ERA 3: 1980 and beyond

Era 3 began at Vanderbilt around 1980, the time that the volume of clinical studies was increasing and research time diminished. Clinical and applied research mainly used equipment obtained with research funds. Industrial collaborations supported the development and testing of new devices for PET, and SPECT applications. New radiopharmaceuticals were tested clinically using tracers produced by the Hospital PET/Cyclotron facility (acquired and used since 1988). Radiopharmaceutical development increased and has been well-integrated with other clinical departments after the VUIIS program took over those developments.  There have since been major contributions to oncology and neuroscience based on the development and testing of novel ligand-bound tracers for optical, nuclear, and magnetic resonance imaging applications. During Era 3, molecular imaging was added to the title of the SNM to read Society of Nuclear Medicine and Molecular Imaging (SNMMI).

Molecular Medicine Focus:  The discovery of DNA dates back to the late 1800s but it was in 1953 that Watson and Crick determined its structure, and unraveled the nature of its code. By the 1980s, the exact code for an increasing number of humans, plants and animals was known. New insights emerged involving processes controlling growth and development, including fundamental determinants of life and death. The normal length of life is encoded and the number of cell divisions is predictable based on the telomere length of an individual’s chromosomes, and the individual’s telomerase activity. Genetic changes come about by spontaneous or induced mutations, that occur when the event type and frequency exceed the capacity of the body’s natural repair mechanisms. Chemicals, viruses, and radiation are known mediators of such changes by base alterations which determine the nature of the proteins and enzymes produced by cells, with characteristic surface markers. Chemicals also cause epigenetic changes, by methylation or demethylation of individual nucleotide bases, or conformational changes in the chromatin core which regulate the on or off state of normal or suppressed coding sequences. Growing knowledge of the cell signaling pathways that control cell function promises to aid in the diagnosis, treatment and repair of abnormal cells.  The development and use of drugs that target particular pathways now enable the treatment of some cancers. The poster child for this is Gleevec, a drug that was genetically engineered for the purpose of blocking tyrosine kinase activity in patients with a specific translocation defect that causes chronic granulocytic leukemia. Ligand-based tracers are now used to target cancers. Other strategies target tumor-associated vessels (anti-angiogenesis agents), by binding to surface markers or intracellular receptors that modulate cell function. Markers of hypoxia are also delineated within tumors, guiding external radiation therapy beams to optimize the delivered tumor-lethal dose.  The high sensitivity and specificity of radioisotope tracers is of key importance and allow real-time monitoring of functional changes. The use of high specific activity nanomolar drugs allows one to follow normal cell processes, with minimum damage to the processed being studied.

1980-2014: Medical imaging capabilities expanded including new instruments, tracers, and molecular targets, along with significant advances in X-ray Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and 4-D ultrasound systems, each with important diagnostic and therapeutic applications. Combined systems (hybrid devices) provided spatially registered anatomic (MRI, CT) and physiologic information (PET/SPECT, and (PET/MRI). Hybrid systems augment knowledge of biochemical and physiological data useful in diagnosis, and therapy. Complementary information facilitates attenuation and motion corrections. The important structural and functional information provided by MRI comes without added radiation dose to patients. Nuclear medicine’s high sensitivity and specificity comes from its use of high specific activity tracers coupled to high targeting affinity ligands. John Gore’s 2014 tabulation illustrates the intersection of the different current biomarkers with different imaging technologies.

New gains in patient outcome will likely follow the use of new MR, NM, US and optical ligand-bound tracers used for diagnostic and therapeutic uses.

Different task-based measures of system performance have moved beyond diagnosis, to include classification based on features extracted from planar and tomographic data. Current SPECT and PET systems make it possible to analyze 4-D slow time-varying transients. The ability to analyze fast transients, (especially through moving structures, i.e. heart/lungs) was first achieved using 3-D cylindrical systems with stationary detectors. Improved MRI protocols provide dynamic information on perfusion, and metabolism alone and in hybrid (PET/MR) systems. Challenging tasks include organ segmentation, and registration of organs and processes in time and space, followed by the extraction of parameters that are useful diagnosis and therapy guides. Imaging science and technology advanced rapidly in ERA 3. Imaging theory advanced from the foundations developed by Beck in the 1960/70s to concepts formulated later by Barrett et al. (Radiological Imaging The Theory of Image Formation, Detection, and Processing, Volume 1, 2 by Harrison H. Barrett and William Swindell (Jan 1982) and Foundations of Image Science by Harrison H. Barrett and Kyle J. Myers (Oct 24, 2003)).

Improvements in the acquisition and processing of data derive from the use of new types of collimation, detectors, electronics, computers and networks developed at nuclear research centers, like CERN, BNL, and UC/Berkeley. University groups in Europe and the USA were quick to adopt these ideas in new systems and approaches. Dynamic SPECT studies were first produced using slow and then fast rotating gamma cameras (Ref. Cellar, Gullberg). Barrett and his U. Arizona Center for Gamma Ray imaging (CGRI) colleagues pioneered in the use of modular gamma cameras, and, and cadmium zinc telluride (CZT) semi-conductors in multi detector stationary arrays surrounding the patient.  These provide ultra-high temporal and spatial resolution systems. The different generations of their systems are shown and discussed on the CGRI web site. The high space band width product (resolvable elements per unit area) obtained using multi pinhole collimators (coded apertures) produced figures of merit that for the first time exceeded the Anger camera.

The CGRI ideas were adopted and commercialized by scientists in Julich, Germany, Utrecht/Delft (The Netherlands), and Hungary. The Julich and Hungary approach used planar coded apertures as collimators in front of gamma cameras to produce 4-D dynamic SPECT images of patients, and small animals. The Milabs (Beekman) system uses multiple pinholes arrayed on a spherical shell surrounding small animals to create high spatial and temporal resolution images of brain, heart, tumors, bones in mice and rats given gamma and PET imaging tracers alone or in combinations.

Different SPECT geometries continued to evolve. The Michigan group led by Rogers and Clinthorne developed a multi detector ring systems  (SPRINT). Sebastian Genna developed an annular NaI camera for brain, and breast imaging.

Genna, S.; Smith, A.P.The development of ASPECT, an annular single crystal brain camera for high efficiency SPECT”. IEEE Transactions on Nuclear Science (1988). 35: 654 – 8.

Novel slit/slat camera collimator designs were developed and incorporated into commercial devices (see Recent Advance in SPECT Imaging by Mark T. Madsen). Several semi-conductor devices have been developed optimized for heart imaging using more efficient collimator designs resulting in important performance gains. Barrett and the Arizona group developed a fast 4D dynamic brain and then heart imaging devices (CGRI), and explored the use of multi-pinhole apertures. The best success was achieved with small animals, mice and rats by the Arizona group and by Freek Beekman, then in Utrecht. Beekman (Milabs) advanced the multi-pinhole technology using spherical collimators with ultra-small pin-holes focusing toward the center of the sphere where a small animal was placed and imaged. With the highest resolution collimators he was able to obtain 200-500 μm resolution in small regions, such as the heart or brain of a mouse. Heavily-shielded collimators allow simultaneous imaging of multiple gamma rays from single photon emitters, including the 511 keV gamma rays from PET tracers.

Commercial manufacturers picked up ideas from University-based research innovations and over the ensuing years added their own advanced multi-detector devices using arrays of focused detectors moved above and below patients to produce maps of organ uptake and whole-body distribution images. Some of the devices had multiple scanning detectors arrayed at different angles, each of which moved in different patterns about the patient. The major aim of these developments was to increase system sensitivity (by the adding imaging receptor area) and resolution (by improved spatial sampling) all of which can lead to improved image quality.
Advanced digital electronics materially improved gamma camera count rate performance as systems were able to acquire and process signals in real-time from the individual PMTs, and archive the list mode data. This has led to significant improvements in gamma camera count rate capability, and image resolution. It is now possible to use the same device for SPECT and PET as one can change the PMT pick off point and electronic gating differently for each application, something that Muehllehner was unable to do in his 1970s opposed gamma camera device. Wong introduced signal processing methods that made it possible to increase the count rate performance of gamma cameras to 2-4 MHz, instead of the 50-200 KHz of then current devices. (Wong ).  A commentary  places the work in context. Wong has gone on to design, and characterize a high performance relatively low cost TOF system that is being manufactured in China. A series of cross section brain images. images

Illustrate the high quality of images it produces.

Solid state imaging devices have been used in research applications since the 1970s, but have been slow to appear in commercial devices. Digirad attempted to introduce a cadmium zinc telluride (CZT) imaging receptor for cardiac applications in 1998. Difficulties in assembling large arrays impeded the commercial success and they switched to CsI. Several manufacturers in 2006 used CZT in tomographic devices. D SPECT introduced a novel approach using an ensemble of 8 tungsten collimated CZT detectors which are directed toward the heart. Each swings through an arc that covers only the cardiac emitting region. A novel slit/slat camera collimator designs was developed by Cardiarc (see Recent Advance in SPECT Imaging by Mark T. Madsen), along with other semi-conductor devices optimized for heart imaging. The but a rotating slit slot collimator sorts data from the different emitting regions resulting in increased sensitivity, providing improved images in shorter times.

Orthogonal strip Si(Li) and Ge(Li) detectors have been tested for research studies for low energy and high energy imaging respectively. The former have high potential for imaging of I-125 labeled compounds especially in animal studies. Compton Cameras have proven their value in astronomy by imaging planar distribution of high energy gamma rays from distant stars. Compton Cameras face a more difficult 3D imaging task in medical applications and despite much effort by talented researchers (Singh, Rogers and Clinthorne, and Walenta, a practical clinical device is still awaited. Recent technological advances in scintillators, solid state detectors, photomultipliers, avalanche photodiodes, and computer-based data acquisition, processing and display systems have accelerated progress since the initial work by Singh. New success is based on spin-offs from NASA, DOD and DOE research. Other advances are being realized from Astronomy developments using high resolution time projection chambers with Anger Camera absorption detectors for Compton Coincidence Imaging (CCI). Significant improvements in image reconstruction methods have been achieved extending List-Mode MLEM algorithms developed by Barrett and the Michigan group. Walesa and Brill worked together on the development of a Compton Camera since 1980 when they were both at Brookhaven National Lab. A NIH STTR grant provided Phase 1 funding for “High Energy Imaging in Support of Radionuclide Therapy”. The project failed to get Phase 2 approval due to failed commercialization support. The project was intended to provide dosimetry data  for  212Bi alpha particle based therapy of malignant melanoma.  CCI was to be used to image the emitted 208Tl 2.6 MeV gamma ray and thus to estimate absorbed dose from an alpha emitter.  A generator was proposed to enable use of 208Tl for cardiac imaging. The study included Heinrich Walenta, and VU collaborators Todd Peterson, Mike Stabin, and Randy.

In the United States, support from the Atomic Energy Commission, ERDA, and DOE (AEC’s subsequent embodiments) diminished steadily as the NIH took on a larger share of support for clinical uses of nuclear technology. NIH then supported research aimed at new understanding of biological and molecular mechanisms of disease, with emphasis on translational research (moving laboratory knowledge to the bed side to improve health care). Since 2010, the U.S. National Labs, once leaders in nuclear medicine research were no longer allowed to use DOE funds for animal/human research. Decreased research funding occurred when large expensive multi institutional studies were needed to establish data supporting evidence-based guidelines for best clinical practices. Increasing attention focuses on balancing costs with expected outcome benefits derived from the use of different imaging procedures in different clinical conditions. Standardization of imaging methods, and efficient means of delivering services, is part of ongoing technical maturation, as part of attempts to constrain the rate of growth of health care costs.

Medical imaging’s expanded capacity allows one to phrase and answer clinical questions on the nature, location and tumor stage, to guide treatment. Radiation Oncology practice uses nuclear medicine images of tumor features to guide dose delivery by external beams to hypoxic and proliferative regions. Intensity modulated external therapy has moved beyond electron accelerated photon sources to include accelerated heavy ions (protons and Hadrons) with the potential to measure in real-time the delivered dose. Hybrid systems that couple real-time spatial and temporal anatomic and physiologic information with therapy are of increasing importance as attention focuses on optimizing treatment outcome. The high sensitivity and specificity of the radioisotope method challenges scientists in non-nuclear areas to narrow the gap in sensitivity and specificity so that non-radioactive tracers can be used when needed to reduce unnecessary radiation dose to radiosensitive organs and populations.

Much of the molecular-based hypothesis testing is done in small animals, mice and rats. For this reason there have been a number of companies that have developed and marketed SPECT, PET, and MRI systems, alone and in combinations (hybrid systems). Siemens was the first, marketing systems developed by CTI/Knoxville up to the mid-2014. The remaining manufacturers and a description of the systems they market follows:

Bruker: www.bruker.com/products/preclinical-imaging.html

Cubresa (SPECT system): www.cubresa.com

Mediso: www.mediso.com

MILabs: www.milabs.com

Sofie Biosciences: www.sofiebio.com, and

TriFoil (preclinical half of former Gamma Medica-Ideas): www.trifoilimaging.com

A series of links on the history of nuclear medicine posted by Otha Linton, also describe moments in history, and provide discussion and illustrations of old and new radiological images.

In the United States, support from the AEC/DOE, diminished steadily as the NIH took on the larger share of support for further development of nuclear medicine. NIH supports research primarily directed at new understanding of mechanisms of disease, with new emphasis on translational research (moving laboratory knowledge to the bed side to improve health care delivery). Since 2010, the U.S. National Labs, once leaders in the field are no longer allowed to use DOE funds in support of animal/human research. Funding needs are likely to grow, as large multi institutional studies are developed to acquire data supporting evidence-based guidelines for best clinical practices. This is needed as increasing attention is given to justifying health care costs from the use of different imaging procedures in specific clinical conditions against expected benefits. Standardization of imaging methods, and the development of more efficient means of delivering high quality procedures, part of the ongoing attempts to constrain the rate of growth and costs of health care.

Medical imaging now allows one to phrase and answer important questions regarding the nature, location and tumor stage, needed to guide effective treatment. Radiation Oncology uses nuclear images of tumor features to guide dose delivered by external beams to hypoxic and proliferative regions. Intensity modulated external therapy has moved beyond electron accelerated photon sources to include accelerated heavy ions (protons and Hadrons) with a new opportunity  to measure real-time dose delivery. Hybrid systems that couple real-time spatial and temporal anatomic and physiologic information with therapy are of increasing importance as one strives to improve therapy outcome. The high sensitivity and specificity of the radiotracer method challenge scientists in non-nuclear areas to narrow the gap in sensitivity and specificity so that non-radioactive tracers can be developed and used especially in procedures involving unusually radiosensitive individuals.

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