estp pathology 2.0 april 17, 2018 magnetic resonance ... · magnetization some atomic nuclei spin,...
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ESTP Pathology 2.0
April 17, 2018
Magnetic Resonance Imaging (MRI)
Applications in Non-clinical Pharmaceutical R&D
Peter Allegrini
Imaging and MRI expert
Consultant
Abraham Nyska
Toxicologic pathologist
Consultant
Enrico Vezzali
Toxicologic pathologist
Idorsia Pharmaceuticals
Robert Maronpot
Toxicologic pathologist
Maronpot Consulting
Thomas Lemarchand
Toxicologic pathologist
TPL Path Labs
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Magnetic Resonance Imaging
Physics Terminology Potential
MRI in R&D #3
Magnetization
Some atomic nuclei spin, resulting in a magnetic moment and
thus align with an external magnetic field (like a compass).
“Magnetization” is the sum of all spins
Alignment either parallel or antiparallel to external field
low sensitivity of MRI
If excited, the spins precess (wobble) like a gyroscope
Precession frequency ω0 (≡ Larmor frequency) is linearly
dependent of external magnetic field B0
𝜔0 = γ𝐵0 The precession process induces electromagnetic radio wave with
Larmor frequency
Basic MR signal of MR images, spectra, etc.
From mri : Phyics by Evert J Blink
MRI in R&D #4
MRI friendly isotopes
From mri : Physics by Evert J Blink
Relevant Isotopes in Biomedical
Research(MRI: Magnetic Resonance Imaging;
MRS: Magnetic Resonance Spectroscopy)
MRI/MRS
MRI
MRS
MRS
MRS
Water
MRI in R&D #5
An MRI Acquisition (simplified)
From MRI made easy (… well almost) by
Prof HH Schild (Schering)
MRI in R&D #6
More physics: T1 relaxation (& it’s close relative T1ρ)
Excited magnetization recovers to its equilibrium state
Relaxation is defined by the T1 relaxation time (or rate)
From J Ridgway (2010). Cardiovascular
magnetic resonance physics for clinicians:
Part I. Journal of cardiovascular magnetic
resonance. 12
MRI in R&D #7
Even more physics: T2 relaxation (& it’s close relative T2*)
From J Ridgway (2010). Cardiovascular magnetic resonance
physics for clinicians: Part I. Journal of cardiovascular magnetic
resonance. 12
The individual spins of a magnetization lose phase coherence (synchronization)
Signal loss (T2 relaxation time or rate)
MRI in R&D #8
Relaxation Times
Important: T1 and T2 relaxation are two independent
processes, which happen simultaneously.
Furthermore: T1 and T2 relaxation are affected by the
close environment and the mobility of the
spins
MRI in R&D #9
Why are T1 resp. T2 important? MR image contrast!
T1, water/proton density, and T2 weighted images of human brain.
T1 weighted T2 weightedWater density weighted
Fat
Protein-rich fluid
Paramagnetic subst.
Tissue
Grey matter darker
than white matter
Water, CSF
Edema, tumor, infarction
Infl., hemorrhage
Bone, air
Water, CSF
Edema, tumor, infarction
Infl., hemorrhage
Tissue
White matter darker
than grey matter
Fat
Protein-rich fluid
deoxyHb
Bone, air
MRI in R&D #10
MR Image resolution
“Highly” resolved MR Images of a rat brain
Digital resolution 78 x 78 µm2; Slice thickness 1.2 mm
From PR Allegrini,
European
Pharmaceutical
Review (2012)
17;20-24
MRI in R&D #11
MR image contrast mechanisms
Relaxation times are the basis of image contrast in most instances
T1 relaxation time T1 weighted images
T2 relaxation time T2 weighted images
Contrast agents (T1 or T2 altering CA)
Inversion recovery (T1 contrast enhancement)
Proton/water density
Oxyhemoglobin to deoxyhemoglobin ratio
Flowing vs. stationary water
Water diffusion coefficient
Arterial spin labeling
Magnetization transfer
Many others ………..
MRI in R&D #12
Criteria for (in vivo) MR imaging approaches
When
Target validation (e.g. phenotyping of genetically modified animals)
PD / efficacy / toxicology/safety studies
What
Answer a biological question in a project (pharmacology, pathophysiology).
If biological question can be answered by various imaging approaches, choose the best suitable modality.
Imaging in competition to other (simpler, cheaper, faster, ...) techniques.
Read out characteristics
Non-invasive: Time course studies to capture dynamic changes, reduce animal experiments
Non-invasive: Integrated in multi-modality studies
Complex techniques: Functional read-outs (organ function in a broad sense)
Versatility: Multiple read-outs in a study
Results
Quantitative (including statistical analyses)
MRI in R&D #13
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Cerebral ischemia in the rat: Pathophysiological cascade
Symptoms
T2 weighted
MRI
Middle cerebral artery occlusion
Lack of perfusion
Hypoxia/ energy failure
Reversible lesion/
Cytotoxic edema
Permanent lesion /
Vasogenic edema (or
cyst, resp.)
Time-of-flight MR-Angiography
seconds
< 5min
minutes
- hours
> 6 hours
T2* weighted MRI
Arterial spin labelling perfusion imaging
Diffusion-weighted imaging
0
months
fMRIBrain function (lack of)
Brain plasticity
MRI in R&D #15
Quantification: Image segmentation and 3D rendering
From Inge A Mulder et al, Front.
Neuroinform.(31. Jan 2017)
MRI in R&D #16
Raw multi-slice MR image stack of cerebral ischemia in the rat 48h after onset of stroke
Segmented image stack of cerebral ischemia in the rat
Se
ge
me
nta
tio
n3
D R
en
de
rin
g
Quantification: MRI vs. Morphometry (gold standard)
MR image taken 2 days post
MCA occlusion: Edema
Matching histological frontal
section: Infarct From PR Allegrini & D Sauer, Magnetic
Resonance Imaging (1992) 773-778
MRI in R&D #17
Quantification: Predictive value
Untreated
Glutamate
receptor
antagonist
2 Days 15 Weeks
From E Weber, PR Allegrini
& D Sauer, in vivo (1993)
335-338
Edema (MRI) 2 days
post MCA occlusion vs.
total volume of atrophy
(morphometry) 2 to 3
months later: r = 0.83
Edema and cyst (MRI) 2 days
and 15 weeks post MCA
occlusion: Treatment effect
MRI in R&D #18
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
The EX-VIVO MRI (or “SMART HISTOLOGY) can be an excellent tool in preclinical
efficacy and safety evaluation, helping to:
Accurately localize the lesion;
Count the lesions;
Measure their volume;
Information about the homogeneity of the lesions.
For EX – VIVO MRI, the fixed samples were transferred from the fixative (like the 10%
buffered formalin) to Fluorinert (a proton-free and biologically inert perfluorocarbon) and,
following the scanning, the tissue were returned to formalin, for further histology
processing.
MRI-based histology – “Smart sections”
MRI in R&D #20
Comparison Classical MRI versus Compact MRI
=
Tempel Brami C, Schiffenbauer Y, Nyska A, Abramovitch R, Ezov N, Spector I, Maronpot RR (2015):
Practical Applications of in vivo and ex vivo MRI in toxicologic pathology using a novel high-performance compact MRI system.
Toxicologic Pathology 43(5):633-50. MRI in R&D #21
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
MRI in Preclinical Safety Evaluation of Stem Cells
Objective
Using compact MRI technology for the assessment of tumorigenicity following
intrathecal transplantation of human Embryonic Stem Cells (hESC) in mice
Protocol
Two mice injected with the vehicle and 3 injected with hESC
Intrathecal Injection within the inter-vertebral (L5 to L6) groove.
Daily clinical evaluation
In vivo MRI on 2 occasions (days 25 & 48)
Sacrifice on day 55, followed by formalin fixation, ex vivo MRI, and histopathology
A Safety Evaluation of Stem-Cells in a Mouse Model
MRI in R&D #23
In-Vivo (A-C) MRI of
Teratoma in the Spinal
Cord of a Mouse 25 (A)
and 48 (B-C) Days, and Ex
Vivo (D) MRI on Day 55,
After Intrathecal Injection
of hESCs
Teratoma in the Spinal cord after Intrathecal
Injection of hESC
Expanding lumbar
lesions (bright areas,
arrows)from day 25 to
48
High magnification of
the spinal teratoma
In Vivo 3D Rendering and
Segmentation of the Spinal
Cord Teratoma on Day 48MRI in R&D #24
In Vivo 3D Rendering
of the Brain Showing
Extent of the
Teratoma
In vivo MRI day 48 (A), ex vivo MRI day 55 (B-C) and
histopathology (D) of 2 different areas of the brain of a NOD-
SCID mouse after intrathecal injection of hESCs, showing
distinctive lesions
Teratoma in the Brain after Intrathecal Injection of
hESC
MRI in R&D #25
Paresis developed in mice injected with the hESC
Both in vivo and ex vivo MRI located abnormal areas in the spinal
column and brain
Histopathology confirmed malignant teratoma
The MRI technique can be used for time course observations for
testing the carcinogenic potential of novel stem cells intended for
clinical use.
The MRI (in vivo and ex vivo) were effective in accurately localizing
the teratomas in the brain and spinal cord.
Results and Conclusions
MRI in R&D #26
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Objective
Evaluation of in vivo MRI as a tool for assessment of degradation of a bio-
degradable implanted device
Protocol
A double layer of a 5x5 mm2 device was implanted in the right paralumbar
muscle of Sprague Dawley rats. A plastic bead was implanted
subcutaneously just over the device to enable accurate localization and
follow-up of the implantation site
MRI in Evaluation of Biodegradable Implanted
Device
MRI in R&D #28
In Vivo Follow-up of Implanted DeviceDay 5 Day 30 Day 60
T1
T2 Inflammation
bead
implant
MRI in R&D #29
Ex Vivo MRI of Implanted Device
implant
MRI in R&D #30
Ex Vivo MRI of Implanted Device - 3D Rendering & Segmentation
Volume of device : 32.2 mm3
MRI in R&D #31
Histopathology of the Implantation Site 60 Days
Post Implantation
Note the Cavities (red arrows) Lined by Mature Connective Tissue Capsule (blue arrow).
No Inflammatory Reaction is Present
MRI in R&D #32
In vivo MRI could detect inflammation related to the implantation process
and follow its progressive reduction. In addition, in vivo MRI was able to
demonstrate the presence of the test device in the para-lumbar muscles up to
16 weeks post implantation.
Accurate quantification of the device volume and shape was possible using
ex vivo MRI.
It can be concluded that the combination of in vivo and ex vivo MRI with
histopathology can help in assessing the tolerability and bio-degradation of biodegradable devices.
Summary and Conclusion
MRI in R&D #33
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Objective
A feasibility study for testing the utility of ex-vivo MRI in evaluating local
subcutaneous toxic (i.e., irritantancy) effects induced by injection of test
compounds
Protocol
The study was performed in pig. Surgically removed infusion sites were analyzed
by EX-MRI, 2 weeks after a 24-hour continuous infusion of different locally irritant
formulations
MRI in Tolerability (Irritancy) Testing of Drugs:
Local Safety of Subcutaneous Formulations in a
Minipig Model
MRI in R&D #35
MRI (T1) Histology
Subcutaneous Drug Injection into Pig Skin MRI vs.
Histology
MRI in R&D #36
Affected Volume 2200 mm3
3-D Rendering and Segmentation (Quantification) of
Affected Volume – Ex Vivo MRI
MRI in R&D #37
Ex-vivo MRI was effective in identifying the location and quantifying the extent
of subcutaneous necrosis and inflammation caused by different formulations
Applying ex-vivo MRI on fixed infusion site samples from different dose
formulations provides a quantitative determination of relative irritancy
Summary and Conclusion
MRI in R&D #38
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Objective
Validate the In vivo and ex vivo compact MRI as a method for the assessment of
anti-cancer efficacy testing in a mouse brain model.
Protocol
Murine GL-261 glioma cells were stereotactically injected into the right brain
hemisphere of CB6F1 mice
MRI in Efficacy Testing of Anti-Cancer Drugs:
Application of Compact MRI in a Mouse Brain
Tumor Model
MRI in R&D #40
Longitudinal Evaluation of Tumor Growth
In Vivo MRI (T2)
Day 15 Day 17 Day 20
axial
coronal
0
5
10
15
15 17 19 21
Exponential
tumor growth
Time (days)
MRI in R&D #41
Tumor volume 6.6 mm3
Day 17 – axial
Tumor Segmentation – Ex Vivo MRI (T2)
MRI in R&D #42
Day 15
Day 20
Correlation of In Vivo MRI vs. Histology
MRI in R&D #43
In vivo and ex vivo MRI evaluation provided a way to follow the time-related
growth, and when applied to an anticancer study, could show time-related
shrinkage of tumors
This model demonstrates the utility of using MRI for longitudinal studies and
would be useful for testing the efficacy of anti-cancer drugs
Summary and Conclusion
MRI in R&D #44
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Objective
Validate the compact MRI as an additional more accurate and high-throughput
method for the assessment of anti-cancer efficacy testing in a mouse lung
metastatic model.
Protocol
Intravenous injection of breast cancer cell line into the tail of 8-10 weeks-old
BALB/c mice. This Tumor is an animal model for Stage IV human breast cancer.
Animals were terminated 18 days post tumor injection and Ex-Vivo MRI scanning
was accomplished on the lungs
MRI in Efficacy Testing of Anti-Cancer Drugs:
Application of Compact MRI in a Mouse Lung
Metastasis Model
MRI in R&D #46
Macroscopic View of the Lungs (Before MRI
Scanning)
Arrows Indicate Nodules of Metastatic Mammary
Cancer
MRI in R&D #47
Ex-Vivo MRI 3D Rendering and Quantification of
Lesions
ROI Modality Color Voxels Volume mm³
lesions MR red 8255 62.9806
MRI in R&D #48
Ex vivo MRI evaluation provided a way to accurately determine the number and volume of
the tumors within the lungs. This method is superior to the currently used macroscopic
counting of the cancer nodule
This model demonstrated the utility of ex-vivo MRI for comparative testing of the
efficacy of anti-cancer drugs
Summary and Conclusion
MRI in R&D #49
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Sham operation Coronary ligation
Effects of vasodilators (Enalapril) in chronic heart
failure induced by coronary ligation in rats
Masson’s
trichrome
sections
Morphometry
gross
detection
Image
analysis fine
detection
MRI in R&D #51
SHAM CHF
Effects of vasodilators (Enalapril) in chronic heart
failure induced by coronary ligation in rats
MRI in R&D #52
Effects of vasodilators (Enalapril) in chronic heart
failure induced by coronary ligation in rats
MRI in R&D #53
Microscopic measurement by morphology and image analysis
Heart + Infarct
Volume
mm3
Sham Vehicle Enalapril
Collagen
Volume
mm3
Sham Vehicle EnalaprilCollagen
%Sham Vehicle Enalapril
Mean 540 475 542 11 56 74 2.0 11.8 13.2
% Sham / Vehicle 88 114 513 132 603 111
Macroscopic measurement by caliperInfarct length
mmSham Vehicle Enalapril
Mean 0.0 10.5 12.1
% Sham / Vehicle 115
MRIHeart
Volume
mm3
Sham Vehicle Enalapril
Infarct
Volume
mm3
Sham Vehicle EnalaprilInfarct
%Sham Vehicle Enalapril
Mean 849 886 932 0 68 80 0.00 6.87 7.24
% Vehicle 105 117 105
Effects of vasodilators (Enalapril) in chronic heart
failure induced by coronary ligation in rats
MRI in R&D #54
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Polycystic Kidney Disease:
• Structure
• Cysts volume
Other possible applications
MRI in R&D #56
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Heart hemodynamics:
• stroke volume
• ejection fraction
• wall thickness
• chambers volume
Other possible applications
MRI in R&D #58
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
Resting state 31P spectrum of calf muscles Dynamic 31P spectra of calf muscle with
simultaneous muscle stimulation
(temporal resolution 30 s)
Recovery period
pH
Other possible applicationsMitochondrial toxicity: assessment of mitochondrial capacity by MR
Spectroscopy (MRS)
Phosphorous spectroscopy (skeletal muscle)
MRI in R&D #60
Energy metabolism: Mitochondrial Toxicity
,0.00
,0.05
,0.10
,0.15
,0.20
,0.25
,0.30
,0.35
,0.40
,0.45
Day -1 Day 9
k PCr[m
in-1]
Vehicle
DPI
$$$*-38%
PCr recovery time rate
signifivantly reduced by
Complex I inhibition
Time [min]
-10 -5 0 5 10 15 20
PC
r [%
of
ba
se
lin
e]
40
50
60
70
80
90
100
110
Animal B2 @ day 9 (Vehicle)
Animal C1 @ day 9 (DPI)
Phosphocreatine recovery
Muscle stimulation Recovery
Statistics
Two Way Repeated Measure ANOVA
Post hoc Fisher LSD Method
Diphenyleneiodonium (DPI): Complex I inhibitor Metformin
(for type 2 diabetes)
Metformin inhibits Complex I
From Wessels B, et al. (2014) Metformin Impairs
mitochondrial Function in Skeletal Muscle of Both
Lean and Diabetic Rats in a Dose-Dependent
Manner. PLoS ONE 9(6) MRI in R&D #61
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
MRI in preclinical development is currently not GLP-compliant *
GLP exceptions to the validation of non-routine endpoints, like MRI, is accepted *
Imaging complementary to histopathology enhances targeted sampling and assessment *
Imaging complementary to histopathology is a desirable complement of a regulatory submission *
Regulatory authorities accept imaging reports, provided sufficient controls **
Only images used for data generation must be authenticated and archived ***
The Scientific and Regulatory Policy Committee (SRPC) of the STP is filing a position paper about
investigative tools in toxicologic pathology and related regulatory approach
* Maronpot RR, Nyska A, Troth SP, Gabrielson K, Sysa-Shah P, Kalchenko V, Kuznetsov Y, Harmelin A, Schiffenbauer YS, Bonnel D,
Stauber J, Ramot Y (2017):Regulatory Forum Opinion Piece: Imaging Applications in Toxicologic Pathology-Recommendations for Use in
Regulated Nonclinical Toxicity Studies. Toxicol Pathol 45(4):444-471
** Long RE, Smith A, Machotka SV, Chlipala E, Cann J, Knight B, Kawano Y, Ellin J, Lowe A (2013)
Scientific and Regulatory Policy Committee (SRPC) paper: validation of digital pathology systems in the regulated nonclinical environment.
Toxicol Pathol 41(1):115-122
*** Tuomari DL, Kemp RK, Sellers R, Yarrington JT, Geoly FJ, Fouillet XL, Dybdal N, Perry R (2007)
Society of Toxicologic Pathology position paper on pathology image data: compliance with 21 CFR Parts 58 and 11.
Toxicol Pathol 35(3): 450-455
Regulatory aspect
MRI in R&D #63
Physics, terminology and potential
Ischemic brain stroke
MRI associated to histology
Stem cells safety
Medical device safety
Drug local tolerance
Drug efficacy in brain primary tumor
Drug efficacy in lung tumor metastasis
Drug efficacy in chronic heart failure by ischemia
Drug efficacy in polycystic kidney disease
Heart hemodynamics
MR Spectroscopy in mitochondrial toxicity
Regulatory aspect
Summary
ESTP Pathology 2.0 MRI in R&D
Abraham Nyska
Enrico Vezzali
Peter Allegrini
Peter Allegrini
Enrico Vezzali
MRI associated to histology
Strengths
• Quantitative data (measurements, counts)
• 3D and deep assessment
• Wide range of contrast (especially for soft tissues)
• Homogeneity/heterogeneity of whole organs (e.g.: uterus or brain)
• Smart histopathology (identification, location, size and correlation)
• Longitudinal and not destructive evaluation 3Rs compliant
• Dual purpose (in vivo & ex vivo)
Weaknesses
• Resolution(giving precision and reproducibility)
=acquisition time
(not always compatible with in-vivo requirements)+
magnetic induction(permanent magnets limited to 1 Tesla magnetic fields)
• Project-specific set-up resources (working hours)
Opportunities
• MRI complementary to histopathology without overlapping
• Granular grading based on measurements (%, number of lesions)
• Accurate (no detectable lesion missed, e.g.: low tumor burden/load)
Challenges
• Large organs
• Physiological movements (peristalsis, respiration, heartbeat)