The  collimation  of the machine means that, while rotating, the X-rays project only a limited portion of the  anatomy  onto the film at any given instant but, as the rotation progresses around the skull, a composite picture of the maxillo-facial block is created. While the arm rotates, the film moves in a such way that the projected partial skull image (limited by the beam section) scrolls over it and exposes it entirely. Not all of the overlapping individual images projected on the film have the same magnification because the beam is  divergent  and the images have differing focus points. Also not all the element images move with the same  velocity  on the target film as some of them are more distant from and others closer to the instant rotation center. The velocity of the film is controlled in such fashion to fit exactly the velocity of projection of the anatomical elements of the dental arch side which is closest to the film. Therefore, they are recorded sharply while the elements in different places are recorded blurred as they scroll at different velocity.


The dental panoramic image suffers from important distortions because a vertical  zoom  and a horizontal zoom both vary differently along the image. The vertical and horizontal zooms are determined by the relative position of the recorded element versus film and generator. Features closer to the generator receive more vertical zoom. The horizontal zoom is also dependent on the relative position of the element to the focal path. Features inside the focal path arch receive more horizontal zoom and are blurred; features outside receive less horizontal zoom and are blurred.


The result is an image showing sharply the section along the mandible arch, and blurred elsewhere. For example, the more radio-opaque anatomical region, the cervical vertebrae (neck), shows as a wide and blurred vertical pillar overlapping the front teeth. The path where the anatomical elements are recorded sharply is called "focal path".


Persons who are to undergo panoramic radiography usually are required to remove any earrings, jewellery, hair pins, glasses,  dentures  or  orthodontic appliances . [ 4 ]  If these articles are not removed, they may create artifacts on the image (especially if they contain metal) and reduce its usefulness. There is also a need for the person to stay absolutely still during the 18 or so second cycle it takes for the machine to expose the film. For this reason, radiographers often explain to the person beforehand how the machine will move. [ 4 ]


Like any medical imaging utilizing  ionizing radiation , there will be a minute degree of direct ionizing damage and indirect damage from  free radicals  created during the ionization of water molecules within cells. A rough estimate of the risk of fatal cancer from a panoramic radiograph is about 1 in 20,000,000. [ 4 ]  The age of the person being imaged also alters the risk, with younger people having a slightly higher risk. E.g. the 1 in 20,000,000 risk would be doubled for someone in the 1-10 age group (1 in 10,000,000). [ 4 ]


1985–1991 – The first attempt to build a dental digital panoramic was of McDavid et al. at  UTHSCSA . [ 5 ]  Their idea was based on a linear pixel array(single pixel column) sensor which was not appropriate for such an application because: a) there is no tomographic effect; b) huge difficulties to collimate the X-rays beam and to control the X-ray dose delivered to the patient; c) poor generator efficiency.


1995 – DXIS, the first dental digital panoramic X-rays system available on the market, created by Catalin Stoichita at  Signet (France) . DXIS targeted to retrofit all the panoramic models.
1997 – SIDEXIS, of  Siemens  (currently  Sirona Dental Systems , Germany) offered a digital option for Ortophos Plus panoramic unit, DigiPan of Trophy Radiology (France) offered a digital option  for the OP100 panoramic made by Instrumentarium (Finland).
1998–2004 – many panoramic manufacturers offered their own digital systems.


Panoramic radiographs have the capability to demonstrate a portion of the neck and display atheromas (calcifications in the  carotid artery ) which are an indication of both local and generalized (systemic)  atherosclerosis . Atherosclerosis of the  coronary arteries  leading to  myocardial infarction  (heart attack), and atherosclerosis of the carotid artery leading to  stroke  are the number one and number three most common causes of death in the United States. [ 6 ]


There is interest to look at panoramic radiographs as a screening tool, however further data is needed with regards if it is able to make a meaningful difference in outcomes. [ 7 ]


Additional research projects have further determined the prevalence rate of these atheromas in the general population (3–5%) [ 8 ] [ 9 ]  and among high-risk groups (over 25% in: recent stroke victims, [ 10 ]  individuals with  obstructive sleep apnea  syndrome, [ 11 ] [ 12 ] [ 13 ]   postmenopausal  women, [ 14 ] [ non-primary source needed ]   type 2 diabetics , [ 15 ] [ 13 ] [ 16 ]  individuals with  dilated cardiomyopathy , [ 17 ] [ 13 ]  and among individuals who have received  radiotherapy  directed at the neck, [ 18 ] [ non-primary source needed ] [ 19 ] [ non-primary source needed ] ). These findings have been corroborated by other several other researchers. [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 13 ]


Atherosclerosis is attributed to risk factors that include cigarette smoking,  hyperlipidemia ,  obesity ,  diabetes mellitus , and  hypertension  (high blood pressure). These factors, however, do not fully account for the risk of disease. Atherosclerosis has been conceptualized as a chronic inflammatory response to  endothelial cell  injury [ 24 ]  and dysfunction possibly arising from chronic dental infection. In 2010, using the previously validated Mattila panoramic radiographic index to quantify the totality of dental infection (i.e., periapical and  furcal lesions ,  pericoronitis  sites,  carious  tooth roots, teeth with  pulpal  caries, and vertical bony defects), Friedlander's group determined that individuals with carotid artery atheromas on their panoramic radiographs had significantly greater amounts of dental infection/inflammation than atherogenic risk-matched controls devoid of radiographic atheromas. [ 25 ] [ non-primary source needed ] [ 26 ] [ non-primary source needed ]  While the Mattila index had been previously used to relate the extent of dental infection to  coronary artery disease , this research is the first to link the full range of dental disease that it measures to panoramic radiographs evidencing calcified carotid artery atherosclerosis.


Perfusion CT  or  CT Perfusion  is a type of  Perfusion Scanning  using  Computed Tomography . It is helpful in the evaluation of the  vascularity  of tissue in the body. In this, the temporal changes in tissue density are measured, providing information about the vascularity of the tissue.
In CT perfusion, a contrast media injection is given, and then the scan is taken. The acquired data are post-processed to obtain perfusion maps with different parameters, such as BV (blood volume), BF (blood flow), MTT (mean transit time), and TTP (time to peak). [ 1 ] [ 2 ]


CT Perfusion plays an important role in the assessment of Acute Ischemic Stroke. It is used to create maps of blood flow, blood volume, and mean transit time to assess the tissue and to differentiate between the core and penumbra in stroke. [ 3 ]


Phase-contrast X-ray imaging  or  phase-sensitive X-ray imaging  is a general term for different technical methods that use information concerning changes in the  phase  of an  X-ray  beam that passes through an object in order to create its images. Standard X-ray imaging techniques like  radiography  or  computed tomography (CT)  rely on a decrease of the X-ray beam's intensity ( attenuation ) when traversing the  sample , which can be measured directly with the assistance of an  X-ray detector . However, in phase contrast X-ray imaging, the beam's  phase shift  caused by the sample is not measured directly, but is transformed into variations in intensity, which then can be recorded by the detector. [ 1 ]


In addition to producing  projection images , phase contrast X-ray imaging, like conventional transmission, can be combined with  tomographic techniques  to obtain the 3D distribution of the real part of the  refractive index  of the sample. When applied to samples that consist of atoms with low  atomic number   Z , phase contrast X-ray imaging is more sensitive to density variations in the sample than  conventional transmission-based X-ray imaging . This leads to images with improved  soft tissue  contrast. [ 2 ]


In the last several years, a variety of phase-contrast X-ray imaging techniques have been developed, all of which are based on the observation of  interference patterns  between diffracted and undiffracted waves. [ 3 ]    The most common techniques are crystal interferometry, propagation-based imaging, analyzer-based imaging, edge-illumination and grating-based imaging (see below).


The first to discover  X-rays  was  Wilhelm Conrad Röntgen  in 1895, where he found that they had the ability to penetrate opaque materials. He recorded the first X-ray image, displaying the hand of his wife. [ 4 ]  He was awarded the first  Nobel Prize in Physics  in 1901 "in recognition of the extraordinary services he has rendered by the discovery of the remarkable rays subsequently named after him". [ 5 ]  Since then, X-rays have been used as a tool to safely determine the inner structures of different objects, although the information was for a long time obtained by measuring the transmitted intensity of the waves only, and the phase information was not accessible.


The principle of  phase-contrast imaging  was first developed by  Frits Zernike  during his work with  diffraction gratings  and visible light. [ 6 ] [ 7 ]  The application of his knowledge to microscopy won him the  Nobel Prize  in Physics in 1953. Ever since,   phase-contrast microscopy  has been an important field of  optical microscopy .


The transfer of phase-contrast imaging from visible light to X-rays took a long time, due to slow progress in improving the quality of X-ray beams and the inaccessibility of X-ray lenses. In the 1970s, it was realized that the  synchrotron radiation , emitted from charged particles circulating in storage rings constructed for high-energy nuclear physics experiments, may have been a more intense and versatile source of X-rays than  X-ray tubes ; [ 8 ]  this, combined with progress in the development of X-rays optics, was fundamental for the further advancement of X-ray physics.


The pioneer work to the implementation of the phase-contrast method to X-ray physics was presented in 1965 by Ulrich Bonse and Michael Hart, Department of Materials Science and Engineering of Cornell University, New York. They presented a crystal  interferometer , made from a large and highly perfect  single crystal . [ 9 ]  Not less than 30 years later the Japanese scientists  Atsushi Momose , Tohoru Takeda and co-workers adopted this idea and refined it for application in biological imaging, for instance by increasing the field of view with the assistance of new setup configurations and  phase retrieval  techniques. [ 10 ] [ 11 ]  The Bonse–Hart interferometer provides several orders of magnitude higher sensitivity in biological samples than other phase-contrast techniques, but it cannot use conventional X-ray tubes because the crystals only accept a very narrow energy band of X-rays (Δ E / E  ~ 10 −4 ). In 2012, Han Wen and co-workers took a step forward by replacing the crystals with nanometric phase gratings. [ 12 ]  The gratings split and direct X-rays over a broad spectrum, thus lifting the restriction on the bandwidth of the X-ray source. They detected sub nano radian  refractive bending of X-rays in biological samples with a grating Bonse–Hart interferometer. [ 12 ]


At the same time, two further approaches to phase-contrast imaging emerged with the aim to overcome the problems of crystal interferometry.
The propagation-based imaging technique was primarily introduced by the group of  Anatoly Snigirev  [ de ]  at the  ESRF  (European Synchrotron Radiation Facility) in Grenoble, France, [ 13 ]  and was based on the detection of "Fresnel fringes" that arise under certain circumstances in free-space propagation. The experimental setup consisted of an inline configuration of an X-ray source, a sample and a detector and did not require any optical elements. It was conceptually identical to the setup of Dennis Gabor's revolutionary work on  holography  in 1948. [ 14 ]


An alternative approach called analyzer-based imaging was first explored in 1995 by Viktor Ingal and Elena Beliaevskaya at the X-ray laboratory in Saint Petersburg, Russia, [ 15 ]  and by Tim Davis and colleagues at the  CSIRO  (Commonwealth Scientific and Industrial Research Organisation) Division of Material Science and Technology in Clayton, Australia. [ 16 ]  This method uses a Bragg crystal as angular filter to reflect only a small part of the beam fulfilling the  Bragg condition  onto a detector. Important contributions to the progress of this method have been made by a US collaboration of the research teams of Dean Chapman, Zhong Zhong and William Thomlinson, for example the extracting of an additional signal caused by  ultra-small angle scattering [ 17 ]  and the first CT image made with analyzer-based imaging. [ 18 ]  An alternative to analyzer-based imaging, which provides equivalent results without requiring the use of a crystal, was developed by Alessandro Olivo and co-workers at the Elettra synchrotron in Trieste, Italy. [ 19 ]  This method, called “edge-illumination”, operates a fine selection on the X-ray direction by using the physical edge of the detector pixels themselves, hence the name. Later on Olivo, in collaboration with Robert Speller at University College London, adapted the method for use with conventional X-ray sources, [ 20 ]  opening the way to translation into clinical and other applications. Peter Munro (also from UCL) substantially contributed to the development of the lab-based approach, by demonstrating that it imposes practically no coherence requirements [ 21 ]  and that, this notwithstanding, it still is fully quantitative. [ 22 ]


The latest approach discussed here is the so-called grating-based imaging, which makes use of the  Talbot effect , discovered by  Henry Fox Talbot  in 1836. [ 23 ]  This self-imaging effect creates an interference pattern downstream of a  diffraction grating . At a particular distance this pattern resembles exactly the structure of the grating and is recorded by a detector. The position of the interference pattern can be altered by bringing an object in the beam, that induces a phase shift. This displacement of the interference pattern is measured with the help of a second grating, and by certain reconstruction methods, information about the real part of the refractive index is gained. The so-called Talbot–Lau interferometer was initially used in  atom interferometry , for instance by  John F. Clauser  and Shifang Li in 1994. [ 24 ]  The first X-ray grating interferometers using synchrotron sources were developed by Christian David and colleagues from the  Paul Scherrer Institute  (PSI) in Villingen, Switzerland [ 25 ]  and the group of  Atsushi Momose  from the University of Tokyo. [ 26 ]  In 2005, independently from each other, both David's and Momose's group incorporated computed tomography into grating interferometry, which can be seen as the next milestone in the development of grating-based imaging. [ 27 ] [ 28 ]
In 2006, another great advancement was the transfer of the grating-based technique to  conventional laboratory X-ray tubes  by  Franz Pfeiffer  and co-workers, [ 29 ]  which fairly enlarged the technique's potential for clinical use. About two years later the group of Franz Pfeiffer also accomplished to extract a supplementary signal from their experiments; the so-called "dark-field signal" was caused by scattering due to the porous microstructure of the sample and provided "complementary and otherwise inaccessible structural information about the specimen at the micrometer and submicrometer length scale". [ 30 ]  At the same time, Han Wen and co-workers at the US National Institutes of Health arrived at a much simplified grating technique to obtain the scattering (“dark-field”) image. They used a single projection of a grid and a new approach for signal extraction named "single-shot Fourier analysis". [ 31 ]  Recently, a lot of research was done to improve the grating-based technique: Han Wen and his team analyzed animal bones and found out that the intensity of the dark-field signal depends on the orientation of the grid and this is due to the anisotropy of the bone structure. [ 32 ]  They made significant progress towards biomedical applications by replacing mechanical scanning of the gratings with electronic scanning of the X-ray source. [ 33 ]  The grating-based phase-contrast CT field was extended by tomographic images of the dark-field signal [ 34 ]  and time-resolved phase-contrast CT. [ 35 ]  Furthermore, the first pre-clinical studies using grating-based phase-contrast X-ray imaging were published. Marco Stampanoni and his group examined native breast tissue with "differential phase-contrast mammography", [ 36 ]  and a team led by Dan Stutman investigated how to use grating-based imaging for the small joints of the hand. [ 37 ]


Most recently, a significant advance in grating-based imaging occurred due to the discovery of a  phase moiré effect [ 38 ] [ 39 ]  by Wen and colleagues. It led to interferometry beyond the Talbot self-imaging range, using only phase gratings and conventional sources and detectors. X-ray phase gratings can be made with very fine periods, thereby allowing imaging at low radiation doses to achieve high sensitivity.


Conventional X-ray imaging uses the drop in intensity through attenuation caused by an object in the X-ray beam and the radiation is treated as rays like in  geometrical optics . But when X-rays pass through an object, not only their amplitude but their phase is altered as well. Instead of simple  rays , X-rays can also be treated as  electromagnetic waves . An object then can be described by its  complex refractive index  (cf. [ 8 ] ):


The term  δ  is the decrement of the real part of the refractive index, and the imaginary part  β  describes the absorption index or extinction coefficient.
Note that in contrast to optical light, the real part of the refractive index is less than but close to unity, this is "due to the fact that the X-ray spectrum generally lies to the high-frequency side of various resonances associated with the binding of electrons". [ 8 ]  The  phase velocity  inside of the object is larger than the  velocity of light   c . This leads to a different behavior of X-rays in a medium compared to visible light (e.g. refractive angles have negative values) but does not contradict the  law of relativity , "which requires that only signals carrying information do not travel faster than  c . Such signals move with the  group velocity , not with the phase velocity, and it can be shown that the group velocity is in fact less than  c ." [ 8 ]


The impact of the index of refraction on the behavior of the wave can be demonstrated with a wave propagating in an arbitrary medium with a fixed refractive index  n . For reason of simplicity, a monochromatic  plane wave  with no  polarization  is assumed here. The wave propagates in direction normal to the surface of the medium, named  z  in this example (see figure on the right). The scalar wave function in vacuum is


Within the medium, the  angular wavenumber  changes from  k  to  nk . Now the wave can be described as:


where   δkz  is the phase shift and   e −β kz  is an exponential decay factor decreasing the amplitude  E 0  of the wave. [ 8 ]


In more general terms, the total phase shift of the beam propagating a distance  z  can be calculated by using the integral


where  λ  is the  wavelength  of the incident X-ray beam. This formula means that the phase shift is the projection of the decrement of the real part of the refractive index in imaging direction. This fulfills the requirement of the  tomographic principle , which states that "the input data to the reconstruction algorithm should be a projection of a quantity  f  that conveys structural information inside a sample. Then, one can obtain a tomogram which maps the value  f ." [ 40 ]  In other words, in phase-contrast imaging a map of the real part of the refraction index  δ(x,y,z)  can be reconstructed with standard techniques like  filtered back projection  which is analog to conventional  X-ray computed tomography  where a map of the imaginary part of the refraction index can be retrieved.


To get information about the compounding of a sample, basically the density distribution of the sample, one has to relate the measured values for the refractive index to intrinsic parameters of the sample, such a relation is given by the following formulas:


where  ρ a  is the atomic number density,  σ a  the absorption  cross section ,  k  the length of the  wave vector  and


where  p  the phase shift cross section.


Far from the absorption edges (peaks in the absorption cross-section due to the enhanced probability for the absorption of a photon that has a frequency close to the resonance frequency of the medium),  dispersion effects  can be neglected; this is the case for light elements ( atomic number   Z <40) that are the components of human tissue and X-ray energies above 20 keV, which are typically used in medical imaging.
Assuming these conditions, the absorption cross section is approximately stated by


where 0.02 is a constant given in  barn , the typical unit of particle interaction cross section area,  k  the length of the  wave vector ,  k 0  the length of a wave vector with wavelength of 1  Angstrom  and  Z  the  atomic number . [ 41 ]  The valid formula under these conditions for the phase shift cross section is:


where   Z  is the  atomic number ,  k  the length of the  wave vector ,  and  r 0  the  classical electron radius .


This results in the following expressions for the two parts of the complex index of refraction:


Inserting typical values of human tissue in the formulas given above shows that  δ  is generally three orders of magnitude larger than   β  within the diagnostic X-ray range.  This implies that the phase-shift of an X-ray beam propagating through tissue may be much larger than the loss in intensity thus making phase contrast X-ray imaging more sensitive to density variations in the tissue than absorption imaging. [ 42 ]


Due to the proportionalities


the advantage of phase contrast over conventional absorption contrast even grows with increasing energy. Furthermore, because the phase contrast image formation is not intrinsically linked to the absorption of X-rays in the sample, the  absorbed dose  can potentially be reduced by using higher X-ray energies. [ 29 ] [ 42 ]


As mentioned above, concerning visible light, the real part of the refractive index n can deviate strongly from unity (n of glass in visible light ranges from 1.5 to 1.8) while the deviation from unity for X-rays in different media is generally of the order of 10 −5 . Thus, the refraction angles caused at the boundary between two isotropic media calculated with  Snell's formula  are also very small. The consequence of this is that refraction angles of X-rays passing through a tissue sample cannot be detected directly and are usually determined indirectly by "observation of the interference pattern between diffracted and undiffracted waves produced by spatial variations of the real part of the refractive index." [ 3 ]


Crystal interferometry , sometimes also called  X-ray interferometry , is the oldest but also the most complex method used for experimental realization. It consists of three beam splitters in  Laue geometry  aligned parallel to each other. (See figure to the right) The incident beam, which usually is collimated and filtered by a monochromator (Bragg crystal) before, is split at the first crystal (S) by  Laue diffraction  into two coherent beams, a reference beam which remains undisturbed and a beam passing through the sample. The second crystal (T) acts as a transmission mirror and causes the beams to converge one towards another. The two beams meet at the plane of the third crystal (A), which is sometimes called, the analyzer crystal, and create an interference pattern the form of which depends on the optical path difference between the two beams caused by the sample. This interference pattern is detected with an X-ray detector behind the analyzer crystal. [ 9 ] [ 43 ]


By putting the sample on a rotation stage and recording  projections  from different angles, the 3D-distribution of the refractive index and thus  tomographic images  of the sample can be retrieved. [ 40 ]
In contrast to the methods below, with the crystal interferometer the phase itself is measured and not any spatial alternation of it.
To retrieve the phase shift out of the interference patterns; a technique called phase-stepping or fringe scanning is used: a phase shifter (with the shape of a wedge) is introduced in the reference beam. The phase shifter creates straight  interference fringes  with regular intervals; so called carrier fringes. When the sample is placed in the other beam, the carrier fringes are displaced. The phase shift caused by the sample corresponds to the displacement of the carrier fringes. Several interference patterns are recorded for different shifts of the reference beam and by analyzing them the phase information  modulo  2 π  can be extracted. [ 40 ] [ 43 ]  This ambiguity of the phase is called the  phase wrapping effect  and can be removed by so-called "phase unwrapping techniques". [ 44 ]  These techniques can be used when the signal-to-noise ratio of the image is sufficiently high and phase variation is not too abrupt. [ 28 ]


As an alternative to the fringe scanning method, the Fourier-transform method can be used to extract the phase shift information with only one interferogram, thus shortening the exposure time, but this has the disadvantage of limiting the spatial resolution by the spacing of the carrier fringes. [ 45 ]


X-ray interferometry is considered to be the most sensitive to the phase shift, of the 4 methods, consequently providing the highest density resolution in range of mg/cm 3 . [ 28 ]  But due to its high sensitivity, the fringes created by a strongly phase-shifting sample may become unresolvable; to overcome this problem a new approach called "coherence-contrast X-ray imaging" has been developed recently, where instead of the phase shift the change of the degree of coherence caused by the sample is relevant for the contrast of the image. [ 46 ]


A general limitation to the spatial resolution of this method is given by the blurring in the analyzer crystal which arises from dynamical refraction, i.e. the angular deviation of the beam due to the refraction in the sample is amplified about ten thousand times in the crystal, because the beam path within the crystal depends strongly on its incident angle. This effect can be reduced by thinning down the analyzer crystal, e.g. with an analyzer thickness of 40  μ m a resolution of about 6  μ m was calculated. Alternatively the  Laue crystals  can be replaced by  Bragg crystals , so the beam doesn't pass through the crystal but is reflected on the surface. [ 47 ]


Another constraint of the method is the requirement of a very high stability of the setup; the alignment of the crystals must be very precise and the path length difference between the beams should be smaller than the wavelength of the X-rays; to achieve this the interferometer is usually made out of a highly perfect single block of silicon by cutting out two grooves. By the  monolithic  production the very important spatial lattice coherence between all three crystals can be maintained relatively well but it limits the field of view to a small size,(e.g.  5 cm x 5 cm for a 6-inch ingot) and because the sample is normally placed in one of the beam paths the size of the sample itself is also constrained by the size of the silicon block. [ 9 ] [ 48 ]
Recently developed configurations, using two crystals instead of one, enlarge the field of view considerably, but are even more sensitive to mechanical instabilities. [ 49 ] [ 50 ]


Another additional difficulty of the crystal interferometer is that the Laue crystals filter most of the incoming radiation, thus requiring a high beam intensity or very long exposure times. [ 51 ]  That limits the use of the method to highly brilliant X-ray sources like synchrotrons.


According to the constraints on the setup the crystal interferometer works best for high-resolution imaging of small samples which cause small or smooth  phase gradients .


To have the superior sensitivity of crystal Bonse-Hart interferometry without some of the basic limitations, the monolithic crystals have been replaced with nanometric x-ray phase-shift gratings. [ 52 ]  The first such gratings have periods of 200 to 400 nanometers. They can split x-ray beams over the broad energy spectra of common x-ray tubes. The main advantage of this technique is that it uses most of the incoming x-rays that would have been filtered by the crystals. Because only phase gratings are used, grating fabrication is less challenging than techniques that use absorption gratings. The first grating Bonse-Hart interferometer (gBH) operated at 22.5 keV photon energy and 1.5% spectral bandwidth.


The incoming beam is shaped by slits of a few tens of micrometers such that the transverse coherence length is greater than the grating period. The interferometer consists of three parallel and equally spaced phase gratings, and an x-ray camera. The incident beam is diffracted by a first grating of period 2P into two beams. These are further diffracted by a second grating of period P into four beams. Two of the four merge at a third grating of period 2P. Each is further diffracted by the third grating. The multiple diffracted beams are allowed to propagate for sufficient distance such that the different diffraction orders are separated at the camera. There exists a pair of diffracted beams that co-propagate from the third grating to the camera. They interfere with each other to produce intensity fringes if the gratings are slightly misaligned with each other. The central pair of diffraction paths are always equal in length regardless of the x-ray energy or the angle of the incident beam. The interference patterns from different photon energies and incident angles are locked in phase.


The imaged object is placed near the central grating. Absolute phase images are obtained if the object intersects one of a pair of coherent paths. If the two paths both pass through the object at two locations which are separated by a lateral distance d, then a phase difference image of Φ(r) - Φ(r-d) is detected.  Phase stepping one of the gratings is performed to retrieve the phase images. The phase difference image Φ(r) - Φ(r-d) can be integrated to obtain a phase shift image of the object.


This technique achieved substantially higher sensitivity than other techniques with the exception of the crystal interferometer. [ 12 ] [ 53 ]  A basic limitation of the technique is the chromatic dispersion of grating diffraction, which limits its spatial resolution. A tabletop system with a tungsten-target x-ray tube running at 60 kVp will have a limiting resolution of 60 μm. [ 12 ]  Another constraint is that the x-ray beam is slitted down to only tens of micrometers wide. A potential solution has been proposed in the form of parallel imaging with multiple slits. [ 12 ]


Analyzer-based imaging (ABI)  is also known as  diffraction-enhanced imaging ,  phase-dispersion Introscopy  and  multiple-image radiography [ 54 ]  Its setup consists of a monochromator (usually a single or double crystal that also collimates the beam) in front of the sample and an analyzer crystal positioned in  Bragg geometry  between the sample and the detector. (See figure to the right)


This analyzer crystal acts as an angular filter for the radiation coming from the sample. When these X-rays hit the analyzer crystal the condition of  Bragg diffraction  is satisfied only for a very narrow range of incident angles. When the scattered or refracted X-rays have incident angles outside this range they will not be reflected at all and don't contribute to the signal. Refracted X-rays within this range will be reflected depending on the incident angle. The dependency of the reflected intensity on the incident angle is called a rocking curve and is an intrinsic property of the imaging system, i.e. it represents the intensity measured at each pixel of the detector when the analyzer crystal is "rocked" (slightly rotated in angle θ) with no object present and thus can be easily measured. [ 54 ]  The typical angular acceptance is from a few microradians to tens of microradians and is related to the  full width at half maximum (FWHM)  of the rocking curve of the crystal.


When the analyzer is perfectly aligned with the monochromator and thus positioned to the peak of the rocking curve, a standard X-ray radiograph with enhanced contrast is obtained because there is no blurring by scattered photons. Sometimes this is referred to as "extinction contrast".


If, otherwise, the analyzer is oriented at a small angle (detuning angle) with respect to the monochromator then X-rays refracted in the sample by a smaller angle will be reflected less, and X-rays refracted by a larger angle will be reflected more. Thus the contrast of the image is based on different refraction angles in the sample.
For small phase gradients the refraction angle can be expressed as


where  k  is the length of the  wave vector  of the incident radiation and the second term on the right hand side is the first  derivative  of the phase in the diffraction direction. Since not the phase itself, but the first derivative of the phase front is measured, analyzer-based imaging is less sensitive to low spatial frequencies than crystal interferometry but more sensitive than PBI.


Contrary to the former methods analyzer-based imaging usually provides phase information only in the diffraction direction, but is not sensitive to angular deviations on the plane perpendicular to the diffraction plane. This sensitivity to only one component of the phase gradient can lead to ambiguities in phase estimation. [ 55 ]


By recording several images at different detuning angles, meaning at different positions on the rocking curve, a data set is gained which allows the retrieval of quantitative differential phase information. There are several algorithms to reconstruct information from the rocking curves, some of them provide an additional signal. This signal comes from Ultra-small-angle scattering by sub-pixel sample structures and causes angular broadening of the beam and hence a broadening of the shape of the rocking curve. Based on this scattering contrast a new kind of image called Dark-field image can be produced. [ 17 ] [ 54 ] [ 56 ]


Tomographic imaging with analyzer-based imaging can be done by fixing the analyzer at a specific angle and rotating the sample through 360° while the projection data are acquired. Several sets of projections are acquired from the same sample with different detuning angles and then a tomographic image can be reconstructed. Assuming that the crystals are normally aligned such that the derivative of the refractive index is measured in the direction parallel to the tomographic axis, the resulting "refraction CT image" shows the pure image of the out-of-plane gradient.


For analyzer-based imaging, the stability requirements of the crystals is less strict than for crystal interferometry but the setup still requires a perfect analyzer crystal that needs to be very precisely controlled in angle and the size of the analyzer crystal and the constraint that the beam needs to be parallel also limits the field of view.  Additionally as in crystal interferometry a general limitation for the spatial resolution of this method is given by the blurring in the analyzer crystal due to  dynamic diffraction effects , but can be improved by using  grazing incidence diffraction  for the crystal. [ 55 ]


While the method in principle requires monochromatic, highly collimated radiation and hence is limited to a synchrotron radiation source, it was shown recently that the method remains feasible using a laboratory source with a polychromatic spectrum when the rocking curve is adapted to the K  α  spectral line radiation of the target material. [ 57 ]


Due to its high sensitivity to small changes in the refraction index this method is well suited to image soft tissue samples and is already implemented to medical imaging, especially in Mammography for a better detection of microcalcifications [ 1 ]  and in bone cartilage studies. [ 58 ]


Propagation-based imaging (PBI)  is the most common name for this technique but it is also called   in-line holography ,  refraction-enhanced imaging [ 59 ]   or  phase-contrast radiography . The latter denomination derives from the fact that the experimental setup of this method is basically the same as in conventional radiography. It consists of an in-line arrangement of an X-ray source, the sample and an X-ray detector and no other optical elements are required. The only difference is that the detector is not placed immediately behind the sample, but in some distance, so the radiation refracted by the sample can interfere with the unchanged beam. [ 13 ]
This simple setup and the low stability requirements provides a big advantage of this method over other methods discussed here.


Under  spatially coherent illumination  and an intermediate distance between sample and detector an interference pattern with "Fresnel fringes" is created; i.e. the fringes arise in the free space propagation in the  Fresnel regime , which means that for the distance between detector and sample the approximation of  Kirchhoff's diffraction formula  for the near field, the  Fresnel diffraction equation  is valid. In contrast to crystal interferometry the recorded interference fringes in PBI are not proportional to the phase itself but to the second derivative (the  Laplacian ) of the phase of the wavefront. Therefore, the method is most sensitive to abrupt changes in the decrement of the refractive index. This leads to stronger contrast outlining the surfaces and structural boundaries of the sample ( edge enhancement ) compared with a conventional radiogram. [ 60 ] [ 61 ]


PBI can be used to enhance the contrast of an absorption image, in this case the phase information in the image plane is lost but contributes to the image intensity ( edge enhancement  of attenuation image). However it is also possible to separate the phase and the attenuation contrast, i.e.  to reconstruct the distribution of the real and imaginary part of the refractive index separately. The unambiguous determination of the phase of the wave front ( phase retrieval ) can be realized by recording several images at different detector-sample distances and using algorithms based on the  linearization  of the  Fresnel diffraction integral  to reconstruct the phase distribution, but this approach suffers from amplified noise for low spatial frequencies and thus slowly varying components may not be accurately recovered.  There are several more approaches for phase retrieval and a good overview about them is given in. [ 62 ] [ 63 ]


Tomographic reconstructions of the 3D distribution of the refractive index or "Holotomography" is implemented by rotating the sample and recording for each projection angle a series of images at different distances. [ 64 ]


A high resolution detector is required to resolve the interference fringes, which practically limits the field of view of this technique or requires larger propagation distances.  The achieved spatial resolution is relatively high in comparison to the other methods and, since there are no optical elements in the beam, is mainly limited by the degree of  spatial coherence  of the beam.
As mentioned before, for the formation of the Fresnel fringes, the constraint on the  spatial coherence  of the used radiation is very strict, which limits the method to small or very distant sources, but in contrast to crystal interferometry and analyzer-based imaging the constraint on the  temporal coherence , i.e. the polychromaticity is quite relaxed. [ 55 ]  Consequently, the method cannot only be used with synchrotron sources but also with polycromatic laboratory X-ray sources providing sufficient spatial coherence, such as  microfocus X-ray tubes . [ 60 ]


Generally spoken, the image contrast provided by this method is lower than of other methods discussed here, especially if the density variations in the sample are small. Due to its strength in enhancing the contrast at boundaries, it's well suited for imaging fiber or foam samples. [ 65 ]  A very important application of PBI is the examination of  fossils  with synchrotron radiation, which reveals details about the  paleontological  specimens which would otherwise be inaccessible without destroying the sample. [ 66 ]


Grating-based imaging (GBI)  includes  Shearing interferometry  or  X-ray Talbot interferometry (XTI) , and  polychromatic   far-field interferometry (PFI) . [ 38 ]  Since the first X-ray grating interferometer—consisting of two phase gratings and an analyzer crystal [ 25 ] —was built, various slightly different setups for this method have been developed; in the following the focus lies on the nowadays standard method consisting of a phase grating and an analyzer grating. [ 26 ]  (See figure to the right).


The  XTI  technique is based on the  Talbot effect  or "self-imaging phenomenon", which is a  Fresnel diffraction  effect and leads to repetition of a periodic wavefront after a certain propagation distance, called the " Talbot length ". This periodic wavefront can be generated by spatially coherent illumination of a periodic structure, like a  diffraction grating , and if so the intensity distribution of the wave field at the Talbot length resembles exactly the structure of the grating and is called a self-image. [ 23 ]  It has also been shown that intensity patterns will be created at certain fractional Talbot lengths. At half the distance the same intensity distribution appears except for a lateral shift of half the grating period while at certain smaller fractional Talbot distances the self-images have fractional periods and fractional sizes of the intensity maxima and minima, that become visible in the intensity distribution behind the grating, a so-called Talbot carpet. The Talbot length and the fractional lengths can be calculated by knowing the parameters of the illuminating radiation and the illuminated grating and thus gives the exact position of the intensity maxima, which needs to be measured in GBI. [ 67 ]  While the Talbot effect and the Talbot interferometer were discovered and extensively studied by using visible light it has been demonstrated several years ago for the hard X-ray regime as well. [ 68 ]


In GBI a sample is placed before or behind the phase grating (lines of the grating show negligible absorption but substantial phase shift) and thus the interference pattern of the Talbot effect is modified by absorption, refraction and scattering in the sample.
For a phase object with a small phase gradient the X-ray beam is deflected by


where  k  is the length of the  wave vector  of the incident radiation and the second factor on the right hand side is the first derivative of the phase in the direction perpendicular to the propagation direction and parallel to the alignment of the grating. Since the transverse shift of the interference fringes is linear proportional to the deviation angle the differential phase of the wave front is measured in GBI, similar as in ABI. In other words, the angular deviations are translated into changes of locally transmitted intensity.
By performing measurements with and without sample the change in position of the interference pattern caused by the sample can be retrieved. The period of the interference pattern is usually in the range of a few  micrometers , which can only be conveniently resolved by a very high resolution detector in combination with a very intense illumination ( a source providing a very high flux) and hence limits the field of view significantly . [ 69 ]  This is the reason why a second grating, typically an absorption grating, is placed at a fractional Talbot length to analyze the interference pattern. [ 26 ]


The analyzer grating does normally have the same period as the interference fringes and thus transforms local fringe position into signal intensity variation on the detector, which is placed immediately behind the grating.
In order to separate the phase information from other contributions to the signal, a technique called "phase-stepping" is used. [ 27 ]  One of the gratings is scanned along the transverse direction term  x g ;  over one period of the grating, and for different positions of the grating an image is taken. The intensity signal in each pixel in the detector plane oscillates as a function of  x g . The recorded intensity oscillation can be represented by a  Fourier series  and by recording and comparing these intensity oscillations with or without the sample the separated differential phase shift and absorption signal relative to the reference image can be extracted. [ 27 ]  As in analyzer-based imaging, an additional signal coming from Ultra-small-angle scattering by sub-pixel microstructures of the sample, called dark-field contrast, can also be reconstructed. [ 30 ]  This method provides high spatial resolution, but also requires long exposure times.


An alternative approach is the retrieval of the differential phase by using  Moiré fringes . These are created as a superposition of the self-image of G1 and the pattern of G2 by using gratings with the same periodicity and inclining G2 against G1 regarding to the optical axis with a very small angle(<<1). This moiré fringes act as carrier fringes because they have a much larger spacing/period (smaller spatial frequency) than the Talbot fringes and thus the phase gradient introduced by the sample can be detected as the displacement of the Moiré fringes. [ 26 ]   With a Fourier analysis of the Moiré pattern the absorption and dark-field signal can also be extracted. [ 70 ]
Using this approach, the spatial resolution is lower than one achieved by the phase-stepping technique, but the total exposure time can be much shorter, because a differential phase image can be retrieved with only one Moiré pattern. [ 71 ]  Single-shot Fourier analysis technique was used in early grid-based scattering imaging [ 31 ]  similar to the  shack-Hartmann wavefront sensor  in optics, which allowed first live animal studies. [ 72 ]


A technique to eliminate mechanical scanning of the grating and still retain the maximum spatial resolution is electronic phase stepping. [ 33 ]  It scans the source spot of the x-ray tube with an electro-magnetic field. This causes the projection of the object to move in the opposite direction, and also causes a relative movement between the projection and the Moiré fringes. The images are digitally shifted to realign the projections. The result is that the projection of the object is stationary, while the Moiré fringes move over it. This technique effectively synthesizes the phase stepping process, but without the costs and delays associated with mechanical movements.


With both of these phase-extraction methods tomography is applicable by rotating the sample around the tomographic axis, recording a series of images with different projection angles and using back projection algorithms to reconstruct the 3-dimensional distributions of the real and imaginary part of the refractive index. [ 27 ] [ 71 ]
Quantitative tomographic reconstruction of the dark-field signal has also been demonstrated for the phase-stepping technique [ 34 ]  and very recently for the Moiré pattern approach as well. [ 70 ]


It has also been demonstrated that dark-field imaging with the grating interferometer can be used to extract orientational information of structural details in the sub-micrometer regime beyond the spatial resolution of the detection system. While the scattering of X-rays in a direction perpendicular to the grating lines provides the dark-field contrast, the scattering in a direction parallel to the grating lines only lead to blurring in the image, which is not visible at the low resolution of the detector. [ 31 ]  This intrinsic physical property of the setup is utilized to extract orientational information about the angular variation of the local scattering power of the sample by rotating the sample around the optical axis of the set-up and collecting a set of several dark-field images, each measuring the component of the scattering perpendicular to the grating lines for that particular orientation. This can be used to determine the local angle and degree of orientation of bone and could yield valuable information for improving research and diagnostics of  bone diseases  like  osteoporosis  or  osteoarthritis . [ 73 ] [ 74 ]


The standard configuration as shown in the figure to the right requires spatial coherence of the source and consequently is limited to high brilliant synchrotron radiation sources. This problem can be handled by adding a third grating close to the X-ray source, known as a  Talbot-Lau interferometer . This source grating, which is usually an absorption grating with transmission slits, creates an "array of individually coherent but mutually incoherent sources". As the source grating can contain a large number of individual apertures, each creating a sufficiently coherent virtual line source, standard X-ray generators with source sizes of a few square millimeters can be used efficiently and the field of view can be significantly increased. [ 29 ]


Since the position of the interference fringes formed behind the beam-splitter grating is independent of wavelength over a wide energy range of the incident radiation the interferometer in phase-stepping configuration can still be used efficiently with polychromatic radiation. [ 27 ]
For the Moiré pattern configuration the constraint on the radiation energy is a bit stricter, because a finite bandwidth of energy instead of monochromatic radiation causes a decrease in the visibility of the Moiré fringes and thus the image quality, but a moderate polychromaticity is still allowed. [ 75 ]  A great advantage of the usage of polychromatic radiation is the shortening of the exposure times and this has recently been exploited by using white synchrotron radiation to realize the first dynamic (time-resolved) Phase contrast tomography. [ 35 ]


A technical barrier to overcome is the fabrication of gratings with high  aspect ratio  and small periods. The production of these gratings out of a  silicon wafer  involves microfabrication techniques like  photolithography , anisotropic  wet etching ,  electroplating  and  molding . [ 76 ]  A very common fabrication process for X-ray gratings is  LIGA , which is based on deep  X-ray lithography  and electroplating. It was developed in the 1980s for the fabrication of extreme high aspect ratio microstructures by scientists from the  Karlsruhe Institute of Technology (KIT) . [ 77 ]
Another technical requirement is the stability and precise alignment and movement of the gratings (typically in the range of some nm), but compared to other methods, e.g. the crystal interferometer the constraint is easy to fulfill.


The grating fabrication challenge was eased by the discovery of a  phase moiré effect [ 38 ]  which provides an all-phase-grating interferometer that works with compact sources, called the  polychromatic far-field interferometer  (see figure on the right). Phase gratings are easier to make when compared with the source and analyzer gratings mentioned above, since the grating depth required to cause phase shift is much less than what is needed to absorb x-rays. Phase gratings of 200 - 400 nanometer periods have been used to improve phase sensitivity in table-top PFI imagers. [ 39 ]  In PFI a phase grating is used to convert the fine interference fringes into a broad intensity pattern at a distal plane, based on the  phase moiré effect . Besides higher sensitivity, another incentive for smaller grating periods is that the lateral coherence of the source needs to be at least one grating period.


A disadvantage of the standard GBI setup is the sensitivity to only one component of the phase gradient, which is the direction parallel to the 1-D gratings. This problem has been solved either by recording differential phase contrast images of the sample in both direction x and y by turning the sample (or the gratings) by 90° [ 78 ]  or by the employment of two-dimensional gratings. [ 79 ]


Being a differential phase technique, GBI is not as sensitive as crystal interferometry to low spatial frequencies, but because of the high resistance of the method against mechanical instabilities, the possibility of using detectors with large pixels and a large field of view and, of crucial importance, the applicability to conventional laboratory X-ray tubes, grating-based imaging is a very promising technique for medical diagnostics and soft tissue imaging.
First medical applications like a pre-clinical  mammography  study, show great potential for the future of this technique. [ 36 ]  Beyond that GBI has applications in a wide field of material science, for instance it could be used to improve security screening. [ 30 ] [ 80 ]


Edge-illumination (EI) was developed at the Italian synchrotron (Elettra) in the late ‘90s, [ 19 ]  as an alternative to ABI. It is based on the observation that, by illuminating only the edge of detector pixels, high sensitivity to phase effects is obtained (see figure).


Also in this case, the relation between X-ray refraction angle and first derivative of the phase shift caused by the object is exploited:


Δ
 α
 =

 1
 k

 ∂
 ϕ
 (
 x
 )

 ∂
 x

 {\displaystyle \Delta \alpha ={\frac {1}{k}}{\frac {\partial \phi (x)}{\partial x}}}


If the X-ray beam is vertically thin and impinges on the edge of the detector, X-ray refraction can change the status of the individual X-ray from "detected" to "undetected" and vice versa, effectively playing the same role as the crystal rocking curve in ABI. This analogy with ABI, already observed when the method was initially developed, [ 19 ]  was more recently formally demonstrated. [ 81 ]  Effectively, the same effect is obtained – a fine angular selection on the photon direction; however, while in analyzer-based imaging the beam needs to be highly collimated and monochromatic, the absence of the crystal means that edge-illumination can be implemented with divergent and polychromatic beams, like those generated by a conventional rotating-anode X-ray tube. This is done by introducing two opportunely designed masks (sometimes referred to as “coded-aperture” masks [ 20 ] ), one immediately before the sample, and one in contact with the detector (see figure).


The purpose of the latter mask is simply to create insensitive regions between adjacent pixels, and its use can be avoided if specialized detector technology is employed. In this way, the edge-illumination configuration is simultaneously realized for all pixel rows of an area detector. This plurality of individual beamlets means that, in contrast to the synchrotron implementation discussed above, no sample scanning is required – the sample is placed downstream of the sample mask and imaged in a single shot (two if phase retrieval is performed [ 22 ] ). Although the set-up perhaps superficially resembles that of a grating interferometer, the underpinning physical mechanism is different. In contrast to other phase contrast X-ray imaging techniques, edge-illumination is an incoherent technique, and was in fact proven to work with both spatially and temporally incoherent sources, without any additional source aperturing or collimation. [ 22 ] [ 82 ]  For example, 100 μm focal spots are routinely used which are compatible with, for example, diagnostic mammography systems. Quantitative phase retrieval was also demonstrated with (uncollimated) incoherent sources, showing that in some cases results analogous to the synchrotron gold standard can be obtained. [ 22 ]  The relatively simple edge-illumination set-up results in phase sensitivity at least comparable with other phase contrast X-ray imaging techniques, [ 83 ]  results in a number of advantages, which include reduced exposure time for the same source power, reduced radiation dose, robustness against environmental vibrations, and easier access to high X-ray energy. [ 83 ] [ 84 ] [ 85 ] [ 86 ]  Moreover, since their aspect ratio is not particularly demanding, masks are cheap, easy to fabricate (e.g.do not require X-ray lithography) and can already be scaled to large areas. The method is easily extended to phase sensitivity in two directions, for example, through the realization of L-shaped apertures for the simultaneous illumination of two orthogonal edges in each detector pixel. [ 87 ]  More generally, while in its simplest implementation beamlets match individual pixel rows (or pixels), the method is highly flexible, and, for example, sparse detectors and asymmetric masks can be used [ 88 ]  and compact [ 89 ]   and microscopy [ 90 ]  systems can be built. So far, the method has been successfully demonstrated in areas such as security scanning, [ 91 ]  biological imaging, [ 83 ] [ 89 ]  material science, [ 92 ]  paleontology [ 93 ] [ 94 ]  and others; adaptation to 3D (computed tomography) was also demonstrated. [ 93 ] [ 95 ]  Alongside simple translation for use with conventional x-ray sources, there are substantial benefits in the implementation of edge-illumination with coherent synchrotron radiation, among which are high performance at very high X-ray energies [ 94 ]  and high angular resolutions. [ 96 ]


Four potential benefits of phase contrast have been identified in a medical imaging context: [ 42 ]


A quantitative comparison of phase- and absorption-contrast mammography that took realistic constraints into account (dose, geometry, and photon economy) concluded that grating-based phase-contrast imaging (Talbot interferometry) does not exhibit a general signal-difference-to-noise improvement relative to absorption contrast, but the performance is highly task dependent. [ 97 ] [ 98 ]  Such a comparison is yet to be undertaken for all phase contrast methods, however, the following considerations are central to such a comparison:


Some of the tradeoffs are illustrated in the right-hand figure, which shows the benefit of phase contrast over absorption contrast for detection of different targets of relevance in mammography as a function of target size. [ 97 ]  Note that these results do not include potential benefits from the dark-field signal.


Following preliminary, lab-based studies in e.g. computed tomography  [ 100 ]  and mammography, [ 101 ]  phase contrast imaging is beginning to be applied in real medical applications, such as lung imaging, [ 102 ]  imaging of extremities, [ 103 ]  intra-operative specimen imaging. [ 104 ]   In vivo  applications of phase contrast imaging have been kick-started by the pioneering mammography study with synchrotron radiation undertaken in Trieste, Italy. [ 105 ]


Theranostics , also known as  theragnostics , [ 1 ]  is a technique commonly used in  personalised medicine . For example in  nuclear medicine , one  radioactive drug  is used to identify ( diagnose ) and a second radioactive drug is used to treat (therapy)  cancerous tumors . [ 2 ] [ 3 ] [ 4 ]  In other words, theranostics combines  radionuclide imaging  and  radiation therapy  which targets specific  biological pathways .


Technologies used for theranostic imaging include  radiotracers ,  contrast agents ,  positron emission tomography , and  magnetic resonance imaging . [ 3 ] [ 5 ]  It has been used to treat  thyroid cancer  and  neuroblastomas . [ 3 ]


The term "theranostic" is a  portmanteau  of two words,  thera peutic and diag nostic , thus referring to a combination of diagnosis and treatment that also allows for continuing medical assessment of a patient. The first known use of the term is attributed to John Funkhouser, a consultant for the company Cardiovascular Diagnostic, who used it in a press release in August 1998. [ 6 ]


Theranostics originated in the field of  nuclear medicine ;  iodine isotope  131 for the diagnostic study and treatment of  thyroid cancer  was one of its earliest applications. [ 7 ]   Nuclear medicine  encompasses various substances, either alone or in combination, that can be used for  diagnostic imaging  and targeted therapy. These substances may include ligands of  receptors  present on the target tissue or compounds, like  iodine , that are internalized by the target through metabolic processes. By using these mechanisms, theranostics enables the localization of pathological tissues with imaging and the targeted destruction of these tissues using high doses of  radiation . [ 7 ]


Contrast agents  with therapeutic properties have been under development for several years. [ 8 ]  One example is the design of contrast agents capable of releasing a  chemotherapeutic agent  locally at the target site, triggered by a stimulus provided by the operator. This localized approach aims to increase treatment efficacy and minimize side effects. For instance,  ultrasound -based contrast media, such as  microbubbles , can accumulate in hypervascularized tissues and release the active ingredient in response to ultrasound waves, thus targeting a specific area chosen by the  sonographer . [ 8 ]


Another approach involves linking  monoclonal antibodies  (capable of targeting different molecular targets) to  nanoparticles . This strategy enhances the drug's affinity and specificity towards the target and enables visualization of the treatment area, such as using superparamagnetic  iron oxide  particles detectable by  magnetic resonance imaging . [ 9 ]  Additionally, these particles can be designed to release  chemotherapy  agents specifically at the site of binding, producing a local  synergistic  effect with antibody action. Integrating these methods with medical-nuclear techniques, which offer greater imaging sensitivity, may aid in target identification and treatment monitoring. [ 10 ]


Positron emission tomography  (PET) imaging in theranostics provides insight into metabolic and molecular processes within the body. The PET scanner detects   photons  and creates three-dimensional images that enable visualization and quantification of physiological and biochemical processes. [ 11 ]  PET imaging uses  radiotracers  that target specific molecules or processes. For example, [18F]  fluorodeoxyglucose  (FDG) is commonly used to assess glucose metabolism, as cancer cells exhibit increased glucose uptake. Other radiotracers target specific receptors, enzymes, or transporters, allowing the evaluation of various physiological and pathological processes. [ 11 ]


PET imaging plays a role in both diagnosis and treatment planning. It aids in the identification and staging of diseases, such as cancer, by visualizing the extent and metabolic activity of tumors. PET scans can also guide treatment decisions by assessing treatment response and monitoring disease progression. [ citation needed ]  Additionally, PET imaging is used to determine the suitability of patients for targeted therapies based on specific molecular characteristics, enabling personalized treatment approaches.  [ 12 ]


Single-photon emission computed tomography  (SPECT) is employed in theranostics, using  gamma rays  emitted by a  radiotracer  to generate three-dimensional images of the body. SPECT imaging involves the injection of a radiotracer that emits single photons, which are detected by a gamma camera rotating around the person undergoing imaging. [ 7 ]


SPECT provides functional and anatomical information, allowing the assessment of organ structure, blood flow, and specific molecular targets. It is useful in evaluating diseases that involve altered blood flow or specific receptor expression. For example, SPECT imaging with  technetium-99m  (Tc-99m) radiopharmaceuticals may be able to assess myocardial perfusion and identify areas of  ischemia  or  infarction  in patients with cardiovascular diseases. [ 13 ]


SPECT imaging helps in identifying disease localization, staging, and assessing the response to therapy. Moreover, SPECT imaging is employed in targeted  radionuclide  therapy, where the same radiotracer used for diagnostic imaging can be used to deliver therapeutic doses of radiation to the diseased tissue. [ 13 ]


Magnetic resonance imaging  (MRI) is a non-invasive imaging technique that uses strong magnetic fields and radiofrequency pulses to generate detailed anatomical and functional images of the body. MRI provides excellent soft tissue contrast and is widely used in theranostics for its ability to visualize anatomical structures and assess physiological processes. [ 8 ]


In theranostics, MRI allows for the detection and characterization of tumors, assessment of tumor extent, and evaluation of treatment response. MRI can provide information on  tissue perfusion , diffusion, and metabolism, aiding in the selection of appropriate therapies and monitoring their effectiveness. [ 14 ]


Advancements in MRI technology have expanded its capabilities in theranostics. Techniques such as functional MRI (fMRI) enable the assessment of brain activation and connectivity, while  diffusion-weighted imaging  (DWI) provides insights into tissue microstructure. The development of molecular imaging agents, such as superparamagnetic  iron oxide   nanoparticles , allows for targeted imaging and tracking of specific molecular entities. [ 14 ]


Theranostics encompasses a range of therapeutic approaches that are designed to target and treat diseases with enhanced precision.


Targeted drug delivery  systems facilitate the selective delivery of therapeutic agents to specific disease sites while minimizing off-target effects. These systems employ strategies, such as  nanoparticles ,  liposomes , and  micelles , to encapsulate drugs and enhance their stability, solubility, and bioavailability. [ 15 ]  By incorporating diagnostic components, such as imaging agents or targeting  ligands , into these delivery systems, clinicians can monitor drug distribution and accumulation in real-time, ensuring effective treatment and reducing systemic toxicity. Targeted drug delivery systems hold promise in the treatment of cancer, cardiovascular diseases, and other conditions, as they allow for personalized and site-specific therapy. [ 15 ]


Gene therapy  is a therapeutic approach that involves modifying or replacing faulty genes to treat or prevent diseases. In theranostics, gene therapy can be combined with diagnostic imaging to monitor the delivery, expression, and activity of therapeutic genes. [ 16 ]  Imaging techniques such as  MRI ,  PET , and  optical imaging  enable non-invasive assessment of gene transfer and expression, providing valuable insights into the efficacy and safety of gene-based treatments. [ 15 ]  Gene therapy has shown potential in treating  genetic disorders , cancer, and cardiovascular diseases, and its integration with diagnostic imaging offers a comprehensive approach for monitoring and optimizing treatment outcomes. [ 16 ]


Radiotherapy  can be integrated with imaging techniques to guide treatment planning, monitor radiation dose distribution, and assess treatment response. Molecular imaging methods, such as PET and  SPECT , can be employed to visualize and quantify tumor characteristics, such as  hypoxia  or  receptor expression , aiding in personalized radiation dose optimization 10 .


Additionally, theranostic approaches involving  radiolabeled  therapeutic agents, known as  radiotheranostics , combine the therapeutic effects of radiation with diagnostic capabilities. Radiotheranostics, including  Peptide receptor radionuclide therapy  (PRRT), hold promise for targeted radiotherapy, enabling precise tumor targeting and dose escalation, while sparing healthy tissues. [ 17 ]  For example, PRRT based on  Lutetium -177 combinations (known as  radioligands ) has emerged as a treatment option for inoperable  metastatic   neuroendocrine tumours  (NET). [ 18 ]


Immunotherapy harnesses the body's immune system to recognize and attack cancer cells or other disease targets. In theranostics, immunotherapeutic approaches can be coupled with diagnostic imaging to assess immune cell  infiltration , tumor  immunogenicity , and treatment response. [ 7 ]  Imaging techniques, such as PET and MRI, can provide valuable information about the tumor microenvironment, immune cell dynamics, and response to immunotherapies. Furthermore, theranostic strategies involving the use of radiolabeled immunotherapeutic agents allow for simultaneous imaging and therapy, aiding in patient selection, treatment monitoring, and optimization of immunotherapeutic regimens. [ 15 ]


Nanomedicine refers to the use of nanoscale materials for medical applications. In theranostics, nanomedicine offers opportunities for targeted drug delivery, imaging, and therapy. [ 7 ]   Nanoparticles  can be engineered to carry therapeutic payloads, imaging agents, and targeting ligands, allowing for multimodal theranostic approaches. These nanocarriers can enhance drug stability, improve drug solubility, and enable controlled release at the disease site. Additionally, nanomaterials with inherent imaging properties, such as quantum dots or gold nanoparticles, can serve as contrast agents for imaging. [ 19 ]


Theranostics has been applied in oncology, contributing to new approaches in the diagnosis, treatment, and monitoring of cancers. By integrating diagnostic imaging and targeted therapies, theranostics offers personalized approaches that improve treatment outcomes and patient care. In oncology, theranostics encompasses a wide range of applications, including the management of various types of cancers such as breast, lung, prostate, and colorectal cancer. [ 8 ]  Molecular imaging techniques, such as  positron emission tomography  (PET) and  single-photon emission computed tomography  (SPECT), enable the visualization and characterization of cancerous lesions, aiding in early detection, staging, and assessment of treatment response. [ better source needed ] [ 20 ]  This allows for more accurate and tailored treatment planning, including the selection of appropriate targeted therapies or the optimization of radiation therapy.


Despite the significant progress, the translation of theranostics into routine clinical practice faces challenges, including the need for standardized imaging protocols,  biomarker  validation, and regulatory considerations. Additionally, there is a continuous need for research and development to further enhance the effectiveness and accessibility of theranostic approaches in oncology. [ 19 ]


Theranostics extends beyond oncology and holds potential in the fields of  neurology  and  cardiology . [ 21 ] [ 22 ]  In neurology, theranostic approaches offer new avenues for the diagnosis and treatment of various neurodegenerative diseases, such as  Alzheimer's disease ,  Parkinson's disease , and   multiple sclerosis . Advanced imaging techniques, including  magnetic resonance imaging  (MRI) and positron emission tomography (PET), allow for the visualization of  neuroanatomy , functional connectivity, and molecular changes in the brain. This enables early detection, precise diagnosis, and monitoring of disease progression, facilitating the development of targeted therapeutic interventions.


Similarly, in cardiology, theranostics play a significant role in the diagnosis and treatment of cardiovascular conditions. Non-invasive imaging modalities like MRI and computed tomography (CT) provide detailed information about cardiac structure, function, and blood flow, aiding in the assessment of heart disease and the guidance of interventions. Theranostic approaches in cardiology involve targeted drug delivery systems for the treatment of conditions such as  atherosclerosis  and  restenosis , as well as image-guided interventions for precise stenting or catheter-based therapies. [ 21 ]


Several challenges remain to be addressed for widespread adoption and integration of theranostics into routine clinical practice. Regulatory considerations will play a role in ensuring the safety, efficacy, and quality of theranostic agents and technologies. Harmonization of regulations across different countries and regions is necessary to facilitate global implementation. [ 23 ]  Cost-effectiveness is a significant challenge, as theranostic approaches can be expensive. [ 23 ]  Strategies to optimize resource utilization and reimbursement models have been discussed. Technical limitations, such as the development of more specific and sensitive imaging agents, improvement of imaging resolution and quality, and the integration of different imaging modalities, require ongoing research and technological advancements. [ better source needed ] [ 24 ]  Ethical considerations surrounding patient privacy, data security, and the responsible use of patient information need to be addressed. [ 24 ]


Tomosynthesis , also  digital tomosynthesis  ( DTS ), is a method for performing high-resolution limited-angle  tomography  at  radiation dose  levels comparable with  projectional radiography . It has been studied for a variety of clinical applications, including vascular imaging, dental imaging, orthopedic imaging, mammographic imaging, musculoskeletal imaging, and chest imaging. [ 1 ]


The concept of tomosynthesis was derived from the work of Ziedses des Plantes, who developed methods of reconstructing an arbitrary number of planes from a set of projections. Though this idea was displaced by the advent of computed tomography, tomosynthesis later gained interest as a low-dose tomographic alternative to CT. [ 2 ]


Tomosynthesis reconstruction algorithms are similar to  CT  reconstructions, in that they are based on performing an inverse  Radon transform . Due to partial data sampling with very few projections, approximation algorithms have to be used. Filtered back projection and iterative, expectation-maximization algorithms have both been used to reconstruct the data. [ 3 ]


Reconstruction algorithms for tomosynthesis are different from those of conventional CT because the conventional  filtered back projection  algorithm requires a complete set of data. Iterative algorithms based upon  expectation maximization  are most commonly used, but are  computationally intensive. Some manufacturers have produced practical systems using off-the-shelf  GPUs  to perform the reconstruction in a few seconds.


Digital tomosynthesis combines digital image capture and processing with simple tube/detector motion as used in conventional computed tomography (CT). However, though there are some similarities to CT, it is a separate technique. In modern (helical) CT, the source/detector makes at least a complete 180-degree rotation about the subject obtaining a complete set of data from which images may be reconstructed. Digital tomosynthesis, on the other hand, only uses a limited rotation angle (e.g., 15-60 degrees) with a lower number of discrete exposures (e.g., 7-51) than CT. This incomplete set of projections is digitally processed to yield images similar to conventional tomography with a limited  depth of field . Because the image processing is digital, a series of slices at different depths and with different thicknesses can be reconstructed from the same acquisition. However, since fewer projections are needed than CT to perform the reconstruction, radiation exposure and cost are both reduced. [ 4 ]


Digital breast tomosynthesis  ( DBT ) [ 5 ]  is  Food and Drug Administration  (FDA) approved for use in  breast cancer screening . [ 6 ]  The benefit for screening has been debated, [ 7 ]  but consensus is being reached that the technology is improving sensitivity compared to two-view digital  mammography  at the cost of a slightly reduced specificity (increased recall rates). [ 8 ]  Because the data acquired are 85 - 160 micron typical resolution, much higher than CT, DBT is unable to offer the narrow slice widths that CT offers (typically 1-1.5 mm). However, the higher resolution detectors permit very high in-plane resolution, even if the Z-axis resolution is less. Another interesting property of breast tomosynthesis is that image quality may vary substantially through the imaging volume. [ 9 ]  DBT reading times are much higher, compared to  mammography  interpretation. [ 10 ]


Photon-counting breast tomosynthesis has been investigated, [ 11 ]  and  spectral imaging  applications, such as  breast density  measurement and lesion characterization, [ 12 ] [ 13 ]  have been investigated on that platform.


Tomosynthesis has a much more limited depth of field than does CT. For this reason, it likely will not be able to replace CT for the evaluation of the deeper organs of the body. However, since bones are often near the skin, multiple musculoskeletal applications of tomosynthesis have been studied, most of which have mostly been used in research with limited use in everyday practice.


Tomosynthesis has been compared to both radiography and CT for the evaluation of healing fractures, especially in the presence of hardware. In a study of patients with wrist fractures, digital tomosynthesis was shown to enable detection of more fractures than radiography while simultaneously providing lower metal artifact than radiography. [ 4 ]


Tomosynthesis has been compared to  digital radiography , with CT as the standard, for the detection of erosions associated with  rheumatoid arthritis . The radiation dose of digital tomosynthesis was very close to that of digital radiography. However, tomosynthesis showed sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 80%, 75%, 78%, 76%, and 80%, compared to digital radiography were 66%, 81%, 74%, 77%, and 71%. [ 14 ]  The slight benefit digital tomosynthesis in this application may or may not justify the slightly increased cost of the modality compared to digital radiography.


Tomosynthesis is also used for x-ray inspection of electronics, [ 15 ]  particularly printed circuit board assemblies and electronic components. Tomosynthesis is usually used where a CT slice is required at high magnification, where conventional CT would not allow the sample to be located close enough to the x-ray source.


Gel dosimeters , also called  Fricke gel dosimeters , are manufactured from radiation sensitive chemicals that, upon irradiation with ionising radiation, undergo a fundamental change in their properties as a function of the absorbed radiation dose.


Over many years individuals have endeavoured to measure absorbed radiation dose distributions using gels. As long ago as 1950, the radiation-induced colour change in dyes was used to investigate radiation doses in gels. [ 1 ]  Further, in 1957 depth doses of photons and electrons in agar gels were investigated using spectrophotometry. [ 2 ]  Gel dosimetry today however, is founded mainly on the work of Gore  et al  who in 1984 [ 3 ]  demonstrated that changes due to ionising radiation in Fricke dosimetry solutions, [ 4 ]  developed in the 1920s, could be measured using  nuclear magnetic resonance  (NMR).


Gel dosimeters generally consist of two types; Fricke and polymer gel dosimeters and are usually evaluated or 'read-out' using  magnetic resonance imaging  (MRI), optical  computer tomography  (CT),  x-ray CT  or  ultrasound .


Since 1999 the DosGel and IC3DDose Conference Series on gel dosimetry has been held at various international venues.


Gore  et al  investigated [ 5 ]  the nuclear magnetic resonance (NMR) relaxation properties of irradiated Fricke or ferrous sulphate dosimetry solutions [ 6 ]  showing that radiation-induced changes, in which ferrous (Fe 2+ ) ions are converted to ferric (Fe 3+ ) ions, could be quantified using NMR relaxation measurements. In 1986 Appleby  et al [ 7 ]  reported that Fricke dosimetry solutions dispersed throughout a gel matrix could be used to obtain three-dimensional (3D) spatial dose information using magnetic resonance imaging (MRI). It was subsequently shown that irradiated Fricke-type gel dosimeters did not retain a spatially stable dose distribution due to ion diffusion within the irradiated dosimeters. [ 8 ]  Fricke solutions with various gelling agents such as gelatine, agarose, sephadex and polyvinyl alcohol (PVA) were investigated along with chelating agents such as  xylenol orange  (XO) to reduce diffusion. Numerous authors subsequently published results of their work to inhibit the ion diffusion with limited success and which was summarised by Baldock  et al  in 2001. [ 9 ]  By the early 1990s the diffusion problem was considered to be a significant one in the advancement of gel dosimetry.


Polymer systems for the use of radiation dosimetry were first proposed as early as 1954, where Alexander  et al [ 10 ]  discussed the effects of ionising radiation on polymethylmethacrylate. Following this, Hoecker  et al [ 11 ]  in 1958 investigated the dosimetry of radiation-induced polymerisation in liquids, and in 1961 Boni [ 12 ]  used poly acrylamide  as a gamma dosimeter. Much later in 1991, Audet  et al [ 13 ]  reported changes in NMR transverse relaxation measurements of irradiated polyethylene oxide. In 1992, Kennan  et al [ 14 ]  reported on NMR longitudinal relaxation studies performed on an irradiated aqueous solution of N,N’-methylene-bis-acrylamide and agarose, which showed that the relaxation rates increased with absorbed dose.


In 1992 a new gel dosimetry formulation was proposed by Maryanski  et a l, [ 15 ]  which was based on the polymerisation of acrylamide and N,N’-methylene-bis-acrylamide (bis) monomers infused in an aqueous agarose matrix. This system was given the acronym BANANA due to the use of the chemical components (bis, acrylamide,  nitrous oxide  and agarose). [ 16 ]  This type of gel dosimeter did not have the associated diffusion problem of Fricke gels and was shown to have a relatively stable post-irradiation dose distribution. The polymerisation reaction occurred by cross-linking of the monomers induced by the free radical products of water radiolysis. In 1994 the BANANA formulation was refined [ 17 ]  by replacing agarose with gelatine and given the acronym BANG (bis, acrylamide, nitrogen and aqueous gelatine), the first of a series of new polymer gel formulations. In 1994 this formulation was patented [ 18 ]  and became commercially available through MGS Research Inc. as  BANG® . Subsequently, due to the naming of the commercial product,  PAG [ 19 ]  became the polymer gel dosimeter acronym of choice for most authors. Numerous authors subsequently published results of work investigating different compositions and formulations of polymer gel dosimeters which were summarised by Lepage  et al . [ 20 ]


Although polymer-type dosimeters did not have the diffusion limitations of Fricke-type gel dosimeters, there was another significant limitation in their use. Due to the nature of their free radical chemistry, polymer gel dosimeters were susceptible to atmospheric oxygen inhibition of the polymerisation processes. As a result, these gel dosimeters had to be manufactured in an oxygen-free environment, [ 21 ] [ 22 ]  such as in a glove box pumped with nitrogen gas. Along with the use of potentially toxic chemicals, [ 23 ]  this was a significant limitation in the introduction of gel dosimetry into the clinic.


During this period a number of studies were undertaken to investigate the clinical applications of radiological tissue-equivalent [ 24 ] [ 25 ] [ 26 ]  PAG-type polymer gel dosimeters using MRI. [ 27 ] [ 28 ] [ 29 ] [ 30 ] [ 31 ]  De Deene  et al [ 32 ]  undertook an investigation into the overall accuracy of an anthropomorphic polymer gel dosimetry phantom for the verification of conformal radiotherapy treatments. It was established that significant issues relating to the accuracy of this dosimetry technique were a result of oxygen inhibition in the polymer gel and MRI imaging artefacts.


Authors continued to investigate clinical aspects of polymer gel dosimetry using MRI including conformal therapy, IMRT and IMAT, [ 33 ] [ 34 ] [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ]  stereotactic radiosurgery, [ 40 ] [ 41 ] [ 42 ] [ 43 ] [ 44 ] [ 45 ] [ 46 ] [ 47 ]  brachytherapy, [ 48 ] [ 49 ]  low energy X-rays, [ 50 ]  high-LET and proton therapy, [ 51 ] [ 52 ] [ 53 ] [ 54 ]  boron capture neutron therapy [ 55 ] [ 56 ]  and tissue inhomogeneities. [ 57 ] [ 58 ]


A significant development in the field of gel dosimetry occurred when results of using an alternative polymer gel dosimeter formulation were published by Fong  et al  in 2001. [ 59 ]  This new type of polymer gel dosimeter, known as MAGIC gel, bound atmospheric oxygen in a metallo-organic complex thus removing the problem of oxygen inhibition and enabling polymer gels to be manufactured on the bench-top in the laboratory. This created what was to be known as a normoxic gel dosimeter, compared with the previous PAG formulation which subsequently became known as a hypoxic gel dosimeter. The MAGIC polymer gel formulation consisted of methacrylic acid, ascorbic acid, gelatine and copper. The principal behind the MAGIC gel is in the ascorbic acid oxygen scavenger. Ascorbic acid binds free oxygen contained within the aqueous gelatine matrix into metallo-organic complexes and this process is initiated by copper sulphate. It was subsequently shown by De Deene  et al  in 2002 that other antioxidants could be used in the manufacture of normoxic gels [ 60 ]  including tetrakis (hydroxymethyl) phosphonium chloride, having first been suggested to  Baldock  by Billingham in 1996. [ 61 ]  Numerous authors subsequently published results of work investigating different compositions and formulations of normoxic polymer gel dosimeters and were summarised by Senden. [ 62 ]  Other work has also included the development of less toxic polymer gels. [ 63 ]


The fundamental science underpinning polymer gel dosimetry was reviewed along with the various 'read-out' and evaluation techniques and clinical dosimetry applications in the 2010 Topical Review publication by  Baldock   et al . [ 64 ]


In June 1995 whilst attending the  American Association of Physicists in Medicine  (AAPM) annual meeting in Boston, US,  Clive Baldock  and L. John Schreiner discussed the appropriateness of organising some form of specialist meeting or workshop on gel dosimetry. In September 1996  Clive Baldock  and Lars Olsson, whilst attending the European Society for Radiotherapy & Oncology (ESTRO) annual meeting in Vienna, Austria initiated the organising of the international conference series on gel dosimetry which began as  DosGel 99 , the 1st International Workshop on Radiation Therapy Gel Dosimetry held in Lexington, Kentucky in 1999 and hosted by Geoff Ibbott. Since 1999, subsequent  DosGel  conferences were held in Brisbane, Australia (2001), Ghent, Belgium (2004), Sherbrooke, Canada (2006) and Crete, Greece (2008). In 2010 the conference was held in Hilton Head, South Carolina, USA and underwent a name-change to  IC3DDose . Subsequent  IC3DDose  conferences were held in Sydney, Australia (2012), Ystad, Sweden (2014), Galveston, Texas, USA (2016), Kushan, China (2018) and virtually (2021).


The aim of the first workshop was to bring together individuals, both researchers and users, with an interest in the application of 3-dimensional radiation dosimetry techniques in the treatment of  cancer , with a mix of presentations from basic science to clinical applications. This has remained an objective for all of the conferences. One rationale of  DosGel 99  was stated as supporting the increasing clinical implementation of gel dosimetry, as the technique appeared, at that time, to be leaving the laboratories of gel dosimetry enthusiasts and entering clinical practice. Clearly by labelling the first workshop as the 1st, there was a vision of a continuing series, which has been fulfilled. On the other hand, the expectation of widespread clinical use of gel dosimetry has perhaps not been what was hoped for and anticipated. Nevertheless, the rapidly increasing demand for advanced high-precision 3D radiotherapy technology and techniques has continued apace. The need for practical and accurate 3D dosimetry methods for development and quality assurance has only increased. By the 6th meeting, held in South Carolina in 2010, the Conference Scientific Committee recognised the wider developments in 3D systems and methods and decided to widen the scope, whilst keeping the same span from basic science to applications. This was signalled by a change of name from  DosGel  to  IC3DDose , a name that has continued to the latest conference, the 11th  IC3DDose  conference, held virtually in May 2021.


Radiation therapy  or  radiotherapy  ( RT ,  RTx , or  XRT ) is a  treatment  using  ionizing radiation , generally provided as part of  cancer therapy  to either kill or control the growth of  malignant   cells . It is normally delivered by a  linear particle accelerator . Radiation therapy may be  curative  in a number of types of cancer if they are localized to one area of the body, and have not  spread to other parts . It may also be used as part of  adjuvant therapy , to prevent tumor recurrence after surgery to remove a primary malignant tumor (for example, early stages of breast cancer). Radiation therapy is synergistic with  chemotherapy , and has been used before, during, and after chemotherapy in susceptible cancers. The subspecialty of oncology concerned with radiotherapy is called radiation oncology. A physician who practices in this subspecialty is a  radiation oncologist .


Radiation therapy is commonly applied to the cancerous tumor because of its ability to control cell growth. Ionizing radiation works by damaging the  DNA  of cancerous tissue leading to  cellular death . To spare normal tissues (such as skin or organs which radiation must pass through to treat the tumor), shaped radiation beams are aimed from several angles of exposure to intersect at the tumor, providing a much larger  absorbed dose  there than in the surrounding healthy tissue. Besides the tumor itself, the radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with the tumor, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumor to allow for uncertainties in daily set-up and internal tumor motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumor position.


Radiation oncology  is the medical specialty concerned with prescribing radiation, and is distinct from  radiology , the use of radiation in  medical imaging  and  diagnosis . Radiation may be prescribed by a radiation oncologist with intent to cure or for adjuvant therapy. It may also be used as  palliative treatment  (where cure is not possible and the aim is for local disease control or symptomatic relief) or as therapeutic treatment (where the therapy has survival benefit and can be curative). [ 1 ]  It is also common to combine radiation therapy with  surgery , chemotherapy,  hormone therapy ,  immunotherapy  or some mixture of the four. Most common cancer types can be treated with radiation therapy in some way.


The precise treatment intent (curative, adjuvant,  neoadjuvant therapeutic , or palliative) will depend on the tumor type, location, and  stage , as well as the general health of the patient.  Total body irradiation  (TBI) is a radiation therapy technique used to prepare the body to receive a  bone marrow transplant .  Brachytherapy , in which a  radioactive source  is placed inside or next to the area requiring treatment, is another form of radiation therapy that minimizes exposure to healthy tissue during procedures to treat cancers of the breast, prostate, and other organs. Radiation therapy has several applications in non-malignant conditions, such as the treatment of  trigeminal neuralgia ,  acoustic neuromas , severe  thyroid eye disease ,  pterygium ,  pigmented villonodular synovitis , and prevention of  keloid  scar growth, vascular  restenosis , and  heterotopic ossification . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The use of radiation therapy in non-malignant conditions is limited partly by worries about the risk of radiation-induced cancers.


It is estimated that half of the US' 1.2M invasive cancer cases diagnosed in 2022 received radiation therapy in their treatment program. [ 5 ]   Different cancers respond to radiation therapy in different ways. [ 6 ] [ 7 ] [ 8 ]


The response of a cancer to radiation is described by its radiosensitivity.
Highly radiosensitive cancer cells are rapidly killed by modest doses of radiation. These include  leukemias , most  lymphomas , and  germ cell tumors .
The majority of  epithelial cancers  are only moderately radiosensitive, and require a significantly higher dose of radiation (60–70 Gy) to achieve a radical cure.
Some types of cancer are notably radioresistant, that is, much higher doses are required to produce a radical cure than may be safe in clinical practice.  Renal cell cancer  and  melanoma  are generally considered to be radioresistant but radiation therapy is still a palliative option for many patients with metastatic melanoma. Combining radiation therapy with  immunotherapy  is an active area of investigation and has shown some promise for melanoma and other cancers. [ 9 ]


It is important to distinguish the radiosensitivity of a particular tumor, which to some extent is a laboratory measure, from the radiation "curability" of a cancer in actual clinical practice. For example, leukemias are not generally curable with radiation therapy, because they are disseminated through the body. Lymphoma may be radically curable if it is localized to one area of the body. Similarly, many of the common, moderately radioresponsive tumors are routinely treated with curative doses of radiation therapy if they are at an early stage. For example,  non-melanoma skin cancer ,  head and neck cancer ,  breast cancer ,  non-small cell lung cancer ,  cervical cancer ,  anal cancer , and  prostate cancer . With the exception of oligometastatic disease,  metastatic  cancers are incurable with radiation therapy because it is not possible to treat the whole body. [ citation needed ]


Modern radiation therapy relies on a CT scan to identify the tumor and surrounding normal structures and to perform dose calculations for the creation of a complex radiation treatment plan. The patient receives small skin marks to guide the placement of treatment fields. [ 10 ]  Patient positioning is crucial at this stage as the patient will have to be placed in an identical position during each treatment.  Many patient positioning devices have been developed for this purpose, including masks and cushions which can be molded to the patient.  Image-guided radiation therapy  is a method that uses imaging to correct for positional errors of each treatment session. [ citation needed ]


The response of a tumor to radiation therapy is also related to its size. Due to complex  radiobiology , very large tumors are affected less by radiation compared to smaller tumors or microscopic disease. Various strategies are used to overcome this effect. The most common technique is surgical resection prior to radiation therapy. This is most commonly seen in the treatment of breast cancer with  wide local excision  or  mastectomy  followed by  adjuvant radiation therapy . Another method is to shrink the tumor with  neoadjuvant  chemotherapy prior to radical radiation therapy. A third technique is to enhance the radiosensitivity of the cancer by giving certain drugs during a course of radiation therapy. Examples of radiosensitizing drugs include  cisplatin ,  nimorazole , and  cetuximab . [ 11 ]


The impact of radiotherapy varies between different types of cancer and different groups. [ 12 ]  For example, for breast cancer after  breast-conserving surgery , radiotherapy has been found to halve the rate at which the disease recurs. [ 13 ]  In pancreatic cancer, radiotherapy has increased survival times for inoperable tumors. [ 14 ]


Radiation therapy (RT) is in itself painless, but has  iatrogenic side effect  risks. Many low-dose  palliative treatments  (for example, radiation therapy to bony  metastases ) cause minimal or no side effects, although short-term pain flare-up can be experienced in the days following treatment due to oedema compressing nerves in the treated area. Higher doses can cause varying side effects during treatment (acute side effects), in the months or years following treatment (long-term side effects), or after re-treatment (cumulative side effects). The nature, severity, and longevity of side effects depends on the organs that receive the radiation, the treatment itself (type of radiation, dose,  fractionation , concurrent chemotherapy), and the patient. Serious radiation complications may occur in 5% of RT cases. Acute (near immediate) or sub-acute (2 to 3 months post RT) radiation side effects may develop after 50 Gy RT dosing. Late or delayed radiation injury (6 months to decades) may develop after 65 Gy. [ 5 ]


Most side effects are predictable and expected. Side effects from radiation are usually limited to the area of the patient's body that is under treatment. Side effects are dose-dependent; for example, higher doses of head and neck radiation can be associated with  cardiovascular  complications,  thyroid  dysfunction, and  pituitary  axis dysfunction. [ 15 ]  Modern radiation therapy aims to reduce side effects to a minimum and to help the patient understand and deal with side effects that are unavoidable.


The main side effects reported are fatigue and skin irritation, like a mild to moderate sun burn. The fatigue often sets in during the middle of a course of treatment and can last for weeks after treatment ends. The irritated skin will heal, but may not be as elastic as it was before. [ 16 ]


Late side effects occur months to years after treatment and are generally limited to the area that has been treated. They are often due to damage of blood vessels and connective tissue cells. Many late effects are reduced by fractionating treatment into smaller parts.