Towards applying NMR relaxometry as a diagnostic tool for bone and soft tissue sarcomas: a pilot study

Abstract

This work explores what Fast Field-Cycling Nuclear Magnetic Resonance (FFC-NMR) relaxometry brings for the study of sarcoma to guide future in vivo analyses of patients. We present the results of an ex vivo pilot study involving 10 cases of biopsy-proven sarcoma and we propose a quantitative method to analyse 1 H NMR relaxation dispersion profiles based on a model-free approach describing the main dynamical processes in the tissues and assessing the amplitude of the Quadrupole Relaxation Enhancement effects due to 14 N. This approach showed five distinct groups of dispersion profiles indicating five discrete categories of sarcoma, with differences attributable to microstructure and rigidity. Data from tissues surrounding sarcomas indicated very significant variations with the proximity to tumour, which may be attributed to varying water content but also to tissue remodelling processes due to the sarcoma. This pilot study illustrates the potential of FFC relaxometry for the detection and characterisation of sarcoma. Magnetic Resonance Imaging (MRI) is a powerful method used in the medical diagnosis of a range of different soft tissue pathologies. The principle of MRI lies in detecting differences in the behaviour of nuclear spins (in most cases from 1 H) between pathological tissues and their healthy counterparts, which can be exploited as a source of contrast to form images. Spin-lattice and spin-spin relaxation times, denoted as T 1 and T 2 respectively, are two important sources of MRI contrast that describe how fast tissues return to magnetic equilibrium after excitation. To simplify calculations one often uses their reciprocal values, R 1 = 1/T 1 and R 2 = 1/T 2 , which are referred to as spin-lattice and spin-spin relaxation rates, respectively 1-3 but convey the same information. R 1 usually shows much better contrast at fields below 0.5 T but most clinical scanners operate at 1.5 T or 3 T to achieve high spatial resolution. Paramagnetic contrast agents are commonly used to improve contrast 4,5 , providing relaxation enhancement caused by strong magnetic dipole-dipole interactions between protons (hydrogen nuclei, 1 H) from the tissues and the paramagnetic centre (typically gadolinium or manganese ions). Despite the huge progress in advanced contrast agents and MRI technology, the early diagnosis and treatment of patients with musculoskeletal (MSK) malignancies (sarcomas) remains a major challenge. Initial detection of MSK malignancies depends upon clinical examination, fine needle aspiration cytology or core biopsy and MRI. MRI is also used in the follow-up and surveillance of patients with suspected local recurrence following treatment. Unfortunately, the imaging characteristics of tissues using conventional MRI are not diagnostic for a large number of soft tissue tumours and therefore careful multidisciplinary interpretation of the combined results are required in reaching a final diagnosis. Despite this, it can still be challenging to estimate tumour aggressiveness or resection margins.

Intracellular Water Lifetime as a Tumor Biomarker to Monitor Doxorubicin Treatment via FFC-Relaxometry in a Breast Cancer Model

“…On the other hand, our group has recently demonstrated that measuring T 1 at lower magnetic field strengths can be very informative and report on the tumor metabolic status (10,11). This is possible because tissue T 1 varies with applied magnetic field strength, with the differences between tissues being higher at lower magnetic field strengths (12)(13)(14)(15). This behavior (often referred to as "T 1 -dispersion", or simply relaxometry) is a marker of disease, but is invisible to conventional, fixed-field MRI scanners.…”

On the Relevance of Soft Tissue Sarcomas Metabolic Landscape Mapping

“…Furthermore, administration of dasatinib and FAK inhibitor 14 resulted in a reshaped metabolic profile both in normal fibroblasts and in desmoid tumor cells, with the cell line differentiation process being led by aminoacyl-tRNA biosynthesis in mitochondria and cytoplasm, as well as by signal transduction amino acid-dependent mTORC1 activation [ 51 ]. Masiewicz et al developed an innovative approach, employing Fast Field-Cycling, an NMR technique that measures spin-lattice relaxation rates over a wide range of magnetic fields, and that, even not being a classic metabolomic approach, provides an extraordinary insight on the molecular dynamics of the modifications of intra and extra-cellular compartments of tumor cells imposed by pathological changes in sarcomas [ 52 ]. The authors investigated spin-lattice relaxation properties of sarcoma using formaldehyde-fixed resections from surgery and analyzed the differences in the spin-lattice relaxation dispersion profiles of musculoskeletal malignancies, tissues adjacent to the tumor, and apparently healthy tissues obtained at the resection margin, with the goal of improving the diagnostic accuracy of musculoskeletal malignancies [ 52 ].…”

Low-Field NMR Relaxometry for Intraoperative Tumour Margin Assessment in Breast-Conserving Surgery

“…The herein reported results show that an approach based on nuclear magnetic resonance (NMR) relaxometry may allow tumour margin assessment on excised tissue specimens without the need for spatial discrimination (i.e., without imaging). It is well known that proton T 1 values of a given tissue decrease as a function of the applied magnetic field strength, thus providing larger differences among the tissues the lower the applied magnetic field strength is [29][30][31]. This behaviour, known as T 1 -dispersion, is closely linked to the mechanisms that drive molecular dynamics within the sample and can therefore be exploited in the search for novel diagnostic markers.…”