Sunday 16th December
Dr Martin Christlieb Gray Institute for Radiation Oncology and Biology, firstname.lastname@example.org Oxford Biomedical Imaging Network
Modern medical imaging
The oncology group at Oxford has just had its second birthday and it was set up in response to the NHS’ need for research into cancer.
The group consist of 450 people and only a tiny minority of these are medical doctors. The research is not about today’s medicine but tomorrow’s treatment.
The department has its own LINAC in the basement of the building which was built “in-house”. This why there is a need for physicists and engineers in the department.
Chemists, biologists and mathematicians are also required.
The picture above appears to be showing a woman smoking, but what is the evidence? She is only holding a cigarette. This is why a video is more important as it gives dynamic information.
The picture above is an X-ray of Roentgen’s wife’s hand. How can we tell it is actually an adult, married woman’s hand? We have to make assumptions.
The gold shows up because it scatters X-rays. It is not to do with biology.
The above picture is of the eastern end of Oxford taken from 10,000ft. Could you use it to get about? Could we use it to identify a hospital that has an A&E department? We need a dynamic map such as Google Earth for this.
Combining functional information and anatomy information gives us more information.
Magnetic resonance imaging has gained six Nobel prizes.
•Otto Stern, USA: Nobel Prize in Physics 1943, “for his contribution to the development of molecular ray method and his discovery of the magnetic moment of the proton”
•Isidor I. Rabi, USA: Nobel Prize in Physics 1944, “for his resonance method for recording the magnetic properties of atomic nuclei”
•Felix Bloch, USA and Edward M. Purcell, USA: Nobel Prize in Physics 1952, “for their discovery of new methods for nuclear magnetic precision measurements and discoveries in connection therewith“
•Richard R. Ernst, Switzerland: Nobel Prize in Chemistry 1991, “for his contributions to the development of the methodology of high resolution nuclear magnetic resonance (NMR) spectroscopy
•Kurt Wüthrich, Switzerland: Nobel Prize in Chemistry 2002, “for his development of nuclear magnetic resonance spectroscopy for determining the three-dimensional structure of biological macromolecules in solution”
•Paul C. Lauterbur, USA and Peter Mansfield, United Kingdom: Nobel Prize in Physiology or Medicine 2003, “for their discoveries concerning magnetic resonance imaging”
MRI machines make use of the fact that body tissue contains lots of water, and hence protons (1H nuclei), which get aligned in a large magnetic field. Each water molecule has two hydrogen nuclei or protons. When a person is inside the powerful magnetic field of the scanner, the protons becomes aligned with the direction of the field. This causes the protons to produce a rotating magnetic field detectable by the scanner—and this information is recorded to construct an image of the scanned area of the body. Magnetic field gradients cause protons at different locations to move at different speeds, which allow spatial information to be recovered using Fourier analysis of the measured signal. By using gradients in different directions 2D images or 3D volumes can be obtained in any arbitrary orientation. MRI provides good contrast between the different soft tissues of the body, which makes it especially useful in imaging the brain, muscles, the heart, and cancers compared with other medical imaging techniques such as computed tomography (CT) or X-rays. Unlike CT scans or traditional X-rays, MRI does not use ionizing radiation.
MRI Field gradients
Magnetic resonance angiography (MRA) generates pictures of the arteries to evaluate them for stenosis (abnormal narrowing) or aneurysms (vessel wall dilatations, at risk of rupture). MRA is often used to evaluate the arteries of the neck and brain, the thoracic and abdominal aorta, the renal arteries, and the legs (called a “run-off”). A variety of techniques can be used to generate the pictures, such as administration of a paramagnetic contrast agent (gadolinium) or using a technique known as “flow-related enhancement” (e.g. 2D and 3D time-of-flight sequences), where most of the signal on an image is due to blood that recently moved into that plane, Gadolinium is used because it can lose three electrons (3+ cations) and become paramagnetic. This means it has magnetic properties in the presence of an external magnetic field (it loses its magnetism when the magnetic field is removed). During the MRI process the magnetic field of the gadolinium and the scanner intermingle. This hi-lights the blood flow giving dynamic information about the blood flow.
Dr Niki Sibson is a neuroscientist who uses MRI and biology to find brain tumours.
In MRI images bright areas contain water. To make MRI less frightening to the public the group use MRI to play a game called “guess the fruit”
Can you guess what they are? I’m afraid I’ve forgotten.
But seriously —
The image above right uses MRI to show up the tumour. It shows up because the tumour breaks up blood vessels. In reality a tumour the size of a small marble is too big. Tumours generate inflammation which helps to show it up.
Target-specific binding of contrast agent
Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumours, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. A targeted MRI contrast agent based on microparticles of iron oxide has been developed that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1).
Early detection of brain metastases using Molecular MRI
Scientists at the Gray Institute for Radiation Oncology and Biology develop first snap shot of tiny brain tumours.
When cancer is diagnosed, we sometimes find that it has spread round the body to form new colonies called metastases. When new colonies form in the brain this can be dangerous because they are rarely detected at a stage when they can be treated effectively and life expectancy once diagnosed is generally only a few months.
Magnetic resonance imaging (MRI) is widely used for diagnosing brain cancer, but it can only see the metastases when they reach about 1 cm in diameter. This means a tumour about the size of a small marble. The problem with the current scans is that they use a magnetic dye that can only highlight the tumour when the tumour has done considerable damage to the blood vessels. This damage allows the magnetic dye to leak into the tumour and stain it in the MRI image. It takes the tumour maybe 6 months to do enough damage to the blood vessels to allow the dye to leak out. This is 6 months during which we could be treating the tumour.
Scientists at the Gray Institute in the Department of Oncology of the University of Oxford are developing an MRI scan that may help detect brain metastases before any damage is done to blood vessels. Dr Niki Sibson and her team have found a technique that should allow us to detect brain metastases when they are less than a millimetre in size, roughly the size of a single grain of fine sugar. Detecting tumours when they are this size could make all the difference in the world to our ability to treat them successfully.
Dr Sibson’s new method relies on the fact that when tumours start to grow in the brain they cause the nearby blood vessels to make a protein called VCAM-1. This protein sticks out of the blood vessel walls into the blood stream. The team have taken tiny balls of iron oxide (rust) and coated them with an antibody that sticks to VCAM-1 and only to VCAM-1. The balls of rust are eight times smaller than a red blood cell. When these particles are injected into a patient they will travel with the blood until they find a blood vessel with VCAM-1 proteins coating the walls. The particles will stick to the proteins and the iron oxide creates a signal change (low magnetic field) that the MRI scanner can detect and produce an image.
The beauty of this approach is not only that it should detect brain tumours very early while they are still treatable, but also that it will work on existing hospital scanners; so there should be no need to replace current equipment.
This exciting research has been published in the journal Proceedings of the National Academy of Sciences USA (Serres et al., Proc.Natl. Acad. Sci. USA 2012) and is the subject of a CR-UK press release dated Monday 26th March 2012.
The three dark spots on the above picture on the left are iron oxide. This method allows tumours as small as 100 micrometres to be seen. There is one problem however and that is it is hard to distinguish tumours from other problems such as strokes. A second problem is that brain tumours tend to be secondary so by the time the brain tumour is diagnosed there could be considerable problems in the body elsewhere.
Image of protein manufacture gives a dynamic image.
As of 2010 there are now ten common characteristics of cancer.
Nuclear medicine PET
http://en.wikipedia.org/wiki/Positron_emission_tomography http://en.wikipedia.org/wiki/Fluorine-18 http://en.wikipedia.org/wiki/Positron_emission http://en.wikipedia.org/wiki/Copper-64 http://en.wikipedia.org/wiki/Half-life http://en.wikipedia.org/wiki/Biological_half-life
Fluorine 18 is a radioisotope of fluorine and is an important source of positrons (decays by positron emission). It has a half-life of about 110 minutes. It is an important isotope in the radiopharmaceutical industry, and is primarily made into fluorodeoxyglucose (FDG) for use in positron emission tomography (PET scans). Malignant tumours have a greater up-take of FDG.
When the positron (antimatter) comes into contact with matter annihilation occurs and gamma radiation is produced. In fact two gamma photons are produce to conserve linear momentum. The reason why there isn’t an angle of 180 degrees between the photons (actually 178.8 degrees) is because of the original movement of the positron. Copper 64 can also be used but its half-life is longer at about 13 hours.
When considering this sort of imaging you have to consider the biological half-life as wells as the radioactive half-life. The biological half-life or elimination half-life of a substance is the time it takes for a substance (for example a metabolite, drug, signalling molecule, radioactive nuclide, or other substance) to lose half of its pharmacologic, physiologic, or radiologic activity,
Zr89 is a radioisotope of zirconium with a half-life of 78.41 hours. It is produced by proton irradiation of natural yttrium-89. Its most prominent gamma photon has energy of 909 keV and is also employed in positron emission tomography imaging, for example, with zirconium-89 labelled antibodies (immuno-PET).
A ring of gamma cameras pick up the gamma photons (each photon has energy of 511 keV). Having a low resolving time (6nS) localises the event better.
The main source of error is the positron distance travelled.
The raw data collected by a PET scanner are a list of ‘coincidence events’ representing near-simultaneous detection (typically, within a window of 6 to 12 nanoseconds of each other) of annihilation photons by a pair of detectors. Each coincidence event represents a line in space connecting the two detectors along which the positron emission occurred (i.e., the line of response (LOR)). Modern systems with a higher time resolution (roughly 3 nanoseconds) also use a technique (called “Time-of-flight”) where they more precisely decide the difference in time between the detection of the two photons and can thus localize the point of origin of the annihilation event between the two detectors to within 10 cm.
Coincidence events can be grouped into projection images, called sinograms. The sinograms are sorted by the angle of each view and tilt (for 3D images). The sinogram images are analogous to the projections captured by computed tomography (CT) scanners, and can be reconstructed in a similar way. However, the statistics of the data are much worse than those obtained through transmission tomography. A normal PET data set has millions of counts for the whole acquisition, while the CT can reach a few billion counts. As such, PET data suffer from scatter and random events much more dramatically than CT data does.
During the lecture we carried out an activity that mimicked the process of image reconstruction.
The idea is to use the coordinate data (a line is drawn from coordinate 1 to coordinate 2 for each set of data) and look for the greatest concentration of crossed lines. This is the most likely position of the tumour.
Tumour hypoxia is the situation where tumour cells have been deprived of oxygen. As a tumour grows, it rapidly outgrows its blood supply, leaving portions of the tumour with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic tumour cells are usually resistant to radiotherapy and chemotherapy, but they can be made more susceptible to treatment by increasing the amount of oxygen in them. Bioreductive prodrugs also play a significant part in dealing with these kinds of cells: they can kill the oxygen-deficient tumour cells selectively as hypoxic cytotoxins. The study of tumours in such conditions was pioneered by Dr L. H. Gray.
Niacinamide, the active form of vitamin B3, acts as a chemo- and radio-sensitizing agent by enhancing tumour blood flow, thereby reducing tumour hypoxia. Niacinamide also inhibits poly (ADP-ribose) polymerases (PARP-1), enzymes involved in the re-joining of DNA strand breaks induced by radiation or chemotherapy.
Professor Gouveneur researches fluorine chemistry. A major spin-off avenue of research resulting from her activities is the preparation of [18F]-labelled radiopharmaceuticals suitable for Positron Emission Tomography (PET), a non-invasive diagnostic tool enabling the study of biochemical and physiological processes. With a half-life of circa 110 min [18F], it is critical to develop radiochemical methods featuring late introduction of the [18F] substituent within the tracer. This chemistry is designed with the aim of using PET to accelerate drug development. She is also working on the synthesis of new tracers to image hypoxia. This project is driven by the clear need in cancer treatment for a non-invasive imaging assay that evaluates the oxygenation status and heterogeneity of hypoxia and angiogenesis in individual patients. Hypoxia imaging brings in information different from that of the commonly use FDG-PET and could therefore play an important role in oncologic imaging. This specific project is carried out in collaboration with Professor John R. Dilworth (Oxford, ICL). On the 24th January 2007, a new radiochemistry laboratory equipped to handle PET and gamma emitting radioisotopes was officially opened with all the necessary equipment to carry out the synthesis of known and novel tracers.
We then carried out another activity – chemical kinetics.
This was designed to show the problem with making the desired chemical if it has a short half-life.
It might take two hours to make a chemical using a chemical with a half-life of twenty minutes so you design a chemical synthesis that puts the radioisotope in at the last minute.
Some reactions can take 18 hours. The chemistry beats radioactivity at the start. The red line is radiochemical yield. 23% yield is the theoretical maximum. Need to make chemistry work faster. Boost it to 50% (this is ten times the speed of radioactivity).
Activity – image reconstruction
Each group of people had ten dice (each one representing one mole of glucose). Each time the dice were thrown the dice with six facing uppermost went to the tumour (the other dice went temporarily onto the other spaces). The body burns glucose but the tumour is highly metabolic so eventually, in this game, you end up with nine dice in the tumour (maybe all ten) and one in the blood.
Patients are kept in a dark room to reduce metabolism.
Picturing glucose take up is a way of finding the tumour so it should, in principle be a means of giving treatment.
The size of the tumour is not important but the chemistry is.
Different tumours could be identified by different glucose uptakes. So treatment should be different.
The liver is very difficult to image due to all the processes going on in it.
At the moment there isn’t specific treatment for each type of tumour.
Dr. Julia A. Schnabel is a University Lecturer in Engineering Science (Medical Imaging) at the University of Oxford, and the Engineering
Fellow at St. Hilda’s College, Oxford. Her research area is in (bio) medical image analysis, in particular nonlinear image registration and motion tracking, image segmentation, and statistical and biomechanical shape and deformation analysis. Some clinical applications she is currently interested in are cancer imaging, perinatal monitoring, and neurodegenerative diseases. Julia has published over 150 international journal articles and peer-reviewed conference papers, is an invited Associate Editor for Medical Physics, on the Editorial Board of Medical Image Analysis, Associate Editor for IEEE Transactions on Medical Imaging, and on the scientific review committee for most major medical imaging conferences and journals.
Unfortunately we ran out of time with this lecture so I can’t really tell you how maths can help in the battle against cancer.
I am hoping that Dr Christlieb may be able to visit our school and explain the work of his research group.
The wonderful world of lasers
Professor Robert Taylor
Department of physics University of Oxford
Since its invention in the early sixties the laser has become one of the most useful optoelectronic devices on the planet.
In this lecture, Professor Taylor traced the history of the laser, talked about how it is exploited today and discussed the various types now used and how they work. A range of lasers were demonstrated during the talk.
Optics is involved in all areas of physics. It is important even at CERN where lasers are used to calibrate the cylinder lengths (distance = speed of laser light x time).
A laser produces coherent, intense radiation in a well-defined beam. Laser stands for Light Amplification by the Stimulated Emission of Radiation. It has uses in: physics research; medicine (skin treatment and surgery); welding and cutting; telecommunications; fusion research; discos; displays; war.
All telescopes now use fibre optics.
Quasi-continuous wave laser diode arrays courtesy of Spectra diode labs.
What is a laser?
It is a device that generates and amplifies electromagnetic radiation (e.g. microwave, IR, visible, UV or X-ray!)
Essential elements are:
(i) Laser medium is made of atoms, molecules, ions or a semiconductor.
(ii) Pumping process to excite these atoms into higher energy levels.
(iii) Suitable optical feedback elements to allow a beam of radiation to bounce back and forth repeatedly through the laser medium.
The laser medium
Electrons in atoms exist in well-defined energy levels. In order to achieve lasing a population inversion is necessary.
A negative temperature gradient is necessary to make the laser work.
Wiggling electrons can produce light of different wavelengths.
Fourier theory gives an uncertainty of an order of 1. Not emitting light from the excited or ground state but both. This is a complicated state. 1nS or 1xE9 Hz. Three or four energy levels are needed to make the laser work.
To produce the required population inversion for laser activity, atoms or molecules must be selectively excited to specific energy levels. Light and electricity are the excitation mechanisms of choice for most lasers. Either light or electrons can provide the energy necessary to excite atoms or molecules to selected higher energy levels, and the transfer of energy is not required to directly promote electrons to a specific upper level of the laser transition. Some approaches can be rather complex, but these often produce better-performing lasers. One frequently utilized approach excites an atom or molecule to a higher energy level than required, after which it drops to the upper laser level. Indirect excitation can be employed to excite atoms in a surrounding gas mixture, which then transfer their energy to the atoms or molecules responsible for producing the laser action.
Professor Taylor showing green and blue laser light. The light becomes visible in the liquid because of scattering.
Before we can explore the question of what is optical feedback we need to answer more fundamental questions about light itself.
What is light?
How can we control it?
Why is the laser beam do well-defined?
What is coherence?
How do we achieve feedback?
The History of light part 1
Earliest reference to a mirror is in Exodus chapter 38 verse 8. It was used in Egypt and made of copper.
Greeks did a lot of work on light. The law of reflection was known by Euclid (300 B.C.E) and published his work in his book called Catoptrics.
The “Burning Glass” or positive lens was alluded to by Aristophanes in his comic play The Clouds (424 B.C.E)
Romans used magnifying glasses in their art work and for kindling fires.
Francis Bacon (1215-94) initiated the idea of using lenses for correcting vision and understood how rays passed through a lens.
In 1608 Hans Lippershey applied for a patent on the telescope and Galileo used it to discover Saturn’s rings in 1610.
The History of light part II
Willebrord Snell discovered the law of refraction in Leyden in 1621.
Newton (1642-1727) decided to do many experiments to investigate the nature of light. He wanted to find out whether it was corpuscular or a wave. At 23 he began working on prisms: “I procured me a triangular glass prism to try therewith the celebrated phenomena of colours”.
Newton concluded that light was made up of corpuscles of various colours – not waves. Huygens in Holland disagreed, and thus began a debate which ran for many years.
n(high) sin i = n(low) sin r
when r = 90 degrees, sin r = 1 and n(low) = 1 for air
so sin i/n(high) = 1/1.33 = 0.7519 therefore I = 48.75 degrees.
The top picture on the right is Professor Taylor looking at refracted laser light reaching the ceiling.
Professor Taylor is demonstrating both reflection and total internal reflection using blue and green lasers.
The History of light part III
Wave theory was reborn by Thomas Young in 1803 and he introduced the principle of interference. However his contemporaries weren’t convinced. The Edinburgh Review said his work was “Destitute of every species of merit”!
Augustin Fresnel (1788-1827) finally revived the wave theory in Paris. He put it on a mathematical basis and calculated diffraction patterns from various obstacles.
James Clark Maxwell (1831-1879) unified light and electromagnetism with his great (but scary!!) work on what became known as “Maxwell’s equations” (very, very scary!!!)
In 1818 Fresnel predicted, in a paper entered in a competition run by the French Academy, that if light was a wave, then divergent light from a source would bend or “diffract” around an object such as a sphere, a circular aperture or a straight edge. Poisson was one of the judges, who was vehemently opposed to the wave theory. He predicted from Fresnel’s paper that a white spot would appear in the shadow of a circular object – he cited this as proof of Fresnel’s wave theory! Arago, another one of the judges went away and verified the prediction experimentally, vindicating Fresnel and proving that light was indeed a wave phenomenon.
If you look very carefully you can just make out the diffraction pattern around the image on the ceiling.
Above is the diffraction pattern from a circular aperture. There is the central bright spot with bright sections (and dark gaps) either side.
Rayleigh scattering is more obvious in the forward direction.
Divergence and spot size gives the characteristic resolution.
The laser an ionise air. Curved mirrors are better than plane mirrors.
The YAG laser and frequency doubling.
On the bench was a set of mirrors. A diode pump laser and a Yag (yttrium aluminium garnet) crystal as a gain medium.
By using a non-linear crystal I Professor Taylor mixed two infra-red photons at 1064 nm to produce one green photon of twice the energy and therefore half the wavelength at 532nm.
We were able to see the transverse laser modes on the screen as the mirror was adjusted.