Adding Value to Liquid Biopsy for Brain Tumors: The Role of Imaging.

Clinical management in neuro-oncology has changed to an integrative approach that incorporates molecular profiles alongside histopathology and imaging findings. While the World Health Organization (WHO) guideline recommends the genotyping of informative alterations as a routine clinical practice for central nervous system (CNS) tumors, the acquisition of tumor tissue in the CNS is invasive and not always possible. Liquid biopsy is a non-invasive approach that provides the opportunity to capture the complex molecular heterogeneity of the whole tumor through the detection of circulating tumor biomarkers in body fluids, such as blood or cerebrospinal fluid (CSF). Despite all of the advantages, the low abundance of tumor-derived biomarkers, particularly in CNS tumors, as well as their short half-life has limited the application of liquid biopsy in clinical practice. Thus, it is crucial to identify the factors associated with the presence of these biomarkers and explore possible strategies that can increase the shedding of these tumoral components into biological fluids. In this review, we first describe the clinical applications of liquid biopsy in CNS tumors, including its roles in the early detection of recurrence and monitoring of treatment response. We then discuss the utilization of imaging in identifying the factors that affect the detection of circulating biomarkers as well as how image-guided interventions such as focused ultrasound can help enhance the presence of tumor biomarkers through blood-brain barrier (BBB) disruption.

Initial Experience of 18 F-FET PET-MR Image Fusion for Evaluation of Recurrent Primary Brain Tumors.

Background An accurate monitoring technique is crucial in brain tumors to choose the best treatment approach after surgery and/or chemoradiation. Radiological assessment of brain tumors is widely based on the magnetic resonance imaging (MRI) modality in this regard; however, MRI criteria are unable to precisely differentiate tumoral tissue from treatment-related changes. This study was conducted to evaluate whether fused MRI and O-(2- 18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) positron emission tomography (PET) can improve the diagnostic accuracy of the practitioners to discriminate treatment-related changes from true recurrence of brain tumor. Methods We retrospectively analyzed 18 F-FET PET/computed tomography (CT) of 11 patients with histopathologically proven brain tumors that were suspicious for recurrence changes after 3 to 4 months of surgery. All the patients underwent MRI and 18 F-FET PET/CT. As a third assessment, fused 18 F-FET PET/MRI was also acquired. Finally, the diagnostic accuracy of the applied modalities was compared. Results Eleven patients aged 27 to 73 years with a mean age of 47 ± 13 years were enrolled. According to the results, 9/11 cases (82%) showed positive MRI and 6 cases (55%) showed positive PET/CT and PET/MRI. Tumoral recurrence was observed in six patients (55%) in the follow-up period. Based on the follow-up results, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 64, 85, 25, 67, and 50%, respectively, for MRI alone and 91, 85, 100, 100, and 80%, respectively, for both PET/CT and PET/MRI. Conclusion This study found that 18 F-FET PET-MR image fusion in the management of brain tumors might improve recurrence detection; however, further well-designed studies are needed to verify these preliminary data.

A cycle-consistent adversarial network for brain PET partial volume correction without prior anatomical information.

PURPOSE: Partial volume effect (PVE) is a consequence of the limited spatial resolution of PET scanners. PVE can cause the intensity values of a particular voxel to be underestimated or overestimated due to the effect of surrounding tracer uptake. We propose a novel partial volume correction (PVC) technique to overcome the adverse effects of PVE on PET images. METHODS: Two hundred and twelve clinical brain PET scans, including 50 18F-Fluorodeoxyglucose (18F-FDG), 50 18F-Flortaucipir, 36 18F-Flutemetamol, and 76 18F-FluoroDOPA, and their corresponding T1-weighted MR images were enrolled in this study. The Iterative Yang technique was used for PVC as a reference or surrogate of the ground truth for evaluation. A cycle-consistent adversarial network (CycleGAN) was trained to directly map non-PVC PET images to PVC PET images. Quantitative analysis using various metrics, including structural similarity index (SSIM), root mean squared error (RMSE), and peak signal-to-noise ratio (PSNR), was performed. Furthermore, voxel-wise and region-wise-based correlations of activity concentration between the predicted and reference images were evaluated through joint histogram and Bland and Altman analysis. In addition, radiomic analysis was performed by calculating 20 radiomic features within 83 brain regions. Finally, a voxel-wise two-sample t-test was used to compare the predicted PVC PET images with reference PVC images for each radiotracer. RESULTS: The Bland and Altman analysis showed the largest and smallest variance for 18F-FDG (95% CI: - 0.29, + 0.33 SUV, mean = 0.02 SUV) and 18F-Flutemetamol (95% CI: - 0.26, + 0.24 SUV, mean = - 0.01 SUV), respectively. The PSNR was lowest (29.64 ± 1.13 dB) for 18F-FDG and highest (36.01 ± 3.26 dB) for 18F-Flutemetamol. The smallest and largest SSIM were achieved for 18F-FDG (0.93 ± 0.01) and 18F-Flutemetamol (0.97 ± 0.01), respectively. The average relative error for the kurtosis radiomic feature was 3.32%, 9.39%, 4.17%, and 4.55%, while it was 4.74%, 8.80%, 7.27%, and 6.81% for NGLDM_contrast feature for 18F-Flutemetamol, 18F-FluoroDOPA, 18F-FDG, and 18F-Flortaucipir, respectively. CONCLUSION: An end-to-end CycleGAN PVC method was developed and evaluated. Our model generates PVC images from the original non-PVC PET images without requiring additional anatomical information, such as MRI or CT. Our model eliminates the need for accurate registration or segmentation or PET scanner system response characterization. In addition, no assumptions regarding anatomical structure size, homogeneity, boundary, or background level are required.

DeepTOFSino: A deep learning model for synthesizing full-dose time-of-flight bin sinograms from their corresponding low-dose sinograms.

PURPOSE: Reducing the injected activity and/or the scanning time is a desirable goal to minimize radiation exposure and maximize patients' comfort. To achieve this goal, we developed a deep neural network (DNN) model for synthesizing full-dose (FD) time-of-flight (TOF) bin sinograms from their corresponding fast/low-dose (LD) TOF bin sinograms. METHODS: Clinical brain PET/CT raw data of 140 normal and abnormal patients were employed to create LD and FD TOF bin sinograms. The LD TOF sinograms were created through 5% undersampling of FD list-mode PET data. The TOF sinograms were split into seven time bins (0, ±1, ±2, ±3). Residual network (ResNet) algorithms were trained separately to generate FD bins from LD bins. An extra ResNet model was trained to synthesize FD images from LD images to compare the performance of DNN in sinogram space (SS) vs implementation in image space (IS). Comprehensive quantitative and statistical analysis was performed to assess the performance of the proposed model using established quantitative metrics, including the peak signal-to-noise ratio (PSNR), structural similarity index metric (SSIM) region-wise standardized uptake value (SUV) bias and statistical analysis for 83 brain regions. RESULTS: SSIM and PSNR values of 0.97 ± 0.01, 0.98 ± 0.01 and 33.70 ± 0.32, 39.36 ± 0.21 were obtained for IS and SS, respectively, compared to 0.86 ± 0.02and 31.12 ± 0.22 for reference LD images. The absolute average SUV bias was 0.96 ± 0.95% and 1.40 ± 0.72% for SS and IS implementations, respectively. The joint histogram analysis revealed the lowest mean square error (MSE) and highest correlation (R2 = 0.99, MSE = 0.019) was achieved by SS compared to IS (R2 = 0.97, MSE= 0.028). The Bland & Altman analysis showed that the lowest SUV bias (-0.4%) and minimum variance (95% CI: -2.6%, +1.9%) were achieved by SS images. The voxel-wise t-test analysis revealed the presence of voxels with statistically significantly lower values in LD, IS, and SS images compared to FD images respectively. CONCLUSION: The results demonstrated that images reconstructed from the predicted TOF FD sinograms using the SS approach led to higher image quality and lower bias compared to images predicted from LD images.

Multimodal assessment of regional gray matter integrity in early relapsing-remitting multiple sclerosis patients with normal cognition: a voxel-based structural and perfusion approach.

OBJECTIVE: There is increasing evidence that gray matter (GM) impairment is strongly associated with clinical performance decline. We aim to perform a voxelwise analysis between regional GM (rGM) perfusion and structural abnormalities in early relapsing-remitting multiple sclerosis patients with normal cognition (RRMS-IC) and explore clinical correlate of early rGM abnormalities. METHODS AND MATERIALS: We studied 14 early RRMS-IC patients and 14 healthy age- and sex-matched controls. Brain perfusion single photon emission computed tomography (SPECT), structural MRI, and a comprehensive neuropsychological examination were acquired from all participants. Neuropsychological tests include expanded disability status scale, minimal mental status examination, short physical performance battery, Wechsler memory scale, and quick smell test. Voxel-based morphometry was used for analyzing SPECT and T1-MR images to identify rGM hypoperfusion and atrophy, respectively (RRMS-IC vs controls (group analysis), and also, each patient vs controls (individual analysis)) (p < 0.001). Then, anatomical location of impaired regions was acquired by automated anatomical labeling software. RESULTS: There was no significant difference in total GM volume between RRMS-IC and healthy controls, however, rGM atrophy and hypoperfusion were detected. Individual analysis revealed more rGM impairment compared with group analysis. rGM hypoperfusion was more extensive rather than rGM atrophy in RRMS-IC. There was no spatial association between rGM atrophy and rGM hypoperfusion (p > 0.05). rGM abnormalities correlated with several relevant minimal clinical deficits. CONCLUSION: Lack of spatial correlation between rGM atrophy and hypoperfusion might suggest that independent mechanisms might underlie atrophy and hypoperfusion. Perfusion SPECT may provide supplementary information along with MRI. ADVANCES IN KNOWLEDGE: Association between rGM atrophy and rGM hypoperfusion and their clinical significance in early RRMS-IC is not well described yet. Our study showed that there is spatial dissociation between rGM atrophy and rGM hypoperfusion, suggesting that different mechanisms might underlie these pathologies.

State-of-the-art modalities in cardio-oncology: insight from a nuclear medicine approach.

Cancer and cardiovascular disease are the most significant causes of morbidity and mortality worldwide. Although the cancer survival rate has increased due to improved treatment approaches, especially targeted therapy, some side effects such as cardiotoxicity decrease the efficiency of the clinical outcome. Radiation therapy and chemotherapy have a long-established history of potential cardiotoxic effects. A new multi-disciplinary and translational field known as cardio-oncology has been developed for the identification, prevention, and treatment of cardiovascular dysfunctions associated with cancer treatment approaches. One of the important tools for detecting and monitoring cardiotoxic effects is non-invasive nuclear cardiac imaging techniques. Cardiac nuclear imaging modalities especially recent findings positron emission tomography (PET) tracers have a quintessential role in the early detection of cardiovascular disorders. Moreover, comprehensive studies are required to investigate novel nuclear medicine treatment approaches such as peptide receptor radionuclide therapy (PRRT), fibroblast activation protein (FAP), and chemokine receptor (CXCR) targeting probes for possible cardiac side effects that play important roles in the treatment of malignancies.

Association of regional cerebral perfusion impairment with gait and balance performance in dizzy patients using brain perfusion SPECT: Voxel-based analysis of a pilot sample.

OBJECTIVES: The purpose of this study was to investigate regional cerebral blood flow (rCBF) reduction in patients with dizziness and perfusion-related clinical impairment using brain perfusion single photon emission tomography (SPECT). METHODS: Thirty-four patients with subjective dizziness and 13 age- and sex-matched healthy controls were studied. Dizziness-related impairments were assessed using the Dizziness Handicap Inventory (DHI) and Short Physical Performance Battery (SPPB). Brain perfusion SPECT scan was acquired from all participants. The carotid intima-media thickness (CIMT) was also measured. Brain perfusion data were qualitatively interpreted in all cases. Voxel-wise analysis was also conducted in 11 patients compared to healthy controls. RESULTS: Thirty-four patients (mean age=53.8±13.4 years, m/f: 19/15) and 13 age- and sex-matched controls (mean age=51.5±13.1, m/f: 7/6) were included. The dizziness severity was mild in 58.8% (n=20), moderate in 26.5% (n=9), and severe in 14.7% (n=5). Qualitative interpretation of SPECT images showed normal scans in 4 (11.2%) patients and abnormal scans in 30 (88.2%) patients. Patients with dizziness showed a significantly decreased brain perfusion in the precuneus, cuneus, occipital lobe (superior and inferior parts), frontal lobe (inferior and middle parts), temporal lobe, parietal lobe (inferior and superior parts), cerebellum, insula, and putamen nucleus. Based on both qualitative SPECT interpretation and voxel-wise analysis, perfusion defect had a significant association with the total SPPB score and the scores of two sub-domains (p<0.05), but not with the DHI (p>0.05) score. CONCLUSION: The perfusion- and atherosclerosis-related impairments of gait and balance were largely independent of subjective dizziness and dizziness severity. Moreover, this study provided support for contribution of perfusion impairment to the disturbance of gait and balance in older populations along with other pathologic processes.

Theranostics in Brain Tumors.

Theranostic nuclear oncology, mainly in neuro-oncology (neurotheranostics), aims to combine cancer imaging and therapy using the same targeting molecule. This approach tries to identify patients who are most likely to benefit from tumor molecular radionuclide therapy. The ability of radioneurotheranostic agents to interact with cancer cells at the molecular level with high specificity can significantly improve the effectiveness of cancer therapy. A variety of biologic targets are under investigation for treating brain tumors. PET-based precision imaging can substantially improve the therapeutic efficacy of radiotheranostic approach in brain tumors.

Feasibility and Therapeutic Potential of Peptide Receptor Radionuclide Therapy for High-Grade Gliomas.

PURPOSE: This pilot study tested the principle that 177Lu-DOTATATE may be applied to patients with high-grade gliomas (HGGs) that are either inoperable or refractory to the standard conventional treatments and also assessed whether this approach could be a viable therapeutic plan in this dilemma. METHODS: In this prospective study, 16 subjects experiencing HGGs that were either inoperable or refractory to the standard conventional treatments were included. All the patients checked for somatostatin receptor expression on the tumors. The patients were treated with 1 to 4 cycles of IV 177Lu-DOTATATE. The primary end point was radiological response after peptide receptor radionuclide therapy, and the secondary end point was improved quality of life using Karnofsky Performance Score and Eastern Cooperative Oncology Group score. RESULTS: In total, 16 subjects (10 males and 6 females) with a mean age of 55.68 ± 13.17 years (26-73 years) participated in the study. Of them, 8 patients were new HGG cases, and 8 patients had recurrent tumors. The participants' responses to treatments were complete remission in 12.5% of (n = 2), partial remission in 31.25% (n = 5), disease stability in 18.7% (n = 3), and disease progression in 37.5% (n = 6). In total, pretreatment and posttreatment Karnofsky Performance Score and Eastern Cooperative Oncology Group scores did not improved (P > 0.05). The patients were followed up from 1 month to 26 months (median, 3 months). CONCLUSIONS: This preliminary result suggests that peptide receptor radionuclide therapy using 177Lu-DOTATATE may be associated with positive effects in patients with HGGs (grade III-IV). However, this approach should be evaluated in a more homogeneous group of patients with more favorable performance status.

Radioimmunotherapy (RIT) in Brain Tumors.

Annually, the incidence of brain tumors has slightly increased and also the patient prognosis is still disappointing, especially for high-grade neoplasms. So, researchers seek methods to improve therapeutic index as a critical aim of treatment. One of these new challenging methods is radioimmunotherapy (RIT) that involves recruiting a coupling of radionuclide component with monoclonal antibody (mAb) which are targeted against cell surface tumor-related antigens or antigens of cells within the tumor microenvironment. In the context of cancer care, precision medicine is exemplified by RIT; precision medicine can offer a tailored treatment to meet the needs for treatment of brain tumors. This review aims to discuss the molecular targets used in radioimmunotherapy of brain tumors, available and future radioimmunopharmaceutics, clinical trials of radioimmunotherapy in brain neoplasms, and eventually, conclusion and future perspective of application of radioimmunotherapy in neurooncology cancer care.

An update on PET-based molecular imaging in neuro-oncology: challenges and implementation for a precision medicine approach in cancer care.

PET imaging using novel radiotracers show promises for tumor grading and molecular characterization through visualizing molecular and functional properties of the tumors. Application of PET tracers in brain neoplasm depends on both type of the neoplasm and the research or clinical significance required to be addressed. In clinical neuro-oncology, 18F-FDG is used mainly to differentiate tumor recurrence from radiation-induced necrosis, and novel PET agents show attractive imaging properties. Novel PET tracers can offer biologic information not visible via contrast-enhanced MRI or 18F-FDG PET. This review aims to provide an update on the complementary role of PET imaging in neuro-oncology both in research and clinical settings along with presenting interesting cases in this context.

Advanced modalities of molecular imaging in precision medicine for musculoskeletal malignancies.

Musculoskeletal malignancies consist of a heterogenous group of mesenchymal tumors, often with high inter- and intratumoral heterogeneity. The early and accurate diagnosis of these malignancies can have a substantial impact on optimal treatment and quality of life for these patients. Several new applications and techniques have emerged in molecular imaging, including advances in multimodality imaging, the development of novel radiotracers, and advances in image analysis with radiomics and artificial intelligence. This review highlights the recent advances in molecular imaging modalities and the role of non-invasive imaging in evaluating tumor biology in the era of precision medicine.