Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia.

We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.

Medical management of Cushing's disease: what is the future?

Cushing's disease (CD) is caused by a corticotroph, adrenocorticotropic-hormone (ACTH)-secreting pituitary adenoma resulting in significant morbidity and mortality. Transsphenoidal surgery is the initial treatment of choice in almost all cases. Remission rates for microadenomas are good at 65-90 % (with an experienced neurosurgeon) but remission rates are much lower for macroadenomas. However, even after postoperative remission, recurrence rates are high and can be seen up to decades after an initial diagnosis. Repeat surgery or radiation can be useful in these cases, although both have clear limitations with respect to efficacy and/or side effects. Hence, there is a clear unmet need for an effective medical treatment. Currently, most drugs act by inhibiting steroidogenesis in the adrenal glands. Most is known about the effects of ketoconazole and metyrapone. While effective, access to ketoconazole and metyrapone is limited in many countries, experience with long-term use is limited, and side effects can be significant. Recent studies have suggested a role for a pituitary-directed therapy with new multireceptor ligand somatostatin analogs (e.g., pasireotide, recently approved in Europe for treatment of CD), second-generation dopamine agonists, or a combination of both. Mifepristone (a glucocorticoid receptor antagonist) is another promising drug, recently approved by the FDA for treatment of hyperglycemia associated with Cushing's syndrome. We review available medical treatments for CD with a focus on the two most recent compounds referenced above. Our aim is to expand awareness of current research, and the possibilities afforded by available medical treatments for this mesmerizing, but often frightful disease.

[The medical management of Cushing's syndrome]. / Tratamiento farmacológico y seguimiento del síndrome de Cushing.

Cushing's syndrome results from prolonged exposure to excessive circulating glucocorticosteroids and is associated with significant morbidity and mortality. While the treatment of choice in most patients is surgical, the metabolic consequences of this syndrome, including hypertension and diabetes mellitus, increase the risks of such surgery. Hypercortisolemia and its sequelae can be efficiently reversed or controlled using medical therapy, either as a temporary measure prior to definitive treatment or as a longer-term treatment in some particularly difficult cases. Drug treatment has been targeted at the hypothalamic/pituitary level, the adrenal glands and at glucocorticoid receptors. The present review discusses the pharmacotherapeutic agents that have been used in Cushing's syndrome and the criteria for their use, as well as recent drugs that may improve the medical treatment of this complex endocrinological disorder in the future. Finally, the short-and long-term follow-up of patients with Cushing's syndrome after surgery is also discussed.

Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus?

BACKGROUND: Major depressive disorder affects a substantial percentage of the U.S. population, and can be highly debilitating. Selective serotonin reuptake inhibitors are commonly prescribed to treat depression, but may not be as effective for more severe or persistent depression. METHODS: The authors review data concerning the effects of corticosteroid synthesis inhibitors (CSIs) in the management of depressive disorders, present a hypothesis as to their possible mechanisms of action based on recent data suggesting synergistic effects of glucocorticoids on extrahypothalamic corticotropin-releasing hormone (CRH), and consider alternative hypotheses. Published reports evaluating the efficacy of CSIs in treating depression are reviewed and presented in light of recent findings regarding actions of glucocorticoids on the central CRH system. RESULTS: Results from open label and double-blind studies by several groups have indicated that CSIs may be efficacious or of adjunctive value in some patients with depression, including those refractory to other agents; however, there is a need for more controlled studies. Several lines of data suggest that the mechanism of action of these agents may not be solely a function of inhibition of adrenal cortisol production. CONCLUSIONS: The authors propose that CSIs may be efficacious in part by reducing glucocorticoid enhancement of CRH action in neurons of the central nucleus of the amygdala and other structures outside the endocrine hypothalamus. Possible effects of systemically administered CSIs on glucocorticoid receptor regulation, neuroactive steroids, and classical monoamine systems are also discussed. We conclude that available clinical data suggest a potential role for CSIs in the management of depressive disorders, especially major depression with psychotic features.

Prolonged remission of severe Cushing syndrome without adrenalectomy in an infant with McCune-Albright syndrome.

A 4 month-old girl presented with severe Cushing syndrome caused by McCune-Albright syndrome. After undergoing 19 months of pharmacologic suppression of cortisol production, she has been in clinical remission for more than 6 years. Adrenalectomy may be avoidable even in severe cases of Cushing syndrome associated with McCune-Albright syndrome.

[Medical treatment for Cushing's syndrome].

Systemic cortisol plays an important role in the metabolism of glucose, lipids and proteins, as well as in the regulation of electrolyte balance. It is well known that the development of the microvascular disease of various organs such as the heart and kidney, in patients with diabetes mellitus, hyperlipidemia and hypertension of which disorders are frequently associated with Cushing's syndrome. Thus, we should treat Cushing's syndrome as soon as possible, since many complications, including cardiovascular diseases and infections, will soon occur when the definite diagnosis is delayed. Adrenalectomy is essential for treatment for Cushing's syndrome even in the patients with pituitary or ectopic ACTH-producing tumor. Some case can not be treated with surgical procedures because of worsened conditions with several complications of infection and diabetes. Then we choose medical treatment. Medical adrenalectomy is achieved by using with mitotane which is usually used for adrenocortical cancer. We commonly treat the patients with Cushing's syndrome due to adrenal tumor and pituitary or ectopic ACTH producing tumor by using metyrapone which mainly inhibits 11-hydroxylase. Metyrapone is also recommended to treat the patients who are not well differentiated Cushing's disease from ectopic ACTH syndrome. We rarely use trilostane which is an inhibitor against 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Replacement therapy with hydrocortisone should be considered if adrenal failure will occur during treatment with those drugs.

Aromatase inhibitors: past, present and future in breast cancer therapy.

Estrogen has been implicated in promoting breast cancer in a majority of women. Endocrine therapy controlling estrogen production has been the guiding principle in treating breast cancer for more than a century. A greater understanding of this disease at a molecular level has led to the development of molecules that inhibit estrogen production by inhibiting the aromatase enzyme, that is the primary source of estrogen in postmenopausal women. This review examines the evolution of aromatase inhibitor (AI) based therapies over the past three decades. The third generation aromatase inhibitors (anastrozole, letrozole and exemestane), which have been found to be extremely specific and effective in an adjuvant/neoadjuvant/extended adjuvant setting are discussed from a biochemical and clinical perspective. A comprehensive discussion of the past, present, and future of aromatase inhibitors is conducted in this review.

Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a.

BACKGROUND: Clinical trial data have shown that among breast cancer patients who were disease free after 5 years of adjuvant treatment with tamoxifen, further extended treatment with the nonsteroidal aromatase inhibitor letrozole reduces breast cancer recurrence. We examined the efficacy and tolerability of extended adjuvant therapy with another aromatase inhibitor, anastrozole, for 3 years among women who had completed 5 years of adjuvant therapy. METHODS: Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a is an extension of ABCSG Trial 6, in which hormone receptor-positive postmenopausal patients received 5 years of adjuvant tamoxifen, with or without the aromatase inhibitor aminoglutethimide, for the first 2 years of therapy. For ABCSG Trial 6a, patients who were disease free at the end of Trial 6 were randomly assigned to receive either 3 years of anastrozole or no further treatment. Efficacy data were analyzed with the use of a Cox proportional hazards regression model with two-sided P values and Kaplan-Meier curves, and tolerability data were estimated using logistic regression analysis with odds ratios and 95% confidence intervals (CIs). RESULTS: ABCSG Trial 6a included 856 patients. At a median follow-up of 62.3 months, women who received anastrozole (n = 387) had a statistically significantly reduced risk of recurrence (locoregional recurrence, contralateral breast cancer, or distant metastasis) compared with women who received no further treatment (n = 469; hazard ratio = 0.62; 95% CI = 0.40 to 0.96, P = .031). Anastrozole was well tolerated, and no unexpected adverse events were reported. CONCLUSIONS: These data confirm the benefit of extending adjuvant tamoxifen therapy beyond 5 years with anastrozole compared with no further treatment. Further research is required to define the optimum length of extended adjuvant therapy and to investigate the possibility of tailoring this period to suit different disease types.

Advanced age and high initial WBC influence the outcome of inv(3) (q21q26)/t(3;3) (q21;q26) positive AML.

AML with inv(3)/t(3;3) are generally considered of having a poor prognosis. For further insight in this rare entity the outcome of 65 inv(3)/t(3;3) positive AML cases were examined with special emphasis o n patient a nd disease related factors at diagnosis. Survival data were available from 35 patients. A hematological CR was achieved in 16/35 patients (46%). Eight patients (50%) relapsed. The median duration of remission was 177 days. Probability of OS was 23% at 2 years. Advanced age and high initial WBC count were associated with shorter OS (p = 0.021 and p = 0.005, respectively). Loss of chromosome 7 was the most frequent additional aberration (n = 34; 52%), followed complex aberrant aberrations (n = 5). Cases with monosomy 7 or the presence of FLT3-length mutations (FLT3-LM)--detected in 13% of cases--were not associated with an even more inferior outcome. Allogeneic stem cell translplantation, performed in 12 cases, resulted in a probability of OS of 62% at 2 years. Our data (1) confirm that inv(3)/t(3;3) AML has a poor prognosis (2) show that age and initial WBC are risk factors for prognosis; (3) suggest that this group may benefit from allogeneic stem cell transplantation.

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.

Nodular pulmonary histoplasmosis in Cushing's disease: a case report and literature review.

Opportunistic infections are well documented in states of steroid excess. To our knowledge, histoplasmosis has not been previously reported in Cushing's disease, and has rarely been reported in patients with exogenous glucocorticoid use. We report a novel presentation of Histoplasmosis as pulmonary nodules in a patient with Cushing's disease. A 45-year-old man with a pituitary macroadenoma and Cushing's disease was treated with transsphenoidal hypophysectomy and radiation therapy. He was receiving Ketoconazole and basal steroid replacement, when he presented with dyspnea. Chest radiograph showed nodular lesions and subsequent biopsy revealed Histoplasma capsulatum. Itraconazole was administered and the patient recovered. The case not only demonstrates the protean manifestations of Histoplasmosis in patients with glucocorticoid excess but it also emphasizes the importance of intensive control of the hypercortisolemia in achieving a favorable outcome.

Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis.

BACKGROUND: Aromatase inhibitors and inactivators have been extensively tested in patients with advanced breast cancer, but it is unclear whether they offer any survival benefits compared with standard hormonal treatment with tamoxifen or progestagens. We performed a meta-analysis of randomized controlled trials that compared several generations of aromatase inhibitors and inactivators with standard hormonal treatment in patients with advanced breast cancer. METHODS: The endpoint that we assessed was survival. Trials were located through searches of PubMed and Cochrane Library (last update March 2006). Relative hazards (RHs) were summarized across trials through fixed- and random-effects analyses, and heterogeneity was assessed with the Q and I2 statistics. All statistical tests were two-sided. RESULTS: Twenty-five different comparisons, with a total of 8504 patients, were included in the meta-analysis. We found statistically significant survival benefits with third-generation aromatase inhibitors and inactivators (vorozole, letrozole, examestane, and anastrazole) (RH = 0.87, 95% confidence interval [CI] = 0.82 to 0.93; P<.001) but not with first-generation (aminoglutethimide) or second-generation (formestane and fadrozole) agents. The difference in the summary effects between these two groups of trials was statistically significant (P = .04). The survival benefit with third-generation agents in first-line trials, in which these agents were compared with tamoxifen (11% RH reduction, 95% CI = 1% to 19%; P = .03), was identical to their benefit in second- and subsequent-line trials in which these agents were compared with other treatments (14% RH reduction, 95% CI = 6% to 21%; P<.001). CONCLUSIONS: Inhibition of the aromatase system, in particular with third-generation aromatase inhibitors and inactivators, appears to be associated with statistically significant improved survival of patients with advanced breast cancer compared with standard hormonal treatments.

[Effects of drugs on the adrenal cortex and its tumors]. / Wirkungen von Medikamenten auf die Nebennierenrinde und ihre Tumoren.

The structure of the normal adrenal cortex is changed by stimulating hormones (ACTH) and inhibiting hormonal drugs (especially glucocorticoids). ACTH induces hyperplasia and lipid depletion in the fascicular and reticular zones, whereas glucocorticoids lead to atrophy and lipid accumulation in both zones. In animal experiments, the adrenostatic drug mitotane causes shrinkage of the cells of the fascicular and reticular zones, whereas metyrapone induces a decrease in the steroid producing organelle system and aminoglutethimide leads to an increase in lipids. In the therapy of patients with adrenocortical cancer, mitotane can cause an increase in of necrosis and fibrosis, but also in intracellular lipid. The ultrastructure shows increased liposomes, more pigment-rich lysosomes and laminated bodies.

Influence of aminoglutethimide and spironolactone on the efficacy of carbamazepine and diphenylhydantoin against amygdala-kindled seizures in rats.

Antagonists of steroid receptors may interfere with seizure phenomena. The present study deals with effects of aminoglutethimide and spironolactone on the action of carbamazepine and diphenylhydantoin in amygdala-kindled rats of both genders. Co-administration of the antimineralocorticoid with carbamazepine at their ineffective doses (50 and 15 mg/kg, respectively) led to significant reduction of the seizure and afterdischarge durations. No anticonvulsant effect was observed when spironolactone was combined with diphenylhydantoin. The concomitant treatment of aminoglutethimide and carbamazepine (both drugs at their subprotective doses of 5 and 15 mg/kg, respectively) resulted in antiseizure activity in respect of all measured parameters, including the afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration. The similar combination of aminoglutethimide with diphenylhydantoin (2.5 mg/kg) significantly shortened the seizure and afterdischarge durations. The antiseizure effect of tested combinations was not sex-dependent and not reversed by hydrocortisone pretreatment. Pharmacokinetic events may be involved only in the interaction between spironolactone and carbamazepine. Among various chemoconvulsants, bicuculline reversed the action of aminoglutethimide on carbamazepine and diphenylhydantoin. The effect of aminoglutethimide on diphenylhydantoin was also abolished by N-methyl-d-aspartic acid and aminophylline. In conclusion, our results suggest that doses of carbamazepine and diphenylhydantoin should be modified in epileptic patients concomitantly treated with aminoglutethimide or spironolactone.

Role of adrenalectomy in ectopic ACTH syndrome.

Evaluation of adrenalectomy in patients diagnosed with ectopic ACTH syndrome was studied. Twenty-three clinical cases diagnosed with ectopic ACTH syndrome were analyzed at Chinese Academy of Medical Sciences and Peking Union Medical College Hospital (PUMCH). Cases consisted of 14 males and 9 females, with mean age of 38 years. All 23 cases had positive clinical, biochemical and radiology evidence for diagnosis of Cushing's syndrome. Sixteen of the 23 cases were treated with total adrenalectomy and the remaining 7 were treated without surgical intervention. Sixteen cases, having no identifiable source of ectopic hormone production, experienced resolution of presenting signs and symptoms after undergoing bilateral or unilateral total adrenalectomy; 1-year survival was 67%, 2-year survival 41% and 5-year survival 15%. In patients treated conservatively without surgical intervention, 1-year survival was 0%. In patients with no identifiable source of ectopic hormone production, bilateral adrenalectomy followed by hormone replacement treatment is effective.

Use of aromatase inhibitors in children with short stature.

Estrogen has been shown to have an important role in skeletal maturation in both males and females. The use of aromatase inhibitors may provide a means to delay skeletal maturation and increase final height in children with short stature. These medications have been used primarily in women with breast carcinoma and also in children with autonomous estrogen production, such as patients with McCune-Albright Syndrome. Several studies have evaluated the safety and metabolic effects in adults. A few studies in children have evaluated the efficacy and safety of these medications. These studies demonstrate a beneficial effect on bone age advancement and predicted adult height. Other studies have evaluated the effects on bone mineral density, lipid metabolism and adrenal function in children. This review summarizes the studies in the pediatric population and some of the metabolic effects in adults.

A comparison of the efficacy of aromatase inhibitors in second-line treatment of metastatic breast cancer.

Randomized clinical trials have established the role of third-generation aromatase inhibitors (AIs) (letrozole, anastrozole, and exemestane) as standard treatment for patients with hormone-sensitive metastatic breast cancer who have experienced disease progression with antiestrogen therapy. Significant gains in clinical efficacy and improved tolerability over progestins (megestrol acetate) and the first-generation AI aminoglutethimide have positioned these agents above previous therapies. Estrogen receptor (ER) status remains the best predictive determinant of endocrine response, and further randomized trials with properly selected patient populations may distinguish individual AIs within this class. A recently completed, randomized, head-to-head phase III trial of letrozole versus anastrozole as second-line endocrine therapy demonstrated a significant difference in objective response rate for letrozole compared with anastrozole (19% versus 12%, respectively; P = 0.014), with similar time to progression. The improved efficacy and safety of AIs as second-line endocrine therapies has spawned trials of their use as first-line endocrine therapy versus tamoxifen for patients with metastatic breast cancer. Based on favorable results from these trials, letrozole and anastrozole have also been approved for use as first-line treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer.