Sorafenib for the Treatment of Progressive Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis.

BACKGROUND: Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC. METHODS: This is a retrospective longitudinal study of 13 patients with progressive metastatic MTC treated with sorafenib 400 mg twice daily between December 2011 and January 2015. The primary endpoints were to evaluate response and progression-free survival (PFS) in patients treated with sorafenib outside a clinical trial. The secondary endpoint was an assessment of the toxicity profile. One patient was excluded because of a serious allergic skin rash one week after starting sorafenib. RESULTS: The analysis included 12 patients with metastatic MTC (median age 48 years), 10 with sporadic and 2 with hereditary disease. The median duration of treatment was 11 months, and the median follow-up was 15.5 months. At data cutoff, 2/12 (16%) patients were still on treatment for 16 and 34 months. According to Response Evaluation Criteria in Solid Tumors analysis, 10 (83.3%) patients showed stable disease, and two (16.6%) had progression of disease; no partial response was observed. The median PFS was nine months. However, three patients with extensive and rapidly progressive disease died within three months of sorafenib treatment. The median PFS excluding these three patients was 12 months. Adverse events (AE) occurred in nine (75%) patients. The main AEs were skin toxicity, weight loss, and fatigue. Five (41.6%) patients needed dose reduction, and one patient discontinued treatment because of toxicity. CONCLUSIONS: Treatment with sorafenib in progressive metastatic MTC is well tolerated and resulted in disease control and durable clinical benefit in 75% of patients. Sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.

Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH (adrenocorticotropic hormone) syndrome.

BACKGROUND: The treatment of advanced medullary thyroid carcinoma (MTC) has evolved significantly over the past decade. The discovery of genetic abnormalities in MTC has led to the development of targeted therapies such as vandetanib and cabozantinib. Other kinase inhibitors (KI), such as sorafenib, have been investigated in this setting and are an alternative therapeutic option. The lack of specificity of these KIs to a single target may result in additional, unexpected effects. In this report, we describe a patient with metastatic MTC and Ectopic ACTH (adrenocorticotropic hormone) Syndrome in whom treatment with sorafenib resulted in complete resolution of hypercortisolism. SUMMARY: A 45-year-old male with progressive metastatic MTC presented with clinical manifestations suspicious for Cushing's syndrome. Investigation revealed ACTH-dependent hypercortisolism suggestive of Ectopic ACTH Syndrome. Treatment with sorafenib 400 mg twice a day was initiated resulting in a rapid and significant reduction of cortisol and ACTH levels associated with dramatic clinical improvement. The rapid and effective control of hypercortisolism in the absence of a significant tumor reduction raises the question of whether sorafenib may have a direct effect on ACTH or cortisol hypersecretion. CONCLUSIONS: This report suggests a previously unknown potential effect of sorafenib on the pituitary-adrenal axis. Further studies will be necessary to investigate the role of sorafenib in other cases of ACTH excess and to understand the mechanisms by which it alters steroid synthesis, action, or secretion.

Incidence of obesity does not appear to be increased after treatment of acute lymphoblastic leukemia in Brazilian children: role of leptin, insulin, and IGF-1.

BACKGROUND/AIMS: It has been reported that children treated for acute lymphoblastic leukemia (ALL) in developed countries show an increased risk of overweight and obesity in adolescence and adulthood. However, the majority of patients who came to our observation in Brazil have low or normal body weight and only one of them was obese. Therefore, we have decided to assess some biochemical parameters possibly related to the intermediate metabolism and body composition in these patients. METHODS: Two groups of subjects were studied: 27 survivors of childhood ALL (14.0 +/- 4.2 years old; post-treatment interval 8.6 +/- 3.9 years) (ALL group) and 17 healthy subjects (12.8 +/- 4 years old) (control group) selected on the basis of their kinship with the patients. RESULTS: 14/27 patients of the ALL group and 4/17 of the control group had leptin levels higher than the normal range for age and sex (p < 0.05). The leptin level was significantly higher in the ALL group (15.5 +/- 1.8 ng/ml) than in the control group (10.7 +/- 2 ng/ml) (p < 0.05). When adjusted by sex, BMI z-score, and age, the level of leptin in patients of the ALL group was 8.5 higher than in subjects of the control group (p = 0.006). Leptin/insulin correlation in the ALL group was 0.08 and in the control group it was +0.585 (p < 0.05). CONCLUSION: The data indicate the presence of alterations in the homeostatic regulatory mechanisms controlling body weight in Brazilian patients treated for ALL in childhood, still, it did not lead to obesity in the absence of favorable environmental conditions.

Hiponatremia prolongada após traumatismo cerebral, tratada com fludrocortisona / Prolonged hyponatremia after brain trauma treated with fludrocortisone

A hiponatremia é uma freqüente complicação do traumatismo craniano e surge, usualmente, nos primeiros dez dias depois do trauma e tem evolução limitada a poucos dias. Os autores apresentam um paciente que desenvolveu hiponatremia no nono dia após um acidente de motocicleta, a qual se prolongou por mais de vinte dias. Essa demorada hiponatremia pôde ocorrer porque o paciente foi tratado, inicialmente, com furosemida, como se tivesse a síndrome inapropriada da secreção do hormônio antidiurético, e com glicocorticóide, como se tivesse insuficiência glandular supra-renal. Contudo, o paciente teve síndrome cerebral perdedora de sal, que pode ocorrer após lesões do sistema nervoso central. Foi tratado com fludrocortisona (0,3 mg/dia) com reposição de sódio e de líquidos. Houve gradual desaparecimento da hiponatremia, e seu perfil físico e neural apresentou progressiva melhora. A fludrocortisona é um mineralocorticosteróide, e seu uso em pacientes com síndrome cerebral perdedora de sal é indicado pela ocorrência de secreção inapropriada do peptídeo natriurético cerebral, que inibe a secreção da aldosterona e, assim, provoca a perda renal de sódio.

Hyponatremia is a frequent complication following cranial traumatism and usually appears in the first ten days after the trauma, usually limited to a few days. The authors report a patient that developed hyponatremia on the 9th day after a motorcycle accident and it lasted twenty more days. The long period of hyponatremia could be explained by the treatment with furosemide, initially given with the assumption that he had inappropriate secretion of antidiuretic hormone syndrome, toghether with glucocorticoid, as if he had adrenal insufficiency. However, the patient had cerebral salt-wasting syndrome, which can happen after lesions of the central nervous system. Then, he was correctly treated with fludrocortisone (0.3 mg/day) and sodium plus fluid replacement. He gradually recovered from the hyponatremia and his physical and neural profile showed progressive improvement. Fludrocortisone is a mineralocorticosteroid and its use in a patient with cerebral salt-wasting syndrome is justified by its counter effect against the oversecretion of brain natriuretic peptide, which inhibits the aldosterone secretion, eventually leading to renal loss of sodium.

Persistence of hyperprolactinemia after treatment of primary hypothyroidism and withdrawal of long term use of estrogen: are the tuberoinfundibular dopaminergic neurons permanently lesioned?

Uso prolongado de altas doses de estrogênio e a presença de hiperprolactinemia crônica pode, pelo menos no rato, provocar lesão nos neurônios dopaminérgicos tuberoinfundibulares (TIDA) responsáveis pelo controle da secreção de prolactina (Prl). Essa ocorrência, ainda não bem documentada em humanos, pode ter ocorrido em uma paciente em tratamento crônico com contraceptivo oral (OC), que veio para consulta por hipotiroidismo primário, hiperprolactinemia e uma massa hipofisária. Após reposição de hormônio tiroidiano, suspensão do tratamento com o OC e a bromocriptina, essa paciente não manteve níveis normais de Prl, necessitando tratamento contínuo com agonista dopaminérgico, mesmo quando a RM da região selar indicava uma situação normal. A função dos neurônios TIDA foi investigada pelo teste do TRH (200µg IV), realizado antes e após 25mg de carbidopa e 250mg de L-dopa a cada 4 horas por um dia. TSH basal (3,9µU/mL) era normal, enquanto Prl (67,5 ng/mL) estava alta; ambos aumentaram apropriadamente após o estímulo com TRH, com picos de 31,8µU/mL (TSH) e 157,8ng/mL (Prl). Após tratamento com carbidopa/L-dopa, os níveis de TSH (1,6µU/mL) e Prl (34ng/mL) diminuíram e a resposta ao TRH foi parcialmente bloqueada (10,3µU/mL e 61ng/mL, respectivamente). Apesar da resposta normal, discutimos a possibilidade que a persistência da hiperprolactinemia é devida a uma lesão dos neurônios TIDA, produzida pelo longo uso de altas doses de estrogênios e pela presença de hiperprolactinemia crônica.

Persistence of hyperprolactinemia after treatment of primary hypothyroidism and withdrawal of long term use of estrogen: are the tuberoinfundibular dopaminergic neurons permanently lesioned?

Long term use of high doses of estrogen and the presence of chronic hyperprolactinemia may, at least in the rat, provoke lesions in the tuberoinfundibular dopaminergic (TIDA) neurons responsible for the control of prolactin (Prl) secretion. This occurrence, which is not yet well documented in humans, may have taken place in a patient on chronic oral hormonal contraceptive (OC) treatment who was seen for primary hypothyroidism, hyperprolactinemia and a pituitary mass. After thyroid hormone replacement, OC withdrawn and bromocriptine treatment, this patient could not maintain normal Prl levels, unless continuously treated with a dopaminergic agonist even when MRI was indicative of a normal situation. Function of TIDA neurons was investigated by TRH test (200 microg IV) performed before and after treatment with 25 mg carbidopa plus 250 mg L-dopa every 4 hours for one day. Basal TSH was normal (3.9 microU/mL) whereas basal Prl was high (67.5 ng/mL); both TSH and Prl levels appropriately increased after TRH: peaks 31.8 microU/mL and 157.8 ng/mL, respectively. After treatment with carbidopa/L-dopa, basal TSH (1.6 microU/mL) and Prl (34 ng/mL) decreased and the response to TRH was partially blocked (10.3 microU/mL and 61 ng/mL, respectively). In spite of a normal response, we discuss the possibility that the persistence of hyperprolactinemia is due to lesion of the TIDA neurons produced by the long term use of high doses of estrogens and by the presence of chronic hyperprolactinemia.

Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment.

A woman affected by Cushing's disease underwent bilateral adrenalectomy followed by radiotherapy of the hypothalamic-pituitary area when she was 18 years old. Thereafter, she used hydrocortisone acetate replacement therapy (35.5 mg divided into two daily doses). At the age of 26 years, the patient exhibited the clinical signs of the Nelson's syndrome, i.e. skin and gingival hyperpigmentation accompanied by amenorrhea, and elevated ACTH plasma levels (2,850 pg/ml, normal range 15-80 pg/ml). The magnetic resonance imaging (MRI) analysis of the sellar region evidenced a pituitary macroadenoma, measuring 14 x 13 mm. The patient was initially treated with cyproheptadine hydrochloride (12 mg/day) for 18 months. There was a partial improvement of the symptoms, with a reduction of the ACTH plasma levels to 112 pg/ml, but without any modification of the tumor mass. Due to sleepiness and weight gain, the cyproheptadine treatment was interrupted and substituted by a cabergoline (0.5 mg twice a week) therapy. Soon after cabergoline was applied an improvement of the clinical symptoms and signs was observed such as a regression of the tumor mass and the normalization of the ACTH plasma titers (38 pg/ml). Later, cabergoline was substituted by bromocriptine (7.5 mg/day) and the plasma levels of ACTH increased again (247 pg/ml), and headache and cutaneous hyperpigmentation were recorded. When cabergoline was reintroduced there was a clinical improvement and normalization of ACTH plasma levels (64 pg/ml). The MRI analysis of the sella region demonstrated a complete remission of the pituitary adenoma. The results obtained show for the first time that a long-term treatment with cabergoline also brings about a complete remission of Nelson's syndrome in the presence of a pituitary macroadenoma.