Long-term effects of inhaled budesonide on screening-detected lung nodules.

BACKGROUND: A previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT. PATIENTS AND METHODS: We analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed. RESULTS: The mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms. CONCLUSIONS: Inhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications. CLINICAL TRIAL NUMBER: NCT01540552.

Estimates of benefits and harms of prophylactic use of aspirin in the general population.

BACKGROUND: Accumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population. METHODS: The effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer. RESULTS: The effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Higher doses do not appear to confer additional benefit but increase toxicities. Excess bleeding is the most important harm associated with aspirin use, and its risk and fatality rate increases with age. For average-risk individuals aged 50-65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period. CONCLUSIONS: Prophylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have favourable benefit-harm profile; longer use is likely to have greater benefits. Further research is needed to determine the optimum dose and duration of use, to identify individuals at increased risk of bleeding, and to test effectiveness of Helicobacter pylori screening-eradication before starting aspirin prophylaxis.

A SNP in steroid receptor coactivator-1 disrupts a GSK3ß phosphorylation site and is associated with altered tamoxifen response in bone.

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)ß phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3ß increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3ß-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3ß phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.

The rexinoid, bexarotene, prevents the development of premalignant lesions in MMTV-erbB2 mice.

Retinoids, vitamin A analogues that bind to retinoic acid receptor (RAR) or retinoid X receptor (RXR), play important roles in regulating cell proliferation, apoptosis, and differentiation. Recently, RXR-selective ligands, also referred to as rexinoids, have been investigated as potential chemopreventive agents for breast cancer. Our previous studies demonstrated that the rexinoid bexarotene significantly prevented ER-negative mammary tumourigenesis with less toxicity than naturally occurring retinoids in animal models. To determine whether bexarotene prevents cancer at the early stages during the multistage process of mammary carcinogenesis, we treated MMTV-erbB2 mice with bexarotene for 2 or 4 months. The development of preinvasive mammary lesions such as hyperplasias and carcinoma-in-situ was significantly inhibited. This inhibition was associated with reduced proliferation, but no induction of apoptosis. We also examined the regulation of a number of rexinoid-modulated genes including critical growth and cell cycle regulating genes using breast cell lines and mammary gland samples from mice treated with rexinoids. We showed that two of these genes (DHRS3 and DEC2) were modulated by bexarotene both in vitro and in vivo. Identification of these rexinoid-modulated genes will help us understand the mechanism by which rexinoid prevents cancer. Such rexinoid-regulated genes also represent potential biomarkers to assess the response of rexinoid treatment in clinical trials.

The AP-1 transcription factor regulates breast cancer cell growth via cyclins and E2F factors.

The activating protein-1 (AP-1) transcription factor transduces growth signals through signal transduction pathways to the nucleus, leading to the expression of genes involved in growth and malignant transformation in many cell types. We have previously shown that overexpression of a dominant negative form of the cJun proto-oncogene, a cJun dominant negative mutant (Tam67), blocks AP-1 transcriptional activity, induces a G(1) cell cycle block and inhibits breast cancer cell growth in vitro and in vivo. We found that AP-1 blockade by Tam67 in MCF-7 breast cancer cells downregulates cyclin D1 transcriptional activity by at least two mechanisms: by suppressing transcription at the known AP-1 binding site (-934/-928) and by suppressing growth factor-induced expression through suppressing E2F activation at the E2F-responsive site (-726/-719). AP-1 blockade also led to reduced expression of E2F1 and E2F2, but not E2F4, at the mRNA and protein levels. Chromatin immunoprecipitation and supershift assays demonstrated that AP-1 blockade caused decreased binding of E2F1 protein to the E2F site in the cyclin D1 promoter. We also found that Tam67 suppressed the expression of the E2F1 dimerizing partner, DP1 and E2F-upregulated cell cycle genes (cyclins E, A, B and D3) and enhanced the expression of E2F-downregulated cell cycle genes (cyclins G(2) and I). Reduced expression of other E2F-regulated genes was also seen with AP-1 blockade and E2F suppression. Thus, the AP-1 factor regulates the expression of cyclin D and E2F (the latter in turn regulates E2F-downstream genes), leading to cell cycle progression and breast cancer cell proliferation.

Lung cancer: the importance of seeing a respiratory physician.

Patients with lung cancer present to and are managed by a variety of clinicians. In this study the effect of involvement by a respiratory physician on the diagnosis, staging, treatment and survival of a large unselected group of lung cancer patients was investigated. The study population was derived from the Scottish Cancer Registry. A total of 3,855 patients diagnosed during 1995 with lung cancer were studied. The data were validated and supplemented by references to medical records. The study found that a respiratory physician had been involved in the initial management of 2,901 (75.3%) patients. These patients were found more likely to have had the cancer diagnosis confirmed by histological methods and to have received active treatment with surgery, radiotherapy or chemotherapy. Survival, 1 yr after diagnosis was higher in patients who saw a respiratory physician (24.4 versus 11.1%) and benefit was found to have remained 3 yrs after diagnosis (8.1 versus 3.7%). Although the patients who had not seen a respiratory physician were generally older, and had more extensive disease, after correcting for age, stage and other prognostic factors, the relative hazard ratio of death for those not managed by a respiratory physician was 1.44. The data from this study supports the recommendations of recent lung cancer guidelines for the early involvement by a respiratory physician.

Pre-clinical applications of transgenic mouse mammary cancer models.

Breast cancer is a leading cause of cancer morbidity and mortality. Given that the majority of human breast cancers appear to be due to non-genetic factors, identifying agents and mechanisms of prevention is key to lowering the incidence of cancer. Genetically engineered mouse models of mammary cancer have been important in elucidating molecular pathways and signaling events associated with the initiation, promotion, and the progression of cancer. Since several transgenic mammary models of human breast cancer progress through well-defined cancer stages, they are useful pre-clinical systems to test the efficacy of chemopreventive and chemotherapeutic agents. This review outlines several oncogenic pathways through which mammary cancer can be induced in transgenic models and describes several types of preventive and therapeutic agents that have been tested in transgenic models of mammary cancer. The effectiveness of farnesyl inhibitors, aromatase inhibitors, differentiating agents, polyamine inhibitors, anti-angiogenic inhibitors, and immunotherapeutic compounds including vaccines have been evaluated in reducing mammary cancer and tumor progression in transgenic models.

AP-1 blockade inhibits the growth of normal and malignant breast cells.

We have previously demonstrated that basal AP-1 transcriptional activity is high in normal human mammary epithelial cells, intermediate in immortal breast cells, and relatively low in breast cancer cells. In this study we investigated whether differences in AP-1 transcriptional activity reflect differences in breast cells' dependence on AP-1 for proliferation. The cJun dominant negative, TAM-67, was used to determine the effect of AP-1 blockade on the growth of normal, immortal and malignant breast cells. We first showed that TAM-67 inhibits AP-1 activity in normal and malignant breast cells. We then determined whether this AP-1 inhibitor affected colony forming efficiency of the immortalized and malignant breast cells. The AP-1 inhibitor reduced colony formation of immortal breast cells by over 50% (by 58% in 184B5 cells and 62% in MCF10A cells), and reduced colony formation in the breast cancer cell line MCF7 by 43%, but did not reduce colony formation in the other breast cancer cell lines (T47D, MDA MB231 and MDA MB 435). We also determined the effect of AP-1 blockade on the growth of normal breast cells using a single cell proliferation assay. Using this assay, the growth of normal breast cells was extremely sensitive to AP-1 blockade, while immortal breast cells were moderately sensitive. We next directly tested the effect of TAM-67 expression on the growth of MCF7 breast cancer cells, using cells stably transfected with TAM-67 under the control of a doxycycline-inducible promoter. Upon induction, TAM-67 was expressed and AP-1 activity was inhibited in these cells. We then measured the growth of these cells in the presence or absence of TAM-67. The results of these studies show that the growth of MCF7 cells was suppressed by the AP-1 inhibitor, TAM-67. These results demonstrate that normal and immortalized breast cells, and some breast cancer cells (such as MCF7), require AP-1 to transduce proliferative signals, while other breast cancer cells (such as T47D, MDA MB 231 and MDA MB 435) do not. These studies suggest that the AP-1 transcription factor is a potential target for future agents for the prevention or treatment of breast cancer.

Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions.

In a search for novel transcriptional intermediary factors for the estrogen receptor (ER), we used the ligand-binding domain and hinge region of ER as bait in a yeast two-hybrid screen of a cDNA library derived from tamoxifen-resistant MCF-7 human breast tumors from an in vivo athymic nude mouse model. Here we report the isolation and characterization of the forkhead homologue in rhabdomyosarcoma (FKHR), a recently described member of the hepatocyte nuclear factor 3/forkhead homeotic gene family, as a nuclear hormone receptor (NR) intermediary protein. FKHR interacts with both steroid and nonsteroid NRs, although the effect of ligand on this interaction varies by receptor type. The interaction of FKHR with ER is enhanced by estrogen, whereas its interaction with thyroid hormone receptor and retinoic acid receptor is ligand-independent. In addition, FKHR differentially regulates the transactivation mediated by different NRs. Transient transfection of FKHR into mammalian cells dramatically represses transcription mediated by the ER, glucocorticoid receptor, and progesterone receptor. In contrast, FKHR stimulates rather than represses retinoic acid receptor- and thyroid hormone receptor-mediated transactivation. Most intriguingly, overexpression of FKHR dramatically inhibits the proliferation of ER-dependent MCF-7 breast cancer cells. Therefore, FKHR represents a bifunctional NR intermediary protein that can act as either a coactivator or corepressor, depending on the receptor type.

Lymphangioleiomyomatosis. A series of three case reports illustrating the link with high oestrogen states.

Lymphangioleiornyomatosis is a rare lung disorder characterised by cystic air spaces and smooth muscle proliferation. The condition, which most commonly presents with dyspnoea, pneumothoraces or cough, is only described in females and is most commonly diagnosed during childbearing years. Three cases are presented which illustrate typical features of the disease and the association with high oestrogen levels. The first had recurrent pneumothoraces during her first pregnancy. The second lady was post menopausal at diagnosis but her symptoms predated her menopause. The third, presented with dyspnoea, abnormal chest sensations and a pneumothorax. She had a history of hyperprolactinaemia with secondary amenorhoea due to low oestrogen levels which had been corrected prior to her presentation. All three patients had reduced gas transfer and abnormalities in spirometry, two had reticular shadowing on their chest radiograph and all had typical appearances on lung computerised tomography. Although disease progression was variable, all patients showed a gradual decline in lung function.

Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo.

BACKGROUND: Most breast cancers, even those that are initially responsive to tamoxifen, ultimately become resistant. The molecular basis for this resistance, which in some patients is thought to involve stimulation of tumor growth by tamoxifen, is unclear. Tamoxifen induces cellular oxidative stress, and because changes in cell redox state can activate signaling pathways leading to the activation of activating protein-1 (AP-1), we investigated whether tamoxifen-resistant growth in vivo is associated with oxidative stress and/or activation of AP-1 in a xenograft model system where resistance is caused by tamoxifen-stimulated growth. METHODS: Control estrogen-treated, tamoxifen-sensitive, and tamoxifen-resistant MCF-7 xenograft tumors were assessed for oxidative stress by measuring levels of antioxidant enzyme (e.g., superoxide dismutase [SOD], glutathione S-transferase [GST], and hexose monophosphate shunt [HMS]) activity, glutathione, and lipid peroxidation. AP-1 protein levels, phosphorylated c-jun levels, and phosphorylated Jun NH(2)-terminal kinase (JNK) levels were examined by western blot analyses, and AP-1 DNA-binding and transcriptional activities were assessed by electrophoretic mobility shift assays and a reporter gene system. All statistical tests are two-sided. RESULTS: Compared with control estrogen-treated tumors, tamoxifen resistant tumors had statistically significantly increased SOD (more than threefold; P=.004) and GST (twofold; P=.004) activity and statistically significantly reduced glutathione levels (greater than twofold; P<.001) and HMS activity (10-fold; P<.001). Lipid peroxides were not significantly different between control and tamoxifen-resistant tumors. We observed no differences in AP-1 protein components or DNA-binding activity. However, AP-1-dependent transcription (P=.04) and phosphorylated c-Jun and JNK levels (P<.001) were statistically significantly increased in the tamoxifen-resistant tumors. CONCLUSION: Our results suggest that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with oxidative stress and the subsequent antioxidant response and with increased phosphorylated JNK and c-Jun levels and AP-1 activity, which together could contribute to tumor growth.

Uterine arterial embolization: factors influencing patient radiation exposure.

PURPOSE: To investigate patient radiation exposures during uterine arterial embolization and the factors responsible for those exposures. MATERIALS AND METHODS: Clinical and procedural factors were evaluated for 42 consecutive procedures performed in 39 patients by one operator. Seven patients were excluded because of early termination (n = 1) or unusual conditions that necessitated extended procedures (n = 6). Fluoroscopic time, number of images acquired, height, and weight were available in the 35 remaining patients, and dose-area product (DAP) was available in 20. Equipment factors were evaluated by using a Lucite phantom in four angiography units from three manufacturers. RESULTS: The mean fluoroscopic time per case decreased from 30.6 to 14.2 minutes between the 1st and 5th quintiles. Mean DAP decreased from 211.4 to 30.6 Gy. cm(2) with dose reduction techniques; this primarily reflected a decreased number of acquired images. Phantom studies demonstrated many significant dose variations with magnification and equipment position. Low-dose and pulsed fluoroscopic modes reduced exposure rates in units so equipped, but roadmapping caused a silent switch to continuous fluoroscopy in two such units, which doubled the exposure rate. CONCLUSION: With operator experience and careful technique, uterine arterial embolization can be performed at radiation exposures comparable to those used in routine diagnostic studies. However, operators must be familiar with the technical parameters of their angiographic equipment.

9-cis-Retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus 40 T antigen-transgenic mice.

Retinoids have been investigated as potential agents for the prevention and treatment of human cancers. These compounds play an important role in regulating cell growth, differentiation, and apoptosis. 9-cis-Retinoic acid (9cRA) is a naturally occurring ligand with a high affinity for both the retinoic acid receptors and the retinoid X receptors. We hypothesized that treatment with 9cRA would prevent mammary tumorigenesis in transgenic mice that spontaneously develop mammary tumors. To test this hypothesis, C3(1)-SV40 T antigen (Tag) mice, which develop mammary tumors by the age of 6 months, were treated daily p.o. with vehicle or two different dose levels of 9cRA (10 or 50 mg/kg) from 5 weeks to 6 months of age. Tumor size and number were measured twice each week, and histological samples of normal and malignant tissue were obtained from each mouse at time of sacrifice. Our results demonstrate that 9cRA suppresses mammary tumorigenesis in C3(1)-SV40 Tag-transgenic mice. Time to tumor development was significantly delayed in treated mice; median time to tumor formation for vehicle-treated mice was 140 days versus 167 days for mice treated with 50 mg/kg 9cRA (P = 0.05). In addition, the number of tumors per mouse was reduced by >50% in mice treated with 9cRA (3.43 for vehicle, 2.33 for 10 mg/kg 9cRA, and 1.13 for 50 mg/kg 9cRA, P < or = 0.002). Histological analysis of the mammary glands from vehicle and treated mice demonstrated that 9cRA treatment also did not affect normal mammary gland development. Immunohistochemical staining of normal and malignant breast tissue and Western blot analysis demonstrated that SV40 Tag expression was not affected by treatment with retinoids. Single doses of 10 and 50 mg/kg resulted in peak plasma concentrations of 3.4 and 6.71 microM, respectively. Daily doses of 9cRA for 28 days resulted in plasma concentrations of 0.86 and 1.68 microM, respectively, concentrations consistent with that seen in humans treated with 9cRA in clinical trials. These results demonstrate that 9cRA suppresses mammary carcinogenesis in transgenic mice without any major toxicity and suggest that retinoids are promising agents for the prevention of human breast cancer.

Chemoprevention of breast cancer.

Despite a recent trend toward improvement in the U.S. breast cancer mortality rate, breast cancer incidence (182,800 new cases anticipated in 2000) and mortality figures (over 40,800 anticipated deaths) remain the highest and second highest, respectively, of all cancers in U.S. women. In 1998, the selective-estrogen-receptor-modulator (SERM) tamoxifen achieved positive results in the Breast Cancer Prevention Trial (BCPT), leading to the Food and Drug Administration (FDA) approval of tamoxifen for risk reduction in women at high risk of breast cancer (the historic first FDA approval of a cancer preventive agent). This brought about a paradigm shift in new approaches for controlling breast cancer toward pharmacologic preventive regimens, called chemoprevention. This paper presents a comprehensive clinical review of breast cancer prevention study, highlighting issues of the extensive study of tamoxifen. These issues include the record of primary tamoxifen results in several breast-cancer risk-reduction settings (primary, adjuvant, and ductal carcinoma in situ [DCIS]); critical secondary BCPT risk-benefit findings (including quality of life issues) and their effects on counseling patients on use of tamoxifen for prevention; ethic minorities; optimal tamoxifen dose/duration; and potential impact on mortality and other issues involved with potential net benefit to society. Other breast-cancer chemoprevention issues reviewed here include women at high genetic risk (especially BRCA1 mutation carriers); raloxifene in breast cancer prevention; other SERMs; SERM resistance; and new agents and combinations currently in development. Very recent developments involving PPAR-gamma ligands, COX-2 inhibitors, and RXR-ligands are discussed in the section on new drug development.

Optimization of a fluoroscope to reduce radiation exposure in pediatric imaging.

BACKGROUND: A new children's hospital provided the impetus to investigate radiation dose and image quality in a fluoroscope that was specially engineered for pediatric fluoroscopy. Radiation protection management recommends radiation exposures that are as low as reasonably achievable, while still maintaining diagnostic image quality. OBJECTIVES: To obtain comparative phantom imaging data on radiation exposure and image quality from a newly installed fluoroscope before and after optimization for pediatric imaging. MATERIALS AND METHODS: Images were acquired from various thickness phantoms, simulating differing patient sizes. The images were evaluated for visualization of high- and low-contrast objects and for radiation exposure. Effects due to use of the image intensifier anti-scatter grid were also investigated. RESULTS: The optimization of the new fluoroscope for pediatric operation reduced radiation exposure by about 50% (compared to the originally installed fluoroscope), with very little loss of image quality. Pulsed fluoroscopy was able to lower radiation dose to less than 10% of continuous fluoroscopy, while still maintaining acceptable phantom image quality. CONCLUSION: Radiation exposure in pediatric fluoroscopy can be reduced to values well below the exposure settings that are typically found on unoptimized fluoroscopes. Pulsed fluoroscopy is considered a requisite for optimal pediatric fluoroscopy.

A multihospital survey of radiation exposure and image quality in pediatric fluoroscopy.

BACKGROUND: Traditionally, pediatric radiologists have been advocates of fluoroscopy systems that provide diagnostic images at the lowest possible radiation dose to the pediatric patient. Manufacturers of fluoroscopic equipment vary as to their claims of "low radiation" exposures. OBJECTIVES: To obtain comparative data on radiation exposure and image quality from four pediatric hospitals, across variants of fluoroscopic equipment (such as pulsed versus continuous fluoroscopy). MATERIALS AND METHODS: Images were acquired from phantoms that simulated the size of a 3-year-old child. Phantom results, both stationary and rotating dynamic, were evaluated for radiation exposure and for image resolution of high- and low-contrast objects. RESULTS: Radiation exposure from the four fluoro units varied widely; the lowest-dose selectable fluoro mode produced exposures varying between 34 and 590 mrads/min among the four fluoro units, and the highest-dose selectable fluoro mode produced 540-2,230 mrads/min. The lowest radiation exposures were produced by pulsed fluoro units, and the very lowest radiation exposure was produced by a fluoroscope that had been especially optimized for pediatric imaging. There was only a small variation in image quality among the hospitals for visualization of stationary objects. A wide variability was noted for detection of objects on the moving phantom. CONCLUSIONS: The variability in the number of detected objects was considerably smaller than the variability in radiation exposure. Pulsed fluoroscopy provides improved resolution for moving objects. Optimization of one hospital's fluoroscope especially for pediatric imaging produced the best ratio of image quality to radiation exposure.

The effect of gadolinium contrast media on radioiodine uptake by the thyroid gland.

OBJECTIVE: Patients with thyroid cancer may require detailed anatomic imaging before 131I therapy. Imaging by contrast-enhanced CT is contraindicated because it may result in saturation of tissues with iodine, decreasing the avidity of thyroid or thyroid cancer cells to subsequent radioiodine for extended intervals. Gadolinium-enhanced MRI offers an alternative to CT for detailed anatomic imaging. However, it is not known whether gadolinium contrast affects uptake of iodine by the thyroid gland since lanthanides affect ion transport in a variety of ways. The objective of this project was to determine whether the gadolinium MRI contrast injection alters thyroid uptake of radioiodine. METHODS: Radioiodine uptake by the thyroid gland was measured at 6 h and 24 h after the oral administration of 100 microCi 123I-Na-I. Three to seven days later, a standard dose (20 mL) of Magnevist (gadolinium DTPA) was administered intravenously. Another capsule of 100 microCi 123I Na-I immediately was given orally, and 6-h and 24-h radioiodine uptake by the thyroid gland was again measured and compared to baseline values. RESULTS: There was no statistically significant difference in uptake of radioiodine uptake by the thyroid gland between baseline values and those acquired immediately after the administration of Magnevist. CONCLUSION: Contrast-enhanced MRI may be safely performed before contemplated determinations of thyroid uptake of radioiodine, 131I therapy for hyperthyroidism, and postsurgical 131I imaging and therapy for well-differentiated thyroid cancer.

Applying Nuclear Regulatory Commission guidelines to the release of patients treated with sodium iodine-131.

OBJECTIVE: This article presents a brief synopsis of the 1997 regulations from the Nuclear Regulatory Commission concerning the release from the hospital of patients treated for thyroid disease with 131I. A simplified checklist is provided to demonstrate the instructions to patients and the new conditions for release of patients containing a higher level of 131I radioactivity than was allowed under the older regulations.

cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype.

We have previously demonstrated decreased Jun/AP-1 activity in the breast cancer cell line MCF-7 when compared to normal or immortalized mammary epithelial cells. In this paper, we overexpress Jun in MCF-7 cells (MCF7Jun) and demonstrate that it results in diverse biologic and biochemical changes, which mimic those seen clinically in breast cancer. Overexpression of Jun causes significant alterations in the composition of AP-1, decreased junB and increased fra-1 expression and results in an increased biologic aggressiveness. MCF7Jun cells exhibit increased cellular motility, increased expression of a matrix degrading enzyme MMP-9, increased in vitro chemoinvasion and tumor formation in nude mice in the absence of exogenous estrogens. Furthermore, MCF7Jun cells are unresponsive to the growth stimulating effects of estrogen and growth inhibitory effects of tamoxifen. Analysis of the estrogen receptor (ER) expression and activity showed that the MCF7Jun cells have no detectable ER. MCF-7 cells overexpressing mutant forms of cJun were responsive to the growth stimulatory effects of estrogen indicating that full-length cJun is required to acquire the estrogen-independent phenotype in breast cancer cells.