Keywords: Probes & Targets, Tumor, Spleen

Motivation: Metastasis is the leading cause of cancer-related mortality worldwide. We must pave new avenues for cancer treatment by interrogating the pro-tumorigenic properties of the tumor macroenvironment. 

Goal(s): We seek to investigate how tumorigenesis metabolically impacts the spleen microenvironment and how it contributes to immune evasion. 

Approach: Proton magnetic resonance spectroscopy was used to identify aqueous spleen metabolites during tumorigenesis. Flow cytometric analyses were conducted to immunophenotype splenic CD8⁺ T cells and to quantify MDSC and T-cell frequencies. 

Results: Tumorigenesis induced common, distinct metabolite changes in mouse spleens. Flow cytometric analyses revealed splenic CD8-T-cell exhaustion and reduced cytotoxic T-cell effector function.

Impact: Tumors drive metabolic spleen alterations that may contribute to reduced CD8⁺ T cells and their exhaustion even before reaching the tumor, contributing to immune suppression and poor prognosis. This may provide metabolism-targeted strategies to improve immune surveillance and immunotherapy.

Keywords: Preclinical Image Analysis, Preclinical, Prostate Imaging for Recurrence Reporting; Prostate cancer; Recurrence; Interreader agreement.

Motivation: PI-RR assessment is not universally validated and has not yet been extensively studied for diagnostic accuracy and interreader variability.

Goal(s): To evaluate the performance of PI-RR for detecting local recurrence in PCa patients with BCR after radiation therapy (RT) or radical prostatectomy (RP).

Approach: 110 patients who underwent MRI and FDG PET/CT were included. A group of four radiologists with varying experience was recruited for recurrence evaluation.

Results: With a PI-RR of 3 as a cutoff, the AUCs ranged from 0.56 to 0.83 after RT and 0.73 to 0.90 after RP across the four readers. The ICC values were 0.54 and 0.68, respectively.

Impact: PI-RR may serve as a clinical guide to improve the management of recurrent PCa by achieving good diagnostic performance and interreader agreement.

Keywords: Preclinical Image Analysis, Tumor, prostate cancer

Motivation: The combination of MRI imaging and PSMA PET/CT imaging has attracted more and more attention. 

Goal(s): Therefore, this study will compare the diagnostic value of ¹⁸F-PSMA-1007 PET/CT imaging and multi-parameter MRI alone and in combination with prostate cancer.

Approach: This study retrospectively collected the clinical, imaging and pathological data of 50 patients with prostate disease who underwent mp-MRI and ¹⁸F-PSMA-1007PET/CT examination in our hospital.

Results: We found that the combination of ¹⁸F-PSMA-1007 PET/CT and multi-parameter MRI can improve the diagnostic efficiency of prostate cancer. ADC value, SUV_max and SUV_max/ADC can distinguish between low-risk and medium-high-risk prostate cancer.

Impact: The diagnostic efficacy of combined multi-parameter MRI (ADC) and ¹⁸F-PSMAPET/CT (SUVmax) is better than that of ADC, SUV_max and SUV_max/ADC with higher sensitivity and specificity. The combination of these two imaging modalities can complement each other and improve the accuracy.

Keywords: Biology, Models, Methods, Whole Body, compressed sensing; metastasis; fluorescence tomography

Motivation: Cancer metastasis  involves multiple organs and traditional bioluminescent imaging lacks spatial resolution to locate metastatic foci.  New MRI imaging protocols need to be developed to image metastasis distribution over the whole mouse body.

Goal(s):

1. Acquire high resolution 3D volumes in an acceptable time frame.
2. Validate findings using cryo-fluorescence tomography (CFT).

Approach:

1. An 8-channel array coil was used to acquire whole body isotropic volumes with compressed sensing.
2. Post imaging CFT datasets were acquired for validation.
   

Results:

1. High contrast volumes of mouse body were acquired at 200x200x200 μm  in 16 minutes.
2. Liver metastatic foci observed.
3. Correspondence of mouse anatomy with MRI and CFT achieved.

Impact: Whole body imaging with 8-channel array coil permits longitudinal visualization of major organs in normal and diseased states.  Compressed sensing optimizes workflow for high throughput screening, and Cryo-Fluorescence tomography can then be used as gold standard for validation of MRI.

Keywords: Other Preclinical, Molecular Imaging, Prostate Cancer Models, Lonidamine, mito-Lonidamine, 1H and 31P MRS, Seahorse, oxygen consumption rate, pH

Motivation: When prostate cancer is treated with external beam radiation therapy (RT) with doses up to 78 Gy, gastrointestinal and genitourinary toxicities are often observed.

Goal(s): Tumor sensitization by mito-lonidamine (mito-LND) will lower RT doses reducing the risk of adverse effects.

Approach: The effects were assessed in vitro and in vivo in prostate cancer models using Seahorse, ¹H and ³¹P MRS respectively.

Results: Our findings showed a sustained and tumor-selective decrease in intracellular pH, bioenergetics, oxygen consumption rate and lactate. Selective tumor acidification, deenergization and oxygenation induced by mito-LND may improve the radiation response in prostate cancer.
 

Impact: Exploiting the modulation of tumor metabolism and microenvironment for improving therapeutic efficacy of radiation therapy (RT) in early stage prostate cancer will lead to improved outcomes in prostate cancer patients.

Keywords: Preclinical Image Analysis, Quantitative Imaging, hypoxia

Motivation: Heterogeneous distributions of hypoxic tissues lead to divergent radiotherapy response. Thus, developing a practical, accurate, and reproducible method of quantifying hypoxia is of great interest.

Goal(s): Establish a repeatable, multiparametric MRI protocol for quantifying hypoxia.

Approach: We induced C6 brain tumors in rats and conducted test-retest TOLD-MRI, DCE-MRI, and DW-MRI exams on each rat. We then analyzed the MRI data to identify spatially distinct physiological clusters within the tumor. 

Results: An initial assessment of repeatability of hypoxia, normoxia, and necrotic tissue localization within a tumor.

Impact: Developing a quantitative and repeatable protocol for quantifying tumor hypoxia will have immediate applications in studies seeking to design, assess, and optimize radiotherapy regimens.

Keywords: Biology, Models, Methods, Cancer, Glioblastoma, hypoxia, vasculature, metabolism, chick embryo CAM model

Motivation: Understanding vasculature, hypoxia and glycolysis in GBM is paramount towards understanding its resistance to therapies, but cannot be done in vitro. The CAM model is attractive as it provides the interaction between host vasculature and the tumour.  

Goal(s): Optimise MRI and MRS to assess hypoxia, tumour-host vasculature and glycolytic metabolism in the GBM-CAM.

Approach: GBM-CAM xenografts were created under normoxic- and hypoxic-conditions. Imaging was performed using microscopy and MRI, and lactate detection via MRS.

Results: Distinct morphological differences in vasculature were identified between conditions. MRI revealed vessel penetration, MRS detected lactate levels, which were significantly higher in hypoxic tumours than in the CAM.

Impact: Developing tools to characterise vascular morphology and quantify lactate levels in the CAM GBM model can shed light on fundamental biological mechanisms, and support the development of therapeutic strategies for the clinic. 

Keywords: Biology, Models, Methods, Cancer, Preclinical; CEST & MT

Motivation: The diffuse growth of paediatric-type diffuse high grade glioma (PDHGG) precludes complete delineation with conventional MRI. 

Goal(s): Molecular imaging with CEST may improve tumour detection.

Approach: Three orthotopic models of PDHGG were assessed using inverse Z-spectrum analysis of CEST data.

Results: Clear distinction between tumour and contralateral normal-appearing brain in ssMT and rNOE maps, which relate to macromolecular content, was observed in two well-defined tumour models when analysed using MTR_Rex and AREX. Similar CEST contrast was also apparent in a third more diffuse model, inconspicuous on T₂w-MRI. This CEST approach can successfully stratify PDHGG tumours in vivo.

Impact: Relaxation compensated CEST metrics provide novel biochemical contrasts in three orthotopic models of paediatric-type diffuse high grade glioma, enabling detection of diffuse disease, highlighting the clinical potential of CEST contrasts to stratifying tumours.

Keywords: Tumors (Post-Treatment), Animals

Motivation: What is the specific efficacy of carbon ion radiation in the treatment of brain gliomas?

Goal(s): To assess the specific effect of carbon ion irradiation in inhibiting the growth and peritumor infiltration of gliomas.

Approach: Establishment of a rat C6 brain glioma model with carbon ion irradiation and assessment of the efficacy response of brain glioma after carbon ion irradiation using MRI multiparametric imaging

Results: MRI multiparametric imaging can reflect the inhibitory effect of carbon ion irradiation on the growth and invasion of gliomas.

Impact: CIRT for glioma is still in the stage of clinical trials, the number of subjects is limited, and its specific efficacy still needs to be explored. Our study provides an experimental basis for the clinical application of CIRT for gliomas.

Keywords: Preclinical Image Analysis, Electron Paramagnetic Resonance

Motivation: Renal tumors in patients affected by Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) are aggressive and metastasize early. The high expression of NAD(P)H quinone oxidoreductase 1 (NQO1) in HLRCC could be a therapeutic target.

Goal(s): Our goal was to determine if NQO1-activated substrates can be used as a therapeutic approach for HLRCC renal tumors.

Approach: In vitro experiments and EPR, DCE, and photoacoustic imaging were performed to study the effect of NQO1-activated substrates on oxygen levels and tumor growth in HLRCC.

Results: Our study demonstrated by EPR imaging that oxygen consumption is induced by NQO1-activated substrates, resulting in ROS production and tumor cytotoxicity.

Impact: We found that NQO1-activated substrates induced non-mitochondrial oxygen consumption in FH-deficient renal tumor cells, triggering oxidative stress-induced cancer cell death. Our results suggest a promising path for NQO1-targeted therapy in HLRCC, necessitating further research and treatment development.

Keywords: Preclinical Image Analysis, Electron Paramagnetic Resonance

Motivation: In the previous study, EPR oximetry unveiled physiological responses to a VEGF inhibitor, but the potential of EPR oximetry in upstream inhibition of the HIF pathway remained unclear.

Goal(s): To determine if Belzutifan, a HIF-2α inhibitor, affects tumor oxygenation as measured by EPR oximetry and to offer a non-invasive biomarker of its therapeutic efficacy.

Approach: Three xenograft models of clear cell carcinoma were treated with Belzutifan and changes in tumor oxygen levels were assessed using EPR oximetry.

Results: We observed significant alterations in tumor oxygenation exclusively in responding tumors, which we attributed to diminished VEGF expression.

Impact: This research underlines the significance of EPR oximetry as a non-invasive tool to detect early responses to HIF-2α inhibitors like Belzutifan, which could profoundly affect the management and therapeutic approach for cancer treatment, guiding personalized medicine.

Keywords: Preclinical Image Analysis, Modelling, Breast, Cancer, Vascular, Image Reconstruction

Motivation: Metronomic chemotherapy shows promise as a cost-effective therapy for vascular normalization. However, it is unclear how to determine the optimal biological dose (OBD). 

Goal(s): Our goal is to use dynamic contrast-enhanced (DCE) MRI and pharmacokinetic analysis for non-invasive measurements of the heterogenous tumor treatment response toward determining the OBD.

Approach: The 4T1 murine orthotopic triple negative breast cancer models were assessed longitudinally using two different dosing schemes, daily and intermittent, using cyclophosphamide. Pharmacokinetic and histological analysis (CD31, Ki67) were conducted. 

Results: The intermittent dosing schedule showed higher V_p, F_p, and K^trans in all tumor regions indicating possible vascular normalization.

Impact: The proposed 3D-UTE-GRASP DCE-MRI method provides a non-invasive platform to assess for optimal biological dose in metronomic chemotherapy. By accurately determining the heterogenous tumor vessel dynamical changes, this platform can be used to enhance treatment response over time. 

Keywords: Biology, Models, Methods, Breast, Vascular, Image Reconstruction, Cancer

Motivation: Breast cancer molecular subtype may affect therapeutic efficacy of metronomic chemotherapy, which currently has not been investigated with non-invasive methods. 

Goal(s): This study is to utilize DCE-MRI for quantitative measurement of treatment response in different breast cancer subtypes. 

Approach: Preclinical orthotopic models 67NR(ER+) and 4T1(triple negative) of breast cancer were treated with the same metronomic chemotherapy, while the heterogenous treatment response was evaluated using DCE-MRI. 

Results:  In both tumor models, treatment induced higher V_p, F_p, and K^trans. The 67NR tumors had higher vascular measures with slower growth rates than the 4T1 tumors.

Impact: The preliminary data in this study suggest that the tumor volume alone does not provide adequate information about the changes induced by treatment, and the treatment response differs substantially between breast cancer subtypes as observed by DCE-MRI parameters. 

Keywords: Small Animals, Cancer, Treatment Response

Motivation: KRAS mutations occur in 90% of pancreatic ductal adenocarcinoma(PDA) with G12Dmutation being the most common.Recent KRAS(G12D) inhibitors have unraveled an exciting therapeutic opportunity for this deadly cancer,as they are being tested in clinical trials. 

Goal(s): However, the prior use of KRAS(G12C)inhibitors in lung cancer treatment showed mere 50% patient response,despite the accurate genetic mutation,calling for biomarkers which can assess the drug-target engagement early on and predict treatment outcome. 

Approach: To test the utility of translational MRI markers in a clinically relevant PDA model for early responses to KRAS(G12D) inhibitor,MRTX1133.

Results: ADC,K^trans and MTR captured MRTX1133 induced early cancer cell death and stroma change.

Impact: Our study in genetically engineered mouse model of pancreatic cancer supports that clinical translatable MRI metrics (ADC, Ktrans and MTR) are promising for capturing early pharmacodynamic responses to KRAS inhibitor MRTX1133.

Keywords: Biology, Models, Methods, Head & Neck/ENT

Motivation: The low specificity of many Thyroid Imaging Reporting and Data Systems (TI-RADSs)  lead to a large number of unnecessary biopsies. 

Goal(s): This study developed and validated a predictive model based on MRI morphological features to improve the specificity.

Approach: A retrospective analysis was conducted on 825 thyroid nodules pathologically confirmed postoperatively. Univariate and multivariate logistic regression was used to obtain β coefficients, construct predictive models and nomogram incorporating MRI morphological features in the training cohort, and validated in a validation cohort. 

Results: Compared with the TI-RADSs, predictive models have better specificity along with a high sensitivity and can reduce unnecessary biopsies.

Impact: predictive models have better specificity along with a high sensitivity and may avoid numerous invasive needle biopsies

Keywords: Probes & Targets, Cancer

Motivation: Only 15-20% of patients with advanced head and neck squamous cell carcinoma (HNSCC) benefit from immunotherapy, with no reliable strategies to quickly predict or determine a patient’s response to treatment.

Goal(s): We aim to evaluate a therapeutic monitoring strategy using MRI by targeting extradomain B fibronectin (EDB-FN) in the tumor stroma.

Approach: Using mouse models bearing HNSCC allografts, we treated and monitored therapeutic efficacy of anti-PDL1 immunotherapy with MRI using MT218, our EDB-FN-targeted contrast agent.

Results: Treatment-responsive tumors exhibited unique expression patterns of EDB-FN compared to controls that were visualized with MT218 MRI, demonstrating the potential for predicting and monitoring HNSCC immunotherapy response.

Impact: We demonstrate that EDB-FN is a potential biomarker for immunotherapy response in HNSCC, and our MRI strategy targeting EDB-FN offers clinicians a potential method for predicting or monitoring immunotherapeutic outcomes to improve the clinical management of HNSCC.