Imaging Tumours Flashcards
What umbrella does most hospital imaging come under
Structural
Name 6 imaging techniques
How can all these methods be used
Fluorescence Ultrasound X Ray (including CT) PET SPECT MRI
By injecting an imaging agent into the blood stream and imaging that
Define molecular imaging
Imaging molecules that are undergoing biological processes at the cellular or subcellular level
What is functional imaging
Imaging properties of tissues beyond their anatomical structure such as the size of their cells or the leakiness of blood vessels
How is energy transferred through space
Electromagnetic radiation
What form is the energy in electromagnetic radiation
Photons
What is an electromagnetic wave
A stream of photons all with the same frequency
What is the most common C isotope
How many neutrons and protons
What is another C isotope
C-12
6 protons and 6 neutrons
C-13 and C-14
Is C-13 stable
Yes
What do unstable C isotopes emit
What are the associated molecules
Gamma rays (Tc-99m) or positrons (F-18)
Name 2 imaging techniques that use MRI machines
MRI
and Magnetic Resonance Spectroscopy
Give the 4 key features of an MRI machine
- A super conducting magnet that provides a strong permanent magnetic field
- Radio frequency antennae (coils)
- Gradient coils to spatially vary the magnetic field
- Console
What do coils do in an MRI machine
Send and receive radio waves of the MRI signal
What is a pulse sequence
The specific set of pulses and timings of radio waves sent from the coil of the MRI machine into the patient
Do all isotope nuclei have spin
No
Name a common isotope that has spin
Hydrogen - 1 which makes up 99.98% of the hydrogen in water
What is the most common isotope of P
Does it have spin
P-31
Yes
Which carbon molecule has spin
C-13
How common is C-13
1% of all C molecules in the universe
What is chemical shift
Different chemicals in the body have NMR signals at different frequencies
What is the unit of the frequency axis in an NMR graph
ppm (part per million) NOT Hz
Why do we use ppm not Hz in NMR
The actual frequency of peaks is proportional to the static magnetic field of the MRI/NMR instrument
What does part per million mean
How many millionths of the static magnetic field the peak is from 0
How might your use C-13 glucose to image muscles
How many peaks would you see when doing this imaging on a resting muscle
Tune the coils of the MRI machine to send and detect C-13 nuclei frequencies
Inject the patient with C-13 glucose and watch its peaks
3 peaks: α-glucose, β-glucose, and glycogen
How is MRS an insensitive technique (2)
A large amount of muscle is used for each spectrum
Results take hours to acquire
Other than water, what molecule is very commonly imaged with clinical scanners
Fat
Why do the 2 H atoms in water only give 1 peak
The water molecule is symmetrical so they have the same frequency
What does turning on a gradient do when imaging water
It changes the magnetic field so it is smaller on the left and larger on the right
1 gradient turning on allows a 1 dimension image to be formed
What are the 3 dimensions produced by using 3 gradient coils in the bore of the MRI
Up down
Left right
In out
What is the main cause of an MRI signal appearing brighter in some places on the scan
What is another cause
Relaxation
Also some tissues have more water than others
What is relaxation
The way NMR signals decay after excitation by a pulse of radio waves
What are the 2 types of relaxation
T1 and T2
What kind of material is paramagnetic
Metal ions
What is the effect of paramagnetic materials on relaxation
A strong shortening effect on both T1 and T2
How can imaging exploit paramagnetism
Contrast agents containing Gadolinium ions can be injected into the blood stream and their presence can be images with MRI
What is fMRI and what is it used for
Functional magnetic resonance imaging
It is a method of detecting the brain’s response to different stimuli
What is the magnetism of Oxy haemoglobin and deoxy haemoglobin
Oxy - diamagnetic
Deoxy - paramagnetic
What does the paramagnetic property of deoxy haemoglobin mean
It changes the relaxation properties of the water in the blood, so MRI pulse sequences can be designed to be very sensitive to the paramagnetism caused by the deoxy Hb/ Oxy Hb ratio
What is the MRI technique that utilises the paramagnetism of the deoxy/Oxy Hb ratio
Blood oxygen Level Dependent MRI
Why does the BOLD signal follow a time lag of a few seconds
This is where neurons are processing an incoming signal from an AP
Why does blood flow increase to allow BOLD MRI
The neurons processing APs in the brain is energetically expensive so local blood flow is increased in this region to raise the amount of glucose and oxygen
Oxy Hb is in excess so the local paramagnetic signals from deoxy haemoglobin gives BOLD signal
What is PET
Position Emission Tomography is a molecular imaging technique that uses an injected tracer molecule which is radioactive and released positrons
What are positrons
Anti matter equivalents of the electron
Ie they are the same size and mass as e- but are only emitted by unstable radioactive nuclei
What happens after a position emitting nucleus has emitted a positron
Eg?
It turns into a different nucleus
F-18 decays to oxygen -18
Does the position emitting substance release positrons at a constant rate?
No it steadily decreases
Where does the positron emitting substance accumulate
In tumours but it does diffuse around the body as well
What happens when positrons are emitted
They pass through the patient’s tissue until it hits an e- (within a few mm of where the positron was emitted
What happens when a positron and e- collide
Both particles are annihilated to produce to produce 2 gamma rays that travel in opposite directions which are detected by the PET detector, showing that the source is somewhere along this straight line
This is specified as many different positrons and straight lines are produced and the cross over point is where the positrons are emitted from
Name 3 positron emitting nuclei
F-18
Carbon-11
Iodine -125
How long is F-18 half life
2 hours
What does F-18 replace when used in PET tracers
Hydrogen or OH groups
What is the most commonly used PET tracer in the clinic
Fluorodeoxyglucose
FDG
Why is FDG used as a PET tracer
It is essentially glucose just with an OH replaced by F-18
This means it can be taken up by cells and phosphorylated to fluorodeoxyglucose-6-phosphate
Which cells give a strong PET signal when FDG is used as the tracer
Cells with high levels of the glucose transporter and hexokinase
How long do you do a PET scan after injection of FDG
30-60 mins
Why can you see the general structure of different tissues in a PET scan
What are the 2 key areas that usually show up
FDG uptake is variable between tissues
Brain, bladder
Why does brain always has high signals in a PET scan
It takes up a lot of glucose to fuel thinking
Why is it difficult to use FDG for brain tumour imaging
The brain always has strong signals
What does SPECT stand for
What radiation does it use
single photon emission computed tomography
Gamma emission
What does SPECT detect
A single gamma ray emission
What nuclei are required for SPECT
Why these
How does their half lives compare to those in PET scans
Technetium-99m
Indium - 111
They are gamma emitters
Longer half lives than PET but weaker signals
What does SPECT rely on to define the direction of the line
What is the apparatus used for this called
Gamma rays passing through a narrow gap and hitting a detector some distance behind it
Collimator
How do the dimensions of the collimator effect it’s efficiency
The narrow the gap, the better the resolution but the worse the signal noise
How does SPECT detect neuroendocrine tumours
Covalent linking of In- 111 to octreotide which binds to the somatostatin receptor
This receptor is over expressed in neuroendocrine tumours
How is glucose converted to pyruvate
What happens to pyruvate now
Glycolysis
It is transferred to mitochondria and passes through the TCA cycle to fuel oxidative phosphorylation
OR
pyruvate can be converted to lactate and exported from the cell
Which are the 2 key enzyme in glycolysis do cancer cells
Upregulate
How do they do this
Hexokinase and Lactate dehydrogenase
Over expressing particular isoforms of these enzymes, often Hexokinase II and LDH-A
How is glucose transported into cancer cells
Via GLUT1 mainly
How is lactate transporter out of cancer cells
By monocarboxylate transporters (mostly MCT1 and 4)
What is the net production of ATP from glycolysis
2 per glucose
As glycolysis produces fewer ATP molecules alone than if the pyruvate went onto the TCA cycle and oxidative phosphorylation, why would the cancer cell up regulate glycolysis specifically
Lots of carbon flowing into glycolysis allows the tumour to use glycolytic intermediates to synthesise building blocks for lipid and DNA synthesis
This allows cell growth and division
What does the export of lactate from the cancer cell promote?
Invasive growth of the tumour through neighbouring tissue
What is used to stage lymphoma patients
FDG PET
Why is FDG PET good for imaging lymphoma tumours
The cancer cells are highly glycolytic and up regulate GLUT and hexokinase expression and therefore take up lots of FDG and phosphorylate it to FDG-phosphate And it is metabolically stuck here
Therefore FDG-phosphate builds up within tumours
How does FDG get metabolically stuck in tumour cells
FDG-phosphate is not a substrate for the 2nd enzyme in glycolysis so cannot progress down the glycolysis pathway
Hexokinase uses ATP to make the phosphorylation one way so won’t convert FDG phosphate back to FDG and tumour cells don’t have a lot of glucose-6-phosphatase (the usual enzyme for the reverse reaction)
Thus FDG-phosphate is stuck
Does FDG labelling work on dying tumours
No as dying tumours have low hexokinase activity and will not accumulate FDG labelling
Why can we use FDG PET fo monitor tumour response to therapy
Dead / dying tumour cells don’t accumulate FDG labelling so you can see the number of living cancer cells rather than just the size of the tumour (which may have swollen during therapy but actually many cells have died)
How can lactate dehydrogenase activity be assessed
Using MRI and hyperpolarised [1-13C] pyruvate
What is a hyperpolariser
A separate machine to an MRI that sits in an adjacent room and it can enhance normal insensitive NMR signals 10,000 times
This is called Dynamic Nuclear Polarisation
What is DNP
Dynamic Nuclear Polarisation
How is DNR achieved
By irradiating a sample, which has nuclear spin, with microwaves whole it sits at a very low temperature
This gives a v large NMR signal which will relax with the time constant T1 until the signal is almost nothing. This means very large signals will decay away over the course of seconds
Are all nuclei with spin suitable for DNP
Yes but some are better than others
What kind of pyruvate is most suitable for DNP
Why
[1-13C] pyruvate
It has a long T1 relaxation time so hyperpolarisation lasts for minutes
Its metabolic product ([1-13C] lactate) also has a long relaxation time
What is [1-13C] pyruvate
Pyruvate with a single 13-C nucleus at the first carbon
How does pyruvate enter cancer cells
Through the same monocarboxylate transporters that allow lactate out of the cell
These are generally up regulated
What does it mean if cancer cell gave up regulated lactate dehydrogenase
[1-13C] pyruvate is converted to [1-13C] lactate at a higher rate than surrounding tissue
This allows DNP to be used effectively
Why is DNP MRI often done as a dynamic series of measures
It images enzymatic conversion
What does apoptosis cause cells to do (which is useful for imaging)?
What about for necrosis
Causes cells to shrink and bud
Necrosis leads to cell swelling, leakiness and cell lysis
What does it mean if an apoptotic cell buds
It turns into an apoptotic body
What will happen to cancer cells that have been treated
How are these changes detected
It will change from a tightly packed mass of cells of a similar size to being a mixture of tiny shrunken and budding cells and large leaky cells and lysed necrotic regions
Using diffusion weighted MRI
How do water molecules move
According to Brownian motion
Molecules collide with each other constantly and move randomly
The sphere of possible positions increases with the time the water is moving
Do MRI pulse sequences use gradients to get positional information?
Yes they use varying magnetic fields caused by currents flowing in specifically shapes wire loops
What does a DW-MRI do
Uses a gradient to “label” each water molecule with a position and then a second gradient to read the new position
What is each pixel in the final image of a DW- MRI machine
An average of billions of water molecules
What would the signal on a DW MRI machine be if none of the water molecules moved in the time between the gradients
The signal would be at a maximum
If the molecules move the signal will be smaller
Why is the signal decrease of DW MRI machines calculable
Water at a known temperature is expected to have a highly predic stable diffusion speed
Why is the measured diffusion in the DW MRI sequence always less than the predicted diffusion speed
The molecules in tissues are always bumping into plasma membranes, organelles, extracellular matrix etc
What is ADC
Apparent Diffusion Coefficient how restricted the water diffusion is in tissue
How can ADC be used to measure treatment effectiveness
Will the ADC value increase or decrease
A reduced cell density will be detected after effective treatment and cell lysis will remove restrictions on water diffusion, leading so a higher ADC value
As both apoptosis and necrosis are occurring both increases and decreases are detected
If an ADC value of a tumour remains unchanged, what does it say about the therapy
Therapy is ineffective
What is the apoptotic “eat me” signal for phagocytes
Externalisation of phosphatidylserine
What is phosphatidylserine
What happens in apoptosis to them
A phospholipid that usually sits in the inner leaflet of the bilayer of the PM
They are shifted to the outer layer where they are recognised and bound by receptors on macrophages
What is Annexin V
How is it used in imaging
A protein that binds specifically to phosphatidylserine
It is covalently linked to a gamma emitting nucleus eg Tc-99m
What do you do with Annexin V -Tc-99m
Inject after her soy and the Annexin V will bind to the apoptotic cells increases local concentration
The Tc-99m emits gamma rays that are detected by a SPECT machine
How is apoptosis imaged by PET
By combining Annexin with a positron emitter eg Iodine 125
How far can oxygen diffuse
2mm
How do tumours grow new blood vessels
Using VEGF
This binds to endothelial cells and activates them to grow new blood vessels
The endothelial cels then secrete PDGF, which attracts smooth muscle cells to form
What feature if tumour vasculature allows us to image them
What technique is used
The leaky quality
MRI
What perfusion contrast agents are used to image tumour vasculature
Gadolinium ion chelates in MRI
Give 5 facts about Gd ion chelates that Make them appropriate for MRI
They bind to Gd tightly so free toxic Gd is not released into the body
They are water soluble so can be cleared by the kidney within hours
They are not transported into cells so remain in the blood or ECF
They cross the ECF faster in regions of leaky vasculature
Gd ions are paramagnetic meaning MRI pulse sequences can exploit its relaxation to make it appear bright
Are blood vessels equally permeable across the body to large molecules
No
They are v impermeable in the brain thanks to the blood brain barrier
What is used to diagnose aggressive brain tumours
How can we see if it worked
Contrast Enhanced MRI which images the break down of the blood brain barrier
Prevention of angiogenesis shows reduced CE MRI signal
What is used in anti angiogenic therapy
How does it work
Bevacizumab
Binds to VEGF-A to stop the growth factor binding to the receptor on endothelial cells
What is TTP
Time to progression
They were free from a worsening of their condition for longer
Does Magnetic resonance require ionising radiation
No
