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Background/Aim: Despite combined therapy consisting of surgery, external X-ray, and medical therapy, a significant number of acromegaly patients continue to have uncontrolled growth hormone (GH) secretion and active disease. These patients, particularly those with large or invasive tumors, require additional therapy to decrease their GH levels. Our aim was to investigate whether patients with documented GH-secreting pituitary adenomas leading to acromegaly would respond with attenuation of GH and insulin-like growth factor-1 (IGF-1) levels after treatment with a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist. Methods: We conducted prospective analyses in the Endocrinology Clinic of the Pamukkale University. Acromegaly patients who had active disease participated in two admissions: before and after 6 weeks of daily treatment with 8 mg of oral rosiglitazone. Four male and 3 female patients have completed the study. Basal and nadir GH levels during an oral glucose tolerance test were determined, and the IGF-1 and IGF-binding protein-3 levels were also measured both before and 6 weeks after the rosiglitazone treatment. Results: Treatment with rosigitazone did not reduce basal and nadir GH levels during the oral glucose tolerance test and the IGF-1 levels in the patient population as a whole (p > 0.05). Conclusions: The PPAR-γ activator rosiglitazone, used at maximum approved dosage, did not reduce plasma GH and IGF-1 levels in patients with acromegaly. Further studies with higher doses and longer duration of PPAR-γ agonist administration would be required to determine its usefulness in the treatment in this group of patients.

Purpose: Postoperative radiotherapy (PORT) results in excellent local tumour control and improvement of excessive hormonal secretion in pituitary adenoma patients where (repeated) surgery was unsuccessful. Despite this benefit, concerns related to possible long term side effects are often quoted to delay or reject this treatment. In previous studies. the incidence of second tumours and mortality in pituitary adenoma patients treated with PORT were compared with a normal reference population. For proper evaluation however, a direct comparison with similar patients treated with surgery alone should be made. The purpose of this study was to assess the impact of PORT on developing second tumours and mortality in pituitary adenoma patients by comparing the incidence with patients treated with surgery alone. Materials: A retrospective study was performed in 462 pituitary adenoma patients (non-functioning adenoma n=256. growth-hormone secreting n=139 and adrenocorticotropic-hormone secreting adenoma n= 67) treated between t959 and 2008 at the University Medical Center Groningen. PORT was performed in 236 pituitary adenoma patients. The different radiotherapy techniques used in this period were divided into techniques with (n=80) or without (n=153) a beam configuration directed into the central body axis of the patient. Most patients received a radiation fractionation scheme of 25 daily fractions of 1.8 Gy in 5 weeks.After pituitary adenoma diagnosis the incidence of tumours and death were investigated using median life expectancy (MLE). MLE was used to correct for year of birth and gender and with the application of years of follow up as a time base for a left-censored log-rank test. Results: Median age at diagnosis was 47 (range 10-83) years and median overall follow-up time was 9 (range 1-49) years. The median follow-up time of patients treated with PORT was 14 (range 1-49) years and 6 (range 134) years in patients treated with surgery alone. Four patients developed an intracranial tumour, 3 of them were treated with PORT. Twenty-one patients treated with PORT developed an extracranial tumour compared to 11 patients treated with surgery alone (RR 1.04 CI 95%, 0.50-2.17, P = 0.917). In 11 out of the 21 patients treated with PORT and diagnosed with an extracranial tumour a central body axis radiotherapy technique was used (RR 1.43 CI 95%, 0.60-3.41, P = 0.425).Forty-five patients treated with PORT died compared to 24 patients treated with surgery alone (RR 1.26 CI 95%, 0.77-2.08, P = 0.358). Conclusions: Postoperative radiotherapy did not increase the incidence of second tumours and mortality in pituitary adenoma patients. Central body axis radiotherapy technique was not associated with an increase in extracranlal tumours.

Purpose: Postoperative radiotherapy (PORT) results in excellent local tumour control and improvement of excessive hormonal secretion in pituitary adenoma patients where (repeated) surgery was unsuccessful. Despite this benefit, concerns related to possible long term side effects are often quoted to delay or reject this treatment. In previous studies. the incidence of second tumours and mortality in pituitary adenoma patients treated with PORT were compared with a normal reference population. For proper evaluation however, a direct comparison with similar patients treated with surgery alone should be made. The purpose of this study was to assess the impact of PORT on developing second tumours and mortality in pituitary adenoma patients by comparing the incidence with patients treated with surgery alone. Materials: A retrospective study was performed in 462 pituitary adenoma patients (non-functioning adenoma n=256. growth-hormone secreting n=139 and adrenocorticotropic-hormone secreting adenoma n= 67) treated between t959 and 2008 at the University Medical Center Groningen. PORT was performed in 236 pituitary adenoma patients. The different radiotherapy techniques used in this period were divided into techniques with (n=80) or without (n=153) a beam configuration directed into the central body axis of the patient. Most patients received a radiation fractionation scheme of 25 daily fractions of 1.8 Gy in 5 weeks.After pituitary adenoma diagnosis the incidence of tumours and death were investigated using median life expectancy (MLE). MLE was used to correct for year of birth and gender and with the application of years of follow up as a time base for a left-censored log-rank test. Results: Median age at diagnosis was 47 (range 10-83) years and median overall follow-up time was 9 (range 1-49) years. The median follow-up time of patients treated with PORT was 14 (range 1-49) years and 6 (range 134) years in patients treated with surgery alone. Four patients developed an intracranial tumour, 3 of them were treated with PORT. Twenty-one patients treated with PORT developed an extracranial tumour compared to 11 patients treated with surgery alone (RR 1.04 CI 95%, 0.50-2.17, P = 0.917). In 11 out of the 21 patients treated with PORT and diagnosed with an extracranial tumour a central body axis radiotherapy technique was used (RR 1.43 CI 95%, 0.60-3.41, P = 0.425).Forty-five patients treated with PORT died compared to 24 patients treated with surgery alone (RR 1.26 CI 95%, 0.77-2.08, P = 0.358). Conclusions: Postoperative radiotherapy did not increase the incidence of second tumours and mortality in pituitary adenoma patients. Central body axis radiotherapy technique was not associated with an increase in extracranlal tumours.

Background: It is unusual to encounter hemorrhagic complications caused by arterial or venous damage during TSS. Problems with these structures can lead to permanent disability or death. Our aim was to quantitatively analyze anatomical and radiologic relationships among the BCS, the CCA, and the pituitary gland, as these structures are accessed during TSS. Methods: Forty-nine formaldehyde-fixed, sellar-parasellar tissue blocks from adult cadavers were used to simulate accessing the BCSs via TSS. In each specimen, size of the pituitary gland and specific characteristics of each BCS and the horizontal segment of each CCA were recorded. Nine other specimens were used for histologic investigation and microanatomical measurements. To attest correlation between clinical data and cadaveric measurements, coronal MRI scans of 22 healthy adults as well as of 28 patients with macroadenomas were analyzed. Results: In cadaveric specimens, distances between both CCAs in the BCS were 17.1 +/- 4.0 mm anteriorly, 20.3 +/- 4.2 mm medially, and 18.8 +/- 4.6 mm posteriorly. In this study, the anterior medial space of the BCS was dominant in 12 specimens on the right side and in 5 specimens on the left; the posterior medial space of the BCS was dominant in 23 specimens on the right side and in 9 specimens on the left side. The right medial BCS was dominant in 35 specimens. On histologic coronal sections, some part of the carotid artery's (CA's) diameter was located below the line passing from the basal dural layer ranging from 5.3% to 65.4%. In normal-sella images, distances between both CCAs were 15.4 +/- 1.8 mm anteriorly, 16.0 +/- 2.8 mm medially, 16.2 +/- 3.4 mm posteriorly. On coronal normal-sella images, some part of the CA's diameter was located below the line passing from the basal dural layer ranging from 16.4% to 66.7%. In macroadenomas, distances between both CCAs were 22.0 +/- 3.6 mm anteriorly, 21.5 +/- 3.8 mm medially, and 20.7.2 +/- 3.7 mm posteriorly. On coronal images, in only 6 of 28 macroadenomas, some part of the CA's diameter was located below the line passing from the basal dural layer ranging from 12.5% to 100%. Conclusions: Our results indicate that a working area of 15.0 +/- 2.6 x 10.3 +/- 2.1 mm is safe during TSS. The position of the CCA posterior segment was notably more caudal than the anterior segment with respect to the basal dura, which should be taken into account during extended exposure. Also, preoperative recognition of the anatomical variations is beneficial for detection of the boundaries of dissection, which is particularly important in the BCS, where variable course of CCAs may transform the anatomical configuration. Slowly growing pituitary adenomas stretch out both CCAs considerably from medial to lateral directions, and they cause widening of intercarotid distances in all segments. Processing of fixation, decalcification, and paraffin embedding for the cadaveric tissue in contrast to physiologically hydrated tissues may change the accuracy of measurements. These measurements are significantly different than those in the radiologic images when arterial blood under pressure is in the CCA as well as when venous blood fills the cavernous sinus as is the case in vivo. In clinical practice, these facts must be taken into consideration in the cadaveric measurements.

Clusterin is a circulating multifunctional glycoprotein produced in several kinds of epithelial and neuronal cells. Clusterin is upregulated during different physiological and pathological states, such as senescence, type-2 diabetes mellitus, Alzheimer disease, and in various neoplasms. Herein, we investigated the immunohistochemical expression of clusterin in non-neoplastic adenohypophysis of human autopsy subjects and pituitary adenomas. We also investigated the association of clusterin increase with age in adenohypophysis of autopsy subjects. Immunohistochemically, clusterin was found positive in the cytoplasm of all adenoma cases, and in the cytoplasm of parenchymal cells, stellate cells, mixed cell follicles and in colloidal material inside of the follicles of non-neoplastic adenohypophysis as well. Clusterin expression in pituitary adenomas was found significantly higher than in non-neoplastic adenohypophyses. In addition, in non-neoplastic adenohypophysis, a significant increase in clusterin expression levels between young (?30 years), middle aged (31 to 60 years), and older (?61 years) subjects (p

Objectives: Phaeochromocytoma (PHEO) occasionally associates with pathological lesions of the adrenal cortex. The coexistence of PHEO and pre-clinical Cushing's syndrome (PCS) of the same adrenal gland has rarely been reported. We report a case of PHEO and PCS originating from the same adrenal gland and discuss the peculiar diagnostic aspects of this entity. Clinical Presentation: A 64 yr old man was hospitalized to evaluate the right adrenal mass which was discovered incidentally by ultrasonography. He had a history of type 2 diabetes mellitus and hyperlipidemia. Blood pressure measurements were all normal during his hospital stay. Laboratory examination showed: urinary catecholamines were markedly increased. HbA1C of 14.3 %, midnight cortisol of 11(µg/dL), cortisol was not suppressed after the overnight 1 mg oral dexamethasone suppression test (DST): 3.42(µg/dL), 24 hr free cortisol in the urine : 213 g/day (10-100), cortisol levels were suppressed more than 50% with 8 mg of dexamethasone. CT scan of the adrenal glands showed a 6 cm well encapsulated right adrenal mass together with a clearly normal left adrenal gland. MRI investigation of the sella turcica revealed a pituitary microadenoma on the right side of the adenohypophysis He was treated with ? and subsequent ß blockers after the diagnosis of PHEO and PCS was made. Right adrenalectomy was performed. The pathology showed typical PHEO with adrenocortical hyperplasia. VMA, metanefrin and free cortisol levels were normalized one month after surgery. Conclusion: The present report is a rare case of PHEO combined with PCS in the same adrenal gland. © 2008 CIM.

Pituitary adenomas extend to the suprasellar region via diaphragmal passage and extend to the cavernous sinus via the medial wall (MW). Better understanding of the dynamics of suprasellar and parasellar extension of sellar region pathologies requires microanatomical comparison of diaphragma sellae (DS) and the MW of the cavernous sinus. This study provides the first detailed quantitative assessment between DS and MW of the cavernous sinus. Microanatomical details and histopathological examinations of the DS and MWs of the cavernous sinus were studied in sphenoid block samples obtained from adult cadavers, and the thicknesses of the DS and the MW of the cavernous sinus were measured. Mean thickness of the DS was 216.73 +/- 51.26 microm in the center and 367.33+/-133.66 microm in the periphery. Mean thickness of the lower third of the MW was 161.53+/-53.86 microm and that of the upper third was 278.46+/-162.79 microm. Difference between the thicknesses of the upper and lower thirds was significant (P

Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease. Fil: Castillo, Victor Alejandro. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina Fil: Giacomini, Damiana Paula. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Páez Pereda, Marcelo. Max Planck Institute of Psychiatry; Alemania Fil: Stalla, Johanna. Max Planck Institute of Psychiatry; Alemania Fil: Labeur, Marta. Max Planck Institute of Psychiatry; Alemania Fil: Theodoropoulou, Marily. Max Planck Institute of Psychiatry; Alemania Fil: Holsboer, Florian. Max Planck Institute of Psychiatry; Alemania Fil: Grossman, Ashley B.. Max Planck Institute of Psychiatry; Alemania Fil: Stalla, Günter K.. Max Planck Institute of Psychiatry; Alemania Fil: Arzt, Eduardo Simon. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina

As for any solid tumour, pituitary adenoma expansion is dependent on neovascularization through angiogenesis. In this process, vascular endothelial growth factor (VEGF) and its receptors VEGFR-1, VEGFR-2 and neuropilin-1 (NRP-1) may play an outstanding role. The intention of this work was to study the expression/localization and possible function of VEGF receptors in pituitary adenomas. VEGF receptor mRNA and protein expression was studied by in situ hybridization, immunohistochemistry and RT-PCR in 6 normal human pituitaries, 39 human pituitary adenomas and 4 rodent pituitary adenoma cell lines. VEGFR-1 expressing somatotroph MtT-S cells were used as a model to study the role of VEGF on cell proliferation and to elucidate the underlying mechanism of action. In normal pituitaries, VEGFR-1 was detected in endocrine cells, whereas VEGFR-2 and NRP-1 were exclusively expressed in endothelial cells. In pituitary tumours, a heterogeneous VEGFR expression pattern was observed by IHC. VEGFR-1, VEGFR-2 and NRP-1 were detected in 24, 18 and 17 adenomas respectively. In the adenomas, VEGFR-1 was expressed in epithelial tumour cells and VEGFR-2/NRP-1 in vessel endothelial cells. Functional studies in VEGFR-1-positive MtT-S cells showed that the ligands of VEGFR-1 significantly stimulated cell proliferation. This effect was mediated through the phosphatidylinositol-3-kinase-signalling pathway and involves induction of cyclin D1 and Bcl-2. Based on our results, we speculate that the ligands of VEGF receptors, such as VEGF-A and placenta growth factor, not only play a role in angiogenesis in pituitary adenomas, but also affect the growth of pituitary tumour cells through VEGFR-1.

Purpose: Postoperative radiotherapy (PORT) results in excellent local tumour control and improvement of excessive hormonal secretion in pituitary adenoma patients where (repeated) surgery was unsuccessful. Despite this benefit, concerns related to possible long term side effects are often quoted to delay or reject this treatment. In previous studies. the incidence of second tumours and mortality in pituitary adenoma patients treated with PORT were compared with a normal reference population. For proper evaluation however, a direct comparison with similar patients treated with surgery alone should be made. The purpose of this study was to assess the impact of PORT on developing second tumours and mortality in pituitary adenoma patients by comparing the incidence with patients treated with surgery alone. Materials: A retrospective study was performed in 462 pituitary adenoma patients (non-functioning adenoma n=256. growth-hormone secreting n=139 and adrenocorticotropic-hormone secreting adenoma n= 67) treated between t959 and 2008 at the University Medical Center Groningen. PORT was performed in 236 pituitary adenoma patients. The different radiotherapy techniques used in this period were divided into techniques with (n=80) or without (n=153) a beam configuration directed into the central body axis of the patient. Most patients received a radiation fractionation scheme of 25 daily fractions of 1.8 Gy in 5 weeks.After pituitary adenoma diagnosis the incidence of tumours and death were investigated using median life expectancy (MLE). MLE was used to correct for year of birth and gender and with the application of years of follow up as a time base for a left-censored log-rank test. Results: Median age at diagnosis was 47 (range 10-83) years and median overall follow-up time was 9 (range 1-49) years. The median follow-up time of patients treated with PORT was 14 (range 1-49) years and 6 (range 134) years in patients treated with surgery alone. Four patients developed an intracranial tumour, 3 of them were treated with PORT. Twenty-one patients treated with PORT developed an extracranial tumour compared to 11 patients treated with surgery alone (RR 1.04 CI 95%, 0.50-2.17, P = 0.917). In 11 out of the 21 patients treated with PORT and diagnosed with an extracranial tumour a central body axis radiotherapy technique was used (RR 1.43 CI 95%, 0.60-3.41, P = 0.425).Forty-five patients treated with PORT died compared to 24 patients treated with surgery alone (RR 1.26 CI 95%, 0.77-2.08, P = 0.358). Conclusions: Postoperative radiotherapy did not increase the incidence of second tumours and mortality in pituitary adenoma patients. Central body axis radiotherapy technique was not associated with an increase in extracranlal tumours.