Radiosurgery

This article is about the medical procedure. For the album by American rock band New Found Glory, see Radiosurgery (album).

Radiosurgery is surgery using radiation,[1] that is, the destruction of precisely selected areas of tissue using ionizing radiation rather than excision with a blade. Like other forms of radiation therapy, it is usually used to treat cancer. Radiosurgery was originally defined by the Swedish neurosurgeon Lars Leksell as “a single high dose fraction of radiation, stereotactically directed to an intracranial region of interest”.[2] In stereotactic radiosurgery (SRS), the word stereotactic refers to a three-dimensional coordinate system that enables accurate correlation of a virtual target seen in the patient's diagnostic images with the actual target position in the patient

Technological improvements in medical imaging and computing have led to increased clinical adoption of stereotactic radiosurgery and have broadened its scope in recent years.[3][4] Notwithstanding these improvements, the localization accuracy and precision that are implicit in the word “stereotactic” remain of utmost importance for radiosurgical interventions today. Stereotactic accuracy and precision are significantly increased by using a device known as the N-localizer[5][6][7][8][9][10] that was invented by the American physician and computer scientist Russell Brown and that has achieved widespread clinical use in several stereotactic surgical[11][12][13][14][15] and radiosurgical systems.

Recently, the original concept of radiosurgery has been expanded to include treatments comprising up to five fractions, and stereotactic radiosurgery has been redefined as a distinct neurosurgical discipline that utilizes externally generated ionizing radiation to inactivate or eradicate defined targets in the head or spine without the need for a surgical incision.[16] Irrespective of the similarities between the concepts of stereotactic radiosurgery and fractionated radiotherapy, and although both treatment modalities are reported to have identical outcomes for certain indications,[17] the intent of both approaches is fundamentally different. The aim of stereotactic radiosurgery is to destroy target tissue while preserving adjacent normal tissue, where fractionated radiotherapy relies on a different sensitivity of the target and the surrounding normal tissue to the total accumulated radiation dose.[16] Historically, the field of fractionated radiotherapy evolved from the original concept of stereotactic radiosurgery following discovery of the principles of radiobiology: repair, reassortment, repopulation, and reoxygenation.[18] Today, both treatment techniques are complementary as tumors that may be resistant to fractionated radiotherapy may respond well to radiosurgery and tumors that are too large or too close to critical organs for safe radiosurgery may be suitable candidates for fractionated radiotherapy.[17]

History

Stereotactic radiosurgery was first developed in 1949 by the Swedish neurosurgeon Lars Leksell to treat small targets in the brain that were not amenable to conventional surgery. The initial stereotactic instrument he conceived used probes and electrodes.[19] The first attempt to supplant the electrodes with radiation was made in the early fifties, with x-rays.[20] The principle of this instrument was to crossfire the intra-cranial target from multiple directions with narrow beams of radiation. The beam paths converge in the target volume, delivering a lethal cumulative dose of radiation, while limiting the dose to the adjacent healthy tissue. Ten years later significant progress had been made, due in considerable measure to the contribution of the physicists Kurt Liden and Borje Larsson.[21] At this time, stereotactic proton beams had replaced the x-rays.[22] The heavy particle beam presented as an excellent replacement for the surgical knife but the synchrocyclotron was too clumsy. Dr. Leksell set his mind on the development of a practical, compact, precise and simple tool which could be handled by the surgeon himself. In 1968, this resulted in the Gamma Knife, which was installed at the Karolinska Institute and consisted of several radioactive sources of cobalt-60 placed in a kind of helmet with central channels for irradiation with gamma rays.[23] This prototype was designed to produce slit-like radiation lesions for functional neurosurgical procedures to treat pain, movement disorders, or behavioral disorders that did not respond to conventional treatment. The success of this first unit led to the construction of a second device, containing 179 cobalt-60 sources. This second gamma knife unit was designed to produce spherical lesions to treat brain tumors and intracranial arteriovenous malformations AVMs.[24] In the 1980s the third and fourth units (with 201 cobalt-60 sources) were installed in Buenos Aires, Argentina, and Sheffield, England.[25] The fifth gamma knife was installed at the University of Pittsburgh Medical Center in Pittsburgh in 1987.

In parallel to these developments, a similar approach was designed for a linear particle accelerator or Linac. Installation of the first 4 mega electronvolt (MeV) clinical linear accelerator began in June 1952 in the Medical Research Council (MRC) Radiotherapeutic Research Unit at the Hammersmith Hospital, London.[26] The system was handed over for physics and other testing in February 1953 and began to treat patients on 7 September that year. Meanwhile, work by at the Stanford Microwave Laboratory led to the development of a 6-MV accelerator, which was installed at Stanford University Hospital, California, in 1956.[27] Linac units quickly became favored devices for conventional fractionated radiotherapy but it lasted until the eighties of last century before dedicated Linac radiosurgery became a reality. In 1982, the Spanish neurosurgeon J. Barcia-Salorio began to evaluate the role of cobalt-generated and then Linac-based photon radiosurgery for the treatment of AVMs and epilepsy.[28] In 1984, Betti and Derechinsky described a Linac-based radiosurgical system.[29] Winston and Lutz further advanced Linac-based radiosurgical prototype technologies by incorporating an improved stereotactic positioning device and a method to measure the accuracy of various components.[30] Using a modified Linac, the first patient in the United States was treated at in Boston Brigham and Women's Hospital in February 1986.

Today, both Gamma Knife and Linac radiosurgery programs are commercially available worldwide. While the Gamma Knife is dedicated to radiosurgery, most Linacs are build for conventional fractionated radiotherapy and require additional technology and expertise to become dedicated radiosurgery tools. This is exemplified by the Novalis Radiosurgery Program, designed to complement conventional Linacs with sophisticated beam shaping technology, treatment planning solutions and image-guidance tools to warrant highest treatment accuracy. An example of a dedicated radiosurgery Linac is the CyberKnife, a compact Linac mounted onto a robotic arm that moves around the patient and irradiates the tumor from a large set of fixed positions, thereby mimicking the Gamma Knife concept.

Clinical applications

Radiosurgery is performed by a multidisciplinary team of radiation oncologists, and medical physicists to operate and maintain highly sophisticated, highly precise and complex instruments, like medical Linacs and the Gamma Knife. The highly precise irradiation of targets within the brain and spine is planned using information from medical images that are obtained via computed tomography, magnetic resonance, and angiography.

Radiosurgery is indicated primarily for the therapy of tumors, vascular lesions and functional disorders. Significant clinical judgment must be used with this technique and considerations must include lesion type, pathology if available, size, location and age and general health of the patient. General contraindications to radiosurgery include excessively large size of the target lesion or lesions too numerous for practical treatment. Patients can be treated within one to five days and on an outpatient basis. By comparison, the average hospital stay for a craniotomy (conventional neurosurgery, requiring the opening of the skull) is about 15 days. Radiosurgery outcome may not be evident until months after the treatment. Since radiosurgery does not remove the tumor, but results in a biological inactivation of the tumor, lack of growth of the lesion is normally considered to be treatment success. General indications for radiosurgery include many kinds of brain tumors, such as acoustic neuromas, germinomas, meningiomas, metastases, trigeminal neuralgia, arteriovenous malformations and skull base tumors, among others. Expansion of stereotactic radiotherapy to extracranial lesions is increasing, and includes metastases, liver cancer, lung cancer, pancreatic cancer, etc.

Mechanism of action

Planning CT scan with IV contrast in a patient with left cerebellopontine angle vestibular schwannoma

The fundamental principle of radiosurgery is that of selective ionization of tissue, by means of high-energy beams of radiation. Ionization is the production of ions and free radicals which are usually deleterious to the cells. These ions and radicals, which may be formed from the water in the cell or from the biological materials can produce irreparable damage to DNA, proteins, and lipids, resulting in the cell's death. Thus, biological inactivation is carried out in a volume of tissue to be treated, with a precise destructive effect. The radiation dose is usually measured in grays, where one gray (Gy) is the absorption of one joule per kilogram of mass. A unit that attempts to take into account both the different organs that are irradiated and the type of radiation is the sievert, a unit that describes both the amount of energy deposited and the biological effectiveness.

Risks

According to a December 2010 article in The New York Times, radiation overdoses have occurred with the linear accelerator method of radiosurgery, in large part due to inadequate safeguards in equipment retrofitted for stereotactic radiosurgery.[31] The U.S. Food and Drug Administration (FDA) regulates these devices, whereas the Gamma Knife is regulated by the Nuclear Regulatory Commission. The NYT article focuses on Varian equipment and associated software, but the problem is not likely limited to that manufacturer.

Types of radiation source

The selection of the proper kind of radiation and device depends on many factors including lesion type, size and location in relation to critical structures. Data suggest that similar clinical outcomes are possible with all of the various techniques. More important than the device used are issues regarding indications for treatment, total dose delivered, fractionation schedule and conformity of the treatment plan.

Gamma Knife

"Gamma Knife" redirects here. For the album by Kayo Dot, see Gamma Knife (album).
NRC graphic of the Leksell Gamma Knife

The Gamma Knife (also known as the Leksell Gamma Knife), a creation of Elekta AB, a Swedish public company, is used to treat brain tumors by administering high-intensity cobalt radiation therapy in a manner that concentrates the radiation over a small volume. The device was invented in 1967 at the Karolinska Institute in Stockholm, Sweden, by Lars Leksell, Ladislau Steiner, a Romanian-born neurosurgeon, and Börje Larsson, a radiobiologist from Sweden's Uppsala University.

A Gamma Knife typically contains 201 cobalt-60 sources of approximately 30 curies (1.1 TBq), each placed in a circular array in a heavily shielded assembly. The device aims gamma radiation through a target point in the patient's brain. The patient wears a specialized helmet that is surgically fixed to the skull, so that the brain tumor remains stationary at the target point of the gamma rays. An ablative dose of radiation is thereby sent through the tumor in one treatment session, while surrounding brain tissues are relatively spared.

Gamma Knife therapy, like all radiosurgery, uses doses of radiation to kill cancer cells and shrink tumors, delivered precisely to avoid damaging healthy brain tissue. Gamma Knife radiosurgery is able to accurately focus many beams of gamma radiation to converge on one or more tumors. Each individual beam is of relatively low intensity, so the radiation has little effect on intervening brain tissue and is concentrated only at the tumor itself.

Gamma Knife radiosurgery has proven effective for patients with benign or malignant brain tumors up to 4 centimeters in size, vascular malformations such as an arteriovenous malformation (AVM), pain or other functional problems.[32][33][34][35] For treatment of trigeminal neuralgia, the procedure may be used repeatedly on patients.

Acute complications following gamma knife radiosurgery are rare,[36] and complications are related to the condition being treated.[37][38]

Linear accelerator based therapies

Main article: megavoltage X-rays

These systems differ from the Gamma Knife in a variety of ways. The Gamma Knife produces gamma rays from the decay of Co-60 of an average energy of 1.25 MeV. A LINAC produces x-rays from the impact of accelerated electrons striking a high z target (usually tungsten). A LINAC therefore can generate any number of energy x-rays, though usually 6 MV photons are used. The Gamma Knife has over ~200 sources arrayed in the helmet to deliver a variety of treatment angles. On a LINAC, the gantry moves in space to change the delivery angle. Both can move the patient in space to also change the delivery point. Both systems use a stereotactic frame to restrict the patient's movement, although on the Novalis Shaped Beam Radiosurgery system and the Novalis Tx Radiosurgery platform, Brainlab pioneered a frameless, non-invasive technique with X-ray imaging that has proven to be both comfortable for the patient and accurate. The Trilogy from Varian, or CyberKnife from Accuray, can also be used with non-invasive immobilization devices coupled with real-time imaging to detect any patient motion during a treatment.

Linear accelerators emit high energy X-rays, usually referred to as "X-ray therapy" or "photon therapy." The term "gamma ray" is usually reserved for photons that are emitted from a radioisotope such as cobalt-60 (see below). Such radiation is not substantially different from that emitted by high voltage accelerators. In linear accelerator therapy, the emission head (called "gantry") is mechanically rotated around the patient, in a full or partial circle. The table where the patient is lying, the 'couch', can also be moved in small linear or angular steps. The combination of the movements of the gantry and of the couch makes possible the computerized planning of the volume of tissue that is going to be irradiated. Devices with an energy of 6 MeV are the most suitable for the treatment of the brain, due to the depth of the target. In addition, the diameter of the energy beam leaving the emission head can be adjusted to the size of the lesion by means of interchangeable collimators (an orifice with different diameters, varying from 5 to 40 mm, in steps of 5 mm). There are also multileaf collimators, which consist of a number of metal leaflets that can be moved dynamically during treatment in order to shape the radiation beam to conform to the mass to be ablated. Latest generation Linacs are capable of achieving extremely narrow beam geometries, such as 0.15 to 0.3 mm. Therefore, they can be used for several kinds of surgeries which hitherto have been carried out by open or endoscopic surgery, such as for trigeminal neuralgia, etc. The exact mechanism of its effectiveness for trigeminal neuralgia is not known; however, its use for this purpose has become very common. Long term followup data has shown it to be as effective as radiofrequency ablation but inferior to surgery as far as recurrence rate for pain is concerned.

A type of linear accelerator therapy which uses a small accelerator mounted on a moving arm to deliver X-rays to a very small area which can be seen on fluoroscopy, is called Cyberknife therapy. Several generations of the frameless robotic Cyberknife system have been developed since its initial inception in 1990. It was invented by John R. Adler, a Stanford University Professor of Neurosurgery and Radiation Oncology and Russell and Peter Schonberg at SCHONBERG RESEARCH, and is sold by the Accuray company, located in Sunnyvale, California. Many such CyberKnife systems are available world-wide, and more recently it has been introduced in countries like India at leading cancer care hospitals like Apollo Specialty hospitals and HCG Bangalore Institute of Oncology.

Cyberknife may be compared to Gamma Knife therapy (see above), but it does not use radioisotopes and thus by definition, does not use gamma rays. It also does not use a frame to hold the patient, as a computer monitors the patient's position during treatment, using fluoroscopy. The robotic concept of Cyberknife radiosurgery allows for tracking the tumor, rather than fixing the patient with a stereotaxic frame. Since no frame is needed, some of the radiosurgical concepts can be extented to treat extracranial tumors. In this case, the Cyberknife robotic arm tracks the tumor motion (i.e. respiratory motion).[39] A combination of stereo x-ray imaging and infrared tracking sensors determines the tumor position in real-time.

Proton beam therapy

Main article: Proton therapy

Protons may also be used in radiosurgery in a procedure called Proton Beam Therapy (PBT) or simply proton therapy. Protons are produced by a medical synchrotron or cyclotron, extracting them from proton donor materials and accelerating them in successive travels through a circular, evacuated conduit or cavity, using powerful magnets, until they reach sufficient energy (usually about 200 MeV) to enable them to approximately traverse a human body, then stop. They are then released toward the irradiation target which is region in the patient's body. In some machines, which deliver only a certain energy of protons, a custom mask made of plastic will be interposed between the initial beam and the patient, in order to adjust the beam energy for a proper amount of penetration. The phenomenon of the Bragg peak of ejected protons gives proton therapy advantages over other forms of radiation, since most of the proton's energy is deposited within a limited distance, so tissue beyond this range (and to some extent also tissue inside this range) is spared from the effects of radiation. This property of protons, which has been called the "depth charge effect" by analogy to the explosives used in anti-submarine warfare, allows for conformal dose distributions to be created around even very irregularly shaped targets, and for higher doses to targets surrounded or backstopped by radiation-sensitive structures such as the optic chiasm or brainstem. In recent years, however, "intensity modulated" techniques have allowed for similar conformities to be attained using linear accelerator radiosurgery.

Notes

  1. ↑ Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier.
  2. ↑ Leksell, Lars (December 1951). "The stereotaxic method and radiosurgery of the brain". Acta Chirurgica Scandinavica 102 (4): 316–9. PMID 14914373.
  3. ↑ De Salles, A (2008). "Radiosurgery from the brain to the spine: 20 years experience". Acta neurochirurgica. Supplement 101: 163–168. doi:10.1007/978-3-211-78205-7_28. PMID 18642653.
  4. ↑ Timmerman, Robert (2006). "Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer". Journal of clinical oncology 24 (30): 4833–9. doi:10.1200/JCO.2006.07.5937. PMID 17050868.
  5. ↑ Brown, Russell A. (1979). "A computerized tomography-computer graphics approach to stereotaxic localization". Journal of Neurosurgery 50 (6): 715–20. doi:10.3171/jns.1979.50.6.0715. PMID 374688.
  6. ↑ Brown, Russell A. (1979). "A stereotactic head frame for use with CT body scanners". Investigative Radiology 14 (4): 300–4. doi:10.1097/00004424-197907000-00006. PMID 385549.
  7. ↑ Brown RA, Nelson JA (2012). "Invention of the N-localizer for stereotactic neurosurgery and its use in the Brown-Roberts-Wells stereotactic frame". Neurosurgery 70 (2 Supplement Operative): 173–176. doi:10.1227/NEU.0b013e318246a4f7. PMID 22186842.
  8. ↑ Brown RA, Nelson JA (2015). "The origin and history of the N-localizer for stereotactic neurosurgery". Cureus 7 (9): e323. doi:10.7759/cureus.323. PMID 26487999.
  9. ↑ Brown RA (2015). "The mathematics of three N-localizers used together for stereotactic neurosurgery". Cureus 7 (10): e341. doi:10.7759/cureus.341. PMID 26594605.
  10. ↑ Brown RA (2015). "The mathematics of four or more N-localizers for stereotactic neurosurgery". Cureus 7 (10): e349. doi:10.7759/cureus.349. PMID 26623204.
  11. ↑ Brown RA, Roberts TS, Osborn AG (1980). "Stereotaxic frame and computer software for CT-directed neurosurgical localization". Investigative Radiology 15 (4): 308–12. doi:10.1097/00004424-198007000-00006. PMID 7009485.
  12. ↑ Leksell L, Jernberg B (1980). "Stereotaxis and tomography. A technical note.". Acta Neurochirugica 52 (1-2): 1–7. doi:10.1007/BF01400939. PMID 6990697.
  13. ↑ Heilbrun MP, Roberts TS, Apuzzo ML, Wells TH Jr, Sabshin JK (August 1983). "Preliminary experience with Brown-Roberts-Wells (BRW) computerized tomography stereotaxic guidance system". Journal of Neurosurgery 59 (2): 217–222. doi:10.3171/jns.1983.59.2.0217. PMID 6345727.
  14. ↑ Thomas DG, Anderson RE, du Boulay GH (January 1984). "CT-guided stereotactic neurosurgery: experience in 24 cases with a new stereotactic system". Journal of Neurology, Neurosurgery & Psychiatry 47 (1): 9–16. doi:10.1136/jnnp.47.1.9. PMC 1027634. PMID 6363629.
  15. ↑ Couldwell WT, Apuzzo ML (1990). "Initial experience related to the Cosman-Roberts-Wells stereotactic instrument. Technical note". Journal of Neurosurgery 72 (1): 145–8. doi:10.3171/jns.1990.72.1.0145. PMID 2403588.
  16. 1 2 Barnett, Gene H. (2007). "Stereotactic radiosurgery-an organized neurosurgery-sanctioned definition". Journal of Neurosurgery 106 (1): 1–5. doi:10.3171/jns.2007.106.1.1. PMID 17240553.
  17. 1 2 Combs, Stephanie (2010). "Differences in clinical results after LINAC-based single-dose radiosurgery versus fractionated stereotactic radiotherapy for patients with vestibular schwannomas". International journal of radiation oncology, biology, physics 76 (1): 193–200. doi:10.1016/j.ijrobp.2009.01.064. PMID 19604653.
  18. ↑ Bernier, Jacques (2004). "Radiation oncology: a century of achievements". Nature reviews. Cancer 4 (9): 737–747. doi:10.1038/nrc1451. PMID 15343280.
  19. ↑ Leksell, Lars (1949). "A stereotaxic apparatus for intracerebral surgery". Acta Chirurgica Scandinavica 99: 229.
  20. ↑ Leksell, Lars (December 1951). "The stereotaxic method and radiosurgery of the brain". Acta chirurgica Scandinavica 102 (4): 316–9. PMID 14914373.
  21. ↑ Larsson, Borje (1958). "The high-energy proton beam as a neurosurgical tool". Nature 182 (4644): 1222–3. doi:10.1038/1821222a0. PMID 13590280.
  22. ↑ Leksell, Lars (October 1960). "Lesions in the depth of the brain produced by a beam of high energy protons". Acta Radiologica 54: 251–64. doi:10.3109/00016926009172547. PMID 13760648.
  23. ↑ Leksell, Lars (September 1983). "Stereotactic Radiosurgery". Journal of Neurology, Neurosurgery & Psychiatry 46 (9): 797–803. doi:10.1136/jnnp.46.9.797. PMID 6352865.
  24. ↑ Wu, Andrew (April 1990). "Physics of Gamma Knife approach on convergent beams in stereotactic radiosurgery". International journal of radiation oncology, biology, physics 18 (4): 941–949. doi:10.1016/0360-3016(90)90421-f.
  25. ↑ Walton, L (1987). "The Sheffield stereotactic radiosurgery unit: physical characteristics and principles of operation". British Journal of Radiology 60: 897–906. doi:10.1259/0007-1285-60-717-897.
  26. ↑ Fry, D.W. (1948). "A traveling wave linear accelerator for 4 MeV electrons". Nature 162 (4126): 859–61. doi:10.1038/162859a0. PMID 18103121.
  27. ↑ Bernier, J (2004). "Radiation oncology: a century of achievements". Nature Reviews. Cancer 4 (9): 737–47. doi:10.1038/nrc1451. PMID 15343280.
  28. ↑ Barcia-Salorio, J.L. (1982). "Radiosurgical treatment of carotid-cavernous fistula". Applied Neurophysiology 45: 520–522. doi:10.1159/000101675.
  29. ↑ Betti, O.O. (1984). "Hyperselective encephalic irradiation with a linear accelerator". Acta Neurochirurgica Supplement (Wien) 33: 385–390. doi:10.1007/978-3-7091-8726-5_60.
  30. ↑ Winston, K.R. (1988). "Linear accelerator as a neurosurgical tool for stereotactic radiosurgery". Neurosurgery 22: 454–464. doi:10.1227/00006123-198803000-00002.
  31. ↑ "A Pinpoint Beam Strays Invisibly, Harming Instead of Healing". The New York Times. 2010-12-28.
  32. ↑ Régis J, Bartolomei F, Hayashi M, Chauvel P (2002). "What role for radiosurgery in mesial temporal lobe epilepsy". Zentralbl. Neurochir. 63 (3): 101–5. doi:10.1055/s-2002-35824. PMID 12457334.
  33. ↑ Kwon Y, Whang CJ (1995). "Stereotactic Gamma Knife radiosurgery for the treatment of dystonia". Stereotact Funct Neurosurg. 64 Suppl 1: 222–7. PMID 8584831.
  34. ↑ Donnet A, Valade D, Régis J (February 2005). "Gamma knife treatment for refractory cluster headache: prospective open trial". J. Neurol. Neurosurg. Psychiatr. 76 (2): 218–21. doi:10.1136/jnnp.2004.041202. PMC 1739520. PMID 15654036.
  35. ↑ Herman JM, Petit JH, Amin P, Kwok Y, Dutta PR, Chin LS (May 2004). "Repeat gamma knife radiosurgery for refractory or recurrent trigeminal neuralgia: treatment outcomes and quality-of-life assessment". Int. J. Radiat. Oncol. Biol. Phys. 59 (1): 112–6. doi:10.1016/j.ijrobp.2003.10.041. PMID 15093906.
  36. ↑ Chin LS, Lazio BE, Biggins T, Amin P (May 2000). "Acute complications following gamma knife radiosurgery are rare". Surg Neurol 53 (5): 498–502; discussion 502. doi:10.1016/S0090-3019(00)00219-6. PMID 10874151.
  37. ↑ Stafford SL, Pollock BE, Foote RL, et al. (November 2001). "Meningioma radiosurgery: tumor control, outcomes, and complications among 190 consecutive patients". Neurosurgery 49 (5): 1029–37; discussion 1037–8. doi:10.1097/00006123-200111000-00001. PMID 11846894.
  38. ↑ Cho DY, Tsao M, Lee WY, Chang CS (May 2006). "Socioeconomic costs of open surgery and gamma knife radiosurgery for benign cranial base tumors". Neurosurgery 58 (5): 866–73; discussion 866–73. doi:10.1227/01.NEU.0000209892.42585.9B. PMID 16639320.
  39. ↑ Schweikard Achim, Shiomi Hiroya, Adler John (2004). "Respiration tracking in radiosurgery". Medical physics 31 (10): 2738–2741. doi:10.1118/1.1774132. PMID 15543778.

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