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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 10-15

Medical cyclotron: Operational aspects and its clinical utility


1 Department of Nuclear Medicine, IGIMS, Patna, Bihar, India
2 Department of Medical Physics, IGIMS, Patna, Bihar, India
3 Department of Radiodiagnosis, IGIMS, Patna, Bihar, India
4 Director, IGIMS, Patna, Bihar, India

Date of Submission05-Nov-2021
Date of Acceptance07-Feb-2022
Date of Web Publication12-Feb-2022

Correspondence Address:
Rajeev Kumar
Department of Nuclear Medicine, IGIMS, Patna - 800 014, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jigims.jigims_45_21

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  Abstract 


Cyclotron is a type of particle accelerator invented by Ernest O. Lawrence in 1930 at the University of California, Berkeley and patented in 1932. Lawrence was awarded the Nobel Prize in Physics 1939 for this invention. It is based on a combination of radiofrequency acceleration and bending of charged particles in a magnetic field. This way the same electrode is used over and over again to give acceleration to the particles. Lawrence built the first cyclotron in 1931 and it produced Protons of 1.25 MeV. In a conventional Cyclotron, the charged particles move in two semicircular metal containers called Dees (because of the D-shaped electrodes). In most of the modern medical cyclotrons, there are four gaps with four pie-shaped Dees 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 to 10-8 Torr), and the Dees are housed in a vacuum chamber. Hydrogen gas is passed through an arc current to produce the ion source for the acceleration in the cyclotron. The ion source is pulled toward the center of Dee structure by applying a positive bias voltage. A high voltage (>36 kV) is applied to the Dee structure with the help of an oscillator. The ion located at the center is thus attracted toward a Dee that happens to be at the 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. In the present scenario, negative ion cyclotron accepted everywhere in the medical field. The objective of this article is to educate the new generation of physicians and share the knowledge of medical cyclotron and its integrity mainly among our colleague apart from nuclear medicine. Hence, that they can understand about this complex and complicated equipment and its medical utility for patients benefit.

Keywords: Fluorine-18-fludeoxyglucose, bias voltage, medical cyclotron, positron emission tomography/computerized tomography, radiopharmaceutical, radio frequency, tumor


How to cite this article:
Kumar R, Kumar A, Kumar S, Suman SK, Biswas NR. Medical cyclotron: Operational aspects and its clinical utility. J Indira Gandhi Inst Med Sci 2022;8:10-5

How to cite this URL:
Kumar R, Kumar A, Kumar S, Suman SK, Biswas NR. Medical cyclotron: Operational aspects and its clinical utility. J Indira Gandhi Inst Med Sci [serial online] 2022 [cited 2022 Aug 17];8:10-5. Available from: http://www.jigims.co.in/text.asp?2022/8/1/10/338364




  Introduction Top


In recent years, there has been a paradigm shift from traditional anatomic imaging to functional or metabolic imaging. Positron emission tomography (PET) is a diagnostic modality used to create high-resolution images of the distribution of a positron emitting radionuclides in the body. It is well-known that functional abnormalities occur in diseased cells much before structural changes. The early detection of functional changes helps in formulating optimal treatment strategies and subsequently leads to the significant reduction of morbidity and mortality.

PET involves the use of ultra-short-lived radioisotopes which have half-lives of few minutes to few hours [Table 1].[1],[2] These isotopes are required to be produced by using a particle accelerator called Medical Cyclotron [Figure 1] and [Figure 2].[3] Medical cyclotrons are circular accelerators in which the charged particles are accelerated to a high speed in a vacuum tank and made to bombard a specific target material [Figure 3] and [Figure 4].[3],[4] The cyclotron can accelerate both positively and negatively charged particles but negative ion cyclotrons are preferred for the production of positron-emitting radionuclides worldwide.[5]
Table 1: List of radioisotopes and radiopharmaceuticals

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Figure 1: Horizontal medical cyclotron

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Figure 2: Box diagram of self-shielded medical cyclotron

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Figure 3: Vertical medical cyclotron

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Figure 4: Self-shielded medical cyclotron

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According to the infrastructures, there are different types of Medical Cyclotron Facility [Table 2][3] [Dtiagrams 1 and 2].[3] At present, in India, we have approximately 25 Medical cyclotron facilities [Table 3] and [Table 4]. There are many more cyclotrons and PET/computerized tomography (CT) centers being planned and likely to be functional in near future. Very soon, India may have a sufficient number of PET/CT and medical cyclotron facilities to serve patients coming from far and remote places in the country.[6],[7]
Table 2: Types of medical cyclotron facility

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Table 3: Number of cyclotron (city wise)

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Table 4: Number of cyclotron (company wise)

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  Medical Cyclotron Top


Medical cyclotron comprises of six main components, namely:[4]

  1. Ion source system,
  2. Radiofrequency (RF) system
  3. Vacuum system
  4. Magnet system
  5. Target system
  6. Extraction system.







  Operational Aspects Top


The operation of a medical cyclotron is controlled by two computers, one located in the console room for operator and the second located inside the cyclotron room that actually executes various commands given by the operator. It also monitors the system status. Before initializing the system various parameters such as temperature, humidity, vacuum status, gas pressure [Table 5], exhaust system, power supply system and chiller status have to be checked and ensured that their water level is at optimal working levels. After initialization, the target is dried and checked for leakage. If the leak test is normal, then bombardment is started by selecting the desired radionuclide through the master computer, which loads the target material in the target assembly automatically. The required proton beam current, bias voltage, ion source gas flow, ion source current, and RF amplitude are selected and the bombardment process is started for desired duration depending upon the amount of activity required and saturation yield of the target. Once the radionuclide is produced it is unloaded from the target and transferred to the radiochemistry synthesis module for further synthesis of PET radiopharmaceuticals. After the transfer of activity, the target is rinsed. This helps to increase the life of the target as well as reduce the exposure level inside the cyclotron shield and make it possible to open the shield on the same day for servicing purposes (if required). Thereafter, shut down of the cyclotron is initiated.[8],[9]
Table 5: Optimum gas pressure required for smooth running of medical cyclotron

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The necessary environmental conditions are required for the smooth running of medical cyclotron:-

  • Ambient temperature 21°C (70° F) and tolerance ± 3°C (5° F)
  • Relative humidity 40%–55%, nonconditioning
  • Cyclotron exhaust 500 cfm
  • Chilled water (inlet water temperature 7°C ± 3°C (45° F ± 5° F).



  Finer Practical Aspects of Daily Protocol Top


Before the bombardment, it is wise to check the following crucial components:[7]

  • The amount of O-18 water in O-18 water bottle
  • Proper position of the target 1 and 2 to prevent any unwanted irradiation of the target which is not in use
  • Acknowledgment switch, whether it is ON or Not.


During bombardment, it is mandatory to monitor the progress of the bombardment and to keep an eye on the various parameters as displayed on the computer monitor. Monitoring of the target pressure during the entire period of bombardment is crucial, if any time there is a reduction in a target pressure, then the process of bombardment is immediately aborted. During the bombardment, the control and feedback parameter should match. If the RF amplitude does not getting the same feedback, then RF tuning is necessary for the same feedback.


  Positron Emission Tomography Radiopharmaceuticals for Clinical Use Top


There is a long list of cyclotrons produced PET radiopharmaceuticals. However, the majority of PET radiopharmaceuticals used in clinical practice are based on fluorine-18 ([18]F). The short positron range of 2.4 mm and physical half-life of 109.7 min make it suitable for better image quality and allow time for radiopharmaceutical synthesis and delivery of radiopharmaceuticals.

The 18O (p, n)18F is well-known nuclear reaction for the production of F-18 in cyclotron facility.[10]

2-deoxy-2-fluorine-18 fluoro-D-glucose

Replacing the hydroxyl group on position 2 of glucose with a hydrogen atom yields a glucose analog, 2-deoxy-D-glucose, that is taken up by cells through the glucose transporters in a competitive manner with glucose. Once inside the cell 2-deoxy-D-glucose is phosphorylated by hexokinase to form 2-deoxy-D-glucose-6-phosphate accumulates within the cell and is not metabolized further as glucose-6-phosphatase is very low or absent in most cancer cells.[10] 18F-fluoro-D-glucose (FDG) is workhorse of PET imaging in oncology. Warburg et al. reported that cancer cells have increased metabolism, increased glycolytic activity and even in the presence of oxygen produces lactic acid and can be traced using PET imaging. 18F-FDG PET/CT have wide horizon for diagnostic imaging apart from oncology as in infective and inflammatory diseases, neurological disorders such as dementia, movement disorders, and epilepsy and detection of viable ischemic myocardium.

18F-fluoride

It uses as a bone-seeking agent. Uptake mechanism is based on an ion exchange process, thereby each fluoride ion exchanges for an hydroxyl ion on the surface of the newly formed hydroxyapatite crystal, followed by chemisorptions into the crystalline matrix with prolonged retention. 18F-Fluoride uptake is increased in both sclerotic and lytic metastases.[11] 18F-Fluoride has also been used for evaluating atherosclerotic plaques.[12]

18F-fluoroethyl-l-tyrosine

It is transported across the cell membrane via specific L-amino acid transporter (LAT). This amino acid tracer is used for brain tumor imaging, to assess response of brain tumor after treatment and for tumor recurrence.

18F-fluoro-dihydroxyphenylalanine

It enters cells through amino acid transport systems (LAT1), it gets metabolized and stored in secretary vesicles. It is used to assess presynaptic dopaminergic dysfunction (in Parkinson's disease), to image brain tumors, medullary thyroid cancer, pheochromocytoma, paraganglioma, neuroblastoma, insulinoma, and congenital hyperinsulinemic hypoglycemia.[13]

18F-fluorothymidine

Thymidine is utilized by proliferating cells for DNA synthesis during the S-phase of the cell cycle. The intensity of 18F-fluorothymidine (FLT) uptake correlates with the extent Ki-67 expression (marker for cell proliferation). 18F-FLT uptake has been shown more tumors specific in various cancers (lung, breast, colon cancers, lymphoma, etc.), and it is also a potential imaging biomarker for response assessment.[14]

Perfusion PET tracers

13N-Ammonia

It has half-life of 9.96 min. It is lipophilic and diffuses into the myocardial cell and trapped by converting into 13N-Glutamine.[4] It is used as myocardial perfusion tracer and quantification of myocardial blood flow, coronary reserve, and brain tumor imaging.

15O-H2O

Ideal radiotracer for quantitative myocardial blood flow measurement. It diffuses freely across the cell membrane, with an extraction rate close to 100%. Its blood pool concentration is high, hence requires subtraction of blood pool activity from the original image.

18F-flurpiridaz

It is an analog of pyridaben an inhibitor of mitochondrial complex-1. It had shown superior image quality and higher diagnostic accuracy for myocardial perfusion imaging and quantification of myocardial blood flow and coronary reserve.[15]

11C-labeled tracers

Short physical half-life of 20 min limits its use to the centers that have on-site cyclotron facility.

11C-choline

Phospholipids are the essential component of the cell membrane and tumor cells have enhanced proliferation and utilize more substrate for the synthesis of the cell membrane. 11C-Choline is indistinguishable from native Choline and used in PET imaging in prostate cancer, parathyroid adenoma, and other malignancies.

11C-methionine

In cancer cells, amino acid transport is upregulated as the level of protein synthesis is increased. It has been mostly used for imaging brain tumors, mainly for differentiating tumor recurrence versus postradiation necrosis[16] localization of parathyroid adenoma, etc.


  Amyloid Imaging Agents Top


Alzheimer's disease is characterized by the formation of beta-amyloid protein and neuro fibrillary tangles. Definite diagnosis has been traditionally based on histopathology demonstration of beta-amyloid plaque on autopsy specimens. However, radiotracer targeting amyloid protein has demonstrated high diagnostic accuracy in identification in the prodromal phase of neurodegenerative disorders. 18F-labeled tracers are 18F-flutemetamol, 18F-Florbetapir, and 18F-florbetaben.[17]


  Conclusion Top


Medical cyclotron is complex equipment requiring delicate handling by highly trained personnel. The aim of this article is to highlight a few finer aspects of medical cyclotron operation, including precautions for the safety and smooth functioning of this sophisticated equipment. Medical cyclotron is the core of nuclear medicine department as it produces radiopharmaceuticals for diagnostic and therapeutic purpose in oncology. Apart from oncology, PET imaging also has a wide range of nononcological indications.

Acknowledgments

The authors would like to thank the staff of the Department of Nuclear Medicine and Cyclotron facility, AIIMS, New Delhi, India, Department of Nuclear Medicine and PET Facility Center, Army Hospital Research and Referral, New Delhi, India, and Medical Cyclotron Servicing team of molecular imaging, Siemens Limited India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Joliot F, Curie I. Artificial production of a new kind of radio-element. Nature 1934;133:201-2.  Back to cited text no. 1
    
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Livingston MS, Blewett JP. Particle Accelerators. New York: McGraw Hill Book Co, Inc; 1962. p. 80-105.  Back to cited text no. 2
    
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AERB Safety Guide no. AERB/RF/RS/SG-3; Medical Cyclotron Facilities. Atomic Energy Regulatory Board, India 12 January 2017. p. 1-20.  Back to cited text no. 3
    
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Satyamurthy N. Electronic generators. In: Phelps ME, editor. PET Molecular Imaging and its Biological Applications. USA: UCLA; 2004. p. 214.  Back to cited text no. 4
    
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Kumar R, Singh H, Jacob M, Anand SP, Bandopadhyaya GP. Production of nitrogen-13-labeled ammonia by using 11MeV medical cyclotron: Our experience. Hell J Nucl Med 2009;12:248-50.  Back to cited text no. 5
    
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Kumar R, Sonkawade RG, Tripathi M, Sharma P, Gupta P, Kumar P, et al. Production of the PET bone agent (18) F-fluoride ion, simultaneously with (18) F-FDG by a single run of the medical cyclotron with minimal radiation exposure – A novel technique. Hell J Nucl Med 2014;17:106-10.  Back to cited text no. 6
    
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Kumar R, Sonkawade RG, Pandey AK, Tripathi M, Damle NA, Kumar P, et al. Practical experience and challenges in the operation of medical cyclotron. Nucl Med Commun 2017;38:10-4.  Back to cited text no. 7
    
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Kaur A, Sharma S, Mittal BR.. Radiation Surveillance in and around cyclotron facility. Indian J Nucl Med 2012;27:243-5.  Back to cited text no. 8
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Kumar R, Sonkawade R, Jacob M, Pandit A, Singh D. Emergency handling in medical cyclotron facility. World J Nucl Med 2011;10:216-25.  Back to cited text no. 9
    
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Yu S. Review of F-FDG synthesis and quality control. Biomed Imaging Interv J 2006;2:e57.  Back to cited text no. 10
    
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Kawaguchi M, Tateishi U, Shizukuishi K, Suzuki A, Inoue T. 18F-fluoride uptake in bone metastasis: Morphologic and metabolic analysis on integrated PET/CT. Ann Nucl Med 2010;24:241-7.  Back to cited text no. 11
    
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Kwiecinski J, Slomka PJ, Dweck MR, Newby DE, Berman DS. Vulnerable plaque imaging using 18F-sodium fluoride positron emission tomography. Br J Radiol 2020;93:20190797.  Back to cited text no. 12
    
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Chondrogiannis S, Marzola MC, Rubello D. ¹8F-DOPA PET/computed tomography imaging. PET Clin 2014;9:307-21.  Back to cited text no. 13
    
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Sanghera B, Wong WL, Sonoda LI, Beynon G, Makris A, Woolf D, et al. FLT PET-CT in evaluation of treatment response. Indian J Nucl Med 2014;29:65-73.  Back to cited text no. 14
[PUBMED]  [Full text]  
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Moody JB, Poitrasson-Rivière A, Hagio T, Buckley C, Weinberg RL, Corbett JR, et al. Added value of myocardial blood flow using 18F-flurpiridaz PET to diagnose coronary artery disease: The flurpiridaz 301 trial. J Nucl Cardiol 2021;28:2313-29.  Back to cited text no. 15
    
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Tripathi M, Sharma R, Varshney R, Jaimini A, Jain J, Souza MM, et al. Comparison of F-18 FDG and C-11 methionine PET/CT for the evaluation of recurrent primary brain tumors. Clin Nucl Med 2012;37:158-63.  Back to cited text no. 16
    
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Barthel H, Sabri O. Clinical use and utility of amyloid imaging. J Nucl Med 2017;58:1711-7.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Abstract
Introduction
Medical Cyclotron
Operational Aspects
Finer Practical ...
Positron Emissio...
Amyloid Imaging ...
Conclusion
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