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Technique, research and benefits
Interface between technology, clinical, human and social science and public health:
Case study interventional radiology
Nicolas Grenier, Bordeaux University Hospital
Interventional Radiology
Why is IR a growing field ?
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
Interventional Radiology
Why is IR so slowered ?
Problems to finance innovation +++
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
Focal therapy of prostate cancer
Problems:
Identification of the PC : - Now possible combining morphological, functional and metabolic data
with MRI : multiparametric MRI
. T2w
. Diffusion-weighted
. Perfusion-weighted
. Spectroscopy
5
T2 Diffusion Perfusion Spectroscopy
Focal therapy of prostate cancer
Problems:
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
Molecular imaging
PET-choline or PET-PSMA
Inadequate for diagnosis (recurrence, staging)
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 phospholipid3 and the resulting
lipopeptide was incorporated into the microbubble shell of BR55
phospholipid membrane phospholipid membrane
C 4 F 10 /N 2 C 4 F 10 /N 2
Heterodimer
peptide
PEG
phospholipid
BR55 microbubble
3Pillai 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.
0
1
10
100
1000
0 100 200 300 400 500 600
Time (s)
rms
²
Prostate tumour
Healthy prostate
x40
Ultrasound imaging of a prostate cancer lesion in a rat Dunning model with BR55
VEGFR2 Targeted Microbubbles
Prostate cancer
VEGFR2 Targeted Microbubbles
Development of hybrid imaging
Development of a bi-functional endorectal probe, US-
optical, 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
J.Boutet et al., J. Biomed. Opt., 2009
FIANIUM
CEA-LETI, VERMON
Sonde bimodale 6 fibres d’excitation
4 fibres de détection
Localisation de la tumeur sur l’image bimodale
Co-registration
Mouse
Medium simulating optical and ultrasound
properties of prostate
Bimodal Ultrasound /Optical probe
Mouse
Medium simulating optical and ultrasound
properties of prostate
Xenograft
tumor
In vivo study :
- 3 nude mice bearing subcutaneous tumors
100 200 300 400 500 600 700 800 900
50
100
150
200
250
300
350
400
450
LIPIDOTS® : Lipidic nanoparticles - Nanoemulsion -
Cœur lipidique Fluorophore lipophile
surfactant Chaines PEG
50 nm
Advantages: •Furtive •Brillance (5x ICG) •Enhanced internalisation •Stability > 5 weeks
Optical targeting : nanotechnologies
80 nm
BiTum - ANR Nanotechnologies 2012
A 2
4 H
96
H
24
0 H
0 0,2 0,4 0,6 0,8 1 1,2
scFvD2B
dye
Fluorescence (nM)
n=3
n=3
In vivo targeting of the prostate tumor by scFvD2B
Souris1
2014-90
96 H
anti-PSMA (scFvD2B) On living cells
Focal therapy of prostate cancer
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Techniques :
Laser ablation
Cryoablation
HIFU
Phototherapy
Irreversible electroporation
- Ablation in the target volume
- Reversible effect at the margins : possibility of modulation of the
microenvironment (treatment of margins)
Focal therapy : MRgFUS
Only possible with image guidance
ExAblate, InSightec
Irreversible electroporation
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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
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Conclusions
IR is part of various combinations of innovative diagnostic and therapeutic approaches
It requires support from research
It requires support from companies and start-ups
It requires multidisciplinary collaboration
……………………….For the greatest benefit of patients
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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
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