MOLECULAR IMAGINGIN THE CANCER FIELD .

PAST, PRESENT AND FUTURE

Dr. Michel HerranzInstituto De Biología Molecular

Y Celular Del Cáncer

IBMCC-CSIC-USAL.

Par a ver est a p elícu la, d eb ed isp on er d e Qu ickTim e™ y d eu n d escom p r esor Gr áfi cos.

Universidad de Salamanca

Consejo Superior deInvestigaciones Científicas

Instituto de Biolog ía Moleculary Celular del Cáncer.

Junta de Castilla y Le ón

Unión Europea

The presence of an untreatable problem generates a research need

A safe, effective drug,device or treatment isthen used for treatment of the problem.

Information obtained from basic research generates ideas for drugs, devices or techniques to treat the problem

Drugs, devices and treatments are tested for safety and efficacy, first in laboratory assays, then in animals, finally in human volunteers

MOLECULARIMAGING

MOLECULARIMAGING

MOLECULARIMAGING

MOLECULARIMAGING

ESCENARIO

Cáncer

CANCER

“Ruptura del comportamiento social de las células debido a mutacionesque 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

DosisPauta de administraciónEfectos 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 PETMR-FDG PET MR-Dopamine PETMR-Dopamine PET CT-MRCT-MR CT-CTACT-CTA

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.

RADIOLOGIC AND IMAGING TEST FOR CARDIOVASCULAR PHENOTYPING

MULTIMODALITY APPROACH

WHERE IS THE STORM?

OCTOBER 2Oth 2006.8.36a.m GMTEU Meteo-Satellite IKF-2343

MULTIMODALITY APPROACH

Clinical Study - Lung Tumour

CT PET

Fused

Clinical Study - Lung Tumour

CT PET

Fused

PHYSIOLOGY

MULTIMODALITY APPROACH

Clinical Study - Lung Tumour

CT PET

Fused

Clinical Study - Lung Tumour

CT PET

Fused

ANATOMY

MULTIMODALITY APPROACH

Clinical Study - Lung Tumour

CT PET

Fused

Clinical Study - Lung Tumour

CT PET

Fused

DIAGNOSIS

MULTIMODALITY APPROACH

Clinical Study - Lung Tumour

CT PET

Fused

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), 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

Computed Tomography (CT)

• 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.

Bone shows up brightBone shows up brightDifferent densities of tissue give inter-mediate results

Different densities of tissue give inter-mediate results

Air is darkAir is dark

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).

Computed Tomography (CT) in arteriovenous malformations

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)

• 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

Positron Emission Tomography (PET)

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) that is attached or “tagged” to a compound we’d like to follow through the body. This process is called labeling.

• One of the big advantages of PET is that the atoms that can be labeled are the same atoms that naturally comprise the organic molecules in the body. Like oxygen, carbon, nitrogen, etc.

• Second important attribute of PET is that the labeled compounds can be introduced into a body in trace quantities (without affecting the normal process of the body). They are called tracers

Commonly Used PET Radioisotopes

109.8 minutesUsually attached to a glucose molecule to produce FDG for observation of brain’s sugar metabolism

Fluorine-18

2.03 minutesAttached to oxygen gas for the study of oxygen metabolism, carbon monoxide for the study of blood volume, or water for the study of blood flow in the brain

Oxygen-15

20.3 minutesStudy of kidney and renal diseaseCarbon-11

Half-lifeUsed forLabeling agent

109.8 minutesUsually attached to a glucose molecule to produce FDG for observation of brain’s sugar metabolism

Fluorine-18

2.03 minutesAttached to oxygen gas for the study of oxygen metabolism, carbon monoxide for the study of blood volume, or water for the study of blood flow in the brain

Oxygen-15

20.3 minutesStudy of kidney and renal diseaseCarbon-11

Half-lifeUsed forLabeling agent

FDG=2FDG=2--fluorofluoro--22--deoxydeoxy--DD--glucoseglucose

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.

dxdytyxyxfftm )sincos(),(}{),(

Procedimiento

+ -180o

511 kev 511 kev

18FDG

radiofármaco

+ -180o

511 kev 511 kev

18FDG

radiofármaco tomógrafotomógrafotomógrafo

Typical PET Studies

FDG Study of Patient with Stroke

“Dead” areas of brainNo glucose metabolism

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.

• Nuclear “spins” are like magnetic dipoles.1H1H

No Applied Field Applied Field

B0

No Applied Field Applied Field

B0

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.

Relaxation

Relaxation

T2 Contrast

CSF

White/Gray Matter

Sig

nal

Time

Long Echo-TimeShort Echo-Time

T1 Contrast

Sig

nal

Time

Sig

nal

Time

Short Repetition Long Repetition

CSF

White/Gray Matter

Decay: T2

Recovery: T1

Cardiovascular MRIAngiography

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 Weeks18 Weeks 19 Weeks

Bi-parietal diameter Length of femur

Measurements of foetus in utero

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

Isidro Sánchez-García

Mª Jesús Pérez-Caro

Michel Herranz

Manuel A. Sánchez

Carolina Vicente-Dueñas

Camino Bermejo

Katja Gutsche

Inés González Herrero

Teresa Malvar

Olga Soto

Mohamed Arji

Iris López Hernández

Teresa Flores Corral

Mº Angeles Nava Rodríguez

Isabel Lara Alvarez

Esther Alonso Escudero

David Pentón

Lab

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tori

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3.

IBM

CC

-CS

IC.U

SA

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Collaborators

Acknowledgeme

ntsPilar PallaresIrene Cuevas LópezAlejandra López García

Santiago LamasCarlos ZaragozaConcepción García-RamaTania R. Lizarbe

Juan Carlos Murciano

Manuel DescoJuan J. VaqueroMarisa Soto

Delfina SanguinoMiguel Angel Piris

Sebastián Cerdán

Marina Benito

Pilar López

Patricia Sánchez

Jesús Ruiz CabelloAntonio HerreraMarien Fernández-VallePalmira Villa ValverdeDavid Castejón

Para ver est a p elícu la, d eb ed isp on er d e Qu ickTime™ y d eu n d escomp resor Gráfi cos.

Universidad de Salamanca

Consejo Superior deInvestigaciones Científicas

Instituto de Biolog ía Moleculary Celular del Cáncer.

Junta de Castilla y Le ón

Unión Europea

Antares Heart. Denice lewis. 1992