Nuclear medicine 2000" Otmar Schober Department of Nuclear Medicine, Westf&lische Wilhelms-Universit&t, W-4400 MOnster, Federal RepuNic of Germany
What will nuclear medicine be like in 2000 A.D.? Prophktes, phgmai means a narrow way between Delphi, Job and valuable routine clinical work. The aim of our work, the destiny of "nuclear medicine 2000", is clinical medicine, with benefit for the individual patient. Over 10 years ago Budinger (•980) concluded that the development of single photon instrumentation and its applications had a high likelihood of success in studies of the brain, but not of the thorax or abdomen, in adults. Potential applications of single-photon emission tomography (SPET) in quantitative studies of the brain using acceptable doses should include:
phy equipment (SPET/PET) has found its way from scientific studies to routine work (8 vs 58, •980 vs •990) (Fig. 1 c). In •990, 15% of the studies in our department were performed by single photon tomographs. The scientific work on monoclonal antibodies (0 vs 22, •980 vs 1990) yields clinical information more in benign diseases, for example in the diagnosis of inflammation, than in the study of tumours.
1. Brain blood volume using technetium 99m (99roTe)labelled red blood cells 2. Brain blood perfusion using iodine 123 (123I)-iodoantipyrine or other lipid-soluble radiopharmaceuticals 3. Brain perfusion studies using inhaled xenon 133 and 127 (133Xe and 127Xe) 4. Dopamine receptor site evaluation using t23I-phentylamine radiopharmaceuticals 5. Measurement of physiological conditions in the brain
Future developments will include an annular single crystal camera for the whole body, with better spatial resolution and the ability for fast dynamic tomographic studies (Holman et al. •990). Why do we still rely on the present technology of absorptive collimation? We should hope that engineers and industry will develop a new detector system based on new technology for localization. By improving detector efficiency by a factor of 1000, we could perform a bone scan with 1 MBq of 99mTc-MDP. The expectation for spatial resolution in PET will be in the range of 3 mm, but the sensitivity and count rate capabilities will be improved by software and hardware innovations (Budinger •990). Overlay techniques, to compare functional data with morphological maps, will be necessary and improve efficacy and efficiency of nuclear medicine methods. Simulations (modelling) of advanced expanded and expensive instrumentation will play an important role (Jordan et al. •989). Knowledge of the constraints of our methods will serve and improve our quality control (Mfiller et al. •990). The increasing number of PET centres and papers presented at scientific congresses reflect future developments. However, future in a positive sense is based on quality; the many centres that have sophisticated instrumentation (" me, too") and publish studies that are not clinically oriented (publish or perish approach) are dangerous to nuclear medicine (Ell 1990).
Six years after the appearance of Budinger's report, Wagner (1986) stated that in the foreseeable future nuclear medicine will be based on the use of tracers for positron emission tomography, with the technology diffusing outward from this core. Clinical demand is not reflected in human studies and clinical publications Scientific clinical studies do not predict the weight and numbers of the studies done in the clinical routine 10 years later (Fig. 1 a, b). The discrepancy is most remarkable between the scientific interest in diseases of the central nervous system, the gastrointestinal tract and the thyroid, which is particularly relevant in Germany because of the iodine deficit in the food in this region. The number of papers on radioimmunoassays (RIAs) in the Journal of Nuclear Medicine and the European Journal of Nuclear Medicine is rapidly decreasing (13 vs 1, 1980 vs 1990), and this may reflect scientific interest in nuclear medicine in our journals. Emission tomogra* Given in part as an invited lecture at the German Nuclear Medicine Congress in T/ibingen 1991.
Radiopharmaceuticals The quantitative structure activity relationship (QSAR), computer-assisted electron clouds, will provide Eur J Nucl Med (1992) 1 9 : 1 - 5
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skeleton kidney infection
1980 (other 28%)
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a new sophisticated method and is one of the keys to radiochemistry in 2000 A.D. (Allen et al. 1990). New tracers, such as labelled somatostatin analogues, microglobulins and labelled receptors, will give new insights into clinical problems (Burchert etal. 1991; Krenning et al. 1989; Schober et al. 1990). Radiochemists will learn from positron-emitting labelled substances (e.g. 76Br vs lz3I-Lisuride) and, with improved understanding of metabolic pathways and biochemistry, will find gamma-emitting pharmaceuticals that are strongly and specifically related to glucose and oxygen metabolism, as demonstrated for myocardial blood flow and carbon 11 (1 ~C)-acetate (Gropler et al. 1991).
Basic research and clinical science
35 30 25 20 15 10 5 0
skeleton kidney infection
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WWU 1990 (n=lO.000) other 2%
70 60 50 40 30 22
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Fig. 1. a Respectivenumbers of clinicallyoriented studies published in the Journal of Nuclear Medicine and the European Journal of Nuclear Medicine in the years 1980 versus 1990. b Number of in vivo examinationsperformedin the Federal Republic of Germany as a whole (estimated to be 2000000; Pretschner 1980) compared with our universityhospital (10000 in vivo examinationsin 1990). e Method developmentin absolute numbers, publishedin the Journal of Nuclear Medicine and the European Journal of Nuclear Medicine in the years 1980 versus 1990
The ratios of frontal versus occipital regional cerebral metabolic rates of glucose (rCMRGlc) are significantly elevated during yoga meditative relaxation. These altered ratios, caused by a slight increase of frontal rCMRGlc and a more pronounced reduction in primary and secondary visual centres indicate holostic behaviour of the brain during the altered state of consciousness obtained in the course of meditative yoga relaxation (Herzog et al. 1991 a). Sophisticated work is done on the neuroanatomical basis and pathophysiology in deaf patients during cochlear implant stimulation and generalized absences. The peri-ictal release of endogenous opioids has been demonstrated in animal models. The Hammersmith group has progressed to human studies. On the quantitative basis of a rational model, they have shown that the increased release of the endogenous opioids at the time of the serial absences precipitated by hyperventilation at the brain stem, posterior cingulate and lateral parietal cortex may have an important role in the suppression of generalized absences (Bartenstein et al. 1991a; Herzog et al. 1991 b). Localization of partial epilepsy and schizophrenia, diagnosis, and follow-up of treatment by more than weak clinical parameters are still major problems. Despite parameters for brain perfusion (99mTc-HMPAO) and benzodiazepine-receptor mapping (123I-Iomazenil), the aim of specific characterization of the clinical situation with these available conventional tracers is not fulfilled (Bartenstein et al. 1991 b; Biersack et al. 1990; Ell and Costa 1989). It is our task to look for and find a few parameters to extract the optimal information from kinetics and uptake on the basis of pathophysiology and biochemistry (Blomqvist et al. 1990; Schober et al. 1988). Because only small patient numbers are seen in each unit, cooperation between different centres might help (Lammerstma and Mazoyer 1990). We should do only one study per patient, if possible.
Und die Jahre, die sich langsam, Tiickisch reihten aus Minuten, Alle brechen auf im Herzen, Alle nun wie Wunden bluten ; Mit der armen, kargen Habe, Aus dem reichen Schacht erbeutet, Mutlos, ein gebrochner Wanderer, In das fremde Land er schreitet. Cited from : Annette yon Droste-Hiilshof." Abschied yon der Jugend
Clinical applications Nuclear medicine 2000 means cooperation, not confrontation, with radiology. In the diagnosis of renovascular hypertension, captoprit scintigraphy is of value in (radiologically proven) significant and severe stenosis but not in subcritical stenosis and occlusion, because only under these conditions are the renin-angiotensin compensation and secondary change of the renogram indicative (Sfakianakis et al. 1988). Nuclear magnetic resonance 2000 means function and spectroscopy (S), and only together with morphological information (I) is nuclear medicine really at the 2000 level (Linden et al. 1989; Schr6ter et al. 1991; Smolarz et al. 1988). We should rely on regional function and concentrate our strength. Assessment of regional cerebrovascular perfusion reserve, differential diagnosis by means of flow and volume measurements, e.g. in microangiopathy versus macroangiopathy, are scientific ideas that might help individual patients with neurological problems (Reiche et al. 1990). Hope is still with nuclear medicine contributions in grading of the tumours, differentiation of recurrence versus necrosis and early follow-up after therapy (Meyer and Schober 1991). Sensitivity, specificity and predictive accuracy of tests for detection of coronary artery stenosis and imaging of hibernating and stunned myocardium are current topics of discussion (Brunken et al. 1989; Go et al. 1990). However, clinically, problems that must and will be solved are silent myocardial ischaemia with highly predictive subsequent events and early indicators for plaque instability after deposition of platelets into an occlusive lesion (Lees et al. 1988; Rosebrough et al. 1990), as well as cardiac neurotransmitter mapping of the adrenergic activity. Discussions with clinicians and development in standard techniques may solve problems like arrhythmias, as has been demonstrated nicely by Weism/iller et al. (1990). There is still a necessity for progress in the transfer of the convincing concept of monoclonal antibodies from the basics and in vitro studies to clinical routine work with diagnostic gain, especially compared with competing morphological methods. Chimeric and human monoclonal antibodies will overcome problems of background in diagnosis and therapy as well as potential
side-effects with murine proteins (Baum et al. 1989). Monoclonal antibodies will play an important role in labelling blood cells, such as granulocytes, owing to their distribution in inflammatory disease, and the bone marrow in malignant disease (Bartenstein et al. 1990; Reske et al. 1989; Sciuk et al. 1991). Heterogeneity of tumours, affinity and specificity are key words that describe the problems of diagnosis and of experimental therapy with radiolabelled monoclonal antibodies. By sophisticated methods labelled cells, e.g. lymphokine activated killer cells, and imaging in malignant melanoma will solve differentiated clinical problems (Sch/ifer et al. 1991), but simple preparation techniques are a criterion of suitability for widespread applications. The possibility of labelling subclasses of the whole lymphocytic population seems to be a promising tool in the differentiation of inflammatory diseases. Actively diseased joints in rheumatoid arthritis have been imaged with 99mTc-CD,-specific (T-helper lymphocytes) antibodies. The incidence of clinical symptoms (Ritchie articular index) correlated with the scans better than radiography or bone scans (Becker et al. 1990).
Therapy Preliminary reports are available on imaging and treatment of B-cell lymphomas with 131i_anti_pan B-cell antibodies, and the future will lead us to human antibodies, both in diagnosis and treatment (Eary et al. 1990). Much more than in earlier times, heterogeneity of the tumours will be considered on a rational basis of calculation (Humm and Cobb 1990; Sgourros et al. 1990). The increase in binding of a labelled monoclonal antibody may lead to successful administration of radioimmunotherapy in EGF-R-positive tumours, like in new tumour spheroid models for therapy of minimal residual disease in neuroblastoma using 131I-MIBG (Senekowitsch and Pabst 1991 a, b). However, the basis of nuclear medicine therapy with nuclides will still be radioiodine therapy of hyperthyroidism and differentiated thyroid carcinoma and, with less importance, 131MIBG therapy of malignant neuroblastoma, phaeochromocytomas and other neuroendocrine lesions, therapy in joint diseases, myeloproliferative diseases and bone pain.
Outlook Ten years ago, Capp (1981) discussed the whole electromagnetic spectrum (microwave imaging, photoelectronic radiology, heavy ion radiography, analogue tomography, digital angiography, nuclear magnetic resonance imaging and spectroscopy, and PET), but to the best of our knowledge, only the last four technologies currently hold promise for 2000 A.D. The clinical value of the dedicated SQUIDs (superconducting quantum inter-
Table 1. Nuclear medicine 2000 Instrumentation
-- Annual single crystal device for the whole body - Detector system for gamma emitters without absorptive collimation - Fast PET systems - detection materials - for first pass analysis and spatial resolution less than 5 mm Radiochemistry
-- Quantitative structure activity relationship - Transfer of knowledge from PET to conventional nuclear medicine - Gamma-emitter-labelled pharmaceuticals which are strongly linked to glucose and oxygen metabolism Clinical science
- Three-dimensionalquantitative regional function in comparison with morphological information - Cooperation with nearly all clinical disciplines - Magnetic resonance function and spectroscopy - Transfer of immunological science to nuclear medicine - Diagnosis and therapy with monoclonal antibodies
ference devices) might be limited to the problems they have been dedicated up to now. The discoveries concerning the chemical basis of physiology, particularly in mental functions, might be as revolutionary as the discoveries in atomic physics at the turn of the century and the revolutions in molecular biology and genetics in the 1950s. Nevertheless, the future of nuclear medicine as an independent discipline lies in clinical medicine, in clinical service, in the diagnosis and treatment of diseases. At least in my view, its primary purpose is not a search for the function of mind on the basis of chemistry (Wagner 1985). This personal view takes no account of economic factors, which are relevant to us all but especially to the developing countries (Peters 1991).
Uniqueness of nuclear medicine The future challenge is in non-invasive specific functional diagnosis and, more importanty, in follow-up with quantified regional metabolism by the uniqueness of nuclear medicine (Table 1).
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