Differential expression of galectin-3 in medullary thyroid carcinoma and C-cell hyperplasia

OBJECTIVE AND DESIGN: Galectin-3 is a beta-galactoside-binding protein that plays a role in cell adhesion and tumour progression. It was shown recently to diagnose malignant follicular thyroid lesions accurately. The reliability of this marker in the differential diagnosis between medullary thyroid carcinoma and C-cell hyperplasia was studied by immunohistochemistry. PATIENTS: Tissue specimens were obtained from 34 patients belonging to families with medullary thyroid carcinoma who underwent prophylactic thyroidectomy for RET gene mutation and/or abnormally increased plasma calcitonin levels. RESULTS: Galectin-3 was expressed in 23 of 25 cases of medullary thyroid carcinoma and in none of the nine cases of C-cell hyperplasia only, giving a sensitivity of 92% and a specificity of 100% for the diagnosis of carcinoma. A significant association was found between higher galectin-3 expression and occurrence of lymph node metastases (P < 0.05). CONCLUSIONS: Galectin-3 is a reliable diagnostic marker of medullary thyroid carcinoma, and its use may provide relevant information for prognosis and therapy.     

From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host’s metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host’s immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.

     

Uncommon Clinical Course of Multiple Osteochondromatosis in a Patient with a Long-Term History of Cushing's Disease

Cushing's disease (CD), the chronic endogenous hypercortisolism derived from an ACTH-secreting pituitary adenoma, and multiple osteochondromatosis (MO), a congenital mesoderm dyschondroplasia, represent two distinct rare neoplastic diseases. Clinical appearance of MO usually occurs during the first-second decade of life. In fact, the growth of osteochondromas parallels the patient's growth, then becoming quiescent after the closure of the epiphyses and the achievement of final stature. Here we describe an uncommon case of a patient with a long-term history of childhood-onset CD, who surprisingly developed MO during the third decade of life, after the remission of CD. Indeed, a female patient had been followed for CD from the age of 12 to the age of 24 years, when CD definitively remitted. At the age of 26 the patient complained progressively worsening backache and pain at level of hips and feet. Standard radiography of skeleton showed multiple bone dysmorphisms at level of the four limbs, spine and pelvis consistent with multiple osteochondromas and exostoses. A diagnosis of MO was performed. Total body bone scintigraphy with ^99mTc-MDP revealed an increased uptake of the radioligand, suggesting an increased metabolic turnover in correspondence of the majority of the osteochondromas. However, the negativity of the majority of the lesions at ^99mTc-DMSA scintigraphy and the histological diagnosis of benign osteochondroma of the only positive lesion at ^99mTc-DMSA evidenced that the high metabolic activity of the osteochondromas was not due to malignant transformation. However, the activity of the lesions was highly surprising considering that they usually become quiescent after the achievement of the final stature. In last analysis, the uncommon characteristics of MO and, particularly, its occurrence after stable remission of hypercortisolism, suggests a possible role of glucocorticoids in influencing the clinical course of the skeletal disease. The inhibitory effect of hypercortisolism on bone growth and maturation could explain the block in the proliferation of skeletal lesions during the developmental age, where CD was in the active phase, and the opposite effect of stimulation of the ostochondromas growth during stable normalization of cortisol secretion, after CD remission.     

Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours

Pituitary tumours express both somatostatin and dopamine receptors. Medical treatment with somatostatin analogues is a cornerstone of GH- and TSH-secreting tumours, while treatment with dopamine agonists is a cornerstone of prolactin-secreting tumours. Dopamine agonists have also demonstrated some efficacy in patients with GH- and TSH-secreting adenomas. Neither ACTH-secreting nor clinically non-functioning tumours have a well-established medical treatment. Nevertheless, some recent results have indicated a potential usefulness of the dopamine agonist cabergoline in patients with pituitary-dependent Cushing's disease. Combination treatment with both somatostatin analogues and dopamine agonists has been poorly investigated. Some studies conducted in small series have documented an additive effect of both drugs in patients with GH-secreting adenomas. Of mention is that none of the studies were randomised and cross-sectional so that the results should be confirmed by other well-designed studies. No data are available in other pituitary tumour histotypes. Preliminary observations in patients with clinically non-functioning adenomas are very promising.     

US-guided percutaneous radiofrequency thermal ablation for the treatment of solid benign hyperfunctioning or compressive thyroid nodules

The aim of the study was to define the effectiveness and safety of ultrasound-guided percutaneous radiofrequency (RF) thermal ablation in the treatment of compressive solid benign thyroid nodules. Thirty-one patients not eligible for surgery or radioiodine (¹³¹I) treatment underwent RF ablation for benign nodules; a total of 33 nodules were treated (2 patients had 2 nodules treated in the same session): 10 cold nodules and 23 hyperfunctioning. Fourteen patients complained of compressive symptoms. Nodule volume, thyroid function and compressive symptoms were evaluated before treatment and at 1, 3 and 6 mo. Ultrasound-guided RF ablation was performed using a Starbust RITA^® needle, with nine expandable prongs; total exposure time was 6 to 10 min at 95° C in one area or more of the nodule. Baseline volume (measured at the time of RF ablation) was 27.7 ± 21.5 mL (mean ± SD), but significantly decreased during follow-up: 19.2 ± 16.2 at 1 mo (–32.7%; p < 0.001), 15.9 ± 14.1 mL at 3 mo (–46.4 %; p < 0.001) and 14.6 ± 12.6 mL at 6 mo (–50.7%; p < 0.001). After treatment, all patients with cold nodules remained euthyroid: five patients with hot nodules normalized thyroid function, and the remaining sixteen showed a partial remission of hyperthyroidism. Besides a sensation of heat and mild swelling of the neck, no major complications were observed. Improvement in compressive symptoms was reported by 13 patients, with a reduction on severity scale from 6.1 ± 1.4 to 2.2 ± 1.9 (p < 0.0001). Radiofrequency was effective and safe in reducing volume by about 50% and compressive symptoms in large benign nodules. Hyperfunction was fully controlled in 24% of patients and partially reduced in the others. (E-mail: mdeandrea@libero.it)     

Growth hormone response to arginine test distinguishes multiple system atrophy from Parkinson's disease and idiopathic late-onset cerebellar ataxia

OBJECTIVE: Multiple system atrophy (MSA) is difficult to distinguish from idiopathic Parkinson's disease (PD) and idiopathic late-onset cerebellar ataxia (ILOCA). This study aimed to evaluate GH response to three different GH stimulation tests in order to establish a reliable test to differentiate these degenerative disorders. DESIGN: Twelve patients with MSA, 10 with PD, eight with ILOCA and 30 healthy controls entered the study. They were submitted to clonidine, arginine, and GH-releasing-hormone (GHRH) + arginine tests in a random manner on three different nonconsecutive days. The peak serum GH response was used as a primary variable for analysis of stimulation tests. By ROC analysis, the optimum cut-off level was considered as the cut-off with the maximal sum of sensitivity and specificity. RESULTS: After clonidine administration, GH peak was significantly lower in patients with MSA than in those with ILOCA (P < 0.05) and in the controls (P < 0.001). At the optimum cut-off level of 5 mU/l, the clonidine test distinguished patients with MSA from those with PD with a sensitivity and specificity of 78%. Moreover, this test distinguished patients with MSA from those with ILOCA with a sensitivity of 100% and a specificity of 75% at a cut-off level of 5 mU/l, and with a sensitivity of 75% and a specificity of 100% at the cut-off level of 7.6 mU/l. After arginine administration, the GH peak was significantly lower in patients with MSA than in those with ILOCA (P = 0.001) and in controls (P < 0.001). At the optimum cut-off level of 5 mU/l, the arginine test distinguished patients with MSA from those with PD with a sensitivity and a specificity of 100%. At a GH peak cut-off value of 3.6 mU/l the arginine test distinguished patients with MSA from those with ILOCA with a sensitivity and specificity of 100%. After GHRH + arginine administration, a significant GH increase was found in all groups of patients and controls. CONCLUSIONS: The GH response to arginine administration is impaired in MSA. Therefore, the arginine test showed the highest diagnostic accuracy to distinguish MSA from both PD and ILOCA, and could be used in the clinical practice of these neurodegenerative diseases.     

Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study

Introduction

Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty.

Sulfur amino acids in Cushing's disease: insight in homocysteine and taurine levels in patients with active and cured disease

BACKGROUND: Cushing's syndrome is associated with an increased cardiovascular risk. Although a series of cardiovascular risk factors have been identified, sulfur amino acids (SAAs), recently indicated as independent cardiovascular risk factors, have been poorly investigated in patients with Cushing's syndrome. AIM: The aim of this cross-sectional controlled study was to evaluate serum and urinary levels and urinary excretion rate (ER) of SAAs in patients with Cushing's disease (CD) during the active disease and after long-term disease remission. SUBJECTS AND METHODS: Forty patients with CD (20 with active disease and 20 with cured disease for at least 5 yr) and 40 controls entered the study. Serum and urinary concentrations and urinary ER of SAAs, namely methionine, cystine, homocysteine, and taurine, were measured by means of cationic exchange HPLC. Serum folic acid and vitamin B12 levels were also evaluated in patients and controls and correlated to SAA levels. RESULTS: CD patients with active disease had higher serum and urinary concentrations of cystine and homocysteine, and lower serum and higher urinary concentrations and ER of taurine than cured patients and controls. Vitamin B12 levels were significantly decreased in patients with active disease compared with cured patients and controls, whereas folic acid levels were slightly decreased in patients than in controls. In patients with active CD, urinary cortisol concentrations were significantly and inversely correlated to serum taurine and directly correlated to taurine urinary ER, and fasting serum glucose levels were significantly correlated to taurine urinary ER. At the multiple regression analysis, urinary cortisol concentrations were the best predictors of taurine ER. CONCLUSIONS: CD is associated with hyperhomocysteinemia and hypotaurinemia. Glucocorticoid excess, acting directly or indirectly, seems to be the most responsible for this imbalance in SAA levels. The long-term disease remission is accompanied by normalization of SAA levels. Hyperhomocysteinemia and hypotaurinemia might contribute to the increased cardiovascular risk of CD.     

Rapidly progressing high o,p'DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: preliminary results

INTRODUCTION: It has been reported that the therapeutic threshold of mitotane, plasma level above 14 microg/ml, is achieved within 3-5 months after o,p'DDD treatment initiation in patients with adrenocortical carcinoma (ACC). OBJECTIVE AND DESIGN: We evaluated pharmacokinetic and tolerance of a high-dose schedule of pure o,p'DDD treatment given in 500-mg tablets of mitotane (Lysodren, Bristol-Myers Squibb, HRA Pharma, Paris, France) in four patients with ACC and two patients with Cushing's syndrome-related endocrine tumours. It was administered at a starting dosage of 3 g/day, which was rapidly increased to 6-9 g/day within 2 weeks according to digestive tolerance and then adjusted according to tolerance and plasma o,p'DDD monitoring. Patients were followed up until they reached the therapeutic threshold of mitotane, and toxicity was recorded. A relationship between o,p'DDD dose and plasma level was sought. RESULTS: The highest starting dosage given ranged between 6 and 9 g a day, during the first two weeks. The daily maintenance dose ranged 4.5-9 g during the next 2 weeks and 3-9 g by the second month of treatment. The therapeutic threshold was reached in all four patients who received o,p'DDD treatment for at least 1 month. Among these four patients, the toxic threshold (plasma mitotane level > 20 microg/ml) was even reached at 6 weeks of therapy in three patients. Grade 1, 2 or 3 toxicity was observed in 3, 2 and 1 patients, respectively. Toxicity resolved after reduction or discontinuation of o,p'DDD therapy. A significant linear correlation was found between plasma mitotane dose and plasma level. CONCLUSIONS: These results suggest that a high-dose o,p'DDD therapeutic schedule is feasible with an acceptable toxicity and may shorten the time required to reach the therapeutic schedule from 3-5 months to 4 weeks. These patients require a close follow-up, combining clinical and plasma o,p'DDD level monitoring every second week. A confirmatory study is ongoing.