Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory disease

Programme leader: Prof. dr. J.L. Bloem

Description

Development of multiparametric imaging techniques in cancer and inflammatory disease

Aim and focus

Biology and pathophysiology of oncologic and inflammatory disorders (including osteoarthritis and neuromuscular disorders) are the basis of this imaging program. Because of overlap in targets for therapy and imaging in oncologic and inflammatory disease models the program uses both disease models. The musculoskeletal system is the main, but not the only system, in which we develop new imaging methods for the two disease entities. Within these clinical imaging themes our endeavors are geared towards unraveling pathophysiology, improving image guided minimally invasive and surgical therapies, monitoring effectiveness of therapy to tailor individual patient’s treatment, increasing cost-effectiveness by  imaging, and developing new technical approaches in data acquisition and post-processing.

Diagnosis and image guided minimally invasive treatment of musculoskeletal neoplasms and tumor-like lesions have been main research topics for many years in close collaboration with the Leiden based Netherlands Committee on Bone Tumors. Research on the topic of joint disease is focused on the early detection of disease in rheumatoid arthritis and spondyloarthritis as well as the assessment of degenerative joint disease (osteoarthritis). The LUMC is expertise center for Duchenne and Becker muscular dystrophy and we are a leading group in quantitative MR imaging to monitor disease progression and therapy follow-up.

We aim to image disease processes with the use of state-of-the-art imaging, including MR (from low cost extremity MR to  7T MR imaging, CT, Nuclear medicine techniques, optical imaging, navigation techniques and hybrid systems. The concurrent development of advanced data post-processing and quantification is of increasing importance in this high technology field, and adds diagnostic value to the imaging data. The cost-effective use of imaging is of ongoing interest. 

Position in international context

The research group, covering data acquisition techniques, development of tracers, clinical application, and post-processing including quantification has, illustrated by international cooperation, awards, honors, and participation in international professional societies and institutions such as ASAS, EORTC, ECR, ESSR, RSNA, Philips, Technical University of Munich, , CHU Cochin, Paris, France, Diakonhjemmet Hospital, Oslo, Norway, University of Michigan, Ann Arbor, MI, US, Vrije Universiteit Brussel, Belgium, The University of Tokyo, Japan, Massachusetts General Hospital/Harvard Medical School, US,  Department of Radiology Leuven, University of Newcastle. There are many international industrial partners; Philips, KARL STORZ GmbH & Co KG, EURORAD, Surgiceye, Oncovision, GE, Hamamatsu Photonics, Biomerin.

Content / highlights / achievements

Main ongoing research themes are; developing criteria with US and MR to allow early diagnosis of inflammatory diseases such as RA and SPA (relatiove to other disorders, degenerative changes, and normal control populations), defining phenotypes related to progression of these inflammatory diseases and impact of therapy including TNF-block. Significant technical advances at 7T MR such as decreasing B0 inhomogeneity, pulse sequence design with limited SAR allowing high resolution joint imaging, sodium imaging as a functional biomarker for osteoarthritis allow high field MR in clinical applied research for inflammatory diseases. In oncology advances have been made in development of new tracers to visualize early cancer, development of hybrid imaging systems to identify viable tumor for local treatment (RF ablation, surgery, etc.), identify viable tumor during treatment to monitor therapy. At 7T MR technical advances allow high resolution imaging of uveal melanoma for navigation of conventional brachytherapy and proton beam therapy. Image analysis  has focused on 1) quantification of joint-space width for osteoarthritis of the hand,  2) quantification of prosthesis-micromotion and dynamic fluoroscopy, and 3) whole-body image analysis for multiple myeloma and spondylo-arthritis monitoring. In muscle imaging state-of-the art quantitative imaging methods at 3T and 7T are now applied in several clinical trials for Duchenne muscular dystrophy. The LUMC is now considered as the primary MRI center for Duchenne muscular dystrophy in the Netherlands, and muscle imaging is part of the NFU Duchenne and Becker  expertise center at the LUMC. 

Within the department we have groups that play a leading role in the field of image guided surgery using fluorescence and radioactivity combined. Within this effort a from-molecule to man concept is pursued, meaning that not only we are active in the tracer development and translation, but we also develop dedicated hardware with industrial partners, a combination of which we evaluate in a clinical setting. This has successfully lead to a number of new products for companies such as: Ge-healthcare, Intuitive Surgical, Hamamatsu, Karl Storz, SyrgicEye and Eurorad.

Several grants have been awarded. These include KWF grants [Targeting CXCR4 with multimodal imaging agents as a means to improve the efficacy of breast cancer surgery via combined pre-, intra-, and postoperative imaging,  Efficacy of FDG-PET in the Evaluation of Cytological indeterminate Thyroid nodules prior to Surgery (EfFECTS), IMPACT: IMaging PAtients for Cancer drug selection, Diagnosis of thyroid cancers], ZONMW grants [Tailoring Cancer Therapy by Imaging Glucose Metabolism, Quantitative PET], [ Antisense therapy for several major rare diseases]; Personal grants [ERC 2012 starting grant van Leeuwen, VIDI 2012 van Leeuwen, LUMC research fellowship (Cruz), Webb];  various other grants [Repetitive 4D-FDG-PET/CT imaging in advanced stage NSCLC patients undergoing individually escalated (chemo)radiotherapy, MIBG scan and Strain Echocardiography in the detection of subclinical cardiovascular effects after (neo)adjuvant breast cancer treatment, Early response measurement in NSCLC, [18F]-Fluorodeoxyglucose Positron Emission Tomography in Lung Tumour Assessment, Duchenne Parent project grants (Brain imaging and cognition in boys with Duchenne muscular dystrophy, a three year follow up] Reumafonds, STW [Atlas-based Image Analysis of Inflammatory Markers on Extremity MRI for Early Identification of Rheumatoid Arthritis” (ESMIRA). This project focusses on automated pattern recognition of MRI of the hand in normal volunteers and early arthritis patients, whole body MR imaging, Automated MRI-based detection of early arthritis], CTMM [early arthritis]’ Industrial grants [novel drugs (treating skeletal metastases of prostate cancer, PVNS, Duchenne), , Clinical validation of diffuse optical spectroscopy imaging in a radiological setting for response monitoring to neoadjuvant chemotherapy, Multiple image analysis innovations for computer-assisted analysis and reading of whole-body imaging (MR &CT), in both a clinical and pre-clinical setting.

Future themes

  • Future themes are defining clinical cost-effective imaging strategies to allow risk profiling and early diagnosis of inflammatory entities including rheumatoid arthritis, SCCH-CRMO-SAPHO spectrum, osteoarthritis, spondyl-arthropathies. Part of this program is defining prevalence in normal asymptomatic populations of imaging parameters currently included as parameters reflecting disease.
  • Image guided intervention is an important focus in oncology. Clinically our department is leading in various combined image guided minimally invasive procedures, for instance in treating HCC. A strong preclinical group is developing hybrid techniques, with the goal to introduce these rapidly in clinical trials. Other examples in oncology are;  The changing treatment of chondrosarcomas. The new treatment philosophy requires differentiation between ACT/grade 1 CS and higher grades; this will be addressed with dynamic MR and PET-CT using different tracers. Fusion of PET, CT and MR data will be a new theme, both from a technical perspective, as well as from a clinical perspective (radiogenomics and cost-effectiveness). We will focus on phenotyping (radiogenomics) tumors and populations with increased (genetic) risk profiles  by combining various imaging techniques allowing quantification of glucose metabolism in combination with angiogenesis (perfusion, vascular tumor wall function), apoptosis, cell integrity, cell density and metabolic tumor volume, phosphor metabolites, hypoxia change to optimize treatment strategies aimed at increasing (disease free) survival and decrease morbidity. Fusion of data in terms of parametric-imaging  heuristic or using an underlying pharmokinetic model but also higher level parameters such as heterogeneity, textural features) will be a technical theme, and these early models will be applied in various tumor models for further development [quantitative phenotyping in symptomatic and asymptomatic groups with increased (genetic) risk profiles].  We are preparing imaging techniques, and strategies, including real time imaging for choroidal melanoma to develop novel tools improving proton beam therapy in the new Medical Delta facility, and we will further explore the possibilities of optical imaging techniques for diagnosis and therapy applications.
  • In skeletal muscle imaging, we will extend our imaging to the upper extremities, based on extrapolation of developing therapies to non-ambulant patients, and quantitative MRI will become a standard part of the Duchenne outpatient work-up in the recently founded NFU expertise center. 

Cohesion within LUMC

Locally this project is embedded in collaboration between multiple departments, including oncology, molecular cell biology, orthopedics, surgery, rheumatology, ophthalmology, gastro-enterology, urology. The program participates in various LUMC population studies including NEO, CHECK, SPACE; and medical delta projects including proton beam therapy. The program is fully integrated in the LUMC research profiles Biomedical imaging, Cancer pathogenesis and therapy, translational neurosciences and Immunity infection and tolerance.