MOLECULAR IMAGING

IN THE CANCER FIELD .

PAST, PRESENT AND FUTURE

Dr. Michel Herranz

Instituto De Biología Molecular
Y Celular Del Cáncer
Pa ra ve r e s t a pe líc u la , de be
d is pone r de Q ui c kTi me ™ y d e
un de s c ompre s or Grá fi c os .

IBMCC-CSIC-USAL.

Universidad de Salamanca

Consejo Superior de
Investigaciones Científicas

Instituto de Biología Molecular

y Celular del Cáncer.

Junta de Castilla y León

Unión Europea
 The presence of an
untreatable problem
generates a research need

Information obtained from basic research generates

ideas for drugs, devices or techniques to treat the
A safe, effective drug, problem
device or treatment is
then used for treatment
of the problem.

Drugs, devices and treatments

are tested for safety and
efficacy, first in laboratory
assays, then in animals, finally
in human volunteers
MOLECULAR
IMAGING

MOLECULAR
IMAGING

MOLECULAR
IMAGING

MOLECULAR
IMAGING
ESCENARIO
Cáncer
 CANCER

“Ruptura del comportamiento social de las células debido a mutaciones

que dan al traste en cuestión de días o meses con centenares de miles de años de evolución”

Joan Massagué. EL PAIS. 22 de Octubre 2004

+
TECNOLOGIA DE IMAGEN
=
TRANSLATION
-Detección
-Pronóstico
-Terapia
IMAGEN MÉDICA
TRANSLATION
-Detección TEMPRANA
-Pronóstico ACERTADO
-Terapia ADECUADA
Fármaco
Dosis
Pauta de administración
Efectos secundarios
Detección Temprana
Early Disease Detection
EARLY DIAGNOSIS BRING DOWN DEATHS
MEDICAL IMAGING. OUT OF SIGHT BUT NOT OUT OF MIND.
One picture as worth ten thousand words
Frederic Barnhard (1927)

?
One picture as worth ten thousand words
Frederic Barnhard (1927)
EVOLUCIÓN
PAST: Cut, then see.
 PRESENT: See, then cut.

Preoperative Imaging

Intraoperative Execution
FUTURE: Combine, see and minimally cut.

Image guidance Augmented reality

MEDICAL TECHNOLOGY TRANSFORMS HEALTHCARE
Role of Diagnostic Imaging in Healthcare
Technical evolution
• Goals:
– Create images of the interior of the living human body from the outside for diagnostic purposes.

• Biomedical Imaging is a multi-disciplinary field involving

– Physics (matter, energy, radiation, etc.)
– Math (linear algebra, calculus, statistics)
– Biology/Physiology
– Engineering (implementation)
– Computer science (image reconstruction, signal processing)
Imaging Modalities
– Anatomical modalities
• Depicting primarily morphology
• X-ray, CT, MRI, US,
• MRA, DSA, CTA and Doppler
– Functional Modalities
• Depicting primarily information on the metabolism of the
underlying anatomy
• SPECT, PET, fMRI, EGG and MEG
• pMRI, fCT, EIT and MRE

MR-FDG PET MR-Dopamine PET CT-MR CT-CTA

 RADIOLOGIC AND IMAGING TEST
FOR CARDIOVASCULAR PHENOTYPING

1) X-Rays

2) CT scan: 3-dimensional cross-sectional views of tissues to determine tumor

density, size, and location

3) MRI: Detailed sectional images using magnetic fields to differentiate diseased

tissue from healthy tissue and to study blood flow. It visualizes tumors hidden
by bone or other structures

4) PET: Computed cross-sectional images of increased concentrations of

radioisotopes in malignant cells, providing information about the biologic activity
of the cells. Differentiates benign & malignant processes and responses to
treatment.

5) Ultrasound: Used to detect abnormalities of a body organ or structure. Sound

wave reflections are projected on a screen and may be recorded.

6) Optical Imaging: Needs an external ligth source (Fluorescence) or chemical

sustrate (Luminiscence). It visualizes processes in tags cells or transgenic
animals.
MULTIMODALITY APPROACH
WHERE IS THE STORM?
OCTOBER 2Oth 2006.8.36a.m GMT
EU Meteo-Satellite IKF-2343
MULTIMODALITY APPROACH

PHYSIOLOGY
Clinical Study - Lung Tumour

CT PET

Fused
MULTIMODALITY APPROACH

ANATOMY
Clinical Study - Lung Tumour

CT PET

Fused
MULTIMODALITY APPROACH

DIAGNOSIS Clinical Study - Lung Tumour

CT PET

Fused
MULTIMODALITY
APPROACH

Clinical Study - Lung Tumour

CT PET

Fused
TÉCNICAS DE IMAGEN
IMAGING TESTS
Rayos-X
 BMI methods: X-Ray imaging

• Year discovered: 1895 (Röntgen, NP 1905)

• Form of radiation: X-rays = electromagnetic radiation
(photons)
• Energy / wavelength of radiation: 0.1 – 100 keV / 10 – 0.01 nm
(ionizing)
• Imaging principle: X-rays penetrate tissue and
create "shadowgram" of
differences in density.
• Imaging volume: Whole body
• Resolution: Very high (sub-mm)
• Applications: Mammography, lung diseases,
orthopedics, dentistry,
cardiovascular, GI
Computed Tomography
 BMI methods: X-Ray computed tomography

• Year discovered: 1972 (Hounsfield, NP 1979)

• Form of radiation: X-rays
• Energy / wavelength of radiation: 10 – 100 keV / 0.1 – 0.01 nm
(ionizing)
• Imaging principle: X-ray images are taken under
many angles from which
tomographic ("sliced") views are
computed
• Imaging volume: Whole body
• Resolution: High (mm)
• Applications: Soft tissue imaging (brain,
cardiovascular, GI)
 Computed Tomography (CT)
Computed tomography (CT), sometimes called CAT scan, uses special x-ray
equipment to obtain many images from different angles, and then join them
together to show a cross-section of body tissues and organs

• A standard tube produces X-rays with

an energy of approximately 150 keV.
• The X-ray focal spot scans across and
around the patient.
• The technique measures the X-ray
attenuation coefficient of the different
tissues in the body.
Air is dark

Bone shows up bright

Different densities
of tissue give inter -
mediate results
 Computed Tomography (CT) in arteriovenous malformations

Tortuous middle cerebral artery. 14 year old boy who

presented with chronic headaches. A cranial-caudad image
including clip planes demonstrates tortuosity of the
middle cerebral artery (arrow). An MRA was initially
performed on this patient, which demonstrated a possible
ACA aneurysm and stenosis of the MCA.

Supraorbital AVM. 12 year old male who presented with

mass involving the left side of the face above the eye. A
left anterior oblique VRT image demonstrates the
arteriovenous malformation and its draining vessels
(arrow).
Positron Emission Tomography
(PET)
 BMI methods: Nuclear imaging (PET/SPECT)

• Year discovered: 1953 (PET), 1963 (SPECT)

• Form of radiation: Gamma rays
• Energy / wavelength of radiation: > 100 keV / < 0.01 nm
(ionizing)
• Imaging principle: Accumulation or "washout" of
radioactive isotopes in the body
are imaged with x-ray cameras.
• Imaging volume: Whole body
• Resolution: Medium – Low (mm - cm)
• Applications: Functional imaging (cancer
detection, metabolic processes,
myocardial infarction)
 Positron Emission Tomography
(PET)
• Noninvasive, diagnostic imaging technique for measuring metabolic activity
in the human body

• Unlike traditional diagnostic tools like x-rays, CT scans or MRI, PET

produces images of the body’s biochemistry

• PET has a significant advantage being able to capture early changes of

biochemical processes within a cell due to a disease
 Physics of PET
• When a positron is emitted, it “finds” a nearby electron and annihilates with it.

• The annihilation creates two x-ray photons that fly off the point of annihilation (at the speed of light) in (nearly) opposite directions.

• The photons, in turn, are captured by a pair of crystals within a ring of these detectors.

• The counts of these coincident events constitute the intensity of the attenuated projections.
 Labeling and Tracers

• PET involves the use of

radioactive atoms (isotopes) Commonly Used PET Radioisotopes
that is attached or “tagged” to
a compound we’d like to follow
through the body. This process
is called labeling. Labeling agent Used for Half-life

• One of the big advantages of Carbon-11 Study of kidney and renal disease 20.3 minutes
PET is that the atoms that can
be labeled are the same atoms Oxygen-15 Attached to oxygen gas for the study 2.03 minutes
that naturally comprise the of oxygen metabolism, carbon
organic molecules in the body. monoxide for the study of blood
Like oxygen, carbon, nitrogen,
etc. volume, or water for the study of
blood flow in the brain
Fluorine-18 Usually attached to a glucose 109.8 minutes
• Second important attribute of
PET is that the labeled molecule to produce FDG for
compounds can be introduced observation of brain’s sugar
into a body in trace quantities metabolism
(without affecting the normal
process of the body). They are
called tracers
FDG=2-fluoro-2-deoxy-D-glucose
 Steps in the PET Process
• Production of positron emitting isotope in a cyclotron.

• Labeling a compound with positron emitter

and preparing it in a form suitable for
administration in humans.

• Administration (injection) of tracer compound and data acquisition

with PET camera.

• Image reconstruction algorithms. Fourier slice theorem gives a

recipe showing the 1-D Fourier transform of a single set of
parallel lines of the sinogram gives the 2-D Fourier transform
of the image density along a unique line in Fourier space.


m(t , )  { f }   f ( x, y)  ( x cos  y sin   t )dxdy

 Procedimiento

18FDG

511 kev +- 511 kev

180o

radiofármaco tomógrafo
 Typical PET Studies

“Dead” areas of brain

No glucose metabolism

FDG Study of Patient with Stroke

NUCLEAR MAGNETIC RESONANCE
 BMI methods: Magnetic resonance imaging
• Year discovered: 1945 ([NMR] Bloch, NP 1952)
1973 (Lauterbur, NP 2003)
1977 (Mansfield, NP 2003)
1971 (Damadian, SUNY DMS)
• Form of radiation: Radio frequency (RF)
(non-ionizing)
• Energy / wavelength of radiation: 10 – 100 MHz / 30 – 3 m
(~10-7 eV)
• Imaging principle: Proton spin flips are induced, and
the RF emitted by their response
(echo) is detected.
• Imaging volume: Whole body
• Resolution: High (mm)
• Applications: Soft tissue, functional imaging
 • Certain atomic nuclei including 1H exhibit
nuclear magnetic resonance. 1H

• Nuclear “spins” are like magnetic dipoles.

Polarization
• Spins are normally oriented randomly.
• In an applied magnetic field, the spins align with the applied
field in their equilibrium state.
• Excess along B0 results in net magnetization.

No Applied Field Applied Field

B0
Relaxation
Relaxation
 T2 Contrast Decay: T2
Short Echo-Time Long Echo-Time

T1 Contrast
CSF
Signal

Short Repetition Long Repetition

White/Gray Matter
Time

Recovery: T1

White/Gray Matter
Signal

Signal
Time CSF Time
Cardiovascular MRI
Angiography
MR Imaging
Ultrasound Imaging
 BMI methods: Ultrasound imaging

• Year discovered: 1952 (clinical: 1962)

• Form of radiation: Sound waves (non-ionizing)
NOT EM radiation!
• Frequency / wavelength of radiation: 1 – 10 MHz / 1 – 0.1 mm

• Imaging principle: Echoes from discontinuities

in tissue density/speed of
sound are registered.
• Imaging volume: < 20 cm
• Resolution: High (mm)
• Applications: Soft tissue, blood flow
(Doppler)
Use of Ultrasound in Obstetrics

18 Weeks 19 Weeks

Bi-parietal diameter Length of femur

Measurements of foetus in utero

 Use of Ultrasound in Obstetrics

Duplex Duplex of flow in umbilical chord

Measurements of blood flow on the foetus in utero

 Duplex Doppler Flow Data

“Signed” velocity “Doppler Power”

Flow pattern at the bifurcation of the carotid artery

Use of Ultrasound in Cardiology modeling
COMPARATIVE
Cardiac modeling evolution
NON-INVASIVE TECHNOLOGY
NON-INVASIVE TECHNOLOGY
Laboratorio 13. IBMCC-CSIC.USAL Isidro Sánchez-García
Universidad de Salamanca
Mª Jesús Pérez-Caro
Michel Herranz
Manuel A. Sánchez Consejo Superior de
Investigaciones Científicas
Carolina Vicente-Dueñas
Camino Bermejo Instituto de Biología Molecular
Katja Gutsche y Celular del Cáncer.

Inés González Herrero Junta de Castilla y León

Teresa Malvar
Olga Soto Unión Europea

Mohamed Arji
Iris López Hernández
Teresa Flores Corral
Mº Angeles Nava Rodríguez
Isabel Lara Alvarez
Esther Alonso Escudero
David Pentón

Collaborators
Acknowledgements
Jesús Ruiz Cabello Delfina Sanguino
Pilar Pallares
Antonio Herrera Miguel Angel Piris
Irene Cuevas López
Alejandra López García Marien Fernández-Valle
Palmira Villa Valverde
Sebastián Cerdán
Santiago Lamas David Castejón
Carlos Zaragoza Marina Benito
Concepción García-Rama Manuel Desco Pilar López
Tania R. Lizarbe Juan J. Vaquero Patricia Sánchez
Marisa Soto
Juan Carlos Murciano
Antares Heart. Denice lewis. 1992