Interface between technology, clinical, human and social science and public health: Case study interventional radiology Technique, research and benefits Nicolas Grenier, Bordeaux University Hospital
Why is IR a growing field? Interventional Radiology Minimally invasive, preserving body integrity, less side-effects A real economic impact : - short recovery - ambulatory patient care - maintaining the patient in his social environment Based on technical innovations : - high investment of companies in this field Allows combination of strategies : - identification of specific targets (molecular imaging) - development of focal therapies - combined with new medical targeted therapies and nanotechnologies. local drug delivery. focal onset of biological effects (gene expression ) 2
Why is IR so slowered? Problems to finance innovation +++ Interventional Radiology Lack of organization from scientific societies for evaluation of clinical and economical impacts 3
Focal therapy of prostate cancer Context : Prostate cancer (PC) is the most common cancer in men The second most common cause of cancer death in men after lung cancer Controversial strategy of repeated biopsies : - Low diagnostic accuracy - the majority of men (i.e. 80%) diagnosed when the disease is at the localised stage - 50% of asymptomatic men do not require active treatment Radical whole-gland surgery or radiotherapy can result in substantial side-effects that are a consequence of damage to surrounding structures: - urinary incontinence (5 20%), - erectile dysfunction (30 70%), - bowel toxicity (5 10%) 4
Problems: Identification of the PC : Focal therapy of prostate cancer - Now possible combining morphological, functional and metabolic data with MRI : multiparametric MRI. T2w. Diffusion-weighted. Perfusion-weighted. Spectroscopy T2 Diffusion Perfusion Spectroscopy 5
Problems: Focal therapy of prostate cancer Accuracy of mpmri has to be precisely defined MR features are not specific Detection rates are influenced by tumour Gleason score, histological volume, histological architecture and location Separation of significant and non significant tumors Identification of lesions to be treated conservatively Solutions? Molecular imaging for identification of cancer? Molecular imaging-guided targeted therapies? Modulation of the microenvironment? 6
Prostate biopsies Systematic biopsies are positive in only 27-40% of all patients with suspected cancer 1 For patients with PSA between 4 and 10ng/ml 2 : the first set of biopsies is positive in 22%, the second in 11%, the third in 5% the fourth in 4% How to improve the sensitivity of repeat biopsies for PCa detection : Targeted biopsies after MRI to identify and localize suspicious areas ( 3mm) Cognitive, MRI-US fusion, CE-US, MRg-biopsies 1-Patel AR, et al, Urology 2004 2- Djavan B et al. J Urol 2000
PET-choline or PET-PSMA Inadequate for diagnosis (recurrence, staging) Molecular imaging Targeted microbubles for US Collaboration with Bracco.Inc (Milan, Italy) Optical imaging Collaboration with : - CEA-LETI, Grenoble - CREATIS, Lyon - Vermont, Tours - Supersonic Imagine, Aix-en-Provence
VEGFR2 Targeted Microbubbles The dimeric peptide was conjugated to a pegylated phospholipid 3 and the resulting lipopeptide was incorporated into the microbubble shell of BR55 BR55 microbubble phospholipid membrane phospholipid PEG Heterodimer peptide C 4 F 10 /N 2 3 Pillai R, Fan H, Marinelli E et al..phospholipid Linked Peptide for Ultrasound Imaging of Angiogenesis Amino acids. The forum for amino acids, peptide and protein research, vol. 37, supplement 1, July 2009, 11 th International congress on Amino Acids Peptides and Proteins, Vienna, Austria, Aug 3 rd -7, 2009.
rms² VEGFR2 Targeted Microbubbles Ultrasound imaging of a prostate cancer lesion in a rat Dunning model with BR55 1000 Prostate tumour Healthy prostate 100 10 x40 1 0 0 100 200 300 400 500 600 Time (s)
VEGFR2 Targeted Microbubbles Prostate cancer
Development of hybrid imaging Development of a bi-functional endorectal probe, USoptical, for PC (project Prostafluo, ANR 2007) Why optical imaging? Possibility of development of molecular tracers Why combined with US? To be able to target transrectal biopsies and focal therapies
Development of hybrid imaging FIANIUM Localisation de la tumeur sur l image bimodale CEA-LETI, VERMON Sonde bimodale 6 fibres d excitation 4 fibres de détection J.Boutet et al., J. Biomed. Opt., 2009
Co-registration In vivo study : - 3 nude mice bearing subcutaneous tumors Bimodal Ultrasound /Optical probe Medium simulating optical and ultrasound properties of prostate Mouse Xenograft tumor 50 100 150 200 250 300 350 400 450 100 200 300 400 500 600 700 800 900
Optical targeting : nanotechnologies BiTum - ANR Nanotechnologies 2012 LIPIDOTS : Lipidic nanoparticles - Nanoemulsion - Advantages: Furtive Brillance (5x ICG) Enhanced internalisation Stability > 5 weeks Cœur lipidique Fluorophore lipophile 50 nm surfactant Chaines PEG 80 nm
96 H 24 H 96 H 240 H A In vivo targeting of the prostate tumor by scfvd2b dye n=3 scfvd2b n=3 0 0,2 0,4 0,6 0,8 1 1,2 Fluorescence (nm) Souris1 2014-90 anti-psma (scfvd2b) On living cells
Techniques : Laser ablation Cryoablation HIFU Phototherapy Irreversible electroporation Focal therapy of prostate cancer - Ablation in the target volume - Reversible effect at the margins : possibility of modulation of the microenvironment (treatment of margins) 17
Focal therapy : MRgFUS Only possible with image guidance ExAblate, InSightec
Irreversible electroporation 19
IR and immunotherapy Modulation of immune response by ablation Combination of ablation (Cryo) with new immunotherapies : - anti CTLA4, anti-pd1 ou anti-pdl1 Enhancement of antitumor immunity and rejection of tumor metastases 20
IR is part of various combinations of innovative diagnostic and therapeutic approaches It requires support from research Conclusions It requires support from companies and start-ups It requires multidisciplinary collaboration.for the greatest benefit of patients 21
Acknowlegements BR55-105 : - Bracco imaging, Milan Prostafluo : - CEA-LETI, Grenoble : JM Dinten, J Boutet, - CREATIS, Lyon : D Vray Bitum : - CEA-LETI, Grenoble : JM Dinten, J Boutet, - CNRS-UMR 5536, RMSB Bordeaux : F Couillaud, C Mazzocco - Department of Pathology and Diagnostics, Veronna: G Fracasso Immunomodulation : - F Cornelis, JF Moreau, P Blanco 22