for the prediction of TERTp-mutation status in patients with IDH-wildtype high-grade glioma. METHODS A total of 159 patients (median age 60.2~years, range 19-82~years) with newly diagnosed IDH-wildtype diffuse astrocytic glioma (WHO grade III or IV) and dynamic 18FFET PET prior to surgical intervention were enrolled and divided into a training (n = 112) and a testing cohort (n = 47) randomly. First-order, shape, and texture radiomic features were extracted from standard static (20-40~min summation images; TBR20-40), early static (5-15~min summation images; TBR5-15), and dynamic (time-to-peak; TTP) images, respectively. Recursive feature elimination was used for feature selection by 10-fold cross-validation in the training cohort after normalization, and logistic regression models were generated using the radiomic features extracted from each image to differentiate TERTp-mutation status. The areas under the ROC curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive value were calculated to illustrate diagnostic power in both the training and testing cohort. RESULTS The TTP model comprised nine selected features and achieved highest predictability of TERTp-mutation with an AUC of 0.82 (95{\%} confidence interval 0.71-0.92) and sensitivity of 92.1{\%} in the independent testing cohort. Weak predictive capability was obtained in the TBR5-15 model, with an AUC of 0.61 (95{\%} CI 0.42-0.80) in the testing cohort, while no predictive power was observed in the TBR20-40 model. CONCLUSIONS Radiomics based on TTP images extracted from dynamic 18FFET PET can predict the TERTp-mutation status of IDH-wildtype diffuse astrocytic high-grade gliomas with high accuracy preoperatively

Differential role of residual metabolic tumor volume in inoperable stage III NSCLC after chemoradiotherapy ± immune checkpoint inhibition

BACKGROUND The PET-derived metabolic tumor volume (MTV) is an independent prognosticator in non-small cell lung cancer (NSCLC) patients. We analyzed the prognostic value of residual MTV (rMTV) after completion of chemoradiotherapy (CRT) in inoperable stage III NSCLC patients with and without immune checkpoint inhibition (ICI). METHODS Fifty-six inoperable stage III NSCLC patients (16 female, median 65.0~years) underwent 18F-FDG PET/CT after completion of standard CRT. rMTV was delineated on 18F-FDG PET/CT using a standard threshold (liver SUVmean + 2 × standard deviation). 21/56 patients underwent additional ICI (CRT-IO, 21/56 patients) thereafter. Patients were divided in volumetric subgroups using median split dichotomization (MTV ≤ 4.3~ml vs. > 4.3~ml). rMTV, clinical features, and ICI-application were correlated with clinical outcome parameters (progression-free survival (PFS), local PFS (LPFS), and overall survival (OS). RESULTS Overall, median follow-up was 52.0~months. Smaller rMTV was associated with longer median PFS (29.3 vs. 10.5~months, p = 0.015), LPFS (49.9 vs. 13.5~months, p = 0.001), and OS (63.0 vs. 23.0~months, p = 0.003). CRT-IO patients compared to CRT patients showed significantly longer median PFS (29.3 vs. 11.2~months, p = 0.034), LPFS (median not reached vs. 14.0~months, p = 0.016), and OS (median not reached vs. 25.2~months, p = 0.007). In the CRT subgroup, smaller rMTV was associated with longer median PFS (33.5 vs. 8.6~months, p = 0.001), LPFS (49.9 vs. 10.1~months, p = 0.001), and OS (63.0 vs. 16.3~months, p = 0.004). In the CRT-IO subgroup, neither PFS, LPFS, nor OS were associated with MTV (p > 0.05 each). The findings were confirmed in subsequent multivariate analyses. CONCLUSION In stage III NSCLC, smaller rMTV is highly associated with superior clinical outcome, especially in patients undergoing CRT without ICI. Patients with CRT-IO show significantly improved outcome compared to CRT patients. Of note, clinical outcome in CRT-IO patients is independent of residual MTV. Hence, even patients with large rMTV might profit from ICI despite extensive tumor load