Tamoxifen trial in healthy women at risk of breast cancer.
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Breast Neoplasms↗
Biomedical subjects
A Costa
Publications and source records attributed to A Costa.
Interleukin-induced vasopressin release is inhibited by L-arginine.
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Animals↗
Cell proliferation as a long-term prognostic factor in diffuse large-cell lymphomas.
The relevance of cell proliferation rate--defined as the 3H-thymidine labeling index (3H-dT LI)--in predicting response to treatment (complete remission, CR), freedom from progression (FFP) and overall survival (OS) was evaluated in 86 patients with diffuse large-cell lymphoma (DLCL). The biologic variable was not associated with most of the established clinical factors, such as gender and age of the patient, performance status, B symptoms, tumor bulk, or extranodal disease, but was directly related to stage. 3H-dT LI significantly predicted short- and long-term clinical outcome. In fact, more patients with slowly proliferating DLCL reached CR and had longer median FFP and OS than patients with rapidly proliferating DLCL. Multiple-regression analysis to evaluate the relative contribution of the different biologic and clinical variables in predicting CR, FFP and OS showed that 3H-dT LI and Ann Arbor stage were the only 2 stable factors, which retained their prognostic significance even in the presence of other conventional factors, and that 3H-dT LI was the most powerful as an indicator of risk of death in DLCL patients.
Adolescent↗
Nitric oxide modulates the release of corticotropin-releasing hormone from the rat hypothalamus in vitro.
There is now considerable evidence that nitric oxide (NO) is an important neuroregulatory agent, but there has been very little investigation of the possible role of NO in neuroendocrine mechanisms. We have previously shown that acute rat hypothalamic explants can be used to study the regulation of hypothalamic neuropeptide release, and we have now utilised this experimental approach to investigate the putative involvement of NO in the control of the principal corticotropin-releasing hormone, CRH. We studied the direct effects of the NO precursor L-arginine (L-ARG), as well as the NO donors molsidomine and sodium nitroprusside, on both the basal and stimulated release of CRH; the stimuli used were non-specific depolarisation with potassium chloride (KCl) and the specific cytokine, interleukin-1 beta (IL-1 beta; 100 U/ml). L-ARG was tested in each experimental condition with and without contemporaneous addition of its competitive antagonist NG-monomethyl-L-arginine (L-NMMA). IL-1 beta-induced CRH release was also investigated in the presence of D-arginine (D-ARG), which is not active as a precursor to NO, and ferrous hemoglobin (Hb), a substance which is a potent inactivator of NO. None of the NO precursors (L-ARG, molsidomine, sodium nitroprusside) or antagonists (L-NMMA or Hb) was able to affect basal CRH release. However, L-ARG 10 and 100 microM were found to significantly inhibit the release of CRH induced by 40 mM KCl; CRH fell to 45% of its stimulated level at the higher dose of L-ARG. This effect was attenuated in the presence of L-NMMA at a ten-fold higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The regulation of hypothalamic corticotropin-releasing factor release: in vitro studies.
Although there are various ways in which the regulation of hypothalamic corticotropin-releasing factor (CRF) may be investigated, the most direct is by the study of CRF secretion from rat hypothalami incubated in vitro. Using this technique, we have found stimulation of secretion by noradrenaline, acetylcholine, serotonin, neuropeptide Y, and interleukins 1 and 6; inhibitory modulation was shown by GABA, substance P, atrial natriuretic peptide, opioid peptides and precursors of nitric oxide. Studies of these interactions demonstrated certain non-linear characteristics which may allow appropriate mathematical models to be devised; this may aid in our understanding of clinical disorders associated with CRF excess.
Animals↗
Fenretinide (4-HPR) in chemoprevention of oral leukoplakia.
A controlled clinical trial has been underway at the Istituto Nazionale Tumori (INT) of Milan since 1988. The goal of the trial is to evaluate the effectiveness of fenretinide (4-HPR) in preventing relapses, new localizations, and carcinomas in patients with benign postoperative diagnoses who have been surgically treated for oral leukoplakias. This paper presents the design and the preliminary results of this study. To date, 137 patients have been randomized, following surgical excision of oral leukoplakia, to receive either 200 mg 4-HPR daily for 52 weeks or no intervention. Twenty local relapses or new localizations have occurred so far in the control group and 9 in the 4-HPR group. Seven patients have interrupted the intervention because of toxicity. No impaired dark adaptation has been observed. We conclude that 4-HPR is well-tolerated and appears to be effective in preventing relapses and new localizations during the treatment period.
Adult↗
Breast cancer chemoprevention: studies with 4-HPR alone and in combination with tamoxifen using circulating growth factors as potential surrogate endpoints.
Fenretinide (4-HPR), a synthetic derivative of retinoic acid, has proven effective at inhibiting in vitro breast cancer cell growth and preventing the progression of chemically induced mammary carcinoma in rodents. Our group has made a particular effort with regard to this molecule in clinical studies aimed at evaluating its pharmacology, toxicity, and efficacy in breast cancer prevention. We have demonstrated that 4-HPR blood levels remain constant during administration for as long as 5 years, that the drug accumulates in the human breast, and that it induces a significant decline of plasma insulin-like growth factor-I (IGF-I) levels. To date, 2,972 Stage I breast cancer patients have been randomized to evaluate the efficacy of a 5-year administration of 4-HPR to prevent new contralateral primary breast cancers. Compliance to protocol and treatment is high and tolerability of the drug is good; only 51 women out of 1,397 (3.6%) had to interrupt drug intake due to toxicity. The only potential limitation to the extensive use of 4-HPR is diminished dark adaptation, which occurs in about one-fourth of the patients and is dependent on the decline of plasma retinol below the threshold level of 100 ng/ml. Plasma levels of (4-methoxyphenyl)retinamide (4-MPR), the principal metabolite of 4-HPR, which are higher in elderly women with a high percentage of adipose tissue, are the major determinants of the retinol decrease. However, about 50% of the patients with altered dark-adaptometry are asymptomatic and the alterations are promptly reversible upon drug discontinuation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Biological markers in hepatocellular carcinoma: potential clinical implications.
The assessment of biological markers as potential indicators of disease aggressiveness is still an open problem in hepatocellular carcinoma. Cell proliferation and extracellular matrix (ECM)-associated antigens and tumor-cell products can be associated with clinical aggressiveness in this tumor type, as has already been demonstrated for others. Cell proliferation, expressed as the in vitro [3H]thymidine labeling index, and ECM-associated antigens, such as type IV collagenase and laminin receptors, were assessed on the same paraffin-embedded samples. A strong association (P = 0.0001) was observed between the expression of collagenase and laminin receptors, with a correlation coefficient (rs) of 0.68. No relationship was found between cell proliferation and ECM-associated antigens. Moreover, the biological markers were generally independent of clinicopathologic features, except for a higher number of collagenase- and laminin receptor-positive cells in large (> or = 5 cm) compared with small (< 5 cm) tumors. In the present series of hepatocellular carcinoma patients, the 3-year clinical outcome was significantly affected by cell proliferation and ECM-associated antigens.
Antigens, Neoplasm↗
Retinoids and tamoxifen in breast cancer chemoprevention.
Chemoprevention is a new branch of oncology which aims to use chemical agents to reduce the incidence of malignant diseases in humans. On the basis of a growing mass of experimental data, it is now felt that the importance of early, precursor lesions of clinically symptomatic cancer should be recognized. Just as in cardiovascular disease, there is now major emphasis on the natural history of tumors and some authors believe that the actual disease process is carcinogenesis, rather than cancer. Indeed, as the chemoprevention of cardiovascular illness with pharmacological agents that either lower blood cholesterol or prevent platelet aggregation is widespread, the effectiveness of different chemical compounds in preventing cancer or, at least in delaying its onset, is presently under investigation. For breast cancer, various agents have been suggested as having chemopreventive effects: vitamins C and E, difluoromethylornithine, selenium, retinoids and antiestrogens. Among retinoids, 4-(N-hydroxyphenyl)retinamide, fenretinide, is at present the most promising molecule, due to its ability to concentrate in the mammary gland. Attention has recently been focussed on tamoxifen because of its effectiveness in reducing the incidence of contralateral tumors in breast cancer patients. Finally, the recent discovery of the steroid receptor superfamily is expected to stimulate further research into combination chemoprevention (the use of multiple agents to achieve synergistic effects while diminishing toxicity). As retinoids and tamoxifen both increase the synthesis or activity or transforming growth factor-beta, a cytokine which is a potent inhibitor of epithelial cell proliferation, tamoxifen and fenretinide are now proposed as the first model of combination chemoprevention in breast cancer.
Breast Neoplasms↗
Immunolike growth hormone substance in tissues from human embryos/fetuses and adults.
GH immunolike reactivity was measured by RIA and IRMA tests in the extracts of tissues from human fetuses (8-32 weeks) and adults. For some fetal tissues a comparison was made with the T4 values obtained in a previous study. Both hormones were already measurable in peripheral tissues at 8 weeks of gestation. The increase in GH was faster than for T4 and it reached the zenith at approximately 20 weeks; thereafter, the GH concentration declined until delivery. In contrast, T4 progressively increased until term. Thirteen tissues were studied both in fetuses and in adults: the GH concentration was about 10 times higher in fetal tissues, with the exception of the brain and the pancreas. The brain showed the lowest GH concentration throughout fetal life and adulthood, whereas the highest GH levels were recorded in adults' pancreas, but they resulted to be artifacts since the RIA values were not confirmed by the IRMA test. In both groups of subjects the highest GH concentrations were found in kidneys, liver and small intestine; the lowest, beyond the brain, in red muscle and cartilage. Thus, the pattern of the quantitative distribution of GH in fetal tissues is the same as in adults, suggesting a functional role of the hormone in the developing human during the prenatal period, in contrast with the concept that high tissue levels of GH are a mere reflection of high GH blood levels. Moreover, in all tissues examined no correlation was found between GH and T4 concentration.
Adult↗
The influence of gender in the evaluation of platelet and plasma catecholamines.
The platelet and plasma levels of catecholamines (CA) were simultaneously studied in a group of normal subjects in order to find possible sex-related changes in the distribution of CA in these two compartments. No significant differences between males and females were observed, but a marked platelet noradrenaline increase was found in the luteal phase as compared to the follicular phase. Furthermore, the platelet and plasma CA levels were strongly correlated in the male group but not in the female group. These results, while confirming the existence of a menstrual-related variability in noradrenergic activity, suggest a sex-related difference in the dynamic balance between platelet and plasma CA levels. The simultaneous assay of platelet and plasma CA enabled this phenomenon to be revealed, whereas the separate evaluation of platelet or plasma CA levels would not have done so.
Adult↗
Effect of CDP-choline treatment on mitochondrial and synaptosomal protein composition in different brain regions during aging.
Several age-dependent modifications of inner mitochondrial membrane and synaptosomal plasma membrane proteins from different brain regions of 4-, 12-, 18- and 24-month-old male Wistar rats, were observed. Some proteins, identified by immunoblotting assay as various subunits of mitochondrial respiratory chain complexes and calmodulin, were particularly impaired. Chronic treatment with CDP-choline at a dose of 20 mg/kg body weight per day for 28 days caused significant changes in the amounts of several of the above mentioned proteins. Most of the proteins, which decreased during aging, showed a significant increase after CDP-choline treatment compared with the corresponding control values at the same age. The effect of CDP-choline might be due to: the increased availability of cytidylic nucleotides, which in the brain are present in limited amounts compared to the other nucleotides; the increased content of total adenine nucleotides; the improvement of brain energy metabolism.
Aging↗
Mammographic patterns in breast cancer chemoprevention with fenretinide (4-HPR).
In 1987 a chemoprevention trial was started at the Istituto Nazionale Tumori of Milan to evaluate the efficacy of fenretinide or 4-HPR (an effective agent against carcinogen-induced epithelial tumours in experimental animals) in reducing the incidence of contralateral breast cancer in women previously treated for an early breast cancer (pT1, pT2, N-). Patients were randomised into two groups: 4-HPR 200 mg/day vs. no treatment. We reviewed the mammograms of 149 patients who received 4-HPR for at least 4 years to examine whether changes seen in the mammary glands of rats could also be seen in women. For each patient, at least five mammograms (one at baseline and four annual controls) of the contralateral breast were classified according to Wolfe's parenchymal patterns (N1, P1, P2, DY). With the daily dosage of 200 mg and after follow-up, no changes in mammographic patterns were observed.
Adult↗
Breast cancer chemoprevention.
Cancer chemoprevention is a new challenging issue for oncology. For breast cancer, different strategies for risk avoidance, chemopreventive measures and chemosuppressive interventions are being investigated. Attention is presently focused on two compounds, the synthetic retinoid fenretinide (4-HPR) and the antioestrogen tamoxifen, and their possible synergism. More data are now available on the expression and regulation of retinoic acid receptors in human breast cancer cells and on the consequences of the interaction of retinoids with plasma retinol binding protein. Mechanistic relationships between retinoids and growth factors like transforming growth factor-beta have been demonstrated in the frame of a central regulatory system of the state of differentiation and proliferation, in which tamoxifen is involved as well. Recent data from different trials using tamoxifen as adjuvant treatment have shown a decrease in the incidence of contralateral new primaries and that it could soon become unethical not to prescribe this drug to all node-negative oestrogen receptor-positive postmenopausal patients.
Breast Neoplasms↗
Flow cytometric analysis of ploidy in colorectal cancer: a multicentric experience.
Ploidy and cell proliferation determined by flow cytometry were assessed on colorectal cancers from patients admitted to two Italian cancer research centres. A total of 181 patients were followed prospectively for 4 years at the Istituto Regina Elena (IRE) of Rome and at the Istituto Nazionale Tumori (INT) of Milan. Fresh (at the IRE) or frozen (at the INT) tumour material and similar procedures were used for subsequent sample preparation. Similar frequencies of aneuploid tumours (63% vs 66%) and superimposable median DNA indices (1.6) were observed for the two case series. In both series, DNA ploidy was generally unrelated to clinico-pathological factors, except for a higher frequency of aneuploid tumours in Dukes' D (88%) than in Dukes' A stage (33%) in the IRE experience. DNA ploidy was a weak prognostic indicator at 3 years but not at 4 years in the IRE case series, and it never exhibited a clinical relevance in the INT experience. Conversely, multiploidy was an indicator of worse relapse-free and overall survival at 4 years in the IRE and INT case series.
Aneuploidy↗
Comparison of flecainide and procainamide in cardioversion of atrial fibrillation.
In this prospective, controlled and randomized cross-over study we tried to establish the efficiency and safety of flecainide vs procainamide for the treatment of acute atrial fibrillation. Eighty patients (30 females, 50 males, mean age: 55 +/- 14 years) were included. Patients entered into the study if they had atrial fibrillation of recent onset (< 24 h) with a ventricular rate > 100 beats.min-1 at rest and were < 75 years of age. Exclusion criteria were any sign of heart failure, conduction disturbances, sick sinus syndrome or acute ischaemic events. Randomly 40 patients received flecainide and 40 procainamide as the first treatment. There were no significant clinical difference between the two groups. Procainamide ws given at a dose of 1 g infused over 30 min, and followed by an infusion of 2 mg.min-1 over 1 h. Flecainide was given at a dose of 1.5 mg.kg-1 over 15 min followed by an infusion of 1.5 mg.kg-1 over 1 h. Drug infusion was continued until maximal dose, intolerance or reversion to sinus rhythm. After 1 h of wash out, patients remaining in atrial fibrillation were started on the second drug. Left atrial size was measured by echo. Serum levels of drug and atrial size did not differ between patients who returned to sinus rhythm and those who remained in atrial fibrillation. Conversion to sinus rhythm was achieved in 37 (92%) of the 40 patients treated with flecainide and 25 (65%) of those treated with procainamide (P < 0.001). The time required for reversion to sinus rhythm was similar between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effects of etoperidone on sympathetic and pituitary-adrenal responses to diverse stressors in humans.
The effects of the psychotropic drug etoperidone on the response to laboratory stressors was investigated in a controlled study. Cardiovascular and hormonal (catecholamines, corticotropin, and cortisol) measurements were made in a group of young, healthy volunteers during a cold pressor test (CPT), a mental arithmetic test (MAT), and insulin-induced hypoglycaemia (ITT). One-week treatment with etoperidone (ETO) (150 mg/day, orally) reduced basal and stress-induced values of systolic and diastolic blood pressure (BP) on CPT, while it did not alter catecholamine output in response to the stressor. Cardiovascular response was also attenuated after ETO on MAT, in the absence of any hormone changes. Adrenocorticotropic hormone (ACTH) and cortisol secretions were markedly reduced on ITT after ETO, whereas catecholamine outflow and cardiovascular parameters were substantially unaffected. These findings on ITT suggest that the anti-serotoninergic and anti-alpha 1-adrenergic activities of ETO may be used in the pharmacological control of the potentially detrimental consequences of the stress response.
Adrenocorticotropic Hormone↗
Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations.
PURPOSE: Monitoring of fenretinide (4HPR) levels, kinetics, and effects on retinal was performed in patients who participated in a phase I trial and who continued to be treated for 5 years as phase III trial patients. Accumulation of 4HPR in the breast was also assessed. PATIENTS AND METHODS: Plasma concentrations of 4HPR, of its main metabolite N-(4-methoxyphenyl)retinamide (4MPR), and of retinol were assayed by high-performance liquid chromatography (HPLC) in breast cancer patients treated orally with 4HPR 200 mg/d for 5 years with a 3-day drug interruption at the end of each month. RESULTS: 4HPR, at 200 mg/d, resulted in average 4HPR plasma levels of approximately 1 mumol/L, which remained steady and caused steady retinol level reduction; 4MPR levels, similar to those of 4HPR, slightly but significantly increased during the first 35 months, but at 5 years they were similar to those at 5 months. During daily treatment, baseline retinol concentrations were reduced by 71%; after a 3-day drug interruption, all patients recovered and the mean reduction was 38%. After discontinuation of 5-year treatment, 4HPR and 4MPR half-lives (t1/2 beta) were 27 and 54 hours, respectively, similar to those reported after 28 daily treatments. After 6 and 12 months, the concentrations of 4HPR were at the limit of detectability (0.01 mumol/L), whereas those of 4MPR were five times higher. Baseline retinol concentrations were already recovered after 1 month. Accumulation of this retinoid in the breast was evidenced by concentrations of 4HPR and 4MPR in nipple discharge and in breast biopsies that were 10 and 20 times higher, respectively, than those found in plasma. CONCLUSION: 4HPR, at 200 mg/d for 5 years, resulted in constant drug plasma levels and constant retinol level reduction. After treatment interruption, 4HPR plasma concentrations decreased at the limit of detectability at 6 months and baseline retinol plasma concentrations were recovered after 1 month.
Adult↗