RPS 1406 - From hyperpolarised MRI to multimodal imaging probes

Purpose:

A prospective observational study, conducted at our institute, for a period of 18 months. Patients with pre-treatment CT chest of the primary tumour at our institution with the histological diagnosis of non-small cell lung carcinoma and data on EGFR and/or ALK rearrangement status were included in this study.

A total of 156 patients, 87/156 (55.8%) males and 69/156 (44.2%) females were included in the study. This study demonstrated that the female gender (p=0.0065), spiculated margin (p=0.0195), GGO (p=<0.0001), pleural retraction (p=0.0023), absence of emphysema (p=0.0003), nodule in primary tumour lobe (p=0.0321), pleural effusion on same side of the tumour (p=0.0003) and metastatic lymphangitis carcinomatosis (MLC) (p=0.0004) were significantly associated with EGFR positivity, while bigger a size of a lesion (p=0.0259), central distribution (p=0.0215) of the primary lesion, pleural retraction (p=0.022), nodules in non-tumour lobe (p=0.003) and MLC (p=0.0159) were significantly associated with ALK mutation status.

This study affirms previous studies for a few CT characteristics and also found new correlations between CT imaging characteristics and the molecular status of NSCLC, providing supporting evidence for molecular targets that can be treated using molecular drugs.

Limitations were the relatively smaller sample size for ALK mutation and that the pattern of contrast enhancement was not studied.

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No funding was received for this work.

Purpose:

Renal cell cancer is the most common renal neoplasm and has recently been recognised for its genetic and metabolic intratumoural heterogeneity, contributing to tumour evolution, aggressiveness and treatment failure. Hyperpolarised [1-¹³C]pyruvate (hp¹³C-pyruvate) magnetic resonance imaging (hpMRI) allows the non-invasive assessment of pyruvate metabolism, but it is not known how this correlates with tissue-based molecular assays.

Tumour metabolism was imaged in three patients with renal tumours using hpMRI. Following injection of hp¹³C-pyruvate, metabolic images were acquired from 3 cm thick axial slices using an 8-channel-array coil on a 3T MRI with a temporal and spatial resolution of 4 s and 1.7 x 1.7 cm in-plane. Lactate concentrations measured using liquid chromatography-mass spectrometry (LC-MS) on perfused and ischaemic tissue samples were correlated with hpMRI-based metabolite signals.

The tumours demonstrated a higher exchange rate for the hp¹³C-label between pyruvate and lactate (k_PL: 0.010 ± 0.004s^-1, mean ± S.D.) than the normal kidney (0.003 ± 0.001s^-1). The parametric maps demonstrated intratumoural metabolic heterogeneity with at least two metabolically distinct tumour regions in each patient and higher metabolic heterogeneity in higher-grade tumours. Metabolic differences observed on imaging were replicated in tissue samples obtained before and after vascular exclusion, despite showing signs of ischaemia. A strong positive correlation (rho = 0.73, p = 0.003) was observed between lactate SNR on imaging and tissue concentrations measured with LC-MS (Figure 2).

Hyperpolarised ¹³C-pyruvate demonstrates metabolic intratumoural heterogeneity in renal cancer and imaging-based lactate levels correlate with steady-state tissue lactate concentrations. Hyperpolarised imaging may guide biopsies to regions of metabolically aggressive regions of the tumour.

Limited patient number with ongoing recruitment.

UK-REC-Numbers: 15/EE/0378, 03/018

Funding by Wellcome Trust, Cancer Research UK.

Purpose:

Extradomain-B fibronectin (EDB-FN) is a marker for epithelial-to-mesenchymal transition (EMT), a biological process associated with tumour invasion, metastasis and drug resistance. EDB-FN is highly expressed in the extracellular matrix of aggressive human breast cancers. For non-invasive accurate detection and risk-stratification of breast cancer, a peptide-targeted gold nanorod, Pep-Sq@AuNRs, is synthesised for sensitive fluorescent, photoacoustic and computed tomography (FL/PA/CT) imaging of extradomain-B fibronectin in aggressive breast tumours.

An EDB-FN-targeted peptide modified gold nanorod, Pep-Sq@AuNRs, was synthesized using a three-step process, and this probe is composed of three moieties. The first moiety is an EDB-FN-targeted peptide (Pep), preferably targeting EDB-FN. The second moiety is a NIR fluorescent dye (Sq), of which its essential properties of NIR FL/PA imaging and phototherapy. The third moiety is gold nanorods (AuNRs), acting as CT/PA contrast agent.

This complex probe can effectively target aggressive MDA-MB-231 triple-negative breast cancer in mice, but not in low-risk slow-growing MCF-7 tumours. The NIR FL/PA signals were activated by EDB-FN for imaging, and the AuNRs were used for CT imaging and photothermal/photodynamic therapy (PTT/PDT). These results demonstrate that trimodal imaging with Pep-Sq@AuNRs may provide accurate detection and risk-stratification of breast cancer.

In summary, we developed a novel platform, Pep-Sq@AuNRs, as a model to distinguish aggressive MDA-MB-231 triple-negative breast cancer and low-risk slow-growing MCF-7 tumours in mice. The results demonstrate that Pep-Sq@AuNRs could effectively target the aggressive MDA-MB-231 triple-negative breast cancer and kill cancer cells by PTT/PDT.

There are no limitations to this study.

The animal handling was approved by the Ethics Committee of Xinhua Hospital, affiliated to Shanghai Jiao Tong University School of Medicine.

The National Natural Science Foundation of China (81901870) and Shanghai Sailing Program (18YF1415600).

Purpose:

Breast cancer is one of the most devastating malignancies in women. Photodynamic therapy (PDT) is widely investigated as alternative treatment for breast cancer due to its unique advantages. In light of upregulated cathepsin-B (CTSB) in breast cancer, we synthesized a targeted near-infrared activatable probe (Pep-SQ@USPIO) for MRI/fluorescent/photoacoustic (MRI/NIR FL/PA) imaging-guided PDT.

Pep-SQ@USPIO based on USPIO core modified with Pep-SQ. The sequence of Pep-SQ consisted of two moieties: the first moiety is fibronectin targeted peptide which labelled with a green fluorescent group, naphthalimide; the second moiety is a NIR fluorescent dye (SQ), of which it’s essential properties of NIR FL/PA imaging and PDT. The two moieties linked via a cathepsin B-sensitive peptide (GFLG) linker. Transmission electron microscopy images, hydrodynamic size profiles, absorption spectra, cck-8 assay and oxidative stress elevation were acquired. The influence of "turn on" the fluorescence signal was studied in vitro and in vivo. The in vivo mice with tumour model was applied to evaluate imaging and photodynamic therapy efficacy.

Pep-SQ@USPIO is almost nonfluorescent with inactivated phototoxicity and successfully applied to MR/PA imaging. After cancer cellular uptake, the cleavage of the GFLG substrate by CTSB led to recovering the quenched NIR FL signal, resulting in a high tumour/normal signal ratio. Upon treatment with 660 nm laser irradiation, generated reactive oxygen species (ROS) would produce PDT and enable remarkable tumour inhibition.

This tumour-specific theranostic probes can precisely diagnose and exerts further selective treatment, which may address challenges faced by traditional medicine in breast cancer.

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All the experimental protocols were approved by the Ethics Committee of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine.

Funding by the National Natural Science Foundation of China (NSFC 81371621).

Purpose:

We visualise bone microdamage with functionalised nanoparticles in excised human phalanx and whole rat specimens. Spectral photon-counting CT using a MARS scanner allowed characterisation of bone microdamage, microarchitecture, mineralisation, and composition. Such characterisation is essential to assess bone quality and the toughening mechanism of bone.

Biological specimens involved imaging of the excised human phalanx followed by incubation in ligand targeted hafnia nanoparticles (HfO₂ NPs) and two rat specimens which were anaesthetised and received scalpel-induced bone microdamage in one hind limb. One rat received functionalised, and the other received non-functionalised, HfO₂ NPs via intramuscular injection. Five hours post-injection, the animals were euthanised and scanned with MARS scanner. MARS is a small-bore photon-counting scanner employing energy resolving detectors and an x-ray tube operated at clinical x-ray energies, 118kVp. Four energy bins (30-45, 45-65, 65-80, 80-118 keV) and energy resolution of 3.5 keV, were used for imaging, with a cubic reconstruction voxel size of 90 µm.

The MARS scanner produced quantitative images of HfO₂ nanoparticles, bone, and soft tissue using energy-dependent differences in x-ray attenuation. For the excised phalanx, HfO₂ nanoparticles highlighted expected regions of bone microdamage at high specificity (> 70% identification success for ≥ 10 mg/mL). In the injured rat limb, measured delivery of ligand targeted HfO₂ nanoparticles was 6.4 mg.

We have shown that spectral photon-counting imaging enables specific identification and quantification of HfO₂ functionalised nanoparticles that were targeted at bone microfractures, an important capability for the assessment of bone quality.

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The ethics committee approval was obtained from Illinois Institutional Animal Care and Use Committee at the University of Illinois Urbana Champaign (protocol #17125).

MBIE number: UOCX1404,MARS bioimaging Ltd. D.P. recipient of academic grants from NIH, NSF and DoD.

Purpose:

To confirm a method for distinguishing various calcium crystals in a range of arthropathies, in preparation for planned imaging studies of excised specimens and patients. Distinguishing crystal-associated arthropathies non-invasively and early in the disease course remains a challenge with traditional imaging techniques. Our method provides 3D maps of 90 µm³ voxels of crystal type that should allow earlier treatment options.

A MARS spectral photon-counting scanner was used to scan calibration rods of three concentrations of each of monosodium urate (MSU), calcium pyrophosphate (CPP) and calcium hydroxyapatite (HA). The images were acquired using four energy channels (20-30, 30-40, 40-50 and 50-80 keV) with a 3.5 keV resolution. The crystal types were distinguished by comparing energy-dependent attenuation coefficients. First, to assess the performance of the system, receiver operating characteristic curves were used. Then the system was tested on the different rods to evaluate identification efficiency.

System performance demonstrates, using pairwise areas under the curves (AUC), that all concentrations of MSU were readily differentiated from the two higher concentrations of CPP and HA with an AUC > 0.90. The highest concentrations of CPP and HA (200 mg/cm³) were well differentiated from each other, while 100 mg/cm³ of CPP and HA showed a fair differentiation. The tests from the rods demonstrate that spectral photon-counting CT can identify high concentrations of CPP and HA (correct identification up to 80%) and significant ability to identify MSU (correct identification up to 90%).

We are able to identify and quantify important calcium crystals across a range of clinically relevant concentrations. This enables us to study arthropathies in excised samples and patients using existing MARS research and human scanners.

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MBIE UOCX1404, MARS Bioimaging Ltd, Medtechcore.

Purpose:

To confirm a method for non-invasively measuring four tissue components in atherosclerotic plaques. We compare the histology of plaques to 3D quantitative images of fat, water, calcium, and iron generated by a spectral photon counting CT.

Arterial plaques obtained from carotid endarterectomy and scanned with a MARS spectral photon-counting CT. Following MARS imaging, the plaques were decalcified and fixed, then stained for protein, lipid, and iron. Histological photos were then taken of the stained tissue slices. The MARS scanner was operated at 120kVp with four energy channels with 3.5 keV resolution. This provided 3D maps of 90 µmcubic voxels of the four tissue components. Reference materials for calibration were ferric nitrate, hydroxyapatite, oil, and water. The four maps of tissue components were compared to corresponding regions within the histological images.

We will present tissue component maps alongside histological images. The images show: 1) regions of lipid deposits; 2) micro and macro calcification; 3) iron deposition; 4) thickness of the fibrous cap; 5) and ulcerations.

We have confirmed that the four maps of tissue components agree with histological analysis. Our technique non-invasively measures key features of some unstable plaque. The measurements are quantitative and in 3D. This enables us to study plaque in excised samples and patients using existing MARS research and human scanners.

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CTY/01/04/036

MBIE, MARS Bioimaging Ltd, MedTechCORE.