Post on 24-Sep-2020
EXPLORER.ucdavis.edu
EXPLORER:
A Total-Body PET Scanner
for Biomedical Research
EXPLORER
Approach the Limits of PET Sensitivity
EXtreme Performance LOng REsearch scanneR
History of the
“Long Scanner” Idea
Terry Jones
1990
Karp et al, 3D imaging characteristics of the HEAD
PENN-PET scanner. J. Nucl. Med. 38: 636-643, 1997
Joel Karp
1997
History of the
“Long Scanner” Idea
*W.W. Moses, “2010 – An Instrumentation Odyssey,”
SNM Mid-Winter Meeting, January, 1999.
40 cm Axial FOV
Short Septa
PET Camera in 2010*
Badawi et al, IEEE Trans Nucl
Sci;47:pp.1228–32, 2000
Ramsey Badawi
2000
History of the
“Long Scanner” Idea
D. Crosetto, IEEE Nucl Sci Symp Conf Record
pp. 2415–19, 2003
Dario Crosetto
2003
68 cm Axial FOV – the “BGO cave”
(Hamamatsu SHR-92000)
M. Watanabe, et al., IEEE Trans. Nucl. Sci. NS-
51: pp. 796–800, 2004
History of the
“Long Scanner” Idea
PQ13. Can tumors be detected when they are 2 to 3 orders of magnitude
smaller than those currently detected with in vivo imaging modalities?
NIH R01 CA170874: Enabling technologies for ultra-high sensitivity PET scanners
History of the
“Long Scanner” Idea
History of the
“Long Scanner” Idea
Ramsey
Badawi
Simon
Cherry
Why Hasn’t This
Been Done Before?
• Technology Wasn’t Ready
– Development of LSO (low dead time allows septa-less operation,
necessary for long FOV)
– More stable / reliable detector modules
– Time-of-Flight (more effective sensitivity)
– Bigger disks & FPGAs (able to take data)
– 3-D reconstruction algorithms
– OSEM (reconstruct images in finite time)
– Faster computers / more memory (reconstruct in finite time)
– Scatter correction algorithms
– Point Spread Function correction
•Clinical Applications Weren’t Ready
– Lot’s to be done with oncology
– Applications gradually demanding longer FOV
Industry Advisory Panel:
Chuck Stearns (GE Healthcare)
Michael Casey (Siemens)
Matthias Schmand (Siemens)
Ling Shao (Philips Healthcare)
Medical Advisory Board:
Richard Wahl (Johns Hopkins)
David Mankoff (Univ. of Pennsylvania)
Michael Graham (Univ. of Iowa)
William Jagust (LBNL)
Pat Price (Imperial College)
Senior Advisors:
Thomas Budinger
Michael Phelps
Ramsey Badawi
Simon Cherry
Jinyi Qi
Terry Jones
Julien Bec
Eric Berg
Martin Judenhofer
Emilie Roncali
Jonathan Poon
Xuezhu Zhang
William Moses
Qiyu Peng
Woon-Seng Choong
Joel Karp
Suleman Surti
Srilalan Krishnamoorthy
EXPLORER Team
Design Parameters
Siemens mCT EXPLORER
Axial FOV (cm) 21.8 200
Ring diameter (cm) 84.9 ~80
Scintillator LSO LYSO
Spatial resolution (mm) 4.1 <4
TOF resolution (ps) 530 <400
Integrated CT unit? Yes Yes
DOI Measurement? No Yes No
Sensitivity Improvement
mCT EXPLORER Ratio
Point Source in Air at FOV Center 24.9% 92.9% 3.7
Point Source w/ Attenuation(27 cm dia. x 200 cm long)
1.6% 3.9% 2.4
Whole Body NECR, 10 mCi(27 cm dia. x 200 cm long)
75.7 2,560 33.8
Pediatric NECR, 0.05 mCi(20 cm dia. x 70 cm long)
3.12 48.0 15.5
Brain VOXTISS 8 NECR, 10 mCi6:1 activity
176 597 3.4
Cardiac VOXTISS 8 NECR, 20 mCiall activity in heart
613 1910 3.1
• Non-TOF Values for NECR Given
• Multiply NECR by 1.4 – 2.8 to Obtain NECRTOF
NECR Comparison
Whole Body
(27 cm dia., 200 cm long)
Challenges
• Scale of System
– ~1M scintillator crystals
– 600 kg of scintillator
• Mechanical Issues
– Structural support
– Access for repair
– Thermal management
(especially if SiPMs used)
• Event Rates (10 mCi in FOV)
– 150 million singles/sec
– 50 million coincidences/sec
– 12 GB/sec data rates
– ~10-40 TB storage per day
Gantry Design
• 5 Separate Gantries w/ Interlocking Covers
• Separable (via Rail System) for Servicing
Electronics Architecture
Detector Crate
Detector Crate
Detector Crate
Detector Crate
Detector Crate
Detector Crate
Detector Crate
Detector Crate
Detector Crate
Detector Crate
Detector Crate
Detector Crate
• Singles Events Processed
by Detector Crates
– One crate services long strip
of modules
• Low Data Rates
– Real-time coinc. processing
– Singles searched for pairs in
different detector crates
– Coincident evts written to disk
• High Data Rates
– Offline coinc. processing
– Crate independently writes
singles events to its own disk
• Module Event Rates Same as Conventional PET
• “Standard” Electronics for Each Detector Module
Current Status
• Simulations and prototype detectors,
electronics and reconstruction
methods completed
• Discussions with potential partner
companies almost complete
• Goal is operational scanner
within 2 years
• “Monkey EXPLORER” prototype
fabricated and ready for initial
testing. Prototype is reconfigured
Siemens mCT camera:
– 40 cm diameter (half mCT dia.)
– 44 cm axial (twice mCT axial)
7 mm
6 mm
5 mm
4 mm
3 mm
2 mm
Image reconstruction:- 1 x 1 x 2 mm voxel size, ~390M events- OSEM (10 iterations, 20 subsets) with resolution modelling- Analytical attenuation correction. No other corrections (normalization, scatter, randoms)
Partner Company
Selection
• Detector Module Performance
– Reliability & stability!!!
– TOF resolution
• Engineering Provided
– “Detector Panel” design
– Cooling / thermal management
– Coincidence electronics
• “Completeness” of Software
– Calibration & setup software
– Data correction software
– Reconstruction software
• “Business” Considerations
– Cost & delivery time
– In commercial product roadmap?
Image Better
EXPLORERConventional PET
• > 6-fold improvement
in SNR
– Reconstruct at higher
spatial resolution
– Detect smaller lesions
– Detect low-grade
disease
– Better statistics for
kinetic modeling
Image Better:
Micrometastases
• Clinical Need
– 140,000 new colorectal diagnoses in US / year
– 60% have adjuvant chemotherapy post-surgery
– 40% are unnecessary (no micrometastases)
• Accurately Image Micrometastases (0.2–6 mm)
– Normal FDG injection (10 mCi)
– Image 330 minutes post-injection (3 half lives)
– Because of tumor kinetics, higher tumor contrast
– Improved sensitivity enables high quality imaging
*Price P M, Badawi R D, Cherry S R , Jones T.Journal of Nuclear Medicine 2014;55:696-697
Image Longer
time
EXPLORER
Conventional PET
• Major increase in dynamic range
can image for 5 more half lives
• 11C> 3 hours
• 18F> 16 hours
• 89Zr> 30 days
Image Longer:11C Imaging / Kinetics
b
c
N
O
ON
O
O
O
PS
HO
O-
Me
OMe
O
O
O
OMe
O
PS O-
N
O
ON
O
O
O
OMe
Me
OH
N
N
N
O
NH2NNa+
Na+
CH3
CH3
CH3
*
*
*
Time (minutes)
0 15 30 45 60 75 90 105
[11C
] L
Y2
18
13
08
co
nc
en
tra
tio
n (
ng
/mL
)
0
100
200
300
400
500Liver
Bile duct
Bowel near bile outflow
Bowel
Time (minutes)
0 15 30 45 60 75 90 105
0
100
200
300
400
500Kidney
Ureter
Spleen
Vertebra
Antisense Oligonucleotide 11C-LY2181308 Uptake
Image Faster
EXPLORER
• Total-body PET in
15-30 seconds
– Image in a single
breath hold
– Reduce effects of
respiratory motion
– Total-body kinetic
imaging with high
temporal resolution
10-20 mins
Conventional PET
15-30 secs
Image Faster:
Mind / Body Interaction
Anxiety Disorder
Bipolar Disorder
Insomnia
Post-traumatic Stress Disorder
Borderline Personality Disorder
ADHD
Major Depressive Disorder
Chronic Fatigue Syndrome
Fibromyalgia
Irritable Bowel Syndrome
Alcoholism
Burnout
Image Gently (Low Dose)
EXPLORER
Conventional PET
• 40-fold reduction in dose
– Whole-body PET at
~0.15 mSv
– Annual natural background
is ~2.4 mSv
– Return flight (SFO-LHR) is
~0.11 mSv
– PET can be used with
minimal risk – new
populations
Image Gently (Low Dose):
Maternal / Fetal Interaction
• Clinical Need
– 15M babies born pre-term (<37 weeks) / year
– 1.1M die because of pre-term complications / year
– Many surviving pre-term babies have problems as adults
(disabled, diabetes, hypertension, heart disease, obesity)
• Identify Problems In Utero
– Trace nutrient transport from mother to fetus
(oxygen, glucose, amino acids, fatty acids)
– Image at <0.05 mSv
• One week of natural background radiation in UK
• Flight between London and San Francisco
Image More Often
EXPLORER
Conventional PET
Image More Often:
Precision Medicine
• Clinical Need
– Heterogeneity in cancer
– Individualized treatment
desired
• Multiple PET Imaging
Sessions
– Suggest best therapies
– Follow treatment
– Assess response to therapy
• Add pharmacokinetics?
– Modify treatment according
to response
11C-DACA Whole Body Distribution
11C-DACA Kinetics
Transformative Areas
of Investigation
Detecting occult low density
multi-system disease
– Ultra-staging of micro-metastases
– Plaques in atherosclerosis
– Inflammation
– Infection
Providing total body kinetics
– Drug delivery / extended time courses /
physiologically based pharmaco-kinetic
models
– Translational pipeline for new
radio-labelled imaging biomarkers
– Toxicology
Studying the interactions between
the body’s organs
–Distribution of tissue blood flow
Enabling low radiation dose studies
– Repeat studies & normal subjects
– Young patients
– Maternal-Fetal
Studying interactive regional
pathologies brain: body
– Anxiety / Depression
– Alzheimer’s Disease
– Metabolic syndrome / obesity
Longitudinal studies
– Precision therapy
– Progressive disease (arthritis, diabetes)
Expanding the commercial future
– Higher clinical throughput
– New applications
Comments & Questions?
Overview of Imaging-Current status from medical
perspective
Pat Price
Imperial College London
2nd Divonne Brainstorming meeting on CERN Medical Applications
Current status from medical prospective
Current clinical use• Anatomical-invasive/real time (RT)• Diagnostic• Functional• Ex-vivo
All need • Increased sensitivity/resolution• Increased specificity• Increased biological information
Imaging in Development of surgery
The Magnetic Resonance
Imaging–Linac System
Jan J.W. Lagendijk, et al Seminars in Radiation Oncology, Volume 24, Issue 3, 2014, 207–209
Cryo-electron microscopy
• Cryogenic Transmission Electron microscope for high-resolution single particle analysis
• Cryo-tomography of biological samples
– Detecting occult low density multi-system disease Ultra-staging of micro-metastases Plaques in atherosclerosis Inflammation Infection.
– Providing total body kinetics Drug delivery /extended time courses /physiologically based PK models Translational pipe line for new radio-labelled imaging biomarkers Toxicology.
– Enabling Low radiation dose studies Repeat studies Normal subjects Young patients Maternal-Fetal
– Studying interactive regional pathologies brain: body Anxiety/Depression Alzheimer’s Disease Metabolic syndrome/Obesity.
-- Studying the interactions between the body’s organs– Expanding the commercial future
New applications Higher clinical throughput.
Total body PET Transformative areas of investigative medicine:
– Detecting occult low density multi-system disease Ultra-staging of micro-metastases Plaques in atherosclerosis Inflammation Infection.
– Providing total body kinetics Drug delivery /extended time courses /physiologically based PK models Translational pipe line for new radio-labelled imaging biomarkers Toxicology.
– Enabling Low radiation dose studies Repeat studies Normal subjects Young patients Maternal-Fetal
– Studying interactive regional pathologies brain: body Anxiety/Depression Alzheimer’s Disease Metabolic syndrome/Obesity.
-- Studying the interactions between the body’s organs– Expanding the commercial future
New applications Higher clinical throughput.
Total body PET Transformative areas of investigative medicine:
Detecting Micro-Metastatic Cancer-The Challenge
No Mets ITC1cell-<0.2mm
Micro Mets
0.2-6mm
Subclinical
6-9mm
Clinical
>1cm
PET Ultra-staging PET MRI CT USS
60 min 18FDG
Current cancer imaging with 18FDG
The challenge micro-metastases
Economics of Better Selection for Adjuvant Chemotherapy
• In the USA alone 140,000 patients diagnosed with colorectal cancer per year. 60% late stage receive adjuvant chemotherapy after surgery
• 44% of post surgical patient do not need adjuvant chemotherapy as do not have micrometastases
• Clinical trials of novel adjuvant therapy based on 5 years survival so long and expensive
• Similar challenges in Neoadjuvant therapy
• Similar issues with breast/lung/prostate etc
HypothesisFor ultra-staging in cancer*
The total body Ultra PET scanner will be 40times more sensitive than conventional scannersfor whole body imaging
&
By waiting 3 half lives; 330 minutes postadministration of 18FDG, the enhanced contrastwill make it possible to measure raised levels ofactivity in organs which correspond to thepresence of microscopic cancer
*Price P M, Badawi R D, Cherry S R , Jones T.Journal of Nuclear Medicine 2014;55:696-697
90 mins after injection
– Detecting occult low density multi-system disease Ultra-staging of micro-metastases Plaques in atherosclerosis Inflammation Infection.
– Providing total body kinetics Drug delivery /extended time courses /physiologically based PK models Translational pipe line for new radio-labelled imaging biomarkers Toxicology.
– Enabling Low radiation dose studies Repeat studies Normal subjects Young patients Maternal-Fetal
– Studying interactive regional pathologies brain: body Anxiety/Depression Alzheimer’s Disease Metabolic syndrome/Obesity.
-- Studying the interactions between the body’s organs– Expanding the commercial future
New applications Higher clinical throughput.
Total body PET Transformative areas of investigative medicine:
b
c
N
O
ON
O
O
O
PS
HO
O-
Me
OMe
O
O
O
OMe
O
PS O-
N
O
ON
O
O
O
OMe
Me
OH
N
N
N
O
NH2NNa+
Na+
CH3
CH3
CH3
*
*
*
Time (minutes)
0 15 30 45 60 75 90 105
[11C
] L
Y2
18
13
08
co
nc
en
tra
tio
n (
ng
/mL
)
0
100
200
300
400
500Liver
Bile duct
Bowel near bile outflow
Bowel
Time (minutes)
0 15 30 45 60 75 90 105
0
100
200
300
400
500Kidney
Ureter
Spleen
Vertebra
Antisense Oligonucleotide Carbon-11-LY2181308 Uptake
Perfusion Dependant Drug Delivery Due to Tumour Microscopic
Heterogeneity
Uniform Perfusion Heterogeneous PerfusionNormal Perfusion
Transit of an inert freely diffusible tracer
Diffusion space
(Physiologically
Exchanging Space)
Inadequate Perfusion
Diffusion space
(Physiologically
Exchanging Space)
NecrosisNormal perfusion
Transit of an inert freely diffusible tracer
Measuring Tumour Heterogeneity with High sensitivity PET
– Detecting occult low density multi-system disease Ultra-staging of micro-metastases Plaques in atherosclerosis Inflammation Infection.
– Providing total body kinetics Drug delivery /extended time courses /physiologically based PK models Translational pipe line for new radio-labelled imaging biomarkers Toxicology.
– Enabling Low radiation dose studies Repeat studies Normal subjects Young patients Maternal-Fetal
– Studying interactive regional pathologies brain: body Anxiety/Depression Alzheimer’s Disease Metabolic syndrome/Obesity.
-- Studying the interactions between the body’s organs– Expanding the commercial future
New applications Higher clinical throughput.
Total body PET Transformative areas of investigative medicine:
Maternal-Fetal Health
• 15M babies/year are born pre-term (<37 weeks) “born too soon”
• 1.1M babies die/year because of pre-term complications
• Many surviving pre-term babies are disabled
• 3M still born babies per year
• Intrauterine growth restriction (IUGR) is due to abnormal placenta function
Intrauterine Growth Restrictionis associated with
• Raised neonatal mortality and morbidity
• Diabetes in adulthood
• Hypertension in adulthood
• Ischemic heart disease in adulthood
• Metabolic syndrome (obesity)
The Case for Maternal-Fetal PETTracing nutrient from the mother to the fetus
(Placenta transport e.g. oxygen, glucose, amino acids, fatty acids)
Drugs and toxins distribution between mother to fetus
Metabolic health of the fetus
Inflammation/infection
Schizophrenia
Autism
Cognitive impairment
Maternal cardiovascular physiology
Placenta transporters
Aim:
Enable the collection of biologically
meaningful PET data at a “cost” of < 0.05mSv
One week of natural background radiation in the UK
One way flight between London-San Francisco
Breaking through the radiation absorbed dose barrier
The potential for low dose functional studies in maternal-fetal medicine using combined PET and MRI Terry Jones and Thomas F. Budinger. Journal of Nuclear Medicine 2013, 54: 2017-2018
Cost (radiation dose)
vs
Benefit (immediate & lifetime impact)
Maternal-Fetal PET
Imaging at the beginning of life and not just at the end
– Detecting occult low density multi-system disease Ultra-staging of micro-metastases Plaques in atherosclerosis Inflammation Infection.
– Providing total body kinetics Drug delivery /extended time courses /physiologically based PK models Translational pipe line for new radio-labelled imaging biomarkers Toxicology.
– Enabling Low radiation dose studies Repeat studies Normal subjects Young patients Maternal-Fetal
– Studying interactive regional pathologies brain: body Anxiety/Depression Alzheimer’s Disease Metabolic syndrome/Obesity.
-- Studying the interactions between the body’s organs– Expanding the commercial future
New applications Higher clinical throughput.
Total body PET Transformative areas of investigative medicine:
The Complexity of the City[Economy/Culture]
Financial
Legal
Health Care
Education
The ArtsRetail
Transport
Energy supplyEthnic Groups
Administration
Using Total Body PET to study the Complexity of the Human Body
Complex organs & tissues/Interacting in a complex system e.g.:• Heart-blood circulation• Brain-Body• Hormone & Peptide producing organs
e.g.: Pancreas/Adrenals/Thyroid/Gut/Gonads
• Mother-fetus
To date Imaging has focused on individual organs
Anxiety Disorder
Bipolar Disorder
Insomnia
Posttraumatic Stress Disorder,
Borderline Personality Disorder,
ADHD
Major Depressive Disorder,
Burnout, Chronic Fatigue Syndrome
Fibromyalgia
Irritable Bowel Syndrome,
Alcoholism
Stress and disease
Brain-Body Positron Emission Tomography
Depression & Anxiety
Psychosis
Projected Applications
of
Total Body PET
Psychiatry
Inflammation
Hypothalamic-Pituitary-Adrenal (HPA) Axis
Gut-Brain Axis
Irritable Bowel Syndrome
Pre-Partum
Post-Partum
Puberty
Hormonal Dependant
1
2
:
Psychiatry
The 10 Year Vision
Using Total Body PET:Molecular/Functional Imaging of the
total body with high sensitivity“Systems Biology”
Clinical Research
Health Care
in
Risks:Foetal Radiation Absorbed - Dose Estimates
0.1mSv/18.5 MBq of 11C administered
Tom Budinger
0.1mSv
Return Flight London-San Francisco: 0.11 mSv