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.

Image Denoising of Low-Dose PET Mouse Scans with Deep Learning: Validation Study for Preclinical Imaging Applicability.

PURPOSE: Positron emission tomography (PET) image quality can be improved by higher injected activity and/or longer acquisition time, but both may often not be practical in preclinical imaging. Common preclinical radioactive doses (10 MBq) have been shown to cause deterministic changes in biological pathways. Reducing the injected tracer activity and/or shortening the scan time inevitably results in low-count acquisitions which poses a challenge because of the inherent noise introduction. We present an image-based deep learning (DL) framework for denoising lower count micro-PET images. PROCEDURES: For 36 mice, a 15-min [18F]FDG (8.15 ± 1.34 MBq) PET scan was acquired at 40 min post-injection on the Molecubes ß-CUBE (in list mode). The 15-min acquisition (high-count) was parsed into smaller time fractions of 7.50, 3.75, 1.50, and 0.75 min to emulate images reconstructed at 50, 25, 10, and 5% of the full counts, respectively. A 2D U-Net was trained with mean-squared-error loss on 28 high-low count image pairs. RESULTS: The DL algorithms were visually and quantitatively compared to spatial and edge-preserving denoising filters; the DL-based methods effectively removed image noise and recovered image details much better while keeping quantitative (SUV) accuracy. The largest improvement in image quality was seen in the images reconstructed with 10 and 5% of the counts (equivalent to sub-1 MBq or sub-1 min mouse imaging). The DL-based denoising framework was also successfully applied on the NEMA-NU4 phantom and different tracer studies ([18F]PSMA, [18F]FAPI, and [68 Ga]FAPI). CONCLUSION: Visual and quantitative results support the superior performance and robustness in image denoising of the implemented DL models for low statistics micro-PET. This offers much more flexibility in optimizing preclinical, longitudinal imaging protocols with reduced tracer doses or shorter durations.

CO2-Driven Nebulization of pH-Sensitive Supramolecular Polymers for Intraperitoneal Hydrogel Formation and the Treatment of Peritoneal Metastasis.

Because peritoneal metastasis (PM) from ovarian cancer is characterized by non-specific symptoms, it is often diagnosed at advanced stages. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) can be considered a promising drug delivery method for unresectable PM. Currently, the efficacy of intraperitoneal (IP) drug delivery is limited by the off-label use of IV chemotherapeutic solutions, which are rapidly cleared from the IP cavity. Hence, this research aimed to improve PM treatment by evaluating a nanoparticle-loaded, pH-switchable supramolecular polymer hydrogel as a controlled release drug delivery system that can be IP nebulized. Moreover, a multidirectional nozzle was developed to allow nebulization of viscous materials such as hydrogels and to reach an even IP gel deposition. We demonstrated that acidification of the nebulized hydrogelator solution by carbon dioxide, used to inflate the IP cavity during laparoscopic surgery, stimulated the in situ gelation, which prolonged the IP hydrogel retention. In vitro experiments indicated that paclitaxel nanocrystals were gradually released from the hydrogel depot formed, which sustained the cytotoxicity of the formulation for 10 days. Finally, after aerosolization of this material in a xenograft model of PM, tumor progression could successfully be delayed, while the overall survival time was significantly increased compared to non-treated animals.

Sterile triggers drive joint inflammation in TNF- and IL-1ß-dependent mouse arthritis models.

Arthritis is the most common extra-intestinal complication in inflammatory bowel disease (IBD). Conversely, arthritis patients are at risk for developing IBD and often display subclinical gut inflammation. These observations suggest a shared disease etiology, commonly termed "the gut-joint-axis." The clinical association between gut and joint inflammation is further supported by the success of common therapeutic strategies and microbiota dysbiosis in both conditions. Most data, however, support a correlative relationship between gut and joint inflammation, while causative evidence is lacking. Using two independent transgenic mouse arthritis models, either TNF- or IL-1ß dependent, we demonstrate that arthritis develops independently of the microbiota and intestinal inflammation, since both lines develop full-blown articular inflammation under germ-free conditions. In contrast, TNF-driven gut inflammation is fully rescued in germ-free conditions, indicating that the microbiota is driving TNF-induced gut inflammation. Together, our study demonstrates that although common inflammatory pathways may drive both gut and joint inflammation, the molecular triggers initiating such pathways are distinct in these tissues.

Walk-through flat panel total-body PET: a patient-centered design for high throughput imaging at lower cost using DOI-capable high-resolution monolithic detectors.

PURPOSE: Long axial field-of-view (LAFOV) systems have a much higher sensitivity than standard axial field-of-view (SAFOV) PET systems for imaging the torso or full body, which allows faster and/or lower dose imaging. Despite its very high sensitivity, current total-body PET (TB-PET) throughput is limited by patient handling (positioning on the bed) and often a shortage of available personnel. This factor, combined with high system costs, makes it hard to justify the implementation of these systems for many academic and nearly all routine nuclear medicine departments. We, therefore, propose a novel, cost-effective, dual flat panel TB-PET system for patients in upright standing positions to avoid the time-consuming positioning on a PET-CT table; the walk-through (WT) TB-PET. We describe a patient-centered, flat panel PET design that offers very efficient patient throughput and uses monolithic detectors (with BGO or LYSO) with depth-of-interaction (DOI) capabilities and high intrinsic spatial resolution. We compare system sensitivity, component costs, and patient throughput of the proposed WT-TB-PET to a SAFOV (= 26 cm) and a LAFOV (= 106 cm) LSO PET systems. METHODS: Patient width, height (= top head to start of thighs) and depth (= distance from the bed to front of patient) were derived from 40 randomly selected PET-CT scans to define the design dimensions of the WT-TB-PET. We compare this new PET system to the commercially available Siemens Biograph Vision 600 (SAFOV) and Siemens Quadra (LAFOV) PET-CT in terms of component costs, system sensitivity, and patient throughput. System cost comparison was based on estimating the cost of the two main components in the PET system (Silicon Photomultipliers (SiPMs) and scintillators). Sensitivity values were determined using Gate Monte Carlo simulations. Patient throughput times (including CT and scout scan, patient positioning on bed and transfer) were recorded for 1 day on a Siemens Vision 600 PET. These timing values were then used to estimate the expected patient throughput (assuming an equal patient radiotracer injected activity to patients and considering differences in system sensitivity and time-of-flight information) for WT-TB-PET, SAFOV and LAFOV PET. RESULTS: The WT-TB-PET is composed of two flat panels; each is 70 cm wide and 106 cm high, with a 50-cm gap between both panels. These design dimensions were justified by the patient sizes measured from the 40 random PET-CT scans. Each panel consists of 14 × 20 monolithic BGO detector blocks that are 50 × 50 × 16 mm in size and are coupled to a readout with 6 × 6 mm SiPMs arrays. For the WT-TB-PET, the detector surface is reduced by a factor of 1.9 and the scintillator volume by a factor of 2.2 compared to LAFOV PET systems, while demonstrating comparable sensitivity and much better uniform spatial resolution (< 2 mm in all directions over the FOV). The estimated component cost for the WT-TB-PET is 3.3 × lower than that of a 106 cm LAFOV system and only 20% higher than the PET component costs of a SAFOV. The estimated maximum number of patients scanned on a standard 8-h working day increases from 28 (for SAFOV) to 53-60 (for LAFOV in limited/full acceptance) to 87 (for the WT-TB-PET). By scanning faster (more patients), the amount of ordered activity per patient can be reduced drastically: the WT-TB-PET requires 66% less ordered activity per patient than a SAFOV. CONCLUSIONS: We propose a monolithic BGO or LYSO-based WT-TB-PET system with DOI measurements that departs from the classical patient positioning on a table and allows patients to stand upright between two flat panels. The WT-TB-PET system provides a solution to achieve a much lower cost TB-PET approaching the cost of a SAFOV system. High patient throughput is increased by fast patient positioning between two vertical flat panel detectors of high sensitivity. High spatial resolution (< 2 mm) uniform over the FOV is obtained by using DOI-capable monolithic scintillators.

Structural connectome alterations in anxious dogs: a DTI-based study.

Anxiety and fear are dysfunctional behaviors commonly observed in domesticated dogs. Although dogs and humans share psychopathological similarities, little is known about how dysfunctional fear behaviors are represented in brain networks in dogs diagnosed with anxiety disorders. A combination of diffusion tensor imaging (DTI) and graph theory was used to investigate the underlying structural connections of dysfunctional anxiety in anxious dogs and compared with healthy dogs with normal behavior. The degree of anxiety was assessed using the Canine Behavioral Assessment & Research Questionnaire (C-BARQ), a widely used, validated questionnaire for abnormal behaviors in dogs. Anxious dogs showed significantly decreased clustering coefficient ([Formula: see text]), decreased global efficiency ([Formula: see text]), and increased small-worldness (σ) when compared with healthy dogs. The nodal parameters that differed between the anxious dogs and healthy dogs were mainly located in the posterior part of the brain, including the occipital lobe, posterior cingulate gyrus, hippocampus, mesencephalon, and cerebellum. Furthermore, the nodal degree ([Formula: see text]) of the left cerebellum was significantly negatively correlated with "excitability" in the C-BARQ of anxious dogs. These findings could contribute to the understanding of a disrupted brain structural connectome underlying the pathological mechanisms of anxiety-related disorders in dogs.

STE20 kinase TAOK3 regulates type 2 immunity and metabolism in obesity.

Healthy adipose tissue (AT) contains ST2+ Tregs, ILC2s, and alternatively activated macrophages that are lost in mice or humans on high caloric diet. Understanding how this form of type 2 immunity is regulated could improve treatment of obesity. The STE20 kinase Thousand And One amino acid Kinase-3 (TAOK3) has been linked to obesity in mice and humans, but its precise function is unknown. We found that ST2+ Tregs are upregulated in visceral epididymal white AT (eWAT) of Taok3-/- mice, dependent on IL-33 and the kinase activity of TAOK3. Upon high fat diet feeding, metabolic dysfunction was attenuated in Taok3-/- mice. ST2+ Tregs disappeared from eWAT in obese wild-type mice, but this was not the case in Taok3-/- mice. Mechanistically, AT Taok3-/- Tregs were intrinsically more responsive to IL-33, through higher expression of ST2, and expressed more PPARγ and type 2 cytokines. Thus, TAOK3 inhibits adipose tissue Tregs and regulates immunometabolism under excessive caloric intake.

Effect of Intracoronal Sealing Biomaterials on the Histological Outcome of Endodontic Revitalisation in Immature Sheep Teeth-A Pilot Study.

The influence of intracoronal sealing biomaterials on the newly formed regenerative tissue after endodontic revitalisation therapy remains unexplored. The objective of this study was to compare the gene expression profiles of two different tricalcium silicate-based biomaterials alongside the histological outcomes of endodontic revitalisation therapy in immature sheep teeth. The messenger RNA expression of TGF-ß, BMP2, BGLAP, VEGFA, WNT5A, MMP1, TNF-α and SMAD6 was evaluated after 1 day with qRT-PCR. For evaluation of histological outcomes, revitalisation therapy was performed using Biodentine (n = 4) or ProRoot white mineral trioxide aggregate (WMTA) (n = 4) in immature sheep according to the European Society of Endodontology position statement. After 6 months' follow-up, one tooth in the Biodentine group was lost to avulsion. Histologically, extent of inflammation, presence or absence of tissue with cellularity and vascularity inside the pulp space, area of tissue with cellularity and vascularity, length of odontoblast lining attached to the dentinal wall, number and area of blood vessels and area of empty root canal space were measured by two independent investigators. All continuous data were subjected to statistical analysis using Wilcoxon matched-pairs signed rank test at a significance level of p < 0.05. Biodentine and ProRoot WMTA upregulated the genes responsible for odontoblast differentiation, mineralisation and angiogenesis. Biodentine induced the formation of a significantly larger area of neoformed tissue with cellularity, vascularity and increased length of odontoblast lining attached to the dentinal walls compared to ProRoot WMTA (p < 0.05), but future studies with larger sample size and adequate power as estimated by the results of this pilot study would confirm the effect of intracoronal sealing biomaterials on the histological outcome of endodontic revitalisation.

Network analysis reveals abnormal functional brain circuitry in anxious dogs.

Anxiety is a common disease within human psychiatric disorders and has also been described as a frequently neuropsychiatric problem in dogs. Human neuroimaging studies showed abnormal functional brain networks might be involved in anxiety. In this study, we expected similar changes in network topology are also present in dogs. We performed resting-state functional MRI on 25 healthy dogs and 13 patients. The generic Canine Behavioral Assessment & Research Questionnaire was used to evaluate anxiety symptoms. We constructed functional brain networks and used graph theory to compare the differences between two groups. No significant differences in global network topology were found. However, focusing on the anxiety circuit, global efficiency and local efficiency were significantly higher, and characteristic path length was significantly lower in the amygdala in patients. We detected higher connectivity between amygdala-hippocampus, amygdala-mesencephalon, amygdala-thalamus, frontal lobe-hippocampus, frontal lobe-thalamus, and hippocampus-thalamus, all part of the anxiety circuit. Moreover, correlations between network metrics and anxiety symptoms were significant. Altered network measures in the amygdala were correlated with stranger-directed fear and excitability; altered degree in the hippocampus was related to attachment/attention seeking, trainability, and touch sensitivity; abnormal frontal lobe function was related to chasing and familiar dog aggression; attachment/attention seeking was correlated with functional connectivity between amygdala-hippocampus and amygdala-thalamus; familiar dog aggression was related to global network topology change. These findings may shed light on the aberrant topological organization of functional brain networks underlying anxiety in dogs.

Dose reduction and image enhancement in micro-CT using deep learning.

BACKGROUND: In preclinical settings, micro-computed tomography (CT) provides a powerful tool to acquire high resolution anatomical images of rodents and offers the advantage to in vivo non-invasively assess disease progression and therapy efficacy. Much higher resolutions are needed to achieve scale-equivalent discriminatory capabilities in rodents as those in humans. High resolution imaging however comes at the expense of increased scan times and higher doses. Specifically, with preclinical longitudinal imaging, there are concerns that dose accumulation may affect experimental outcomes of animal models. PURPOSE: Dose reduction efforts under the ALARA (as low as reasonably achievable) principles are thus a key point of attention. However, low dose CT acquisitions inherently induce higher noise levels which deteriorate image quality and negatively impact diagnostic performance. Many denoising techniques already exist, and deep learning (DL) has become increasingly popular for image denoising, but research has mostly focused on clinical CT with limited studies conducted on preclinical CT imaging. We investigate the potential of convolutional neural networks (CNN) for restoring high quality micro-CT images from low dose (noisy) images. The novelty of the CNN denoising frameworks presented in this work consists of utilizing image pairs with realistic CT noise present in the input as well as the target image used for the model training; a noisier image acquired with a low dose protocol is matched to a less noisy image acquired with a higher dose scan of the same mouse. METHODS: Low and high dose ex vivo micro-CT scans of 38 mice were acquired. Two CNN models, based on a 2D and 3D four-layer U-Net, were trained with mean absolute error (30 training, 4 validation and 4 test sets). To assess denoising performance, ex vivo mice and phantom data were used. Both CNN approaches were compared to existing methods, like spatial filtering (Gaussian, Median, Wiener) and iterative total variation image reconstruction algorithm. Image quality metrics were derived from the phantom images. A first observer study (n = 23) was set-up to rank overall quality of differently denoised images. A second observer study (n = 18) estimated the dose reduction factor of the investigated 2D CNN method. RESULTS: Visual and quantitative results show that both CNN algorithms exhibit superior performance in terms of noise suppression, structural preservation and contrast enhancement over comparator methods. The quality scoring by 23 medical imaging experts also indicates that the investigated 2D CNN approach is consistently evaluated as the best performing denoising method. Results from the second observer study and quantitative measurements suggest that CNN-based denoising could offer a 2-4× dose reduction, with an estimated dose reduction factor of about 3.2 for the considered 2D network. CONCLUSIONS: Our results demonstrate the potential of DL in micro-CT for higher quality imaging at low dose acquisition settings. In the context of preclinical research, this offers promising future prospects for managing the cumulative severity effects of radiation in longitudinal studies.

Direct co-registration of [18F]FDG uptake and histopathology in surgically excised malignancies of the head and neck: a feasibility study.

PURPOSE: Recent technical advancements in PET imaging have improved sensitivity and spatial resolution. Consequently, clinical nuclear medicine will be confronted with PET images on a previously unfamiliar resolution. To better understand [18F]FDG distribution at submillimetric scale, a direct correlation of radionuclide-imaging and histopathology is required. METHODS: A total of five patients diagnosed with a malignancy of the head and neck were injected with a clinical activity of [18F]FDG before undergoing surgical resection. The resected specimen was imaged using a preclinical high-resolution PET/CT, followed by slicing of the specimen. Multiple slices were rescanned using a micro-PET/CT device, and one of the slices was snap-frozen for frozen sections. Frozen sections were placed on an autoradiographic film, followed by haematoxylin and eosin staining to prepare them for histopathological assessment. The results from both autoradiography and histopathology were co-registered using an iterative co-registration algorithm, and regions of interest were identified to study radiotracer uptake. RESULTS: The co-registration between the autoradiographs and their corresponding histopathology was successful in all specimens. The use of this novel methodology allowed direct comparison of autoradiography and histopathology and enabled the visualisation of uncharted heterogeneity in [18F]FDG uptake in both benign and malignant tissue. CONCLUSION: We here describe a novel methodology enabling the direct co-registration of [18F]FDG autoradiography with the gold standard of histopathology in human malignant tissue. The future use of the current methodology could further increase our understanding of the distribution of radionuclides in surgically excised malignancies and hence, improve the integration of pathology and molecular imaging in a multiscale perspective. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05068687.

Community Survey Results Show that Standardisation of Preclinical Imaging Techniques Remains a Challenge.

PURPOSE: To support acquisition of accurate, reproducible and high-quality preclinical imaging data, various standardisation resources have been developed over the years. However, it is unclear the impact of those efforts in current preclinical imaging practices. To better understand the status quo in the field of preclinical imaging standardisation, the STANDARD group of the European Society of Molecular Imaging (ESMI) put together a community survey and a forum for discussion at the European Molecular Imaging Meeting (EMIM) 2022. This paper reports on the results from the STANDARD survey and the forum discussions that took place at EMIM2022. PROCEDURES: The survey was delivered to the community by the ESMI office and was promoted through the Society channels, email lists and webpages. The survey contained seven sections organised as generic questions and imaging modality-specific questions. The generic questions focused on issues regarding data acquisition, data processing, data storage, publishing and community awareness of international guidelines for animal research. Specific questions on practices in optical imaging, PET, CT, SPECT, MRI and ultrasound were further included. RESULTS: Data from the STANDARD survey showed that 47% of survey participants do not have or do not know if they have QC/QA guidelines at their institutes. Additionally, a large variability exists in the ways data are acquired, processed and reported regarding general aspects as well as modality-specific aspects. Moreover, there is limited awareness of the existence of international guidelines on preclinical (imaging) research practices. CONCLUSIONS: Standardisation of preclinical imaging techniques remains a challenge and hinders the transformative potential of preclinical imaging to augment biomedical research pipelines by serving as an easy vehicle for translation of research findings to the clinic. Data collected in this project show that there is a need to promote and disseminate already available tools to standardise preclinical imaging practices.

DC vaccines loaded with glioma cells killed by photodynamic therapy induce Th17 anti-tumor immunity and provide a four-gene signature for glioma prognosis.

Gliomas, the most frequent type of primary tumor of the central nervous system in adults, results in significant morbidity and mortality. Despite the development of novel, complex, multidisciplinary, and targeted therapies, glioma therapy has not progressed much over the last decades. Therefore, there is an urgent need to develop novel patient-adjusted immunotherapies that actively stimulate antitumor T cells, generate long-term memory, and result in significant clinical benefits. This work aimed to investigate the efficacy and molecular mechanism of dendritic cell (DC) vaccines loaded with glioma cells undergoing immunogenic cell death (ICD) induced by photosens-based photodynamic therapy (PS-PDT) and to identify reliable prognostic gene signatures for predicting the overall survival of patients. Analysis of the transcriptional program of the ICD-based DC vaccine led to the identification of robust induction of Th17 signature when used as a vaccine. These DCs demonstrate retinoic acid receptor-related orphan receptor-γt dependent efficacy in an orthotopic mouse model. Moreover, comparative analysis of the transcriptome program of the ICD-based DC vaccine with transcriptome data from the TCGA-LGG dataset identified a four-gene signature (CFH, GALNT3, SMC4, VAV3) associated with overall survival of glioma patients. This model was validated on overall survival of CGGA-LGG, TCGA-GBM, and CGGA-GBM datasets to determine whether it has a similar prognostic value. To that end, the sensitivity and specificity of the prognostic model for predicting overall survival were evaluated by calculating the area under the curve of the time-dependent receiver operating characteristic curve. The values of area under the curve for TCGA-LGG, CGGA-LGG, TCGA-GBM, and CGGA-GBM for predicting five-year survival rates were, respectively, 0.75, 0.73, 0.9, and 0.69. These data open attractive prospects for improving glioma therapy by employing ICD and PS-PDT-based DC vaccines to induce Th17 immunity and to use this prognostic model to predict the overall survival of glioma patients.

Preclinical comparative study of [18F]AlF-PSMA-11 and [18F]PSMA-1007 in varying PSMA expressing tumors.

A wide variety of 18F-labeled PSMA-targeting PET radiotracers have been developed, including [18F]AlF-PSMA-11. As there is only limited data on the comparison with other 18F-labeled PSMA PET tracers, a comparative preclinical study between [18F]AlF-PSMA-11 and [18F]PSMA-1007 was conducted. Mice with varying PSMA expressing tumors (C4-2, 22Rv1 and PC-3, each n = 5) underwent two PET/CT scans with both [18F]AlF-PSMA-11 and [18F]PSMA-1007. Ten additional mice bearing C4-2 xenografts were subjected to ex vivo biodistribution with either [18F]AlF-PSMA-11 (n = 5) or [18F]PSMA-1007 (n = 5). Absolute SUVmean and SUVmax values were significantly higher for [18F]PSMA-1007 scans in both C4-2 tumors (p < 0.01) and 22Rv1 tumors (p < 0.01). In C4-2 xenograft bearing mice, the tumor-to-organ ratios did not significantly differ between [18F]AlF-PSMA-11 and [18F]PSMA-1007 for liver, muscle, blood and salivary glands (p > 0.05). However, in 22Rv1 xenograft bearing mice, all tumor-to-organ ratios were higher for [18F]AlF-PSMA-11 (p < 0.01). In healthy organs, [18F]PSMA-1007 uptake was higher in the liver, gallbladder, small intestines and glands. Biodistribution data confirmed the increased uptake in the heart, small intestines and liver with [18F]PSMA-1007. Absolute tumor uptake was higher with [18F]PSMA-1007 in all tumors. Tumor-to-organ ratios did not differ significantly in high PSMA expressing tumors, but were higher for [18F]AlF-PSMA-11 in low PSMA expressing tumors. Furthermore, [18F]PSMA-1007 showed higher uptake in healthy organs.

Positron Emission Tomography-based Dose Painting Radiation Therapy in a Glioblastoma Rat Model using the Small Animal Radiation Research Platform.

A rat glioblastoma model to mimic chemo-radiation treatment of human glioblastoma in the clinic was previously established. Similar to the clinical treatment, computed tomography (CT) and magnetic resonance imaging (MRI) were combined during the treatment-planning process. Positron emission tomography (PET) imaging was subsequently added to implement sub-volume boosting using a micro-irradiation system. However, combining three imaging modalities (CT, MRI, and PET) using a micro-irradiation system proved to be labor-intensive because multimodal imaging, treatment planning, and dose delivery have to be completed sequentially in the preclinical setting. This also results in a workflow that is more prone to human error. Therefore, a user-friendly algorithm to further optimize preclinical multimodal imaging-based radiation treatment planning was implemented. This software tool was used to evaluate the accuracy and efficiency of dose painting radiation therapy with micro-irradiation by using an in silico study design. The new methodology for dose painting radiation therapy is superior to the previously described method in terms of accuracy, time efficiency, and intra- and inter-user variability. It is also an important step towards the implementation of inverse treatment planning on micro-irradiators, where forward planning is still commonly used, in contrast to clinical systems.

Performance evaluation of a micro-CT system for laboratory animal imaging with iterative reconstruction capabilities.

BACKGROUND: In recent years, there has been a rapid proliferation in micro-computed tomography (micro-CT) systems becoming more available for routine preclinical research, with applications in many areas, including bone, lung, cancer, and cardiac imaging. Micro-CT provides the means to non-invasively acquire detailed anatomical information, but high-resolution imaging comes at the cost of longer scan times and higher doses, which is not desirable given the potential risks related to x-ray radiation. To achieve dose reduction and higher throughputs without compromising image quality, fewer projections can be acquired. This is where iterative reconstruction methods can have the potential to reduce noise since these algorithms can better handle sparse projection data, compared to filtered backprojection PURPOSE: We evaluate the performance characteristics of a compact benchtop micro-CT scanner that provides iterative reconstruction capabilities with GPU-based acceleration. We thereby investigate the potential benefit of iterative reconstruction for dose reduction. METHODS: Based on a series of phantom experiments, the benchtop micro-CT system was characterized in terms of image uniformity, noise, low contrast detectability, linearity, and spatial resolution. Whole-body images of a plasticized ex vivo mouse phantom were also acquired. Different acquisition protocols (general-purpose versus high-resolution, including low dose scans) and different reconstruction strategies (analytic versus iterative algorithms: FDK, ISRA, ISRA-TV) were compared. RESULTS: Signal uniformity was maintained across the radial and axial field-of-view (no cupping effect) with an average difference in Hounsfield units (HU) between peripheral and central regions below 50. For low contrast detectability, regions with at least ∆HU of 40 to surrounding material could be discriminated (for rods of 2.5 mm diameter). A high linear correlation (R2  = 0.997) was found between measured CT values and iodine concentrations (0-40 mg/ml). Modulation transfer function (MTF) calculations on a wire phantom evaluated a resolution of 10.2 lp/mm at 10% MTF that was consistent with the 8.3% MTF measured on the 50 µm bars (10 lp/mm) of a bar-pattern phantom. Noteworthy changes in signal-to-noise and contrast-to-noise values were found for different acquisition and reconstruction protocols. Our results further showed the potential of iterative reconstruction to deliver images with less noise and artefacts. CONCLUSIONS: In summary, the micro-CT system that was evaluated in the present work was shown to provide a good combination of performance characteristics between image uniformity, low contrast detectability, and resolution in short scan times. With the iterative reconstruction capabilities of this micro-CT system in mind (ISRA and ISRA-TV), the adoption of such algorithms by GPU-based acceleration enables the integration of noise reduction methods which here demonstrated potential for high-quality imaging at reduced doses.

Recent advancements in 18F-labeled PSMA targeting PET radiopharmaceuticals.

Prostate specific membrane antigen (PSMA) is an attractive target for molecular imaging of prostate cancer and several other solid tumors because of its overexpression in prostate carcinoma and tumor neovasculature, respectively. While currently most commonly used PSMA PET radioligands are 68Ga-labeled compounds, the short half-life and relatively low available radioactivity of gallium-68 have led to a steep increase in the development of 18F-labeled PSMA ligands. Several 18F-PSMA tracers such as [18F]DCFPyL and [18F]PSMA-1007 are already established in clinical practice, but there are still several drawbacks to be considered. Radiofluorination is often a multistep and time-consuming process requiring harsh labeling conditions. The limited sensitivity in the lower PSA ranges raises the need for improving the binding affinity of the ligands. Due to the metallic character of therapeutic radionuclides, there is very limited experience with 18F-PSMA tracers that can be applied for a theranostic approach. However, developments in the past few years have brought forward several improvements in these fields. These include the application of new radiosynthesis pathways for radiofluorination that reduces the process complexity, new approaches for the design of the pharmacophore, improving target interaction and the introduction of radiohybrid ligands, allowing labeling of the ligand with both diagnostic and therapeutic radionuclides. In this review, we will give an overview of these recent advancements of 18F-labeled PSMA PET radioligands.

Non-invasive cell-tracking methods for adoptive T cell therapies.

Adoptive T cell therapies (ACT) have demonstrated groundbreaking results in blood cancers and melanoma. Nevertheless, their significant cost, the occurrence of severe adverse events, and their poor performance in solid tumors are important hurdles hampering more widespread applicability. In vivo cell-tracking allows instantaneous and non-invasive monitoring of the distribution, tumor homing, persistence, and redistribution to other organs of infused T cells in patients. Furthermore, cell-tracking could aid in the clinical management of patients, allowing the detection of non-responders or severe adverse events at an early stage. This review provides a concise overview of the main principles and potential of cell-tracking, followed by a discussion of the clinically relevant labeling strategies and their application in ACT.

White Matter Integrity in a Rat Model of Epileptogenesis: Structural Connectomics and Fixel-Based Analysis.

Introduction: Electrophysiological and neuroimaging studies have demonstrated that large-scale brain networks are affected during the development of epilepsy. These networks can be investigated by using diffusion magnetic resonance imaging (dMRI). The most commonly used model to analyze dMRI is diffusion tensor imaging (DTI). However, DTI metrics are not specific to microstructure or pathology and the DTI model does not take into account crossing fibers, which may lead to erroneous results. To overcome these limitations, a more advanced model based on multi-shell multi-tissue constrained spherical deconvolution was used in this study to perform tractography with more precise fiber orientation estimates and to assess changes in intra-axonal volume by using fixel-based analysis. Methods: dMRI images were acquired before and at several time points after induction of status epilepticus in the intraperitoneal kainic acid (IPKA) rat model of temporal lobe epilepsy. Tractography was performed, and fixel metrics were calculated in several white matter tracts. The tractogram was analyzed by using the graph theory. Results: Global degree, global and local efficiency were decreased in IPKA animals compared with controls during epileptogenesis. Nodal degree was decreased in the limbic system and default-mode network, mainly during early epileptogenesis. Further, fiber density (FD) and fiber-density-and-cross-section (FDC) were decreased in several white matter tracts. Discussion: These results indicate a decrease in overall structural connectivity, integration, and segregation and decreased structural connectivity in the limbic system and default-mode network. Decreased FD and FDC point to a decrease in intra-axonal volume fraction during epileptogenesis, which may be related to neuronal degeneration and gliosis. Impact statement To the best of our knowledge, this is the first longitudinal multi-shell diffusion magnetic resonance imaging study that combines whole-brain tractography and fixel-based analysis to investigate changes in structural brain connectivity and white matter integrity during epileptogenesis in a rat model of temporal lobe epilepsy. Our findings present better insights into how the topology of the structural brain network changes during epileptogenesis and how these changes are related to white matter integrity. This could improve the understanding of the basic mechanisms of epilepsy and aid the rational development of imaging biomarkers and epilepsy therapies.