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In x-ray phototherapy of brain tumours, the tumour is loaded with iodine and exposed to kilovoltage x-rays. Due to the high photoelectric cross sections of iodine, substantial photoelectric interactions occur. The flux of photoelectrons, characteristic x-rays and Auger electrons produce a localized dose enhancement. A modified computed tomography scanner, CTRx, can be used both for tumour localization and delivery of the dose enhancement therapy. Monte Carlo methods were employed to simulate the treatment of iodinated brain tumours with a CTRx. The calculated results reveal the effect of tumour iodine concentration on dose distribution, the degree of skull bone sparing with the application of multiple arcs, and the homogeneity of tumour dose distribution versus iodine concentration. A comparison with 10 MV stereotactic radiosurgery treatment shows the potential of CTRx treatment relative to conventional treatment modalities.

Brain masses diagnosed in 47 pet dogs as tumors by CT scans, and confirmed in 12 dogs by necropsies, were injected with iodinated contrast media and treated by a modified CT scanner, the CTRx. Twenty-six dogs that received six or more weekly treatments of about 5.6 Gy per fraction, of which about 25% was contributed by radiation from the iodine, for a median total dose of 39 Gy, had a median survival of 230 days. This compares well with the 150 days reported for 25 dogs given 46-48 Gy of cobalt-60 radiation to the whole brain, and is significantly greater than the 6 to 13 days in untreated historic controls.

Introduction To determine the tobacco industry's policy and action with respect to radioactive polonium 210 ((210)Po) in cigarette smoke and to assess the long-term risk of lung cancer caused by alpha particle deposits in the lungs of regular smokers. Methods Analysis of major tobacco industries' internal secret documents on cigarette radioactivity made available online by the Master Settlement Agreement in 1998. Results The documents show that the industry was well aware of the presence of a radioactive substance in tobacco as early as 1959. Furthermore, the industry was not only cognizant of the potential "cancerous growth" in the lungs of regular smokers but also did quantitative radiobiological calculations to estimate the long-term (25 years) lung radiation absorption dose (rad) of ionizing alpha particles emitted from the cigarette smoke. Our own calculations of lung rad of alpha particles match closely the rad estimated by the industry. According to the Environmental Protection Agency, the industry's and our estimate of long-term lung rad of alpha particles causes 120-138 lung cancer deaths per year per 1,000 regular smokers. Acid wash was discovered in 1980 to be highly effectively in removing (210)Po from the tobacco leaves; however, the industry avoided its use for concerns that acid media would ionize nicotine converting it into a poorly absorbable form into the brain of smokers thus depriving them of the much sought after instant "nicotine kick" sensation. Conclusions The evidence of lung cancer risk caused by cigarette smoke radioactivity is compelling enough to warrant its removal.

Ataxia-telangiectasia is a syndrome with many facets, involving a progressive cerebellar ataxia, immunodeficiency, cancer susceptibility, radiosensitivity, defects in DNA repair/processing, chromosomal breakage and rearrangements, elevated serum alphafetoprotein, and premature aging. Ataxia-telangiectasia is an autosomal recessive disorder, rare in outbred populations; carriers of the ataxia-telangiectasia gene may be as common as 1 in 60 and have subclinical radiosensitivity and cancer susceptibility. One estimate suggests that 8.8% of patients with breast cancer could be carriers of ataxia-telangiectasia. These carriers may be responsible for underestimating normal tolerance doses for radiation therapy by 15% to 20%; thus by preselecting and excluding carriers of ataxia-telangiectasia from cohorts of patients with cancer, conventional radiation doses might be increased so as to improve greatly the efficacy of radiotherapy. The genes for the 3 most common ataxia-telangiectasia complementation groups, which include 97% of tested families, have recently been localized to the long arm of chromosome 11.

RATIONALE AND OBJECTIVES The hypothesis that nonionic contrast medium administered during excretory urography may cause cytogenetic damage was tested. METHODS Micronuclei were scored in peripheral blood lymphocytes obtained from 33 patients before and after excretory urography with ioversol, a nonionic contrast medium. RESULTS The examination resulted in a highly significant (sign test, P = .005) increase in the median (range) counts of micronuclei per 1,000 binucleate from 18 (0 to 31) before to 24 (5 to 40) after excretory urography. CONCLUSIONS Nonionic ioversol produces a statistically significant increase in the chromosome damage of lymphocytes from patients undergoing excretory urography. This increase is similar to that reported for the ionic contrast media, ioxaglate and iothalamate, and equal to that produced by 6 to 7 cGy of 100-kilovolt x-rays.

Spontaneous brain tumors in 25 pet dogs were diagnosed and treated with a modified Cr scanner. Five or more weekly 9-Gy fractions resulted in marked clinical improvement in most dogs and a significant decrease in tumor size in many dogs without adverse effects from the radiotherapy.

Norman, A., Cochran, S. T. and Sayre, J. W. Meta-analysis of Increases in Micronuclei in Peripheral Blood Lymphocytes after Angiography or Excretory Urography. Radiat. Res. 155, 740-743 (2001). Meta-analysis of 10 studies confirms a significant increase in the frequency of micronuclei in peripheral blood lymphocytes after angiography or excretory urography; the weighted average increase is 4.2 (95% confidence interval 2.8-5.6) per 1000 binucleate lymphocytes, about the same increase in micronuclei as that produced in vitro by a diagnostic X-ray dose of 4 cGy. The analysis failed to reveal a significant effect of the specific contrast medium used in the X-ray examinations on the increased frequency of micronuclei. These results are consistent with the hypothesis that the effect of the contrast media is limited to the enhancement, by the photoelectric effect, of the X-ray dose absorbed by the lymphocytes irradiated while suspended in the contrast medium. Therefore, an estimate of increased cancer risk based on elevated frequencies of micronuclei or chromosome aberrations in peripheral blood lymphocytes may be greatly exaggerated whenever the radiation damage is largely confined to the cells circulating in the blood, as it is in people who have recently had X-ray examinations that use intravenous injections of contrast medium. Such examinations include angiography, excretory urography and CT scans, which are received annually by millions of people.

Purpose: This Phase I study was designed to evaluate the computed tomography (CT) scanner as a device for radiation therapy of human brain tumors (CTRx). This first use in humans of a modified CT for treatment was founded on extensive research experience with canine tumors. An additional objective was to increase the therapeutic radiation dose to tumors compared to normal tissue by concentration of infused contrast material in tumors, an effect available at diagnostic x-ray energies but not at megavoltage energies. Methods and Materials: A small metastatic brain tumor in each of eight patients received 3–5-weekly fractions of 5 Gy equivalent per fraction from a CT scanner modified to deliver radiation therapy. In each patient, one additional tumor, lying completely outside the volume treated by CTRx, served as a control. The tumor receiving CTRx was treated after infusion of iodinated x-ray contrast media (CM) for dose enhancement. Many of these patients also received conventional 40 Gy whole brain radiation, before, during, or after CTRx treatment. Results: None of the patients showed adverse reactions to the CM or necrosis of the normal brain from the CTRx boost radiation. Monte Carlo calculations of the radiation dose distributions in a model tumor showed that the CTRx irradiation of tumors carrying 10 mg or more of iodine per gram of tumor was as good or better than the dose distribution from conventional 10-MV X-rays. The treated tumor in two of the patients vanished after four treatments, whereas a control tumor in one patient remained constant and grew 4-fold in another patient. Conclusion: The CTRx concept effectively combines a modified CT scanner as a diagnostic device, as a simulator dedicated to radiotherapy, and as a treatment machine. Thus, CTRx could be very useful for radiation oncologists in controlling CM-enhanced and other small brain tumors.

Linoleic acid (LA) administered orally as safflower oil (SFO), which is 76% LA, produced remission in 6 out of 8 dogs with mycosis fungoides (MF). Following each feeding of SFO on 5 successive days to a normal dog peak plasma levels of non-esterified (free) LA in excess of 200 microM were observed. No clinical toxicity was observed from the SFO feedings in the normal or MF animals at the levels of SFO (3 ml/kg) used in these studies. However, a marked rise in white blood cells (WBC) and lymphocytes and a marked transient drop in the serum glutamine transaminases SGOT and SGPT was noted both in the normal and MF animals. These effects of LA may be significant for the remission of MF.

When brain tumours are loaded with iodinated contrast media (CM) and exposed to x-rays, the photoelectrons, Auger electrons and fluorescent x-rays from the iodine enhance the radiation dose absorbed by the tumour. A modified CT scanner, the CTX, can be used to localize the tumour and to deliver the dose enhancement therapy. Monte Carlo calculations are presented here of the central-axis radiation depth dose in a brain containing a tumour loaded with an iodine concentration of 5 mg ml-1 and irradiated with the CTX operated at various kV settings. The dose enhancement factor (DEF) is also calculated for various field sizes and for 5 mg ml-1 of gadolinium in the tumour when the CTX is operated at 140 kV. The calculated values of the DEF are close to published experimental results.

We tested three radiobiologic models, the nominal standard dose (NSD), the biologic index of reaction (BIR), and the linear quadratic (LQ) models to determine which best predicts normal tissue injury in radiation therapy. Clinical data for radiation myelopathy, rib fracture and pericardial effusion were used for all three models to predict injury. We assumed that on the average injuries occurred at higher equivalent doses of radiation than were received by patients who were not injured. We used a t-test to determine whether there were in fact significant differences in the mean values of the equivalent doses among the injured and non-injured. The means were calculated for the four sets of injury by the three models. For the LQ model it was necessary to choose a value for the parameter α β ; the results were not sensitive to the choice over the range of 1 2 to 12 Gy. None of these models showed a significant difference between injured and non-injured patients for all four sets of data. The BIR model showed significant differences in three sets, the LQ model was significant in two and marginally significant in one set, and the NSD was significant in two sets. This analysis illustrates therefore, that the linear quadratic model can be adopted for analysis of clinical data with results that are no worse and possibly better than the NSD model.

Many tumors in the brain and in other tissues can be delineated precisely in images obtained with a CT scanner. After the scan is obtained the patient is taken to another room for radiation therapy and is positioned in the beam with the aid of external markers, simulators or stereotactic devices. This procedure is time consuming and subject to error when precise localization of the beam is desired. The CT scanner itself, with the addition of a collimator, is capable of delivering radiation therapy with great precision without the need for external markers. The patient can be scanned and treated on the same table, the isocenter of the beam can be placed precisely in the center of the lesion, the beam can be restricted to just those planes in which the lesion appears several arcs can be obtained by simply tilting the gantry, and the position of the patient in the beam can be monitored continuously during therapy. We describe here the properties of the CTX, the CT scanner modified for therapy.

Positive lymph modes are a direct demonstration that a specific tumor has been able to metastasize in a specific patient, and the ability to metastasize determines the probability of relapse

The age dependence of poor cosmesis from breast irradiation and the frequency of micronuclei (MN) in buccal cells provide indirect evidence for the presence of a relatively radiosensitive subpopulation of ataxia telangiectasia (AT) heterozygotes in breast cancer patients

We have examined the metabolic behavior of several triiodobenzoic acid derivatives because of the observed mutagenicity and cytotoxicity of 3-amino-5-acetamido-2,4,6-triiodobenzoate (I) and 3,5-diamino-2,4,6-triiodobenzoate (II). Measurements were facilitated using iodine-131 (131I)-labeled compounds. Drug retention in rabbits was monitored with a gamma camera. Metabolic products were studied by column and thin-layer chromatography. 3,5-Diacetamido-2,4,6-triiodobenzoate (diatrizoate) was partially deacetylated by liver microsomes to I and II. II was transformed in part to another substance whose structure remains undetermined. About 1% of nominal doses of I, II, and diatrizoate were retained for several days following intracardiac injection in rabbits. The rabbit did not appreciably acetylate I to diatrizoate and converted some of II to a urinary metabolite which was similar to that formed by liver microsomes. I was present in human urine following excretory urography with diatrizoate, but II was not detected. Manufacturers of diatrizoate should further reduce the level of free aromatic amines in preparations of diatrizoate. A method of doing so is reported.

The loading of tissue with iodine can result in the enhancement of the radiation dose absorbed from low-energy x-ray or gamma ray sources. We have explored the potential of this phenomenon for radiation therapy. We have demonstrated the effect of iodine concentration and radiation quality on this dose enhancement in lymphocytes, we have calculated the effect of such enhancement on depth dose distributions in the brain, we have estimated the iodine content in two human brain tumors during computerized tomography (CT) scans, we have studied the dispersion of the iodine contrast media after direct injection into rabbit tumors, and we have demonstrated that the combination of x-ray and contrast media injection is far more effective than either agent alone in causing the regression of mouse tumors. These results suggest that there may be a therapeutic advantage from loading tumors with iodine and treating them with low-energy photons.

Acentric chromosome fragments produced in cells by irradiation or other agents give rise to micronuclei in daughter cells. The micronuclei can be readily counted in large numbers of cells thereby providing a sensitive measure of chromosome aberrations. Previous studies have shown a consistent elevation of micronuclei count following the use of diatrizoate contrast materials. This study was undertaken to compare the micronuclei counts of patients receiving sodium iothalamate with those receiving sodium diatrizoate. Our results indicate that sodium diatrizoate produced significantly greater cytogenetic damage than the sodium iothalamate agents.

We have adapted a multiparameter cell sorter to measure the distribution of fluorescence polarization in cell populations. Measurements carried out on EL4 cells show that the percent polarization of fluorescein fluorescence decreases with increasing fluorescence intensity. This inverse relationship between polarization and intensity is shown both within the cell population and by the average values of the two quantities during both the increase and decrease of fluorescence intensity. The quantitative relation between intensity and polarization is different in hypertonic than in isotonic media. These results suggest that polarization measurements carried out at a fixed time after incubation of cells with fluorescein diacetate, which is converted to fluorescein within the cells, may depend in part on the rate of fluorescein accumulation, and that agents that have been reported to change the polarization of fluorescein in living cells may do so by changing the kinetics of fluorescein accumulation.

SummaryThe appearance of micronuclei (MN) is delayed with respect to cell division in populations of irradiated human lymphocytes, so that the length of time in culture, as well as the number of divisions, is a factor in MN assays. Using two assays that control for cell kinetics, we measured the yield of cells with MN exposed to graded doses of 60Co gamma rays and 90 KVP X-rays. The yields showed a non-linear increase with dose. They can be represented by two straight lines: the one in the range below 0·15 Gy has a slight slope, the other in the range above 0·15 Gy has a significantly greater slope. The radical scavengers cysteamine and glycerol, which reduced the MN yields sharply at 3 Gy, were less effective at 0·3 Gy, indicating that terminal deletions arising from the direct ionization of DNA are a major source of the MN induced by low radiation doses. It is likely that the non-linear dose response is due to the saturation of a DNA repair process.

Summary Loading tissue with iodine enhances the radiation dose absorbed from low energy X-rays. In order to test whether this is a useful procedure for treating brain tumors, we infused radiographic contrast media into rabbits carrying VX-2 brain tumors and delivered 15 Gy of 120 kVp X-rays in 3 fractions to the tumor. From CT scans we estimated that the dose enhancement was approximately 30%. The median survival times, after tumor detection on CT, of untreated rabbits, treated with radiation alone, and treated with radiation plus contrast media were 3, 25.5, 38.5 days, respectively. The repeated infusion of contrast media, 3.5 g of iodine per kg of body weight, did not affect kidney function as measured by serum creatinine levels. This method of enhancing radiation dose in brain tumors therefore appears promising.

The frequency of micronuclei assayed in lymphocytes obtained from 73 young adults increases significantly with the age, but not the sex, of the donor. The dose of medical X-rays absorbed by the lymphocytes in the 2 years before the examination has no significant effect on micronucleus frequency, provided the data are adjusted for age. However, a small significant increase in frequency is associated with X-ray examinations that involve the injection of contrast media into the blood.

Summary The RBE for 125 I relative to 30 keV X-rays, 4 MeV X-rays and 137 Cs gamma rays was determined using the induction of micronuclei in human lymphocytes as the biological test system. The 125 I photons were as effective as the 30 keV X-rays. If a micronuclei count of 50 per 1500 cells is used as the endpoint, the RBE for 125 I was found to be about 1.8 and 1.6 when 4 MeV X-rays and 137 Cs gamma rays were used as the reference radiation, respectively.

We have found that by increasing the bromodeoxyuridine (BUdR) concentration to 4 × 10−4 M in cultures and using the conventional harlequin staining procedure we can distinguish the proliferating lymphocytes by their blue color from the non-proliferating cells which have red nuclei. The micronuclei (MN) are also blue and are associated with the proliferating cells. The high BUdR concentration does not appear to affect the yield of MN. By scoring the MN only in the (blue) proliferating cells the MN assay is made less sensitive to perturbations in the lymphocyte cultures caused by radiation or by variations in the culture time on PHA concentration. Moreover, the frequency of cells with MN approximately doubles and thus comes into better agreement with the frequency of cells with chromosome aberrations. A better agreement yet can be achieved by correcting the assay for the effect of cell division.

Measurements of the intensity and polarization distributions of fluorescein fluorescence in human lymphocyte populations show changes within minutes after exposure of the cells to the mitogens phytohemagglutinin and Concanavalin A. The distributions of polarization, which before mitogen exposure show essentially a single peak, after exposure develop a second peak at a lower value of polarization. Simultaneously, the intensity distributions show a shift to higher levels of intensity. These shifts can be modeled on the basis of a subpopulation of lymphocytes responding to mitogen. Interpretation of the results is complicated by many factors that may influence the shape of the polarization distributions. In particular we show that the measurements are sensitive to the concentrations of phytohemagglutinin, Concanavalin A, Ca++, K+, fluorescein diacetate, the incubation time and the specific donor. Nevertheless, fluorescein fluorescence measurements provide a rapid and sensitive method for studying the physiology of lymphocytes and for identifying responding lymphocyte subpopulations.

B-mode scans of castor oil in a wedge-shaped container provide gray level maps. The relation between the gray levels and the amounts of absorbing medium can be used to measure the effects of electronic gain, transducer characteristics, and the overall gray level performance of different ultrasound systems. We report results from four units and ten transducers for varying scanning depths.

A new and practical test for evaluating the fertility of a male subject has been developed. Twenty-eight donors whose semen had induced at least one pregnancy resulting in a normal delivery and 61 patients attending our infertility clinic were studied. Semen smears stained with acridine orange were read on a fluorescence microscope; sperm heads appeared either green (fertile) or red ( nonfertile ). We introduce the concept of an "effective sperm count" which is obtained by multiplying the percentage of green-fluorescing sperm by the actual sperm count. Of our fertile subjects, 27 of 28 (96.4%) exhibited an effective sperm count of greater than or equal to 50 million/ml, while 60 of 61 (98.3%) infertile patients fell below this value. The percent green correlates with neither actual sperm count nor motility, indicating that this test measures a new parameter of male fertility.

Lymphocytes cultured with 4 X 10(-4) M bromodeoxyuridine (BrdU) and stained by the harlequin procedure show wide variations in the colour and texture of their interphase nuclei. We demonstrate that we are able, by inspection, to identify four sets of nuclei: small dark nuclei (D) in cells that have not transformed in response to mitogenic stimulation; red nuclei (R) in transformed cells that have not synthesized DNA in culture; speckled nuclei (S)--red speckles on a bluish background--in cells that are synthesizing DNA for the first time in culture; blue nuclei (B) in cells that have completed one or more cycles of DNA synthesis. By using this modified harlequin stain to score the fraction of proliferating cells, and using the modified or conventional harlequin stain to determine the relative frequencies of mitotic cells in the first, second, or later divisions, we are able to estimate the fraction of lymphocytes in the original blood sample that can divide in culture. In addition, we show that the technique lends itself to automation. For this we have digitized black and white video images of the cells and extracted features based on the distribution of optical densities in the nuclei. Discriminant analysis carried out on these descriptors resulted in the correct classification of the three major groups R, S and B with an accuracy of 80.3%, 58.5% and 85.1%, respectively.

A rabbit brain tumor model using transplanted VX-2 carcinoma had an 85% rate of successful implantation. Rabbits lived 8.5 +/- 1.3 days. The tumor doubling time was 0.5 to 2.6 days. Some tumors were shown as early as four days after implantation and all tumors were seen by ten days after implantation. Two of three rabbits receiving radiation therapy to the tumor had significant extension of life. This model is a useful radiologic research tool.

We have calculated the distribution of DNA contents in micronuclei (MN) induced by ionizing radiation in human lymphocytes on two assumptions: the MN arise from acentric chromosome fragments (ACF), and the ACF result from the random breakage and rejoining of chromosomes. Measurements show that about 80 per cent of MN have a DNA content in the range of 0·5-6 per cent of the G1 nucleus. This group is consistent with the model and shows little dependence on radiation dose over the dose range of 0·5-4 Gy, or on lymphocyte culture time, varying from 48 to 76 hours. The MN with DNA content from 6 to 20 per cent of the G1 nucleus are probably the result both of spindle defects and of DNA synthesis in MN.

Exposure measurements made during a diagnostic radiological study revealed that heavy set patients pay a higher price in absorbed dose than lighter people.

Micronuclei counts in blood samples from 9 patients before and after angiocardiography have confirmed previous results suggesting the diatrizoate contrast medium was largely responsible for the observed cytogenetic damage. To discover the agents in the medium causing the cytogenetic damage, we exposed human lymphocyte cultures to diatrizoate and to the monoamino- and diamino-derivatives of triiodobenzoic acid. The results show the amino-derivatives are capable of inhibiting mitosis and inducing micronuclei and chromosome aberrations at lower concentrations than diatrizoate.

Current diagnostic cardiac studies in infants and children result in longer x-ray exposure times and in more angiocardiograms per patient. Blood samples removed before and immediately after such studies in 20 infants and children have shown chromosome damage in all. The damage was equal to an in vitro absorbed dose in the range of 20 to 50 rads. Since the effect was considerably greater than that calculated from the x-ray exposure dose to the patient, it is concluded that the damage is mainly due to the contrast agent used in angiocardiography. Long-term follow-up studies on such patients are indicated.

There is growing evidence that a fraction of cancer patients, perhaps as high as 15%, is radiation sensitive because of the action of specific genes. It seems likely that in the near future we shall be able to identify these patients by DNA probes. Therefore, we have calculated the impact on radiation therapy of removing these patients and treating the rest more aggressively. In particular, we assumed that the radiation oncologist will treat with an effective therapeutic dose corresponding to a 5% risk of serious normal tissue injury. Our results, in several instances, show a considerable increase in local control when the 5, 10, or 15% of the most radiosensitive patients are removed from the treated group. This is so, even if we assume that the tumor cells, as well as the normal cells, in radiosensitive patients are more radiosensitive than the tumor cells in patients of normal radiosensitivity.

Measurements of chromosome aberrations or micronuclei in lymphocytes obtained from 7 patients indicate that angiocardiography produced chromosome damage corresponding to an average absorbed dose of about 50 rads. This is an order of magnitude larger than was estimated from the exposure rate. Experiments on lymphocytes suspended in solutions of methylglucamine and sodium diatrizoate (Renografin) or sodium diatrizoate alone (Hypaque) indicate that the chromosome damage observed in the patients is due in larger part to two effects: (a) an increased absorption of x rays as compared to blood and (b) a breakage of chromosomes even in the absence of x rays.

Measurement of fluorescence polarization (P) gives information about the immediate environment of the fluorescent molecule. We used a flow polarimeter to investigate the factors influencing P of fluorescein in mammalian cells to determine whether such measurements are useful for characterizing heterogeneous cell populations. Fluorescein was introduced into cells by incubation with FDA. Measurements of the intensity of fluorescence (TI) and polarization (P) revealed an unexpected dependence: P decreased with increasing intensity of fluorescence. This may be accounted for by the classical model of the binding of small molecules to protein in which P is dependent on the ratio bound to unbound molecules. We have been able to estimate the quenching due to binding and construct a Scatchard plot. We estimated a wavelength shift from in vitro data consistent with the dependence of P on wavelength seen in our cell work. Generally, the distributions of P are symmetrical. Photon statistics broadens the P distribution of dim cells. However, structure does develop in the P distribution when the cells are deprived of calcium or incubated in the cold. This appears as a shoulder on the P distribution or resolves into two peaks. Calcium deprivation may differentially affect a subpopulation of cells whose significance remains to be explored in various cell types.

We have measured the grain density - the number of grains per unit length - over the centromere and noncentromere regions of metaphase chromosomes in autoradiographs of human lymphocytes. When the chromosomes were labeled in G/sub 0/ by uv-induced unscheduled DNA synthesis, the grain density was two to four times larger over the centromere than over the noncentromere regions. When the labeling was done by scheduled DNA synthesis in S or unscheduled synthesis in M, the grain densities were approximately equal over both regions.

To identify the components in a microsomal fraction from the small intestinal mucosa of mice that were responsible for preventing the proliferation of Ehrlich ascites tumor (EAT) cells, we subjected the fraction to thin-layer and gas chromatography. Assays for cytotoxicity against EAT cells in vitro indicated that linoleic acid, which was present in the free fatty acid fraction at a surprisingly high concentration, was probably the major component responsible for the antitumor activity. In further assays, using the water-soluble salt sodium linoleate, we found that sodium linoleate was more effective in vitro in killing human chronic lymphocytic leukemia lymphocytes than normal lymphocytes and mouse leukemic thymocytes than normal thymocytes. We also found that a single intraperitoneal injection of 1 mg of sodium linoleate into Swiss-Webster mice one day after the mice were inoculated with EAT cells increased the median survival from 18 (in the controls) to 48 days (in the treated mice) and prevented tumor growth completely in over 40% of the treated mice. These results are consistent with the hypothesis that linoleic acid plays a significant role in keeping the small intestine from developing primary cancers. Results also suggest a potential role for sodium linoleate in cancer therapy.

SummaryPhysiological concentrations of linoleate reduce the frequency of micronuclei and chromosome aberrations in mouse bone marrow cells in vivo and of micronuclei in human lymphocytes in vitro when adminstered one hour after exposure of the cells to gamma rays.

Administration of x-ray contrast agents during heart catheterization examination increases the absorbed radiation dose in tissue. To estimate the dose absorbed by the blood of children undergoing diagnostic heart catheterization and angiocardiography, a number of measurements and calculations were conducted. First, entrance and exit exposures to the patient were measured with thermoluminescent dosimeters calibrated for the diagnostic x-ray energy range. Second, a dose enhancement factor was calculated from mass energy absorption coefficients for various concentrations of the contrast media and at selected x-ray energies. Third, the dose enhancement factor was estimated from survival of peripheral blood lymphocytes suspended in varying concentrations of the contrast agent during exposure to graded doses of x-rays. Fourth, a mean absorbed dose to the patient's blood was calculated using (a) the dose enhancement factor determined above, (b) an estimate of the mean exposure in the irradiated body volume calculated from the entrance and exit exposure measurements, (c) an effective iodine concentration in the blood during the exposure time, and (d) a ratio correcting for the distribution and circulation of the blood. For eight pediatric patients monitored, absorbed doses to the blood ranged between 3 and 12 rad. These values were two to three times greater than the expected dose without administration of a contrast agent.

We have defined variants (V) resistant to 6-thioguanine (TG) by their ability to divide at least once during a 72-h incubation in a medium containing 0.2 mM TG. We blocked cytokinesis by adding cytochalasin B (CB) after 30 h in culture. The cells that had undergone nuclear division were identified by their content of 2 or more nuclei. The long incubation period allowed slow growing V to be counted. As a result we scored an order of magnitude more V than have been reported in assays using the conventional 30–40 h culture times. In the γ-ray dose range of 0–0.5 Gy we scored 80 V per 1000 surviving lymphocytes per Gy — a result some two orders of magnitude larger than has been reported previously.

Acentric chromosome fragments produced in cells by irradiation or other agents give rise to micronuclei in daughter cells. The micronuclei can be counted readily in large numbers of cells which provides a sensitive measure of chromosome aberrations. Previous studies have shown that the presence of contrast material enhances the radiation-induced yield of micronuclei in vitro. This may be due to the dose enhancement effect and the chemical action of contrast media or their derivatives. Micronuclei were scored in peripheral blood lymphocytes obtained from 26 patients before and after excretory urography (ExU). The results show a consistent and significant increase in the counts after ExU amounting to about one third of the counts blood samples before the examination. We have also measured radiation exposures in this group and estimated an average exposure to the circulating lymphocytes of about 0.2R (0.52 X 10(-4) C/kg). We conclude that the contrast medium contributed significantly to the increase in micronuclei.

A brief review of flow cytometry is presented. Emphasis is on the construction of relatively simple instruments and on their application to problems in medical physics. Among these are the problems of measuring the biological parameters that determine the response of tumors to therapy and of measuring the biological damage in people exposed to ionizing radiations.