New prospective for non-invasive detection, grading, size evaluation, and tumor location of prostate cancer.

BACKGROUND: PSA blood test and other present screening tools fail to provide the required sensitivity and specificity and, at early stages, lack correlation with tumor grade, volume, and location. Thus alternative approaches are highly desired. We present and assess a novel method for PCa detection, grading, volume evaluation and tumor location, based on non-invasive zinc concentration mapping in the gland by means of a dedicated rectal probe. METHODS: Zinc-concentration values measured in histologically examined tissue fragments from needle biopsy of 598 patients were analyzed. They were used to generate computer simulated zinc-concentration maps, further analyzed with image-processing tools. The tumor detection performances versus Gleason grade were assessed. RESULTS: A significant increase of zinc depletion with increasing Gleason pattern (grade) classification was established. Tumor detection performance in zinc-concentration maps progressively improves with the cancer's first component score. Reliable information on the location, size and Gleason-grade combination of the lesion can be extracted for clinically relevant volumes. CONCLUSIONS: Zinc depletion in the prostate peripheral zone is the basis for a novel, non-invasive PCa detection, localization, volume evaluation and grading method. Its realization and application as a pre-biopsy and pre-treatment examination, or a follow-up tool, relies on the development of a dedicated transrectal probe. It should have significant impact on biopsy effectiveness, point at a possible extraprostatic extension and provide critical data for focal treatment. The information on tumor grade and distribution may have an important impact on disease management.

Cadmium: in vivo measurement in smokers and nonsmokers.

Absolute amounts of cadmium (in milligrams) in the left kidney and concentrations of cadmium (micrograms per gram) in the liver were measured in vivo in 20 healthy adult male volunteers. Organ cadmium levels of smokers were significantly elevated above those of nonsmokers. No relationship was evident between body stores of cadmium (liver and kidney) and cadmium or beta 2-microglobulin in urine or blood. The average total body burden of cadmium in man at age 50 is estimated to be 19.3 milligrams for nonsmokers and 35.5 milligrams for smokers (38.7 pack-year smoking history). Biological half-time for the whole body was, on average, 15.7 years (10- to 33-year range). Dietary absorption was 2.7 micrograms per day. Cigarette smoking resulted in the absorption of 1.9 micrograms per pack.

Evaluating the cancer detection and grading potential of prostatic-zinc imaging: a simulation study.

The present work deals with the analysis of prostatic-zinc-concentration images. The goal is to evaluate potential clinically relevant information that can be extracted from such images. In the absence of experimental images, synthetic ones are produced from clinically measured zinc-concentration distributions in certified benign and cancerous tissue samples, classified by the lesion grade. We describe the method for producing the images and model the effect of counting statistics noise. We present in detail the image analysis, which is based on a combination of standard image processing and segmentation tools, optimized for this particular application. The information on lowest zinc value obtained from the image analysis is translated to clinical data such as tumour presence, location, size and grade. Their confidence is evaluated with the help of standard statistical tools such as receiver operating characteristic analysis. The present work predicts a potential for detecting small prostate-cancer lesions, of grade (4+3) and above, with very good specificity and sensitivity. The present analysis further provides data on the pixel size and image counting statistics requested from the trans-rectal probe that will record in vivo prostatic-zinc maps in patients.

Quantitative discrimination between oil and water in drilled bore cores via Fast-Neutron Resonance Transmission Radiography.

A novel method utilizing the Fast Neutron Resonance Transmission Radiography is proposed for non-destructive, quantitative determination of the weight percentages of oil and water in cores taken from subterranean or underwater geological formations. The ability of the method to distinguish water from oil stems from the unambiguously-specific energy dependence of the neutron cross-sections for the principal elemental constituents. Monte-Carlo simulations and initial results of experimental investigations indicate that the technique may provide a rapid, accurate and non-destructive method for quantitative evaluation of core fluids in thick intact cores, including those of tight shales for which the use of conventional core analytical approaches appears to be questionable.

Evaluation of body composition and nitrogen content of renal patients on chronic dialysis as determined by total body neutron activation.

Total body protein (nitrogen), body cell mass (potassium), fat, and water were measured in 15 renal patients on maintenance hemodialysis (MHD). Total body nitrogen was measured by means of prompt gamma neutron activation analysis; total body water was determined with tritium labeled water; total body potassium was measured by whole body counting. The extracellular water was determined by a technique utilizing the measurement of total body chloride and plasma chloride. When compared with corresponding values of a control group of the same age, sex, and height, the protein content, body cell mass, and total body fat of the MHD patients were within the normal range. The only significant change was an increase in the extracellular water/body cell mass ratio in the male MHD patients compared to the controls. The lack of significant difference of the nitrogen values of the MHD patients compared to matched controls suggests that dialysis minimizes any residual effects of uremic toxicity or protein-calorie malnutrition. These findings further suggest that there is a need to reevaluate the traditional anthropometric and biochemical standards of nutritional status for MHD patients. It was concluded that it is particularly important to measure protein stores of MHD patients with low protein intake to ascertain nutritional status. Finally, in vivo measurement of total body nitrogen and potassium for determination of body composition provides a simple, direct, and accurate assessment of the nutritional status of MHD patients.

Comparison of methods of estimating body fat in normal subjects and cancer patients.

Total body fat can be indirectly estimated by the following noninvasive techniques: determination of lean body mass by measurement of body potassium or body water, and determination of density by underwater weighing or by skinfold measurements. The measurement of total body nitrogen by neutron activation provides another technique for estimating lean body mass and hence body fat. The nitrogen measurement can also be combined with the measurement of total body potassium in a two compartment model of the lean body mass from which another estimate of body fat can be derived. All of the above techniques are subject to various errors and are based on a number of assumptions, some of which are incompletely validated. These techniques were applied to a population of normal subjects and to a group of cancer patients. The advantages and disadvantages of each method are discussed in terms of their ability to estimate total body fat.

In vivo measurement of body nitrogen by analysis of prompt gammas from neutron capture.

A method for the in vivo determination of body nitrogen by prompt gamma photons from neutron capture is described. An 85-Ci 238Pu-Be source provides the neutrons. The gamma detection system consists of two 15.24 x 15.24 cm Nal(TI) detectors placed above the patient. Absolute value of body nitrogen is determined using body hydrogen as an internal standard. The reproducibility of the method is +/- 3% for a body dose of 26 mrem.

Gamma resonance absorption. New approach in human body composition studies.

The main stream of body elemental analysis is based on the delayed, prompt, and inelastic neutron interactions with the main elements found in the human body, and subsequent analysis of the measured delayed or prompt gamma ray spectra. This methodology traditionally was, and still is, applied for whole body analysis and requires relatively high radiation doses. A new method, based on gamma nuclear resonance absorption (GNRA), is being established at Brookhaven National Laboratory as part of its body composition program. The method is element specific with a high tomographic spatial-resolution capability, at a small fraction of the radiation dose used in the current system. The new system, with its components and capabilities, is described below.

Gamma ray nuclear resonance absorption: an alternative method for in vivo body composition studies.

We have evaluated gamma ray nuclear resonance absorption (gamma-NRA) on nitrogen, a mature technology proposed and developed by Soreq NRC for detecting explosives, as an alternative to neutron activation for in vivo assaying of body nitrogen. The principles of the gamma-NRA method are outlined, and a test facility constructed at McMaster University's Accelerator Laboratory is described. The results of a feasibility study recently performed there on phantoms and animal tissue are presented and discussed. gamma-NRA is a full imaging technique that essentially constitutes element-specific absorptiometry--i.e., it can generate projections of the mass distribution for a specific element, along with a conventional radiograph of the patient. From the transmission profile of an individual scanned by 9.17 MeV gamma rays, local or whole body nitrogen content can be determined via the resonant attenuation undergone when the beam encounters regions of nitrogen concentration. The advantages of gamma-NRA over neutron activation are (a) radiation doses delivered to the body are at least one order of magnitude lower, thus allowing repeated measurements on individual patients and also rendering the method ethically acceptable for application to children; (b) gamma-NRA is inherently free from uncertainties related to nonuniform distributions of the element in question within the body; (c) it is applicable to patients of varying size and shape; and (d) it yields both nitrogen images and conventional radiographic images of the body.

Effects of caloric restriction on body composition and total body nitrogen as measured by neutron activation.

The purpose of this study was to compare the effects of two isocaloric diets (800 Kcals) on the changes in body composition during weight reduction. While the protein content of both diets was 70 g, the carbohydrate content of diet A was 10 g and that of diet B was 70 g. The various parameters of body composition were determined as follows: Total body potassium (TBK) by 40K counting, total body water (TBW) by the tritiated water technique, total body nitrogen (TBN) by prompt gamma neutron activation analysis (PGNAA) and total body fat was estimated by measuring the skinfold thickness. Routine serum chemistries were performed every 2 wk and serum insulin and triiodothyronine by radioimmunoassay were done at 4-wk intervals. Seventeen obese women who were at least 30% above ideal body weight volunteered for the outpatient study, (group A--10 subjects, group B--7 subjects). At the end of the 12 wk study, the percent changes in the above parameters of body composition were not significantly different for the two groups. The biochemical changes were consistent with the degree of caloric restriction. We conclude that: (1) the technique of prompt gamma neutron activation analysis can be used effectively to determine long term changes in total body nitrogen during weight reduction, (2) loss of lean tissue (water, potassium and nitrogen) as well as fat tissue occurred during weight reduction. The loss of TBN in absolute quantities was less for diet A compared to diet B; however, there was no significant difference between the two diets when the data was expressed as a percent change from the baseline values, and (3) TBK determination probably provides the best estimate of total body fat.

Compartmental body composition of cancer patients by measurement of total body nitrogen, potassium, and water.

Quantitative measurement was made of body composition in patients with several forms of neoplastic disease. Total body nitrogen was determined by means of the prompt gamma neutron activation technique; total body potassium was measured with the use of a whole body counter. The mass and protein content of the muscle compartment and nonmuscle lean tissue were estimated by application of the technique of compartmental analysis. Total body water, determined simultaneously with the use of tritium label, provided a measure of lean body mass. From these data, the body fat can be inferred. The prompt gamma neutron activation and whole body counting techniques represent a considerable advance over the balance and radioisotope techniques used in earlier studies. The new techniques make possible sequential studies over prolonged periods of time with a considerable degree of accuracy. The loss of body weight by patients with solid tumors consisted primarily of the loss of muscle mass and body fat. Even in severe wasting, the patients appear to retain significant amounts of body fat. It is the skeletal muscle which is predominantly lost; the visceral life-supporting system is, to a considerable extent, spared. The nonmuscle tissue including the visceral fraction did not change in this study, and actually appeared to increase in size when comparison was made with the normal contrast population. The loss of total body water was slight in the cancer patients studied.

Feasibility of noninvasive analysis of lead in the human tibia by soft x-ray fluorescence.

A postmortem study was conducted to assess the feasibility of measuring bone lead concentrations noninvasively in vivo. Characteristic L x rays were induced with an external source of 125I in the superficial tibial cortex of the intact legs of six adults who had no history of occupational exposure to lead. Tibial lead concentrations in the same bones subsequently determined by flameless atomic absorption spectroscopy varied from 15 to 35 micrograms Pb/g wet weight. The upper limit for the modern normal range of lead in the bone is about 25 mg Pb/g wet tissue. The linear correlation coefficient (r) between the measurements made with x-ray fluorescence and lead concentration by absorption spectroscopy was 0.90. Radiation doses of 10 mGy (1 rad) to 1 cm2 of skin, with associated doses to the marrow of adjacent bone of about 0.6 mGy (60 mrad), yielded net lead fluorescence signals ranging from one to seven times the standard deviation of background.

Silicon measurement in a lung phantom by neutron inelastic scattering.

A study was made to assess the feasibility of determining the silicon level in human lungs in vivo by measuring the gamma rays arising from the neutron inelastic scattering reaction 28Si(n, n' gamma)28Si. Neutron energies in the range 5--8 MeV represent the best compromise between the conflicting requirements of high energy for good detection statistics and low energy to minimize the dose to the subject. The sensitivity of measurement was enhanced by pulsing the neutron beam and counting only during the period of bombardment. This effectively reduced the background counts emanating from thermal neutron reactions in the phantom and from the fast neutron reaction 31P(n, alpha)28 A1. In measurements with an anthropomorphic phantom, no interference peaks from other prompt inelastic scattering reactions were observed. With one Ge(Li) detector of 19% relative efficiency, a detection limit of 0.6 g of silicon per 10 mSv was obtained. On this basis, it is estimated that six Ge(Li) detector of 25% efficiency each would be capable of measuring 0.15 g of silicon in the lungs, the average level found in nonoccupationally exposed adults.U

A facility for in vivo measurement of lithium.

A facility for measurement of Li in-vivo based on measurement of exhaled HT gas has been constructed and tested. Li present in the brain of therapeutically treated individuals could be measured with a dose to the brain of 1 rem. It will be possible to locate grossly the non-uniformity of Li, left-right or front-back sides of the brain, by choosing the proper energy of neutrons. Experiments with larger animals such as sheep are planned.

Applications of nuclear technologies for in vivo elemental analysis.

The objectives of this Department of Energy sponsored program are (1) to improve existing nuclear techniques, and (2) to develop new techniques for the analysis and solution of both medical problems and those associated with environmental pollution. Measurement facilities developed, to date, include a unique whole body counter, (WBC); a total body neutron activation facility (TBNAA); and a partial body activation facility (PBNAA). A variation of the prompt gamma neutron activation technique for measuring total body nitrogen has been developed to study body composition of cancer patients and the effect of nutritional regimens on the composition. These new techniques provide data in numerous clinical studies not previously amenable to investigation. The development and perfection of these techniques provide unique applications of radiation and radioisotopes to the early diagnosis of certain diseases and the evaluation of therapeutic programs. The PBNAA technique has been developed and calibrated for in vivo measurement of metals. Development has gone forward on prompt gamma neutron activation for the measurement of cadmium, x-ray fluorescence (XRF) for measurement of lead, and nuclear resonance scattering (NRS) for measurement of iron. Other techniques are being investigated for in vivo measurement of metals such as silicon and beryllium. Cardinal to all toxicological studies of Cd and other metal pollutants is an accurate and sensitive noninvasive technique for measuring organ burdens. In keeping with the mission of Brookhaven, these facilities have been made available to qualified scientists and members of the medical community throughout the world.

Nuclear resonant scattering of gamma rays--a new technique for in vivo measurement of body iron stores.

A technique for the measurement of body iron utilising nuclear resonant scattering of gamma rays has been developed. 847 keV photons emitted from a gaseous 56MnCl2 source are resonantly scattered from 56Fe present in the body. Measurement is made using large volume Ge(Li) detectors. The spatial uniformity of activation, the sensitivity of the detection system and the limits of detection have been investigated. Measurements were made on a liver phantom. The resonance scattering technique permits determination of normal levels of Fe in the liver with a radiation dose of 2 rem.

A comparison of 252Cf and 238Pu, Be neutron sources for partial-body in vivo activation analysis.

A comparison is made of the isotopic neutron sources 252 Cf and 238 Pu, Be for partial-body in vivo neutron activation analysis. Depth distributions of thermal neutron fluences in a water phantom are very similar for the two sources. The peak depth occurs at 5 cm. This value is approximately 2 cm less than the values obtained with uncollimated neutrons produced in broad-beam irradiations. With respect to the fluence-to-dose ratio, the 252 Cf neutrons have an advantage of approximately 1.4 over the 238 Pu, Be source. The use of 252 Cf offers two additional advantages for the investigator. First, it minimizes the on-line fast-neutron damage in Ge(Li) semiconductor detectors. Secondly, it is subject to much less stringent transport regulations that 238 Pu, Be. The latter feature takes on particular importance in view of the increasing usefulness of transportable instruments for in vivo cadmium measurements at the workplace.

In vivo determination of prostatic zinc: phantom feasibility study.

This paper describes a phantom-based feasibility study for a potential in vivo determination of zinc in prostate, which could bring about improved diagnosis of prostate cancer. An x-ray fluorescence topographic technique was developed, which will permit determination of the Zn content in the prostate through the rectum, namely behind a 2-3 mm thick layer of the rectal wall. The topographic approach, together with a reconstruction method developed here, minimizes the interference of Zn from non-prostatic tissue. The phantom studies show that it will be possible to determine Zn in a prostatic compartment behind a few mm thick layer of tissue using a specially designed transrectal probe. Such a probe is currently under development in our laboratories.

A facility for in vivo measurement of kidney and liver cadmium by neutron capture prompt gamma ray analysis.

An in vivo method for the determination of Cd levels in human kidney and liver has been developed. The method allows detection of absolute quantities of Cd in the left kidney and Cd concentration in the liver. The limit of detection of cadmium is 2.5 mg for the left kidney and 1.8 microgram/g (wet weight) for the liver, for a localized dose of 670 mrem. The effects of patient positioning, organ geometry and liver-kidney interference on the measurement have been investigated using an Alderson phantom.

An improved calibration for the in vivo determination of body nitrogen, hydrogen, and fat.

Additional investigation of the authors' original technique for measuring total body nitrogen by prompt gamma neutron activation has demonstrated the need for certain changes in the calibration procedures in order to apply the method to studies of patients with abnormal metabolism. In the present technique, total body nitrogen, hydrogen, and fat were derived, simultaneously, from data obtained by neutron capture gamma-ray analysis combined with the measurements of body weight, total body water, and total body calcium. In this improved calibration technique total body nitrogen is more accurately measured, not only in normal subjects, but also in obese subjects and in patients with marked changes in hydration, such as cancer patients. The fat values calculated do not rely on a fixed relationship of total body water or total body potassium with lean body mass as in the previous studies, but are calculated as the difference between body weight and the sum of body water, protein and bone mineral ash. This improved technique has been applied to the study of three groups of subjects, the general population with a normal weight distribution and two extremes represented by obese and cancer patients.