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B Allolio

Publications and source records attributed to B Allolio.

At least 19 recordsLinked to original sources
PubMed2006

Adrenocortical carcinoma -- improving patient care by establishing new structures.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and highly malignant tumour with a poor prognosis. Patients present with signs of steroid hormone excess (e.g., Cushing's syndrome) or symptoms due to an abdominal mass. DIAGNOSIS: In case of an adrenal mass, hormonal workup before surgery is required for differential diagnosis, perioperative management, and for follow-up. The imaging of choice is CT or MRI with MRI being of additional use when invasion of big vessels is suspected. Apart from that, the use of 18-FDG-PET is becoming increasingly established. TREATMENT: Surgical resection is the therapeutic option of choice in stages 1 - 3. In stage 4, the adrenolytic compound mitotane is part of the first-line treatment, but often needs to be combined with cytotoxic chemotherapy. Most patients will eventually have a recurrence, so adjuvant treatment (mitotane/tumour bed radiation) has to be considered in high risk patients, even if randomized controlled trials on adjuvant treatment are still lacking. STRUCTURAL PROGRESS: Several national and European structures have recently been established in order to increase our knowledge of ACC, improve therapeutic options and diagnostic procedures, and promote research. GANIMED, as a Germany-wide network of experts on adrenal diseases, has been founded allowing for improved gathering of data and joint studies. ENSAT (European Network for the Study of Adrenal Tumours) has been brought to life, aiming at European standards for therapy, diagnosis and tumour banking. Since 2003, patients can be enrolled in the German ACC Registry. France and Italy have also developed a central registry to collect nationwide data from patients with ACC. For the first time, patients with metastatic/unresectable ACC can participate in a prospective controlled randomized trial comparing two different cytotoxic chemotherapy regimes (FIRM-ACT).

Adrenal Cortex Neoplasms↗
PubMed2004

Adrenal tumors: how to establish malignancy ?

Discerning malignancy in adrenal tumors largely influences disease management and is, therefore, of utmost importance to both patient and physician. Clinical presentation (e.g. virilization) and baseline hormonal evaluation (e.g. high serum DHEAS) are occasionally of great value but usually provide only limited help in predicting malignancy. The probability of malignancy is clearly related to tumor size, as almost all lesions <3 cm are benign whereas a diameter of >6 cm indicates a high risk of malignancy. Computed tomography (CT) and magnetic resonance imaging (MRI) both contribute significantly to the characterization of adrenal masses. If the attenuation of a homogeneous mass with smooth border is 10 Hounsfield units or less in unenhanced CT the diagnosis of a lipid rich adenoma is established. Similarly, enhancement washout of more than 50% in CT at 10-15 min suggests a benign lesion. In MRI both rapid contrast enhancement after gadolinium followed by rapid washout and signal intensity loss using opposed-phase image in chemical shift analysis also indicate the presence of an adenoma. In contrast, adrenal carcinomas--but also pheochromocytomas--typically present as inhomogeneous lesion with intermediate-to-high intensity on T2 images in MRI. Margins and enhancement after contrast media in CT are irregular in adrenal carcinoma. Other imaging techniques either offer little additional information (NP-59 scintigraphy) or have not yet been fully established (positron emission tomography). Fine needle aspiration/cut biopsy is at present restricted to patients with a known extra-adrenal malignancy and suspected adrenal metastasis as the only evidence of disseminated disease. Adrenal tumors classified as benign undergo follow-up imaging to assess tumor growth. If an increase in diameter of >1 cm is seen, surgical removal is recommended. Even after tumor removal the diagnosis of dignity may remain difficult. Diagnostic scores together with new immunohistological markers are the methods of choice to assess malignancy. In conclusion, an interdisciplinary approach with a structured use of available diagnostic tools is needed to classify adrenal tumors correctly.

Adrenal Gland Neoplasms↗
PubMed2004

Failure of recombinant human growth hormone treatment to improve congestive heart failure in hypopituitarism.

Growth hormone (GH) deficiency decreases left ventricular (LV) contractility, induces LV chamber dilatation and promotes progression to congestive heart failure. It is, however, controversial, whether GH replacement therapy in addition to standard medical heart failure therapy should be considered as routine treatment in GH deficient patients with heart failure. In the present report of a 64-year-old GH deficient patient with heart failure, we demonstrate by using Doppler echocardiography, magnetic resonance imaging and 31P NMR spectroscopy that even a 12 month period of GH replacement therapy had no sustained effect on morphometric or functional parameters of LV performance nor on clinical signs or symptoms of heart failure. It is concluded that GH replacement therapy should currently not be regarded as standard heart failure therapy in patients with GH deficiency and should only be employed under careful monitoring including close follow-up in a standardized way.

Echocardiography, Doppler↗
PubMed2003

Enhancement of dehydroepiandrosterone solubility and bioavailability by ternary complexation with alpha-cyclodextrin and glycine.

In the present work we investigated the possibility of improving dehydroepiandrosterone (DHEA) solubility and bioavailability by high-energy cogrinding with alpha-cyclodextrin (alpha-Cd) in the presence or absence of different auxiliary substances (glycine, biomaltodextrin, poly(vinyl pyrrolidone), poly(ethylene glycol) 400). In all cases, ternary products exhibited higher drug solubilizing properties than the binary DHEA-alpha-Cd coground system. Glycine was the most effective component. The best combinations, corresponding to 1:1:2 and 1:2:3 drug-alpha-Cd-glycine molar ratios, were characterized by differential scanning calorimetry and X-ray powder diffractometry and evaluated for dissolution rate. The presence of glycine favored destruction of DHEA crystalline structure during cogrinding, as evidenced by the strong reduction in both time and vibration frequency of milling necessary to obtain total drug amorphization. Both ternary products showed better dissolution properties than the drug alone, affording, respectively, a 40 and 60% increase of dissolution efficiency. The 1:2:3 coground product was then selected for in vivo bioavailability studies in women suffering from adrenocortical insufficiency. DHEA and DHEA sulfate blood levels were significantly higher (p < 0.001) after oral administration of the coground product than after oral administration of untreated drug, with a 100% increase in the area under the curve (AUC) of concentration versus time. Moreover, the time to reach maximum concentration (t(max)) decreased from 2.2 with the untreated drug to 0.5 h with the coground product, and the mean permanence time of DHEA within physiological levels was four times longer for the coground product compared with the untreated drug. These results indicate that the developed product is particularly suitable for oral DHEA formulations in hormone replacement therapies.

Adrenal Cortex Diseases↗
PubMed2003

[Adrenal crisis. Diagnostic and therapeutic management of acute adrenal cortex insufficiency].

Acute adrenal insufficiency is a rare but life-threatening disorder that develops as a result of inadequate adrenal steroid production. Early diagnosis is key for effective and life-saving treatment of the affected patients. The main clinical features are non-specific, thus often leading to misdiagnosis and invasive diagnostic work up, in particular in patients with previously unknown disease. Adrenal crisis in patients with known chronic adrenal insufficiency is nowadays rare, but can only be prevented by structured patient education on stress-related glucocorticoid dose adjustment. Outcome of adrenal crisis is crucially determined by the physician's clinical competence and immediate initiation of specific treatment.

Acute Disease↗
PubMed2003

High diagnostic accuracy of adrenal core biopsy: results of the German and Austrian adrenal network multicenter trial in 220 consecutive patients.

Incidentally detected adrenal tumors are a common finding during abdominal ultrasonography, computed tomography, and magnetic resonance imaging. Although most of these lesions are benign adenomas, adrenocortical carcinomas and metastases constitute 5% to 10% of all tumors. Adrenal biopsy may be helpful, but its diagnostic value is controversial and disputed, and prospective studies have not yet been performed. Therefore, the diagnostic accuracy of adrenal core biopsy was evaluated in a prospective multicenter study involving 8 surgical centers in Germany and Austria. A total of 220 biopsies from surgical specimens of the adrenal gland were punctured in an ex vivo approach and processed for pathohistologic diagnosis using paraffin sections, routine staining, and immunohistochemistry (keratin KL1, vimentin, S100 protein, chromogranin A, synaptophysin, neuron-specific enolase, D11, MiB-1, and p53 protein). The evaluating pathologist was blinded for clinical data from the patients. A total of 89 adrenal adenomas (40.5%), 22 adrenal carcinomas (10.0%), 55 pheochromocytomas (25.0%), 15 metastases (6.8%), 16 adrenal hyperplasias (7.2%), and 23 other tumors (10.5%) were studied. Nine cases were excluded due to incomplete data (n = 2) or insufficient biopsy specimen (n = 7). In the remaining 211 tumors, compared with the final diagnoses of the surgical specimen, bioptic diagnoses were absolutely correct in 76.8% of the cases, nearly correct in 13.2% of the cases, and incorrect in 10% of the cases. Pheochromocytomas were correctly diagnosed in 96% of the cases, cortical adenomas were correctly or nearly correctly reported in 91% of the cases, cortical carcinomas were correctly or nearly correctly reported in 76% of the cases, and metastases were correctly or nearly correctly reported in 77% of the cases. Of the 39 malignant lesions, only 4 were misclassified, 2 as benign and 2 as possibly malignant. This resulted in an overall sensitivity for malignancy of 94.6% and specificity of 95.3%. Our findings suggest that adrenal core biopsy is a useful method for identifying and classifying adrenal tumorous lesions if sufficient biopsy specimens can be obtained. However, in clinical practice it remains to be shown whether the benefits of biopsy outweigh the risks of the procedure.

Adenoma↗
PubMed2003

Testosterone undecanoate: a useful tool for testosterone administration in rats.

A major obstacle of testosterone (T) treatment in experimental animals is the difficulty of maintaining long-term physiologic/anabolic steady serum levels after exogenous T administration. In two complementary studies we investigated the pharmacokinetic properties of different T formulations in male rats. Study I. Mature male Wistar rats (> 380 g, n = 4 - 7/group) were divided into four treatment groups: (1) sham-operated non orchiectomised (non-ORX) and placebo; (2) orchiectomised (ORX) and subcutaneous testosterone pellets (TP) (15, 25, 75 mg/60 days release or placebo pellets); (3) ORX and a single injection of testosterone undecanoate (TUD) (31, 62.5 or 125 mg/kg body weight subcutaneously (s.c.) or vehicle; (4) ORX and testosterone propionate (Tprop) (10, 20, 40 mg/month) or vehicle as a single injection s.c. Serum T was measured at baseline and in weekly intervals for 4 weeks. Study II. Mature male Wistar rats (180 - 200 g) were randomly assigned to one of 5 experimental groups (n = 5 - 6/group): (1) normal untreated rats (controls); (2) ORX untreated rats, and non-ORX rats receiving one of three treatment options; (3) 250 mg/kg body weight TUD i.m. (TUD 250); (4) 500 mg/kg body weight TUD i.m. (TUD 500); (5) 100-mg testosterone pellet/90 days release s.c. (TP 100). Serum T was measured at baseline and in intervals for 6 weeks after T administration. In both studies, the kinetic profile of TUD showed favourable continuous steady state levels over several weeks. In contrast, testosterone release by subcutaneous pellets resulted in a shorter than expected duration of elevated serum T levels with high inter-individual variability. Tprop administration led to only a short-lasting serum T increase with low serum T levels already 14 days after injection. In conclusion, a single injection of TUD (100 mg/kg body weight s.c.) is effective in inducing physiological testosterone levels in ORX rats for a minimum of four weeks. High dose TUD (500 mg/kg body weight i.m.) given as a single injection results in supraphysiological anabolic testosterone concentrations for up to six weeks in non-ORX rats. TUD was superior to other T release preparations and represents a convenient and effective tool for T administration in experimental animals.

Anabolic Agents↗
PubMed2002

[Recurrent hypertensive crises associated with severe orthostatic hypotension due to baroreflex failure syndrome].

The baroreflex mechanism is a central part of the regulation of the cardiovascular system, particularly in the control of vagal and sympathetic outflow to the heart and the peripheral circulation. Failure of the baroreflex is a rare cause of secondary hypertension. It is characterized by drastic changes in sympathetic activation and blood pressure following complete denervation of the baroreflex. Here, we report a case of baroreflex failure following bilateral carotid artery surgery and radiation. Moreover, postoperative orthostatic hypotension with recurrent syncope suggests a rare subform, the selective baroreflex failure, where efferent parasympathetic activity is preserved. Both high blood pressure and orthostatically induced syncope improved substantially after treatment with clonidine.

Baroreflex↗
PubMed2002

Expression of HER-2/neu receptor protein in adrenal tumors.

The HER-2/neu protein is overexpressed in many human carcinomas obtained from different tissues and may represent a useful target for therapy with the commercially available monoclonal antibody trastuzumab (herceptin). Novel therapeutic options are needed for metastasized adrenocortical cancer. Therefore, we studied expression of the HER-2/neu cell surface receptor protein using three different antibodies in 12 adrenal adenomas, 17 adrenocortical carcinomas and 5 pheochromocytomas. Normal adrenals (n = 5) served as controls. One adenoma showed very weak membranous immunostaining with the Dako antibody, two others showed a nonspecific cytoplasmic staining pattern. A nonspecific reaction in the cytoplasm was demonstrable in seven carcinomas with the Novocastra antibody. In all pheochromocytomas, a granular intracytoplasmic and, rarely, slightly membranous immunostaining with the Dako antibody was found. From our data we conclude that specific and significant membranous immunostaining indicating strong overexpression (grade 3) of HER-2/neu protein is not present in adrenocortical tumors. The granular cytoplasmic immunostaining of the medulla may be helpful for differentiation of adrenocortical tumors from pheochromocytomas.

Adrenal Cortex Neoplasms↗
PubMed2002

Characterization of the human and mouse genes encoding the tuberoinfundibular peptide of 39 residues, a ligand of the parathyroid hormone receptor family.

The polypeptide TIP39 (tuberoinfundibular peptide of 39 residues) is a potent activator of the parathyroid hormone (PTH)-2 receptor (P2R) and an antagonist of the PTH-1 receptor (P1R). To clarify its possible physiological function(s), we studied its interaction with the human P1R and P2R and examined the expression of TIP39 in man and mouse. To find out possible sites of this ligand interaction in the organism, we identified the genes encoding the TIP39 protein precursors of Homo sapiens and Mus musculus in the databases of the human and mouse genome projects respectively. We then obtained the full-length cDNAs of both species by RACE-PCR. The deduced TIP39 preprohormones consist of an N-terminal 30 amino acid (aa) signal peptide followed by a 29 aa TIP39 precursor-related peptide, an Arg-Arg processing site, and the actual 39 aa TIP39 sequence. The first 23 aa of the actual TIP39 sequence, thought to contain the P2R receptor activation site, are identical in man and mouse and thus phylogenetically conserved. By contrast, the 16 aa C-terminal portion showed a higher degree of diversity (75% aa identity). By using RT-PCR, TIP39 was found to be highly expressed in human central nervous system tissues, trachea, fetal liver, and, to a lesser degree, in human heart and kidney. Using in situ hybridization, TIP39 mRNA expression was revealed in various areas of the mouse brain. In a homologous human cell model using human embryonic kidney 293 cells stably transfected with human P1R and P2R, human TIP39 did bind to P1R with moderate affinity (IC(50) approximately 10(-7)-10(-6 )M), but showed higher affinity binding to P2R (IC(50) approximately 10(-8)M), comparable to the affinity of human N-terminal PTH (hPTH(1-34)) to this receptor. In P2R-transfected cells, the cAMP pathway was activated more efficiently ( approximately 10-fold) by TIP39 as a ligand compared to hPTH(1-34). In P1R-transfected cells, only hPTH(1-34) but not TIP39 was able to elicit a cAMP response, but TIP39 was able to directly antagonize the cAMP-stimulating effect of hPTH(1-34) on this receptor. In conclusion, we could show a possible function of TIP39 for the human organism as a potent activator of P2R (e.g. in brain) as well as an antagonist of the action of PTH and/or PTH-related protein on P1R (e.g. in bone and kidney). The physiological role of TIP39 in calcium metabolism with regard to these actions remains to be determined. The tools developed in this work will allow us to investigate the possible role of TIP39 as a locally or systemically secreted ligand modulating the function of the PTH receptor family.

Animals↗
PubMed2002

Clodronate inhibits adrenocortical cell proliferation and P450c21 activity.

Bisphosphonates (BPs), specific inhibitors of osteoclasts, are well established in the management of skeletal metastases in breast cancer. Recent studies have suggested that these compounds may also directly influence tumor cell proliferation. As adrenocortical cancer frequently leads to bone metastases, we investigated the effects of clodronate (CLO) in the human adrenocortical cancer cell line NCI-H295 and in primary cultures of bovine adrenocortical cells. Both the non-amino BP CLO and the amino BP pamidronate (PAM) exhibited a dose-dependent antiproliferative effect in both cell types (cell viability in NCI-H295 cells: 100 microM CLO: 98+/-8%; 500 microM CLO 76+/-6%; 1000 microM CLO 53+/-2; 10 microM PAM 96+/-3%; 50 microM PAM 46+/-6%; 100 microM PAM 11+/-1% vs untreated control cells: 100+/-10%; P<0.01). FACS analysis in NCI-H295 cells treated with either CLO or PAM demonstrated both apoptotic and necrotic cell death. However, while during PAM treatment cell number and hormone secretion decreased in parallel, we observed specific impairment of steroidogenesis in the presence of CLO with a dose-dependent increase in the 17-OH-progesterone/cortisol ratio (100 microM CLO 134+/-30%; 500 microM CLO 284+/-10%; 1000 microM CLO 545+/-130% vs 100+/-20% in control cells; P<0.01). Further analysis in ACTH-stimulated bovine adrenal cells using stable isotope dilution/gas chromatography-mass spectrometry demonstrated CLO-induced inhibition of adrenal 21-hydroxylase (P450c21) activity leading to a dose-dependent increase in the 17-OH-progesterone/11-deoxycortisol ratio. In conclusion, we demonstrate a dose-dependent antiproliferative effect of CLO and PAM in adrenocortical cells. In addition, for the first time, we describe a suppressive effect of CLO on steroidogenesis via inhibition of adrenal 21-hydroxylase (P450c21) activity.

Adrenal Cortex↗
PubMed2001

Endothelial capillaries chemotactically attract tumour cells.

Directional migration of capillaries towards tumour implants is generally assumed to be regulated by chemotaxis. Preliminary evidence has also been presented for the existence of a reverse chemotactic signalling pathway, with capillaries attracting tumour cells via paracrine factors. By using a variety of endothelial cell types and tumour cell lines, this study has systematically investigated chemotaxis between endothelial cells and tumour cells in two- and three-dimensional systems. Checkerboard analysis revealed faint attraction of human umbilical vein endothelial cells (HUVECs), but not porcine aortic endothelial cells (PAECs), by tumour cells. In reverse, both PAECs and HUVECs potently induced chemotactic migration of tumour cells. Using a microcarrier-based fibrin gel assay, directional migration of endothelial cells towards tumour cells was not observed. In reverse, tumour cells were strongly attracted by endothelial cells. Identification of endothelium-derived chemotactic molecules may provide a valuable approach for the treatment of tumour metastasis.

Animals↗
PubMed2001

Angiotensin II type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms.

OBJECTIVE: Type 1 angiotensin II (Ang II) receptors transduce most of the known actions of Ang II, including steroidogenesis and trophic actions on the adrenal cortex. We investigated the type 1 Ang II receptor expression in adrenocortical tissues to define its regulation in adrenocortical neoplasms and to compare its expression with that of the ACTH receptor (ACTH-R). PATIENTS AND MEASUREMENTS: Poly A RNA was extracted from tumour tissue and electrophoresed through a 1.0% agarose gel, blotted and hybridized with alpha32P-CTP labelled PCR generated type 1 Ang II receptor cDNA probe. Receptor autoradiography was performed on slices from normal adrenals and tumour tissue by incubation with 125I-Sar1, Ile8-Ang II with and without pretreatment with cold Ang II or with the selective type 1 receptor antagonist losartan. RESULTS: Ang II type 1 receptor mRNA was high in cortisol producing (CPA; n = 5) and aldosterone producing (APA; n = 4) adenomas (normal adrenals 100 +/- 12% vs. 180 +/- 16% in CPA and 154 +/- 26% in APA, mean +/- SEM), but was low in nonfunctioning adenomas (NFA; n = 2; 2 +/- 1%). ACTH receptor mRNA followed a similar pattern (CPA 178 +/- 17, APA 196 +/- 30, NFA 0%, carcinomas 56 +/- 11%) with a good correlation between Ang II type 1 receptor and ACTH-R mRNA of r = 0.692, P = 0.0019. Receptor autoradiography in normal adrenals demonstrated Ang II type 1 receptors predominantly in the zona glomerulosa. In tumour tissue, mainly type 1 receptor expression was found confirming the Northern blot data. CONCLUSIONS: Angiotensin II type 1 receptor and ACTH receptor expression seems to be correlated with the functional status of adrenocortical tumours, suggesting regulation by similar factors. The predominant receptor expressed in adrenocortical tumours is the Angiotensin II type 1 receptor whereas type 2 receptor expression is minimal.

Adenoma↗
PubMed2001

Octreotide LAR treatment throughout pregnancy in an acromegalic woman.

We report a 24-year-old woman with active acromegaly despite pituitary surgery and irradiation who received continuous octreotide LAR treatment for the control of GH excess throughout her pregnancy. The patient delivered a healthy girl following an uneventful pregnancy. Despite a substantial materno-fetal transfer of octreotide, postnatal development was normal with length parameters around the 50th percentile at 3 months of age. In almost all previously described cases (n = 13) octreotide was stopped after the diagnosis of pregnancy was established. No side-effects of mother or fetus have been reported. Octreotide treatment in pregnancy seems to be feasible and safe. Due to the still-limited number of reported cases, the potential benefits of octreotide treatment should be weighed carefully against its possible risks.

Acromegaly↗