Path B: Research Projects

DOSIMETRY STUDIES
→ Radiopharmaceutical Dosimetry: Interest in dosimetry was a major focus of the early instrument development, calibration and analysis work carried out under our AEC contract. Analysis methods focused on imaging first with planar scanning devices, and later with Anger cameras (planar followed by tomographic devices). Gene Johnston, Ron Price, and Randy in turn became members of the SNM Medical Internal Radiation Dose (MIRD) Committee  that produced guidelines on quantitative imaging methods and dose estimates for tracers in common use. Computational support for the MIRD Committee was provided by ORNL (Walter Snyder and later Keith Eckerman) and ORAU (Roger Cloutier and later Evelyn Watson, aided in house by Mike Stabin and Rick Sparks). Many of the Vanderbilt dosimetry projects grew out of clinical studies  using  131I Hippuran (renal tubular function), 131I Albumen (cysternography), 133 Xe (pulmonary ventilation), and 131I  iodocholesterol (adrenal imaging). 131I  dosimetry and modeling studies also focused on thyroid dose in patients treated for hyperthyroidism and thyroid cancer. One fundamental study was done by Jerry Jones to test the validity of the reciprocity theorem in response to a question raised by Walter Snyder.

Good dosimetry information for new tracers being used in patients was critical to the future of nuclear medicine. The goal was to administer tracers in amounts that produced images of benefit to patient management, while avoiding unwanted side effects. The need was especially acute when little was known about the biological distribution and turnover of new drugs.. The set points changed as instruments improved and new drugs evolved. The intent was to keep a 10-fold margin below which no damage would be observed. Initial calculations involved crude geometric distributions for which analytic relations could be solved. In 1956, the comprehensive text on Radiation Dosimetry by Hine and Brownell summarized what was then known regarding the calculation of dose from simple static sources to adjacent and remote targets. The practical problem was that the tracers moved through the body, decaying in transit, and dynamic equations were needed to estimate realistic absorbed doses. Typically, these were based on data obtained in animals, and then extrapolated to man. The National Bureau of Standards (NBS) defined and distributed standard sources, and published data on good instrumentation and measurement practices.

→ Medical Internal Radiation Dose (MIRD) Committee: Bob Loevinger was the leading physicist at NBS. Marinelli and Quimby were the physicists at Memorial Hospital (MH) in New York who did the dose estimates for their early human studies. Mones Berman was the staff Engineer, later assigned the task at MH of developing mathematical formalisms that could be used their and by others to analyze the pharmacokinetics and associated dose distributions when using new tracers. In 1956, he began a lifelong project in which he developed a powerful general purpose software simulation and analysis tool that produced estimates of absorbed dose distributions from injected radioactive drugs. For this,, he developed a computer program, SAAM (Simulation, analysis, and modeling) which was distributed first by the NIH, and later by the Resource for Kinetic Analysis at the U. Washington, Seattle, by former NIH staff. Over time SAAM has been used widely and effectively for dose and various pharmacokinetic compartmental analysis tasks, and we were among its early users. SAAM became the tool and method promulgated by the Medical Internal Radiation Dose Committee (MIRD) that was formed by the Society for Nuclear Medicine (SNM). SAAM was originally hosted on an IBM 7094 in Washington. Mones later developed a remote access version CONSAAM that he distributed to users. To adapt the code to Standard computing configurations (including the Vanderbilt Sigma 7) was a task that Ron Price took on during 6 months that Ron worked in Bethesda with Mones. Once this was completed, Ron installed and used SAAM on the VU Sigma 7 for various modeling tasks, including the 59Fe studies. Later, NIH former Berman associates moved to Univ. Washington, and commercialized the program for use on PCS, and Mac computers. WINDSAAM was developed at NIH and continues to be distributed and supported for PC and Mac users.

Gene was the first Vanderbilt faculty member to be on the SNM MIRD Committee. The need for guidelines and regulations regarding the safe use of newly emerging radiopharmaceuticals as the number and rate of new uses appeared and the MIRD Comm. took on this challenge. Gene was the dosimetry expert on the NCRP report on the Factors involved in the Choice of Radiopharmaceuticals for Use in Diagnosis and Therapy. In 1968, the first MIRD Primer was published, and since has been updated three times due to its timely import.


IRON METABOLISM
Ron Price provided leadership on many of the research studies going on in the Division. He initially worked with Gene Johnston on quantitative 59Fe measurements, expanding on studies that Bob Heyssel and Cliff McKee had initiated. The basic data came from plasma disappearance, red cell appearance in blood, with body losses based on whole body counting. The initial Whole Body Counter (WBC) data was obtained with patients seated on the Marinelli chair, but later organ activity data was obtained by scanning patients supine with the scanning detector system. The most important 59Fe  measurements were made with a dual opposed pair of heavily shielded tapered single bore collimators, each approx. 7” long. 2” thick tapered sidewalls with a 1.5” front, 5″ back opening opposed to the 5″ diameter side-shielded detector. This was used to scan the whole body in a rectilinear raster. The scan took 20-30 minutes after a 10 uCi I.V. injection of ferrous citrate dissolved in the patient’s own plasma. Quantitative data on uptake in liver, spleen, sampled marrow sites and the whole body, were combined with serial blood samples providing plasma clearance and RBC incorporation data. The system was sufficiently sensitive that valid kinetic data were acquired out to more than 120 days following injection. Classical earlier ferrokinetic modeling studies were based on the blood kinetics, in some cases supplemented by probe collected organ data . Comprehensive analysis required multi compartment modeling analysis and advanced software tools and this is what led Ron to the NIH to work with Mones to make the tools available on generally available computers. Heyssel had collected Fe-59 turnover data on patients with different hematological diseases. With the advent of the high energy scanning capability in the modified WBC, and new, computing tools, we were able to extract additional information on ferrokinetics including marrow transit time and associated marrow dose. The Vanderbilt measurements provided the main supporting data included in support for the MIRD Report (Robertson JS, Price RR, Budinger TF, Fairbanks VF, Pollycove M, Radiation absorbed doses from iron-52, iron-52, iron-55 and iron-59 used to study ferrokinetics, 1983, J Nucl Med).


CONJUGATE IMAGING
 Gene Johnston was Randy’s first graduate student. His work defined the limits and uses of conjugate imaging (CI) methods (promulgated by Jim Sorenson from Wisconsin) for quantitating organ activity using planar imaging. Gene presented his work on quantitative imaging with scanners at the 1968 Salzburg meeting of the IAEA. Gene’s work evaluated the accuracy and limitations of CI for quantitating the amount of radioactive material embedded in different organs and body regions. The dose from I-131 to normal organs has always been of interest as its chemistry makes it a favorite tracer for many imaging and therapy tasks. Organ kinetics and dose distributions vary significantly when diseases affect the normal outflow tract and alter the normal bio distribution. In such cases, the normal organ dose can be very high, approaching therapy levels. This was true in kidney studies where long-term retention of 131I labeled Hippuran, for example, in patients with failing renal transplants where kidney can be as high as 8 Gy), This was also seen when obstruction occurs with a physical block, or by a prolonged cortical medullary transit time.

By 1972, Nuclear Medicine had grown to the point that it was an AMA Board Certified medical specialty. Similar progress was experienced elsewhere in Europe and Asia. The MIRD primer was updated several times since 1976 to include many MIRD Radiation Dose Estimates that provide guidance relating to patient dose, and procedural conduct. Standard man geometry was first used to estimate dose to different organs. With the passage of time, anatomic models became more realistic, and male and female organs and body habitus were defined based on realistic CT defined body regions. Additional tools have been developed and distributed for calculation of organ, sub organ, and cell level microdosimetry. 131I labeled Albumen was used to assess cerebrospinal fluid circulation kinetics in patients suspected of low-pressure hydrocephalus, a condition in which prolonged intracranial retention can occur. Gene published several papers on such matters with Ed Staab and Joe Allen (chief VU neuroradiologist).

The National Council on Radiation Protection (NCRP) Committee provides guidance on the safe uses of radiation in medicine. In the early 1970s, Randy was selected to organize and Chair a NCRP Committee to produce a nuclear medicine guidance report. The Comm. included a number of distinguished people: Saul Winchell and Paul Numeroff covered radiopharmaceuticals, Bob Beck and Jim Adelstein. Covered Instrumentation and Systems Analysis, Gene Johnston covered Dosimetry, and George Taplin was the Clinical liaison. The report had a broad scope and was entitled: “Factors Influencing the Choice and Use of Radionuclides in Diagnosis and Therapy”. The NCRP publication led to a local collaboration with Horace Williams and Bob Nash, faculty in the School of Engineering, with expertise in statistical decision theory. The problem was how to include weighting factors in a modeling tool that would allow testing of different actions against the costs and benefits of different actions when planning therapy. The risks of different actions included the risk of doing different somethings, including doing nothing, , each of which to be associated with a calculable risk. There was a section in the NCRP report on decision analysis mostly written by Jim Adelstein, but we were unable to create a tool, or define an acceptable dollar value for the costs of different actions vs. the ultimate costs, i.e. death from an unwanted consequence, and quality of life lost. In diagnosis, it was clear that the benefits would always exceed the risks given that the risk of doing nothing in the presence of curable disease will always exceed the small statistical risk of low diagnostic radiation doses. We took 8 years to publish our report, by which time Gene had left to work as the Chief Physicist in nuclear medicine at UNC, Chapel Hill, rejoining Ed Staab who was then Head of nuclear medicine.

Jerry Jones stayed on for 11 additional years after finishing his PhD in Physics. Shortly thefeafter, the NCRP formed a committee to  report on the status of experimental verification of internal radiation dose calculations – in particular the standard man absorbed fraction/S factor work done at ORNL by Snyder and his associates. My thesis project had been to check this with Tc-99m on patients receiving liver scans, so I was invited to serve. The  Scientific Committee No. 55, and its report, NCRP 83  was entitled The Experimental Basis for Absorbed-Dose Calculations In Medical Uses of Radionuclides with the following members:

James Robertson, Chairman (Mayo Clinic)

Kathryn Lathrop (University of Chicago)

Martin Berger (NIH)

John Poston (Texas A&M)

Jerry Jones (Vanderbilt)

Ken Vanek (USAF, Keesler Medical Center, from the University of Florida program), and

Gordon Brownell (Massachusetts General Hospital,  a legend in medical physics).

See some NCRP Jones Anecdotes on the meeting.


WHOLE BODY COUNTER (WBC) AND CLINICAL SCANNER ANALYSES
Watts thesis was entitled: Methods for Quantitative Assay of Radioactivity in Man in which he described the design and evaluated the workings of the new scanning system in the whole body counter. .Jim and Gene performed a system performance study with our new Ohio Nuclear dual opposed clinical scanner. They imaged and compared the imaging performance with different sized hot and cold objects at different depths in a scattering media as seen by 3” and 5”and 8” detectors”.. The outputs of each of the detectors were recorded in the DEC PDP-9. The 8” focused collimator viewed a hourglass shaped field of view. A narrower hourglass profile was seen with 3″ diameter detectors, the near and far fields were broadest with the 8″ diameter collimators. We tested the effects of different collimator profiles on object detection tasks by filling the outer rings of the 8” collimator holes with lead powder, and thus we shimmed the field of view to simulate 5”, and 3” collimators, and data collected with each allowed us to compare the predicted vs. observed performance. We used different size objects containing different amounts of activity at different depths with different background contrast levels. To simulate in vivo tumor detection (variable background distributions), we added data collected from spheres of different diameters containing different levels of activity, at different depths to normal brain studies obtained with the different collimators. As expected, lesions at the collimator focus plane were best detected with the 8” wide-angle collimator. However, lesions near to and far from the focal plane were better imaged with the 3 and 5-inch detector. We did not properly account for true noise as we scaled counts from high-activity ball images by dividing them to represent lower activity tumors. The noise level would have been higher for the lower activity balls if imaged for the same time as the high activity tumors, and hence we did not properly account for different levels of noise. We realized this too late after presenting the data at meetings but never published the data.


F59 AND I131 DOSIMETRY
Norm Dyer was the graduate student, and then faculty member who conducted the Vanderbilt Fe-59 studies in support of the Hahn follow-up study and topic of this Norman Dyer Dissertation[1] He also  assessed I-131 uptake in the fetus in response to ongoing discussions regarding fallout hazards from nuclear testing. We did a study in collaboration with Ob-Gyn faculty in which we measured dose to the fetus from both 131I and 59 Fe given to the mother in support of the follow up of the Hahn study patients. His studies included novel applications of neutron activation analysis. Other studies were carried out on sheep in collaboration with Millie Stahlman and her neonatal research group.

→ The Hahn study data files recorded the amount of 59 Fe fed to the mother, and the amount of 59 Fe sampled in the mother’s blood at different time intervals. The amount of activity transferred to the fetus was not known and the absorbed dose by different organs in the fetus was the quantity we needed to correlate with any late effects observed in the follow-up study. To collect the data we needed to administrer stable tracers to pregnant mothers, as one could no longer justify giving 59 Fe to any radiation sensitive populations for research purposes. We obtained enriched 58 Fe from ORNL (a very valuable commodity) and after using only a small amount, we returned the remainder at the end of the study. A group of women from 20 to 44 weeks gestation gave informed consent, and the tracer was given by mouth to some, and IV to others . Blood samples were obtained at intervals thereafter and from the babies after the were delivered. In addition, 50 Cr labeled RBCs were used to determine the patient’s RBC blood volume, while plasma volume was inferred based on hematocrit. Data were analyzed and dose calculated using reference organ masses. Again, the amount of stable tracers was assayed by NAA following irradiation in the Georgia Tech reactor. From these data, doses to the children in the Hahn study were calculated. This workwas also reported at the IAEA Conference “Nuclear Activation Techniques in the Life Sciences” , in Bled, Yugoslavia, April 1972.


FETAL DOSE STUDIES
Additional studies were done in a small group of women scheduled to receive therapeutic abortions. They were all young women from 8 to 24 weeks gestation who gave IRB approved informed consent. They were each given small amounts of 131I and 59 Fe one day before the scheduled abortion. The mother’s thyroids were counted. After the fetus was delivered and dissected, the 131I and 59 Fe activity in the organs and remaining carcass were determined. Results of these studies along with a handful of other reports constitute the best-published information on fetal 131I and 59 Fe dosimetry. In addition to the human maternal fetal transfer data, bidirectional transfer was assessed in sheep. 59 Fe was administered to the ewe and 55 Fe was administered to the in-utero lamb, and bidirectional transfer of iron was thereby measured. Dyer’s fetal 131I data along with data from Titus Evans (Iowa) are key values used in the Berkovski ICRP fetal 131I dose model.

→ Study of timing of intracranial bleeding in premature infants:  Mildred Stahlman was Head of Neonatology, and a leader in the management of premature births. One of the problems encountered with preemies was that some of the children who did not survive through the critical period were found at autopsy to have blood clots in their cerebral ventricles, and the question was whether this occurred prior to, during or after delivery. Determining when this occurred had therapeutic implications. In order to establish the probable time of bleeding, a study using stable tracers was designed and Norm Dyer carried out the project. He labeled the new born infant’s first of several possible blood transfusions with 50Cr bound to red blood cells. If the baby died, neutron activation of blood samples and tissue from the ventricle bleed would provide a probably clot-timing curve. The blood samples taken throughout the baby’s treatment and the blood clots from the cerebral ventricles were obtained from autopsy, and sent to the Georgia Tech reactor for neutron activation. On return to Vanderbilt, the samples were counted for 51Cr and 59 Fe,  the results of which indicated that the blood clots occurred near the time of death.  This study was done to determine what type of management of post partum procedures might be used to avert ventricular bleeds. However, a significant finding was that the infants had reduced red cell volumes.  A program of red cell volume measurements with 51Cr was instituted to improve premature infant health care.


BONE MINERAL CONTENT
Our first bone mineral content analysis studies were done in the arm and wrist bones in1966. Gene and Ron made and studied bone density using different home made phantoms, first with NaI detectors, and later with solid-state detectors. During his first year in Medical School, Levi Watkins, the first black medical student at Vanderbilt, worked with us in these early studies. Watkins did fine in Medical School, and although he did not go on with nuclear medicine, he had a highly successful career at Johns Hopkins ending up as a Full Professor in Thoracic Surgery, and later with a position in the Dean’s Office. Bob Heyssel had been at Vanderbilt when Levy worked in nuclear medicine. He enjoyed watching over and promoting Levy’s career while Bob was CEO at Hopkins. Levi now has a named distinguished annual Vanderbilt lectureship in his honor.


QUANTITATIVE IMAGING
The scanning geometry in the WBC made it possible to do whole body transmission as well as emission and body composition studies. Body thickness was needed to correct for attenuation of the passage of low energy isotopes in leaving the imbedded organ site. It was also useful for mapping the distribution of bone mineral content of the bone by the differential attenuation in bone and soft tissue as a function of energy. 153Gd was used as the dual energy source. Ron’s and Kent Larsen’s work included the first published (1976) whole body bone mineral content scan. This was a measure primarily of Ca and P content, but we also attempted to calibrate it to be a measure of regional calcium content. This was done using data obtained from three subjects (REJ, ND, and ABB), who served as normal volunteers at Brookhaven National Lab (BNL) for calcium determination by NAA.

Quant_Imaging_Table

Each of the normal volunteers received a short neutron exposure from a distributed Pu/Be source. Following neutron exposure the activated 49Ca was immediately counted in the BNL multi crystal whole body counter. In this way one was able to correlate bone mineral density measured by X-ray transmission to body Calcium content. Normal values were of interest to BNL and us because of our interest in fundamental measures of body composition.

It turned out that 2 of the 3 subject’s results were in the normal Ca range , while ABB was at the upper limit of normal, but below the levels found in BNL measured values in acromegaly patients. His increased level correlated with extensive bone spurs seen radiographically and on Lunar, bone density studies. His elevated density, 1.32-g/cm2 had a significantly elevated z score of 2.3. (The earlier bone mineral density measurements made on the others have not been found. More data are given in Kent Larsen dissertation (K.H. Larsen, PhD Physics 1979. Measurement of Regional and Total Body Bone Mineral Content In Vivo Using Transmission Scanning and Neutron Activation Analysis).

Kent worked with Ron Price and Randy Brill to extend the transmission scanning technique developed by John Cameron and others at the University of Wisconsin to the spine and whole body.  The method was first used for point measurements by moving a source-detector system across the forearm.  An Ohio Nuclear scanner was used to extend the method to include partial body BMC measurements (arm and spine).  The steel room Whole Body Scanner was used for total body BMC measurements.  A computer program (written by Jim Patton) monitored the position of the scanner and recorded count rates at both energies of the 153Gd source.   Partial body measurements were made on 70 patients undergoing treatment for osteoporosis or osteomalacia over a period of 2 years.

In addition to the measurement of total bone mineral (Ca and P) using the transmission scanning technique, Kent worked on a technique to measure Ca using neutron activation analysis.  Some of the work was done at the Oak Ridge Associated University Special Training Division using their 252Cf irradiation facility.  Calcium and total mineral were measured in some excised bones using both techniques and were then ashed.  The measured BMC was compared to the weight of the ash (assumed to be primarily bone mineral).  One subject in the study (Randy) had both the total body BMC measurement at Vanderbilt and the total body calcium measurement using NAA at Brookhaven National Lab.  The results were 1.35 kg Ca and 4.15 kg total mineral giving a Ca/Ca+P ratio of 0.32.  This agrees well with the 0.38 – 0.44 ratios in the excised bones especially considering that the two scans on Randy were done several years apart.  Kent also designed an irradiation device using 252Cf to measure calcium in the forearm.  The design was done using 2 computer programs (MORSE and ANISN) obtained from the Radiation Shielding Information Center at Oak Ridge and with the help of Dan Kedem at the Soreq Nuclear Research Centre in Israel.  The final design of the facility predicted accurate measurements could be made with minimal dose to the patient and could also be used for neutron radiography and in-vitro irradiations but was never built due to lack of funding.


TUMOR IMAGING
In the search for improved cancer imaging agents, radioactive bismuth was noted to have a very high uptake in brain tumors (reported by John McAfee, at an SNM conference). To compare Bi to other tumor avid tracers, we did a multi tracer uptake study in dogs with spontaneous lymphomas. This was Kay Flanagan Kosik’s MS thesis project in which each tumor-bearing dog, was given a mixture of 5 or 6 tumor seeking and normative radioactive tracers. These included: 67Ga, 75Se Methionine, 131I Albumin,208Bi, and 51Cr RBC. At autopsy, multiple enlarged lymph nodes were excised, weighed and counted and the fraction of the injected activity (FIA) assessed. A wide variation in uptake of the different agents was found in different tumors in the same animal and between animals. Histology on the tumors was not done, and more specific tumor specific correlations were lacking. Nonetheless, she found as much as 100 fold differences. In some, the Bismuth uptake was the highest, while in others it was the lowest. The significant variability of tumor avidity may have been due to differences in tumor stage, or fractional size in the different tumors, but the results were preliminary and the experiment was not repeated. It is hard to get people to give their pets for scientific research, and hard on the researchers as well. There was little enthusiasm in the group for going forward and the study was concluded. An interesting counting observation was that although the solid-state detectors had a spectral selectivity advantage, higher efficiency was found using large NaI detectors, and this made them the detector of choice for use in this study.
That is, when it was desired to quantify all radionuclides in a sample , large NaI detectors are better to use than lower sensitivity solid state  detectors (Spectral stripping computer analyses were done by Norm Dyer).


ADRENAL IMAGING
The uptake of 131I Iodo cholesterol in adrenal glands and tumors was done in collaboration with Grant Liddle and his endocrine colleagues. Grant was the world leading expert in Pituitary/Adrenal diseases, and this attracted many patients with adrenal tumors to VUMC. The Beierwaltes U. Michigan nuclear medicine group marketed different forms of radio-iodinated cholesterol, which we bought and used to study many patients with adrenal cortical tumors. The low sensitivity of 1/4″ thick NaI crystal on gamma cameras captured few of the relatively high-energy gamma rays from 131I. Thus, images were count-poor and noisy even from active functioning tumor tissue. Images were computer captured and with the patient in place, we injected a kidney seeking trcer for anatomic correspondence. The lower energy kidney tracer, 203Hg chlormerodrin) was easily separated from the 365 keV 131I. By color-coding the superimposed images, one viewed the relative anatomic location of the tumor as an aid to the surgeon. It worked well for large tumors, but small tumors were difficult to detect and were not regularly identified with confidence.


BLOOD FLOW STUDIES
→ Central Circulation: 
Blumgart and Weiss did the first important tracer studies in man in1926 in which they measured the central circulation They measured the central circulation transit times in patients with cardiac disease and in normal subjects using a probe detector counting the transit time by measuring emanations from Radon gas in solution as the bolus arrived at the far side of the body. With the advent of gamma cameras nuclear medicine tracers in the mid 1960s were able to image and quantify brain blood flow. Initial studies were limited to describing asymmetries in flow through the right and left arterial inflow and outflow channels of the brain viewed from anterior, posterior, and vertex views.

In the study of kidney function, transit times, and anatomic deformations were analyzed. At Vanderbilt, computer-coupled gamma cameras captured the data and homegrown computer programs were used routinely in clinical and research studies. Computer codes submitted by different researchers were disseminated via Oak Ridge (BCTIC), which supported different approaches to the display and analysis of flow transients.

Parametric Images: Time-coded parametric maps made it possible to display kinetic features in a single image by pixel encoding different flow and turnover parameters, in so-called functional or parameter images. In parametric maps, the time that the activity curve reached a peak in each pixel could be color coded. Other parameters, such as time to fall to half the max value, etc. could also display in/or outflow parameters.. Best results were obtained using different data smoothing methods. Temporal smoothing was done along the time line, and spatio-temporal smoothing was done with cubic weighted 3x3x3, or 5x5x5 filters to smooth or sharpen contour boundaries depending on the chosen filter factors. Displaying images at meetings was a problem before computers came on the scene, so we often took our VCR to show our data at meetings to get around device compatibility issues.

→ Cardiac Blood Flow: Cardiac uptake is a convolution of blood flow and organ trapping. Initial studies were static images, as sensitivity was too low for flow studies. Our earliest study imaged the distribution of 32 keV emitting 132Cs with the Picker 3” rectilinear scanner. The uptake was poor and the peak to scatter ratio was bad. 42K (imaged by Love, Jackson, Mississippi) was a better biological tracer, but its 1.2 MeV gamma required a heavily shielded gamma scanner. 43K was later produced at ORNL but its 800 keV emissions were also too energetic for the gamma camera, and 201Tl became the favored tracer, but its energy spectrum was also sub optimal for the gamma camera.. Ultimately, a series of 99mTc labeled blood flow tracers became the agent of choice. The 81Rb/81mKr generator seemed like a potentially important agent 81Rb for cardiac and spleen blood flow measurements. Since K, Rb, and Cs are in the same Periodic chart family, they all share cardiac avidity. Thus,  the best functioning heart regions have the best uptake. The case for Rb was that it is strongly picked up in well-perfused myocardium, and it decays rapidly to 81mKr, a noble gas that rapidly clears from the heart in proportion to regional blood flow. Thus, well-perfused regions have elevated Rb/Kr ratios, that grow as the short-lived 81mKr (190 keV daughter) is washed out. Metaphysics made and distributed 81Rb generator for 81mKr lung ventilation studies, and encouraged us to test its potential for imaging myocardial ischemia. They gave/sold us a massive pinhole collimator for use with the Anger camera. Unfortunately, the scatter from the Rb into the Kr window diminished the image quality and the scatter and distortion correction methods were not effective in producing useful images. The proposed use of the Rb/Kr generator for spleen blood flow was based on the sequestration of labeled heat-treated Rb-81 labeled RBCs, with the Rb/Kr ratio providing a measure of flow when properly calibrated. This also did not take off for general use.

→ Cardiac Shunt Quantification: Darko Ivancevic came in 1973 from Zagreb (Simonevic’s Department in the Rebro Clinic.) Darko had spent a sabbatical year in Kellersohn’s Orsay lab working with the group of accomplished French nuclear cardiologists. Darko’s plan was to create an atlas illustrating the different appearances of congenital heart defects based on probe-recorded flow data. To minimize inverse square sensitivity changes due to cardiac wall motion, he designed and used a dual probe system. The crystal in the lateral flat field collimated probe was farther from heart than the anterior probe (and thus was less sensitive to depth changes during heart contractions). The data from both probes were collected simultaneously to record the temporal transits through the right and left heart. The output from both was captured in our CAMAC data collection system. Chamber flow information was extracted using mathematical modeling tools, and the work was published in the Knoxville IAEA Dynamic Imaging Symposium. Darko returned to Zagreb, after two years after successfully working side by side with Tom Graham (Head Pediatric Cardiologist) in the Cath Lab studying patients with known/suspect cardiac shunts. This was a time when surgical repair of such defects was active.. Unfortunately, when
Darko left, no one took on his role and the study stopped. Darko died of pancreas cancer in 2004 in Zagreb after a long and distinguished career.

→ Renovascular Hypertension (RVHP): We participated in John Oates and Tad Inagami’s SCOR (Special Center) research grant on renovascular hypertension (RVHP). Radiographic angiography was used to delineate the anatomic features of RVHP, namely a tortuous renal artery. This information when coupled with increased plasma rennin levels had high anatomic and biochemical predictive information value. Nuclear medicine’s initial role was to conduct and interpret renograms performed on patients referred for clinical evaluation of hypertension. The renogram project was started under a nationwide VA grant coordinated by Belton Burrows at the Boston VA Hospital. They provided centers with a Picker dual probe system with data plotted on a chart recorder. Problems with poor data recording lead to its replacement by a digital buffer system. The system was flaky, and with the assistance of an Electrical Engineering colleague, Gene Denman, the system was made to work with much tweaking. From this experience, we learned how difficult it was to work with and upgrade clinical systems. Gene would come over in the late afternoon, take apart the system to identify and fix faults. With the upgrade only partially completed, he had to stop and put the system back as best one could to make it available for use with the next day’s patients. Very frustrating to all. Initially, we reported half times and relative amplitudes of the different phases of the uptake and turnover of 131I-hippuran, a measure of renal tubular transport. Paul Scheibe, ADAC computer founder, marketed a renograms analysis service. Dual probe recorded data was transmitted by phone to ADAC in Palo Alto. A compartmental model was used to analyze the data separating out cortical and medullary transit times, and right/left differences, with output data returned for a fee. Ron and Juan Touya used SAAM models and gamma camera data on 99mTc-DTPA, and 131I Hippuran for similar purposes but were never able to identify specific parameter(s) that differentiated patients with and without RVHP.

We also used quantitative video densitometry systems developed for Cardiac angiography studies to analyze images obtained in patients with RVHB, . With these we derived supplemental quantitative information on blood flow. Dan Kedem, and his wife Drora were two talented physicists from Israel who worked with us for two years. Dan was on leave from the Soreq Nuclear Research Lab where he was Research Director and Drora was a gifted mathematician, who joined in the research. They developed methods to measure systolic and diastolic flow based on contrast flow profiles. They used digital cine-video densitometry to measure blood velocity and blood flow in the descending aorta of human subjects. They injected very small, compact boluses of opaque dye during different phases of the cardiac cycle, and analyzed flow through a portion of the aorta and other vessels. From the density vs. time curves at different radial locations, they calculated velocity distribution over vessel cross-sections. The velocity distribution obtained was nearly parabolic. Velocity and flow calculations were also made at different phases of the cardiac cycle. However, they were unable to analyze flow transients in the renal arteries.


DATA ANALYSIS
Much effort was put into modeling transport through the kidneys. We used Berman’s SAAM program but we never identified a specific parameter(s) that identified patients with RVHP. The scientist responsible for the development of the ADAC system, Paul Scheibe developed and marketed an analysis service for renograms analysis. Data recorded by the dual probe systems was transmitted electronically to Palo Alto where he was located. He used a compartmental model to analyze the data separating out cortical and medullary transit times, and right/left differences, and sent the data back for a fee. Over the years, Ron, and Juan Touya, in particular, used our own data based on gamma camera acquired data, and published the methods and observed results, but the results did not successfully pin point patients with RVHP. (Insert references).


RADIOGRAPHIC ANGIOGRAPHY
Radiographic angiography was used to delineate the anatomic features of RVHP, namely a tortuous renal artery. This information when coupled with increased plasma rennin levels, had high anatomic and biochemical predictive information value. We used quantitative video densitometry to analyze images in patients with RVHB, using systems described in the next section. With these we derived supplemental quantitative information on blood flow using the video densitometry resources we installed and used to analyze routine patient studies, as well as animal research (studies done on week ends and off hours). Dan Kedem, and his wife Drora were two talented physicists from Israel who worked with us for two years. Dan was on leave from the Soreq Nuclear Research Lab where he was Research Director and Drora was a mathematical whiz, who joined in the analysis and study conduct. They developed methods that measured systolic and diastolic flow based on contrast flow profiles. They used digital cine-video densitometry to measure blood velocity and blood flow in the descending aorta of human subjects. They injected very small, compact boluses of opaque dye during different phases of the cardiac cycle, and analyzed flow through a portion of the aorta and other vessels. From the density vs. time curves at different radial locations, they calculated velocity distribution over vessel cross-sections. The velocity distribution obtained was nearly parabolic. Velocity and flow calculations were also made at different phases of the cardiac cycle.


BI-PLANE RADIOGRAPHIC ANGIOGRAPHY SYSTEMS
Earl Wood’s Mayo Clinic radiology research group pioneered in the development of quantitative X-ray imaging systems. Wood collaborated with Homer Warner, one of Wood’s first post docs. Homer was an electrical engineer/physician on the Utah faculty who went on to make many important contributions to computer-assisted cardiology and medical informatics. Randy worked with Homer while in Medical School at Utah on a kinetic modeling project and followed the Utah and Mayo collaborations thereafter.

We modeled the Vanderbilt quantitative image recording system on the Mayo systems. We used an analog multiplexing system we obtained from Hamamatsu to record up to 8 different analog transducer readings on video media along with the image data from the biplane image intensifiers from which the x-ray data were recorded. The data were read out at video frame rates, and up to 600 frames of data were recorded on the NASA supplied Video Disk. For longer studies, data were buffered on an Ampex VR1100 tape drive. The Vanderbilt Cardiac Cath Lab for many years was jointly staffed by Radiology and Cardiology. Clyde Smith was the Radiologist who provided technical and professional support. The Cardiologists did the interventions while Clyde supervised the X-ray procedures and clinical interpretations were made in joint sessions. Bud Friesinger, and Tom Graham were the cardiologists working with Clyde. The Cath Lab was above the WBC area, and we coax cable connected our nuclear medicine computers to support the acquisition, analysis and processing of data from the biplane angiography system used for patients and at off hours for animal studies. Hamamatsu’s loaned talented engineer, Hitoshi Ida, and their loaned multiplexer allowed us to record and analyze data before commercial systems were available for such tasks. Joint publications recorded the results. When Clyde and Randy left, the Cath Lab reverted to Cardiology, and the collaboration ended.


NUCLEAR CARDIOLOGY
The evolution of cardiac imaging was slow at first as tracers and instruments improved. We tested 132Cs in 1965 and later 42K that was too energetic for clinical use. . We produced parametric images shunt and cardiac chamber flow profiles. We used 201Tl and the different emerging new  99mTc labeled compounds. Differences in rest exercise patterns revealed locations of myocardial defects. The studies were done in nuclear medicine, but interpretations were done jointly with cardiologists. Marvin Kronenberg was an active participant along with Bud Friesinger in clinical and research collaborations. The nuclear medicine physicians in the 70s (Patton, Born, Grove, Touya) became skilled in the clinical interpretation of rest exercise patterns indicative of redistribution of flow to viable but hypo perfused cardiac territories. Later, in the 80s and 90s, when 18F was available from the VU cyclotron Sandler and Patton explored new systems and uses of dual isotope SPECT and FDG using high energy collimators, with simultaneous imaging of 511 keV for 18F, a metabolic tracer, and 140 KeV from Tc-99m Sestamibi, a blood flow tracer. This work is further described in ERA 3. Viewing bulls eye plots that statistically compare patient values against normal expectation in an anatomically relevant planar projection assists in analysis of flow deficits. Another important development to be described in ERA 3 is the development and testing of a semiconductor detector-based camera device designed by Sandler and Patton in collaboration with an Israel Company for cardiac imaging.

Nuclear cardiology and nuclear oncology studies have now become the most frequently used nuclear medicine procedures.


MORBID OBESITY STUDIES: EVALUATION OF DIFFERENT FORMS OF SURGICAL THERAPY
The whole body counter has been used at Vanderbilt, and elsewhere to measure absorption and excretion of vitamins, minerals, and other nutrients, without the need to hospitalize patients to achieve complete collections of stool and urine. Surgeons were quick to recognize the importance of nutritional and fluid balance in preparing and following patients after surgery. The need for such measures was recognized and well used by Bill Scott, the Chair of Surgery while investigating different surgical approaches to decrease absorption of calories by shortening the small body where absorption takes place.

→ Bill Scott was a distinguished surgeon and Chair of Surgery, who pioneered in surgical treatment of morbid obesity. Some of his patients weighed more than 500 pounds, and had to be weighed on commercial scales in the loading dock of the Hospital. In order to study these patients in the whole body counter, we had to shore up the patient bed. We added steel rail along all side of the bed, and presumed it passed the two Meneely test. Patients came from near and far, including one pair of 500 + pound twins from Israel. Dr. Scott worked with VU colleagues including nutritionist, Ray Meng (lipids) and Harold Sandstead, (internist and Zn specialist) working with Bill Darby (Head of the Nutrition program and Biochemistry Department). We investigated the effects of diversion of different amounts of small bowel on the loss of vitamin, and minerals from the gut. The whole body counter was an ideal tool for the measurement of changed in lean body mass (based on 40K measurements), and on the changes in absorption of radiolabeled vitamins (57Co Vit B-12), and 131I labeled lipids, and hormones (131I thyroxine). In many literature reports, Ron Price and Sandy Sandstead took the lead, with Bill Scott an ever-present colleague. The findings revealed a rapidly increasing rate of complications when the length of the small intestine was less than 28 inches. Patients who were not careful to restrict fat intake, developed diarrhea, sweatiness, tachycardia, unpleasant symptoms characterizing the dumping syndrome. Many patients were so ill, that they had to have the operative procedure undone, i.e. the bypassed bowel had to be reconnected. Current operative procedures continue in patients with morbid obesity, involving stomach plication, and less dramatic shortening of the small intestine, leaving the terminal portion of the ileum intact for Vit B12 absorption.

→ Harold Sandstead was an active participant in the Bill Scott obesity studies. He also studied Zn and its effects on wound healing, and in the effects of lead poisoning having encountered 21 patients at the local VA hospital. It turned out that the VA patients were all “moonshiners” who used the coils from car radiators in the distillation process. Sandy investigated their thyroid function status, including I-131 neck uptake counts with and without TSH stimulation. Mildly diminished thyroid trapping with normal I-131 TSH response, and normal thyroxin turnover studies was seen using the whole body counter. Most of the lead poisoned patients’ excreted increased amounts of Pb in the urine at baseline, and EDTA challenge tests brought out 10 fold increases. Iodine uptake in the thyroid was low in all but one of the 17 men with lead poisoning, and all increased their uptake when given TSH. Striking increases were noted in all but 3 of the patients. The patients had normal PBI levels in all but 2 where the levels were depressed. The turnover of IV injected 131I labeled thyroxin was indistinguishable from results observed in 8 normal subjects. The conclusion was that Pb caused injury to the thyroid trapping and concentrating mechanism, but that the gland was able to respond normally to the high levels of TSH administered in clinical response tests. None of the patients were clinically hypothyroid. These results are consistent with current information on the biochemical effects on Pb on the thyroid.


SIMULATION AND MODELING STUDIES USING SAAM
We needed access to a computer-based general-purpose mathematical modeling tool for dosimetry and kinetic modeling for different studies. The most pertinent system at the time was the SAAM program developed by Mones Berman. In the 1940s, Mones worked as an electronics technician at the Memorial Hospital. Since Memorial was among the first to test new diagnostic and therapeutic tracers in patients, Mones was tasked to make the needed dose calculations. This embarked him on a career during which he developed a general purpose-modeling tool (SAAM: simulation, analysis and modeling). This is now in general use for dosimetry and different systems analysis models of transport physiology. The program in the 60s was running on the IBM 7094 at the NBS, where Randy used it with Mones for 131I bone marrow dose calculations. To increase user awareness of and access to SAAM, Randy and Betty Maskewitz (ORNL/RSIC) arranged a meeting at Oak Ridge where Mones discussed the SAAM program. Interest was great, and when Ron and Mones talked, it was agreed that Ron would go the Bethesda for 6 months to work with Mones and Marge Weiss to recode SAAM to be able to run on generally available computing systems. During the six months Ron worked in Mones’ lab, he recoded the program to run on the Vanderbilt XDS Sigma 7, under a standard operating system. At that point, Mones agreed to release the code for general use, not previously wanting to deal with user problems associated with installing and using the complex code. Having successfully accomplished the recoding task and with expertise in its use, Ron returned to Vanderbilt where he applied SAAM to a number of projects. Key SAAM applications at Vanderbilt include analyses of Fe-59 data collected in normal subjects, patients with PNH, hemolytic anemia, and isolated red cell aplasia. The 59Fe data were the main data included in the MIRD publication. In addition, SAAM was used to analyze data on 131I treated hyperthyroid patients (TTFUS), which Randy had brought with him from NIH. We received NIH grant support to model and compare turn over of diagnostic and therapy doses in hyperthyroid patients. The question was whether doses received during the therapy would be lower than the treatment planning doses predicted. Working with Sain Ahuja (a High Energy physics Vanderbilt Post Doctoral fellow), Ron modeled the radiation effect as a time varying parameter to test whether there was a time (and dose) varying decrease in the thyroid uptake coefficient. The results in over 100 carefully studied treated patients who had multiple measurements of 131I in blood, thyroid, and urine, revealed no significant change in thyroid kinetics due to therapy in contrast to a clear therapy effect previously reported after 10-100 fold higher doses given in therapy of thyroid cancer (Berman and Singh).

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