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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5255_Библиотеки_им_академика_М_И_Перельмана
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Nuclear medicine in diagnosis and therapy — An overview252
Radionuclide therapy in myeloproliferative disorders
Polycythemia Vera is a clonal, chronic progressive myeloproliferative disorder characterized by
absolute increase in red blood cell mass, which arises from a neoplastic clone of a pleuripotent
stem cell. Radionuclide treatment involves the use of 32P, which gets actively incorporated into
the proliferating cells and is taken up primarily by the bone, spleen and liver. The high radiation
dose to the bone marrow accounts for the treatment effect. A standard dose of 111 MBq given
intravenously is used for this purpose. Essential thrombocytopenia, characterized by unremitting
elevation of thrombocytes, can also be treated by 32P. The dose used for this purpose is 110
MBq/sqm body surface area given intravenously.
Radiolabeled monoclonal antibodies
Monoclonal antibodies (MAB’s) are proteins, made in the laboratory from a single copy of a
humanised antibody. The most common antigen they seek is CD20. CD20 is found on most
lymphoma B-cells and on many normal B-cells. This makes it an ideal target for an antibodybased treatment. Bexxar (
antibody) are radiolabelled monoclonal antibodies used for the treatment of patients with CD20
positive, low-grade, follicular. non-Hodgkin’s lymphoma (NHL), with or without transformation,
where the disease is resistant to Rituximab and has relapsed following chemotherapy.
131
I- labeled anti CD20 antibody) and Zevalin (90Y- labeled anti CD20
Intra-arterial Therapy
Intra-arterial therapy is used for the treatment of hepatocellular carcinoma, cholangiocarcinoma
and hepatic metastasis. It is based on the fact that the vascular supply of hepatic tumors derives
almost exclusively from the hepatic artery as compared to the normal liver, which is supplied
predominantly by the portal venous system. Direct hepatic arterial injection of the
radiopharmaceutical can therefore be used for targeted therapy with minimal systemic toxicity.
This intra-arterial approach is reserved for inoperable tumors, which may become resectable
following treatment. It is of value in small tumors in the absence of portosystemic shunting.
labelled lipiodol and
188
with
Re-lipiodol are minimal as compared with
188
Re labelled lipiodol are used for this purpose. The radiation safety issues
131
I- labelled lipiodol.
131
Injection of radiopharmaceuticals into serosal cavities
Injection of radiopharmaceuticals into serosal cavities is used for the treatment of malignant
effusion, which does not respond to conventional therapy. Injection can be into the pleural,
pericardial or peritoneal cavity. It is also used for the treatment of omental disease due to ovarian
carcinoma. 32P as colloidal chromic phosphate is used for this purpose.
Endovascular Brachytherapy
One of the standard revascularization procedure for stenotic coronary artery is percutaneous
coronary angioplasty (PTCA). However, there is a high recurrence rate of restenosis post PTCA.
I-
Nuclear medicine in diagnosis and therapy — An overview 253
Numerous methods have been tried in the past to prevent restenosis, albeit with partial success.
One of the recent concepts in therapeutic nuclear medicine is endovascular brachytherapy. This
method can be used to prevent restenosis by locally delivering radiation at the stenotic site. Beta
(32P and 90Y) and gamma emitters (
in titanium wire or
192
Ir seeds (approx. 70 mCi) in nylon catheter can be inserted in the occluded
192
Ir) have been tried in this regard. 32P (1-2 mCi) impregnated
vessel at the stenotic site to locally deliver optimum radiation dose. This radiation causes the
death of smooth muscle cell in the media of the vessel musculature inhibiting its proliferation,
hence preventing restenosis. This modality of treatment is still in the experimental stages and
requires further investigation before it is routinely put to clinical practice.
Other applications in therapy
The ability of radioisotopes to locally deliver radiation has also been used in the treatment of
carcinoma prostrate.
125
I and
103
Pd seeds are implanted in the prostatic tissue causing local
radiation damage.
Recent Advances
Somatostatin receptor imaging
Somatostatin is a 14-amino-acid peptide hormone found on many cells of neuroendocrine origin.
It acts as a neurotransmitter in the central nervous system. Somatostatin receptors have been
demonstrated on the surface of human tumor cells which includes the cells with amine precursor
uptake and decarboxylation (APUD) properties such as pituitary tumors, endocrine pancreatic
tumors, carcinoids, paragangliomas, small cell lung cancers, medullary thyroid carcinomas and
pheochromocytomas. Other non-APUD cells may also bear somatostatin receptors, such as
activated lymphocytes, astrocytomas, and some breast carcinoma.
Derivative, [
111
In-DTPA-D-Phe1]-octreotide has a high affinity for somatostatin receptors with
similar biological properties as octreotide and is hence useful for the diagnosis of many tumors
of neuroendocrine and non-neuroendocrine origin. Other benefits include the absence of human
antibody response allowing for repeated administration, whole body imaging, more informed
patient management decisions, optimal therapy selection based on tumor biochemistry and
monitoring of therapy. Yttrium labeled octreotide could be a valuable alternative or additional
therapeutic option to the currently available conventional treatment modalities for tumors with
somatostatin receptors. Although experience with 90Y-DOTA-D-Phe1-Tyr3-octreotide therapy is
still limited, preliminary studies have demonstrated useful activity in tumors with positive
pentetreotide scans.
111
In-labeled Octreotide
111
In-
Apoptosis Imaging
Apoptosis is a cell death process characterized by morphological and biochemical features
occurring at different stages. Once triggered, apoptosis proceeds with different kinetics depending
upon the cell types and culminates with cell disruption and formation of apoptotic bodies. A
Nuclear medicine in diagnosis and therapy — An overview254
critical stage of apoptosis involves the acquisition of surface changes by dying cells that eventually
results in the recognition and uptake of these cells by phagocytes. Annexin V assay provides a
simple and effective method to detect apoptosis at a very early stage. Phosphatidylserine is
translocated from the inner (cytoplasmic) leaflet of the plasma membrane to the outer (cell
surface) leaflet soon after the induction of apoptosis. Annexin V protein has a strong, specific
affinity for phosphatidylserine & PS on the outer leaflet bends to labeled annexin V, providing
the basis for a simple staining assay.
Neoangiogenesis
Neoangiogenesis (i.e. blood vessel growth, vascularization) is stimulated when hypo-oxygenated
cells secrete factors that stimulate proliferation and migration of endothelial cells in an attempt
to restore oxygen homeostasis. It is a key event in tumor growth and metastasis, chronic
inflammatory disease, and cardiovascular disease. Tumors depend on sufficient blood supply for
their growth. They are able to promote new blood vessel formation (neoangiogenesis) via
angiogenic factors. Inhibition of this process results in tumor involution or necrosis. RGD (ArgGly-Asp) peptides are described to antagonize neoangiogenesis, e.g., by binding to alpha (v)
beta-3 receptors on blood vessels. In order to visualize neoangiogenesis in tumors in vitro and
in vivo, an RGD analogue [c (Arg-Gly-Asp-D-Tyr-Lys)], coupled to the chelator diethylene
triamine pentaacetic acid (DTPA) has been used. This analogue can be radiolabelled with both
111
In and
alpha (v) beta-3 receptors on neovascular blood vessel sections of different major human cancers,
like prostate and breast cancer, which express these receptors.
125
I. The
125
I-labelled analogue appears to bind specifically and with high affinity to
Tc- Aprotinin Scintigraphy
Amyloidosis is a disorder of protein metabolism in which protein is deposited extracellularly in
a charecterstic fibrillar pattern leading to gradual organ impairment, failure and death. Scintigraphy
is needed for assessing the distribution of lesions and assessing the response to therapy. TcAprotinin scintigraphy has been tested to be fairly sensitive and specific for this purpose. It acts
as a non-invasive modality to perform a whole body survey and also helps in localizing sites for
biopsy.
Gamma-detecting intra-operative probe
The Gamma-detecting intraoperative probe is a small, hand-held radiation-detecting device that
uses auditory signals and meter read-outs of counts detected. The intraoperative gamma probe
can be used effectively to improve diagnostic accuracy, to reduce operative time and decrease
perioperative morbidity.
References
1. Coltman JW, Marshall FH. Some characteristics of the photomultiplier radiation detector (abstract).
Phys Rev 1947; 72: 528.
Nuclear medicine in diagnosis and therapy — An overview 255
2. Cassen B, Curtis L, Reed C. A sensitive directional gamma ray detector. U.C.L.A. Report 49, University
of California, Los Angeles, 1949.
3. Cassen B, Curtis L, Reed C. A sensitive directional gamma ray detector. Nucleonics 1950; 6: 78.
4. Anger HO. The scintillation camera: a new instrument for mapping the distribution of radioactive
isotopes. U.C.R.L. Report 3845,1957.
5. Anger HO. Scintillation camera. Rev Sci Instrum 1958; 29: 27.
6. Kuhl DE, Edwards RQ. Image separation radioisotope scanning. Radiology 1963; 80: 653.
7. Ter-Pogossian MM, Phelps ME, Hoffman EJ, Multani NA. A positron emission transaxial tomography
for nuclear imaging (PETT). Radiology 1975; 114(1): 89-98.
8. Lorberboym M, Rahimi-Levene N, Lipszyc H, Kim CK. Analysis of red cell mass and plasma volume
in patients with polycythemia. Arch Pathol Lab Med 2005; 129(1): 89–91.
9. Baschieri L, Benedetti G, deLuca F, Negri M. Evaluation and limitations of the perchlorate test in the
study of thyroid function. J Clin Endocrinol Metab 1963; 23: 786-791.
10. Beirwaltes WH: Horizons in Radionuclide Therapy 1985 Update. J Nucl Med 1985; 26: 421-427.
11. Susan EM Clarke. Radioiodine Therapy of the Thyroid. Nuclear Medicine in Clinical Diagnosis and
Treatment. 2nd edition. eds. Murray IPC, Ell PJ, Van Der Wall Hans, H. William Strauss; Churchill
Livingstone, 1998; 1049-1062.
12. Cornelius A. Hoefnagel, Valerie J. Liwington. MIBG Therapy. Nuclear Medicine in Clinical Diagnosis
and Treatment. 2nd edition. eds. Murray IPC, Ell PJ, Van Der Wall Hans, H. William Strauss;
Churchill Livingstone 1998; 1067-1082.
13. Delbarre F, Cayla J, Menkes C. La synoviorthese par les radioisotopes. Presse Med 1968; 76(22):
1045-50.
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Part – III
Cyclotron, PET, CT and MRI
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Medical Cyclotron: Basic Principles and
Operation
G.S. Pant and S. Senthamizhchelvan
One of the most significant achievements of the 20th century is the development in
nuclear technology. Progress in nuclear physics in understanding the fundamental properties
of the nucleus has historically marched in steps with the progress in particle accelerators (1,
2). The first major development took place in 1934 with the invention of the cyclotron by
Ernest Lawrence in Berkeley, California. This development of physics has been optimally
utilized in medicine for the production of radioisotopes that are extremely useful for medical
diagnosis. This chapter describes the basic principle of a medical cyclotron and its operation
for radionuclide production.
Cyclotron
Cyclotrons are circular accelerators, which can accelerate charged particles to high energy.
Accelerated charged particles such as protons are used to produce positron emitting
radioisotopes. Production of radioisotopes involves collision between positively charged
particle and the nucleus of an atom. A high energy beam, of positively charged particles, is
required to overcome the repulsive force in approaching the target nucleus. The beam also
should have high intensity to increase the probability of collision between the charged
particles and the atomic nuclei.
In a conventional cyclotron the charged particles move in two semicircular metal
containers called dees (because of the D shaped electrodes) as shown in figure 1. In a
conventional cyclotron the ion beam experiences acceleration only while passing through
the gap between the dees. It is better to have more gaps to get more acceleration per orbit. In
most of the modern medical cyclotrons there are four gaps with four pie shaped dees (Figure
25 9
260
Medical Cyclotron: Basic Principles and Operation
2) instead of two. The particles pass through the same acceleration gap many times with
increasing radius before they acquire the desired energy. The entire accelerating system is
maintained at high vacuum (10–6 – 10–7 Torr) and the dees are housed in a vacuum chamber.
Hydrogen (or deuteron) gas is passed through an arc current to produce the ion source for
acceleration in the cyclotron. The ion source is pulled towards the centre of dee structure by
applying a bias voltage. A high voltage (>30 kV) is applied to the dee structure with the help
of an oscillator (radio frequency alternating potential in tens of MHz). The ion (or ions)
located at the center is thus attracted towards a dee that happens to be at opposite potential
at that particular moment. As the magnetic and electric fields (in dees) in the cyclotron are
at right angles to each other the ion beam moves in a circular path inside the hollow dees.
Figure 1: Schematic representation of a cyclotron
A potential difference is maintained between the dees that alternates in time with a
period (t). This potential difference creates an electric field across the gap between the dees.
The charged particles are initially attracted from the ion source near the center towards one
of the dees and move with a small velocity. They move in a semicircular path inside the dees
and arrive at the gap between dees after time (t/2). The alternating potential is adjusted so
that one of the dees is at an opposite potential with respect to the other when the particles
arrive at the gap between them. Each particle is therefore accelerated across the gap by the
electric field and gains energy. The ion beam gains energy by being attracted into, and
repelled from, as it passes through each dee edge. Therefore four dees will provide eight
acceleration per beam orbit. The main characteristic of the cyclotron is synchronization
between oscillating radio frequency (RF) field and the revolution frequency of charged
particles. The charged particles move in a circular orbit between two magnetic poles in a
plane known as the median plane.
GSPant\Newbook\Final-2008\17-chp\260
Medical Cyclotron: Basic Principles and Operation
Figure 2: Schematic representation of four pie shaped dees in a cyclotrons
261
Basic Principle
In a cyclotron a positive or negative ion beam is injected from the ion source into the centre
of the dee structure. It gets accelerated towards the dee that is at an opposite potential
relative to the ion beam at that instant. As the ion beam travels inside the hollow dee
electrode, its velocity remains constant because it does not experience any electric potential.
However it will encounter the magnetic field acting at right angle to the plane of its motion.
The operation of a cyclotron is based on the principle that the period of the motion of a
charged particle in a uniform magnetic field is independent of the velocity of the particle.
The particle moves in a circular path with a force equal to Bqv, where B is the magnetic
balanced by the centrifugal force of mv2/r, r being the radius of the orbit and m its mass.
Thus Bqv = mv2/r or r = mv/Bq (1)
This is the basic equation on which a cyclotron works. As has been explained, particles
get accelerated only in the gaps between the dees. It moves at a constant speed while inside
the hollow dee electrodes. As it passes the gap it gets accelerated and velocity increases.
The radius also increases according to equation-1. Assuming a true semicircular D, the
particle will traverse it in time (t) :
t = r/v (2)
or t = m/Bq (3) from eqn 1 and 2
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