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PET/MRI is an emerging dual-modality imaging technology that requires new approaches to PET attenuation correction (AC). We assessed 2 algorithms for whole-body MRI-based AC (MRAC): a basic MR image segmentation algorithm and a method based on atlas registration and pattern recognition (AT&PR). Eleven patients each underwent a whole-body PET/CT study and a separate multibed whole-body MRI study. The MR image segmentation algorithm uses a combination of image thresholds, Dixon fat-water segmentation, and component analysis to detect the lungs. MR images are segmented into 5 tissue classes (not including bone), and each class is assigned a default linear attenuation value. The AT&PR algorithm uses a database of previously aligned pairs of MRI/CT image volumes. For each patient, these pairs are registered to the patient MRI volume, and machine-learning techniques are used to predict attenuation values on a continuous scale. MRAC methods are compared via the quantitative analysis of AC PET images using volumes of interest in normal organs and on lesions. We assume the PET/CT values after CT-based AC to be the reference standard. In regions of normal physiologic uptake, the average error of the mean standardized uptake value was 14.1% ± 10.2% and 7.7% ± 8.4% for the segmentation and the AT&PR methods, respectively. Lesion-based errors were 7.5% ± 7.9% for the segmentation method and 5.7% ± 4.7% for the AT&PR method. The MRAC method using AT&PR provided better overall PET quantification accuracy than the basic MR image segmentation approach. This better quantification was due to the significantly reduced volume of errors made regarding volumes of interest within or near bones and the slightly reduced volume of errors made regarding areas outside the lungs.

Multimodality imaging and, more specifically, the combination of PET and CT has matured into an important diagnostic tool. During the same period, concepts for PET scanners integrated into an MR tomograph have emerged. The excellent soft-tissue contrast of MRI and the multifunctional imaging options it offers, such as spectroscopy, functional MRI, and arterial spin labeling, complement the molecular information of PET. The development of a fully integrated PET/MRI system is technologically challenging. It requires not only significant modifications of the PET detector to make it compact and insensitive to magnetic fields but also a major redesign of the MRI hardware.

Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16 Ink4a /p19 Arf ( Cdkn2a ) or p21 Cip1 ( Cdkn1a ) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication. The growth of cancer cells can be stably arrested by cytokine-induced senescence. Here, the authors show that cancers with defects in senescence-inducing cell cycle regulator pathways are resistant to immune checkpoint blockade.

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of immunocompromised humans, caused by the opportunistic fungal pathogen Aspergillus fumigatus . Inadequacies in current diagnostic procedures mean that early diagnosis of the disease, critical to patient survival, remains a major clinical challenge, and is leading to the empiric use of antifungal drugs and emergence of azole resistance. A non-invasive procedure that allows both unambiguous detection of IPA and its response to azole treatment is therefore needed. Here, we show that a humanised Aspergillus -specific monoclonal antibody, dual labelled with a radionuclide and fluorophore, can be used in immunoPET/MRI in vivo in a neutropenic mouse model and 3D light sheet fluorescence microscopy ex vivo in the infected mouse lungs to quantify early A. fumigatus lung infections and to monitor the efficacy of azole therapy. Our antibody-guided approach reveals that early drug intervention is critical to prevent complete invasion of the lungs by the fungus, and demonstrates the power of molecular imaging as a non-invasive procedure for tracking IPA in vivo. Invasive pulmonary aspergillosis is a life-threatening fungal lung disease devoid of specific rapid diagnosis and with limited therapeutic options. Here, the authors show how state-of-the-art imaging approaches can enable specific diagnosis and therapy monitoring of this infection.

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ −/− mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients.

Hans Wehrl et al . use a multimodal approach to demonstrate the feasibility of measuring functional brain responses in activated and resting states with PET and MRI simultaneously. Using this method, which allows brain function studies to be conducted on multiple time and metabolic scales, they could tease apart the complex relationships between neural activity, blood flow and oxygenation that form the basis of the blood oxygen level–dependent (BOLD) effect. Combined positron emission tomography (PET) and magnetic resonance imaging (MRI) is a new tool to study functional processes in the brain. Here we study brain function in response to a barrel-field stimulus simultaneously using PET, which traces changes in glucose metabolism on a slow time scale, and functional MRI (fMRI), which assesses fast vascular and oxygenation changes during activation. We found spatial and quantitative discrepancies between the PET and the fMRI activation data. The functional connectivity of the rat brain was assessed by both modalities: the fMRI approach determined a total of nine known neural networks, whereas the PET method identified seven glucose metabolism–related networks. These results demonstrate the feasibility of combined PET-MRI for the simultaneous study of the brain at activation and rest, revealing comprehensive and complementary information to further decode brain function and brain networks.

For quantitative PET information, correction of tissue photon attenuation is mandatory. Generally in conventional PET, the attenuation map is obtained from a transmission scan, which uses a rotating radionuclide source, or from the CT scan in a combined PET/CT scanner. In the case of PET/MRI scanners currently under development, insufficient space for the rotating source exists; the attenuation map can be calculated from the MR image instead. This task is challenging because MR intensities correlate with proton densities and tissue-relaxation properties, rather than with attenuation-related mass density. We used a combination of local pattern recognition and atlas registration, which captures global variation of anatomy, to predict pseudo-CT images from a given MR image. These pseudo-CT images were then used for attenuation correction, as the process would be performed in a PET/CT scanner. For human brain scans, we show on a database of 17 MR/CT image pairs that our method reliably enables estimation of a pseudo-CT image from the MR image alone. On additional datasets of MRI/PET/CT triplets of human brain scans, we compare MRI-based attenuation correction with CT-based correction. Our approach enables PET quantification with a mean error of 3.2% for predefined regions of interest, which we found to be clinically not significant. However, our method is not specific to brain imaging, and we show promising initial results on 1 whole-body animal dataset. This method allows reliable MRI-based attenuation correction for human brain scans. Further work is necessary to validate the method for whole-body imaging.

The classical approach of using adjacent pieces of fresh-frozen tissue for various omics analysis from the same sample possesses a risk of biological mismatch between arising from intrinsic tissue heterogeneity. We propose an alternative approach of tissue cryogenic pulverization and lyophilization before distribution for omics studies for a more reliable analysis. Here, we compare individual omics layer readouts from fresh-frozen adjacent tissue pieces and homogenized powder in mouse brain, kidney, and liver. Genomics, transcriptomics, proteomics, and metabolomics analyses showed comparable RNA integrity, DNA methylation, and coverage of transcripts, proteins, and metabolites across both methods. Moreover, the homogenized-lyophilized powder usage led to reduced heterogeneity between biological replicates. We conclude that the cryogenically pulverized-lyophilized tissue approach not only maintains a critical molecular feature coverage and quality but also provides a homogenous basis for various omics analysis enhancing reproducibility, sample transport, storage and enabling multi omics base on one and the same tissue aliquot.

Although brain research has taken important strides in recent decades, the interaction and coupling of its different physiological levels is still not elucidated. Specifically, the molecular substrates of resting-state functional connectivity (rs-FC) remain poorly understood. The aim of this study was elucidating interactions between dopamine D2 receptors (D2R) and serotonin transporter (SERT) availabilities in the striatum (CPu) and medial prefrontal cortex (mPFC), two of the main dopaminergic and serotonergic projection areas, and the default-mode network. Additionally, we delineated its interaction with two other prominent resting-state networks (RSNs), the salience network (SN) and the sensorimotor network (SMN). To this extent, we performed simultaneous PET/fMRI scans in a total of 59 healthy rats using [11C]raclopride and [11C]DASB, two tracers used to image quantify D2R and SERT respectively. Edge, node and network-level rs-FC metrics were calculated for each subject and potential correlations with binding potentials (BPND) in the CPu and mPFC were evaluated. We found widespread negative associations between CPu D2R availability and all the RSNs investigated, consistent with the postulated role of the indirect basal ganglia pathway. Correlations between D2Rs in the mPFC were weaker and largely restricted to DMN connectivity. Strikingly, medial prefrontal SERT correlated both positively with anterior DMN rs-FC and negatively with rs-FC between and within the SN, SMN and the posterior DMN, underlining the complex role of serotonergic neurotransmission in this region. Here we show direct relationships between rs-FC and molecular properties of the brain as assessed by simultaneous PET/fMRI in healthy rodents. The findings in the present study contribute to the basic understanding of rs-FC by revealing associations between inter-subject variances of rs-FC and receptor and transporter availabilities. Additionally, since current therapeutic strategies typically target neurotransmitter systems with the aim of normalizing brain function, delineating associations between molecular and network-level brain properties is essential and may enhance the understanding of neuropathologies and support future drug development.

Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo , it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.