Molecularly Imprinted Polymers Doped with Carbon Nanotube with Aid of Metal-Organic Gel for Drug Delivery Systems.

PURPOSE: The incidence of breast cancer worldwide has been on the rise since the late 1970s, and it has become a common tumor that threatens women's health. Aminoglutethimide (AG) is a common treatment of breast cancer. However, current treatments require frequent dosing that results in unstable plasma concentration and low bioavailability, risking serious adverse reactions. Our goal was to develop a molecularly imprinted polymer (MIP) based delivery system to control the release of AG and demonstrate the availability of this drug delivery system (DDS), which was doped with carbon nanotube with aid of metal-organic gel. METHODS: Preparation of MIP was optimized by key factors including composition of formula, ratio of monomers and drug loading concentration. RESULTS: By using multi-walled carbon nanotubes (MWCNT) and metal-organic gels (MOGs), MIP doubled the specific surface area, pore volume tripled and the IF was 1.6 times than the reference. Compared with commercial tablets, the relative bioavailability was 143.3% and a more stable release appeared. CONCLUSIONS: The results highlight the influence of MWCNT and MOGs on MIP, which has great potential as a DDS.

Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment.

The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH-sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (∼90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of -omics-based analysis to accelerate anticancer DDS.

Hepatic effects of aminoglutethimide: a model aromatic amine.

Primary aromatic amine drugs are structural alerts in drug development because of their association with a high incidence of idiosyncratic drug reactions (IDRs). If biomarkers could be found that predict IDR risk, it would have a major impact on drug development. Previous attempts to do this through screening of hepatic gene expression profiles in rodents treated with aromatic amine drugs found limited changes. Of the drugs studied, aminoglutethimide (AMG) induced the most changes, and this led to a more comprehensive study of its effects on the liver. Brown Norway rats treated with AMG for up to 14 days showed only a transient elevation of glutamate dehydrogenase. Pathway-specific PCR arrays found few AMG-induced gene changes associated with an immune response and, of these changes, the majority were involved with innate immunity such as Tlr2, Ticam2, CD14, and C3. AMG treatment also led to significant changes in the apoptosis and mitochondrial panel of genes. It was recently found that AMG does induce significant changes in the bone marrow of rats, and agranulocytosis is a common IDR caused by AMG. In contrast, liver injury is not a common IDR associated with AMG. Therefore, the liver may be able to effectively deal with AMG reactive metabolites, and changes observed in this study may be involved in adaptation. Myeloperoxidase is also known to be able to oxidize aromatic amines to reactive metabolites, and these observations suggest that metabolism outside of the liver may be important for the mechanism of aromatic amine-induced IDRs.

Efficacy of tamoxifen ± aminoglutethimide in normal weight and overweight postmenopausal patients with hormone receptor-positive breast cancer: an analysis of 1509 patients of the ABCSG-06 trial.

BACKGROUND: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial. METHODS: ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5-24.9 kg m(-)(2)), overweight (BMI=25-29.9 kg m(-)(2)), and obese (30 kg m(-)(2)) according to WHO criteria. RESULTS: Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0·018) and a worse overall survival (OS; HR: 1·49; Cox P=0·052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0·24) and OS (HR: 0.99; Cox P=0·97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0·03) and a worse OS (1.47; Cox P=0·11) compared with normal weight patients. CONCLUSION: BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.

Changes in gene expression induced by aromatic amine drugs: testing the danger hypothesis.

Virtually all drugs that contain a primary aromatic amine are associated with a high incidence of idiosyncratic drug reactions (IDRs), suggesting that this functional group has biological effects that may be used as biomarkers to predict IDR risk. Most IDRs exhibit evidence of immune involvement and the ability of aromatic amines to form reactive metabolites and redox cycle may be responsible for initiation of an immune response through induction of cell stress, as postulated by the Danger Hypothesis. If true, danger signals could be biomarkers of IDR risk. A previous attempt to test the Danger Hypothesis found that sulfamethoxazole (SMX), the only aromatic amine tested, was also the only drug not associated with an increase of cell stress genes in mice. To ensure that these observations were not species-specific, and to determine biomarkers of IDR risk common to aromatic amines, rats were treated with SMX and two other aromatic amine drugs, dapsone (DDS) and aminoglutethimide (AMG), and hepatic gene expression was determined using microarrays. As in mice, SMX induced minimal gene changes in the rat, and none indicated cell stress, whereas DDS and AMG induced several changes including up-regulation of enzymes such as aldo-keto reductase, glutathione-S-transferase, and aldehyde dehydrogenase, which may represent danger signals. Early insulin-induced hepatic gene (Eiih) was up-regulated by all three drugs. Some mRNA changes were observed in the Keap-1-Nrf2-ARE pathway; however, the pattern was significantly different for each drug. Overall, the most salient finding was that the changes in the liver were minimal, even though aromatic amines cause a high incidence of IDRs. The liver generates a large number of reactive species; however, the ability of aromatic amines to be bioactivated by cells of the immune system may be why they cause a high incidence of IDRs.

Age-dependent role of steroids in the regulation of growth of the hen follicular wall.

BACKGROUND: The ovaries are the primary targets of senescence effects in mammalian and avian species. In the present study, relationships between reproductive aging, sex steroids and the growth pattern of the pre-ovulatory follicle wall were investigated using young hens with long clutch (YLC), old hens with long clutch (OLC), old hens with short clutch (OSC), and old hens with interrupted long clutch (OILC). METHODS: Experiment 1: Hens were sacrificed 1.5 and 14.5 h after ovulation. Experiment 2: YLC and OILC hens were sacrificed 3.5 h after treatments with LH and/or aminoglutethimide (AG), an inhibitor of steroid synthesis. Volumes of pre-ovulatory follicles (F1-F5) and plasma concentrations of ovarian steroids were determined. Experiment 3: Granulosa and theca cells from F3 follicles of OSC and/or YLC hens were exposed in vitro to estradiol-17beta (E2), testosterone (T) and LH and the proliferative activity of the cells was examined using CellTiter 96 Aqueous One Solution Assay. RESULTS: In YLC and OLC groups, the total volume of F1-F5 follicles rose between 1.5 and 14.5 h after ovulation (P < 0.01), negatively correlating with the plasma level of E2 (P < 0.01). There was no growth of pre-ovulatory follicles in the middle of the ovulatory cycle in the OSC group, with a positive correlation being present between E2 and the follicular volume (P < 0.05). In young hens, AG caused a rise in the total follicular volume. This rise was associated with a fall in E2 (r = -0.54, P < 0.05). E2 enhanced proliferation of granulosa cells from YLC and OSC groups. The proliferative activity of granulosa and theca cells of YLC hens depended on the interaction between T and LH (P < 0.01). CONCLUSIONS: These data indicate for the first time that the growth pattern of pre-ovulatory follicles during the ovulatory cycle changes in the course of reproductive aging. E2 seems to play a dual role in this adjustment; it stimulates the growth of the follicular wall in reproductive aged hens, whereas it may inhibit this process in young birds. T and LH are apparently involved in the growth regulation during the pre-ovulatory surge in young hens.

Cyclin D1 expression in breast cancer patients receiving adjuvant tamoxifen-based therapy.

PURPOSE: The objective of our study was to determine the clinical relevance of cyclin D1 expression in hormone receptor-positive breast cancer patients who were treated with tamoxifen-based therapy. EXPERIMENTAL DESIGN: We assessed expression of cyclin D1 in surgical specimens of breast carcinoma by means of immunohistochemistry. Patients had been enrolled in either Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 05 or ABCSG Trial 06 and received tamoxifen as part of their adjuvant treatment. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathologic factors. RESULTS: Cyclin D1 was expressed in 140 of 253 (55%) tumors of ABCSG Trial 05 and in 569 of 948 (60%) tumors of ABCSG Trial 06. Expression of cyclin D1 was associated with poor outcome in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors compared with patients with cyclin D1-negative tumors [adjusted hazard ratio (HR) for death (ABCSG Trial 05), 2.47; 95% confidence interval (95% CI), 1.08-5.63; P = 0.03; adjusted HR for death (ABCSG Trial 06), 1.78; 95% CI, 1.36-2.34; P < 0.0001]. Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors [adjusted HR for relapse (ABCSG Trial 05), 2.73; 95% CI, 1.50-4.96; P = 0.001; adjusted HR for relapse (ABCSG Trial 06), 1.52; 95% CI, 1.14-2.04; P = 0.005]. CONCLUSION: Cyclin D1 expression is an independent poor prognostic factor in women with early-stage, hormone receptor-positive breast cancer who received adjuvant tamoxifen-based therapy.

Is pseudo-Cushing's syndrome in a critically ill patient "pseudo"? Hypothesis and supportive case report.

OBJECTIVE: To propose a new hypothesis regarding the possible role of glucocorticoid excess in patients with an extended acute illness, based on a patient's presentation and therapy in a critical care situation. METHODS: We present a detailed case report, review the related literature, and suggest the need for prospective studies to determine the appropriate intervention in critically ill patients with pseudo-Cushing's syndrome. RESULTS: A 50-year-old woman with diabetes and obesity who underwent vertical banded gastroplasty had postoperative complications, including refractory gastrostomy leakage, peritoneal and abdominal wall infections, and multiorganism sepsis despite intensive antibiotic therapy and surgical drainage procedures. Her physical appearance, elevated and relatively nonsuppressible plasma cortisol levels, and radiologic study supported a tentative diagnosis of Cushing's syndrome in a critically ill patient. Intravenously administered itraconazole and rectally administered aminoglutethimide were used to suppress endogenous glucocorticoid synthesis. Glucocorticoids were administered at dosages that provided 1/3 to 1/2 of her expected maximal daily cortisol secretion during her complicated hospital course. Insulin resistance declined with adrenal suppression and infection control, and wound healing improved dramatically. Adrenal suppression was discontinued, and she was reevaluated for hypercortisolism. Results of all studies for Cushing's syndrome were normal and remained so 1 year later. CONCLUSION: In our patient, substantially increased glucocorticoid levels were associated with severe insulin resistance, retarded wound healing, and persistent infections. Suppression of endogenous cortisol production and replacement with more physiologic concentrations of glucocorticoid were associated with clinical improvement and appeared to contribute to her recovery. Review of the literature leads us to propose the following hypotheses: (1) that considerably increased stress-induced cortisol concentrations in critically ill patients may contribute to adverse outcomes and (2) that therapeutic suppression of the persistent and substantially elevated glucocorticoid levels in selected cases may be a beneficial therapeutic option.

Studies of the role of steroid hormone in the regulation of oocyte maturation in cattle.

BACKGROUND: The objective of this study was to investigate whether the steroid hormone(s) secreted from cumulus-oocyte complexes (COCs) is a prerequisite for bovine oocyte maturation and cumulus expansion using aminoglutethimide (AGT), a P450 cholesterol side-chain cleavage inhibitor. METHODS: In experiment 1, COCs were cultured in maturation medium with various concentrations of AGT for 22 h to determine the effective concentration of AGT to inhibit steroid hormone secretion, meiotic maturation and cumulus expansion. In experiment 2, COCs were cultured in conditioned medium (CM) and TCM-199 medium with or without 10 mM AGT to check whether steroid hormones secreted from COCs were responsible for oocyte maturation and cumulus expansion. Experiments 3 and 4 were carried out to determine whether exogenous progesterone or estradiol-17beta was able to overcome the inhibitory effects of AGT on oocytes maturation and cumulus expansion. COCs cultured in 10 mM AGT-containing medium supplemented with various concentrations of progesterone or estradiol-17beta for 22 h were examined for oocyte maturation and cumulus expansion. RESULTS: Experiment 1 showed that a concentration of 10 mM AGT in medium was sufficient to block steroid hormone secretion, oocyte maturation and cumulus expansion, and that these inhibitory effects were fully reversible. In experiment 2, the addition of 10 mM AGT to CM did not significantly prevent oocyte maturation and cumulus expansion, implying that CM contains the steroid hormone(s) secreted from COCs, which are closely associated with oocyte maturation and cumulus expansion. The results in experiments 3 and 4 demonstrated that the addition of any concentration of progesterone or estradiol-17beta in the medium did not reduce the inhibitory effects of AGT on oocyte maturation and cumulus expansion. CONCLUSION: Our results indicate that bovine oocytes surrounded by cumulus cells are prevented from maturation and cumulus expansion through the inhibition of steroid secretion due to AGT, and that these inhibitory effects of AGT on oocyte maturation and cumulus expansions can not be overcome by the addition of either progesterone or estradiol-17beta in the medium. These observations suggest that some steroid hormone(s) other than P4 and E2 secreted from bovine COCs is essential for their meiotic maturation and cumulus expansion.

Effect of combination therapy with aminoglutethimide and hydrocortisone on prostate-specific antigen response in metastatic prostate cancer refractory to standard endocrine therapy.

A prospective study was performed to investigate the combination of the aromatase inhibitor aminoglutethimide and hydrocortisone in androgen-independent prostate cancer with changes in prostate-specific antigen (PSA) level as main determinant for response. Thirty-five patients were treated with aminoglutethimide 1000 mg daily and hydrocortisone acetate 40 mg daily. PSA measurements were performed every month. If evaluable lesions were present, objective tumor assessment was done by computed tomography scan and X-ray investigations. In 12 patients (37%) the PSA value showed a confirmed response with a decline in serum level of at least 50%. Median time to progression in responding and all patients was 10.5 and 4.5 months, respectively. Median duration of response in responding patients was 9 months. Median survival for these two groups was 23 and 14.5 months, respectively. Of seven patients with measurable disease, two showed a partial response and five a stable disease. Improvement in general condition, pain and feeling of well-being was noted in two-thirds of patients. Therapy was well tolerated with mainly grade I and II adverse events in 20% of patients. We conclude that aminoglutethimide is a valuable second-line therapy for patients with androgen-independent prostate cancer.

Growth retardation as well as spleen and thymus involution in latent TGF-beta binding protein (Ltbp)-3 null mice.

The latent TGF-beta binding protein (LTBP)-3 is an extracellular matrix (ECM) protein that binds the small latent complex (SLC) of TGF-beta. Disruption of the Ltbp-3 gene by homologous recombination in mice yields mutant animals that display multiple skeletal abnormalities. In addition, these mice have retarded growth. On an inbred 129 SvEv background, half of the Ltbp-3 mutant mice die between 3 and 4 weeks after birth. These mice show severe involution of the thymus and spleen and a sharp reduction in the numbers of CD4/CD8 double positive T-cells in the thymus. The thymus and spleen defect is caused by elevated corticosterone levels in the serum and can be reversed by injection of aminoglutethimide (AMG), an inhibitor of steroid synthesis. This result indicates that the thymus and spleen defect is a secondary defect due to high corticosterone levels probably induced by stress of unknown etiology.

Antidepressant-like effect of Ro5-4864, a peripheral-type benzodiazepine receptor ligand, in forced swimming test.

This study examined the effects of peripheral-type benzodiazepine receptors in the forced swimming test. PK 11195 (1-(2-chloro-phenyl)-N-methyl-N-(1-methylpropyl)-1-isoquinoline carboxamide) and Ro5-4864 (7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one) were i.p. injected in mice, according to an acute (1 or 24 h) and a repeated (14 days) schedule. Pretreatment with the agonist, Ro5-4864, significantly reduced immobility time 1 h after treatment but not 24 h after it, whereas the antagonist, PK11195, did not interfere with the test parameters. Nevertheless, PK11195 pretreatment inhibited the Ro5-4864 antidepressant-like effect. Animals repeatedly treated with Ro5-4864 had a similar profile of action with no sign of motor impairment or locomotor activation as evaluated in the rota-rod and open-field tests, respectively. Aminoglutethimide pretreatment, which blocks the early step of steroid synthesis, inhibited the antidepressant-like effect of Ro5-4864. The present findings suggest an antidepressant-like profile for the benzodiazepine, Ro5-4864, that seems to involve steroid synthesis as underlying mechanism.

Randomized trial of tamoxifen versus tamoxifen plus aminoglutethimide as adjuvant treatment in postmenopausal breast cancer patients with hormone receptor-positive disease: Austrian breast and colorectal cancer study group trial 6.

PURPOSE: To determine whether the addition of aminoglutethimide to tamoxifen is able to improve the outcome in postmenopausal patients with hormone receptor-positive, early-stage breast cancer. PATIENTS AND METHODS: A total of 2,021 postmenopausal women were randomly assigned to receive either tamoxifen for 5 years alone or tamoxifen in combination with aminoglutethimide (500 mg/d) for the first 2 years of treatment. Tamoxifen was administered at 40 mg/d for the first 2 years and at 20 mg/d for 3 years. RESULTS: All randomized and eligible patients were included in the analysis according to the intention-to-treat principle. After a median follow-up of 5.3 years, the 5-year disease-free survival in the aminoglutethimide plus tamoxifen group was 83.6% versus 83.7% in the monotherapy group (P =.89). The corresponding data for overall survival at 5 years were 91.4% and 91.2%, respectively (P =.74). More patients failed to complete combination treatment (13.7%) because of side effects as compared to tamoxifen alone (5.2%; P =.0001). CONCLUSION: Aminoglutethimide given for 2 years in addition to tamoxifen for 5 years does not improve the prognosis of postmenopausal patients with receptor-positive, lymph node-negative or lymph node-positive breast cancer.

A phase II study of cisplatin and vinorelbine in patients with metastatic breast cancer.

BACKGROUND: To evaluate the efficacy and safety of the combination of cisplatin and vinorelbine in metastatic breast cancer. PATIENTS AND METHODS: Cisplatin (80 mg/m(2) day 1) and vinorelbine (25 mg/m(2) days 1 and 8) were administrated every 3 weeks to 52 patients (mean age 57 years; range 35-75 years) with metastatic breast cancer. Thirty-two patients were previously untreated for metastatic disease. Treatment was repeated for a maximum of six cycles. RESULTS: Objective responses were obtained in 27 patients (52.9%; complete response 9.8%). The response rate was similar in pretreated and untreated patients (50% and 54.7%, respectively; P = 0.7). ECOG performance status was good (grade 0 or 1) in 55.7% of patients at baseline assessment and in 90.3% at the end of treatment (P = 0.0001). Median time to progression was 8.5 months (8.5 months in first-line and 8.7 months in second-line patients). Median survival was 16.6 months (21.2 months in first-line and 16.1 months in second-line patients). Grade 3/4 toxicity included neutropenia (44% in first-line, 60% in second-line patients), nausea (17.3%), anemia (17%), asthenia (3.8%) and thrombocytopenia (1.9%). There were no cases of febrile neutropenia or treatment-related deaths. Alopecia did not develop in any of the patients. CONCLUSIONS: Cisplatin plus vinorelbine is active and tolerable in metastatic breast cancer, in untreated and pretreated patients.

Elevation of soluble tumor necrosis factor receptor II in non-febrile patients with acute myeloid leukemia.

BACKGROUND: Tumor necrosis factor alpha (TNF) and its cellular and soluble (s) receptors (TNF-R) are important mediators in acute myeloid leukemia (AML) and infectious complications during cytoreductive therapy. We investigated the serum concentrations of sTNF-RII in previously untreated patients with AML at the onset of cytoreductive therapy and in non-febrile chemotherapy-associated neutropenia. PATIENTS AND METHODS: Of 54 eligible patients with AML, serum concentrations of sTNF-RII could be evaluated in 25 non-neutropenic, non-febrile and in 11 neutropenic, non-febrile patients. RESULTS: At baseline, non-neutropenic, non-febrile AML patients showed high median serum sTNF-RII concentrations of 3,804 pg/mL. In neutropenia, there was a non-significant trend (p = 0.18) to lower median sTNF-RII levels of 3,246 pg/mL. CONCLUSIONS: Serum sTNF-RII concentrations in non-febrile AML patients before chemotherapy are in the range of levels reached in uncomplicated febrile episodes in otherwise healthy individuals. This must be taken into account when evaluating the cytokine profile for sepsis in patients with therapy-associated neutropenia. Concentrations are still elevated in neutropenia, suggesting that a normal number of leukocytes is not necessarily required for the activation of the TNF ligand/TNF receptor system in AML.

Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer. A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age.

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N = 94), the TAM+AG+H (N = 83), and the TAM+FLU (N = 81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p = 0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are -9-19% and for TAM vs. TAM+FLU -4-25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM + FLU group, respectively (p = 0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG +H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.

Prognosis in adult AML is precisely predicted by the DISC-assay using the chemosensitivity-index Ci.

We prospectively investigated the correlation between DISC-assay results and clinical response and also survival in patients with AML using a new method of evaluation.

Long-term medical treatment of ectopic ACTH syndrome.

BACKGROUND: The morbidity of hypercortisolemia due to ectopic production of ACTH by various tumors may be greater than the morbidity of the tumor itself. METHODS: We report three cases of long-term treatment of ectopic ACTH syndrome due to metastatic bronchial carcinoid, islet cell carcinoma, and malignant thymoma tumors. Clinical and biochemical eucortisolemia was achieved in each case and was sustained from 24 to 55 months. We review the therapeutic options and their reported efficacy. RESULTS: Cessation of therapy resulted in recurrence of hypercortisolemia in each case, showing the effectiveness of therapy. CONCLUSION: Long-term treatment of ectopic ACTH-induced hypercortisolemia by blocking adrenal steroidogenesis is clinically effective and well tolerated.

Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3).

BACKGROUND: The study compares letrozole and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with antioestrogens. PATIENTS AND METHODS: 555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicentre trial. The primary endpoint was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patient was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit. RESULTS: Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Transient nausea was the most frequent event with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10% on AG), rash with AG (11%, 1% on 0.5 mg, 3% on 2.5 mg letrozole). CONCLUSIONS: Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-oestrogens.