Ionizing radiation in medical diagnostics, material analysis and radiotherapy of cancer

3. Applications of ionizing radiation
- nuclear and radiation methods -
3.1. Nuclear and radiation methods
3.2. X-ray diagnostics
3.3. Radiation measurement of mechanical properties of materials
3.4. Radiation analytical methods of materials
3.5. Radioisotope tracking methods
3.6. Radiotherapy
3.7. Technological use of radiation

3.1. Nuclear and radiation methods - general properties
In this chapter we will try to give a brief overview of radioisotope measurement methods and applications of ionizing radiation in various fields of science and technology, health care, industry, ecology, etc. Before we discuss specific radiation methods, we will mention some common characteristics of these methods.
Note + apology: The application methods of ionizing radiation are discussed here from a physical point of view, without details of technical solutions, rather than from the point of view of individual special fields of application; the exceptions are methods of X-ray diagnostics, radiotherapy and especially nuclear medicine (where reference is made to a detailed and complete explanation - Chapter 4 " Radioisotope scintigraphy "). I therefore ask for the leniency of experts for specific methods, when they do not find a some technical or medical aspects for practical use in their field; I also apologize for any inaccuracies and excessive simplifications in these aspects. I focus here mainly on the interpretation of the physical nature.
  Radioisotope and radiation methods have some important advantages :

• Nuclear processes are practically independent of the usual external conditions (see §1.2, section "General laws of atomic nucleus transformation") such as temperature, pressure, humidity, etc.
• Radiation can penetrate even to places otherwise inaccessible. Methods based on penetrating gamma radiation enable non-contact measurement "remotely", without the need for sampling, in otherwise inaccessible places, non-destructive and non-invasive measurement of processes within the organism, etc. The same is true for non-destructive radiation influencing events in inaccessible places - eg radiotherapy (§3.6).
• Some radiation methods are characterized by very high sensitivity (eg neutron activation analysis).
• Virtually all nuclear and radiation methods use electronic radiation detection. When detecting radiation, the measured quantities are converted into electrical signals that can be efficiently and precisely processed by electronic methods, including digital computer evaluation.

In addition to higher technical and cost demands, a certain disadvantage of radiation methods may be the risk of harmful effects of ionizing radiation on materials and human health; however, this risk can be eliminated or minimized by ensuring appropriate radiation protection - see Chapter 5 "Biological effects of radiation - radiation protection".

Does the material glow or not after the application of radiation?
This is a frequently discussed issue, especially in the general public. It is argued that "During irradiation, a given object (including possibly the human body) absorbed radiant energy - and this energy should then be gradually radiated back ! ". In the vast majority of common applications of radiation, this seemingly logical argument is flawed. Photon radiation, X and gamma, passes through a substance at the speed of light (corpuscular radiation only a little slower) and from the moment it leaves the substance it no longer occurs in it. The radiation "does its job" in the substance and then immediately disappears. Only physico-chemical (or later biological) effects of radiation can persist :
¨ When irradiated with X, g, b radiation with energies less than about 10MeV, excitations and ionizations of the atoms of the irradiated substance occur, accompanied by secondary radiation and possibly chemical radiation effects. Thus, during exposure, the irradiated object emits secondary radiation, the intensity of which represents a fraction of a percentage of the intensity of the primary beam. After the end of the radiation flow, deexcitation and recombination of atoms occur almost immediately (within about 10^-8 sec.) and the substance then does not radiate at all. This radiation behaves like light to a certain extent: when we stop the irradiation ("go out"), the radiation immediately disappears (it is "dark"). Thus, the patient does not shine after X-ray examination or after normal radiotherapeutic irradiation of gamma or X, does not shine objects after X-ray fluorescence analysis or defectoscopy, does not shine materials after radiation sterilization.
¨ A more complex situation can occur with irradiation with neutron radiation (even at low energies - slow neutrons) and in general with high-energy radiation, the quantum of which has an energy higher than about 10MeV. In this case, the radiation can cause nuclear reactions, in which radionuclides can be formed in originally non-radioactive materials. Such a substance may "glow" for some time after irradiation. Not because "accumulated energy" is emitted, but because nuclear activation has taken place in material. Thus, the samples glow after neutron activation analysis, targets irradiated in nuclear reactors and accelerators glow strongly, weakly and for a short time also patients after radiotherapy with radiation higher than 10MeV, more significantly after hadron radiotherapy (see §3.6 "Radiotherapy", part "Hadron radiotherapy"). And, of course, patients shine after the application of a radioactive substance to the body in nuclear medicine - not by radiating some absorbed energy, but by the lingering radioactivity accumulated in the organism. The intensity of this radiation decreases exponentially with the rate given by the half-life of the used radionuclide and the rate of its excretion from the body.

Types of radiation methods
For applications of ionizing radiation, both closed emitters are used - X-ray, closed radioisotope, particle accelerators, as well as open emitters - radioactive liquids, gases or aerosols. All applications of ionizing radiation can be divided into two basic groups :

1. Radiation measuring, analytical and detection methods
This large group of methods uses the properties of ionizing radiation to measure certain physical and technical quantities, to analyze the properties of substances and to study and detect certain processes in natural and industrial systems or in living organisms (see also section "Introskopy" below).
  In terms of the nature of primary and secondary radiation, as well as the relative position of the radiation source, the analyzed object and the detector, these methods can be further divided into four groups :

• a) Absorption transmission measurements
  A significant group of applications of ionizing radiation is based on measuring the absorption of radiation in substances, mostly penetrating electromagnetic radiation X and gamma, less often also corpuscular radiation. The examined object is located between the radiation source and the detector - it is shines through, while the detector measures the attenuation of radiation or a change in its spectrum as it passes through the analyzed object - Fig.3.1.1a. These methods can be used to measure and monitor material thickness and density, liquid level, gas mixture composition, detect the presence of smoke, monitor humidity, etc. The most important methods of this kind are X-ray diagnostics in medicine and defectoscopy in the industrial area.

Fig.3.1.1. Geometric arrangement of the radiation source, the analyzed or irradiated object and the detector in various applications of ionizing radiation.
a) Transmission measurements of radiation absorption. b) Scattering and fluorescence measurements. c) Emission radiation measurement. d) Measurement of radioactive samples. e) Radiation irradiation of objects.

• b) Scattering and fluorescence measurements
  In these methods, the radiation source and the detector lie in the same "half-space" with respect to the measured sample - Fig.3.1.1b. We irradiate the analyzed object with the primary radiation source and use the detector to measure the secondary radiation generated in the sample by appropriate physical mechanisms - Compton scattering or the formation of characteristic X-rays due to the photoeffect. In addition to some less commonly used methods of measuring thickness or density by means of radiation scattering, this mainly includes X-ray fluorescence analysis and X-ray diffraction crystallography.
  Note: This method of measurement is sometimes referred to as "reflection". However, this is misleading, as no laws of geometric optics (such as the law of reflection or refraction) apply to the interaction of ionizing radiation. Only scattering, absorption and re-emission (fluorescence) of radiation occur.
  
• c) Emission radiation measurements
  For emission radiation methods, we do not have an external emitter, because the source of radiation is the examinated object itself, which is radioactive, Fig.3.1.1c. Radioactivity is either introduced (applied) into the examined object in the form of a radioindicator (tracking methods, nuclear medicine - scintigraphy), or it is induced inside the object by irradiation with suitable radiation, which causes nuclear reactions in the sample nuclei, in which the initially inactive nuclei turn into radioactive ones (this is the case with activation analysis, especially neutron activation analysis).
  
• d) Measurement of radioactive samples
  taken from irradiated materials or substances with applied radioactivity - Fig.3.1.1d. This includes tracking methods in biology and medicine (nuclear medicine) or neutron activation analysis.
  Sample measurements are sometimes combined with other nuclear and radiation methods, as indicated by the arrows between Figures 3.1.1c, d, e. E.g. during dynamic scintigraphy of the kidneys (which is the emission method according to Fig.3.1.1c) blood samples are taken and measured to determine the glomerular filtration of the kidneys (see §3.4 "Dynamic scintigraphy of the kidneys" in the book "OSTNUCLINE - mathematical analysis and evaluation of scintigraphic studies").

Introscopy
Radiation measuring, analytical and detection methods belong to a wider field, sometimes called introscopy (Latin intro = inside , Greek scopeo = observation ; literally "looking inward") - non-destructive examination of the internal structure of objects and the processes taking place in them, using physical methods: sound waves (including ultrasound), electromagnetic field and electromagnetic waves (light - eg classical endoscopy in medicine, radio waves, UV, X and g-radiation - nuclear medicine), fluxes of elementary particles (accelerated electrons, protons, neutrons, heavier ions). These methods are used mainly in medicine (from classical stethoscope, through optical endoscopy to ultrasound sonography, X-ray diagnostics and gammagraphy), but also in a number of scientific and technical and industrial applications (defectoscopy, activation analysis, X-ray fluorescence analysis and more). All of these methods, when using ionizing radiation or nuclear physics methods, will be described in more detail below.

2. Radiation irradiation and technological methods
Here, the energy transferred to the substance during irradiation is used - Fig.3.1.1e, ionization of substances and subsequent physical, chemical and biological effects of ionizing radiation in the irradiated object. In the field of medical applications, this includes radiotherapy, industrial applications include some radiation-technological processes in chemistry (such as polymerization), sterilization of materials, production of radionuclides.

  The following paragraphs (§3.2-§3.7) will describe individual specific methods of ionizing radiation application, some briefly (industrial applications), others in detail (X-ray diagnostics, radiotherapy; in a special reference to a separate chapter 4 "Radionuclide scintigraphy" dedicated to methods of nuclear medicine).

Collimation of ionizing radiation
In the vast majority of processes of ionizing radiation, this radiation is emitted almost isotropically in all directions *).
*) Exceptions are the interactions of high-energy particles, where due to the relativistic laws of conservation of momentum, the resulting particles and radiation are kinematically directed (collimated) in the direction of motion of primary high-energy particles.
  However, we often need to direct the radiation to a certain angle, or to concentrate it in a certain place; radiation in other directions can be undesirable - disruptive or even harmful and dangerous. This routing, or collimation of radiation, can be performed in two basic ways :
¨ Electromagnetic collimation of charged particles
In the case of corpuscular radiation of charged particles, suitable direction - collimation - can be achieved by the action of electric and magnetic fields, which exert a force on the charged particles. This deflects the direction of movement of the particles (beam), which can be directed to the desired location.
¨ Mechanical absorption collimation of radiation
However, a simpler way, which works both for charged particles and for g and X radiation, is to use collimators.  A collimator is a mechanical and geometric arrangement of materials absorbing a given type of radiation, that transmits only radiation from certain desired directions (angles), while absorbing and retaining radiation from other directions *).
*) However, such absolutely sharp collimations cannot always be achieved in practice. For the case of penetrating high-energy radiation gamma, partial cross-radiation trought the shielding occurs at the peripheral edges of the collimator, in which creates a kind of "half-shadow" ("penumbra") in the edge parts of the collimated beam.
  Collimators are used in virtually all applications of ionizing radiation. Most of them are simple collimators in the shape of various tubes or orifices (as shown in a simplified way, for example, in Fig.3.1.1). Intricately configured collimators then play a key role especially in scintigraphy (imaging collimators with a large number of holes - §4.2 "Scintillation cameras", part "Collimators"), in X-ray diagnostics(§3.2 "X-ray diagnostics") and in radiotherapy (eg multi-lamellar MLC collimators - §3.6 "Radiotherapy", passage "Modulation of irradiation beams").
Electronic collimation of radiation
In some special detection and imaging systems, another method of directional radiation selection, so-called electronic collimation, is used without the use of a mechanical collimator. It is based on the specific behavior of quantum ionizing radiation in the detection system - the propagation of pairs (or more) of quantums in certain precisely given directions, their coincident detection by a system of a number of detectors and subsequent positional and angular reconstruction of the direction of quantum propagation. This analysis makes it possible to select for further processing only those quanta of radiation that have the desired direction - to perform electronic collimation and display the distribution of radiation in a given field. The electronic collimation method is used in positron emission tomography PET (see §4.3 "Tomographic cameras, part "PET cameras") and in some complex detection systems such as ring imaging Cherenkov RICH detectors (see ....), trackers and muon detection systems for accelerators (see §2.1, section "Arrangement and configuration of radiation detectors").

Imaging using radiation - radiography
The very concept of imaging is based on the ability of our eyes to perceive light, its intensity, wavelength and spatial distribution, from which we create basic ideas about the shapes, size and placement of objects in space. If we want to get an objective idea of an object, its structure, changes and processes taking place in it, the most clear is to obtain the relevant data in pictorial form. This applies to an inanimate object, a living organism, the human body, or perhaps a distant galaxy in universe. This imaging is performed by visualizing the physical fields with which the examinated object interacts, or which brodcasts. That is, by means of various types of radiation, with which we irradiate the object, or which the object itself emits. The transmitted, reflected, scattered or emitted radiation is detected by suitable position-sensitive detectors, which display the spatial distribution of the radiation field (or its planar projections) and possibly also its other properties (especially the energy of quantum radiation) - see §2.1 "Methodology of ionizing radiation detection".
  Radiography is the collective name for measuring quantity and displaying distribution radiation from studied objects that emit radiation either primarily, or secondarily when they are irradiated from external radiation sources. This imaging is performed using photochemical manifestations in photographic emulsions, fluorescence of luminescence of screens and especially physical processes in electronic imaging detectors. This includes a number of methods from the fields of X-ray diagnostics, radiation defectoscopy, gammagraphy (scintigraphy) using radiopharmaceuticals. Imaging methods using different types of radiation are discussed below.
   About the X-ray image in the following §3.2 "X-rays - X-ray diagnostics" (including the appendix "X-ray telescopes"). Autoradiography - photographic imaging of the distribution of the beta-radioindicator in the examined preparations in close contact of the photographic emulsion with the sample is described in §2.2 "Photographic detection of ionizing radiation", passage "Autoradiography". Gamma-ray imaging is discussed in detail in Chapter 4 "Radionuclide Scintigraphy", especially for applications in nuclear medicine (however, there are also brief methods for g- imaging from space - gamma-telescopes, "High-energy gamma cameras").
  In addition to the visual observing and evaluating the thus obtained image is often also important mathematical analysis of the images, either static (filtering, comparing data from different locations of images or between various images) or dynamic (evaluation and quantification of temporal changes in different parts of the image reflecting the dynamics of the respective processes in displayed object); these aspects are discussed in detail for the field of scintigraphy in §4.7 "Mathematical analysis and computer evaluation in nuclear medicine".

3.2. X-radiation , X-ray diagnostics
The oldest, most widespread and still probably the most important application of ionizing radiation is X-ray diagnostics (rtg diagnostics, often also called radiodiagnostics, popularly called "x-raying"). From a physical point of view, we will here discuss the instrumentation and methods of X-ray diagnostics :

Discovery of X-radiation
In the last decades of the 19th century, a number of researchers have experimented with high-voltage electric discharges in dilute gases. The so-called cathode rays were discovered , which were later found to be fast-moving electrons (see also §1.1, section "Structure of atoms"). These experiments with discharges in the cathode ray tube were also performed in 1895 by W.C.Röntgen in a laboratory in Würtzburg. In the darkroom, he observed the fluorescence caused by cathode rays on luminescent screens. He tried to cover the cathode ray tube with black paper and found that the luminescent screen glowed as it approached even the tube thus covered; even when he inserted a thick book between the tube and the screen. Only when he placed a metal object between the tube and the screen, did a shadow appear on the screen. And as he accidentally placed his hand between the cathode ray tube and the screen, faint outlines of bones appeared on the screen. It was clear that unknown penetrating rays is emitted from the cathode ray tube - the "X- rays", as Roenrgen called them (letter X as a symbol for something unknown - an unknown variable in mathematics, an unknown person in a detective story). This radiation can penetrate trought paper and fleshy tissue, but metal objects and bones are "opaque" to this radiation. Furthermore, Roentgen found that this radiation caused the blackening of the photographic plate.

Discovery of X - radiation . Left: Laboratoy of W.C.Röntgen in Würtzburg. Middle: Röntgen shows off its X-rays. Right: X-rays were independently of Röntgen at the same time discovered also by H.Jackson and A.A.Campbell-Swinton, but they did not deal with medical applications.

Immediately after his discovery of penetrating radiation emanating from the cathode ray tube in 1895, Roentgen himself took the historically first X-ray image on a photographic plate, namely his wife's hand (Fig.3.2.1 on the right, even with a ring). Both Roentgen and other physicians have been aware from the beginning of the great importance of newly discovered radiation for medicine. Roentgen thus became the first radiologist...
  Roentgen and other researchers initially thought, that penetrating radiation originated in the diluted gas of the cathode ray tube. In further experiments it was shown, that the source of X-rays is not the discharge in the gas itself; this ionization only supplies the electrons, that are accelerated and their impact on the anode excite the braking X-rays. The removal (exhaustion) of gas and the use of a hot cathode emitting of electrons will increase the efficiency of X-rays - vacuum X-ray tubes have developed over the course of several decades (described in detail below).
Note: A brief reflection on the extent to which the discovery of X-rays was the result of chance or methodological procedure, is given in §1.0 "Physics - fundamental natural science", passage "Significant scientific discoveries - chance or method?".

Fig.3.2.1. The principle of X-ray diagnostics.
Left: Basic principal scheme of X-ray imaging. Middle: X-ray spectrum emitted from the the X-ray tube (filtered).
Right: The first X-ray image taken by Roentgen himself - his wife's hands even with the ring (according to other sources, it was perhaps the hand of his friend Prof. of anatomy A.Koelliker..?..).

Origin and properties of the X-ray image
When using X-rays for imaging (especially in medicine), its basic properties of penetrating even materials opaque to light are used. The basic principal scheme of X-ray transmission imaging is in the left part of Fig.3.2.1. The penetrating electromagnetic X-rays with a photon energy of about 20-150 keV (wavelengths of about 5 to 50 picometers), generated in the X-ray tube, pass through the examined object (organism tissue), while part of the radiation is absorbed depending on the thickness and density of the tissue, while the remainder portion passes through the tissue and is displayed either photographically or on a luminescent screen, more recently using electronic detectors. In the body, X-rays are most absorbed by bones, less by soft tissues, least by body cavities and by air. When exposed to X-rays, an X- ray image of the examined tissue is created, which is a projection shadow image of density, showing differences in density of tissues *). In other words, an X-ray image is created by projecting X-rays from the focus of the anode, through tissue structures within the organism with different absorption coefficients and different thicknesses, onto a film or imaging detector. Different absorptions of X-rays in different tissues are assigned different intensities in gray scale in the image; this assignment is realized either in an analog manner (film blackening) or digitally (electronic imaging detectors + computer, see below). This creates an image reflecting the size, shapes and arrangement of tissues and organs in the body, including possible changes induced by pathological processes.
*) Differentiated absorption of X-rays are the basis for formation of X-ray image. This absorption depends on the layer thickness, density and proton number of the irradiated substance. Soft tissues have a lower density and lower absorption of X-rays - more radiation is transmitted through these places, we get a clearer image or greater blackening of photographic material. The bones with calcium content are denser and absorb more X-rays - less passes through it, we get a less intense image or less blackening of the photographic film in these places. In Fig.3.2.1 on the right is an X-ray image on a photographic film.
   X-rays interact with tissue atoms mainly through two processes, discussed in more detail in §1.6, section "Interaction of gamma and X-rays": photoeffect and Compton scattering (formation of electron-positron pairs does not occur here due to the low energy of photons used in X-ray diagnostics; an insignificant exception may be portal and tomo-therapeutic images on radiotherapy irradiators, see §3.6 "Radiotherapy"). Both of these processes are involved in the different absorption of radiation in individual tissues (and also in the different absorption in normal and pathological districts within the same tissue), depending on the thickness, density of the substance and the proton number of the atoms. X-ray diagnostics is based on this different absorption of X-rays in different tissues, as well as differences of absorbtion in their physiological or pathological conditions.
Chemical (atomic-elemental) composition of tissues and organs?
Different tissues and organs differ in their chemical composition, which may or may not be reflected in their different densities. If two adjacent structures in the body have the same or close absorption coefficient (linear attenuation coefficient) for the X-rays used, they will be indistinguishable from each other on X-ray images - they will appear identical, even if their material (chemical, elemental) composition is significantly different. Differentiation or classification of different tissue types by standard X-ray imaging is therefore very difficult and often impossible.
  A certain possibility of at least partial resolution of the material composition of the displayed structures is measurement - imaging - at different X-rays energies - X-rays spectrometry. We will deal with these possibilities below in the sections "Electronic X-ray imaging detectors" - "Spectrometric Photon-counting X-ray imaging", "X-ray detectors for CT" and "CT with 2 X-rays - DSCT: Dual Source and Dual Energy CT".

X-ray image quality
Three parameters are important for high-quality X-ray imaging and recognition of fine structures and anomalies :
¨ Sharpness and resolution ability of imaging
For the projection image sharpness is important the small size of the impact focus, from which the X-radiation is emitted (see below, "The design of the X-ray tube"). For classical X-ray diagnostics, the focus is about 0.5¸2 mm, but for X-ray microscopy, an almost point focus with a diameter of the order of micrometers is required. Closely related to sharpness is the spatial resolution of the image *). Sharpness and resolution can also be affected by the properties of the imaging medium - photographic film, amplifying films, electronic imaging detectors. The resolution of the X-ray image is around 0.5-2 mm, depending on the size of the focus (at X-ray microscopy can be a thousand times better!).
*) Resolution is defined as the smallest distance between two "point" objects, at which they still displayed as two separate structures; or equivalently as the half-width of the point object image profile. At shorter distances, both objects already appear as one, they are not distinguished. As in photography, resolution is often measured in the maximum number of lines per millimeter [lp/mm] that can still be distinguished; in practice, the real X-resolution is around 2-5 lp/mm. The quality of X-ray imaging in terms of real resolution is sometimes quantified in detail using the so-called modulation transfer function MTF, indicating using Fourier harmonic analysis, what details of the examined object can be displayed with the given contrast. The issue of resolution, contrast and recognizability of lesions on X-ray images is largely similar to scintigraphic imaging - it is discussed in detail in §4.2, section "Scintigraphic image quality and detectability of lesions".
   Significant deterioration in sharpness and resolution occurs especially when the image is blurred due to patient movement during exposure - motion blur. With modern devices, this risk is minimized by shortening the exposure time, thanks to the simultaneous increase the intensity of X-rays. Also, the movements of certain structures inside the body - heart beating or breathing movements - lead to image blur. This adverse effect can be eliminated by gating (trigration) and image synchronization in certain phases of cardiac pulsation or respiration - ECG-gating, respiratory-gating.
¨ The contrast of the imaging ,
which expresses the gradient of displaying differences in X-rays absorption using a gray scale, is given by two factors. First of all, it is the ratio of absorption coefficients for different types of displayed tissue. It depends mainly on the differences in the density of individual areas of tissue; where this difference is negligible or non-existent, we can sometimes increase it by applying contrast agents (see below). The contrast in absorption further depends on the energy of the X-rays. For thinner layers of soft tissue, soft X-rays (approx. 20 keV) are more suitable, which interact mainly with a photoeffect with a steeper difference in absorption depending on density (the greatest contrast is achieved for X-rays close to the binding energy of electrons on K or L shells). Harder X-radiation (approx. 80-100 keV) is required to display thicker layers and denser materials (eg skeletal structure). Contrast in image is negatively affected by Compton scattered radiation (see "secondary diaphragms" below).
   An important geometrical-anatomical factor, significantly worsening the contrast of the X-ray image and the overall recognizability of the lesions, is the cross-radiation and superposition of X-rays from individual layers of tissues and organs at different depths, generally with different densities. This adverse effect is largely eliminated in CT imaging.
   For digital devices, the contrast can be additionally increased by computer processing ( post-processing ) - a suitable brightness modulation of the image. In such processing, the so-called bit depth is important - the number of bits in which the image is created in the process of analog-digital conversion.(ADC) from an electronic X-ray detector to an image matrix in a computer. When displayed, the bit depth indicates the maximum number of shades of gray that we are able to display in the image - the larger this number of shades of gray, the more depicted we show particularly small differences in density and fine detail. A higher number of bits in the image allows you to emphasize the details in the image using suitable display windows for brightness modulation - stretching a certain small range of brightness values in the image to the full range.
  The relationship between the most commonly used bit depth b and the maximum number of shades of gray is as follows (given by the power of 2 ^b ) :
2 bits = 2 shades (white and black only); 4 bits = 16 shades; 8 bits = 256 shades; 12 bits = 4096 shades; 14 bits = 16384 shades; 16 bits = 65536 shades; 24 bits = 16777216 shades.
Although a large number of shades (tens and hundreds of thousands) are no longer directly distinguishable by the eye, this allows by the use of narrow display windows to emphasize density gradients.
¨ Number of photons in the image - statistical noise
To obtain a quality well-exposed image, a certain optimal number of X-ray photons is needed. In films and luminescent screens, this number of photons is mainly determined by sensitivity the material used, so that the image is not underexposed or overexposed. With digital imaging detectors, we can additionally adjust the brightness of the image, but the image quality is still determined by the following factor : X-ray emission, its interaction and imaging detection is subject to stochastic quantum laws, leading to quantum statistical fluctuations in photon flux. With insufficient X-ray photons, the image is "noisy", composed of disturbing artificial brighter and darker spots and clusters of dots, where fine structures and details can disappear. If we have the registered number of N photons of X-rays in a given element (pixel) of the image, then the local statistical fluctuations - scattering, relative error - are SD = 1/ÖN. To obtain a well-drawn image with statistical fluctuations of less than 3%, more than 1000 photons must be recorded in each element of the image, for 1% of the fluctuation there must be more than 10,000 pulses/element.
   For digital imaging detectors - flat panels (described below) - the quality of the X-ray image in terms of noise depends on the sensitivity of the sensor: this is given by the detection quantum efficiency DQE (Detection Quantum Efficiency), which is the percentage of photons X-rays incident on the detector, that are actually recorded by the detector and used to create the image (the rest is uselessly absorbed by the input window or detector material without scintillation or electrical response). For digital X-ray images, especially CT, the statistical noise of the image is expressed in Hounsfield units HU (introduced below in the section "X-ray tomography -CT", passage "Origin of the density image"); in a good picture, the SD noise should not exceed about 20-30 HU. The total number of photons for the exposure of a given image is set by the product of the X-ray current and the exposure time (see below "X-raytube", section "Braking X-rays") - "milliampere-seconds" [mAs]; it can also be electronically controlled using automatic exposure - see below "Setting X-ray parameters".
¨ Artifacts on an X-ray image
Under certain circumstances, some structures that do nothave their origin in the displayed object, may appear on X-ray images - they are false artifacts . They can be caused by inhomogeneities, defects or impurities on the photographic film or reforcing foils, inhomogeneities in the flat-panel detectors, unwanted objects (eg metal) in the X-ray beam. In CT imaging, so-called structural artifacts may occurs, arising during the reconstruction of transverse sections in places with sharp differences in density, especially at the transition of bone and soft tissue.

X-ray tube
Source of X-rays for X-imaging is a special vacuum tube called X-ray tube or X-ray lamp. From an electronic point of view, the X-ray tube is simply a classic diode connected in a circuit with a high voltage of approx. 20-200 kV. So it has two metal electrodes :

--> Cathode
formed by a thin metal wire wound into a narrow spiral. A metal that is very resistant to temperature is suitable for the heated filament of the cathode - it has a high melting point, is strong and mechanically stable, and has a low output work of electron emission. Tungsten is most often used, which has a high melting point of 3300 °C. It is basically similar to the tungsten filaments of classical light bulbs (but where it is the emission of light, not electrons).
   An electric current (several Amperes) is applied to this metal wire, which heats up the fiber to a temperature of approx. 2000 °C. Thermoemission then releases electrons from the metal - the heated cathode emits electrons. The release of electrons occurs when, during their thermal movement, the electrons acquire a kinetic energy higher than the output work of the electrons from the given metal. As the temperature of the metal increases, the electron thermoemission density increases significantly. The dependence of the thermoemission intensity J on the metal temperature T is described by Richardson's formula :
J = F . T2. e-w/(k.T) ,
where J is the current density of emitted electrons [A/cm2] - current per unit area of the emitting surface of the metal, T is the absolute temperature of the metal [°K], w is the output work of electrons [eV], k=8.62.10-5 eV/° K is Boltzman's constant. Electron emission has the character of a quantum tunneling effect (§1.1, passage "Tunneling effect").
F is a material-dependent constant [A/(cm2.°K2)], for tungsten it has a value of F~ 60 A/(cm2.°K2). The output work of electrons from tungsten is w=4.5 eV and it starts emitting electrons when heated to a temperature higher than 2000 °C, but effective emission only occurs at temperatures of 2300-2500 °C.
For the X-ray cathode, instead of pure tungsten, a thorium-coated tungsten filament is sometimes used, which has a lower electron work function of only 2.6 eV. The cathode from this thoriated tungsten effectively emits electrons already at a temperature of 1700-1900 °C. The lower operating temperature extends the life of the cathode by about three times.A metal that is very resistant to temperature is suitable for the heated filament of the cathode - it has a high melting point, is strong and mechanically stable, and has a low output work of electron emission. Tungsten is most often used, which has a high melting point of 3300 °C. It is basically similar to the tungsten filaments of classical light bulbs (but where it is the emission of light, not electrons).
An electric current (several Amperes) is applied to this metal wire, which heats up the fiber to a temperature of approx. 2000 °C. Thermoemission then releases electrons from the metal - the heated cathode emits electrons. The release of electrons occurs when, during their thermal movement, the electrons acquire a kinetic energy higher than the output work of the electrons from the given metal. As the temperature of the metal increases, the electron thermoemission density increases significantly. The dependence of the thermoemission intensity J on the metal temperature T is described by Richardson's formula:
            J   =   F . T² . e^-w/(k.T)    ,
 where J is the current density of emitted electrons [A/cm²] - current per unit area of the emitting surface of the metal, T is the absolute temperature of the metal [°K], w is the output work of electrons [eV], k=8.62.10^-5 eV/°K is Boltzman's constant. Electron emission has the character of a quantum tunneling effect (§1.1, passage "Tuneling effect").
   F is a material-dependent constant [A/(cm².°K²)], for tungsten it has a value of F~ 60 A/(cm².°K²). The output work of electrons from tungsten is w=4.5 eV and it starts emitting electrons when heated to a temperature higher than 2000 °C, but effective emission only occurs at temperatures of 2300-2500 °C.
For the X-ray cathode, instead of pure tungsten, a thorium-coated tungsten filament is sometimes used, which has a lower electron work function of only 2.6 eV. A small amount of thorium, mixed into tungsten, in a wire heated to about 2500°C, drifts to the surface layer, where it causes more efficient thermoemission of electrons. The cathode from this thoriated tungsten effectively emits electrons already at a temperature of 1700-1900 °C. This lower operating temperature extends the life of the cathode by about three times.
   If there were no positive voltage on the anode, these emitted electrons would form an electron cloud around the cathode and their repulsive force would prevent further thermoemission (this is the case around the filament of a light bulb). However, at a sufficiently high positive voltage (>60kV) at the anode, thermoemission electrons are continuously diverted away from the cathode and rapidly move towards the anode, an electron cloud is not formed. However, if the anode voltage is relatively low (<40kV), part of the emitted electrons will no longer reach the anode and a larger or smaller electron cloud remains around the cathode, preventing stronger thermoemission of electrons. Stronger heating of the cathode no longer leads to higher thermoemission and to a greater electron current through the X-ray.
 Cathode in the shape of a flat emitter
Some new X-ray tubes instead of the classic spiral fiber have a heated cathode using the so-called flat emitter technology. It consists of a rectangle of heated thin sheet, masked by several holes. By setting a negative voltage between the cathode and emitter slits, a very sharply localized incident focus on the anode can be more accurately achieved.
--> Anode
Electrons emitted from the cathode are attracted to the anode *) with a high positive voltage, while they are accelerated by a strong electric field to the kinetic energy E = U.e, given by the high voltage U between the cathode and the anode (ie E = approx. 20¸200 keV). Just before the impact on the anode, it obtains an electron with charge e and mass m_e a very high velocity v = Ö(2.e.U/m_e) (for voltage U = 60kV, the electrons will have a kinetic energy of 60keV and an impact velocity of approximately 150000 km/s, which is half the speed of light). Upon impact with the anode, the electrons brake rapidly, converting some of their kinetic energy to hard electromagnetic radiation - X-rays of two types: bracking and characteristic radiation (the origin and properties of these two types of radiation are discussed below). This X-ray leaves the anode and flies out of the tube (Fig.3.2.1 left).
*) The anode, the electrode located opposite the cathode, was formerly also called anticathode, especially in the cathode ray tubes.
   The anode is made of a heavy material (most often tungsten), which has a high electron density, so the incident electrons are sharply braked by a large repulsive force, which, according to the laws of electrodynamics, turns part of their kinetic energy into braking electromagnetic radiation - X-ray photons. However, the efficiency of this process is relatively small - only about 1% of the total kinetic energy of electrons is transformed into X-ray photons, the rest is converted into heat. The reason is that only about 1% of electrons penetrate deep enough inside the atoms of the anode material, up to the L or K shell, only where large Coulomb electric forces act, causing a sharp change in the speed of the electrons and thus effective excitation of hard braking ratiation. The other electrons transfer their kinetic energy to the electrons and atoms of the crystal lattice, which results in heat.
Note: The X-ray tube can be considered the simplest particle accelerator (§1.5 "Elementary particles", part "Charged particle accelerators") - it is a linear electrostatic accelerator of electrons, the source of which is a hot cathode, the (inner) target is the anode, the braking (+characteristic) X-rays comes out.
 X-ray tube volt-ampere characteristic
For the electronic operation of the x-ray tube, it is important how the electron current [mA] by the X-ray tube depends on the anode voltage [kV] - the volt-ampere characteristic - and also on the incandescent current [A] of the cathode. When the cathode is heated (e.g. with a current of approx. 5A, to a temperature of approx. 1500 °C), as the anode voltage increases, the electron current through the cathode gradually increases (still more electrons from the cloud around the cathode reach the anode) and then reaches saturation - all electrons released by thermoemission fall on anode and there are no more free electrons that could fly to the anode at a higher anode voltage.
   The cathode current characteristic of the X-ray tube is also important - the dependence of the resulting electron anode current on the cathode glow current. This characteristic is different at different anode voltages. Generally, as the glow current increases, the anode current also increases initially, but only up to a certain value. At a low anode voltage (<40kV), saturation occurs - increasing the glow current no longer leads to an increase in the anode current: the electric potential is not sufficient for all thermo-emitted electrons to fly to the anode, an electron cloud is formed around the cathode. Only at a high anode voltage (>60kV) do all the electrons released by thermoemission fall on the anode and the effect of the electron cloud and saturation does not occur.
--> 3rd electrode - grid ?
In addition to the cathode and anode, in some types of X-ray tubes, we can rarely find a third electrode - a wire grid, located between the cathode and the anode, in close proximity to the cathode. The electrical voltage applied to this grid very sensitively modulates the flow of electrons (i.e. anode current) and thus also the intensity of X-radiation. Applying a higher negative voltage to the grid can very quickly interrupt the anode current and thus the emission of X-rays (sometimes used for fast x-ray cinematography).

Braking X-rays
Braking radiation is a consequence of the laws of Maxwell's electrodynamics, according to which every uneven ("accelerated" or "decelerated") movement of an electric charge emits electromagnetic waves - see §1.5 "Electromagnetic field. Maxwell's equations.", Larmor's formula (1.61 '), monograph "Gravity, black holes and space-time physics". Therefore, even when the electron is braked after hitting the anode, the sharper the braking (the greater the deceleration a in the mentioned formula), the more intense and harder the electromagnetic radiation is generated - see also §1.6, passage "Braking radiation".
  The effective cross section for the production of braking radiation is generally given by the highly complicated Bethe-Heitler formula (derived from quantum radiation theory, corrected by the Sauter and Elwert factors of the Coulomb shielding of the electron shell). For a not very wide range of kinetic energies E_e of incident electrons (tens to hundreds of keV) and proton numbers Z of target material (medium to heavy materials), the overall efficiency of brake radiation production h can be approximated by a simplified formula :
                           h = E _e [keV] . Z . 10 ^-6   [photons / electron] .
By converting the number of electrons n_e to the current I = n_e .q_e/t and by substituting the value of the charge of the electron q_e = 1.6.10^-19 C (= 1.6.10^-16 mAs) from this relation the resulting flux of photons I_X [number of photons /s.] braking radiation depending on X-ray tube current I [mA] and anode voltage U [kV] :
                           I _X = U. I. (Z /1.6). 10 ¹⁰   [photons / s.] ,
which will be used below in the section "Setting X-ray parameters". Only a relatively small part (only about 1%) of the original kinetic energy of the incident particle changes to braking radiation when braked in the matter. Most of the energy, with multiple Coulomb scattering, is eventually transferred to the kinetic energy of the atoms of the anode substance - it is converted into heat.
  Total energy spectrum of X-rays (braking + characteristic), emitted from the anode of the X-ray tube, is drawn below in Fig.3.2.5 at the top right. The graphic form of the energy spectrum I(E) of continuous braking X-rays is approximated by the so-called Kramers formula :
                           I (E) = K. I. Z . (E_max - E) ,
where I(E) is the relative intensity of energy photons E , K is a constant, Z is the proton (atomic) number of the anode material, E_max is the maximum energy of X-ray photons, given by the kinetic energy of incident electrons. It is clear that I(E_max) = 0 and the formula is valid only for E < E_max .
  It is logical that the efficiency of brake radiation production is higher for high Z - large electric Coulomb forces act around such nuclei, causing abrupt changes in the velocity vector of the incident electrons that get close to the nucleus. The efficiency of braking radiation [number of photons /electron] increases with energy E_e incident electrons. Low-energy electrons are usually scattered on the outer shells of the atoms of the anode material and emit soft radiation, which often does not even reach the X-ray energy range. The higher the energy of the incident electrons, the more likely they are to penetrate deeper into the anode atoms, close to the nucleus, where the greatest electrical forces act, significantly changing the electron velocity vector, leading to higher energy and efficiency of braking X-ray production. However, the overall energy efficiency - the ratio of the total energy of the emitted photons to the energy of the incident electrons - is lower for higher energies (due to the higher percentage of low-energy photons). And the heat losses in the target (anode) are higher.
   The braking X-rays produced by the X-ray tube have a continuous spectrum from energies close to zero to the maximum energy, given almost by the value of the anode voltage - Fig.3.2.1 in the middle (here is the spectrum after partial filtering of the softest component - see below). The energy of the braking radiation depends on the speed (acceleration) at which the electrons are braked on impact with the anode surface. The individual electrons penetrate at different depths into the atoms of the anode material, thus emitting different wavelengths or energies of photons. Those electrons, which "softly" brake with repeated multiple scattering on the outer electron shells of the anode atoms, emit a series of photons of low-energy braking (and characteristic) radiation; some of them fall into the area of soft X-rays, others into the area of UV and visible light (this resulting low-energy photons are often absorbed in the anode material and do not fly out). The deeper the electrons penetrate into the interior of the anode atoms, the closer to the nucleus, the faster the intense Coulomb forces change their velocity vector and the harder the braking X-rays are produced. The shortest wavelengths arise for electrons that have penetrated to the level of the K shell and closer to the nucleus, where they can be braked almost on-time. Depending on the impact factor of individual electrons relative to the anode atoms, which is random, all possibilities are continuously realized - such a different degree of electron braking causes a mixture of radiation of different wavelengths or photon energies - the result is a continuous spectrum of braking radiation. Low-energy X-ray photons are the most represented in this continuous spectrum, only a very small percentage at the end of the spectrum corresponds to high energies, close to the energy of incident electrons, given the high voltage between the cathode and the anode of the X-ray tube (see Fig.3.2.5 below).
The wavelength and energy of X-rays
By its nature, X-radiation are electromagnetic waves of short wavelength of about 10^-9-10^-11 m, which, however, are emmited as quantum - photons - with an energy of about 5keV-200keV ( "The particle-wave duality"). Earlier (until the 1960s) it was customary to characterize X-rays with a wavelength of l and in the older literature was given the so-called Duan-Hunt relation l_min [nm] = h.c/e.U @ 1.234/U [kV] between the voltage U [in kilovolts] at X-ray tube and the minimum wavelength l_min [in nanometers] of the resulting braking X-rays *). A Kramer's formula for the spectrum was given in the form I(l) = K.Z.I.[(l/l_min) - 1]/l² (in this form it was compiled by H.A.Kramers in 1923; at that time X-rays were described only by wavelength).
   This manner was very disadvantageous and misleading, especially in relation to the creation mechanism of this radiation in X-ray tubes, where the values of the accelerating voltage in [kV] occur. Now is abandoned long ago, the X-ray spectrum is expressed fundamentally by the photon energy E_X [keV], which in X-ray tube is derived directly from the voltage U (maximum energy E_Xmax @ U, mean energy <E_X > » U/3] and the Duan-Hunt relation has lost its importance.
*) The Duan-Hunt formula actually just a differently written relation E_X = h /l between the energy of the photon E_X in [keV] and the wavelength l in [nm] for the situation, when all the kinetic energy E = U.e of the electron of charge e , accelerated by the voltage U, is converted into a photon X-rays (corresponds to the energy E_Xmax and the wavelength l_min ).
Characteristic X-rays
In addition to braking X-rays with a continuous spectrum, a certain smaller amount of characteristic X-rays with a line spectrum (characteristic pair of peaks Ka, Kb) is emitted, the energy of which does not depend on the anode voltage, but is given by the anode material; for the most commonly used tungsten, these are the 59.3+67.2 keV peaks (and also the L peak around 10keV), which appear as "bumps" on the continuous curve of the spectrum (Fig.3.2.1 in the middle).
   The characteristic X-rays are caused by two processes :
¨ Direct process of the impact photoeffect at the internal energy levels of the electron shell in the atoms of the anode material - fast electrons penetrate into the atoms and eject bound electrons from the K and L shells. When electrons jump from the L shell to the emptied shell K (K-series), or from the shell M to L (L-series), the difference of energies is then radiated in the form of photons of electromagnetic radiation - characteristic X-radiation (cf. also with Fig.1.1.3 in §1.1).
¨ Indirect process of photoelectric absorption of braking radiation - braking X-rays, generated by the above-mentioned mechanism during the braking of accelerated electrons, interact with other atoms inside the anode substance, among others by a photon photoeffect (described in §1.6, part " Interaction of gamma and X-rays ", Fig.1.6.3 left), emitting electrons from the inner shells, followed by an electron jump and the emission of characteristic X-rays, similar to the previous case.
   The impact electron photoeffect and the emission of photons also occur when electrons jump in the outer shells, but the energy of these photons is low and this radiation is covered by continuous braking radion at the beginning of the spectrum.
   A certain minimum (threshold) anode voltage is required for the formation of characteristic X-rays, higher than the binding energy of electrons on the K-shell of atoms of the anode material (for tungsten it is about 70keV, for molybdenum 20keV). If the anode voltage is lower, only continuous braking radiation is generated in the X-ray, and when the threshold voltage is exceeded, the spectrum contains both continuous braking and peaks of characteristic X-rays.
  The proportion of characteristic X-rays in the total spectrum of the X-ray tube depends on the anode material and the anode voltage. For a tungsten anode, it is approximately 30% at a voltage of 100 kV and only about 3% at a voltage of 200 kV.

X-ray tube design
Unlike conventional electron tubes used in low-current electronics, X-rays tubes have a relatively robust design (they resemble screens or transmitter electron tubes in size), given by two circumstances. On the one hand, it is a very high voltage, reaching hundreds of kilovolts. The second circumstance is thermal heating: electrons incident at high speed on the anode convert only a small part of their energy into X-rays, the vast majority of their kinetic energy is converted into heat - the anode of the X-ray tube is heated strongly. To dissipate this heat, the anode must have a relatively massive construction; in addition, anode rotation or cooling is used (described below). One of the technical parameters is maximum power of the X-ray tube [kW] - peak electrical power input of the X-ray tube, which the X-ray tube can still "withstand" without overheating and thermally damaging.
  The most commonly used material for the anode of an X-ray tube is tungsten, a heavy and heat-resistant metal. To improve the thermal properties of the anode, especially the heat capacity, rhenium-alloyed tungsten (10%) is often used, or the anode is composed of several layers - alloyed tungsten, molybdenum, graphite. For X-ray tubes for X-rays around 20keV for mammography, the anode is made of molybdenum.
  X-rays tubes can be divided into two main groups, which govern their design (+ the third group of special constructions listed below) :
¨ X-rays tubes for industrial irradiation and radiotherapeutic use ,
which do not require focusing of electrons to an almost point focus and which have a fixed (non-rotating) anode. High energy and X-ray intensity are common requirements here; the anode is actively cooled by the flow of cooling medium through its interior.
¨ X-rays tubes for X-ray diagnostics
with focusing of the electron beam into the focus and mostly with a rotating anode (to prevent local overheating of the focus). Below we will deal mainly with these X-rays tubes for radiodiagnostics. The anode target material is mostly tungsten, for low X-ray energies (around 20-40keV) molybdenum is used as the anode target material; the X - ray tube is additionally equipped with a beryllium exit window - see below "X-ray mammography".
¨ Special types of X-ray tubes  
Microfocus X-ray tube have an extremely small impact focus of electrons on the anode, of the order of micrometers. This is achieved by placing a special set of electrodes (electron optics - "objective") between the hot cathode and the anode, focusing electrons from the cathode into a very narrow beam incident almost point on the target-anode. They provide very high sharpness and resolution of the image, but only limited power (intensity, fluence) of X-rays. They are used for X-ray microscopy and CT defectoscopy (see below §3.3, section "Radiation defectoscopy").
  For special purposes (especially spectrometric and micro -X-rays), the X- ray tubes with a frontal transmission anode (Target Transmission X-ray Tube ) are constructed, where the beam of accelerated electrons impinges on the thin front-located anode, the resulting X-rays passing through the material of the thin anode to the outside of the tube where it is used. It can also be designed as the above-mentioned microfocus.
  In addition to the usual tightly closed (sealed) evacuated X-ray tubes, so-called open X-ray lamps are sometimes constructed. They have a metal casing that the user can open, replace the cathode filament and anode material (tungsten, copper, molybdenum, etc.) as needed, and close the tube again and evacuate.

Fig.3.2.2. Special microfocus X-ray tube with transmission anode for X-ray microscopy

Historical development of X-ray tubes
X-ray tubes originally evolved from discharge lamps, which are gas-filled glass tubes with electrodes to which a voltage of the order of hundreds of volts is applied. The next stage was Crookes cathode ray tubes - discharge lamps with very dilute gas, on the electrodes of which a high voltage of the unit of up to tens of kilovolts is applied. The classic radiant discharge practically no longer occurs here, but the ionization of the atoms of the diluted gas releases electrons, accelerated by a high voltage towards the anode - the cathode radiation originated. In addition to the fluorescence of the flask or inserted objects, there is also a secondary penetrating photon radiation - X-rays (discovered by Roentgen and independently by other researchers), braking and characteristic. Cathode ray tubes also played an important role in atomic physics, with their help J.J.Thomson discovered electrons, which allowed them to penetrate the structure of atoms.
  The first "cold cathode" X-rays tubes were actually Crookes cathode ray tubes with specially modified electrodes. An important milestone was the creation of a vacuum X-ray tube with a hot cathode, constructed by W.D.Coolidge in 1913 (shown in Fig.3.2.1 on the left). Later, with increasing performance, the anode rotation as well as other technical improvements and special designs were added to X-ray imaging diagnostics (see below). Experiments with X-ray laser sources are currently being performed- whether the excitation of characteristic X-rays in a high-temperature plasma generated by a laser beam or braking X-rays on the impact of accelerated electrons on a target. On the sidelines, we can note that the most complicated special "X-ray tube" (sources of X-rays) can be considered wigglers and undulators of electron synchrotrons (see §1.5, section "Charged particle accelerators").

Electron focusing, focal point
In order to achieve good sharpness and resolution of the projection shadow transmission image in X-ray diagnostics, it is necessary that the X-ray beam comes from an almost point source. In X-ray tubes for X-ray diagnostics, the red-hot filament - a tungsten spiral - is embedded in a recess or focusing slit of the cathode, which has a negative polarity, so that its repellent effect clusters electrons into a narrow strip *). After acceleration by high voltage, the electrons then fall into a relatively sharply localized place of the anode - the impact focus, which has a rectangular shape due to the elongated shape of the filament. Real, optical focus the resulting X-ray is a geometric projection of this radiating surface on the anode, i.e. the impact focus, into a plane perpendicular to the beam of radiation used for imaging. The originally rectangular impact focus is reduced in the longitudinal direction due to the inclined, tilted surface of the anode; its projection in the direction of the display has an almost square shape, usually 0.5-2 mm in size.
*) These X-rays tubes usually have two cathode fibers - shorter and longer. By switching the heating current, one or the other fiber can be heated and thus the size of the impact focus on the anode can be changed.
  Some new X-rays tubes, instead of the classic incandescent fiber, have an incandescent cathode solved by the so-called flat emitter technology. It consists of a rectangle of hot thin sheet metal, masked by several holes. By adjusting the negative voltage between the cathode gap and the emitter, a very sharply localized impact focus can be achieved more precisely.
Asymmetry of the X-ray beam from the focus, heel effect
In the first approximation, the X-ray is emitted from the impact focus isotropically, with the same intensity in all directions. However, some of the incident electrons penetrate below the surface of the anode and the X-rays generated there are partially absorbed and attenuated as they pass through the anode material. This leads to a change in the shape of the radiation pattern from the target at the anode, to a certain angular asymmetry of X-ray beam emanating from the chamfered anode: for an angle of about 30° in the direction of the cathode, the radiation intensity is about 5% higher than in the center (0°), in the opposite direction (to the anode disk) about 15% lower. This shaping of the radiation characteristics are sometimes referred to as anode heel effect, some "heel shape", "skew". This phenomenon may manifest itself in some minor inhomogeneity of the X-ray image, especially during exposures of large imaging fields, or during X-ray mammography. This inhomogeneity is smooth and gradual, so it does not interfere with visual evaluation; however, digital evaluation is sometimes computer-corrected.
 Anode cooling and rotation
As mentioned above, the vast majority (almost 99%) of the kinetic energy of the electrons hitting the anode is converted into heat. This released heat must be effectively dissipated to prevent overheating of the anode. At low powers, passive infrared radiation from the heated anode to the surroundings is sufficient. X-ray tubes for high performance (without focus, e.g. in industrial use) have an actively cooled anode - inside the anode there is a cavity through which the cooling liquid flows.
  In diagnostic X-ray tubes, electrons fall into a small, sharply localized spot on the anode - the impact focus - about 1 mm in size. At higher powers, this impact focus on the anode can heat up strongly locally. It is necessary to ensure that the temperature of the focus is lower than the melting point of the anode material (usually tungsten). Local overheating of the focus, where the electrons fall, can be prevented by rotating the anode *): the cathode is eccentrically placed in the X-ray tube, the anode in the shape of a conical disk (about 5-10 cm in diameter) rotates around the longitudinal axis, so that the electron beam always falls to a different place the circumference of the anode, making the heating and heat dissipation more uniform (Fig.3.2.3 left). Although X-rays emanate from the same place - the focus, which is against the stationary cathode, this place is due to the rotation of the anode constantly formed by another physical part of the anode disk; the heat is thus better dissipated in the anode material.
*) Anode rotation
Because the anode is located inside a high vacuum tube, its rotation cannot be ensured by a mechanical transmission from the outside (via the shaft). No bearing is so tight that no air enters the tube over time - the vacuum would be broken. Rotation of the anode is driven electromagnetically: inside the anode neck of X-ray tube is mounted on the bearings a metal cylinder connected by a shaft on the anode - serves as a rotor. From the outside the X-ray tube are disposed coils supplied with alternating current - those forming the stator, giving the rotating magnetic field which, by electromagnetic induction (eddy currents are induced in the rotor), rotates by a roller and an anode inside the tube (Fig.3.2.3 left). From an electromechanical point of view, such an X-ray tube is actually a small asynchronous electric motor. The rotation speed of the anode is usually 50Hz (3000 rpm), also 10-12,000 rpm is used for high power X-ray tubes. A certain problem is the wear of the bearings on which the anode rotor is anchored. These bearings are highly mechanically and thermally stressed, they are inside the vacuum space out of the possibility of maintenance and lubrication (only "dry" lubrication with silver or lead metal powder is used) - their wear is usually the main limiting factor of X-ray tube life.
  In some X-ray tubes, hydrodynamic lubrication of bearings with a thin layer of suitable molten metal is sometimes used (a kind of "aqua-planing" of the shaft in liquid metal, with minimal friction). One suitable metal is gallium, which has a low melting point of about 130 °C and a sufficiently high boiling point of 2204 °C, so that even at relatively high temperatures of several hundred °C, the vacuum does not contaminate its vapor. Furthermore, such a lubricating contact surface in the bearing efficiently dissipates heat from the anode. Before the actual operation, after switching on the device, the bearing is first heated and only after the melting of the lubricating metal does the rotation of the anode begin, which is then maintained continuously even outside the exposure, until the device is switched off. The bearing is heated and the required temperature is maintained by the effect of eddy currents induced in the rotor (these are the same eddy currents which, by their interaction with the rotating magnetic field of the stator, drive the rotation of the anode). Special so-called eutectic alloys are also used to lubricate the anode bearing metals which are liquid even at normal temperatures (eg gallium, indium and tin in an alloy of suitable ratio, with a melting point of -10 °C).
  From a mechanical point of view, the rapidly rotating massive anode behaves like a flywheel, preserving its vector of rotational momentum. If we try to tilt the X-ray tube with a rotating anode (change the direction of its axis), due to the gyroscopic effect, the rotating anode puts up resistance and its bearings are stressed by considerable forces. This is especially the case with CT tomography devices, where the X-ray tube orbits around the examined object relatively quickly. Therefore, X-ray tude with double-sided anchoring of the anode axis are sometimes used here. The shaft of the rotating anode, passing through the whole X-ray tube, is mounted in bearings at both ends. The cathode portion of the X-ray tube then has two protrusions: one on the side for mounting and feeding the eccentrically located cathode, the other in the middle for mounting the second anode bearing. When the rotary anode shaft is anchored on both sides, the gyroscopic forces are distributed and the bearings are significantly less stressed.

Fig.3.2.3. Design of X-ray tubes used in radiodiagnostics.
Left: Classic X-ray lamp with rotating anode. Right: X-ray tube rotating as a whole (STRATON type), with the front anode in direct contact with the oil cooling bath and with the magnetic deflection of the electrons from the cathode.

Although the rotation of the anode prevents local overheating of the impact focus on the anode, during longer operation the anode heats up strongly as a whole and this heat is only slowly transferred by infrared radiation through a vacuum out of the X-ray lamp to the cooling medium. It is therefore necessary to observe certain time delays between individual exposures in order for the anode to cool down. Another disadvantage of the rotating anode is the wear of the bearing inside the vacuum flask, which cannot be lubricated or otherwise maintained from the outside. In addition, when the bearing wears, unwanted fumes are released into the vacuum space of the X-ray tube.
 X-ray tubes rotating as a whole
For higher performance, a new construction arrangement of the X-ray tube rotating as a whole, with direct cooling of the anode, was therefore developed. A beam of accelerated electrons from an axially positioned cathode, deflected by the magnetic field of the deflection coils (located outside the tube) *) impinges peripherally on the opposite front anode, which is in direct contact with the cooling oil bath from which the X-ray tube is immersed - Fig.3.2.3 on the right. The resulting heat from the impact focus is thus immediately dissipated away. The X-ray tube rotates as a whole around its longitudinal axis connecting the cathode to the center of the anode, the X-rays emanating in the lateral direction (similar to a conventional Coolidge-type tube). The heating and anode voltage is conducted to the X-ray tube by means of collecting rings, on which electric brushes slide (slip-ring technology, similar to that of electric motors for direct current). The main advantage of this design is the substantially better cooling of the anode, which is in direct contact with the cooling medium, while there are no mechanically moving parts inside the vacuum space. The bearings on which the entire X-ray tube is mounted are easily accessible and can be effectively lubricated. This leads to the possibility of achieving higher performance and significantly extending the life of the X-ray tube.
*) The current through the deflection coils must be precisely set depending on the accelerating anode voltage: the higher the voltage [kV] at X-ray tube is set, the higher the current must flow through the deflection coils so that the electron beam is properly bent and hits the desired location at the anode edge. By electronic control of the current in the deflection coils, it is thus possible to set the desired position of the impact focus of the electrons on the anode. By controlling the deflection current, it is possible to define several foci that can operate simultaneously in multiplex operation.
   Furthermore, X-ray tubes of this design can be significantly smaller and lighter at the same or higher power than conventional X-ray tubes with a rotating anode. This is very advantageous in new technologies of high - speed multi-slice CT devices, where the rotational mechanics are strongly stressed by centrifugal, gravitational and gyroscopic forces. The first type of X-ray tube rotating as a whole (rotating envelope tube) is Straton (developed by Siemens in 2004).
 High performance x-ray tubes with rotating anode
Another newer type of X-ray tube is Vectron (from the same manufacturer), with high performance - max. anode current 1300mA at voltage up to 90kV and 800mA at 150kV. Unlike the Straton, it reverts to Coolidge's earlier classic design of a fixed X-ray tube with a rotating anode, with bearings lubricated by a molten metal eutectic alloy. The anode has a high heat capacity and is cooled by infrared radiation through the vacuum into the cooling medium. Instead of oil, water is used as a cooling medium (high voltage sources - generators - are also cooled with water), which has a higher specific heat capacity than oil. The cathode is formed by flat emitter technology. It has a very small focus on the anode of 0.4×0.5 mm, independent of the kV setting, even at high X-ray power. The electron beam is deflected electronically very quickly (4000 times per second) and creates two foci in the multiplex mode (this creates two overlapping projections in the z-axis).
   Also other manufacturers supply high-performance high-resolution X-ray tubes - GE (Performinx HDw), Philips (iIMRC), Toshiba (Megacool Vi).

Electric power supply of the X-ray tube
The X-ray tube, as an electronic source of radiation, requires an appropriate power supply, supplying electrical energy generating X-rays and providing other functions necessary for the correct operation of the device. The X-ray tube has three basic power supplies :
¨ The heating current source
for the X-ray tube cathode. It is a heating transformer, they supply a low voltage of usually 6-12V and a current in the range of approx. 0.5-10 A on their secondary winding, with the possibility of continuous regulation (see below "Setting the X-radiation parameters").

Fig.3.2.4. Electric power supply of X-ray tube
Above: High anode voltage source. Middle: AC voltage for anode rotation. Bottom: Cathode heating voltage.
Note: This arrangement of X-ray tube under high voltage, with a hot cathode, rotating anode and X-ray emission I practically show on the "work table" as an experimental demonstration.

¨ High voltage source
- anode voltage for accelerating electrons in X-ray tube. This is a voltage in the range of mostly about 20kV-150kV; it can also be lower for special X-ray machines for spectrometric use, and up to 400 kV in industrial applications. The basis of this source (also called a generator) is a high-voltage transformer, which transforms the mains voltage (220V/380V) upwards - either directly from the mains voltage to the required value, or more recently via an electronic oscillating circuit. The high-voltage transformer has a high conversion ratio (given by the ratio of the number of turns on the primary and secondary windings) of the order of 1000 or more.
  Newer devices use high-frequency sources high voltage. The mains voltage is first rectified and smoothed. This DC voltage is supplied to the high-frequency oscillator (inverter), which uses thyristors to generate an AC voltage of about 10kHz with sharp edges. This is then in the high voltage transformer converted to high AC voltage, which is further rectified and smoothed (see below). The advantage of this solution is that the high-frequency transformer can have significantly smaller dimensions and weight at the same power than a conventional transformer with a frequency of 50Hz. This high-frequency oscillator and transformer solution, enabling highly efficient transformation of electrical energy - power, current, voltage - is called an inverter in electronics.
  The value of the anode voltage can be regulated either continuously or stepwise in suitable steps. This is achieved using an autotransformer which is preceded before a high voltage transformer. The autotransformer regulates the mains voltage in the range of approx. 20-220V, which is then multiplied by the high-voltage unit by a constant ratio (approx. 1: 1000). In the case of electronic high-frequency sources, the high-voltage regulation is carried out by means of frequency control.
  The AC high voltage is rectified by vacuum or semiconductor diodes. The simplest rectification is one-way ("single- pulse") by means of one diode connected in series (or without rectification, the rectification is performed by the X-ray tube herself *), when the emission of radiation occurs only in the positive half-period of alternating current.
*) In fact, the X-ray tube itself is basically a diode that can take care of the rectification itself. For older and simpler devices, therefore, the X-ray tube was supplied with alternating voltage, while the emission of X-rays occurs only in half-periods when there is a positive voltage at the anode. The disadvantage of this solution is the increased proportion of the soft component of radiation (arising at the beginning and end of the half-period, when the instantaneous voltage is significantly lower), and at higher powers also the possibility of reverse current ("backfire") - in the opposite half-period, the secondary electrons emitted from the heated focus of the anode, can accelerate towards the cathode, which they bombard with high kinetic energy and can damage it.
  Two-way rectification is more perfect ("two-pulse") using 4 diodes in a bridge Graetz connection, or 2 diodes in a double secondary winding, where there is always a positive (pulsating) voltage at the anode and the X-ray tube operates in both half-periods of AC voltage. In the past, sometimes a three-phase mains supply of a three-phase high-voltage transformer is used and 6 diodes in a bridge connection are used for rectification - only a slightly pulsating DC voltage is generated (which never drops to zero, but only by about 15% of the peak voltage), the pulsations have a frequency of 300Hz; it is sometimes referred to as six-pulse smoothing. A three-phase high-voltage transformer can have two triple secondary coils, phase-shifted by 60°; after rectification by means of 12 diodes in a bridge circuit, only a slightly pulsating DC voltage is obtained (with a frequency of 600Hz it fluctuates only by about 4% - "12-pulse smoothing"), close to the right smoothed DC voltage.
  All these cumbersome solutions of heavy current electrical engineering are already abandoned here, in principle high-frequency (HF) high-voltage sources are used. With these high-frequency high-voltage sources, capacitor smoothing can be performed very well after rectification, thus obtaining a minimally pulsating DC voltage (with a high frequency of only small pulses).
   The value of high voltage on X-ray tube is expressed in thousands of volts - kilovolts [kV]. If a pulsating voltage is applied between the anode and the cathode of the X-ray tube, the maximum energy of the emitted X-rays is given by the maximum positive value of the anode voltage, which is expressed as [kVp] - "number of kilovolts in the peak".
¨ Power supply for anode rotation ,
which is an alternating voltage (in the simplest case mains 220/380V), applied to the stator coils, creating a rotating magnetic field for X-ray anode rotation. At a mains voltage frequency of 50Hz, the fundamental frequency of rotation of the anode is 3000rpm; by segmenting the stator coils, lower speeds of 1500, 1000, 750, 600 rpm can be achieved. To achieve higher speeds, the X-ray stator must be powered by an electronic oscillator, providing a frequency higher than 50Hz. A higher starting voltage is first applied to the stator, which is reduced to about 1/3 after spinning to maintain synchronous speed. The speed of the anode (rotor) can be electronically monitored on the basis of the current flowing at a given voltage through the stator coils when the rotating magnetic field is excited (after reaching the synchronous speed this current decreases significantly). Only after the anode has been rotated to the required speed can the high anode voltage start and the exposure begin. In order to prevent the X-ray anode from rotating unnecessarily for a long time, the opposite phase of alternating voltage is connected to the respective stator coils for a while after the exposure, whereby the rotating magnetic field reverses its direction and the rotation of the anode is electromagnetically braked (for some types, a separate winding is installed in the stator for braking, a DC supply for magnetic braking of the rotor is also used). Exceptions are anodes with molten metal (gallium) lubricated bearings, which rotate continuously, even between exposures, as described above.
  Current X-ray devices also use other electronic power circuits to supply electric motors for sliding and rotating movements, X-ray tubes cooling, as well as control and regulation electronics, including detection and evaluation circuits.
X-ray tube cover
During actual operation in X-ray machines, the X-ray tube is encapsulated in a special metal cover (made of aluminum alloys) of cylindrical shape *). The cover is shielded from the inside by lead sheet approx. 3 mm before unwanted penetration of X-rays into the surroundings. At the ends of the housing there are bushings through which voltage is applied between the anode and the cathode by means of well-insulated high-voltage cables, and a low heating voltage is then applied at the cathode end. In the middle part *) of the cover there is an exit window (of course unshielded, to which the X-ray tube must be turned with its impact focus) made of a light material, mostly acrylic glass, through which the X-ray beam comes out for the respective use. In power X-rays tubes, the space between the X-ray lamp and the walls of the package is filled with a cooling medium - transformer oil. The oil environment also increases the electrical strength of circuits - prevents high voltage electric shocks. To eliminate the mechanical stress on the cover due to the thermal expansion of the cooling oil, a rubber expansion membrane is built in a suitable place on the wall of the X-ray tube cover (prevents, for example, the cover from bursting when the X-ray tube overheats).
*) For Straton X-ray tubes, the housing has a double cone shape and the exit window is near the end where the anode is. The appropriate location of the impact focus on the anode opposite the output window in the housing is ensured by deflection coils (incl. the angle of their rotation), located from the outside in the narrowed part of the housing - Fig.3.2.2 on the right.
  Smaller, low-power X-ray instruments sometimes use a compact design: a high-voltage transformer (for the anode) with a winding of heating current for the cathode is built into the common housing together with the X-ray tube. Only 220V mains supply is then conduct to such a compact system.
Collimation and localization system
The following is a collimation system, consisting of a tubus with adjustable orifices defining the geometric shape of the X-ray beam. The apertures are adjusted so that the X-ray beam covers only the displayed area and other parts of the body are not unnecessarily irradiated. For visual localization and adjustment of the displayed field a light navigation system is installed in the X-ray tube collimation system - the light from the filament lamp or LED is guided by optical projection through the collimation system so as to achieve a conformity between the visible light field and the X-ray field. Before the examination, it is possible to adjust the position of the displayed field on the film cassette or display panel, as well as on the surface of the patient's body.
Mechanical design of X-ray devices
The cover with X-ray tube and collimation system, together with the opposite film cassette or imaging panel, are mounted on special stands of several types and constructions, according to the required X-ray imaging methodology - Fig.3.2.5. For skiagraphic imaging, the X-ray is most often mounted on top of a vertical stand (column tripod mounted on the floor or ceiling mount) with the possibility of easy mechanical movement. The film cassette or display panel is mounted at the bottom of the stand, again with the possibility of sliding. Between them is a sliding bed with the patient for examination while lying down. For standing (or sitting) imaging, the X-ray tube with the collimation system is rotated horizontally, the opposite cassette or flat-panel is on a separate vertical stand (so-called vertigraph). The horizontal movement (travel) of the X-ray tube can be realized by means of rails mounted on the ceiling or floor of the examination room. Displacements of individual parts of the X-ray system can be manual or motorized, using electronically controlled electric motors. For new systems, the so-called autotracking is implemented - automatic synchronous coupling of display panel and X-ray tube displacements (equipped with a collimation system). Some systems for sciagraphy and sciascopy have the ability to turn or tilt the X-ray stand, imaging panel, and the bed for various angles, from horizontal to vertical - such a system is called an X-ray tiltable wall and has a wide range of uses.
  For flexible sciascopic imaging, the X-ray tube and the opposite imaging detection system are often mounted on a special stand in the shape of the letter "C" - the so-called C-arm - Fig.3.2.3b., or the so-called U-arm - Fig.3.2.3c. These arms can be rotated using electric motors to different angles around the patient, allowing flexible display in different projections. These systems (which are sometimes mobile) are used in a wide range of applications, such as digital subtraction angiography (see below DSA - Fig.3.2.3), X-ray navigation of interventional procedures, afterloading in radiotherapy (see §3.6, section "Brachyradiotherapy" - Fig.3.6.7) and others.
  A separate category of X-ray device design solutions is transmission X-ray tomography CT, where the X- ray tube and the opposite electronic detection system are mounted on a portal rotary stand - gantry - described in more detail below "X-ray tomography - CT", Fig.3.2.4. This includes also special constructions of X-ray imaging devices, installed directly on IGRT radiotherapeutic irradiators (see §3.6, section "Isocentric radiotherapy", Fig.3.6.1c) or tomotherapy (§3.6, part "Modulation of irradiation beams", Fig.3.6.4a).
  Further technical details of the construction of X-ray devices and their accessories are already outside the scope of this physically focused treatise...

X-ray tube aging and damage
Like almost any device or electronic component, even X-ray tubes can be subject to adverse changes due to "aging", load and operational damage. Over time, material degradation, vacuum, and wear of rotary bearings occur. Several types of adverse changes in X-ray tube properties can occur :
--> "Burning out" of the cathode filament
The red-hot cathode, providing electrons by thermoemission, is mostly made of tungsten wire, which is highly heat-resistant (melting temperature is 3400 degrees). However, when annealing at high temperatures, tungsten evaporates slowly, often unevenly, so that the spiral can become quite thin in some places. This can limit the life of the cathode spiral.
--> Violation of the X-ray tube vacuum
Small leaks can occur between the glass and metal parts of the x-ray bulb, allowing air to gradually enter the vacuum environment of the x-ray tube over longer periods of time. From the metal parts, especially from the heated ones, and from the stressed rotary bearings of the anode, unwanted fumes also evaporate and release into the environment of the X-ray tube.
--> Local overheating of the impact focus on the anode
At high powers, the impact focus can be strongly locally heated to temperatures briefly exceeding the melting temperature of the anode material. This results in small micro-damages, various pits and cracks. The production of X-rays is then no longer perfectly homogeneous...
--> Wear of the anode rotary bearings
The high temperature and rotation frequency lead to a large mechanical load on these bearings. The wear of the bearings leads to greater noise during the operation of the X-ray tube and deterioration of the stability of the focus. Wear can be prevented to a large extent by lubrication of the bearings, in the case of high-performance X-ray tubes, lubrication using a molten metal eutectic alloy is used.

Setting of X-ray parameters
To optimize X-ray diagnostics, it is necessary to set suitable X-radiation parameters. In the electrical circuit of the X-ray tube we can regulate and set two basic electrical parameters as required (the third is only time, the fourth is realized by mechanical arrangement) :
¨ Anode voltage U [kV] ,
which is a high voltage supplied between cathode and anode, determines the maximum and mean energy of the photons of the resulting X-rays, its "hardness". The maximum energy of X-rays in [keV] is numerically practically equal to the anode voltage U in [kV], the mean energy is slightly higher than 1/3 of the max. energy. With increasing anode voltage, the whole spectrum of X-rays shifts towards higher energies (shorter wavelengths) and increasing the relative proportion of higher energies (harder short-wave components).
   In practice, the anode voltage varies in a wide range from about 20kV to 200kV (depending on the type of displayed structures), in the industrial use of X-rays then higher.
Note: The energy - hardness - of X-rays emitted is often referred to in X-ray jargon as the "quality" of X-radiation.
¨ Anode current I [mA]
flowing through the X-ray tube, determines the intensity (fluence) of X-radiation emitted by the X-ray tube I_X. It is most easily regulated by changing the heating of the cathode - the glowing stream - and thus the temperature of the cathode fiber. The glow current can be regulated simply by means of a rheostat in the glow circuit (in the glow transformer circuit), more recently with special electronic circuits equipped with transistors and thyristors. At higher heating of the cathode fiber, more electrons are emitted, a larger stream of electrons flows through the X-ray tube and a higher intensity of X-rays is emitted (but see "Volt-ampere characteristics of X-ray tube"). The average X-ray tube current is in the range units of mA to about 200mA, the peak current can be significantly higher (in pulse mode). E.g. an X-ray tube with a tungsten anode (Z=74) supplied with an anode voltage U = 120 kV at a X-ray tube current of 1 mA emits X-rays with an intensity I_X of approximately 6.10¹³ photons /s. (follows from the approximate relationship for braking radiation production efficiency given above in "X-ray tube", passage "Braking X-rays").
¨ Exposure
is the total amount of X-rays photons, which determines the quality of X-rays images and also the radiation exposure of the patient. It is given by the product of radiation intensity I_X (photon fluence /s.) and exposure time T - it is therefore proportional to the product of anode current by X-ray tube [mA] and exposure time [s]: "milliampere-seconds" mA.s = Q, which is the total charge Q electrons or the electrical amount that passes through the X-ray lamp during exposure (the coefficient of proportionality h is given above in the section "Braking X-rays"). At Q= 1 mAs, approx. 10¹³ of photons is radiated from the anode, of which only a small part is used for X-ray imaging - of most photons flying in different directions, only a relatively narrow conical beam is selected by collimation, low energy photons are further removed by filtration (see below).
Note: The energy of X-rays does not depend on the magnitude of current, time or electrical amount.
  For the acquisition of common skiagraphic images of soft tissues, the exposure to X-rays of about 2 - 6 mAs is used, for the skeleton about 20 - 80 mAs, for CT even 200 mAs. In modern X-ray devices capable of operating in a pulsed mode with high instantaneous power, a high current value [mA] at a short exposure time [s] is preferred to achieve the desired exposure [mAs] - thus reducing the risk of blurring the image with patient movement.
   Based on empirical experience, the recommended value of anode voltage [kV] and exposure [mAs] is determined for each type of X-ray examination, providing a quality image of the required structures at a relatively low radiation exposure. Some devices also use automatic exposure, which electronically switches off the anode voltage in the generator - and thus the exposure - after reaching a certain preset "amount" of X-rays. For the purposes of automatic exposure, the flux of transmitted X-rays is monitored by means of ionization chambers placed behind the film cassette or behind the flat panel. For digital imaging detectors, presetting the total number of pulses stored in the digital image can also be used to interrupt the exposure. Similarly, exposure optimization works for CT instruments, where according to the signal level from the detectors in the pre-planning radiographic display of SPR (topogram), the optimal current values [mA] can be automatically adjusted during self-diagnostic scanning - ATCM (Automatic Tube Current Modulation), see below "CT".
The already generated X-rays are subsequently treated by filtration :
¨ Filtration, collimation 
The soft X-rays of longer wavelengths and the low energy of photons at the beginning of the continuous spectrum of X-radiation are of no significance for diagnosis, they are usually absorbed in the skin and shallow layers of tissue - causing only unwanted radiation exposure. Therefore, it is removed by filtration - an aluminum or copper plate about 1.5-4 mm thick is inserted into the radiation path, which absorbs the soft component of X-rays to a large extent, while transmitting the harder component - see the shape of the spectra in Figure 3.2.5. The initial partial filtration of the generated X-rays is already created by passing through the material of the anode, the glass flask of the X-ray tube, the cooling oil, the material of the cover and the outlet window (thus the X-ray tube glass flask itself acts inherently as a partial filter, equivalent to about 0.5 mm Al; similarly the cooling oil and the X-ray tube cover window).
   In some special cases when we need sharper and more selective filtering of certain areas of the energy, so used filtration K-edge (K-edge filter). It is based on significantly increased ("resonant") absorption of photon radiation at energy equal to or slightly higher than the binding energy of electrons on the K-shell of atoms of the material used (see §1.6, section "Interaction of gamma and X-rays", Fig.1.64). By combining a standard filter (Al, Cu) and a filter made of a suitable heavier material using the K-edge effect, we obtain a bandpass filter, selecting a certain section of energies from a continuous spectrum of X-rays. This is especially true for mammography, where a molybdenum or rhodium filter cuts off photons of higher energies than about 20-23keV to achieve better contrast (see "X-ray mammography" below). Also for DEXA methods - analysis of absorption using two X-ray energies (see below "CT with 2 X-ray tubes- DSCT: Dual Source and Dual Energy CT").
   The geometric delimitation of the X-ray beam is performed by collimation (mentioned above) .

Fig. 3.2.5. Basic scheme of X-ray examination.
Left: Arrangement of X-ray tube, filter, DAP-meter, primary and secondary diaphragm, film or detector. Right: Energy spectra of X-rays from X-ray tube, after filtration and after passing through the patient.

Scattered X-rays
When X-rays interact with matter, Compton scattering of photons on free or weakly bound electrons occurs, among other things. These scattered photons fly out of the tissue with lower energy and in different directions. The proportion of scattered radiation is greater the larger the patient (and is also higher for harder X-rays from tube - higher voltage [kV]). Scattered radiation degrades the quality of the X-ray image - it reduces its contrast. The possibility of suppressing scattered radiation is mentioned in the following paragraph. This Compton-scattered X-rays further cause some small radiation exposure even outside the X-ray beam itself from the X-ray tube. This radiation exposure is not high, scattering albedo of the human body for X-rays is less than 1% (albedo was discussed in §1.6, section "Interaction of radiation passing through matter") . At a distance of 1 m, the radiation dose is about 0.1 mGy /1 mAs, in 2 meters only about 0.005 mGy /1 mAs. Nevertheless, during X-ray examinations, radiation workers should not stay in the examination room during the exposure, unless necessary, but in a shielded control room - the exception is, for example, interventional radiological procedures.
Filters and apertures for X-ray imaging
In the practical diagnostic application of X-rays, it is important to use filters and collimating screens - Fig.3.2.5. Suitable primary apertures ensure the geometric delimitation of the X-ray beam, reaching only the necessary examined area (a sharp image with high spatial resolution is ensured by the fact that the radiation comes from an almost point focus on the anode by X-ray tube, as described above). Immediately behind the X-ray tube is placed a primary filter, most often made of aluminum sheet, which absorbs low-energy photons (from the beginning of the continuous X-ray spectrum), which are not usable for imaging (they would penetrate only into the subcutaneous tissue) but would increase the patient's radiation exposure (mentioned above). This is followed by a tubus with adjustable diaphragms for the geometric delimitation of the X-ray beam (size of the imaging field). A thin plane-parallel ionization chamber is usually mounted on the outlet window of the tube for monitoring the exposure to X-rays, the so-called DAP meter (see below "Radiation load during X-ray examination"), allowing to determine the radiation dose of the patient during X-ray examination - Fig.3.2.5 top left.
   A secondary aperture is then placed between the patient and the film (or screen or imaging detection system, flat panel). It is a lattice formed by parallel or diverging absorption lamellae (lead strips) which, through their gaps, transmit only primary X-rays passed in the direction of the original beam, while secondary Compton-scattered photons (moving in other directions) are absorbed in the partitions. It is therefore a collimator, which attenuates the radiation only minimally in the primary direction, while the attenuation of the obliquely transmitted scattered radiation is considerable. The quality of the secondary screen is determined by the grid density (number of lamellae per centimeter) and the grid ratio (the ratio between the distance of the absorbent strips and their height). Suppression of secondary scattered radiation significantly improves the contrast of the X-ray image. On the other hand, the secondary aperture also absorbs some of the useful X-rays (eg with a Bucky aperture, the attenuation is about 1.8 times), so it is necessary to increase the exposure. Three types of secondary screens (grids) are used :
- Converging focused Bucky-Potter screen (approx. 10 slats /cm). The Bucky screen has relatively thick partitions (approx. 1 mm), which would be projected into an X-ray image and have a disturbing effect. This disturbing raster is eliminated by moving the aperture during exposure, blurring its image and disappearing into the overall background.
- Parallel fine Lysholm screen (40-60 slats /cm).
- Ultrafine Smith screen (density >100 lamellae /cm). Due to too high absorption, it is not used in practice.
Terminological note: In radiodiagnostics, it is often customary to use the not very precise generic name "aperture". More precisely, however, these are collimators and filters.

Visualization and recording of X-ray images
X-rays, carrying density information after passing through the displayed tissue, is invisible to us, so it is necessary to "make it visible" or register it using suitable material and electronic methods. There are basically three ways to display this X-ray :
- Visual observation of the image on a luminescent screen
A luminescent screen is a plate or foil on which is coated with a layer of suitable material (such as zinc sulphide, .......), in which fluorescence is produced upon interaction with ionizing X-rays. Thus, we can see a projection density image on the luminescent screen via X-rays. The advantage of this simplest method was the possibility of continuous dynamic observation - sciascopy. However, the main disadvantage is the low sensitivity and high radiation exposure of both the patient and the radiologist...
- Imaging on photographic film
Ionizing X-rays cause a photochemical reaction in suitable photographic materials, mostly containing silver bromide. This photographic emulsion, coating on the surface of a plastic film, forms a photographic film in which the incident X-rays form a latent photographic image - is described in more detail in §2.2 "Photographic detection of ionizing radiation". After development, we receive a negative density photographic image in X-rays.
- Scanning with an electronic imaging detector,
which registers incident X-rays, converts it into electrical impulses and, after procesing by complex electronic circuits, creates digital density images in computer memory - this most advanced method is described in more detail below "Electronic imaging X-ray detectors"...
Amplifiers and digital sensors of X-ray image; indirect and direct digitization
Direct X-ray photographic film for display belongs to the past, and is gradually replaced by more sophisticated technologies. To increase the sensitivity of the scanning X-ray suitable image enhancement methods are used in the image, more recently methods of electronic image capture. This makes it possible to significantly reduce the required intensity of X-rays and thus the radiation dose for the patient, as well as to reduce the undesired exposure for radiation workers.
- Amplifying foils
 During photographic skiagraphy, amplifying luminescent foils are attached to the film, the task of which is to convert X-rays into light, which is exposed by the photographic film. It consists of a layer of phosphor dispersed in an emulsion of gelatin or nitrocellulose. Use calcium tungstenate (emits blue light), lanthanoxid bromide (blue light), gadolinium-carryover (green light), barium chloride (blue light)... The film has to be sensitized to the color of the light from the phosphor. It is already abandoned.
- Xeroradiography ,
where a positively charged semiconductor (selenium) plate is used instead of film. The incident photons of X-rays there evoke a photoeffect, in which the photoelectrons locally compensate for the original positive charge - a latent electrostatic image is created ; in the copier, powder particles of dye are then attracted to differently charged places of the plate, which are finally printed on paper where a visible image is created. It is also abandoned.
- Memory foils
replace the film in the X-ray cassette and retain a latent electron image after radiation exposure. The sensitive layer usually contains europium atoms (BaFCl: Eu²⁺, instead of Cl it can be iodine or bromine). The impact of X-rays photons excites in the sensitive layer of the film, electrons are released from the europium atoms, which are trapped in the halide metastable levels of so-called "electron traps" - a latent electron image is formed . This latent image is made visible after exposure by photostimulation using a laser infrared beam: a "trapped" electron is released into the conduction band, after which the electron is captured on the excited surface in the luminescent center, followed by deexcitation to baseline, accompanied by photon emission of light. This light is registered by a sensitive photomultiplier, the generated electrical pulses are sampled and converted by an analog-to-digital converter into digital image information. The device that reads and digitizes the latent image is called a digitizer - it is an indirect digitization of an X-ray image. It will be temporarily used for some time...
- Image intensifiers
During sciascopy, the image on the fluorescent screen ("shield") is amplified by a special image tube - image intensifier. The light image created by the impact of X-rays photons on the fluorescent screen of the inlet window of the tube causes a photoelectric effect on the enclosed photocathode by its emitted photons of visible light. The emitted photoelectrons are accelerated by a voltage between the photocathode and the anode (approx. 10-20 kV) and directed by electron optics to a second luminescent screen, where they create a reduced inverted image, but its brightness is more than 1000 times greater than the original image. This image is then optically captured by a video camera and displayed on a TV screen or computer monitor. It is still used for older devices, new devices are already supplied with digital flat-panels.
- Electronic imaging detectors - flat panels 
All of the above image amplifiers or television sensors are only a temporary technical solution. New systems are equipped with an electronic digital image sensor on a compact so-called flat panel, consisting of a scintillator (e.g. cesium iodide CsI: Tl or based on gadolinium Gd₂O₂S:Tb - GOS; see §2.4 of scintillators, the "Scintillators and their properties") and semiconductor optoelectronic amorphous silicon (a -Si). The detection panel consists of a large number of elements - cells, pixels, assembled into an image matrix of about 2000 x2000 elements, and more. The most perfect imaging detectors are semiconductor pixel detectors (SPD), see §2.5 "Semiconductor detectors". The pulses from the individual elements of the detector are stored in multiplex mode with the help of an analog-to-digital converter (ADC) directly into the computer's memory - they create a digital X-ray image. Only this technology of so-called direct digitization belongs to the future... - it was described in more detail below in the section "Electronic X-ray imaging detectors".
Note: The terminology of "direct" and "indirect" digitization is temporary and will be abandoned soon: all X-ray images will be automatically primarily digital (using of technology now called "direct digitization").

Electronic imaging detectors of X-radiation
The former X-ray imaging using photographic film or a luminescent screen is now generally being replaced by electronic imaging detectors - Fig.3.2.6. The advantage is significantly higher detection sensitivity and wide possibilities of electronic and computer image processing (digitization). All these imaging detectors are based on modern technologies called quantum optoelectronics (photonics), which use an internal or external photo effect to convert photons into electrical signals.
¨ Image intensifier
Electronic imaging with image intensifier was widely used in the 1960s - 1980s - Fig.3.2.6 left. The image intensifier is a special vacuum tube with two windows - input and output. On the inside of the inlet window is a layer of scintillator (mostly cesium iodide) and below it a thin metal layer of photocathode. The incident X-rays cause flashes of light in the input scintillation layer, which by photoefect eject electrons from the photocathode. The electrons thus generated are then attracted by annular accelerating and focusing electrodes, to which a high positive voltage is connected (gradually increasing up to about 30 kV at the anode at the output scintillator). This electro-optical system, acting as a conjunctive "electric lens", throws electrons onto an output scintillator (mostly ZnS: Ag), where the accelerated electrons produce intense flashes. Thus created reduced, inverted but very clear ("amplified", intense) image is then captured by an optical TV camcorder and (analog) displayed on the TV screen. Later, digital CCD camera imaging with computer image recording was used. Image intensifiers or TV sensors were just temporary technical solution, the future belongs to fully digital X-ray image sensors - flat panels :

Fig.3.2.6 Electronic imaging detectors in X-ray diagnostics.
Left: X-ray acquisition using an image intensifier. Middle: Flat-panel with indirect (scintillation) and direct (semiconductor) conversion of X-rays into electrical signals. Right: Ring-arranged CT detectors with fast ceramic scintillators and photodiodes.

¨ Flat - panels
Modern and more advanced electronic X-ray imaging detectors are so-called flat panels ( flat - they have the planar shape of a thin plate), which provide signals for direct digital X-ray image. The detection panel consists of a large number of elements - cells, pixels, assembled into an image matrix of about 2000 x 2000 image elements, and more. The level of the electrical signal from each pixel is proportional to the intensity, resp. the number of X-rays photons incident on a given location of the flat-panel. From electronic multiplex registration circuits (multiple read-out) the image signal via the ADC is fed to the image matrix of the computer, in the individual elements ( pixels) of which information about the intensity of X-rays from the corresponding location of the irradiated object is stored. In terms of the method of detection and converting X-rays into electrical signals, flat panels of two types are constructed :
- Scintillation detection (indirect conversion) ,
when photons of X-rays impinge first on the layer of scintillator material (most commonly used cesium iodide CsI: Tl) *) in which they evoke flashes of visible light (scintillators and their use for the detection and spectrometry of ionizing radiation is discussed in detail in §2.4 "Scintillation detection and gamma-ray spectrometry"). This scintillation light then enters the semiconductor photodiodes (mostly silicon - a-Si - amorphous silicon is used as the semiconductor material), in which an electric charge is released by the internal photo effect (electrons and "holes") and the light is thus converted into an electrical signal - Fig.3.2.6b. The term "indirect conversion" here means, that X-rays are first converted in the scintillation layer into visible light, which is then converted into an electrical signal in the photodiodes. This flat panel design is currently the most widely used.
*) Scintillation crystals of some flat panels have a "fibrous" design. They are composed of densely spaced thin vertical needles. This design reduces the lateral scattering of light scintillations, leading to a sharper image.
ISS technology
Some new types of flat panels with scintillation conversion have a somewhat curious design with "opposite orientation" with respect to Fig.3.2.6b: the displayed X-rays are coming on the side of the layer of photodiodes and reading TFT transistors, passes through this layer and then impinges on the CsI scintillation crystal. Scintillation interactions then usually occur in a layer near the photodiodes, thereby reducing lateral scattering by scintillation and improving resolution. This solution, referred to as ISS (Irradiated Side Sampling) technology , is made possible by the electronic miniaturization of the photodiode and reading circuit layer, which is thin and has virtually no effect on the transmitted X-rays.
- Semiconductor detection (direct conversion) ,
where photons of X-rays fall directly into semiconductor detectors (suitable material is CdTe, CdZnTe, or Si for lower energy). Absorbed X-rays create electron-hole pairs, electrons in a strong electric field drift to the anodes, where they generate short electrical pulses (approx. 10^-9 s). The amplitude of these pulses is proportional to the energy of the absorbed X-ray photons. Thus, photons X release electric charges through their interaction and are directly converted into an electrical signal (the general principle of semiconductor detectors is given in §2.5 "Semiconductor detectors") - Fig.3.2.6c. They are also constructed in smaller dimensions (in the order of centimeters - MEDIPIX ) with a very high density of miniature image elements (high image resolution) and are used in special laboratory methods such as X-ray microscopy (mentioned above), or animal X-ray imaging. Flat panels with direct semiconductor detection are still only rarely used in clinical X-ray diagnostics, but they certainly have a future. Compared to scintillation conversion, they have significant advantages and provide new possibilities in X-ray imaging :
Spectrometric Photon-counting X-ray imaging
During X-ray diagnostics, the examined tissues and organs are irradiated with X-rays with a continuous spectrum of a wide range of energies - almost from zero to the maximum energy, given by the value of high voltage in the X-ray tube. In scintillation conversion, all signals from the photodiodes are registered integrally, regardless of the energy of the X-photons from which they originate. Including electronic noise of detection system, which may be dominant at low X-ray flux. However, direct semiconductor detection allows independent registration of individual X-ray photons: "photon couting". And then electronic analysis of the amplitudes of these pulses - performing spectrometry of the detected X-rays.
Terminological note: Instead of the name "photon-counting imaging", which was introduced in the field of radiodiagnostics, the name "photon-spectrometry imaging" would be more apt from a physical point of view, as energy (spectrometric) analysis of detected X-rays photons is important here (rather than simple "photon counting").
  By suitable setting of the lower discriminant level of the amplitude analyzer (to a value corresponding to approx. 20 keV) it is possible to completely cut off the electronic noise of the detector. We obtain contrast images with reduced noise, given only by statistical fluctuations of the detected X-rays. This allows you to reduce the radiation dose while maintaining good image quality.
  By using two or more different amplitude- energy windows of the analyzer, images can be obtained for different energies of transmitted X-rays. We can then use the material-specific difference in the absorption of X-rays of different energies for material-tissue differentiation of the displayed structures, which otherwise show the same density attenuation in a conventional X-ray image. It can be, for example, a material differentiation of the composition of kidney stones. This possibility of material analysis in X-ray images is discussed in more detail below in the section "Dual- and multi-energy X-ray imaging. Material composition analysis.".
Adverse effects at spectrometric photon-counting detection
Under optimal conditions, photon-counting detectors can provide better energy separation with less overlap than with dual energy X-ray technology. But there are some adverse physico-electronic influences that reduce this energy separation. X-ray photons absorbed around the boundaries of the detection pixels can be divided - shared - by neighboring cells in the detector. In the material of the detector, excitation and deexcitation of electrons on the K-shell also occurs with the emission of fluorescent photons, that can escape and be detected in neighboring cells. At high intensities (flux) of X-rays, the dead time and the pile-up effect of semiconductors are also adversely affected, whereby some signal pulses overlap and are not registered separately, but as a single pulse. This signal-sharing between cells, dead time, and pile-up effect of semiconductor detectors can impair spectral separation, spatial resolution, and detection efficiency.
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Terminological note:  Please do not confuse indirect and direct X-ray conversion in flat panels with indirect and direct digitization of X-ray images! It has nothing to do with it, here it is always a direct digitization, only with a different physical-technological design.
  In both cases of the flat panels, the electrical signal from the photodiodes or semiconductor detectors is sensed by a special matrix of TFT (Thin Film Transistors) transistors implanted in thin-film integrated circuit technologies on a glass support. Scanning, so-called read-out, takes place in multiplex mode in the X and Y directions - it provides coordinate pulses about the position of the X-ray photons detection location in the flat panel. These coordinate pulses are converted to digital form by an analog-to-digital converter (ADC) and stored in the corresponding memory addresses in the image matrix of the computer - a digital X-ray image is created. The transfer of image data to the acquisition computer from some modern flat panels is solved wirelessly using modems (WiFi).
  Electronic imaging flat-panels are also used in verification and dosimetric systems of so-called image- guided radiotherapy with modulated beams - in isocentric irradiators with a linear accelerator and in cybernetic gamma knifes (§3.6, part "Isocentric radiotherapy" and "Stereotactic radiotherapy SBRT"); they are sometimes abbreviated EPID (Electronic Portal Image Device).
¨ X-ray detectors for CT
The current CT X-ray detectors work on a similar principle as flat-panels with indirect conversion. They consist of a large number of semicircular arranged elements, each of which is a small scintillation crystal (scintillators based on rare earth-doped silicon oxides, such as lutetium and yttrium - LYSO, or gadolinium oxisulphide, with a very short flash duration are now used), optically coupled with photodiode; see below "X-ray tomography - CT", section "X-ray detectors for CT ".
  Instead of scintillation detectors, semiconductor detectors are gradually being introduced, which convert X-ray photons directly into electrical signals. This method, called photon-counting CT, provides more quality images with lower noise and the possibility of spectrometric analysis .......
Properties of electronic X-ray detectors
An important characteristic of electronic imaging detectors is their spatial resolution, which is the smallest distance of two "point" objects at which they still appear as two separate structures; or equivalent to the half-width of the point object image profile (FWHM). At shorter distances, both objects appear as one, they are not distinguished. The resolution is given mainly by the size of the individual pixels of the detector (this limits the smallest possible point that can be displayed), it is also affected by the scattering of X-rays and light in the detector and the processes of converting X-rays into electrical signals. As in photography, resolution is often measured at the maximum number of lines per millimeter [lp/mm], which can still be distinguished. Modern flat-panels theoretically reach up to 10 lp/mm, which corresponds to a resolution of 0.1 mm; in practice, however, the real resolution is around 2-5 lp/mm. The quality of X-ray images in terms of real resolution is sometimes quantified in detail using the so-called modulation transfer function MTF, which indicates using Fourier harmonic analysis, which details of the object can be displayed with a given contrast.
  Another important parameter of electronic X-ray detectors is the sensitivity of the sensor. It is reported numerically using the detection quantum efficiency DQE (Detection Quantum Efficiency), which is the percentage of X-ray photons incident on the detector that is actually recorded by the detector and used to create the image (the rest is uselessly absorbed by the input window or detector material, without a scintillation or electrical response).   Electronic imaging detectors enable more detailed analysis of fine structures using enlarged image sections - so-called "zoom" or "magnification". In the case of image intensifiers, this is an analog zoom (achieved by changing the voltage), in which a smaller part of the input area is "stretched" over the entire image at the output. In the flat panel it is a digital zoom - additional software zoom of the selected part of the image, without changing the resolution. If we want to maintain a high image quality on the magnified image (maintain the same signal-to-noise ratio as in the basic image), it is necessary to increase the number of incident photons, which will increase the dose. Digital X-ray systems, including CT, are equipped with software providing a number of other options for computer image editing - post-processing.

Dual- and multi-energy X-ray imaging. Material composition analysis.
Different tissues and organs differ in their chemical composition, which may or may not be reflected in their different densities. If two adjacent structures in the body have the same or close absorption coefficient (linear attenuation coefficient) for the X-rays used, they will be indistinguishable from each other on X-ray images - they will appear identical, even if their material (chemical, elemental) composition is significantly different. Differentiation or classification of different tissue types by standard X-ray imaging is therefore very difficult and often impossible. Standard X-ray diagnostics, using X-rays from a continuous-spectrum from X-ray tube, is basically only anatomical-morphological, density-based, not functional-physiological.
  A certain possibility of at least partial resolution of the material composition of the displayed structures is measurement - imaging - at different X-rays energies - X-rays spectrometry. By using two or more different energy windows, images can be obtained for different energies of the transmitted X-rays. We can then use the material-specific difference in the absorption of X-rays of different energies for material-tissue differentiation of the displayed structures, which otherwise show the same density attenuation in a conventional X-ray image. This could, to some extent, overcome the traditional limitations of X-ray diagnostics to a mere density morphology ..?..
  Different types of substances (and tissues) differ not only by specific values of linear attenuation coefficients m for X radiation of a certain energy, but also by somewhat different dependence m(E_X) of absorption for different energies E_X of radiation X. This is due to different electron density configuration at different atomic and the molecular composition of the analyte. For X-rays of energies used in X-ray diagnostics (approx. 20-150 keV) there is an interaction with tissue by photoeffect and Compton scattering - §1.6 "Ionizing radiation", section "Interaction of gamma and X-rays", Fig.1.6.3. For the effective cross-section of the photo effect, the approximate dependence s(E_X) ~ Z⁵/E_X ³ applies, where E_X is the energy of X-rays photons and Z is the proton - atomic number of the substance (Compton scattering absorption is only slightly dependent on E_X energy). For the passage of X-rays through a substance of density r, the linear absorption coefficient will be m(E_X,r) ~ r. Z_eff ⁴ /E_X ³, where Z_eff is the average - "effective atomic number" of this irradiated substance.
  Mathematical analysis of the exponential laws of absorption I = I_o.e^-m(Ex).d for individual energies E_X and tissue types with absorption coefficients m(E_X) (by logarithm the relevant exponential equations are converted to linear) can determine the proportion of absorption in different tissues with different effective atomic number. This can in principle be used to additionally distinguish different types and compositions of tissues based on differences in the density images of the same site, obtained with different energies E_X of radiation. This method of differential density analysis DEXA (Dual Energy X-ray Absorptiometry) is similar to that used for density images in "Bone Densitometry" (see Fig.3.2.11 below).
  Not only does this provide more detailed anatomy images, but in some cases it allows different types of tissue to be distinguished (eg bones, blood vessels, adipose tissue), different types of kidney stones, deposition of sodium urate crystals in joints (gout), or quantification of contrast medium distribution in myocardium.
Virtual X-ray images
A notable benefit of two- and multi-energy X-rays imaging is the ability to subtract - suppress, remove - structures of a particular material from images: create virtual images, in which are remove certain significant structures that can be disruptive and overlap some other important details. Differences in atomic numbers make it possible to distinguish calcium and iodine using the dual-energy imaging technique. It is, for example, the identification and removal of bone images, which improves the direct visualization of blood vessels with iodine contrast agent. In a similar way, images of calcified plaques (which over-cover the lumen of the vessel) within the vessels can be identified and removed from CT images in angiography with contrast agent, allowing a clearer visualization of the patency of the vessels and areas of stenoses. Or create virtual images with iodine removal to more clearly assess the underlying soft tissues, or better visualize smaller kidney stones (which could be overwhelmed by the presence of iodine contrast agent).

Angiographic image of a section of the aorta. Up: Calcified plaques at several sites of the stenosis over-cover the lumen of the vessel. Down: Calcium plaques can be identified and subtracted in the 2-energy analysis, providing a clearer visualization of vascular patency in the area of stenoses (indicated by arrows). (Angiographic images were taken by MUDr. .... from the Radiodiagnostic Institute of the University Hospital Ostrava) ! replace with our image!

Realization of dual- and multi-energy X-ray imaging
Dual or multi-energy X-ray imaging can be technically performed in basically four alternative methods :
At the resource level :
-> Use of two X-ray tubes with different anode voltages. This is described below in the section "CT with 2 X-rays - DSCT: Dual Source and Dual Energy CT", Fig.3.2.9.
-> Use of one X-ray tube, whose anode voltage is electronically switched between low value (approx. 50 kV) and high value (approx. 120 kV). It is desirable that this switching be fast enough so that there are no motion changes between the energies (when used in CT, it is recommended in milliseconds).
At the detector level :
-> A dual-layer detector with one X-ray tube with the use of two layers of detectors that selectively detect the low- and high-energy component of X-rays (mentioned above in the section "X-rays detectors for CT", section "Dual-layer CT detectors").
-> Spectrometric Photon-couting X-ray imaging with one X-ray tube and semiconductor detectors, enabling flexible energy spectrometry of detected X-rays (described in the section "Electronic X-ray imaging detectors", paragraphs "Semiconductor detection (direct conversion)" and "X-ray detectors for CT"). This method is the physically most perfect, providing a multi-energy imaging.
  We deal with the physical and technical aspects of these methods in the sections "Electronic X-ray imaging detectors" - "Spectrometric Photon-counting X-ray imaging", "X-ray detectors for CT" and "CT with 2 X-rays - DSCT: Dual Source and Dual Energy CT ".

X-ray planar imaging - skiagraphy, sciascopy
X-ray projection
The human body is a complex 3D system of a large number of differently arranged tissues, organs, bones, body cavities, etc. During X-ray transmission imaging, these individual structures can be mually "ovesshadowing" and overlap each other - this can prevent their good display and recognition of possible anomalies. This interference and the overlap of the displayed structures substantially depends on the angle of transmission beam. As a rule, it is possible to find the projection angle for which the lesion is best shown, without disturbing from surrounding structures. Based on the long-term experience of radiologists, certain projections are prescribed for planar X-ray examinations of each organ or area, that provide the best imaging - eg anterior-posterior AP projections, anterior-posterior PA, left LL (latero-lateral, also SIN-sinister) or right RL (right-lateral, also DX-dextrum) side projections, oblique projections left LAO (left anterior oblique), LPO (left posterior oblique), or right RPO, RAO and other projections and special positions. The problem of overlapping structures is largely eliminated in CT X-ray tomography - see "X-ray tomography - CT" below, which provides images from different angles and projections.
  In terms of X-ray imaging and processing, planar X-ray diagnostics are divided into two groups :
¨ Skiagraphy
In simple X-rays imaging, called skiagraphy, incident X-rays passed through the examined tissue on photographic film containing silver halides (silver bromide), in which photochemical reaction leads to the release of silver from the bond in the compound - formed latent image, which is in development in the developer visualized with the density of grains of colloid silver; the remaining silver bromide is dissolved in the stabilizer. The blackening density of the film is proportional to the amount of X-rays passed. The resulting X-ray photographic image represents a negative imaging of tissue density: sites with low density (soft tissues) have lower absorption and therefore high blackening, sites with high density (eg bones) absorb X-rays more and are therefore shown light (low blackening) on the film.
   For X-ray imaging, special films are used, the emulsion of which is thicker and contains an increased content of silver halides compared to conventional photographic materials *). Films are produced in various sizes - the smallest fields of approx. 2x2cm are used for dental X-ray diagnostics, the largest formats of approx. 43x43cm for lung imaging, or 96x20cm on the spine. At X-ray imaging, films are stored in a special light-tight cassette, provided with metal marks and letters at the edge, which are projected onto the film during exposure, are visible after development and ensure the geometric orientation and identification of the image. In the dark chamber, they are then removed from the cassettes, special concentrated developers are used to develop them, providing high contrast and saturation of the blackening of the film; the process of developing, setting and drying is carried out in developing automats.
*) The photochemical sensitivity of films is relatively low for X-rays. To increase the sensitivity (and thus reduce the required amount of X-rays, reduce the radiation exposure of the patient), amplifying luminescent foils were attached to the film, now all this is abandoned.
   Overall, however, the use of films and the "wet process" is in decline, it is mostly already abandoned. The future belongs to electronic digital X-ray imaging (see below). In connection with this, in the case of modern digital devices, the difference between skiagraphy and sciascopy is largely blurred - in a computer system it is possible to choose whether the recording of a digital image will be static or dynamic.
¨ Skiascopy
Skiascopy or fluoroscopy is a continuous visual observation of an image of the transmitted X-rays, originally on the fluorescent screen ("shield"). Direct sciascopy was used very often in the past, but due to the high radiation exposure of the examining radiologist (and also the patient), it has already been abandoned. Indirect sciascopy is performed on devices equipped with an image intensifier and electronic image capture, more recently direct electronic digital image capture by flat panel (see below). This indirect sciascopy is now used to investigate of dynamic processes (coronary arteriography, transhepatic cholangiography, ...) and in interventional procedures where visual inspection is required - X-ray navigation of precise work performed inside the body *) - insertion of various probes and catheters, implantation of pacemakers, coronary angioplastics, insertion of vascular or uterorenal stents, ... etc. - see below "Subtraction angiography", Fig.3.2.7. In radiotherapy, it is the introduction of radiophores by afterloading during brachytherapy (see §3.6, section "Brachyradiotherapy").
*) To reduce the radiation exposure, pulse mode is now used in sciascopic imaging : the X-ray does not glow continuously, but periodically turns on only for short moments (approx. 0.1 sec. with a repetition rate of approx. 4 frames/sec.), during which produces an image. To improve the visual quality of the images thus generated sequential frames use is sometimes so called recursive filter, consisting of the weighted summation of several consecutive images.
   X-ray tube and an opposing imaging detection system are often mounted on a special "C" shaped stand - called C-arm - Fig.3.2.7b. This arm can be rotated to different angles using electromotor, which allows quality display in various projections. Similar flexible possibilities of movements of the X-ray tube and the imaging detector around the patient are provided by the so-called U-arm (independent movement of the X-ray tube and the detector on the stand) - Fig.3.2.7c. Alternatively, so-called tiltinable walls can be used; these possibilities were mentioned above, the section "Mechanical design of X-ray devices".

Contrast agents. Subtraction radiography.
One of the main difficulties in soft tissue X-ray imaging is the small differences in the absorption of X-radiation by individual tissues *), leading to low image contrast and difficulty in distinguishing some structures.
*) The tissues of the human body are mainly formed by atoms of light elements (hydrogen, carbon, oxygen, nitrogen, sodium, ...) and have a similar density of just over 1 g/cm³. Therefore, the absorption coefficients for X-rays in individual tissues do not differ much (with the exception of more massive bones and lighter aerated lungs).
   In certain cases, the natural absorption differences between the tissues can be increased and thus the resulting contrast of the X-ray image can be improved by applying suitable contrast agents. Contrast agents artificially increase the contrast of tissue imaging by causing greater differences in the X-ray absorption of the examined tissue relative to the surrounding environment. Usually we try to increase the absorption of X-rays by using substances containing atoms of heavy elements such as barium (cavities, eg stomach) or iodine (vessels, organs). X-rays are strongly absorbed by these substances, which negatively highlighting the cavities that are filled with them (stomach, digestive tract, blood vessels). If such a substance is introduced into the examined area - the gastrointestinal tract, blood vessels, bile or urinary tract, the structure filled in this way shows a significantly increased absorption of X-rays and is clearly and contrastily displayed on the X-ray image, including possible defects and anomalies. After application, contrast agents can enter into the organ under investigation either directly (direct application to the gastrointestinal tract or blood vessels), or indirectly via metabolism (imaging of structures in the liver or kidneys).
   Contrast agents are classified according to various criteria. According to water solubility: insoluble (barium suspension, iodine substances oil and suspension) and soluble (hydrosoluble). According to their ionization (dissociation) in solution: ionic (dissociate in solution into anion bearing contrast iodine and cation) and nonionic. According to pharmacokinetics, metabolism in the body and route of excretion: nephrotropic (excreted by the kidneys) used for angiography, urography, contrast CT; hepatotropic (excreted by the liver and bile) for cholangiography. In terms of the achieved change in X-ray absorption, we divide contrast agents into two basic types :
¨ Positive contrast agents , which increase the absorption of X-rays. The most commonly used contrast agents are based on barium and iodine .
Barium sulphate (BaSO₄) is a water-insoluble compound whose suspension ("barium slurry") is used in the examination of the digestive tract.
Currently, the most commonly used contrast agents are based on iodine, which has two advantageous properties :
1. ¹²⁷I shows high absorption for X-rays of the energies used in X-ray diagnostics - it provides a good positive contrast of the structures into which it enters.
2. Iodine can form compounds with a number of organic substances that behave in the body in the necessary well-defined way. In such an organic substance, the absorption properties for X-rays are given by the bound iodine atoms, while the other organic part of the molecule determines the pharmacokinetics and distribution of the substance in the organism - where the substance "gets" or where it is taken up and excreted.
   Iodine contrast agents are used in the form of organic compounds in which iodine is tightly bound, mostly in the benzene nuclei of cyclic (aromatic) hydrocarbons. It is mainly triiodaminobenzoic acid, where 3 iodine atoms are attached to the benzene nucleus (1,3,5-triiodo-2-aminobenzoic acid derivatives, they are usually ionic and non-ionic). Furthermore, pyridine derivatives with one or two attached iodine atoms in the molecule are used (they usually have the character of ionic substances).
   Water-soluble (hydro-soluble) contrast agents, especially ionic ones, can cause some undesirable side effects in the body, allergic reactions can be dangerous.
¨ Negative contrast agents reducing X-ray absorption. These are mainly gases (air, carbon dioxide) that are applied to the cavities (eg the spinal canal). Today, they are practically no longer used .
   In some cases, especially in the digestive tract, the so-called double contrast is used : first a positive contrast agent (barium suspension) is applied and then a negative contrast agent - air (from effervescent powder), which expands the positive contrast agent to the walls of the examined volume.
X-ray subtraction radiography. DSA
A special method of increasing the contrast is the so-called subtraction radiography, consisting in the subtraction of two images of the same area, differing in the presence and absence, or distribution, of the contrast agent. The goal of subtraction is to highlight anatomical structures that would be little clear, indistinct, and difficult to recognize on conventional X-rays images.
   In the early days of the method (50s and 60s), film (photographic) subtraction was used, in which an X-ray image with a contrast agent was combined and overlaid with a negatively displayed image without a contrast agent. This combination (masking) created the resulting subtraction image, in which only structures filled with contrast material are visible. Further technical development, leading through analogue television subtraction, has resulted in the method of digital subtraction, which is the most perfect and now used exclusively. This method is used mainly for the selective imaging of the arterial and venous vascular bed - the contrast agent is injected at the appropriate time using a specially inserted catheter. It is called digital subtraction angiography (DSA) for arterial bed or phlebography for venous imaging.

Fig.3.2.7. a) Principle scheme of digital subtraction radiography operation. b) X-ray tube with electronic image sensor mounted on a C-arm. c) X-ray device in U-arm arrangement.

A simplified diagram of the principle of digital subtraction radiography is drawn in Fig.3.2.7a. The X-ray beam from the X-ray tube illuminates the patient's body and the transmitted radiation is detected by a digital image sensor ( flat-panel), consisting of a scintillator and a sensitive CCD image sensor. The most perfect imaging detectors are SPD semiconductor pixel detectors (see §2.5 "Semiconductor detectors"), mounted in so-called flat panels described above in the section "Electronic X-ray imaging detectors", Fig.3.2.6 in the middle. The X-ray tube and the detector are placed opposite each other on the so-called C-arm (Fig. 3.2.7b). First, a native X-ray image of the examined area without a contrast agent (formerly called a mask) is scanned into the computer's memory, and then an X- ray image after application of a contrast agent. Numerical digital subtraction of the native image from the contrast-enhanced image subtracts and cancels out all structures that have not changed (eg skeleton) and remains only what makes the two images different: contrast-filled cavities and vessels. The resulting subtraction image is created, in which only the structure filled with contrast medium is selectively displayed, while all other anatomical structures are more or less cancels.
  Proper subtraction can be adversely affected or impaired by tissue movements during the examination (in the time interval between the two images), such as breathing movements, heart pulsation, patient movement. To eliminate these adverse effects, a number of images are recorded at short intervals, from which images suitable for subtraction are selected. In addition, to monitor the kinetics of cardiac activity, the sequence of scanned images is synchronized with the ECG signal and images corresponding to end-diastole and end-systole are subtracted; it is thus possible, among other things, to obtain an image of the ejection fraction and to reveal possible disorders of the heart wall motility.
Tomographic 3D digital rotational angiography 
If angiography is performed on the C-arm, then by rotating the system (X-ray tube - detector) around the patient, a con-beam CT - imaging can be acquired and reconstructed - tomographic 3D digital rotational angiography, with the possibility of flexible spatial assessment of vascular patency at different sites.
The historical name "angio-line" 
Frequently used name "angioline" comes from the time when angiography performed on X-ray films (60th-70th years). At that time, a series - line - of cassettes with X-ray films in a row had to be prepared for the skiagraphic device, which were exchanged and exposed in quick succession after the injection of the contrast medium. They were then developed and inspected for where the contrast agent had gradually reached - or not - due to the occlusion of the vessel.
X-ray navigated interventional procedures
Subtraction angiography was originally developed as a diagnostic method. With the help of modern angiographic equipment and advanced methods of vascular medicine, in addition to diagnostics, it is possible to immediately perform the necessary interventional performance under detailed control of X-ray imaging immediately after finding out the pathological conditions in the vascular bed. These are, for example, coronary angioplasty (PTCA) - dilation of the narrowed coronary artery of the myocardium using a special catheter equipped with a balloon at the end, with possible by installation of a so-called stent, which remains stretched inside the coronary vessel and prevents it from shrinking again.

X-ray tomography - CT
Classical X-ray image is planar - it is a two-dimensional projection of tissue density to a certain plane. However, real tissue is a three-dimensional object, so a planar image that is a two-dimensional projection of tissue, can capture only part of reality. We cannot find out anything from the planar image about the arrangement of the tissue in the "deep third dimension", perpendicular to the displayed plane. Planar images have serious pitfalls in this respect - the possibility of overlapping and superposition of structures stored at different depths. Although we help here by displaying in several different projections, but the risk of a false finding or non-detection of an anomaly in the depths of the organism, covered by another structure, can never be ruled out. In the planar display occurs shine trough the X-rays from different depths, the superposition and accumulating information on the distribution density from all depht layers of tissues and organs in a common image. The resulting response in the image is the sum of the contributions from the individual layers of tissue - not only from the sites of the examined lesion, but also from the layers located above the lesion and below the lesion. In this way, the details of the structure of the examined organ at a certain depth can be overlaped by pictorial information from more distant and closer layers. The individual tissues and organs are shown in summary on the planar image, they overlap. We are not always able to unambiguously determine which organs and structures the X-rays have gone through and been weakened by. Superposition of radiation from different depths of the imaged object further leads to a reduction in the contrast of the imaging of structures and lesions.
   To overcome these disadvantages of planar X-ray diagnostics and to obtain a complex imaging of structures at different depths, transmission X-ray tomography *) has been developed to provide a three-dimensional imaging of tissue density in an organism. One of the main advantages of tomographic imaging is significantly higher contrast imaging of lesions that do not overlap on radiation from surrounding layers on transverse sections.
*) Greek tomos = section - tomographic imaging consists of certain sections (slices), primarily transverse, a larger number of which creates a three-dimensional image. The examined area is divided into a large number of thin layers (transverse sections), which are each scanned separately at many different angles, and from the local attenuation of X-rays, the density image of the layer is mathematically reconstructed in a computer. We can then view the examined area on the computer screen in individual thin layers - as if we were "cutting" the patient transversely, looking inwards at each incision and then folding it again (without damage).
  The forerunner of the current CT computed tomography was motion tomography : the X-ray tube and the examination table with the patient moved in opposite directions to each other in such a way that for a layer at a certain depth both movements were compensated and a sharp image was obtained, while in the other layers the image was motion blurred and al the less clear. However, the quality and contrast of such an image were not great (completely incomparable with CT), the method is long abandoned.
   Tomographic X-ray imaging is achieved by shine trough the examined area at a number of different angles (in the range 0-180-360°): the X-ray tube and the X-ray detector located opposite it circulate around the patient's body *), while a narrow beam of X-ray shine trough the examined tissue and its passed intensity is detected and converted into an electrical signal (Fig.3.2.8a); the attenuation of the beam due to tissue absorption is evaluated. From the larger number of individual integral values obtained by passed X-radiation under a series of angles 0-360°, the absorption map is then reconstructed by back projection, creating a cross-sectional density image of the examined area in a plane perpendicular to the X-ray and opposite detector rotation axis - see "Density image formation" below. In this image, structures stored at different depths in the organism are sensitively and with high resolution are displayed - it is a tomographic image. In such an image, we have endless possibilities of viewing the scanned object from all angles and in various layers (sections).
*) The X-ray tube and the opposite detection system are mounted on a special annular stand called gantry (gantry = portal, through-supporting construction), enabling the X-ray tube - detector system to rotate around the examination bed by means of an electric motor.
   By gradual longitudinal linear displacement of the patient with respect to the X-ray tube - detector system, we can create a series of cross-sectional images (individual layers), which placed next to each other create a three-dimensional tomographic image of the examined area. Due to the computational complexity of the reconstruction procedure, this can only be done with the help of a computer - therefore this method is called computerized tomography CT (Computerized Tomography) or computed tomography. The exact name "X-ray Transmission Computerized Tomography" did not take hold due to its length.

Fig.3.2.8. X-ray computerized tomography CT.
a) Basic principal scheme of CT. b) Principle of spiral multi-slice CT. c) Example of 64-slice CT instrument.

In addition to spatial tomography imaging, the main advantage of CT compared to conventional X-ray imaging is significantly higher contrast - is able to recognize and display even slight differences in the linear coefficients of attenuation of X-ray, that penetrates trough the examined tissue. This is primarily due to the principle of transverse section imaging using a narrow beam without being affected by adjacent layers and electronic X-ray detection, which is able to capture finer differences and a wider range of dynamics than conventional X-ray film. Methods of computer reconstruction and image filtering, as well as the possibility of flexible setting of optimal image modulation (brightness, contrast) also contribute to the excellent density resolution. Computer software for CT also has a number of tools for structural image editing, creation of three-dimensional images of certain organs, reconstruction of sections in other planes than the initial transverse in which the patient was scanned.
   The result of CT are real "anatomical sections" of the patient's body, on which organs and tissues can be seen separately, in contrast to planar X-ray imaging, where they are shown in summary and overlap.
  Before starting the actual diagnostic acquisition of CT, a trial, "exploratory" or "planning" planar radiographic acquisition CT, abbreviated SPR (Scan Projection Radiograph), is usually performed; it is also known as Scanogram or Topogram. It is scanned by a stationary (non-rotating) system of X-ray tube and detectors, mostly in AP or PA projection, in which the bed and patient move over the gantry. This creates a planar image similar to classical skiagraphy. This image is then used to determine the beginning and end of the displayed area of the body. Furthermore, the SPR image can be used for automatic exposure - obtaining absorption (attenuation) data for automatic regulation of the anode current [mA] by X-ray tube ATCM (Automatic Tube Current Modulation) in order to optimize the relationship between quality image and radiation exposure of the patient. This anatomical dose modulation technology significantly reduces the radiation dose in real time while maintaining the quality of the images.

Development of tomographic imaging method. 5 generations of CT devices.
General efforts to reconstruct a three-dimensional image based on a two-dimensional image (or a set of one-dimensional projections) date back to 1917, when J.Radon derived an integral transformation (now called the Radon transformation) between a set of line integrals and a set of transverse section points. In 1963, A.Cormack applied these results and extended them to the case of X-rays passing through partial absorption by a three-dimensional object. And in 1972, G.N.Hounsfield completed the development of the first CT instrument. 
   In the following years, the great advantages of CT were proven and these devices became very widespread. During the technical development, there were also significant changes in the design of individual electronic and mechanical parts of CT devices. In view of this technical development, CT devices are usually divided into five generations :
¨ 1st generation: X-rays from the X-ray tube were collimated into a thin beam (cylindrical "pencil" shape) and after irradiation and passing trough the patient it is detected by the opposite detector (as shown in Fig. 3.2.4a), rotating together with the X-ray tube.
¨ 2nd generation: X-rays from the X-ray tube are collimated into a fan shape and after passing through the patient it is detected by a larger number of detectors, placed in a row on a circular section opposite the X-ray tube, rotating together with the X - ray tube.
¨ 3rd generation: X-rays from the X-ray tube are collimated into the shape of a wider fan similar to the 2nd generation, but the transmitted radiation is detected by a large number of detectors placed on a circular arc in several rows (Fig.3.2.8b) - more slices - multi-slice CT. The continuation of the 3rd generation devices are the spiral high-speed multidetector MDCT systems described below .
¨ 4th generation: the detectors are arranged stationary in a complete circle (several rings lying next to each other) around the patient, while only the X-ray tube rotates.
¨ 5th generation: cardio-tomograph with electron beam - EBT - Electron Beam CT , described below, Fig.3.2.10.
   In the end, the 4th generation devices did not become very widespread, because at a higher price they do not bring significant benefits for clinical practice compared to modern design solutions for generation 3. devices (high-speed multidetector systems MDCT, see below). And the 5th generation, electron beam CT, due to its enormous complexity and cost, did not penetrate into clinical practice at all, it remained only as a technical interest...
   Along with the technical improvement of X-ray CT, the tomographic principle was also used in other imaging modalities. In addition to optical CT, scintigraphic tomographic methods were developed - SPECT single photon emission tomography and PET positron emission tomography (Chapter 4 "Scintigraphy", §4.3 "Tomographic cameras". And also the most complex tomographic imaging method of nuclear magnetic resonance NMRI (§3.4, part "Nuclear magnetic resonance").
   Note: For special technical purposes of imaging the structure of small objects, is used the so-called X-ray micro-tomography (mCT) mentioned below (§3.3, section "Radiation defectoscopy").

Formation of the density image
If, according to Fig.3.2.4 on the left, the X-ray beam emitted by the X-ray tube and falling on the examined area has an initial intensity (photon fluence in 1 s.) I_o , then its intensity I after tissue passage will be I = I_o . e ^{- Sm(i, j). Dx} , where m(i, j) is the linear attenuation factor of X-radiation penetrating the tissue site at coordinates (i, j) and Dx is the magnitude (length in the beam direction) of the tissue element. The values of the coefficients m(i, j) depend on the local density and the proton number of the individual sites (i, j) of the tissue. By logarithm, this relationship can be adjusted to the form: ln (I/I_o) = Sm(i, j). Dx, which states that the logarithm of the ratio of the intensities of X-rays entering and leaving - transiting the examined tissue, is equal to the sum of the products of the linear attenuation coefficients m and Dx paths that the X-rays photons at each point of the tissue overcome.
   By measuring at different positions (angles) of the X-ray tube and the detector, a number of values of the attenuation ratio ln (I/I_o) are obtained. The computer then basically solves a system of linear equations of the above shape, which obtains the values of the linear X-ray attenuation coefficients of tissue elements in individual sites (i, j) of tissue - a picture of tissue density in a transverse section is formed.
   In practice, the above straightforward procedure does not progressing. The resulting transverse CT image is obtained by computer reconstruction from one-dimensional profiles of the intensity distribution of the transiting X-ray beam when rotating the X-ray tube and opposite detectors around the examined object. For this reconstruction, the method of filtered back projection is usually used, sometimes even a more perfect (but computationally demanding) method of iterative reconstruction *).
*) Iterative reconstruction is a mathematical algorithm for finding the most accurate image by successive approximations and refinement of the initial "rough" image. It is based on an image obtained by back projection and consists of several repetitions four consecutive steps - "reconstruction loops": 1. In the first step, they are calculated from the image created by the back projection, in the opposite way, again as if the original data. 2. These are then compared with the "raw" data actually captured during detection. 3. New data for rear projection will be adjusted according to the differences found. 4. The image is recalculated and the whole operation is repeated. After several repetitions of these iterations, we obtain a clear and high-quality image. The number of iterations can be set and optimized. Correction algorithms and noise filtering methods are included in the procedure. This method provides higher quality images with reduction of noise and artifacts created during reconstruction. Furthermore, in some examinations, we can significantly reduce the patient's exposure and radiation dose, while maintaining sufficiently high-quality images.
   These reconstruction methods, which are analogous to SPECT, are briefly described in §4.3 " Tomographic scintigraphy ", passage "Computer reconstruction of SPECT " *). The central and controling software algorithm of the reconstruczion is sometimes called the kernel (core, grain).
*) I apologize to professional radiologists that it is not included in this chapter. Our professional materials are primarily focused on nuclear physics and radionuclide scintigraphy (I didn't want to duplicate it...). This angle of view may be perhaps inspiring also for colleagues in the field of X-ray diagnostics ..?..
   The density of the examined tissue is usually compared with the density of water and in the CT image is numerically presented in the so-called Hounsfield units HU = 1000. (m_tissue - m_water) / m_water , introduced by a leading pioneer in the CT, G.N.Hounstfield (along with A.L.Cormack). The use of a factor of 1000 (instead of the usual 100%, where we would get decimal values) reflects a high density resolution CT. The value of HU = -1000 corresponds to zero density (vacuum, air), for water it is HU = 0, bones have a density of the order of HU = 100 ¸ 1000, sometimes even higher. Aerated lungs have HU approx. -800, fat HU = -40 ¸ -120, soft tissue density is HU = 20 ¸ 80. Such a large range of densities is not able to display linearly in brightness; also the human eye is only able to distinguish a few tens of shades of gray. For optimal image presentation, we therefore help by appropriate modulation of image brightness and contrast. If we are interested in differences in tissues with a similar density (this is usually the case in soft tissues), we use this modulation to select only a narrow part of the whole range of densities - the so-called window, whose range of densities is displayed in the entire brightness range of the screen, with eventually increased contrast setting. We get well-drawn images of the required structures and by moving the windows we can gradually obtain detailed information about tissues with different densities.

X-rays detectors for CT
The task of these detectors is to capture photons of X-rays passing through the examined tissue and convert them into electrical signals for further electronic processing for the purpose of computer reconstruction of density sections. In general, the principles set out in Chapter 2 "Detection and spectrometry of ionizing radiation" apply to this area, with the proviso that mostly detection is applied, rarely the spectrometry. The basic requirement here is a high sensitivity of X-ray photon detection and a high detection rate, ie a short dead time.
   In principle, three types of detectors can be used to detect X-rays in CT :

• Ionization chambers
  filled with compressed xenon gas (multiple anodes and cathodes in one tube form a series of detectors). This older detectors is already abandoned.
• Scintillation detectors
  with scintillation crystals NaI(Tl), CsI(Tl), Bi₄Ge₃O₁₂ (BGO), Lu₂SiO₅(Ce) (LSO), Lu_1,9Y_0,1SiO₅ (LYSO), CdWO₄; the latter four have the advantage of high detection efficiency at small dimensions (the properties of scintillators are discussed in detail in §2.4, section "Scintillators and their properties"). Scintillators based on ceramic materials (silicon oxides), doped with rare earths (such as lutetium, gadolinium or yttrium) and possibly and other elements, sometimes referred to as UFC (Ultra Fast Ceramic) - ultra-fast ceramic detectors. The detection cells have an active size of about 0.8x0.8 - 1x1 mm².
    The absorbed X-rays produce visible light in the scintillator. Scintillation flashes are detected by photodiodes or phototransistors mounted on the back of each detection element; this is just simple detection, not spectrometry. The resulting electrical pulses, registered during the measurement time of a given projection, are integrated for each element, written to a computer, and the resulting reconstruction of the cross-sectional images is performed.
  Dual-layer CT detectors
  Ring detectors consisting of two layers of scintillation detectors have been developed for simultaneous CT detection of lower and higher energy X-rays in the DECT (Dual Energy CT) method with one X-ray tube with higher voltage (apox. 140 kV). The "light" upper layer consists of low-density (yttria-based) scintillation detectors. The bottom "heavy" layer consists of high density scintillation crystals (based on gadolinium oxysulfide). After passing through the patient, the X-rays first strike the upper layer, in which only low-energy X-rays are selectively absorbed and thus detected, while the high-energy photons penetrate this layer into the lower layer, in which they are efficiently absorbed and scintillating detected.
    Photodiodes are attached to all scintillation elements of the upper and lower layers. The pulses from the photodiodes of both layers are processed separately, their reconstruction creates twoo CT images of cross sections, with density modulated by the absorption of lower and higher energy X-rays. Using DEXA analysis, an approximate material specification of the displayed structures can be performed (was discussed in more detail in the section "Dual- and multi-energy X-ray imaging. Material composition analysis.").
• Semiconductor detectors
  X-ray photons fall directly into semiconductor detectors (suitable material is CdTe, CdZnTe - CZT), where they interact to release electric charges and are thus directly converted into an electrical signal (the general principle of semiconductor detectors is given in §2.5 "Semiconductor detectors"). The semiconductor detection method in X-ray diagnostics is generally described above in the section "Electronic X-ray imaging detectors", paragraph "Semiconductor detection (direct conversion)". It has significant advantages over scintillation conversion and provides new possibilities in CT imaging :
  Spectrometric Photon-counting CT
  Direct semiconductor detection allows independent registration of individual X-ray photons: "photon couting". And then electronic analysis of the amplitudes of these pulses - performing spectrometry of the detected X-rays *). By using two or more different amplitude- energy windows of the analyzer, CT images can be obtained for different energies of transmitted X-rays. We can then use the material-specific difference in the absorption of X-rays of different energies for material-tissue differentiation of the displayed structures, which otherwise show the same density attenuation in a conventional CT image. This possibility of material analysis in CT images is discussed in more detail below in the section "Dual- and multi-energy X-ray imaging. Material composition analysis.".
  *) Terminological note: Instead of the name "photon-counting CT", which was introduced in the field of radiodiagnostics, the name "photon-spectrometry CT" would be more apt from a physical point of view, as energy (spectrometric) analysis of detected X-rays photons is important here (rather than simple "photon counting").
    A semiconductor ring detection system in CT could consist of a large number of small CZT detectors (in direct analogy with conventional scintillation detectors). However, a simpler and more advantageous arrangement has also been developed: A detector consisting of longer semiconductor layers (1.5-3 mm thick) with a common cathode and pixelated anode electrodes. A voltage of approx. 800-1000 V is applied between the electrodes. The absorbed X-rays create electron-hole pairs in the semiconductor layer, electrons drift to the anodes in a strong electric field, where they generate short electrical pulses (approx. 10^-9 s). The amplitude of these pulses is proportional to the energy of the absorbed X-ray photons. The advantage of this arrangement is, in addition to a more compact design, a somewhat increased geometric detection efficiency (by about 20%), because there are no optical separation partitions between the individual detector elements (for scintillation cells, the partitions are about 0.1-0.2 mm wide).

X-ray detectors for CT (these are only basic schematic drawings, there is no drawn the curvature of the arc arrangement, or lamellas against scattered radiation).
a) X-ray scintillation detection, the most used method. b) Dual-layer detector registering low and high X-ray energy separately. c) System of semiconductor pixel X-rays detectors - photon-couting CT, enabling spectrometric analysis of X-rays; here are the individual detectors. d) Spectrometric photon-couting CT in the technology of tape semiconductor detectors with a common cathode and pixelated anodes.

Multidetector, multi-slice and spiral CT; Cone-Beam CT
Gradual scanning of CT images by a system of one X-ray tube and one detector, as described so far here according to Fig. 3.2.4a for easier explanation of the method, was used in the first generations of CT equipment in the 70s and 80s. Its disadvantage was considerable slowness (one cut lasted several minutes). Newer generations of CT devices already use a larger number of detectors (approx. 1000). An X-ray tube is circled, the beam of primary radiation of which is obscured by a collimator into the shape of a fan (with an angle of approx. 40°), and opposite it a corresponding circular section with a system of 300-1000 detectors (Fig.3.2.8b). The scanning time of one slice is reduced to less than 1 second.
  The first types of CT devices had a rotating part - X-ray tube and detectors - connected to the static power supply and evaluation part by a cable, which did not allow continuous rotation (after one revolution, the X-ray tube with the detector had to return to its initial position, or the direction of rotation had to be changed so that the cable did not twist). Newer types (since the 1980s) use "slip-ring" technology with electric brush scanning to power and transmit the signal, enabling fast and continuous rotation (with an unlimited number of revolutions in the same direction).
   The original generation of CT instruments scanned only one cross section of the examined area during one rotation. To increase the speed of CT examination of larger areas, it is always used in newer generations of devices several detectors, resp. several detector rings, placed side by side in the axial (longitudinal) direction - MDCT (Multi Detector CT). This allows (with a suitable shaping of the X-ray beam from the X-ray tube) the simultaneous scanning of several transverse sections side by side, the examination of several thin layers simultaneously. We are talking about so-called multi-slice CT devices - 4, 6, 8, 16, 64 and more - slice. The technical design of CT devices is constantly improving. The number of detectors and the speed of rotation of the gantry rotor increases (now approx. 0.3 s./revolution) - these are high-speed multidetector systems MDCT. Individual transverse sections can be scanned in two ways :
- Sequential scanning , where only the X-ray tube + detector system rotates, but the bed does not move with the patient. The individual layers are scanned gradually - independently by individual rings of detectors.
- In the case of so-called spiral CT (helical) , in addition, during the rotation of the X-ray tube there is a slow automatic movement of the bed with the patient (the X-ray tube path effectively appears as a spiral) - Fig.3.2.8b, c, followed by three-dimensional reconstruction; here, in principle, it is possible to achieve whole-body CT imaging. The horizontal distance by which the lounger moves between two adjacent X-ray tube cycles - the "rise" of the spiral - is called pitch factor [mm].
ECG-synchroized CT angiography
A significant technical advance in the field of cardiac imaging is non-invasive electrocardiographically synchronized angiography by multidetector computed tomography - MSCTA. The main use of this method is twofold :
1. MSCT native calcium score - detection and quantification of calcificates in coronary arteries (calcium content in coronary artery plaques). Usually, risk groups are assessed according to Agaston's calcium score (up to 5 groups).
2. MSCT coronarography - contrast imaging of epicardial coronary arteries to diagnose the extent and severity of coronary involvement in ischemic heart disease.
   By combining both methods, we can display the soft and calcified part of the plaque, determine the nature, extent and severity of the disease, with possible indications for invasive examination with determination of the method of revascularization.
Cone-Beam CT
For some purposes, a CT image with a widely collimated cone-beam CT (CBCT ) is used, which shines through the patient and impinges on the opposite flat-panel imaging (its principle is described in §3.2, passage "Electronic X-ray imaging"). The X-ray tube and the opposite flat-panel rotate around the examined object on a common gantry. Such a CBCT system is installed on radiotherapy irradiators (linear accelerators) using the image-controlled radiotherapy technique - IGRT (§3.6, section "Modulation of irradiation beams"), or is used in small dental CT devices (listed below).
CT with 2 X-rays tubes - DSCT: Dual Source and Dual Energy CT
Another technical improvement of CT consists in the construction of devices that have 2 X-ray tubes - two X-ray tube/detector systems (placed perpendicular to each other), which can scan simultaneously, Fig.3.2.9. The device is referred to as Dual Source CT (DSCT). It can work in two basic modes, providing two advantages :
¨ 1. Both X-ray tubes operate at the same voltage
Þ "dual system" - increasing the speed and shortening the acquisition time with reducing the time resolution to about 80ms. This is especially important for CT of the heart (with a higher heart rate).

Fig.3.2.9. CT device with two X-ray tubes - Dual Source CT and Dual Energy CT.

¨ 2. Booth X-ray tubes operate at different anode voltage (eg. 140kV and 80kV **)
Þ possibility of scanning with dual-energy (DECT - Dual Energy CT): each of the two X-ray tubes creates X-rays of different energies. We get twoo different density images of the same place. This allows not only to better quantify the density distribution, but also to determine the tissue composition using the method of differential density analysis DEXA (Dual Energy X-ray Absorptiometry) *) - similar analyzes of density images as in "Bone densitometry" (see Fig.3.2.11 below). It provides not only detailed images of the anatomy, but it will allow you to distinguish different types of tissue (distinguish eg bones, blood vessels, adipose tissue), different types of kidney stones, deposition of sodium urate crystals in joints (bottoms), or quantify the distribution of contrast agent in myocardial infarction (and to assess functional impairment in morphological coronary artery disease).
*) Different types of substances (and tissues) differ not only by specific values of linear attenuation coefficients m for X radiation of a certain energy, but also by a somewhat different dependence m(E_X) of absorption for different energies E_X of X-radiation. This is due to the different electron density configuration for the different molecular composition of the analyte. Mathematical analysis of the exponential laws of absorption I = I_o.e^-m(Ex).d for individual energies E_X and tissue types with absorption coefficients m(E_X) (by logarithm the relevant exponential equations are converted to linear) it is possible to determine the proportion of absorption in different tissues. This can in principle be used to additionally distinguish different types and compositions of tissues based on differences in the density images of the same site, obtained with different X-ray energies.
**) X-ray spectra for 80 and 140 keV are continuous and partially overlap. In addition to the different anode voltages, two different effective energies of X-rays are also achieved by special sharp filtration using the K-edge effect (mentioned above in the section "Filtration, collimation").
Multiplex DECT
An alternative to dual energy tomography DECT with two X-ray tubes is the use of a single X-ray tube - detector system, in which performs the multiplex switching voltage in X-ray tube during spiral scanning.
2-layer CT detector
Other alternative options DECT tomography with one X-ray tube is the use of two layers of detectors, that selectively detect the low- and high-energy X-ray component (mentioned above in the section "X-ray detectors for CT", section "Two-layer CT detectors").
Spectrometric Photon-couting CT
Furthermore, it is likely that the entire DECT technology with two X-ray tubes will be replaced in the future by a photon-couting CT system with one X-ray tube and semiconductor detectors, enabling flexible energy spectrometry of detected X-rays (described above in the section "Electronic X-ray imaging detectors", paragraphs "Semiconductor detection (direct conversion)" and "X-ray detectors for CT").

Quality control and imaging properties of CT devices
Testing of imaging properties of CT devices is performed using special phantoms of cylindrical shapes - see "Phantoms and phantom measurements", section "Tomographic phantoms for CT".

Electron Beam CT (EBT)
In addition to the described CT design, now "classic" with a rotating X-ray tube, a completely different, physically interesting solution has been developed that does not contain an X-ray tube at all. X-rays are created by the impact of fast electrons, fired by an "electron gun", on a metal target ring - anode, inside which the object under investigation is located (Fig.3.2.10). The electron beam from the electron gun is directed to the desired location of the target ring by magnetic deflection by means of deflection coils, powered by a suitable electrical signal. By supplying the deflection coils with alternating electric current of a suitable periodic course, the electron beam rotates at an angular frequency w and, during this circular motion, gradually strikes individual points on the circumference of the target ring. In each affected area, braking X-rays are generated , the beam of which shines through the examined object (patient's body) at a corresponding angle. Thus, a rotating electron beam generates a rotating source of X-rays around the circumference of the target ring, as if an X-ray tube were rotating there. The braking X-ray passes through an annular collimator with radially oriented septa, which shapes it into a fan-shaped bundle.
   This X-ray, passed through the examined object (patient's tissue), is detected electronically (as with conventional CT) by means of an annular array of detectors, overlapping the collimator from the inside. With a suitable geometric arrangement of the collimator septum, they shield the X-radiation that would come directly from the target ring to the back of the individual detectors. Newer types of EBT devices have several side-by-side target rings and several ring arrays of detectors.

Fig.3.2.10. Basic principle scheme of X-ray tomography using electron beams

This design solution has two advantages :
¨ It does not contain any mechanically moving parts - the rotation of the beam is electromagnetic.
¨ Allows very fast tomography - the electromagnetically deflected beam can rotate much faster than is achievable with mechanical rotation. This is advantageous for monitoring fast processes such as gated CT - in Fig. 3.2.5, ECG trigger pulses are fed to the acquisition computer together with pulses from X-ray detectors.
  However, the disadvantage here is the considerable complexity and cost (price) of the device, due to which this type of device has not yet become very widespread in practice. It is probably not possible to expect a greater expansion of these systems in the future either, as rapid technical progress in the construction of conventional CT - high-speed multidetector MDCT systems (or with two X-rays) solves most of the advantages of EBT, are cheaper and more advantageous for common practice. The result is that electron beam CT, due to its enormous complexity and cost, did not penetrate into clinical practice at all, it remained only as a technical interest...

X-ray bone densitometry
Radiographic examination of the skeleton is one of the most common and most important X-ray diagnostics, especially the finding of fractures and other bone defects. A special method in this area is bone densitometry - a method for determining the density of bone tissue based on the degree of X-ray absorption, determined by X-ray absorption photometry (Radiographic Absorptiometry - RA).
    The simplest method is to transmission a narrow beam of X radiation with a single energy (SPA - Single Photon Absorptiometry). The disadvantage of this method is that it is not possible to determine from the total absorption of X-rays, which part is caused by bone and which part by soft tissue.
    A more advanced densitometric method is X-ray absorption photometry using two energies of the X-ray beam (DEXA - Dual Energy X-ray Absorptiometry), such as a pair of effective energies of 50keV + 100keV, or 35keV + 75keV. Here are used the different ratios of X-ray absorption in soft tissue and in bone at low energy and at high radiation energy - different values of linear attenuation coefficients m. By mathematical analysis of the exponential laws of absorption I = I_o.e^{-m . x} for individual energies and tissue types (by logarithmization the relevant exponential equations are converted to linear) the proportion of absorption in soft tissue and bone itself is determined, from which (after appropriate callibration) can be determined bone density.
  It is calibrated with a suitable bone phantom (or hydroxyapatite), the instruments have their internal calibration phantoms. The bone mineral content is quantified using the Bone Mineral Content (BMC) parameters in [g/cm] and the Bone Mineral Density (BMD) area density in [g/cm²]. These parameters are compared with sets of reference (normal) values and relative indices (ratios) called scores are determined: the T-score compares the measured BMD values with the average BMD value of young healthy adults of the same sex; the Z-score compares BMD with mean normal values for a given age and sex. Bone Homogeneity Index (BHI) is also sometimes monitored.

Fig.3.2.11. Schematic diagram of a DEXA imaging digital X-ray densitometer. On the right is an example of a DEXA device for whole-body imaging.

Modern X-ray densitometric devices use irradiation of the examined area with a diverging ("pyramidal") X-ray beam with subsequent detection of the transmitted radiation by a digital image sensor into the computer's memory - Fig.3.2.11. Here, appropriate absorption calculations are performed between the low (L) and high (H) X-ray energy images to obtain a final skeletal density image that provides both bone mineral content and density and morphological skeletal structure information. The most advanced devices of this type make it possible to perform whole-body image diagnostics of bone tissue, determine the content of muscle mass, adipose tissue, water and minerals in individual parts of the body.
Detectors for X-ray densitometry 
For the detection of transmitted X-rays, either NaI(Tl) or CaWO₄ scintillation detectors are used, or semiconductor detectors mostly based on CdZnTe (cadmium-zinc-telluride - CZT), which have a high detection efficiency. In modern imaging densitometers, the detectors are arranged in a 2-dimensional mosaic configuration with high spatial resolution - they form a digital X-ray image sensor, such as a flat panel measuring 20 × 20cm and a matrix of 512 × 512 elements that scans the entire displayed area during a single exposure.
    Bone densitometry plays a key role in the diagnosis of osteoporosis - pathological reductions in mineral and organic bone mass, leading to a weakening of bone strength. Osteoporosis is one of the most common disorders of bone metabolism and is one of the most common causes of fractures in the elderly, especially in postmenopausal women. Early diagnosis of incipient osteoporosis (osteopenia) is important for the use of effective treatment to slow or stop osteoporosis before irreversible disorders in the bone structure.
Note: Non-radiation methods of bone densitometry are also used. Ultrasound densitometry determines bone density based on the attenuation of the sound signal and the speed of its propagation in tissue.

X-ray mammography
Another important specialized method of X-ray imaging is mammography - imaging of possible inhomogeneities and areas of increased tissue density in a woman's breast, which could indicate a tumor process. In order to achieve the best possible image contrast and resolution of the smallest possible lesions, it is necessary to compress the breast using a compression plate *) and shine trough the tissue thus formed into a layer about 7 cm thick with soft X-rays with an energy of about 20 keV. Low-energy X-ray photons interact with tissue atoms primarily through the photoeffect, which provides a higher absorption contrast between tissues with small differences in density. Due to this low energy, a special X-ray tube with a molybdenum anode and a beryllium output window, focus size 0.1-0.3 mm, is used in the mammograph. A molybdenum or rhodium filter is used to filtration the X-ray beam, which cuts off photons higher energies than about 20keV (K-edge Mo) or 23keV (K-edge Rh) - the so-called K-edge effect mentioned above in the passage "Filtration, collimation" is used.
*) Note: Compression of breast tissue also leads to one minor advantage in terms of radiation protection: compression temporarily restricts blood flow and partially causes hypoxia of tissue cells. This somewhat reduces the radiobiological effect of X-rays, as hypoxic cells are less sensitive to radiation ("oxygen effect"- §5.2 "Biological effects of ionizing radiation", part "LQ model").
    Imaging was performed with a cassette with X-ray film equipped with an image intensifier, or more recently using electronic image capture - a semiconductor flat panel with direct image digitization. A secondary Bucky diaphragm is placed between the imaged tissue and the film or imaging detector to reduce the proportion of scattered radiation, reducing the contrast of the image. The resulting X-ray image of the breast is called a mammogram or mastogram. Under suitable circumstances, it is possible to detect a tumor as small as about 4 millimeters. Mammography is suitable not only for the examination of women with symptoms or suspicion of breast cancer, but also for screening - searching for early stages of breast cancer.

Fig.3.2.12. X-ray mammography.   The breast is inserted between the X-ray tube and the imaging flat panel and compressed with a plastic compression plate.   On the X-ray mammographic image, we can observe normal density without defects (top right) , or lesions of increased density that may indicate a tumor (bottom right) .

The X-ray mammography apparatus can be supplemented by a so-called mammographic stereotaxy device, which captures two images of a given lesion in oblique projections at two given angles (usually ± 15°). Evaluation of the change in the position of the lesion on these two stereo images allows precise targeting of the displayed structures suspected of the tumor process - their location and marking with a suitable marker (such as mandren, wire or dye), with the possibility of sampling by biopsy for histological examination.
Alternative mammography methods
In addition to the most commonly used X-ray mammography, there are some other examination methods based on different principles :
¨ Ultrasonic mammography showing possible lesions based on their different density and elasticity (ultrasonography is briefly discussed in §4.6, passage "Ultrasound sonography").
¨ NMRI mammography - imaging by nuclear magnetic resonance.
¨ Radioisotope scintimammography showing increased accumulation of a suitable radiopharmaceutical in the tumor tissue (see Chapter 4 "Scintigraphy"); it can be performed as planar, SPECT or PET scintigraphy. A specific method of PEM positron emission tomography is described in §4.3, passage "Positron emission mammography (PEM)".
¨ Electroimpedance mammography sensing the electrical conductivity (impedance) of mammary gland tissues. A weak electric current is introduced into the tissue by means of electrodes placed on the skin in the vicinity of the examined area, and also by means of electrodes the distribution of electric potentials on the surface is sensed. From these data it is possible to reconstruct the spatial distribution of local tissue impedance - electroimpedance image. A different electrical conductivity is observed in the tumor tissue from the surrounding tissue.

Dental X-ray diagnostics
A separate category of smaller specialized X-ray devices are dental X-rays devices used in dentistry. There are three types of devices :
¨ Intraoral X-ray is a very simple device: a small X-ray tube of a compact design with a narrow tube is placed on the movable arm (a high voltage source of approx. 50 - 70 kV is usually encapsulated in X-ray tube cover). A small rectangle of X-ray film is placed on the back of the teeth and exposed to X-rays from the front. After developing the film, the relevant tooth (or several teeth) and its placement in the gums, including posiible defects, are displayed.
¨ Panoramic X-ray OPG (orthopantomogram), also called DPR (Dental Panoramatic Radiograph ). The X-ray tube and the X-ray film or imaging flat panel located opposite, it rotate (orbiting) during the exposure and describe a circular or elliptical trajectory around the patient's head (jaw) so that the focal layer, given by compensating of mutual movement of X-ray tube and film (or imaging detector), is passed through the center of the jaw line along its entire length. This creates a developed panoramic image of the entire jaw. In the simplest case, this is achieved with a single motor, but a better panoramic view is achieved with devices with 2 or 3 motors, which perform rotation in multiple axes with better adaptation to the shape of the jaw. The best focusing of all jaw areas is achieved with multifocals OPG devices, where a larger number of images in different focal layers are captured, with subsequent evaluation.
¨ Dental CT is a reduced version of the classic cone-beam CT (mentioned above) with imaging detectors of about 3 x 4 - 15 x 15 cm. Sometimes panoramic X-rays are combined with dental CT into one system. Dental CT is used in maxillofacial surgery, dental implants and in the diagnosis of pathological lesions in the area.

Radiation exposure of patients during X-ray examination
Using the current modern X-ray technique, the radiation exposure of patients is relatively low. The high sensitivity of imaging detectors and computer image processing enables optimization, during which high-quality X-ray images with low radiation exposure can be obtained.
    The absorbed radiation dose D [mGy] during X-ray examination of a certain area of the body is basically given by the product of the intensity of X-rays (this is given by the X-ray tube current [mA]), exposure time [s] and corresponding coefficients :
            D = G. mAs .
Coefficient G it includes a number of factors, such as the efficiency of X-ray production by X-ray tube, its energy given by the voltage [kV] in X-ray tube, filtration, distance, tissue absorption coefficients. It is measured using phantoms, most often water-filled "aquariums" (for planar X-rays), or cylinders with a diameter of 16 cm (head) or 32 cm (chest) for CT, equipped with ionization chambers, thermoluminescence or semiconductor detectors. The probability of biological stochastic effects is proportional to this absorbed radiation dose [mGy] and the size of the irradiated area [cm³].
    In planar X-ray diagnostics, this is quantified using the the quantity of surface dose DAP (Dose Area Product) [mGy.cm²], which is the product of the input dose of X-rays and the size (area S) of the irradiated field: DAP = D. S. The effective dose D_ef [mSv] for the patient, expressing the effects of radiation on the organism as a whole, is then calculated as the product: D_ef = E_DAP . DAP, where the coefficient E_DAP (regionally normalized effective dose [mSv mGy^-1 cm^-2]) includes averaged tissue (organ) weighting factors w_T for structures in the irradiated area.
    Specially calibrated radiometers, so-called DAP-meters, are used to measure the radiation dose of patients during planar X-ray imaging *), measuring product of absorbed dose and irradiated area (Dose Area Product). The DAP meter is a thin transmission plane-parallel ionization chamber mounted on the output collimator (aperture) of the X-ray tube, the area of which covers the entire (maximum) field of X-rays - Fig .3.2.5 at the top left. The ionization current generated by the passage of X-rays from the X-ray tube toward the patient, after appropriate calibration, indicates the areal dose of DAP that the defined imaged field of the patient's body receives.
*) Radiometers of this type are sometimes also called KAP-meters , measuring the product of kerma in the air and the irradiated area (Kerma Area Product). For X-rays used in X-ray diagnostics, the kerma and dose values are practically identical. As discussed in §5.1 "Effects of radiation on matter. Basic quantities of dosimetry .", passage "Exposure, kerma, terma", the relationship between dose and kerma D = K.(1-g) applies, where g is the fraction of energy of released charged particles that are lost during radiation processes in the material. For diagnostic X-rays, the value of g is only fractions of a percent.
    The product of the kerma and the surface is the integral of the kerma in the air over the beam surface in a plane perpendicular to the central axis of the beam. The value of the product of the kerma and the area is almost independent of the distance from the focus of the X-ray tube (if we neglect the attenuation of the radiation in the air, the backscattered radiation and possibly the X radiation arising outside the focus).
    For CT imaging, the radiation exposure is quantified using a quantity linear dose DLP (Dose Length Product) [mGy.cm], which is the product of the absorbed dose D and the length L irradiated area: D = DLP . L.
    The effective dose D_ef [mSv] for an X-rayed patient, expressing the stochastic effects of radiation on the organism as a whole, is then calculated as the product:
           D_ef = E_DAP . DAP for planar display, or D_ef = E_DLP . DLP for CT imaging,
where coefficients E_DAP or E_DLP - regionally normalized effective dose [mSv mGy^-1 cm^-1 ] - include averaged tissue (organ) weighting factors w_T for structures in the irradiated area (§5.1 "Basic quantities of dosimetry", passage "Radiobiological efficiency of radiation") .
    How these measured exposure parameters are used to determine radiation doses and their optimization in X-ray examinations is briefly discussed in §5.7 "Radiation exposure in radiation diagnosis and therapy".

Other imaging diagnostic methods. Hybrid imaging systems.
X-ray diagnostics is the oldest and so far the most important imaging method in medicine. With technical progress, especially in the field of electronics and computer technology, some other alternative imaging methods of medical diagnostics have developed. They are: Ultrasound sonography , Nuclear magnetic resonance , Thermography ; recently, electroimpedance imaging of tissue has begun to be applied. The whole chapter 4 then describes in detail another important imaging method - Scintigraphy.
    These methods are physically compared in §4.6 "Relationship between scintigraphy and other imaging methods", where their diagnostic benefits and their complementarity in the algorithm of complex diagnostics are discussed. In recent years, hybrid imaging systems have been increasingly emerging, combining CT X-ray imaging with scintigraphic SPECT or PET imaging, or with nuclear magnetic resonance NMRI. And also hybrid imaging + irradiation technologies in radiotherapy (§3.6 "Radiotherapy", part "Modulation of irradiation beams", passage "Hybrid integration of imaging and irradiation technologies").

The basic aspects of evaluation and acquisition of diagnostic information from images of the mentioned radiological modalities are given in §4.7 "Visual evaluation and mathematical analysis of diagnostic images".

------------------------ Small physical-technical interest ---------------------- -

X-ray telescopes
The X-ray diagnostics discussed above is a transmission method based on the passage of X-rays through an object. X-radiation are a means of analyzing the structure of an object under investigation. However, there are situations where we primarily need to search for and display the sources of X-rays themselves, their position and distribution in space. And "at a distance", whether small (analytical and examination methods of materials) or large (detection of X-rays in universe) - to perform X-ray telescopy.
     Telescopes working in the field of X-radiation must have completely different optics than normal visible light telescopes. In the optical telescope, spherical or parabolic lenses and mirrors are used, on which light rays fall at a large angle (almost perpendicular) and refract or reflect so that they converge and intersect near the focus where the image is formed. The lenses are not usable for X-rays at all. Under certain circumstances, reflection on a mirror is applicable, but the beam must strike the reflecting surface of the mirror at a very small angle, almost tangentially. Due to the high energy of the photons and the short wavelength of the X-radiation, the X-rays must fall very obliquely, practically "sliding" on the surface, because when incident at larger angles (or even perpendicular), the X-rays photons would penetrate below the mirror surface and interact individually with electrons and atoms of its material (photoeffect or Compton scattering, see §1.6 "Interaction of gamma and X-rays") - part would pass, most would be absorbed in it; no display would be created. At a very oblique impact, from the point of view of the photon, the number of free electrons in the metal surface per unit length will increase geometrically (the electron density will increase effectively), so that the X-ray photon will interact collectively with a large number of free electrons, similar to the reflection of a light wave from a metal surface: according to the laws of electrodynamics, the electromagnetic wave-photon is reflected from the metal surface at the same angle as the angle of incidence. Or, from the point of view of the reflecting surface, the wavelength of the incoming radiation (its projection) is effectively extended, which will therefore behave similarly to light. It's a bit like throwing a stone very obliquely, almost parallel to the water surface and he bounces, or it jumps above the surface several times. However, in practice this mechanism only works for soft X-rays, up to about 30keV.

^{Fig.3.2.13. Principle of a mirror X-ray telescope}

X-ray optics are therefore based on an almost tangential impact, where the X-ray beam impinges almost parallel to the surface, only then is it reflected. Such reflective surfaces must be very precise and smooth, their "roughness" must not exceed a thousandth of a mm. The X-ray telescope consists of one or more very precisely shaped coaxial metal surfaces, inclined at a very small angle with respect to the optical axis of the system (Fig.3.2.13). This reflecting surface may have a conical shape, but the combination of paraboloid and hyperboloid provides optimal optical properties. The reflecting surfaces are arranged almost parallel to the incident rays, which are therefore reflected at a very small angle - first from the paraboloid and then from the hyperboloid - to the focal plane, where they form an image of the X-ray source from which the X-rays came. Here the radiation is sensed by detectors. The more advanced types of X-ray telescopes are multi-mirror, consisting of a number of very precisely shaped, carefully adjusted and embended in each other coaxial parabolic and hyperbolic mirrors. The central part of the system is shielded by an X-ray absorbing material.
    X-ray telephoto of this kind were constructed in the 1960s and 1990s mainly by R.Giaccomi and his collaborators. They constantly improved them and installed them on space satellites: UHURU in 1970, HEAO-2, Chandra in 1999. With these instruments was revealed many X-ray sources in space - X-ray binaries, supernova remnants, neutron stars, galaxies active nuclei, the clouds of ionized gas in galaxy clusters (on the X-radiation from space and its origin see §1.6 , the "Cosmic ray" passage "Cosmic X and gamma rays"). Current X-ray telescopes achieve very good angular resolution (<0.5 arcseconds), spectral (energy) resolution (1eV), as well as high luminosity and sensitivity to X-rays also higher energies. They are the basic tools of the so-called X-ray astronomy.
    In the area of even shorter wavelengths, ie higher photon energies, X-ray telescopes are followed by the issue of gamma-telescopes, briefly discussed at the end of §4.2, section "High-energy gamma cameras").

3.3. Radiation measurement of mechanical properties of materials
The properties of the interaction of different types of ionizing radiation with matter provide a number of possibilities for non-contact non-destructive measurement of some mechanical and structural properties of various objects and materials. Most of these methods work in the experimental setup schematically shown in Fig.3.1.1a,b in §3.1. The analyzed object or sample is irradiated with a suitable type of radiation, whereas the detector measuring the changings of the primary radiation caused by the analyzed object.

Radiation measurement of thickness and density
If we shine through a material with a given value of the linear attenuation coefficient m, the absorption and attenuation of radiation is exponentially dependent on the thickness of the material - see the section "Absorption of radiation in substances" in §1.6 "Ionizing radiation". By measuring the radiation absorption, the thickness of the material and its changes can be determined without contact (in the basic arrangement according to Fig.2.8.1 on the left). For thin light materials such as paper or plastic foils, beta radiation is suitable, the source can be radionuclides ⁹⁰Sr + ⁹⁰Y (harder radiation b E_b= 0.546 + 2.27MeV, mass half-thickness of absorption d_1/2 = 90mg/cm², suitable for thicker layers), ⁸⁵Kr (E_b = 670keV, d_1/2 = 23mg/cm² ), ¹⁴⁷Pm (E_b = 224keV, d_1/2 = 5mg/cm²). To measure denser materials (such as metals), g- radiation is used, emitted by radionuclides ²⁴¹Am (60keV), ¹³⁷Cs (662keV), ⁶⁰Co (1173 + 1332keV). With these methods, it is possible to measure (scan) the relevant objects, or even continuously monitor the thickness of the produced foil or rolled metallurgical material on the conveyor belt.
    The attenuation of radiation as it passes through the substance is also significantly dependent on the density of the monitored material. With a known (constant) material thickness, we can monitor the density of the material and its changes based on the attenuation of the transmitted radiation beam. Densitometers of this type are used, for example, in monitoring the transport of substances by pipeline (in the chemical or food industry) or belt conveyors (coal treatment plants, dosing of components in metallurgy, etc.).
Note: If the measured sample is accessible from one side only, it is sometimes used to measure the thickness and density of the scattering method: the object is irradiated with a beam of radiation and the intensity of Compton backscattered radiation (Fig.2.8.1 in the middle) is monitored, which depends on the thickness and density of the material. This is the case with pipe walls, boilers and closed vessels, or in boreholes (logging measurements). However, the accuracy and sensitivity of these scattering methods is lower than for transmission methods.

Radiation level meters
Radiation level meters determine the height of a liquid column based on the attenuation of the radiation beam g by the liquid, depending on whether the radiation passes through liquid or air. In addition to liquids, bulk materials can also be monitored in this way. This non-contact method is important where other methods cannot be easily used - for example in overpressure and underpressure vessels, or for liquids aggressive or heated to high temperatures. The most commonly used g- emitters are radionuclides ¹³⁷Cs (662keV) and ⁶⁰Co (1173 + 1332keV), or ²⁴¹Am (60keV).
    The geometric arrangement of the radiator and detector is most often horizontal, where the radiator and the detector are placed on the sides of the tank opposite each other and detect the level (in the simplest case, one radiator and one detector are used, whose response after amplification switches the relay contacts when the level reaches the measured point). In a vertical arrangement, the source and detector are below and above the tank, so that the attenuation of the radiation as it passes through the liquid column is exponentially dependent on the level height in the tank; the level height can be monitored continuously.

Neutron measurement of humidity
This method is based on the elastic scattering of fast neutrons on hydrogen nuclei (contained in water), which of all elements most effectively scatter and decelerate neutrons. The humidity meter consists of a source of fast neutrons (usually ²⁴¹Am in a mixture with beryllium, activity of about one hundred MBq to units of GBq) and a detector of slow neutrons (see §2.6). Either a transmission arrangement can be used, where the attenuation of the flux of neutrons from the source due to their scattering on the hydrogen nuclei is measured, or reflective, where the increase in the flux of slowed neutrons due to their scattering in the surrounding material containing hydrogen nuclei is measured.
    The neutron method of measuring the moisture content of materials is used in many industries, eg in the chemical industry, construction, agriculture, mining. It is most often used to measure the moisture content of bulk materials such as soil, sand, mortar mixtures, ores, coal and coke, grain, etc.
Note: The response of neutron flux is given by the total volume humidity. If it is necessary to determine the mass humidity, sometimes combined neutron + gamma probes containing a neutron source and a g- radiation source (eg ¹³⁷Cs) and a neutron detector and a g detector are used (it is often combined into one compact probe). From the response to radiation g it is possible to determine the density of a material, from the neutron response its moisture; the conversion of bulk moisture to mass moisture can then be realized electronically in the evaluation unit of the device.

Radiation defectoscopy
Another method, based on differences in the absorption of penetrating radiation in substances, is radiation defectoscopy. During casting, cooling, welding, machining and operation of products and parts of machines and equipment, inhomogeneities, cavities, cracks and similar internal defects can occur, which impair the mechanical properties of the part and can lead to machine failure. Defectoscopy in general is a method of non-destructive examination of structure ("defects") in the macroscopic consistency of a material.
    Radiation defectoscopy allows by non-destructive analysis of inhomogeneities to detect possible cracks and other anomalies in construction materials and finished products. The basic scheme of defectoscopic measurement is similar to the above-described X-ray diagnostics in medicine. The analyzed object is irradiated with a collimated beam of penetrating radiation X or g, while the transmitted radiation is displayed on a photographic film - radiography, or is displayed on a fluorescent screen or electronic detector to a computer - radioscopy. The absorption of ionizing radiation depends on the thickness and density of the material (see the exponential relationship in the section "Absorption of radiation in substances" in §1.6), so that the weakened areas are reflected in greater blackening of the film.
    Possible inhomogeneity or crack will appear on the film after development as a local defect in an otherwise homogeneous blackening of the emulsion. Films and developers are used, ensuring the highest possible steepness of the blackening curve, so that even small inhomogeneities of transmitted radiation are displayed in sufficient contrast. The blackening of the film is usually evaluated visually using special transmission lamps, or they can be evaluated photometrically. Now the films are gradually being abadonded - the transmitted radiation is detected by a sensitive electronic detector. The detector, a digital semiconductor flat imaging detector ( flat panel), detects the intensity of gamma or X-ray radiation that passes through the material and the occurrence of a defect (cracks, cavities, etc.) is reflected in a change in the intensity of the measured radiation at a given location.
  For defectoscopy of steel objects, either X-rays with an energy of about 60-400keV from technical X-rays tube, or g- rays from suitable radionuclides are used - iridium ¹⁹² Ir, selenium ⁷⁵ Se, cesium ¹³⁷ Cs, cobalt ⁶⁰ Co, occasionally also hard braking radiation g with energy up to 10MeV produced by a linear or circular electron accelerator (braking of electrons on a target). Hard gamma radiation or braking radiation must be used especially when shine trough of metals (steel) with a thickness greater than 100 mm, where ordinary X-rays are no longer sufficient. For radiography of thinner layers, on the other hand, softer photon radiation is more suitable, which provides a higher contrast of the displayed small defects (from the radionuclides, the aforementioned Ir-192 or Se-75 is suitable).
    Defectoscopy is used especially where high demands are placed on the quality of materials and components. These are, for example, gas pipelines, turbine blades, reactor pressure vessels, bridge structures, etc.
X-ray microscopy, micro-CT
So -called micro-X-ray tubes are used for structural analysis of small objects (such as electronic components or small castings). The special X-ray tube has a very small impact focus (only a few micrometers), so the X-ray beam emanates almost from a point source and provides high sharpness and image resolution. The measured sample is placed very close to the X-ray tube and the film or imaging detector at a greater distance - there is a projection magnification of the image. For this purpose, X-ray lamps with a thin front so-called transmission anode are sometimes used (see §3.2, section "X -rays", passage "Special types of X-ray tubes"), which allows you to bring the displayed object as close as possible to the focus on the anode and thus achieve high magnification at a small distance between the illuminated object and the imaging detector. For X-ray microscopy (XRM) mainly soft X-rays of approx. 20 - 60keV are used. Low-energy photons of X-rays interact with the atoms of the investigated substance mainly by the photoeffect, which provides a higher absorption contrast between areas with small differences in density. In large special laboratories, very soft X-rays (approx. 2 - 10keV - around the K- or L-edge of the absorption spectrum of the examined material, where the absorption and imaging contrast is greatest) from the synchrotron undulator are used for X-ray microscopy (see §1.5, section "Charged particle accelerators", section "Accelerators as synchrotron radiation generators"), with the possible use a crystal monochromator and a Fresnel zone plate, acting as a connecting lens of X-ray optics. Either scan mode or display using special pixel detectors is used. These are very demanding laboratory methods!

X-ray microscopy with a special microfocus X-ray tube with a transmission anode.

CT X-ray tomography or micro-tomography (mCT) is also used for detailed 3D analysis of small objects, the principle of which is analogous to the above-described medical X-ray tomography (§3.2, section "X-ray tomography - CT"). The main difference is that the X-ray tube and the detection system do not rotate during the measurement, but the displayed object rotates between the static X-ray tube and the imaging detector. The passed X-rays, measured by an imaging detector for a number of different angles of the rotating sample, are reconstructed into cross-sectional images, the set of which forms a 3-D image of the analyzed object.

Safety inspection of materials
The X-ray inspection of baggage, used in recent years at airports, is also based on the principle of radiation measurement of mechanical properties (density) of materials. Small X-ray machines - an X-ray tube and an opposite electronic imaging detector - are installed at the baggage counter for air traffic, between which checked baggage passes. The resulting absorption image is immediately projected on the display, sometimes with a "pseudo" color display (artificial assignment of colors to grayscale), in order to recognize mainly metal objects (such as weapons).

X-ray diffraction analysis of the crystal lattice structure
When X-rays fall on a substance with a crystal structure, diffraction of part of the X-rays occurs, during which this radiation ir reflected from the regular structure of the crystal lattice - X-rays elastically scattered on the electrons of the measured crystal. Subsequently, interference of this difracted X-radiation may occur. In the diffraction interference picture is then encoded information about the internal structure of the crystal.
    At the incidence of monochromatic X - rays with a wavelength of l » 0.1 nm (comparable to the distance between the ions forming the crystal lattice), the rays may be amplified in one direction, weakened or disturbed in others. X-rays are amplified and form an interference maximum if the so-called Bragg condition is met, so that the path angle of two rays is an integer multiple of the wavelength of the radiation: n. l = 2.d. sin J, where J is the angle formed by the incident beam with the crystal plane, d is the distance between two adjacent crystal planes (lattice constant), l is the wavelength of the X-ray radiation used and n = 1,2,3, ... is integer. In this situation, the intensity of the scattered waves adds up. For a given crystal having a lattice constant d is thus interfering peaks at the diffraction is reached only at certain values of l and J. Usually, 1st order angular spectra (n = 1) are scanned, where the maximum is most pronounced, only to distinguish some details, higher order spectra are analyzed (low intensity - significant prolongation of exposure time).

Fig.3.3.2. Principle arrangement of X-ray diffraction analysis of crystal lattices

Apparatus for measuring the diffraction called diffractometer consist of a goniometer, in whose center is stored analyte and on whose one arm is a source of X-radiation and the other arm a detector measuring the intensity I_X of X-radiation. By turning the goniometer, the angles J are measured, for which the maximum intensity I_X of the "reflected" X-ray, i.e. the interference maximum, is detected in the reflection mode. The measurement in the transmission mode is rarely used, when the diffraction of X-radiation passed through the sample is measured. Possibly, display of the diffraction pattern on photographic film or electronic imaging detector. The X-ray continuous spectrum monochromator is included either in the primary beam or in the secondary diffraction radiation path. For a detailed analysis of the structure of single crystals, the angles of the X-ray tube J₁ and the detector J₂ are measured independently and another goniometer is included, enabling the sample to rotate even in the perpendicular direction (Bragg-Brentan diffractometer). X- ray tube with microfocus is used in X-ray microdiffraction (its construction was described above in the section "Special types of X-ray tubes" and the use in the previous paragraph "X-ray microscopy; micro-CT "); in the most demanding applications also synchrotron X-rays (§1.5, section "Synchrotron radiation generators").
    X-ray diffractometry is used in many areas of materials research, especially for the analysis of the crystal structure of substances - both single crystals (single crystal X-ray structural analysis) and polycrystalline and powder materials (powder X-ray structural analysis). Also in the non-destructive analysis of archaeological and artistic objects.
Note: It can also be used to decompose continuous (polychromatic) X-rays and obtain a monochromatic component.

Positron annihilation spectrometry
Positron annihilation spectrometry is used to analyze local electron densities and configurations in substances. It is based on spectrometric measurements of the positron lifetime in substance (PLS - Positron Lifetime Spectroscopy). If we irradiate the analyzed material with positrons, fast positrons slow down in the substance in the path of a few micrometers (in a time of about 10 picoseconds) and under normal circumstances they can (via an unstable positronium) annihilate with electrons. However, they can be retained in places of structural irregularities in the crystal lattice (pores with reduced electron density) and annihilate with a delay with electrons from the surroundings. In order to determine the lifetime of positrons, we first need to detect the moment of formation (emission) of the positron. This is possible when the radioactive source of positrons synchronously emits gamma radiation from the excited level of the daughter nucleus.
    The investigated material is thus locally irradiated with a mixed b⁺- g emitter (most often ²² Na), while the lifetime of positrons is determined by measuring the delayed coincidences between the detection of the g photon from the radiating radionuclide (at ²²Na it is g 1274 keV) and detection the g 511 keV annihilation photon.
    In the case of the most common use of a b⁺- g emitter Na²² the detection radiometric apparatus consists of two gamma-detectors (scintillation or semiconductor) :
1. A detector set to a 1274 keV photopeak of gamma daughter nuclide deexcitation radiation ²²Ne. This is the "start" impulse of the time coincidence analysis, indicating the moment of positron formation.
2. Detector set to 511keV of annihilation radiation generated by e^- e⁺ positron annihilation. This is the "final" impulse of time coincidence analysis, determining the moment of positron extinction .
    In solids maters without structural defects the lifetime of positrons is about 0.25ns, in positrons annihilating in defects it is extended to about 0.75ns. With this method it is possible to observe defects in material structure of about 0.1 to 1 nm - dislocations, vacancies, clusters of vacancies, clusters, or precipitates. It is used to monitor the technology of preparation of various materials (plastics, metals, conductors, insulators, semiconductors) and also to monitor the influence of the environment and technologies on materials (fatigue and "aging" of materials, thermal and radiation effects, etc.).

3.4. Radiation analytical methods of materials
The methods of atomic and nuclear physics, as well as the properties of different types of radiation, provide important tools for the analysis of the material and elemental composition of various objects. Most of these methods work in the experimental arrangement ideologically shown already in the introductory Fig.3.1.1a,b in §3.1. The analyzed object or sample is irradiated with a suitable type of primary radiation, the interaction of which with atoms or nuclei creates secondary radiation, which "brings out" some information about the composition of the material. This radiation is detected and analyzes. From the large number of different atomic, nuclear and radiation analytical methods, we will present only a certain selection of the typical and more frequently used ones, with an emphasis on the physical nature, without excessive technical details.

X-ray fluorescence analysis
This method of non-destructive determination of the chemical (elemental) composition of substances is based on the measurement of the secondary fluorescence characteristic X-rays induced by the primary irradiation of the examined sample. The measured sample is most often irradiated with photon radiation - either X-rays from an X-ray lamp or gamma radiation from a suitable radionuclide - Fig.3.4.1 (irradiation with charged particles is mentioned at the end of this passage). The interaction of this photon radiation with the atoms of the examined sample cause, among other things, a photoeffect (see the passage "Interaction of gamma radiation" in §1.6 "Ionizing radiation") mostly on the K shell (if the radiation energy is higher than the binding energy of the electron on this shell), after which when the electrons jump from the higher shell (L) to the released place, a characteristic X-radiation (K series) is emitted, whose energy is unambiguously determined by the proton number Z of the atom. If a photoeffect occurs on the shell L, then the characteristic X-radiation of the series L is emitted by the electron jump from the shell M.
    The energies (spectral lines K_a,b) of fluorescent X-rays are characteristic for each element, the amount of emitted photons of characteristic radiation is directly proportional to the number of atoms of a given species, thus a measure of the concentration of a given element. By spectrometric analysis the energy (wavelength) of the resulting fluorescent radiation can be used to determine which elements are present in the sample under investigation, and the amount (concentration) of these elements in the sample can be determined according to the intensity of the individual fluorescence peaks.
    The method of exciting characteristic X-rays by primary gamma rays is sometimes referred to as XRF (gamma-induced X-ray Fluorescent Emission).

Fig.3.4.1. Typical arrangement of radiation source, analyte and detector in X-ray fluorescence analysis. At the top right is the detailed structure of the peaks Ka,b of the characteristic X-ray, measured by a semiconductor Ge(Li) detector.

The energy of the primary excitation radiation g or X is most suitable only slightly higher than the binding electrons on the shell K (or L) in the atoms of the analyzed elements; then the highest effective cross section is for the photo effect. Therefore, different irradiation sources are used for lighter, medium and heavy elements. Thus, in addition to the X-ray lamp, radionuclides emitting soft X-rays such as iron ⁵⁵Fe (X Mn L-series 5.9-6.5keV), curium ²⁴⁴Cm (X Pu L-series 12-23keV ) are used for the irradiation of the examined samples for the analysis of light elements, for medium-heavy elements americium ²⁴¹Am (g 60keV) , for analysis of heavy elements such as gold, tungsten, lead, uranium, etc., then cobalt ⁵⁷Co (g 122 + 136keV), cesium ¹³⁷Cs ( g 662keV), cer ¹⁴⁴Ce (g 140keV).
    Scintillation detectors are used to detect characteristic X-rays for simpler and indicative measurements (such as geological survey and ore prospecting, metal content control in metallurgy, etc.), but a high-resolution semiconductor detector must be used for more accurate and complex laboratory analysis, and multichannel analyzer. For quantitative analysis, a correction for interfering Compton scattered radiation g must be made and, of course, careful calibration of the device.
   Characteristic X-rays have four very close energy lines (related to the fine structure of electron levels K and L), which are referred to as K_a1, K_a2, K_b1, K_b2 - Fig.3.4.1 top right. E.g. for lead these energies are 72.8, 74.97, 84.8, 87.3 keV, for gold 66.99, 68.81, 77.9, 80.1 keV, for iron the energy of X-rays is only 6.4 keV, for aluminum 1.5keV (for these low energies it is practically no longer possible distinguish lines K_a and K_b). Thus, for light elements, the X-ray energy is very low and difficult to detect. X-ray fluorescent analysis is therefore particularly suitable for determining content of heavier elements.
   To excite characteristic X-rays, primary irradiation with charged particles that ionize the atoms of the substance is sometimes used, followed by deexcitation and emission of X-rays. The method of particle-induced X-ray emission is called PIXE (Particle-Induced X-ray Emission). It usually irradiates by protons with an energy of about 2-4 MeV, the surface layer of the sample is analyzed to a depth of about 5 mm.
   X-ray fluorescence analysis has the great advantage of being fast, accurate and reproducible, does not require any chemical processing of samples, which can be used in all states of matter. The examined material is not damaged in any way and no artificial radioactivity is generated. It is possible to examine entire objects, without the need for sampling - this is a non-destructive method. It is therefore suitable, among other things, for the analysis of the composition of art objects, which can help their temporal or authorial classification, finding out the origin, as well as verifying their authenticity.

Activation analysis
This nuclear-analytical method is based on the irradiation of a test sample with such radiation (type and energy) that enters the nuclei of the investigated atoms and causes nuclear reactions there. During these reactions, radiation (especially gamma) is emitted, but mainly unstable isotopes are formed from originally stable nuclei - radionuclides, which subsequently decay by radioactive transformation a or b with subsequent emission of photons g. Either the secondary radiation emitted during the nuclear reaction itself is measured, but above all the g- spectrum is measured, emitted by radionuclides generated by nuclear reactions due to primary irradiation. The analysis of this spectrum determines the elemental composition of the sample (qualitative and, if necessary, quantitative).
    Neutron activation analysis NAA 
(also called induced or instrumental neutron activation analysis INAA , see below) is a highly sensitive method of analysis of chemical composition of substances, based on neutron capture (reaction n, g) in the nuclei of the test substance, thus forming radioactive nuclei (see §1.3 "Nuclear reactions"): ^NA_Z + n ® ^N+1B*_Z; B* ® B + g_P; ^N+1B_Z ® ^N+1C*_Z+1 + e^-(b) + n; C* ® C + g_D. During this reactions, two types of gamma radiation are emitted: immediately after neutron capture, it is g_P radiation, followed by radioactive decay of activated nuclei, g_D radiation is emitted - lower part Fig.3.4.2. Irradiation of the examined sample with neutrons thus results in the formation of radionuclides - "activation" of the sample; after by spectrometric analysis of which energies and radiation intensities (especially g) emitted from the activated sample, can be determined the relevant radionuclide and "traced" the corresponding (inactive) starting nuclide contained in the sample, the activation of which this radionuclide was created (Fig.3.4.2). Using a suitable calibration, its content (concentration) in the examined material can also be determined.

Fig.3.4.2. Typical procedure for neutron activation analysis.

Neutron irradiation of the analyzed samples is performed either in irradiation chambers in a nuclear reactor as shown in the figure (nuclear reactor is a powerful source of neutrons, see §1.3, section "Fission of atomic nuclei"), or using neutrons from special accelerators, so-called neutron generators (§1.5, part "Charged particle accelerators", passage "Neutron generators"). In the laboratory conditions and in the terrain is also used radionuclide neutron sources, a blend of the alpha-emitter with a light element (e.g. a -radionuklide ²⁴¹Am in a mixture with beryllium, reactions a,n occur), or a heavy transuranic radionuclide (most often californium 252), during the spontaneous fission of which neutrons are released (§1.3, "Transurans"). For neutron activation analysis, mainly slow neutrons with energies of about 0.001-0.55 eV are used , which have a high effective cross-section of capture by many nuclei. From neutron sources, which usually provide fast neutrons with energies of the order of MeV, the neutron beam is first led to the moderator and the samples are irradiated only by slowed neutrons.
    For complex NAA, the detection of gamma radiation from neutron-irradiated samples is usually performed by semiconductor g-spectrometers with high energy resolution (§2.5 "Semiconductor detectors") in order to identify the exact energies of gamma radiation and to distinguish peaks often in close proximity. For some simpler applications, where it is enough to measure the representation of one or a few elements, scintillation detectors can be used (which do not have such good energy resolution, but have higher detection efficiency - §2.4 "Scintillation detection and gamma-ray spectrometry"). If the measurement of the activated sample is extended by the simultaneous - coincidence - detection of two or more quanta of emitted gamma radiation by means of two spectrometric detectors, the method is referred to as coincidence activation analysis CINAA (Coincident INAA). The method is suitable when the activation results in radionuclides with a cascade deexcitation emitting a pair of photon quanta (such as ⁶⁰Co). Coincidence measurement then sharply reduces the background of interfering impulses. Detection can optionally be combined with position-sensitive detectors (such as semiconductor pixel detectors) that register soft g- radiation or charged particles, especially electrons b^-, which are emitted by activated nuclei in coincidence with photons g. In this way, the spatial distribution of the analyzed element in the sample can be displayed.
    In terms of adjustment of measured samples, two methods of activation analysis are used :
¨ Instrumental INAA activation analysis, where the irradiated sample is measured directly, without chemical treatment, on a g- spectrometer. This is the simplest and most common way to implement NAA. In the respective device, the neutron source and the g- spectrometer are sometimes integrated in one compact device, which can be used not only in the laboratory, but also in the field. Such measurements can also be performed in a non-destructive way: We irradiate the analyzed object or its part with a neutron source, we measure the induced radiation g, after which we can return the object to its original use (unless it is activated too strongly by long-term radionuclides).
¨ Radiochemical RNAA activation analysis, in which the sample is first subjected to chemical separation after irradiation - either to remove interfering radionuclides (which could overwhelm the analyzed radionuclides or to interfere with them), or to increase the concentration of required radioisotopes. This method is used less often for considerable labor and laboratory complexity.
    In terms of the time relationship between irradiation and measurement, neutron activation analysis is divided into two categories :
l Subsequent - delayed gamma-neutron activation analysis DGNAA (Dellayed Gamma-ray Neutron Activation Analysis), where gamma radiation measurements from the sample are performed after the end of the neutron irradiation (as in Fig.3.4.2 in the middle). The "subsequent" (delayed) radiation g_D is measured here, arising from b -radioactivity of activated nuclei ^N+1B_Z ® ^N+1C*_Z+1 + e^-(b) + n by deexcitation of excited levels of the daughter nucleus: C* ® C + g. This is the most commonly used method, suitable where neutron activation produces radionuclides with a longer half-life (minutes and longer).
l Immediate ( prompt *) gamma-neutron activation analysis PGNAA (Prompt Gamma-ray Neutron Activation Analysis), when the measurement of emitted g-radiation is performed during neutron irradiation (Fig.3.4.2 on the right). Radiation g of two types (origins) here is measured from the irradiated sample with a gamma spectrometer : 1. Immediate photons g_P , usually emitted very quickly after neutron capture from excited levels of activated nuclei B* ® B + g. 2. Radiation g_D arising subsequently from b -radioactivity of activated nuclei ^N+1B_Z ® ^N+1C*_Z+1 + e^- (b) + n by deexcitation of excited levels of the daughter nucleus: C* ® C + g. This method is suitable when neutron activation produces short-term radionuclides (which would usually decay during the time between irradiation and sample measurement), or stable nuclides, or radionuclides with pure b- decay or a small proportion of g- radiation (then applied here the immediate photons g_P generated after neutron radiation capture). The prompt NAA automatically falls into the category of instrumental activation analysis mentioned above.
*) In a sense, the method of neutron stimulated gamma emission can also be included in this category, when the sample is irradiated with fast neutrons, the inelastic scattering of which leads to excitation of nuclei in the analyzed sample. During subsequent deexcitation, g- radiation of characteristic energies for individual nuclides is emitted. The presence and concentration of the respective elements and their isotopes can be determined by spectroscopic detection of this g- radiation, performed during neutron irradiation. This method was also experimentally tested for the purpose of in vivo gamma imaging in medicine (see §4.3, passage "Neutron stimulated emission computed tomography NSECT").
    Neutron activation analysis can achieve extremely high sensitivity (it allows to detect even 10^-12 g of element in 1 g of sample), so it is suitable for detecting trace amounts substances, eg trace element content in plant and animal tissues, water pollution, purity of semiconductor materials, etc.
Note: For special purposes of biological research, in vivo neutron activation analysis is sometimes used : the relevant part of the organism is irradiated with neutrons (from reactor or neutron generator), followed by a gamma imaging of the distribution of induced beta radioactivity (accompanied by gamma), mapping the distribution of the test substance in tissues and organs.
    In addition to neutron activation, proton and gamma-activation analysis are also rarely used, in which protons accelerated on an accelerator, such as a cyclotron, are used to activate the nuclei of the sample (causes reactions of proton capture [p, g], or reactions of type [p, n], [p, d], [p, a]), or high-energy gamma radiation (causes photonuclear reactions [g, n], [g, p], at higher energies more particles can be ejected from the nucleus [g, 2n], [g, d], [g, 2p], [g, a] ), arising as braking radiation by electrons accelerated in betatron, microtron or linear accelerator.

Mössbauer spectroscopy
Mössbauer spectroscopy is a non-destructive analytical method based on the so-called Mössbauer effect of resonant nuclear absorption of g radiation - see §1.6, section "Interaction of gamma radiation". The sample is irradiated with monochromatic radiation g and the detector measures the intensity of transmitted or "reflected" (resonantly scattered) radiation as a function of subtle changes in radiation energy g, which varies in a narrow range due to Doppler effect by precisely controlled mechanical movement of the source relative to the sample by a linear motor. Radiation g it must have an energy exactly corresponding to the excited level of the core of the sample under examination. The Doppler effect compensates for the energy loss of the reflected nuclei, resonant absorption of photons g, accompanied by a maximum of absorption and subsequently emission of a photon of the same energy.
    This method is applicable to substances containing elements which form as daughter nuclei of suitable radioisotopes and have excited levels emitting radiation g ; the samples are irradiated with radiation g from such a radioisotope. The fine position of the absorption maxima depends on the properties of the chemical bond in which the atoms containing the analyzed nuclei participate, on the properties of the crystal lattice, as well as on the internal magnetic and electric fields in the crystals. By analyzing the fine structure of the Mössbauer spectrum (which is the dependence of the absorption of g on the feed rate of the source relative to the sample), some internal chemical and physical properties of the investigated material can be determined.
   This method is suitable for ⁵⁷Fe, ⁵⁷Co, ¹²⁹In, ¹¹⁹Sn, ¹²¹Sb *). It is mainly used on materials containing iron ⁵⁷Fe. It allows the analysis of the distribution of iron in the material in various crystallographic positions, its degree of oxidation, analysis of ferromagnetic materials, alloys, minerals, etc. For analytical purposes, the samples are made into a thin film or powder (weighing several grams).
*) The number of suitable elements (nuclei having a suitable radionuclide emitting g radiation from a suitable excited level of a stable daughter nucleus) suitable for this analysis is very limited , so the significance of Mössbauer spectroscopy is not comparable to such methods as activation analysis, X-ray fluorescence analysis or defectoscopy...
   In the Mössbauer spectrometry of iron, the radionuclide ⁵⁷Co is used as the radiation source g, which decays to an excited ⁵⁷Fe nucleus with a half-life of 270 days by electron capture. This nucleus emits 692keV (0.14%), 136keV (11%), 122keV (87%) and 14.4keV (9%) g radiation when deexcited. It is the radiation g of the partial transition from the excited level with an energy of 14.4 keV, that is suitable for excitation of resonant nuclear absorption due to its low energy. Due to the high Debye temperature Fe (360 °K), the Mössbauer effect occurs even at normal laboratory temperatures, wheres the Doppler frequency shift required to compensate for the reflection of the ⁵⁷Fe core is achieved by mechanical displacement of the source at speeds of only the order of 1 mm/s.
    Note: High sensitivity Mössbauer effect of resonant nuclear absorption g -radiation 14.4keV of ⁵⁷Fe was used in 1960 by R.V.Pound and G.A.Rebka to measure the gravitational frequency shift in the Earth's gravitational field, which was an important test of Einstein's general theory of relativity as a physics of gravity and spacetime - see §2.4 "Physical laws in curved spacetime" in the book "Gravity, black holes and space - time physics".

Mass spectrometers and separators
Mass spectrometers and separators, used in physical chemistry and radiochemistry, work in a similar arrangement as the magnetic spectrometer of charged particles according to Fig.2.6.1 on the left - see §2.6, section "Magnetic spectrometers". The analyte is ionized in the ionization chamber, the formed cations of charge e are accelerated by an electric field and ions with a constant velocity v are selected in a velocity filter (consisting of, for example, a crossed electric and magnetic field). These then fly through the input slit into the magnetic field of intensity (induction) B, in which they describe a circle with radius R = (v/e.B) .m, proportional to the mass m. The ions of different weights describe different paths and thus fall on different places of the base - the device thus separates ions of different weights (given the weight of the core). By changing the magnetic field, ions of corresponding masses are gradually focused into the detector - a mass spectrum is created. In the mass separator, a suitable target is installed instead of the detector, on which the incident ions of the selected mass are absorbed.
    Magnetic mass spectrometry is a complex method for the most accurate analysis of the representation of elements and their individual isotopes in the analyzed substances. Magnetic mass separation makes it possible to isolate completely pure samples of a precisely defined isotopic composition, but only in very small quantities.

Gas ionization analyzers
As ionizing radiation (a or b) passes through a gaseous medium, absorption and ionization depend on the density and composition of the gas. The flow ionization chamber with a built-in emitter a or b can thus serve as an analyzer for checking the composition of the gases.
Fire detectors
The ionization fire detector consists of two electrodes with an air gap. Radiation a from the applied layer of radionuclide (most often ²⁴¹Am, approx. 30 kBq) generates an ionization current in gas between the electrodes. In the presence of smoke between the electrodes, the absorption of the gas environment changes and thus the ionization current changes, which is registered by the electronic circuits of the fire alarm system.
Electron capture radiation detector - ECD
To detect compounds with high electron affinity (such as the Freons, chlorinated pesticides and other halogenated compounds ) may be a radiation electron capture detector (ECD - Electron Detector Capure). It consists of a cylindrical ionization chamber filled with an inert gas (eg argon), one electrode (cathode) of which is provided with a layer of a low-energy radiator b, usually ⁶³Ni (activity approx. 300MBq). The emitted radiation b creates an ionization of the gas atoms, a certain ionization current flows through the chamber. When a gas containing high electron affinity atoms enters the chamber, these atoms absorb the electrons in the ionized gas and the ionization current through the chamber decreases, which is electronically registered. Such chambers are often used as a terminal detector in gas chromatography columns.

Nuclear magnetic resonance - analytical and imaging method
Nuclear magnetic resonance (NMR) is a very complex physical-electronic method, based on the behavior of magnetic moments of atomic nuclei under the action of an alternating radio frequency signal in a strong permanent magnetic field. This originally analytical method was later improved and developed even as an important imaging method.
Note: We have included nuclear magnetic resonance among nuclear and radiation methods, even though it does not contain any ionizing radiation. However, it is a method based on the findings of nuclear physics - the properties of atomic nuclei. A physical phenomenon called nuclear magnetic resonance - NMR, was investigated in the 1940s (F. Bloch, E.M.Purcell) and was initially used in chemistry as sample NMR spectrometry . In the 1970s and 1980s, NMR imaging methods also began to develop (pioneers were P.Lauterbuer, P.Manfield, A.Maudsley, R.Damadian, 1977) - see below.
    We will try to briefly outline the principles and methodology of NMR. However, due to the considerable principal and technical complexity of NMR (only scintigraphy can partially compete with it), we must observe the maximum brevity...
Physical principle of NMR
Phenomenon of nuclear magnetic resonance it can generally occur during the interactions of atomic nuclei with an external electromagnetic field. Each nucleon (proton and neutron) has its own "mechanical" angular momentum - spin (nucleons belong to fermions with spin 1/2, see §1.5 "Elementary particles"). According to the laws of electrodynamics, this rotational angular momentum of nucleons creates - induces - its own elementary magnetic moment m_p = 1.41.10^-27 J / T, equal to 2.79 times the so-called Bohr nuclear magneton *) - it is discussed in more detail in §1.1, passage "Quantum momentum, spin, magnetic moment", paragraph " Magnetic moment ". Due to the spins of their nucleons, atomic nuclei therefore generate a very weak magnetic field - they have a certain magnetic moment m. However, only atomic nuclei with an odd nucleon number have spin and magnetic moment, because the spins and magnetic moments of paired protons and neutrons cancel each other out - they are zero. The magnetic moment of the nucleus is formed by an unpaired nucleon - a proton or neutron. Magnetic resonance imaging can therefore be observed only in nuclei with odd nucleon numbers - especially hydrogen ¹H, then in ¹³C, ¹⁵N, ¹⁹F, ²³Na, ³¹P, etc.
*) Nuclear magneton m_N is a physical constant expressing the proton's own dipole magnetic moment induced by its spin: m_N = e.h /2m_p , where e is the elementary electric charge (proton, electron), h is the reduced Planck's constant, m_p is the rest mass of the proton. In the system of SI units, its value is approximately m_N = 5.05.10^-27 J /T. It is analogous to the Bohr electron magneton m_e = e.h / 2m_e , which, however, is 1836 times larger, in the ratio of the mass of the proton and the electron. It is interesting that even a neutron, although electrically uncharged, has a non-zero magnetic moment m_n = -0.966.10^-27 J /T somewhat smaller and of the opposite sign than a proton. It turns out that the magnetic moment of nucleons has its origin in their quark structure (§1.5., part "Quark structure of hadrons" and §1.1, passage "Magnetic moment").
Magnetic moments of nuclei in a magnetic field 
Under normal circumstances, due to the thermal motion of atoms, the directions of spins and magnetic moments of individual nuclei are chaotically "scattered", their orientation is random and disordered (Fig.3.4.4a), elementary magnetic fields cancel each other out on average, on a macroscopic scale the substance shows no magnetic properties (we do not mean ferromagnetic substances, where it is the effect of electrons in atomic shells) . However, if we place the analyzed substance in a strong magnetic field (of intensity or induction B of the order of several Tesla), the magnetic moments of the nuclei are oriented in the direction of the vector B of this external magnetic field (at least partially).- the magnetic moment of the nuclei is parallel to the magnetic field lines (Fig.3.4.4b). The stronger the magnetic field, the more perfect this arrangement *). Outwardly, this results in non-zero magnetization vector M in the direction of the external magnetic field induction B. The magnitude of the magnetization vector is proportional to the strength of the external magnetic field B and the percentage of concordantly oriented mag. moments of nuclei in matter. A sufficiently strong magnetic field B is now mostly realized by means of a superconducting electromagnet, the winding of which must be permanently cooled by liquid helium (physical principles of superconducting magnets are briefly discussed in §1.5, section "Electromagnets in accelerators", passage "Superconducting electromagnets").
*) However, the extent of this arrangement is actually very small ! In commonly used magnetic fields 1-3T, for every 1 million hydrogen nuclei, only about 7-20 nuclei are on average in a state of uniform orientation. The vast majority of nuclei are as a result of thermal motion, it is oriented in different directions, including the opposite one (this is expressed by Boltzmann's law of distribution.) In this sense, it is necessary to take Fig.3.4.4b only as a symbolic scheme, which shows only those few nuclei that acquire concordant orientations.
  Since conventional material, e.g. water or tissue, contains about 10²² hydrogen nuclei per 1 gram, even a small excess of oriented nuclei provides a measurable magnitude of the magnetization vector and the radio frequency response signal.
Larmor frequency, radiofrequency excitation and relaxation 
In the magnetic field B, the nuclei (with a non-zero magnetic moment m) behave as magnetic dipoles, which are acted upon by a pair of forces m.B . This will cause the core to rotate the axis of its magnetic moment around the direction B - it will perform a precessional movement (similar to the precessional movement of a gyroscope or children's "spinning top" around the vertical direction in the gravity field) by the so-called Larmor frequency
       w_L = g . B  , or    f_L = ^{g .B} /_2p ,
where g is the gyromagnetic ratio of the nucleus, which is the ratio of the magnetic moment of the nucleus and its "mechanical" moment of inertia [ rad · s ^-1 · T ^-1] . The precession movement occurs when the external magnetic field changes or the angle of the magnetic moment in this field changes and lasts as long as the mag. the moment does not stabilize in the rest position.
    If we send a short alternating electromagnetic signal into such a magnetically polarized substance by means of another coil (high-frequency - HF, or radio-frequency - RF) (whose frequency resonates with the above-mentioned Larmor precession f_L of a given type of nucleus in a magnetic field), the direction of the magnetic moment of the nucleus temporarily deviates from the direction determined by the vector B of the external magnetic field (Fig.3.4.4c) *). The deflection of the magnetization vector is caused by the magnetic component of the excitation RF pulse. The angle of this deflection is proportional to the amplitude (energy) of the RF pulse and its duration. The most commonly used RF pulses are 90° or 180°.
*) Fulfillment of the resonance condition: The nuclei are able to efficiently receive energy from an alternating electromagnetic field only if the Larmor frequency of the nucleus precession and the frequency of the electromagnetic pulse are the same. The preceding nuclei thus resonate with an electromagnetic pulse at a given Larmor frequency - hence the name "magnetic resonance".
    After the unwinding of the excitation, signal occurs relaxation (at a constant rotation Larmor frequency) at which they emit electromagnetic waves with decreasing intensity until the magnetic moment of the spiral return back again in the direction B. These electromag. waves will induce alternating voltage in the receiving coils - "echo" radiofrequency signal **). This relaxation signal (sometimes referred acronym FID - Free Induction Decay) , has a sinusoidal course with exponentially decreasing amplitude (see below Relaxation times). It is a useful signal that carries information about the inner structure of the analyte. Frequency of this signal is equal to the above-mentioned Larmor precession and for a given force B of the external magnetic field is determined by the gyromagnetic ratio g of the nucleus, ie the type of nucleus, the amplitude of the relaxation signal is proportional to the concentration of nuclei of the given species- thus nuclear magnetic resonance can be used to analyze of the composition of substances : what elements and in a what concentration are contained in the sample. E.g. for hydrogen nuclei (protons) the gyromagnetic constant has the value g = 2.675.10^-8 s^-1 T^-1 and in the magnetic field of induction 1Tesla Larmor's NM the resonant frequency is 42.574MHz, at 1.5T it is 63.58MHz - the area of radio waves (short waves) . For heavier nuclei is proportionally lower .
**) Phasing of a large number of nuclei : The NMR receiving coils are, of course, not able to detect the relaxation radiation of one or a few nuclei. To obtain a measurable signal, deexcitation of a large number of nuclei (> about 10¹² ) is required, namely synchronously and at the same phase ! If phasing disruption occurs, the MNR signal drops sharply or disappears (cf. below "Relaxation times - T2").
    Gnoseological note :
Quantum behavior: For the sake of clarity, we have not yet explicitly included the quantum behavior of the magnetic moment, we considered its continuous behavior. The orientation of the magnetic moment vector of nuclei in a magnetic field actually acquires discrete quantum states - parallel (0°), perpendicular (90°) and antiparallel (opposite, 180°) with the direction of the vector B  magnetic induction of an external magnetic field. The basic, energetically lowest state is parallel, while the perpendicular or antiparallel configuration has a higher energy- excited state. From the fundamental to the excited state of the magnetic moment, the nuclei pass by absorbing a quantum of electromagnetic energy, which must be exactly equal to the difference in energy between the two states. The respective frequency corresponds to the resonant Larmor frequency. During deexcitation, an electromagnetic signal of the same frequency is then emitted . The precession rotation of the magnetic moment of nuclei in a magnetic field is again just our model idea of how to clearly explain the behavior of nuclei in a magnetic field ...

Fig. 3.4.4. Nuclear magnetic resonance - simplified schematic representation.
a) The magnetic moments of the nuclei in the analyte normally have chaotically scattered directions.
b) By the action of a strong magnetic field B, the mag. moments of nuclei partially orient in the direction of the vector B .
c) By sending a RF electromagnetic field, these oriented nuclei deviate from the B direction, eg by 90°. After switching off this RF field, a relaxation occurs, during which the deflected nuclei when its return at precession rotation will emit an electromagneic NMR signal with exponentially decaying amplitude.
d) Simplified schematic diagram of NMR imaging equipment. For simplicity, only one radio frequency (RF) coil is drawn, which electronically switches alternately to transmit and receive modes; usually there are separate transmitting and receiving RF coils. (ADC = analog-to-digital converter, DAC = digital-to-analog converter) .

Radio frequency coils
RF coils are a kind of "antennas" of the NMR system, that transmit excitation RF signals towards the analyte, or receive response RF signals from the relaxing nuclei in the analyte. In principle, the same coil can be used as the transmitting and receiving coil, which is electronically switched to the transmitting and then to the receiving mode (as symbolically drawn in the diagram in Fig.3.4.4d). However, better detection of the response NMR signal can be achieved by using a separate receiving RF coil. Due to the relatively high Larmor frequency (tens of MHz), RF coils have a very simple design: they are formed by a loop of wire of circular or rectangular shape, which is placed close to the analyzed material (sample or area of interest in the organism). Sometimes they are suitably shaped (bent into a saddle or cylindrical shape) to achieve better homogeneity of the RF signal in the analyzed area.
  A short but very strong radio frequency alternating current, of high amplitude, is introduced into the transmitting coil in various time sequences, instantaneous power up to tens of kW. In the receiving coil, a response signal is then induced from the relaxing nuclei, on the contrary, with a very low amplitude (of the order of millivolts), which for further electronic processing must be significantly amplified in a narrowband high-frequency amplifier. For NMRI imaging (see below), special RF receiving coils of various sizes and shapes are used to tightly encircle the analyzed area - for imaging the brain, joints, spine, etc.
NMR spectroscopy and analysis
NMR spectroscopy is performed in such a way, that the frequency of the excitation RF signal gradually increases, this signal intermittently supplies the coils in the transmitting mode, there is always a switch to the receiving mode and the intensity of the RF signal is measured - echo - transmitted by a sample placed in the magnetic field B_o during the back relaxation of the magnetic moments of the nuclei. The frequency at which the resonant maximum occurs, the Larmor frequency, determines the type of nucleus (the highest is for hydrogen - 42.6 MHz for B = 1Tesla), the intensity of the resonant maximum determines the concentration of the relevant atoms in the sample. All nuclei of one isotope, inserted into the same magnetic field, should resonate at the same frequency by themselves. However, if the atoms of these nuclei are part of chemical compounds, the distribution of electrons in their environment differs and these electrons cause electromagnetic shielding of the nuclei. The effective magnetic field acting on the nucleus is then no longer B_o, but B = B_o . (1- s), where the shielding factor s , describing the shielding intensity, slightly depends on the chemical composition of the analyte. This change in the effective magnetic field causes a so-called chemical frequency shift in the NMR signal spectrum .
    Another effect affecting the fine structure of the NMR spectrum is the mutual interaction of the nuclei of neighboring atoms mediated by valence electrons. As a result of these interactions, the splitting of the resonant maxima of the studied nuclei is observed into 2-4 lines at a distance of about 20 Hz - there is a multiplicity of signal .
    Detailed analysis of frequencies, intensities and multiplicities in the NMR spectrum can therefore provide information on the chemical composition and structure of organic and inorganic substances. Modern NMR spectrometers are computer controlled, and the induced NMR signal is analyzed using a Fourier transform .
Relaxation times
After switching off the high-frequency excitation field, the deflected nuclei relax in the magnetic field - they return in a spiral path to the original equilibrium state in the direction B_o (which we refer to here as the "z" axis), which is observed in the receiving coil as a free reverberation of the induced RF signal with an exponential decrease in amplitude. The rate of this relaxation (or fading time) is influenced by the interaction of nuclear spins with surrounding atoms and the mutual interaction between nuclear spins. The NMR signal also encodes information about the surrounding atoms and molecules - information about the chemical composition and structure of the substance. The decay time of the resonant signal is characterized by two relaxation times T₁ and T₂ .
    Relaxation time T1 , sometimes called spin-lattice (the name comes from the original use of NMR for the analysis of solids with a crystal lattice) , represents the basic time constant of relaxation of magnetic moments of nuclei from the deflected position to the equilibrium position in the direction of the permanent magnetic field. It captures the speed at which the deflected core releases energy to electromagnetic waves and the environment during relaxation, while the longitudinal magnetization in the z-axis direction returns to the original value of M_o according to the exponential law: M_Z = M_o.(1 - e ^{-t / T1}) . It is defined as the time, during which the longitudinal magnetization at relaxation reaches (1-e)- times the original value M_o, whereby the signal drops to 63% (if the excitation of the magnetic moment of the core by 90° was performed).
    The relaxation time T2 , sometimes called spin-spin, expresses the time constant with which, due to the mutual interaction of spins and magnetic moments of adjacent nuclei, leading to the dephasing of the precessional motion of magnetic moments, the magnetization decreases in the transverse direction x-y: M _XY = M_{o XY} e ^{- t / T 2} . T2 is defined as the time during which the transverse magnetization M_XY decreases e-times.
    Note: The receiving coil in the MRI actually detects a shorter relaxation time marked T2* after the excitation pulse has ended. In addition to the relaxation time T2, it is caused by a steeper decrease in the transverse component of the material magnetization due to small changes in the inhomogeneity of the magnetic field, leading to desynchronization. In MRI imaging, this phenomenon is usually negative, it can be corrected or eliminated in the so-called "spin-echo sequence" - see below.
    The relaxation times T1 and T2 are the result of the interaction of resonant nuclei with their surroundings and characterize the chemical properties and structure of the investigated material. In medical use, they are often significantly different for healthy and tumor tissue.
  In the most commonly used external magnetic field of 1.5 T, the relaxation times T1 and T2 of water and some human tissues (in the physiological state) have the following approximate values :

Relaxation times are characteristic of different substances and tissues - they depend on the concentration of nuclei, temperature, size of molecules, chemical bonds. It can be seen from the table that, for example, hydrogen nuclei tightly bound in fat or protein molecules relax much faster than protons weakly bound in water molecules.
NMR imaging - MRI
The NMR method originally served as an analytical method for the composition and structure of samples. Advances in electronics and computer technology in the 1970s and 1980s made it possible to use the NMR signal to create an image of proton density in an object under investigation. This created the NMR imaging method (NMRI - Nuclear Magnetic Resonance Imaging; the word "nuclear" is often omitted and the abbreviation MRI is used) - Fig.3.4.4d.
    In order to be able to detect NMR signals separately and locally from individual places of the examined object (organism or tissue) and use it to create an image , it is necessary to ensure spatial-geometric coding of coordinates in the examined object. This can be achieved by superimposing an additional gradient magnetic field in the direction of the X, Y, Z axis on the main constant homogeneous field B_o. These gradient magnetic fields in the direction of each X, Y, Z axis are generated by a respective pair of gradient coils. By changing the gradient magnetic field, we achieve that the magnetic resonance will always occur in a different place of the examined object. By this gradient magnetic coding of spatial coordinates we can then perform NMR imaging.
Gradient coils 
are "additional" electromagnets located in suitable places inside the main strong electromagnet. They are wound with copper wire or metal tape, dimensioned for relatively high currents of tens or hundreds of amperes. Gradient coils are supplied in pulse sequences with a relatively strong current (approx. 500A) from electronically controlled sources, which allow fast and accurate setting of the strength and direction of the excited magnetic field - an additional gradient field. They produce gradients in the range of about 20-100 mT /m. In order for MRI imaging not to take an enormously long time, the rate of gradient changes needs to be relatively high - it reaches about 100-200 Tm^-1 .s^-1; it requires a certain voltage (approx. 50-300V) to overcome the inductance of the gradient coils - the power supplies of the gradient coils are relatively robust (power). Strong current surges in the gradient coils when interacting with the magnetic field cause mechanical vibrations, which causes considerable noise during MRI. Longitudinal gradient coils (in the Z direction ) have turns wound in the same direction as the main coil, X (gradient in the left-right direction) and Y (gradient in the up-down direction) are formed by saddle-shaped coils with vertically wound turns.
    Note first the longitudinal gradient field B_z(z) in the Z direction. His superposition with the main mag. field B_o causes the actual "local" value of the magnetic field B = B_o + B_z(z) to depend on the z coordinate : B = B(z). If we send a high-frequency pulse of a certain frequency f to a sample placed in this slightly inhomogeneous gradient magnetic field, the magnetic resonance signal will be transmitted by atomic nuclei only from a thin layer of the sample with coordinate z , for which the resonance condition f = g .B(z) /2p is satisfied. By varying the frequency f of high-frequency excitation pulses, or the intensity of the longitudinal gradient field B_z, is changes the position of the layer, in which the magnetic resonance response signal is generated. In this way, information about the dependence of the spatial distribution of the density of the nuclei in the direction of the Z axis is captured - the electronic-geometric coding of this coordinate is achieved - the layer z .
  The representation of the spatial distribution of the density of nuclei in a given layer z in the transverse directions X and Y is then obtained by the action of another, transverse, gradient magnetic field in the direction of the X and Y axis, whereby the investigated layer decomposes into elementary volumes - "pixels", in which is determined intensity of the relaxation NMR signal, and also its decay times. By changing these gradient fields, data are obtained for individual sites in the z layer and their computer reconstruction yields a cross-section image of the proton density in the examined layer z (Fig.3.4.4d right). By electronic analysis of relaxation times of the NMR signal is also generated cross-sectional images in the relaxation times T1 and T2 (referred to as T1 or T2 - weighted images). The set of cross-sectional images for different values of the z-coordinate then creates a 3-dimensional tomographic image of the investigated area in proton density and relaxation times in individual "voxels". Using computer graphics, it is then possible to create images of any sections of the examined area, which are brightly modulated in a wide range of shades of gray (from white to black), to distinguish the structure of tissues and organs.
    The basic subject of NMRI imaging is hydrogen nuclei - imaging of proton density and relaxation times. This is why NMRI is sometimes referred to as "hydrogen topographic imaging". The intensity of such an NMR image mainly reflects the amount of water at each locationin the examined tissue and the nature of the binding and distribution of hydrogen molecules in the cells and extracellular space, as well as the distribution of fat and proteins. Based on these structural differences, different tissues can be distinguished from each other in MRI images - such as water, muscle, fat, gray matter and white matter in the brain.
    In general, two basic information is captured locally in NMRI images :
1. Density distribution of nuclei producing nuclear magnetic resonance - most often the proton density PD of hydrogen in the tissue. PD images essentially capture the anatomical structure of tissues and organs, and are largely similar to CT X-rays, which map the electron density of tissues.
2. Distribution of relaxation times T1 and T2 related to the chemical composition and structural state of the tissue in individual places. Such images are called T1 and T2 - weighted .
    About to what extent to which the proton density PD and the times T1 and T2 will be represented in the resulting MRI image, - how and with what this image will be modulated - "weighted" - is determined by pulse sequences: time sequence of transmitted RF pulses and "echo" response signals (will be discussed in more detail below) .

Fig.3.4.5 MRI images of the brain (transaxial section, without pathology) in proton density, relaxation times T 1 and T 2 and in a special FLAIR sequence to suppress the water signal.
(MRI brain images were taken by Jaroslav Havelka, MD, head of the MRI RDG department at the University Hospital Ostrava )

Proton densities and especially relaxation times are different not only for different types of tissues (see table above), but also differ depending on the physiological or pathological condition of the same tissue. This makes NMRI imaging an important diagnostic method in medicine, including in the field of tumor diagnostics.
    Note: As with X-ray diagnostics, NMRI also uses contrast agents to increase the contrast of images of certain structures (eg cavities or blood vessels), but not on a density but on a magnetic basis - ferromagnetic compounds, mostly based on gadolinium . Pulse sequence in NMRI
In medical MR imaging, it is desirable to create images with sufficient high contrast between different tissue types so that the MRI radiologist can best answer the clinical diagnostic question. Optimal image contrast between different tissues with different densities and rexation times can be achieved by suitable excitation of magnetic moments of nuclei and subsequent measurement of their response MR signal: by setting parameters of pulse sequence - time sequence of transmitted electromagnetic excitation pulses RF and subsequent measurements of the "echo" of the electromagnetic signal emitted by the relaxing nuclei. The first parameter here is the intensity (energy) of the transmitted radio frequency excitation pulse (RF), which determines the predominant angle of deflection (tilt) of the magnetization vector of the analyzed nuclei - 90° or 180°. The higher the excitation intensity radiated into the analyzed target tissue, the higher the percentage of reversal of the magnetic moment of the nuclei and the stronger the response signal and more time is required for relaxation. Another parameter is the time interval TR , in which we repeatedly apply individual radiofrequency excitation pulses. The shorter this interval, the less time there is for T1 relaxation. The third parameter is the time TE (echo time) between the excitation pulse and the detection of the response resonant signal. The longer this time, the less nuclei with a shorter relaxation time T2 will contribute to the measured resonant signal. The completely approximate values of the pulse sequence times for obtaining the basic types of MRI images at B = 1.5 T are :
    PD: TR = 1000 ms, TE = 5-30 ms; T 1 -weighted: TR = 10 ms, TE = 5-30 ms; T 2 -weighted: TR = 1000-2000 ms, TE = 80-100 ms.
    In connection with these regularities, several significant sequences of transmission of excitation radiofrequency pulses and subsequent detection of response relaxation signals have been developed (sometimes called "MRI techniques" in MR jargon ) :   
-> Saturation - recovery sequence in which 90° RF pulses are transmitted at regular intervals. Upon arrival of each RF pulse, the magnetization vector rotates 90° and relaxation begins with different times T1 in different tissues. When another RF pulse arrives, the z-component of the magnetization will be different in different tissues. With a suitable repetition period TR of excitation RF pulses, we can set the optimal contrast of the desired tissues at times T1 . This simplest MRI technique is now rarely used, it has been replaced by the inversion-recovery sequence below, providing higher contrast.
-> Spin - echo sequence consisting of a 90° RF pulse followed by a 180° RF pulse. After the magnetization vector has been flipped into the xy plane due to a 90 ° RF pulse, T 2 (resp. T2 *) relaxes, during which phasing occurs. However, the subsequent 180° RF pulse has a "refocusing" effect - it flips the individual spins in the xy plane by 180 ° and the spins are phased again. The result is an echo signal in the receiving coil, the amplitude of which depends on the relaxation times T 1 and T 2 of the tissue (unfavorable T2 * does not apply here, because the effect of magnetic field inhomogeneity on phasing is eliminated by 180 ° pulse phasing) . The character and contrast of the display can be adjusted using the times TR and TE. With short TR and short TE we get T 1-weighted image, long TR and short TE provide a proton density image, long TR and long TE provide a T 2 -weighted image. Due to this variability of imaging options, spin-echo is the most commonly used MRI technique.
-> Inversion - recovery sequence, consisting of a sequence of 180 ° and the following 90 ° RF pulse. The initial 180 ° pulse inverts the magnetization vector to the opposite, after which T 1 relaxation takes place . With a time interval TI - inversion time , a 90 ° RF pulse then follows, which flips the magnetization vector into the xy plane. A RF signal dependent on T 1 is detected in the receiving coilrelaxation time of the displayed tissue. The contrast of the image can be adjusted appropriately using the TI time. A significantly more contrasting image can be achieved than with the saturation recovery technique.
By a special setting of the time T1 = T 1 .ln2, the suppression of the image of the tissue having this relaxation time T 1 is achieved . By setting the short inversion time TI (approx. 140ms with a 1.5T magnet) - the so-called short time inversion recovery STIR - the suppression of the fat signal is achieved in the image . Conversely, by extending the time TI (to about 2600ms) - fluid attenuation inversion recovery FLAIR - we can achieve suppression of the water signal. Other fine details and anomalies in the structure of the examined tissues can then be better assessed on such "cleaned" images.
-> Gradient - echo sequence begins with a 90 ° RF pulse (which tilts the magnetization vector to the xy plane), after which a magnetic field gradient is applied. The nuclei in adjacent atoms will thus show a precession with a slightly different Larmor frequency, which will cause spin phasing. The application of the second mag. gradient with the opposite sign, which rephases the spins and at this point the echo is measured. Used to obtain a T 2 -weighted image.
-> .......... sequence ............ ? add more sequences? ........... ? complete the picture of the graphic sequence diagram? ...
    Computer analysis of MRI images obtained with appropriate sequences (mentioned above) can create special image modulations - such as water or fat signal suppression images . Other special sequences are used for functional MRI (mentioned below) :
-> Susceptibility weighted imaging ( SWI ) shows tissues with slightly different magnetic susceptibility. It uses an extended gradient-echo sequence for display in T 2 * . Its main variant is Blood oxygenation level dependent (BOLD) , see fMRI below .
-> Diffusion weighted imaging (DWI) shows the diffusion of water inside tissue elements, manifested by Brownian motion of molecules. Using a spin-echo sequence with the application of 2 gradients, a subtle effect is registered, in which Brownian-moving water molecules show a different phasing-phasing relationship when reversing the mag. gradient; this leads to a slightly weaker T 2 signal.
MRI Magnetic Resonance Spectrometry MRI
Magnetic resonance imaging (MRS) can be supplemented by the magnetic resonance spectrometry (MRS) described above, which enriches this examination with additional physiological information . Chemical analysis is performed here by analyzing the chemical shift of the Larmor frequency imaging structures in-vivo, eg choline or lipid levels. Chemical shifts are very fine, so this method is demanding not only in terms of signal analysis, but also requires high intensity (recommended at least 3 T) and homogeneity of the magnetic field.
Functional magnetic resonance imaging - fMRI 
Magnetic resonance imaging may be a suitable method for non-invasive imaging of the function of various tissues and organs (along with "molecular" imaging in nuclear medicine - .....). So far, fMRI has found application mainly in functional brain imaging, mapping neuronal activity . Neurons (which do not have internal energy stores) they need to get sugar and oxygen quickly for their increased activity. The hemodynamic response to this need causes an increase in blood perfusion at a given site, but mainly a greater release of oxygen from the blood than inactive neurons. This leads to a change in the relative levels of oxygenated oxyhemoglobin and non-oxygenated deoxyhemoglobin in the blood at sites of neuronal activity.
    In this respect, two basic methods of indirect mapping of neuronal activity are used :
- Local increase of perfusion at the site of increased neuronal activity - perfusion fMRI .
- Change in the ratio of oxygenated and non-oxygenated blood at the site of neuronal activity. The method is called BOLD fMRI (Blood Oxygen Level Dependent). Changes in the relative levels of oxy- and deoxy-hemoglobin can be detected based on their slightly different magnetic susceptibility. Basic hemoglobin without bound oxygen (deoxyhemoglobin) has slightly paramagnetic properties, but when oxygen is bound to it (oxyhemoglobin), it behaves slightly diamagnetically. If more deoxyhemoglobin accumulates at a certain site in the brain tissue, a slightly stronger MRI signal is obtained from it than from the sites where deoxyhemoglobin predominates.
  MRI functional imaging of the brain is performed after neurological activation, either motor (eg movement of fingers) , visual, linguistic or cognitive.
The physical-electronic implementation of NMRI 
NMR imaging isthe most complex imaging method. The operation of the device for NMR imaging is electronically very complicated and demanding, so it must be controlled by a powerful computer with sophisticated software - Fig.3.4.4d. In the multiplex mode, the process of transmitting a sequence of radio frequency pulses, modulation of gradient magnetic fields, sensing and analysis of relaxation signals of magnetic resonance, reconstruction and creation of the resulting images, as well as a number of other transformation and correction procedures are synchronously controlled. Since these are harmonic (sinusoidal) waveforms, scanning and reconstruction are performed using Fourier analysis - in the frequency so-called K-space. It is a set of matrices defined in the memory of the MRI evaluation computer, into the individual elements of which the frequencies, amplitudes and coordinates of MRI signals are recorded. From these "raw" data, the resulting MRI images are created using Fourier transform and other analytical methods.
    Note: Electron paramagnetic resonance (EPR) is based on a similar principle as NMR . The magnetic moments of the electron shells of atoms are used here .........

3.5. Radioisotope tracking methods
Radioisotope tracking or indicator methods are used to monitor the hidden movement and distribution of matter within physical, chemical or biological systems, or in various technological devices. A suitable "labeled" substance with bound radionuclide is introduced into the system - the so-called radioindicator, whose movement and behavior in the system is then monitored on the basis of detection of ionizing radiation emitted during radioactive transformations of nuclei in the radioindicator. The movement and distribution of the radio indicator can be monitored in two basic ways :

• Sampling from suitable places of the monitored system, their adjustment and measurement with a suitable detector (g or b).
• External detection of emitting radiation radiation g by detector placed in suitable places of the examined system (occasionally inside, mostly outside the monitored system).

Radioisotope tracking methods are used in many fields of science and technology, industry, agriculture and especially medicine. Here we will briefly mention a few technical and general biological applications, we will focus in more detail below on applications in nuclear medicine.
    Radioisotope tracking methods were first tested in 1913 by the chemist G.Hevesy, who found that radioisotopes have the same chemical behavior as stable isotopes of the same element. However, unlike stable isotopes, radionuclides can be "visible" through the penetrating radiation generated by the transformation of nuclei.

Radioisotope scintigraphy and nuclear medicine
Nuclear medicine is a field dealing with diagnostics and therapy using radioactive substances in open form, applied to the internal environment of the organism.
  Radioactive isotopes react chemically in the same way as stable isotopes of the same element - therefore they behave in the organism's metabolism in the same way as non-radioactive isotopes of a given element. However, due to the fact that radioactive isotopes are "visible" through penetrating radiation, which arises during radioactive transformations of their nuclei, it is possible to monitor the movement and metabolism of elements and compounds containing radionuclides - radioindicators - in the body and thus investigate the functions of individual organs. Depending on the organ whose function is to be examined, the specific substance (radiopharmaceutical) shall be labeled with an appropriate radioisotope. After application to the body, the movement and metabolism of this substance is monitored - mainly imaging with a gamma camera, possibly supplemented by measurement of samples (blood or urine).
Radioisotope diagnostics in vivo - scintigraphy
In radionuclide diagnostics in vivo in nuclear medicine, the patient is administered (usually intravenously, sometimes orally or by inhalation) a small amount of a suitable g - radioactive substance - the so-called radioindicator or radiopharmaceuticals. The radioindicator used is specific to individual organs and types of examinations. The applied radioactive substance enters the metabolism of the organism and is distributed there according to its chemical composition - physiologically or pathologically it accumulates in certain organs and their parts and is subsequently excreted or regrouped. Gamma radiation emanates from the deposition sites of the radioindicator, which, due to its penetration, passes through the tissue out of the organism. Using sensitive detectors, we measure this radiation g and thus determine the distribution of the radioindicator in individual organs and structures inside the body.
    The most perfect devices of this kind are gamma cameras (scintillation cameras) - using them we display in radiation g the distribution of the radioindicator in the organism. This method, called scintigraphy, thus makes it possible to obtain not only anatomical information, but mainly to tell about organ functions and metabolism. By mathematical evaluation of scintigraphic images, we can obtain curves of the time course of the radioindicator distribution and calculate dynamic parameters characterizing the function of the relevant organs.

Schematic arrangement of the entire process of scintigraphic examination - from the application of a radioindicator to the patient, through the process of scintigraphic imaging with a gamma camera, evaluation, mathematical analysis and quantification, to the interpretation and determination of diagnosis.

The tomographic gamma camera SPECT (Single Photon Emission Copied Computerized Tomography) slowly rotates around the patient's body, scans scintigraphic images from various angles and then uses computer reconstruction to create cross-sectional images (sections perpendicular to the camera's axis of rotation), from which computer graphics can be used to construct spatial (3-dimensional) images of the distribution of the radio-indicator in the organs inside the body.
    The PET gamma camera (Positron Computerized Tomography) detects photons of gamma annihilation radiation (511 keV energy) flying in opposite directions during the annihilation of positrons, emitted by b⁺ radioindicator administered to the patient. These photons of annihilation radiation are coincidentally detected by an annular scintillation detectors, and by computer reconstruction of the line projections of the coincidence sites, images of cross-sections are generated and, if necessary, 3D images similar to SPECT.
    Nuclear medicine provides specific methods for the examination of virtually all organs and thus cooperates with a wide range of clinical disciplines. The most widespread use is mainly in  cardiology, nephrology, neurology, oncology, thyrology, gastroenterology.
    Nuclear medicine methods are among the least burdensome non-invasive diagnostic examination methods. Due to the high sensitivity of the detectors, only a very small amount of radiopharmaceutical is applied to the patient, which is needed to obtain quality image information. The radiation exposure in methods in nuclear medicine is comparable (and often smaller) as in X-ray examinations *).
*) During X-ray examination, the source of ionizing radiation is a device (X-ray tube) and the radiation dose depends, among other things, on the number of images performed, or on the extent of the area scanned during CT. In scintigraphy, the source of radiation is not a diagnostic device, but the patient himself, resp. its investigating body. Thus, we can take any number of scintigraphic images without changing the radiation exposure of the patient.
  Radionuclide scintigraphy is described in detail in Chapter 4 "Radioisotope scintigraphy".

Radiation-guided surgery - sentinel nodes
An important radioisotope tracking method of nuclear medicine is local radiation measurement with a closely collimated miniature gamma-ray detection probe in radiation-guided surgery in the detection of so-called sentinel nodes. In the surgical treatment of cancer, it is important to remove not only the primary tumor, but also, if possible, other tissues into which the tumor cells could be infiltrated. These tumor cells spread from the primary site mainly through the lymphatic pathways, so that the lymph nodes around the tumor site are the first to be affected. If we apply a suitable radioindicator of colloidal state to the peripheral part of the tumor lesion (most often ^99mTc nanocolloid, particle size approx. 50-600 nm, activity approx. 40-150 MBq), it will propagate through the lymphatic pathways and capture and accumulate in those nodes, that are lymphatically associated with the tumor site. The first such node in the lymphatic "watershed" of a tumor foci is called the sentinel node. The accumulation of the radioindicator in the nodes can be displayed scintigraphically. However, the most important thing is to monitor the radioindicator during the actual surgical procedure, when using a collimated detection probe, the surgeon can find a sentinel node containing the radioindicator directly in the operating field.
*) Along with the radioindicator, a blue dye is applied at the same time, which also penetrates the nodes, so that the surgeon can recognize the sentinel node also by its blue coloration.
    After application of the radioindicator, scintigraphic imaging is performed with the displayed nodes marking, then the patient goes to his own surgery, during which a detection gamma probe is used both for perioperative sentinel node detection and for radioactivity detection in an already operated node. This is followed by histological examination of the sentinel node to classify the type of tumor, which will help optimize the further course of therapy. ......"...."......

In vitro diagnostics. Radioimmunoassay - radiosaturation analysis
In nuclear medicine, in vitro radioisotope diagnostic methods are also used, where (non-radioactive) samples taken from patients are analyzed using radioisotope techniques - radiochemical and at the same time biochemical. Most often it is a radioimmunoassay (RIA) or radiosaturation analysis (RSA), which is used to highly sensitively determine the concentration of complex biological substances in the blood serum - hormones, tumor markers and other biologically important substances. It is based on an immunochemical reaction antigen with a specific antibody (Ab - antibody). A competitive immunoreaction is used in which the radiolabeled Ag* antigen "competes" for binding sites on the antibody (which is present in a limited amount in the reaction mixture) with the unlabeled antigen. An appropriate antibody labeled with the appropriate radionuclide Ag* (usually I-125-radioiodine) is added to the sample analyzed, which reacts with given hormone to form an insoluble Ag*-Ab complex. After removal of the unbound fraction (rinsing with water), a compound remains in the sample, the activity of which will depend on the concentration of hormone in the analyzed sample - the amount of labeled antigen-antibody Ag* -Ab complex is inversely proportional to the concentration of antigen to be determined. The more test substance present in the primary sample, the smaller the amount of labeled Ag* -Ab antigen-antibody complex formed and the lower the activity in the final sample. It is measured in a well scintillation detector (see §2.7, section "Automatic measurement of a series of samples") . These methods are of great importance for endocrinology.
  RIA or RSA methods reached their greatest development in the 1970s and 1980s, when they were widely performed in radiochemical RIA laboratories at the departments of nuclear medicine. Then they gradually moved from nuclear medicine workplaces to clinical biochemistry laboratories. Since the 1990s, they have been gradually extruded and replaced by fluorescent and chemiluminescent optical methods, without the use of radionuclides and ionizing radiation...

Radioisotope therapy
In addition to diagnostics, nuclear medicine also includes therapy with open radionuclides, eg treatment of hyperthyroidism and thyroid cancer, blood diseases, palliative and curative therapy for various types of tumors, joint diseases - see below for more details in §3.6 "Radiotherapy", part "Radioisotope therapy".

Nuclear medicine - interdisciplinary field
Nuclear medicine, due to the physical nature of its methods and instrumentation used, is an interdisciplinary field. Besides doctors (specialist and certified in the field of nuclear medicine), nurses and laboratory technicians, are working in team work as well as experts from other professions - physicist, electronics, radiochemicist, pharmacist. Along with medical and physical-technical aspects, considerable attention is also paid to radiation protection of workers and patients in the workplaces of nuclear medicine when working with radioisotopes (see Chapter 5 "Biological effects of ionizing radiation. Radiation protection").

A detailed description of the principles, methods and clinical use of nuclear medicine is in Chapter 4
" Radionuclide scintigraphy " .

Autoradiography
- photographic imaging of the distribution of the beta-radioindicator in the examined preparations in close contact of the photographic emulsion with sample is described in §2.2 "Photographic detection of ionizing radiation", passage "Autoradiography".

3.6. Radiotherapy
Radiotherapy is a physico-medical field using the biological effects of ionizing radiation for therapeutic purposes. The vast majority of it is a therapy of tumor diseases, cancer - radiation oncology, to a lesser extent, some degenerative and inflammatory disorders are treated with radiation. Recently, so-called radiosurgery has sometimes been used, especially for vascular and neurological malformations (see the "Stereotactic radiotherapy" section). Before we focus on our own radiotherapy, we will mention some biological aspects of cancer, diagnostics and non-radiation therapeutic methods (chemotherapy, biological therapy) - to put the issue in a broader context.

Tumors - their nature and origin
Tumors, especially malignant, are among the most common and most serious diseases, threatening the health and lives of patients. During the formation of a tumor, pathological tissue mass (neoplasm) is formed, usually irreversible, in which uncontrolled proliferation of tumor cells takes place, at the expense of healthy tissue; there is no feedback in the body to stop this growth. Tumor cells can grow into the surrounding tissue and migrate through lymphatic or blood vessels to other parts of the body (establish metastases). With its uncontrolled division of the mass of tumor cells, it suppresses the surrounding healthy tissue, disrupts it and can thus violate the function of important organs. The cause of such a condition it is not exactly known *), it lies deep inside the cell structure, probably in mutational changes in DNA. Prevention and causal treatment of tumor diseases - cancer - is therefore difficult.
*) Only some risk factors were observed, which contribute to the formation of tumors or increase the probability of their occurrence. They are various chemical substances, so-called carcinogens, such as some cyclic hydrocarbons and cigarette smoke, the composition of food. Or biological effects - some viruses (so-called oncoviruses ), whose RNA can (via so-called reverse transcriptase) enter the DNA of eukaryotic cells and alter their genetic information, they can cause tumor transformation of cells (or they may not lead directly to tumor formation, but prevent an immune response that would be able to recognize tumor cells and destroy them). Then there are genetic factors , hereditary predisposition (hereditary genomic imprinting eg in Nyemegen syndrome, Ataxia teleagiectasia, Bloom's syndrome, Fanconi anemia, Xeroderma pigmentosum, Li-Fraumeni syndrome of the mutated TP53 gene encoding p53); it is caused by a specific mutation in the tumor suppressor genes (TP53 gene mutation in Li-Fraumeni syndrome, NF1,2 in neurofibromatosis, BRCA1,2 in hereditary breast and ovarian cancer, APC in colorectal polyposis, WT1 and Wilms' kidney tumor, RB1 in retinoblastoma, MLM gene mutation in malignant melanoma). Of the physical influences, it is ultraviolet radiation acting on the skin and especially harder ionizing radiation, as discussed in detail in §5.2 "Biological effects of ionizing radiation".

Carcinogenesis - the formation of tumors
Under normal circumstances, a multicellular organism is a system of individual tissues and organs, consisting of a large number of cells, performing their function in a harmonious community for the benefit of the whole organism. This cooperation and "social behavior" of cells is ensured by very intricate and complex regulatory processes, including signals from monitoring the external environment, transmission of signals to the internal environment of the cell, cellular response, evaluation of signals and their coordination with other signals. Cells that do not fit into this regulatory mechanism (due to damage or loss of their function) are eliminated by the mechanisms of "programmed" cell death, apoptosis. Also, cell proliferation is precisely controlled to meet the needs of the tissue and the organism - dynamic balance, tissue homeostasis. Disruption of regulatory mechanisms can cause various pathological conditions and diseases of the body. One of them is a violation of the regulation of cell division: in some cell a genetic change (mutation) occurs that allows it to survive, divide and produce daughter cells that do not "listen" to the regulatory mechanisms of tissue homeostasis. This can create a gradually expanding population of mutated cells - a clone of tumor cells, multiplying at the expense of healthy tissue.
    Tumor formation (carcinogenesis) is a complex multi-step process in which several mutations gradually accumulate, which do not harm the altered cells, but on the contrary favor them and allow their rapid division regardless of the needs of the organism. The following factors are important for the origin and development of cancer :
¨ Cell cycle deregulation
To maintain tissue homeostasis (a balanced number of functional cells of a given tissue) it is necessary to control the rate at which cells form, develop and die - cell cycle regulation. Due to some mutations, autonomic growth (mitogenic) factors in the cell, their autocrine production, or loss of sensitivity to signals that stop the cell cycle may occur. In particular, p21 and p27 proteins are involved in cell cycle regulation and division, which may bind to and inhibit the activity of certain kinases (serving as regulators of DNA replication and cell division); the content of these regulatory proteins in tumor cells tends to be reduced. On the contrary, the activity of some kinases (§5.2, section "Cells - basic units of living organisms", passage "Proteins, enzymes, kinases") is increased in tumor cells. It is mainly a tyrosine kinase - an enzyme which transfers phosphate to the hydroxyl group of the cyclic amino acid tyrosine, thereby affecting the function and activity of the respective protein. Increased epidermal growth factor receptor (EGFR) tyrosine kinase activity leads to increased intracellular signaling, disrupting cell cycle regulation. This increased EGFR activity may be due to increased expression of the EGFR ligand (which is the epidermal growth factor EGF), or by a mutation in the EGFR tyrosine kinase domain that results in sustained ligand-independent activation of the mutated receptor. Another receptor which promotes cell growth and division, the epidermal growth factor receptor HER2 (Human Epidermal Receptor), also called erbB2, in the increased presence of which there is an excessive division of cells, which can lead to the formation of a tumor. Also, deregulated signal transduction through the P3K / Akt / mTOR phosphatidylinositol-3-kinase signaling pathway provides cells with stimuli for unrestricted growth and survival, which can lead to tumor growth.
    Disruption of cell cycle regulation can lead to the proliferation of such altered cells independently of the environment, independent of the needs of the tissue and the organism - it is usually the first stage of carcinogenesis.
¨ Inhibition of apoptosis
Another important mechanism for maintaining tissue homeostasis is the regulation of the rate at which "excess" cells in the tissue population die. The usual way in which cells undergo controlled death is apoptosis (described in more detail in §5.2, section "Effect of radiation on cells", passage "Mechanisms of cell death", where the internal and external signaling pathways of apoptosis are discussed) - "programmed" cell death, actively controlled by the cell . The apoptotic program is potentially present in all cells, it is triggered by internal signals (DNA damage, hypoxia, ...) or external "death signals" that the cell receives from regulatory mechanisms in the tissue. Properly functioning apoptosis, triggered by external regulatory mechanisms from the tissue, provides effective protection against excessive cell proliferation. Apoptosis triggered by internal mechanisms then acts as a protection against the survival and proliferation of mutated cells with damaged DNA. Inhibition (blockage, damage) of apoptosis - apoptic resistance of cells - allows developing tumor cells to survive and multiply, despite the organism's interest. Apoptosis can be disrupted, for example, by altering the TP53 gene encoding the p53 protein, increasing the concentration of the anti-apoptotic Bcl-2 gene in mitochondria (protecting mitochondrial membranes - preventing cytochrome c penetration and caspase chain triggering proteolytic degradation in the cytoplasm) and other unexplored factors.
Note: This is mainly a suppressed apoptosis induced by external regulatory mechanisms of the tissue. However, with strong irradiation of tumor cells, which causes severe irreversible DNA damage, internally activated apoptosis occurs .
¨ Immortilization of cells
Most common somatic cells can only reach a certain limit in the number of their divisions, the so-called Hayflick limit (about 40-60 cycles); then the cells lose their ability to divide. This is due to mitotic shortening of DNA telomeres (about cell cycle, telomere shortening, cell senescence, apoptosis, etc. see also §5.2 "Biological effects of ionizing radiation"). This limit in the number of divisions would automatically stop the growth of the tumor population. Increased occurrence of an active enzyme called telomerase (in co-production with tankyrase), or mechanisms of homologous recombination of telomere sequences (discussed in §5.2, part "DNA, chromosomes, telomeres"), however, they are able to ensure complete replication of DNA ends (prevent telomere shortening) - gaining unlimited replication potential, so-called immortilization -"immortality"of cells. Unregulated and unrestricted division of clonogenic tumor cells, which break free from the mechanisms of tissue homeostasis, is the essence of tumor diseases.
¨ Inhibition of immunogenity
The immune system is fundamentally capable to recognize tumor cells and destroy them. Some tumor cells, however, they lose their immunogenicity *) or the immune system is impaired - these cells are outside the control of the immune mechanisms and may cause their uncontrolled proliferation.
*) Many tumor cells have the CD47 protein on their surface, which protects them from white blood cells (physiologically, this protein occurs on the surface of blood cells to protect them from its own white blood cells) and therefore cannot be destroyed by the immune system.
¨ (neo)Angiogenesis
In the initial stages (tumor size up to about 0.5-1 mm), tumor cells are supplied with oxygen and nutrients by diffusion from the surrounding intercellular environment of the tissue in which the tumor grows. As the number of tumor cells increases, this supply is no longer sufficient - there is hypoxia of the tumor tissue, accompanied by the expression of special interleukins, especially HIF1 (hypoxia-iducible transcription factor), inducing the production of vascular endothelial growth factor VEGF (as well as VEGF mRNA expression). The regulatory mechanisms in the tissue can respond to this by angiogenesis - the formation of new blood vessels, ensuring the blood supply to the tumor tissue and its rich supply of oxygen and nutrients, as well as flushing out metabolic waste. Tumor growth is dependent on angiogenesis - it necessarily requires a sufficient supply of nutrients and oxygen, which are provided by newly formed blood vessels. Each increase in tumor volume is associated with the growth of new capillaries.
    Tumor neo-angiogenesis or neovascularization is an important milestone in the progression of cancer, allowing tumors to grow to macroscopic size, threatening tissue and whole organism. Blood flow to the tumor tissue also allows the spread of tumor cells through the bloodstream - the formation of metastases (see below).
    The issue of carcenogenesis is very complex, with a number of unexplored factors. In addition to mutations of known and coding genes in DNA, so-called "genetic litter" or "unnecessary DNA" sequences can also may manifest, which via the respective RNA can function as regulatory "triggers" or "switches" of intracellular processes (see also §5.2, part "DNA, chromosomes, telomeres") .

Types of tumors
Tumors and tumors disease (lat. tumor = swelling, edema), often collectively referred to as carcinoma or cancer, are characterized by a large number of species and great variability. They are divided according to several criteria :
l According to health severity :
× Benign tumors (lat. Benignus = harmless, friendly, generous ) are usually localized and isolated from the surrounding tissue by encapsulation, do not grow into other tissues and do not form distant metastases. They do not have to create major damage or difficulties for the organism (they can often remain in the tissue - but beware of the risk of malignant degeneration!), if necessary, they can usually be successfully surgically removed.
× Malignant tumors (lat. malignus = evil, evil-bearing ) , grow destructively and infiltratively - tumor cells grow into the intercellular spaces of the surrounding tissues (which suppress and disrupt), the cells are released and spreads through the blood or lymphatic route to other tissues and organs, where they often form distant secondary "daughter deposits", so-called metastases (Greek meta = change, stasis = place ® change of place, relocation). Even after removal of the primary tumor site, metastases can continue to grow and form more metastases. Due to metastatic spread (dissemination) can lead to the uncontrolled spread of the disease, often to the whole organism (generalization).
l According to the organ from which the tumor primarily originates :
- eg breast, lung, bronchogenic, prostate, etc. Some types of tumors have special names, depending of their location and origin, with the suffix "-oma" - eg melanoma or melanoblastoma (skin tumor of melanocyte cell ), glioma or glioblastoma (primary brain tumor, also astrocytoma ), lymphoma (tumor growth of lymphoreticular tissue), etc. A malignant tumor of hematopoietic tissue, manifested by an increase in white blood cells (which are immature and do not perform their normal function), is called leukemia .
l According to the location of metastatic involvement - eg metastasis of breast cancer to the liver, skeleton, etc.
l By tissue and cell nature :
- Epithelial tumors called (in the narrower sense) carcinomas are the most common type of cancer. According to the cell layer from which they originate, they are further divided into squamous cell and basal cell carcinomas (these names come from skin tumors).
According to the microscopic appearance of cancer cells (for histologic observation) and shape of the tumor growth is sometimes used designation papillary (warty - tumor forming warty or fimbriate formations), tubular (forming a tubular structure), medullary (marrow), ductal (outlet pipe), lobular (lobe ) and the like.
Benign tumors arising from the glandular epithelium are called adenomas .
- Mesenchymal tumors , called sarcomas, come from connective tissues. They occur less often.
    The resulting terminology of specific types of tumors is often formed by combining the names of individual categories - eg prostate adenocarcinoma, osteosarcoma in the skeleton, etc.
Anatomical extent - progression - of tumor disease (staging)
To assess the possibilities of optimal therapy, the progression of cancer is crucial - how the tumor growth in the body has spread, how far it has penetrated. The anatomical extent (progression, staging) of cancer is often assessed according to three "TNM" criteria : T-tumor, N-nodes, M-metastases; the higher the number, the greater the range and propagation :
T- extent of the primary tumor: T0 (no signs of primary tumor), T1 (tumor up to 2 cm in size), T2 (2-4 cm), T3 (tumor larger than 4 cm), T4 (larger tumor growing into other structures).
N - presence and extent of infiltration in regional lymph nodes: N0 (no infiltration in nodes), N1 (metastasis in one node, <3cm), N2 (bilateral metastases <6cm), N3 (metastases > 6cm). Alternatively, N2 indicates 2-4 and N3 more than 4 metastases in regional nodes. There are different T and N numbering conventions according to the type and location of the tumor.
M- presence of distant metastases: M0- without metastases, M1 - occurrence of distant metastases.
    Tumor TNM classification is not used for hematological and lymphatic malignancies (leukemia, lymphomas), which are not localized but diffuse.
    A simpler classification of the progression is into four stages of cancer, also called FIGO classification (Federation International of Gynecology and Obstetrics) :
Stage I. - a smaller tumor with local growth, without any dissemination (corresponds to T1, N0, M0).
Stage II.- larger tumor with local growth, without dissemination or with minimal regional infiltration (corresponds to T2, N0-1, M0).
Stage III . - large local tumor with regional infiltration (T3-4, N2, M0).
Stage IV. - tumor involvement with infiltration into other tissues or with distant metastases (corresponds roughly to T2-4, N2-4, M1).
    The choice of treatment method and its success depend on all these aspects. In general, the success of therapy is greatest in isolated well-differentiated tumors in the early stages without metastatic infiltration (eg T1-2, N0-1, M0). In the late stages with extensive metastatic infiltration (generalization), treatment is difficult and usually not very successful ...
Degree of tumor cell differentiation - grading
Tumor tissue cells were formed by mutation and malignant transformation (see above "Carcinogenesis - tumor formation") of originally normal cells of a certain healthy tissue or organ in which the tumor originated. Thus, they carry many of the properties of these original cells, but some of their other properties differ. The degree of tumor differentiation - the extent to which tumor cells differ from the cells of the normal tissue from which they originated - is referred to as grading (lat. Gradus = state, degree of a particular process ). If the tumor cells retain some of the properties of the original tissue, from by degeneration arose, it is a differentiated tumor. However, tumor cells often lose the properties of the original tissue - an undifferentiated (anaplastic) tumor is formed, which is largely autonomous, without binding to the regulatory mechanisms of the original tissue. Tumor grading is sometimes quantified using scores : G1 (well differentiated), G2 (moderately differentiated), G3 (poorly differentiated), G4 (undifferentiated - anaplastic). The prostate ca system uses a multi-level Gleason grading score system (up to 10 degrees).
    The risk of cancer also depends on the size of the tumor cells. The small cell type of tumor usually has rapid infiltrative growth with frequent metastatic dissemination.
Cellular heterogeneity of tumor tissue
In the initial stages, after its formation, the tumor is formed by a substantially homogeneous population of mutated cells that have escaped the regulatory mechanisms of tissue homeostasis and initiated uncontrolled division. In later stages, however, histocytological analyzes have shown that tumor tissue often contains two or more clones of cells with different biological properties - it is already heterogeneous. This is due to the increased fragility of DNA and the genetic instability of tumor cells, which may undergo further mutations upon repeated division. Tumor heterogeneity complicates treatment, because different parts of the tumor may have different radiosensitivity. A similar effect is also caused by possible hypoxia of some parts of the tumor (see "6R" below, section "Oxygen effect").
    The specific type and nature of the tumor can be most reliably determined by histological analysis of a sample of tumor tissue under a microscope. An experienced pathologist usually recognizes the origin and type of tumor cells *) and also whether the tissue is benign or malignant. Histological examination should always precede therapy.
*) However, tumor cells that look similar under a microscope and are histologically classified in the same category, may have genetically different causes malignant behavior. Regulatory mechanisms not encoding RNA derived from as yet unexplored "genetic litter", "unnecessary" DNA (it is also mentioned in §5.2, section "DNA, chromosomes, telomeres") may also be involved . This can significantly complicate the chain of diagnostics ® therapy of cancer.
    A more detailed classification of tumors and their clinical properties is beyond the scope of this physically focused treatise.

Diagnostics of tumor disseases
The success of any therapy depends to a large extent on careful diagnosis - both on the primary examination before treatment and monitoring the response during therapy and subsequent long-term follow-up. This is increasingly true of cancer. Malignant tumors are characterized by some specific characteristics :
- They are structures with a higher density than the surrounding tissue; also for ultrasound they usually show increased echogenicity than the surrounding tissue.
- They consist of metabolically active cells - they usually have increased metabolism.
- They usually have increased vascularization, increased blood flow and increased energy consumption. However, they may also contain hypoxic districts.
- Tumor cells may contain some general cellular antigens on their surface, or they may carry specific antigens.
- In addition, tumor cells may contain some special receptors in their cell membrane.
    All of these features can be used for diagnostic imaging and for targeted therapy .
× Primary diagnostics of tumors
This involves the finding of the primary tumor, its location and extent before surgery, as well as the discovery of possible metastases to determine the progress of further treatment. In addition to visible or tactile superficial and shallow lesions, primary tumor diagnosis is performed mainly using physical imaging methods - X - ray diagnostics (planar, now mainly CT - §3.2), ultrasound sonography, radionuclide gammagraphy (planar, SPECT, now mainly PET - chapter 4), NMRI nuclear magnetic resonance. Tumors located on the walls of body cavities and tubes (stomach, intestines, uterus) can be recognized by optical endoscopic methods. It should be noted, that none of the imaging methods alone will determine the malignant nature of the disease! Imaging methods must therefore be combined with biochemical and especially histological methods (see below).
    Because some tumors can produce specific substances (either by the tumor cells themselves or when they interact with the body's immune system), biochemical analytical methods of blood or tissue samples are also important . These are mainly various types of tumor markers - complex organic molecules (mostly protein composition), whose increased expression in the body is the result of the tumor process - such as determining the concentration of PSA at the prostate, or markers CA19-9, CEA, AFP. Recently, the (immuno) histochemical determination of Ki-67 antigen (or MKI67 weighing 360 kDa; the name comes from a study in Kiel, Kiel - clone 67 in bowl 96) , which is associated with cell proliferation - with ribosomal DNA transcription. Furthermore, determination of the apoptotic gene p53 (or its mutation) or the anti-apoptotic gene Bcl-2. Or cytological examination by flow cytometry.
"Molecular" gammagraphic imaging  
Most imaging methods provide only morphological-anatomical information on the presence, size and shape of tissue, differing in density from the environment. In the CT and NMRI images, we show the tumor mass, which with its density or proton density and relaxation times T1, T2 differs from the surrounding tissue, but we do not capture whether there are viable and proliferating tumor cells in the displayed anomalous tissue. Although gammagraphy (scintigraphy) does not excel in spatial resolution, it captures the functional metabolic properties of lesions - blood circulation, metabolism, drainage and other functions of tissues and organs - at the "molecular-biochemical" level (see §4.9.6 "Oncological radionuclide diagnostics"). In particular PET display distribution of ¹⁸F-fluoro-deoxyglucose (FDG), ¹⁸F-3-fluoro-3-deoxy-thymidine (FLT), ¹⁸F-fluorocholine and labeled monoclonal antibodies, provides contrast images of viable and proliferating tumor lesions.

Example of PET/CT scintigraphy with 18FDG in a patient with lymphoma.     PET images show multiple foci of increased glucose metabolism in the lymph nodes of the neck, left axilla, mediastinum, retroperitoneum, pelvis and groin, indicating viable tumor neoplasia.     Physiologically, 18-FDG deposited in the brain, in the hollow of the kidney, bladder, light diffusion in the liver and spleen, the variable is the accumulation in the myocardium     The transversal section shows separately a significant deposit in the area of the supraclavicular (marked by arrows) for the assessment of metabolic accumulation using SUV values [g/ml] :       The SUVmax of the bearing in the nadklicek is 11.5, with the reference SUVmax liver 2.9 and the mediastinum 1.4. (PET / CT images were taken by Martin Havel, MD, Ph.D., head of the PET / CT department of KNM FN Ostrava )

This method is also suitable for monitoring the response of tumor tissue to radiotherapy, as it displays metabolically active tumor tissue, in contrast to inactivated cells; it is thus possible to monitor the "success" of the therapy. Among other things, it is able to recognize tumor recurrence (with proliferating cells) from other structures, necrotic or connective tissue. The ¹⁸F-FMISO and ¹⁸F-FETNIM radioindicators show cellular hypoxia, which is important for tumor angiogenesis and for planning radiotherapy (radiosensitivity, oxygen effect - see below "Physical and radiobiological aspects of radiotherapy").
    
                      Normal whole-body scintigram bone                      Multiple metastases (breast ca) to the skeleton
    To display bone metastasis, at an early stage of infiltration, proves best bone scintigraphy (whole-body scintigraphy in PA and AP projection, with possibly targeted SPECT images of suspicious sites) after osteotropic radiopharmaceuticals, which are phosphate complexes, whose accumulation reflects increased osteoblastic activity in response to tumor bone destruction. Planar whole-body scintigraphy of the skeleton is useful to supplement with a combined SPECT/CT image with image fusion, to specify the anatomical location of the lesions. In thyroid cancer, the diagnosis is based on scintigraphy after application of radioiodine ^{131 or 123}I.
    Labeled peptides that bind to peptide receptors on the surface of some types of tumor cells are mainly used in neuroendocrine tumors containing somatostatin receptors (the cyclic peptide somatostatin is a hormonal substance that has a inhibitory effect on the production of certain hormones, especially growth; Greek soma = body, statizo = stand, stop ). An artificial somatostatin analogue, octreotide, labeled with indium - ¹¹¹In-pentetreotide (OctreoScan), or ⁶⁸Ga -DOTATOC for PET scintigraphy is used to visualize the respective tumors and to predict the effect of somatostatin analog therapy. The logical sequence of diagnostics using these radioindicators is their labeling with therapeutic radionuclides with application for radioisotope biologically targeted radiotherapy, see below "Radioisotope therapy", section "Radionuclide therapy of tumors and metastases".
    In addition, some non-specific indicators of tumors are used, the increased accumulation of which in tumor tissue is based on their ability to penetrate pathologically altered permeability of walls and capillaries and bind within viable cells. Used ^99mTc-MIBI and tetrofosmin mainly in lymphomas and mammary tumor (mammoscintigraphy). In oncological diagnostics, gallium scintigraphy (mostly planar whole-body imaging, supplemented with possibly SPECT images) with ⁶⁷Ga-citrate. Chemically, Ga ions are analogs of Fe ions, bind to the transport protein transferrin, and accumulate in proliferating tumor tissues, particularly lymphomas. Gallium-67 scintigraphy is now abandoned and replaced by PET scintigraphy with ¹⁸FDG. Indirectly, tumor processes can sometimes be inferred from other scintigraphic examinations, such as dynamic scintigraphy of the kidneys and liver.
Multifactorial image analysis - radiomics
Using the methods of "machine learning" and artificial intelligence, procedures of so-called radiomics were developed - sophisticated image analysis in conjunction with statistical processing of data from a large number of patients, which can recognize even hidden informations, directly invisible visually. These analyzes can reveal some similarities and coincidences, helping to refine the likely diagnosis of tumor types, or predict response to therapy and course of disease. It is discussed in Chapter 4, §4.7, paragraph "Multifactorial statistical analysis of images, radiomics".
Histological examination
If anomalous tissue (neoplasm) that could be of tumor origin is found by imaging or other examination methods, histological examination must be performed: a small sample of tissue is taken by biopsy and then viwed under a microscope. Histological examination is also performed on "suspicious" tissues removed during surgery. According to the shape, size and other characteristics of the cells, it is usually possible to distinguish whether it is a benign or malignant tissue and what kind of possible tumor cells they are (as mentioned above). All this macroscopic and microscopic diagnostic information determines the optimal way to treat cancer.
× Diagnostics for cancer therapy planning
If the primary diagnosis of cancer is confirmed, the stage of preparation of therapy begins - a decision on the basic strategy and methodology of therapy: whether it will be a surgical solution, chemotherapy, radiotherapy, eventual its combinations (see "Cancer therapy" below). If radiotherapy is planned, X-ray CT, NMRI and gammagraphy (especially PET) images can be used to determine the exact location and extent of the tumor site and to plot the regions of interest (ROI) of the irradiated volume - GTV, CTV and finally PTV in the irradiation plan (see below the section "Planning of radiotherapy"). The base is now used CT images (respectively NMRI), but these mainly reflect morphological page, but do not capture the behavior of biological tissue. It is therefore useful to also gamagraphic views, especially PET images of the distribution of ¹⁸FDG or ¹⁸FLT, respectively ¹⁸F-choline. By analyzing these PET images (eg by determining SUV levels - see §4.2, section "Scintigraphic image quality and detectability of lesions"), we can determine the "Biological Target Volume" (BTV) of tumor tissue formed by viable proliferating cells. By transferring of these images to a radiotherapy planning system and computer image fusion (CT, NMRI) + PET we can then refine the volume of the target lesion, especially CTV for IMRT radiotherapy. According to the distribution of tumor cell viability, we can further modulate the dose within the tumor site and increase (escalation, boost) doses to risk areas within the tumor.
l Predicting the response to cancer therapy
Predicting the biological response to planned treatment is a very difficult task in medicine in general. In cancer therapy, certain basic information can already be obtained from the results of primary imaging and histological diagnostics. However, there are ways to indirectly assess the specific behavior of tumor tissue for the planned type of treatment using gamma imaging methods, especially PET.
l Monitoring the distribution of cytostatics and monoclonal antibodies
The success of chemotherapy depends, among other things, on whether the cytostatics or monoclonal antibodies used accumulate (uptake) sufficiently in the tumor foci. Nuclear medicine can be used to predict the chemotherapeutic effect. Methods for radionuclide labeling of some chemotherapeutics have been developed: after "trial" diagnostic application of a small amount of such labeled radioindicator, we can display its distribution and assess how selectively it is taken up in tumor tissue (as well as in healthy tissues that could thus be undesirably affected by by radiation) - in this way, the respective chemotherapeutic agent will be taken up during the actual therapeutic application. A similar "trial" diagnostic application of a smaller amount of g- radioindicator can be used in radioisotope therapy (see "Radioisotope Therapy" below).
l Imaging Dendritic Cell Migration
One of the basic preconditions for the success of immunotherapy with dendritic cells activated by antigens of a particular tumor tissue (see "Cancer Therapy" below, "Immunotherapy" section) is their migration to peripheral lymph nodes and then to the tumor locus. If we label these activated dendritic cells before their re-application to the body using a suitable radioindicator (¹¹¹In-oxin is tested), while maintaining their viability, we can scintigraphically map their migration to the lymph nodes after their application.
    The predictive role of imaging cell apoptosis is discussed in the following paragraph.
× Monitoring the biological response to cancer therapy
In addition to the primary diagnosis, it is desirable to monitor how successful the therapy is and what its side effects are on healthy tissues, organs and the whole organism. In terms of time relation to therapy, monitoring of biological response can be divided into prediction of biological effect before therapy (mentioned above) or at the beginning of therapy, monitoring of early response during therapy and monitoring of late response and overall long-term development disease after treatment. To assess the late tumor response, the basis for monitoring the tumor site in CT or NMRI images - a comparison of the size (volume) of the displayed tumor lesion before and after therapy to assess the reduction of tumor mass. However, CT and NMRI images capture only the morphological situation, not the biological development of tumor tissue and the metabolic activity of cells - we do not recognize in them what part of the depicted lesion of different density is formed by viable tumor cells and what part by necrotized or connective tissue. It is therefore useful to use "molecular" gammagraphy using SPECT and PET methods to reliably monitor the tumor response. These are mainly the already mentioned images of the ¹⁸ FDG or ¹⁸FLT distribution, performed before and after therapy (or during therapy), on which possibly we compare SUV values. Molecular gamma imaging allows the visualization of important factors influencing the response of tumors to therapy. Another "line" - radiobiological modeling - is the assessment of the radiotherapeutic effect using the quantities TCP, NTCP, UTCP, discussed below in the section "Prediction of the radiotherapeutic effect - the probability of cure of a TCP tumor and damage to normal NTCP tissue".
    Immediately after the end of radiotherapy, no macroscopic change can be detected in the irradiated tumor - the changes take place first at the molecular level. Only a few weeks to months apart, these nitrocellular processes result in the extinction of most of the cells in the tumor population; only this can be accompanied by observable morphological changes.
l Early tumor response - imaging of cell apoptosis
However, functional molecular imaging in gammagraphy provides other unique possibilities. Radioindicators have been developed to monitor one of the main radiobiological mechanisms of cancer therapy (both radiotherapy and chemotherapy): cell apoptosis. In cell apoptosis (see §5.2, section "Effect of radiation on cells", section "Cell apoptosis") in the early phase, among other things, irreversible membrane depolarization occurs, the uncovering of phospholipids on the cell surface, increased permeability of the plasma membrane, then at a later phase the integrity of the cell wall is violated and finally to cells disintegration and their phagocytosis. It is in the early phase of apoptosis that the special radiopharmaceuticals shows an affinity for apoptotic cells *): they either bind to phospholipids on the surface, or penetrate the cell membrane and accumulate in the cytoplasm of apoptotic cells. The result is a selective accumulation of radioindicator in apoptotic cells and tissues, while they hardly enter in tissues formed by normal viable cells or necrotic tissues.
 
By gammagraphic imaging of the distribution of these radioindicators (it is appropriate to use dynamic gammagraphy - time factor of accumulation) we obtain positive images of those places, where apoptosis occurs most intensively - whether due to irradiation, cytotoxic substances or ischemia. By molecular imaging of the distribution of cell apoptosis, we can monitor the very early response of cells and tissues to therapy (radiotherapy or chemotherapy), already at the beginning and during therapy. It basically allows the prediction of the tumor response: we apply "experimentally" one or two fractions and on gammagraphic images we can assess whether apoptosis is taking place in the target tissue sufficiently intensively, or whether there are regions of apoptotic resistance in the heterogeneous tumor. Early imaging of apoptosis can play a significant role in biological individual ("personalized") therapy of a particular patient.
*) Three types of radioindicators of apoptosis are in the stage of laboratory development and preclinical studies (see also §4.8 "Radionuclides and radiopharmaceuticals for scintigraphy") :
- Protein ^99mTc-Annexin V (for SPECT imaging) - binds to phospholipids on the surface of apoptotic cells;
- ¹⁸F-ML-10 [2- (5-Fluoro pentyl) -2-methyl malonic acid] - a small molecule that penetrates the wall of apoptotic cells and accumulates in their cytoplasm. Approx. 400MBq is applied.
- Peptide ¹⁸F-CP18 [triazole-containing pentapeptide] - maps Caspase-3 activity, accumulates in apoptotic cells.

Combination of diagnostics and therapy - theranostics
New diagnostic imaging methods, especially molecular imaging in nuclear medicine, allow to integrate individual (personalized) diagnostics and targeted therapy (or prevention) of serious diseases into a common field, for which it was newly using the name theranostics (created by composing names: therapy + diagnostics => Theranostics). Scintigraphy makes it possible to determine the concentrations of biologically active substances directly at the sites of their targeted action, which enables optimal and individual dosing, with the possibility of predicting effects and monitoring the results of therapy - it is discussed in more detail in §4.9, section "Theranostics".

Therapy of tumor diseases
In terms of goal and effectiveness, we generally distinguish between two types of treatment: Curative therapy (Latin cura = treatment) with the aim of complete cure of cancer, especially in the localized stage. In more severe and advanced cases, then palliative therapy (Latin pallium = mantle), alleviating and slowing down the course of the disease and its difficulties. In terms of time sequence, we also recognize two procedures: Induction therapy - initial treatment to achieve remission of the disease. After this primotherapy (possibly also simultaneously), adjuvant therapy is often applied - auxiliary, supportive or securing treatment (Lat. adiuvo = support, help), especially to reduce the risk of recurrence due to possible micro-seeding around the original tumor.
  The treatment of tumors is currently based on three main methods: surgery, chemotherapy and radiotherapy, with these three main therapeutic approaches are often combined - multimodal treatment. In the surgical treatment of cancer, physical removal is performed - resection or ablation (Lat. Ablatio = removal, distant) of the tumor tissue. It is desirable to remove not only the primary tumor with the "safety margin", but also, if possible, other tissues into which the tumor cells could be infiltrated: these are mainly the surrounding lymph nodes located in the lymphatic "river basin" of the tumor location (see also above §3.5, passage "Radiation-guided surgery - sentinel nodes"). In addition to classical surgical techniques, radiofrequency ablation and stereotactic ablative radiosurgery SRS (sterotactic radiosurgery) are also used - see the "Stereotactic radiotherapy" section.
  For non-surgical treatment of cancer, we would ideally need some "magic missiles" that would penetrate the body in a non-invasive manner, target and destroy only the tumor cells, while maintaining undamaged healthy surrounding tissue. Because tumor tissue is made up of cells that are not very different from the healthy cells of the surrounding tissues, we do not have such an ideal and selective "shot": treatment focused against tumor cells will always more or less damage even some healthy cells, tissues and organs. However, there are certain physical and biological factors that at least partially promote the targeted destruction of tumor cells and minimize damage to healthy tissues.
  In terms of the place of action in the body, we can divide the therapy of cancer into two methodological approaches :
l Local tumor control , in which we try to stop tumor growth and destroy cells in a particular tumor site of known location and extent. It is performed mainly by the method of radiotherapy - targeted delivery of a high radiation dose to the tumor site. This approach is effective for well-defined tumors of small or medium size, without distant metastases.
l Systemic therapy performed by application of suitable drugs into the organism, which enter the tumor foci and stop the proliferation or kill the tumor cells there. These include chemotherapy with cytostatics and biological therapy, and in part targeted radionuclide therapy. This whole-body systemic action has its advantages and disadvantages. The advantage is the action on multiple tumor foci and hidden metastases, the presence and location of which we sometimes do not even know. The disadvantage is the side effects on healthy cells and tissues, into which the chemotherapeutic agents also enter, through the blood and lymphatic way. Systemic therapy is chosen in cases of more extensive tumor disease with metastatic infiltration. And also as an adjuvant therapy to reduce the risk of recurrence and metastasis.
  Below, first will be briefly described methods of systemic and targeted chemotherapy and biological treatment, then more detailed methods of targeted radiotherapy using physical and radiobiological aspects.
Chemotherapy and biological treatment
Under chemotherapy generally means treating diseases by administering chemicals - drugs that are the product of chemical synthesis or isolated from natural materials (especially plants) - and which cause desirable (bio)chemical reactions in the organism. Chemotherapy of cancer is most often performed using cytostatics - substances that stop or inhibit the growth and division of cells (Greek: kytos = cavity, cell; statikos = stopping). Their preferential antitumor effect is due to the fact that they act primarily on rapidly dividing cells. However, they also affect healthy physiologically dividing cells in the body, which leads to undesirable side effects. A number of cytostatics are known, which act by different mechanisms and at different stages of the cell cycle. There are two basic mechanisms of action of cytostatics :
1. Action on DNA , which disrupts cellular function, prevents replication, it can be evaluated by the cell cycle control nodes as irreparable damage ® activation of the internal signaling pathway of apoptosis (in this respect the mechanism is similar to ionizing radiation).
2. Effects on other cellular structures, especially microtubules, which violates the very act of cell division - it acts as a "mitotic poison". The cells are thus inactivated, they cannot divide further, they undergo apoptosis either directly or following a "mitotic disorder" (see §5.2, passage "Mechanisms of cell death").
    In more detail, four diffrent mechanisms of action of cytostatics are distiguished, according to which these substances are divided :
l Alkylation cytostatics - react with bases in the DNA, e.g. guanine, by their alkylation - by transferring the carbon radical group C_2nH_2n+1 (alkyl). This leads to DNA cleavage or the formation of a two-stranded junction. This damage to DNA inactivates cells, prevents them from dividing (DNA strands cannot untwist and separate), and ultimately leads to apoptosis. A cytostatic effect has long been observed with nitrogen mustard analogues. From this group, chlorambucil, cyclophosphamide or ifosfamide are used (own cytostatic effect has only their metabolite oxycyclophosphamide formed in the nucleus), as well as fludarabine and bendamustine .
Platinum cytostatics also belong to this group. The longest used cytostatic of this species is cisplatin (cis- [PtCl₂ (NH₃)₂]), an inorganic molecule that binds to guanine bases in a DNA molecule; more recent are the organic compounds carboplatin and oxaliplatin, where platinum atoms are attached to cyclic ("aromatic") hydrocarbons.
l Microtubule inhibitors - react with microtubules in cells, prevent the formation of a mitotic spindle - mitotic poisons. These are two types of chemicals that have opposite mechanisms of microtubular action, but result in similar cytotoxic effects :
- yew terpenides - taxanes. The alkaloids paclitaxel (contained in yew Taxus brevifolia ) and docetaxel (from yew Taxus braccata) are used, which stabilize microtubule polymers (inhibition of microtubule depolymerization) and prevent chromosome separation during anaphase.
- vinca alkaloids - vincristine, vinblastine, vinorelbine, which bind to tubulin and prevent its polymerization into microtubules.
l Antimetabolites blocking the synthesis of purine and pyrimidine DNA bases required for cellular replication. Substances with a structure similar to purines and pyrimidines - fluoropyrimidines, especially methotrexate or 5-fluorouracil (5-FU) preparations are used. More recently, the 5-FU precursor, capecitabine, is preferably used, from which the active substance 5-fluorouracil is formed by enzymatic transformations only in the body, preferably in tumor tissue (the enzyme thimidine phosphorephilase, which participates in the final phase of the conversion of inactive capecitabine to active 5 -FU, is contained in tumor cells usually in a significantly higher concentration than in cells of healthy tissue - selective effect).
l Topoisomerase inhibitors in S-phase of the cell cycle prevent the untwist of the DNA double helix during the replication process (in which the enzyme topoisomerase is involved). This leads to the induction of DNA breaks that can cause cell death. The original substance of this kind was camptothecin, an alkaloid isolated from the Chinese tree Camptotheca acuminata. However, its synthetic derivatives topotecan and irinotecan have more suitable pharmacological properties.
l Antitumor antibiotics are originally substances that inhibit the growth and multiplication of microorganisms, therefore used in the treatment of infectious diseases, as well as antifungal agents and the like. They are secondary metabolites of microorganisms (bacteria, mold), many of which are now prepared artificially (by synthetic or semi-synthetic methods). As most of them contain in their chemical structure several groups of cyclic hydrocarbons ("benzene nuclei") characteristic of anthracene, they are also called anthracycline antibiotics. In addition to the antibiotic effect, in some of these substances have also been found an immunosuppressive effect and a cytostatic, antitumor, antiproliferative effect. The mechanism of the cytostatic effect is probably binding to DNA - their molecules have the ability to be incorporated between DNA base pairs; DNA breaks occur, intercalation bonds are formed with a transcription disorder (tight connection of both strands of DNA prevents its copying before cell division and transcription into RNA), DNA breaks down (the effect is similar to that of radiation or alkylating cytostatics). The enzyme topoisomerase is also blocked, which is involved in changes in the spatial arrangement of DNA during replication prior to cell division; when it is blocked, the individual parts of the DNA do not come together, that break down. An example is doxorubicin, bleomycin, epirubicin, idarubicin, mitomycin C.
    This group also includes, in part, rapamycin, originally isolated from the bacterium Streptomyces hygroscopicus discovered in soil on Easter Island Rapa Nui; it is also called sirolimus (Lat. siro = pit dug in the soil, limus = mud, sludge). It ranks among the macrolide antibiotics that block protein synthesis in microorganisms by binding in ribosomes. Due to its immunosuppressive effects, it is used in transplants as protection against adverse immune reactions that can lead to transplant rejection. By inhibiting the protein kinase (mTOR *), it blocks a number of intracellular processes, leading to a decrease in cell proliferative activity. It prevents cells from moving from the G1 phase of the cell cycle to the S phase, causing cell cycle arrest. It increases the sensitivity of tumor cells to radiotherapy and the effectiveness of chemotherapy. Rapamycin thus also belongs to the group of kinase inhibitors listed below, where its new derivatives temsirolimus and everolimus are used.
*) Rapamycin, mTOR
mTOR (mammalian Target Of Rapamycin ) - this very misleading name comes from the fact that the relevant protein kinase was first discovered when rapamycin was applied to the ca of breast. An alternative name is "mechanic target of rapamycin". It was later shown that mTOR also works in other types of tumor cells. The PI3K/Akt/mTOR signaling cascade is significantly involved in the process of carcinogenesis, and its inhibition may be an important factor in cancer therapy.
l Antioxidants are known primarily as cancer prevention. However, it has been shown that some antioxidants (such as reveratrol, genistein, baikalein) damage DNA and kill dividing cells. This could be used in anticancer therapy. Their advantage is that, despite their genotoxicity, they do not have mutagenic effects. So far, it is in the stage of biological research.
l Bisphosphonates act as inhibitors of osteoclastic bone resorption. They can therefore be used for the secondary treatment of bone tumors, especially metastases, where they act primarily against bone erosion; it is not a cytostatic. Effective nitrogen bisphosphonate is mainly zoledronic acid. In combination with eg docetaxel, there is an additive synergistic antitumor effect - potentiation of the cytostatic effect.
    Individual cytostatics are sometimes combined, eg FOLFOX (oxaliplatin + 5-fluorouracil + folic acid), XELOX (capecitabine + oxaliplatin), FOLFIRI (5-fluorouracil + irinotecan) and others. A common disadvantage of classical cytostatics is their systemic non-specific effect - they act not only on tumor cells, but also on healthy physiologically dividing cells. This leads to a number of often serious side undesirable (toxic) effects. Therefore, a new variant of targeted "transport" of a suitable cytostatic preparation directly to cancer sites is being tested, using microcapsules up to 5 mm in size. Such tiny capsules, formed from a suitable organic substance and carrying a cytostatic inside, pass through the vascular system and the fine blood capillaries after application. They can be monitored sonographically or by magnetic resonance imaging; the moment they reach the tumor, they can be disrupted by an ultrasound wave, releasing the cytostatic at the required place - in the tumor.

Chemical structure of some cytostatics used in chemotherapy of cancer

Targeted biological therapy
In recent years, knowledge of molecular biology and genetics has developed rapidly, revealing, among other things, complex mechanisms of cellular communication and specific molecules that are important for malignant cell transformation. These could become the target of specific therapeutic interventions: to identify and target certain structures in tumor cells in order to prevent further proliferation of tumor tissue. Targeted biological treatment is based on these mechanisms, the strategy of which is directed against selected types of molecules and their signaling pathways involved in the malignant behavior of cells of the respective tumor types. Together with more effective therapy, these procedures make it possible to reduce undesirable side effects. Currently, the main interest is focused on the so-called growth factors (stimulating cell growth and division) and their receptors, especially EGFR, HER2 and VEGF (see below).
    A new class of drugs is being developed that selectively block the activity of these oncogenic proteins, with minimal damage to normal cells. These are mainly two groups of substances with different mechanisms of action :
l Monoclonal antibodies
are special proteins from the group of immunoglobulins (or fragments thereof), which are obtained from a cloned population of one species of activated B-lymphocyte from the plasma of an immunized organism. The monoclonal antibody therefore has precisely defined properties and specifically binds to the respective receptors. Some monoclonal antibodies seek to approach an ideal therapeutics - a "magic arrow" that would hit only target pathological cells and have no detrimental effects on other healthy cells. However, this cannot yet be achieved 100% ..!..
 Structure of monoclonal antibodies
The molecular weight of monoclonal antibodies is around 150 kDa. The structure of immunoglobulin protein molecules is often schematically represented by the shape of the letter " Y " (in the figure on the left - a). The branched part - arms - consists of two heterodimers, it is formed by four polypeptide parts, arranged in two mirror-identical pairs of "heavy" and "light" chains. They are internally linked by a disulfide bond (SS). Light and heavy chains contain constant and variable regions. The variable regions, located at the ends, contain short amino acid sequences (sometimes called "hepervariable"), that determines the binding antigenic specificity of an antibody. Therefore, these arms are referred to as Fab (Fragment antigen binding). The "foot" in the antibody scheme consists of two heavier chains, referred to as Fc (crystallizing fragment ) . This constant region of Fc is responsible for the effector functions of the antibody (interaction with T-lymphocytes, macrophages) - activation of systems leading to the destruction of target cells.
 Preparation of monoclonal antibodies - hybridoma technology
Because we can't cultivate directly the desired clones of activated B-lymphocytes efficiently enough, the preparation of monoclonal antibodies is complex biochemical technology. Very suitable "auxiliary carriers" for preparing of monoclonal antibodies have proven to be myeloma cells (otherwise known as tumor cells of myeloma, a hematooncological disease of the bone marrow caused by uncontrollable proliferation of myeloma cells), which, due to their unlimited replication capabilities and longevity, are very suitable for cultivation and fusion in vitro. Thus, the formation of these "helper" myeloma cells is first induced in experimental laboratory animals. These are then harvested and cultivated in vitro. Meanwhile, in another laboratory animal, an injection of a particular antigen elicits an immune response with B-cell activation and subsequent production of antibodies. These B-lymphocytes are taken from the lymphatic system (usually a spleen sample) of the animal used and then fused in vitro with a colony of myeloma cells. From this fusion, hybrid cells (called hybridomas) are formed, which retain the properties of both myeloma cells and the desired B-cell clone, divide rapidly, and produce antibodies of B-cell (used in the fusion). Using special separation methods, only hybridomas producing only one desired antibody clone - a monoclonal antibody - are selected from them.
    This resourceful biotechnology was first developed in 1975 by G.F..Kohler and C. Milstein in the Molecular Biology Laboratories of the University of Cambridge and the Institute of Immunology in Basel (for this method they received the Nobel Prize in 1984).

Monoclonal antibodies . a, b) Schematic diagram and illustration of the basic structure. c) Mouse monoclonal antibody. d, e, f) Chimeric, humanized and human antibody.

The laboratory animals used in the process of preparing monoclonal antibodies are almost always mice, so that the mouse monoclonal antibody (c) is primarily generated. For its human use can sometimes lead to undesirable immune reactions - immunogenicity due to the development of human-anti-mouse antibodies HAMA (Human Anti-Mouse Antibodies). On the one hand, this prevents (makes it impossible) the binding of the monoclonal antibody to the target antigen and, on the other hand, can also lead to immune anaphylactic reactions. Therefore, there is an effort to replace parts of the molecules (which do not encode antigen binding regions) with human immunoglobulin sections - to humanize antibodies using sophisticated biochemical-genetic methods ("genetic engineering"). From the original hybridone line producing murine antibodies of a given targeting, the RNA was prepared and further in a reaction catalyzed by an enzyme reverse transcriptase, a complementary cRNA -. By polymerase reactions were multiplies segment encoding the antigen binding site. By this genetic sequence are replaced the corresponding region in the human immunoglobulin gene. Thus formed resulting new gene is inserted into a suitable recipient mammalian cell, which then synthesizes a monoclonal antibody with a predominant human immunoglobulin content. The humanized monoclonal antibody has constant regions from a human immunoglobulin, and only the variable region, encoding antigenic specificity, is derived from a murine antibody. The antibodies thus transformed have the desired antigenic specificity and show only minimal immunogenicity. In this way, chimeric (cross) antibodies (content of about 60% human antibody), humanized (content of more than 90% human antibody) or 100% human antibody are generated - in Fig. d), e), f). The more "animal" the antibody, the greater the risk of immunogenicity can be expected. Humanization of monoclonal antibodies leads to a reduction in unwanted immunogenicity, but on the other hand also to a possible reduction in their effectiveness ...
 Antibody fragments 
The larger the protein molecule, the slower and more difficult it is to penetrate the target tissues. Therefore, instead of "whole" antibodies, suitable antibody fragments are prepared, containing only regions with preserved antigenic specificity. Most commonly, these are Fab´ fragments containing domains necessary for antigen binding, but not part Fc this interacting as effector.
 Nomenclature of monoclonal antibodies 
The nomenclature of monoclonal antibodies is elaborated so that the basic type and the most important properties (targeting) of a specific preparation (antibody) can be identified from the name. The name consists of 4 parts: prefix - designation of the target structure - biological type (origin) - suffix (it is always - mab: monoclonal anti body) :

Example are rituximab, a chimeric monoclonal antibody (-xi-), whose variable portion mediating contact with the tumor cell CD20 antigen (-tu-), is of murine origin and the remainder of the antibody is of human origin.
  In the literature, other more detailed divisions are sometimes given - in the target structure for specific types of tumors (-co (l) - colon tumor, -go (v) - ovarian tumor, -ma (r) - breast tumor, -me (l ) - melanoma, -neu (r) - nervous system, -pr (o) - prostate tumor, -vi (r) - viruses .....), in biological origin other possibilities (-a- rat, -e - hamster, -i- primates, .....); however, we do not encounter these names in practice... In some preparations, in addition to the monoclonal antibody itself, the name is also given biochemically conjugated substances (eg ibritumomab tiuxetan - ......).
 Biological effects of monoclonal antibodies
In order to produce the desired effect (therapeutic or diagnostic), the antibody must first reach the target tissues and cells. Therapeutic monoclonal antibodies are administered intravenously by slow infusion of the solution. Monoclonal antibodies have relatively large molecules with masses around 150 kDa, min. 100 times larger than conventional cytostatics. Therefore, they have slower distribution kinetics and more difficult to penetrate tumor tissue, with slow diffusion through the interstitial space. Their distribution in the tumor is usually inhomogeneous, especially in larger tumors.
    Monoclonal antibodies have the ability to react with the particular antigen against which they are targeted. If the target structure is a receptor ligand, this ligand is neutralized. If the target structure is a receptor on the surface of the cell membrane, the signaling pathway associated with it is blocked. Many monoclonal antibodies thus have inhibitory effects on certain ligands and signaling pathways (or sometimes stimulatory ones).
    A frequent goal of treatment is the elimination - kill of a certain type of cells - the depletion process. The condition for binding to target cells is the presence of appropriate receptors. The antigen-binding complementarity of an antibody is given by the variable regions at the ends of the Fab chains, while the fixed Fc region mediates subsequent effector functions on target cells. After successful binding of the antibody, three different mechanisms of the resulting cytocidal effect can occur :
- Activation of complements - membrane glycoproteins C1-C9, which by their proteolytic effects attack cytoplasmic cell membranes and cause their penetration. The cell dies and the released chemicals cause an inflammatory reaction with the accumulation of leukocytes (cf. §5.2, passage "Mechanisms of cell death").
- Induction of phagocytosis - fixed Fc region of bound antibody (lower part of the letter " Y " in the scheme) specifically binds to the Fc receptor of some types of leukocytes, especially macrophages, which thus recognize and subsequently phagocytose tumor cells.
- Induction of apoptosis after antibody binding to the cell surface, with destruction of mitochondria and proteolytic caspase chain (detailed explanation in §5.2., passage "Apoptosis"; in the picture on the top right "External signaling pathway of apoptosis").
Immunogenicity of Monoclonal Antibodies 
Monoclonal antibodies, as immune-active agents, when administered to the body can form "anti-antibodies against antibodies", which can neutralize their effect and, in addition, to causing adverse anaphylactic effects - has already been discussed above. Immunogecality most often occurs in murine antibodies (HAMA, in about 10%), rarely in chimeric antibodies, very rarely in humanized. Before using murine antibodies, it is therefore desirable to perform a laboratory biochemical test for HAMA antibodies, its possible positivity should then be a contraindication to the use of these products.
 Use of monoclonal antibodies
In addition to oncology (see below), monoclonal antibodies are also used against autoimmune diseases, organ transplant rejection, inflammatory diseases. Also as antibacterial and antiviral.
    Monoclonal antibodies are mainly used in oncology for stand-alone targeted biological therapy of cancer (see below). In addition, cytotoxic substances or radioisotopes can bind to them, which only "guide" these antibodies, approach or bind them to the target cells - antibody conjugates with suitable effector components are formed.
 Radiolabeled antibodies - radioimmunoconjugates
An important new method of biologically targeted therapy of cancer is the combination of targeted binding of monoclonal antibodies with the biological effects of ionizing radiation from radionuclides. Radioimmunoconjugates have a beta or alpha radionuclide bound in an antibody molecule, for a biologically targeted radionuclide therapy - see below "Radioisotope therapy with open emitters". The monoclonal antibody does not serve as a primary therapeutic here, but provides the "delivery" and get closer of the radioactive substance to the tumor cells. The advantage of these radioimmunoconjugates is that in order to achieve a biological effect, it is not necessary to bind them to each tumor cell, but emited radiation by the effect of "crossfire" has a radius of action of several tens of cell diameters (see below Fig.3.6.8 in "Radioisotope therapy"). They are therefore effective even in the neighboring cells which have insufficient expression of a tumor antigen.
    Some monoclonal antibodies labeled with a gamma or positron radionuclides, are used in nuclear medicine as radioindicators in scintigraphic diagnostics- §4.8 "Radionuclides and radiopharmaceuticals for scintigraphy", passage "Immunoscintigraphy". It is mainly in tumor diagnosis, but also, for example, in the diagnosis of inflammatory foci using antigranulocyte monoclonal antibodies.
  Monoclonal Antibodies in Oncology
A number of monoclonal antibodies are used in oncology therapy, some of which are briefly listed :
Cetuximab - a chimeric monoclonal antibody that competitively binds to the extracellular domain of epidermal growth factor EGFR (HER1) and inhibits the binding of other possible tumor growth activators; panitumumab has similar effects .  
Trastuzumab (herceptin) acts as a monoclonal antibody against HER2 (Human Epidermal Receptor), binding to the extracellular domain of HER2 and thereby blocking epidermal growth factor access to its receptor; this prevents activation of the signaling pathway of cell processes and tumor growth (which is HER2 - positive). Pertuzumab, which binds to the dimerization domain of HER2 and thus prevents its dimerization with other HER receptors, has similar effects. The combination of trastuzumab + pertuzumab is being tested to increase the effect of HER2-signaling blockade (possibly + docetaxel), which shows synergistic activity. The combination of herceptin with aromatase inhibitors (such as anastrozole or ietrozole) has also been tested in hormone-dependent tumors. And in general, herceptin in combination with the chemotherapeutic agents capecitabine or 5-fluorouracil and cisplatin is indicated in various HER2-positive metastatic tumors.
Bevacizumab (Avastin) is a humanized monoclonal antibody to Vascular Endothelial Growth Factor (VEGF), which captures circulating VEGF in plasma, thereby inhibiting tumor neoangiogenesis. Ranibizumab (Lucentis), which is used in ophthalmology in the treatment of vascular-related macular degeneration of the retina, has similar effects.
Rituximab - a chimeric monoclonal antibody of the IgG1 type, specifically directed against the CD20 antigen, is a frequently used preparation in malignant B-lymphomas.
Ipilimumab is a monoclonal antibody that activates CTLA-4 targeting, where cytotoxic T cells can recognize and destroy tumor cells (it turns off the inhibitory mechanism and allows T cells to function). It is used to treat melanoma, non-small cell lung cancer, ca bladder and ca prostate.
Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody, also acting as a control node inhibitor, that blocks activated T cells from attacking tumor cells. It is also used in malignant melanoma (in combination with ipilumomab), lung ca and kidney ca.
Atezolizumab acts as an inhibitor of PDL1 programmed cell death ligand. It is mainly used in non-small cell lung ca.
    Another possible mechanism involved in the anti-tumor effect of some monoclonal antibodies is the "labeling" of a cell on the surface of which the relevant receptor is present; the cells thus labeled are then attacked and destroyed by the body's immune processes. The efficacy of monoclonal antibodies in tumor therapy depends on the presence and function of appropriate receptors on tumor cell membranes. If these receptors are scarce, or are dysfunctional or mutated, the antibody is ineffective ...
    Monoclonal antibodies can also be "carriers" to which a suitable chemotherapeutic or radionuclide binds. A long-used radioactive preparation of this species is Ibritumomab Tiuxetan labeled with ⁹⁰Y (Zevalin) for non-Hodgkin's lymphomas. More recently, lilotomab labeled ¹⁷⁷Lu, targeted against CD37, is used here. However, the ¹⁷⁷Lu or ²²⁵Ac labeled anti-PSMA ligand (PSMA-617) in prostate cancer appears to be the most promising, which is able to cure even advanced metastatic hormone-independent prostate cancer.
For more details see below "Radioisotope Therapy", passae "Radioimmunotherapy".

Dual-targeted (bispecific) monoclonal antibodies
Various factors are involved in cancer (as well as some other serious diseases - inflammatory, autoimmune, degenerative) and there are a number of complex processes taking place with multiple signaling pathways between cells. Although monoclonal antibodies (MAb) can effectively affect specific signaling pathways, it is often difficult to achieve satisfactory curative results with one given preparation. Therefore, different types of chemotherapeutical are sometimes combined. However, this can bring additional problems with unwanted interference, side effects, the possibility of unwanted immune responses.
In the field of monoclonal antibodies, however, an alternative "more elegant" solution is also possible in principle: Develop such antibody molecules that have two binding sites aimed at two different antigens of the given process. These so-called bispecific antibodies (BsAb) with double targeting ("two in one") can then show better therapeutic effects than classical unidirectionally targeted monoclonal antibodies. Two mediators are targeted by a single molecule.
    Various specific ligands binding to different receptors can be incorporated into the Fab arms of antibody molecules in several ways. Either by cross-linking two antibodies with two different pairs of variable Fab fragments with different antigen binding. Or, instead of one of the chains, e.g. "b", another "b' " with a different targeting is chemically attached to the Fab arm - a Fab' fragment is created. Or, alternatively, heavy and light chain variable regions cloned from two different antibodies are created in the IgG antibody. There are other more complicated options...
    We briefly list some bispecific antibodies that have already found clinical application :
-> Blinatumomab in malignant B-lymphoid cells in non-Hodkinson's lymphoma, specific for CD19 and CD3 on effector T-lymphocytes.
-> Mosunetuzumab is a monoclonal antibody used to treat follicular lymphoma. It binds bispecifically to CD20 contained in B-lymphocytes and to CD3 found in T-cells. T-cells are thereby stimulated to destroy lymphoma tumor cells.
-> Emicizumab is a bispecific antibody for the treatment of hemophilia A. It binds to both activated coagulation factor IX and factor X, whose activation it mediates.
-> Amivantamab is a bispecific monoclonal antibody used to treat non-small cell lung cancer (a special type with an insertion mutation of exon 20 of the epidermal growth factor receptor EGFR). It targets the epidermal growth factor (EGF) receptor and the mesenchymal-epithelial transition (MET) receptor.
-> Cadonilimab binds simultaneously to PD-1 and CTLA-4 antigens, which are expressed at much higher levels in tumor tissues compared to normal tissues. These two targets mediate increased cellular cytotoxicity and cellular phagocytosis. Bispecific cadonilimab (which replaces the combination of nivolumab and ipilimumab) shows promising efficacy in cervical, gastric, hepatocellular carcinoma.
-> Faricimab (RG7716) is used in ophthalmology for the therapy of vascular-related macular degeneration. It targets both the vascular endothelial growth factor VEGF-A and the angioprotein inhibitor ANG-2. It stabilizes the blood vessels in the retina and shows better effects than the currently used aptamer pegaptamib (Macugen) or the monoclonal antibody ranibizumab (Lucentis).