Thyroid radiation doses during radioimmunotherapy of CEA-expressing tumours with 131I-labelled monoclonal antibodies

A number of radioimmunotherapy (RAIT) trials with iodinated antibodies have shown a high variability in the radiation doses to the thyroid. Therefore, the aim of this study was to evaluate which factors influence these thyroid doses during RAIT with 131iodinated monoclonal anti-carcinoembryonic antigen (CEA) antibodies. Data from 36 patients with CEA-expressing tumours were analysed. The patients underwent RAIT with the 131I-labelled IgG1 anti-CEA antibody, MN-14 (Ka = 10(9) l mol-1) or its F(ab')2 fragment (activity range 45.8-220.0 mCi). The thyroid was blocked with 120 mg iodine (lugol's orSSKI solution) and 400 mg perchlorate per day, starting 1 day prior to the first study. Blood clearance and molecular composition of labelled plasma compounds were determined by blood sampling and size-exclusion high-performance liquid chromatography analysis. The cumulated activities of tissues were determined from daily imaging and blood clearance data. Doses were derived from the MIRD scheme. Thyroid radiation doses showed a high variability, between 1.2 and 37.7 cGy mCi-1 (mean +/- S.D.: 11.1 +/- 8.3 cGy mCi-1), corresponding to absolute doses between 2.5 and 43.6 Gy. However, the maximal iodine uptake in the thyroid was 2.4 +/- 1.9 microCi mCi-1 (range 0.2-10.0 microCi mCi-1), which was less than 1% of the injected activity, indicating that more than 99% of the thyroid was blocked in all cases. No correlation was found between these thyroid doses and conditions leading to an enhanced exposure to free radioiodine, such as unbound I- in the mAb preparation, rapid metabolic breakdown of the labelled antibody due to human anti-mouse antibodies (HAMA), or immune complex formation with circulating antigen. However, a relationship between the thyroid doses and the patients' compliance in taking their Lugol's and perchlorate blocking medications, as well as to a relatively high variability in the biological half-life of the iodine in the thyroid (range from 31.1 h to virtual infinity), is indicated. No rising TSH titres or other signs of (latent) hypothyroidism were seen in these patients during a 2 year follow-up period. Longer follow-up was not possible because of the terminal condition of most of the patients. These data show that thyroid doses in an appropriately blocked individual given a standard, non-myeloablative dose of RAIT, are generally lower than those assumed to be required to cause late hypothyroidism. Even if higher activities are used, potential hypothyroidism may be overcome easily by hormone replacement. Thyroid doses are independent of parameters leading to an enhanced exposure of the thyroid to free radioiodine, suggesting that patient compliance in taking their blocking medication may be the most crucial factor for reducing thyroid doses in RAIT with 131I-labelled antibodies.     

The relative effectiveness of exposure to 131I at low doses

BACKGROUND: Reactive oxygen and nitrogen derived species produced by activated neutrophils have been implicated in the damage of mucosal proteins including the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the active inflammatory lesion in patients with inflammatory bowel disease (IBD). This study investigated the efficacy of currently used IBD therapeutics to prevent injury mediated by reactive oxygen and nitrogen derived species. METHODS: GAPDH activity of human colon epithelial cells was used as a sensitive indicator of injury produced by reactive oxygen and nitrogen derived species. HCT116 cells (10(6)/ml phosphate buffered saline; 37 degrees C) were incubated in the presence of 5-aminosalicylic acid (5-ASA), 6-mercaptopurine, methylprednisolone, or metronidazole before exposure to H2O2, HOCl, or NO in vitro. HCT116 cell GAPDH enzyme activity was determined by standard procedures. Cell free reactions between 5-ASA and HOCl were analysed by spectrophotometry and fluorimetry to characterise the mechanism of oxidant scavenging. RESULTS: GAPDH activity of HCT116 cells was inhibited by the oxidants tested: the concentration that produced 50% inhibition (IC50) was 44.5 (2.1) microM for HOCl, 379.8 (21.3) microM for H2O2, and 685.8 (103.8) microM for NO (means (SEM)). 5-ASA was the only therapeutic compound tested to show efficacy (p<0. 05) against HOCl mediated inhibition of enzyme activity; however, it was ineffective against H2O2 and NO mediated inhibition of GAPDH. Methylprednisolone, metronidazole, and the thiol-containing 6-mercaptopurine were ineffective against all oxidants. Studies at ratios of HOCl:5-ASA achievable in the mucosa showed direct scavenging to be the mechanism of protection of GAPDH activity. Mixing 5-ASA and HOCl before addition to the cells resulted in significantly greater protection of GAPDH activity than when HOCl was added to cells preincubated with 5-ASA. The addition of 5-ASA after HOCl exposure did not restore GAPDH activity. CONCLUSIONS: Therapies based on 5-ASA may play a direct role in scavenging the potent neutrophil oxidant HOCl, thereby protecting mucosal GAPDH from oxidative inhibition. These findings suggest that strategies for the further development of new HOCl scavenging compounds may be useful in the treatment of IBD.     

131I therapy for pediatric thyroid cancer

Azido-3'-deoxy-thymidine (AZT) is a drug extensively used in the treatment of AIDS. AZT was incubated in vitro either with the pituitary-hypothalamus complex (PHc) or the intact pituitary (PI) of male rats. The PHc is comprised of the hypothalamus and the attached pituitary gland. After a preincubation period, the PHc or PI was incubated for 1 or 2 h with Krebs-Ringer bicarbonate buffer or either of two different concentrations of AZT (1 and 10 microM). In the control incubations, the PHc released less prolactin (PRL) and more follicle-stimulating hormone (FSH) and luteinizing hormone (LH) than the PI, indicating that hypothalamic control of the pituitary was exerted in vitro, presumably by diffusion of releasing and inhibiting hormones from the neurohypophysis to the anterior lobe of the hypophysis. Both concentrations of AZT evoked a significant increase in release of PRL and a decreased release of LH and FSH from the PHc. In the case of LH, the higher concentration of AZT partially suppressed LH release within 1 h. The other effects were not dose-related and were observed after incubating the tissue with AZT for 2 h. However, incubation of the PI with AZT failed to alter anterior pituitary hormone release, illustrating that the site of action of AZT is in the hypothalamus. We hypothesize that AZT blocks DNA synthesis resulting in suppression of synthesis and consequent release of hypothalamic hormones that control release of pituitary hormones in vitro. The results raise the possibility that AZT may alter hypothalamic-pituitary function in vivo.     

Recommended restrictions after 131I therapy: measured doses in family members

Previous studies have shown that levels of plasma brain natriuretic peptide (BNP) increase in an early phase of acute myocardial infarction. However, the relations between plasma BNP levels and left ventricular remodelling, which occurs long after acute myocardial infarction, are not fully understood. Venous plasma BNP levels were measured 2, 7, 14, 30, 90 and 180 days after the onset of acute myocardial infarction in 21 patients. Left ventricular end-diastolic volume index (EDVI, ml/m2) in acute (5 days) and chronic (6 months) phases were assessed by electron-beam computed tomography using Simpson's method. The remodelling group (n=9) was defined by an increase in EDVI >/=5 ml/m2 relative to the baseline value. Plasma BNP levels on days 2, 7, 14, 30 and 90 were significantly higher in the remodelling group than in the non-remodelling group (n=12, P<0.05). Sustained elevation of plasma BNP levels was noted from day 2 (61+/-12 pmol/l) to day 90 (55+/-12 pmol/l) and significantly decreased on day 180 (24+/-3 pmol/l) in the remodelling group. In contrast, plasma BNP levels significantly decreased from day 2 (25+/-4 pmol/l) to day 90 (9+/-1 pmol/l) and reached a steady level thereafter in the non-remodelling group. Plasma BNP levels on day 7 correlated positively with an increase in EDVI (r=0.70, P<0.001) from the acute to chronic phase. More importantly, the sustained elevation of plasma BNP (percentage decrease smaller than 25%) from day 30 to day 90 identified patients in the remodelling group with a sensitivity of 100% and a specificity of 83%. In conclusion, not only the high levels of plasma BNP in an acute phase, but also the sustained elevation of plasma BNP in a chronic phase, may be associated with progressive ventricular remodelling occurring long after acute myocardial infarction.     

Percent 131I uptake and post-therapy 131I scans: their role in the management of thyroid cancer

Renal disease in patients infected with human immunodeficiency virus (HIV) often presents with significant proteinuria and progressive renal failure; focal glomerulosclerosis is the most common renal pathology identified. To our knowledge, we report the first case of nephrotic-range proteinuria and preserved renal function in an HIV-infected patient in association with disseminated histoplasmosis. The initial level of proteinuria was 12.5 g/24 h. The patient developed a concomitant lesion on his neck, which was biopsied and identified as Histoplasma capsulatum by fungal stains and culture. The serum CF titer of antibody against yeast antigens of H. capsulatum was 1:8. The level of serum albumin decreased to 2.0 g/dL, and the level of serum cholesterol increased to 284 mg/dL. Immunohistochemical staining of renal biopsy tissue demonstrated immune complexes within the mesangium; H. capsulatum antigen was also demonstrated in the mesangium. Therapy with oral itraconazole resulted in marked clinical improvement. The findings in this case emphasize the need to rule out treatable causes of the nephrotic syndrome in AIDS, especially in cases of immune-complex glomerulonephritis.     

Radon exhalation rates and gamma doses from ceramic tiles

This study was carried out to assess the possible radiological hazard resulting from the use of zircon in glaze applied to tiles used in buildings. The 226Ra content of various stains and glazing compounds was measured using gamma spectroscopy and the 222Rn exhalation rates for these materials were measured using adsorption on activated charcoal. The radon exhalation rates were found to be close to or less than the minimum detectable values for the equipment used. This limit was much lower than the estimated exhalation rates, which were calculated assuming that the parameters controlling the emanation and diffusion of 222Rn in the materials studied were similar to those of soil. This implied that the 222Rn emanation coefficients and/or diffusion coefficients for most of the materials studied were very much lower than expected. Measurements on zircon powders showed that the 222Rn emanation coefficient for zircon was much lower than that for soil, indicating that only a small fraction of the 222Rn produced by the decay of 226Ra was able to escape from the zircon grains. The estimated increase in radon concentration in room air and the estimated external gamma radiation dose resulting from the use of zircon glaze are both much lower than the relevant action level and dose limit.     

Thyroid doses resulting from the Ukraine Chernobyl accident--Part I: Dose estimates for the population of Kiev

In the context of the radiation exposure of the Ukrainian population resulting from the Chernobyl accident, the quantification of the thyroid doses due to iodine incorporation is of special interest. This first part of a series of planned publications deals with the dose and risk estimation for Kiev citizens. Although these doses are expected to be considerably lower than those for some other regions of Ukraine, the investigations started with this population because the quantification of the thyroid doses due to iodine incorporation is of special interest. This first part of a series of planned publications deals with the dose and risk estimation for Kiev citizens. Although these doses are expected to be considerably lower than those for some other regions of Ukraine, the investigations started with this population because of the availability of rather reliable measurements and because of the size of this population. The methods developed allowed the estimation of individual thyroid doses. The average values of individual thyroid doses for five age groups (birth years 1983-1986, 1979-1982, 1975-1978, 1971-1974, and < 1971) are 104, 62, 19, 18, and 41 mGy, respectively. The collective thyroid doses were estimated as 83 x 10(3) person-Gy for those born before 1971 and as 38 x 10(3) person-Gy for younger inhabitants. The numbers of expected thyroid cancers in the whole Kiev population are 66 and 130, respectively.     

Atmospheric dispersion and deposition of 131I released from the Hanford Site

Approximately 2.6 x 10(4) TBq (700,000 Ci) of 131I were released to the air from reactor fuel processing plants on the Hanford Site in southcentral Washington State from December 1944 through December 1949. The Hanford Environmental Dose Reconstruction Project developed a suite of codes to estimate the doses that might have resulted from these releases. The Regional Atmospheric Transport Code for Hanford Emission Tracking (RATCHET) computer code is part of this suite. The RATCHET code implements a Lagrangian-trajectory, Gaussian-puff dispersion model that uses hourly meteorological and release rate data to estimate daily time-integrated air concentrations and surface contamination for use in dose estimates. In this model, iodine is treated as a mixture of three species (inorganic gases, organic gases, and particles). Model deposition parameters are functions of the mixture and meteorological conditions. A resistance model is used to calculate dry deposition velocities. Equilibrium between concentrations in the precipitation and the air near the ground is assumed in calculating wet deposition of gases, and irreversible washout of the particles is assumed. RATCHET explicitly treats the uncertainties in model parameters and meteorological conditions. Uncertainties in 131I release rates and partitioning among the nominal species are treated by varying model input. The results of 100 model runs for December 1944 through December 1949 indicate that monthly average air concentrations and deposition have uncertainties ranging from a factor of two near the center of the time-integrated plume to more than an order of magnitude near the edge. These results indicate that approximately 10% of the 131I released to the atmosphere decayed during transit in the study area, approximately 56% was deposited within the study area, and the remaining 34% was transported out of the study area while still in the air.     

Consensus proposal on the use of 131I in the treatment of thyrotoxicosis and thyroid cancer

A consensus meeting held by the Chilean Endocrinological Society reached to 22 consensus proposals on the use of iodine-131 in hyperthyroidism and thyroid cancer, that are reported in this paper. Some of these propositions are: 1) Hyperthyroidism: A previous 131I uptake test must be performed. A calculated or an ablative dose should be administered. Hypothyroidism must be considered an objective rather than a complication. In patients with cardiovascular risk, normal thyroid function must be attained with prophythioturacil. In cases of treatment failure, the dose should not be repeated before six months. It must be used with used with caution in children and teenagers. 2) Thyroid cancer: A iodine free diet is recommended prior to the therapeutic dose. A 100 mCi complementary ablative dose should be given after surgery, with a posterior exploration. This examination must not be done routinely, and if required, a 5 mCi dose should be used. For the treatment of metastases, a dose of 150 to 200 mCi is recommended. There is no radiation risk in hyperthyroidism or thyroid cancer. The only absolute contraindication is pregnancy. Recommendations for radiological protection are formulated. Hospitalization is suggested to protect other people from radiation exposure.     

The clinical assessment of cancer tests: a statistical approach to the prediction of "false positive" rates from controls

As the sensitivity of the new in vitro cancer detection techniques increases, a larger number of "false positive" results can be expected from control populations apparently free from malignant disease at the time of the test. An attempt is made to predict the number of unexplained positives, together with the expected age and sex distribution, using published cancer registration statistics. The predicted numbers are compared with the observed numbers of unexplained positives in two clinical trials of the MEM test.     

Potential effects of climatic change on radiological doses from disposal of Canadian nuclear fuel waste

The environmental assessment of deep geologic disposal of Canadian nuclear fuel waste considers many processes that could affect radionuclide transport to humans over thousands of years. Climatic change is an important feature that will occur over these long times. Glaciation will likely occur within the next 100,000 years over much of Canada, and its impact on radiological doses has been assessed previously. In the present study, we investigate the potential effect of short-term climatic change, usually associated with global warming caused by increases in atmospheric trace gases. We study the main biosphere transport pathways causing a radiological dose to humans from 129I, which is the most important radionuclide in disposal of Canadian used nuclear fuel. Irrigation of a garden with contaminated well water is the main pathway and it can be affected by changes in temperature and precipitation. A cold, wet climate decreases the need for irrigation, and this decreases the radiological dose. A drastic climatic change, such as an increase in temperature from 10 to 20 degrees C and decrease in precipitation from 0.3 to 0.2 m during the growing season, is estimated to increase the dose by a factor of four. This is a relatively small change compared to the range of doses that arise from the variability and uncertainty in many of the parameters used in the environmental assessment models. Therefore, it is likely that the results of probabilistic dose assessment models can include the consequences of short-term climatic change.     

Hospital discharge policy in thyroid cancer patients treated with 131I: the effect of changing from fixed time to exposure rate threshold

Juvenile myelomonocytic leukemia (JMML) carries a poor prognosis. The endogenous production of cytokines by the JMML cells contributes to their growth and therapeutic resistance. Interleukin (IL)-4, IL-10, and IL-13 inhibit cytokine production in monocytes. We have now studied whether these cytokines can inhibit JMML cell cytokine production, thereby potentially reducing the malignant cell load in this disorder. We found that IL-10, but not IL-4 or IL-13, dose dependently inhibited JMML cell production of the hemopoietic growth factors granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and IL-1beta. Similarly, IL-10, but not IL-4 or IL-13, suppressed JMML colony formation and cell viability. This was not due to the absence of receptors because we could detect mRNAs for the IL-4 and the IL-13 receptor alpha subunits and the IL-2 common gamma subunit in JMML cells. Furthermore, the receptors were active since both IL-4 and IL-13 up-regulated surface expression of MHC class II and down-regulated CD14 antigens on JMML cells and monocytes. Unlike activated monocytes, the JMML cells did not produce IL-10. It is suggested that the loss of cytokine inhibitory effects of IL-4 and IL-13 could play a role in the pathogenesis of this disorder. On the other hand, the inhibition of cytokine production, growth, and viability of JMML cells by IL-10 suggests that this cytokine may have a therapeutic potential in JMML.     

131I treatment of 131I negative whole body scan, and positive thyroglobulin in differentiated thyroid carcinoma: what is being treated?

Several aspects of the management of differentiated thyroid cancer cause considerable controversy. Among these is the role of 131I therapy in patients after thyroidectomy. There is no controlled study to demonstrate whether this treatment reduces the recurrence rate or improves mortality. Because of the overall excellent prognosis, it is unlikely that a controlled study will ever be conducted. Most frequently, patients have a diagnostic scan with 131I to determine whether radioiodine would be an appropriate therapy and to judge much to be prescribed, based on the extent of abnormalities seen on the scintiscan. Serum thyroglobulin (Tg) has been found to be a valuable tumor marker, with very good sensitivity and specificity. In most patients, the result of whole-body 131I scintiscan and Tg measurement give concordant results. However, in some patients, Tg is measurable, but the diagnostic scan with 131 is normal. There has been data published about treatment of these patients with therapeutic doses of 131I. The author questions whether this treatment is appropriate, prompted by seeing and hearing of patients who were treated with therapeutic doses of 131I, but had no abnormal uptake of the therapeutic doses and who had no improvement in serum Tg level. These patients have no clinical evidence of disease, and the only abnormality is measurable Tg. Since large doses of radioiodine are not without problems, a controlled clinical trial should be developed to evaluate efficacy in this situation.     

Effect of postoperative 131I treatment on thyroglobulin measurements in the follow-up of patients with thyroid cancer

Correlation of serum thyroglobulin (Tg) levels with recurrent cancer was performed in 200 patients who had undergone a subtotal thyroidectomy for well-differentiated thyroid carcinoma. Patients were divided into three groups: (1) those not treated postoperatively with radioactive iodine, (2) those treated with low dose (30 mCi) radioactive iodine, and (3) those treated with high dose (50-250 mCi) radioactive iodine. Tg levels proved to be reliable in detecting recurrent thyroid cancer regardless of the dose of radioactive iodine given postoperatively. These results reinforce the recommendation of using the Tg assay as the primary method of following these patients postoperatively, even when there was less than a total thyroidectomy and ablation with radioactive iodine.     

Thyroid nodule and cancer in pregnant women]

157 bacterial isolates from cases with urinary tract infections (UTI) were studied for their susceptibility to some of the available quinolones as compared to other commonly used antimicrobial agents in UTI. Resistance to nalidixic acid was observed in 62.4% of isolates whereas for pefloxacin, norfloxacin, ciprofloxacin and lomifloxacin it was 54.7%, 52.5%, 51.5% and 50.3% respectively. Aminoglycosides and third generation cephalosporins showed resistance in fewer isolates. Gentamicin resistance was observed in 21% and corresponding figure for amikacin, cefotaxime and ceftriaxone was 7%, 8.9% and 12.1% respectively. Nitrofurantoin showed resistance in 36.3% of isolates and 48% isolates were resistant to cephalexin. The minimum inhibitory concentration (MIC) of quinolones was more than 64 mcg/ml which is > 8 times in resistant strains as compared to sensitive isolates.     

Leukemia developing after 131I treatment for thyroid cancer in a patient with Werner's syndrome: molecular and cytogenetic studies

A 40-year-old female patient with Werner's syndrome (WS) suffering from thyroid cancer and myelodysplastic syndrome (MDS) is reported. She had been diagnosed as having WS complicated with thyroid cancer seven years previously. Total thyroidectomy and radioactive iodine (131I, 100 mCi/year) therapy for seven years had slowed the progression of thyroid cancer. She suffered a sudden onset of MDS at the age of 40 years. After six months she died from overt leukemia. We found an additional chromosome aberration of chromosome 10 in the progression of leukemia from MDS.