Massimo Scanarini

Effect of Everolimus on Cell Viability in Nonfunctioning Pituitary Adenomas

CONTEXT Pituitary adenomas can cause specific syndromes due to hormone excess and/or determine sellar mass symptoms. Pituitary cell growth can sometimes be influenced by medical therapy, such as for somatotroph adenomas treated with somatostatin analogs or prolactinomas treated with dopaminergic drugs. However, nonfunctioning pituitary adenomas (NFAs) are still orphans of medical therapy. Everolimus (RAD001), a derivative of rapamycin, is a well-known immunosuppressant drug, which has been recently shown to have antineoplastic activity in several human cancers. OBJECTIVE The objective of the study was to investigate the possible antiproliferative effects of RAD001 in human NFAs. DESIGN We collected 40 NFAs that were dispersed in primary cultures, treated without or with 1 nm to 1 microm RAD001, 10 nm cabergoline, 10 nm SOM230 (a somatostatin receptor multiligand), and/or 50 nm IGF-I. Cell viability and apoptosis were evaluated after 48 h, and vascular endothelial growth factor (VEGF) secretion was assessed after an 8-h incubation. Somatostatin and dopamine subtype 2 receptor expression was investigated by quantitative PCR. RESULTS In 28 cultures (70%), Everolimus significantly reduced cell viability (by approximately 40%; P < 0.05 vs. control), promoted apoptosis (+30%; P < 0.05 vs. control), inhibited p70S6K activity (-20%), and blocked IGF-I proliferative and antiapoptotic effects. In selected tissues cotreatment with SOM230, but not cabergoline, exerted an additive effect. Everolimus did not affect VEGF secretion but blocked the stimulatory effects of IGF-I on this parameter. CONCLUSIONS Everolimus reduced NFA cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signaling but not VEGF secretion, suggesting that it might represent a possible medical treatment of invasive/recurrent NFAs.

Histological and ultrastructural study of intracranial saccular aneurysmal wall

SummaryThe material studied consists of 10 cases of intracranial saccular aneurysms. Four came from autopsies, and in each of the other six aneurysmal wall was obtained at surgery after clipping of the aneurysm. The most significant findings from this pathological study are the almost complete disappearance of the internal elastic lamina at the level of the aneurysmal neck, sclerosis of the muscle coat, and in satellite vessels and vasa vasorum disruption of the internal elastic lamina and partial luminal occlusion. The importance of ischaemic changes in the aneurysmal wall is discussed. Rupture of the aneurysm at the distal extremity of the sac depends probably on the progressive brittleness of its wall which becomes sclerotic and less resistant to the blood pressure within. Splitting or rupture of the aneurysm appears to be dependent on degenerative ischaemic alterations in its wall.

Increased Rate of Intracranial Saccular Aneurysms in Acromegaly: An MR Angiography Study and Review of the Literature

BACKGROUND The concurrence of intracranial aneurysms and acromegaly has been reported and debated previously. Our study in a large number of patients aimed to verify whether acromegaly patients carry a higher risk of harboring intracranial saccular aneurysms and to evaluate the possible relationship using clinical, laboratory, and imaging techniques. MATERIALS AND METHODS A total of 152 of 161 consecutive acromegaly patients (median age, 55.7 yr; 82 females) underwent neuroimaging evaluation of the circle of Willis. Clinical data (disease duration and disease control, hypertension, smoking history, diabetes and dyslipidemia, previous surgery or radiotherapy, previous or current pharmacological therapy), laboratory findings (GH and IGF-I at onset and shortly before examination), and pituitary adenoma imaging features (size and invasiveness of the cavernous sinus) were recorded. RESULTS Twenty-six patients (17.3%) harbored 40 newly diagnosed intracranial aneurysms; two other patients had previously undergone aneurysm clipping due to subarachnoid hemorrhage. Ten patients had multiple aneurysms; most of the aneurysms were located in the intracranial tract of the internal carotid artery (67.5%); no aneurysms belonged to the vertebrobasilar circulation. The presence of intracranial aneurysms correlated with GH serum values at disease onset (P < 0.05) and showed a trend to a positive correlation with poor disease control (P = 0.06); no other laboratory, clinical, and radiological findings correlated with the presence of intracranial aneurysms. CONCLUSIONS GH serum excess seems to carry an increased risk of developing intracranial aneurysms. A neuroradiological evaluation of the intracranial circulation might therefore be considered in the diagnostic work-up of patients affected with acromegaly.

Volumetric MRI analysis of hippocampal subregions in Cushing's disease: A model for glucocorticoid neural modulation

Several preclinical studies have demonstrated neuronal effects of glucocorticoids on the hippocampus (HC), a limbic structure with anterior-posterior anatomical and functional segmentation. We propose a volumetric magnetic resonance imaging analysis of hippocampus head (HH), body (HB) and tail (HT) using Cushings disease (CD) as model, to investigate whether there is a differential sensitivity to glucocorticoid neuronal damage in these segments. We found a significant difference in the HH bilaterally after 12 months from trans-sphenoidal surgical selective resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary micro-adenomas. This pre-post surgery difference could contribute to better understand the pathopysiology of CD as an in vivo model for stress-related hypercortisolemic neuropsychiatric disorders.

Pituitary abscesses: Report of two cases and review of the literature

SummaryTwo cases of pituitary abscess are reported. Bacteriological and histological findings of both cases are discussed, together with data available from the literature.

Predicting late recurrence in surgically treated patients with Cushing's disease

Cushings disease (CD) has an uncertain prognosis because patients achieving remission after transsphenoidal pituitary neurosurgery (TSS) may relapse. We aimed to identify factors predicting relapse, focusing on desmopressin (DDAVP) and corticotropin‐releasing hormone (CRH) tests after surgery.

Folliculo-Stellate Cells of Human Pituitary Adenomas: Immunohistochemical Study of the Monocyte/Macrophage Phenotype Expression

Folliculo-stellate cells (FS) represent a small percentage of anterior pituitary elements of still undetermined embryological origin. They are sparse among endocrine pituitary cells and are characterized by the lack of secretory granules and by the presence of few branching processes inserted between hormone-secreting cells. Although FS cell role is still under discussion, recent reports showed that they produce monocyte-derived cytokines able to influence the hormone production and modulate the immunoendocrine connections. In this study we applied three monocyte-macrophage markers (HAM56, KP1, HLA-DR) to 15 pituitary adenomas in order to ascertain whether FS cells belong to the macrophage lineage. In this case FS cells could be considered the resident macrophages of the pituitary. FS cells were identified according to the reactivity to S-100, GFAP and vimentin. We confirm that S-100 represents the most useful marker for these cells that were detected scattered between tumor cells in more than half of the adenomas. GFAP stained only a percentage of FS cells, while vimentin recognized in addition to stellate cells endothelia, perivascular and infiltrating macrophages. We were unable to detect the expression of the macrophage markers on S-100 and GFAP reactive cells. Indeed, HAM56, KP1 and HLA-DR-positive cells were mostly round, small size and located in the perivascular and septal positions where FS cells were never detected. Lack of expression of monocyte-macrophage lineage markers by FS cells in pituitary adenomas suggests their preferential neuroectodermal origin. However, further studies on normal human pituitary will be needed before ruling out a possible role for FS cells as resident pituitary macrophages.

Primary brain stem haematomas. Diagnosis and treatment

SummaryCase histories are reported of 18 patients in whom the diagnosis of primary brain stem haematoma5 and brain stem haemorrhage13 was made by computed tomography (CT).The possibility of an early diagnosis of brain stem haematoma, and the differential diagnosis of brain stem haemorrhage by a combination of clinical and tomodensitometric criteria is emphasized.It is concluded that CT is a highly reliable method for the diagnosis, location, and management of brain stem haematoma.

Corticotropin releasing hormone stimulation test: diagnostic aspects in Cushing’s syndrome

The effect of exogenous ovine Corticotropin-Releasing Hormone (oCRH) on plasma ACTH and cortisol levels was investigated in 10 normal volunteers and in 37 patients with Cushing’s syndrome (26 with pituitary-dependent disease, 5 with an adrenal adenoma, 2 with an adrenal carcinoma and 4 with bilateral nodular hyperplasia). In all normal subjects and in patients with Cushing’s disease, oCRH 100 μg as a bolus produced an increase in both plasma ACTH and cortisol. The peak of ACTH occurred after 15–30 min, while plasma cortisol showed highest levels between 30 and 60 min after oCRH administration. The hormonal response in Cushing’s disease showed great variability with a clear hyperresponsiveness at least in 6 out of 26 patients with Cushing’s disease. A slight and delayed response occurred in 3 cases of bilateral nodular adrenal hyperplasia, while a fourth case showed hyperresponsiveness similar to that found in pituitary-dependent Cushing’s disease. No response was observed in patients with an adrenal tumor. Eleven patients with Cushing’s disease were tested before and 1 month after pituitary microadenomectomy. After surgery basal cortisol levels were reduced in 10 and became unresponsive or less responsive to oCRH. ACTH patterns were variable with a normal response only in few cases. Although this test seems of limited value in the diagnosis of hypercortisolism, it is a useful tool to differentiate some types of Cushing’s syndrome (adrenal tumor from pituitary-dependent Cushing’s disease). Variable patterns of response in cases with bilateral nodular adrenal hyperplasia limit the usefulness of this test in recognizing this rare form of hypercortisolism.

Concurrent Primary Intracranial Tumours of Different Histogenesis

The occurrence of intracranial tumours of diverse histogenesis can be considered occasional. In a careful survey of the literature we have encountered 63 cases of concurrent intracranial tumours: we report five personal observations, too. This review raises the question as to whether the conjoint occurrence of two intracranial tumours is purely coincidental. The statistical analysis of the cases of concurrent intracranial tumours, and the comparison between the frequency found for each different tumour when it is solitary and when it is coincident in a same patient, suggests that a casual connection can be found between tumours of diverse histogenesis.