VEGF, VEGF165b and EG-VEGF expression is specifically related with hormone profile in pituitary adenomas.

Vascular endothelial growth factor (VEGF), its inhibitory splice variant, VEGF165b and Endocrine Gland derived VEGF (EG-VEGF) have a controversial role in pituitary gland. We aim to study VEGF, VEGF165b and EG-VEGF expression in pituitary adenomas. A significant correlation was found between growth hormone (GH) and VEGF secretion (P=0.024). For prolactinomas, VEGF and prolactin expression, had a P-value of 0.02 for Kendall coefficient and a P-value of 0.043 for the Spearman coefficient. VEGF-mRNA amplification was detected in both tumor cells and folliculostellate cells. VEGF165b was positive in 16.66% of pituitary adenomas. EG-VEGF was significantly correlated with prolactin (P=0.025) and luteinizing hormone (P=0.028). Our data strongly support VEGF, VEGF165b and EG-VEGF as important players of pituitary adenomas tumorigenesis. Particular hormonal milieu heterogeneity, special vascular network with an unusual reactivity to tumor growth correlated with variability of VEGF, VEGF165b and EG-VEGF secretion may stratify pituitary adenomas in several molecular groups with a direct impact on therapy and prognosis.

Idiopathic Intracranial Hypertension After Surgical Treatment of Cushing Disease: Case Report and Review of Management Strategies.

BACKGROUND: Idiopathic intracranial hypertension (IIH) in patients with Cushing disease (CD), after treatment, is rarely described, in adults. The cause is believed to be multifactorial, potentially related to a relative decrease in cortisol after surgical resection or medical treatment of a corticotroph pituitary adenoma. We investigate our center's CD database (140 surgically and 60 medically [primary or adjunct] treated patients) for cases of IIH, describe our center's experience with symptomatic IIH, and review treatment strategies in adults with CD after transsphenoidal resection. CASE DESCRIPTION: We present the case of a 22-year-old woman who presented with worsening headache, nausea, vomiting, blurry vision, diplopia, visual loss, and facial numbness 14 weeks after surgical resection of adrenocorticotropic hormone-positive pituitary adenoma. Her CD had been in remission since surgery, with subsequent adrenal insufficiency (AI), which was initially treated with supraphysiologic glucocorticoid replacement, tapered down to physiologic doses at the time the IIH symptoms developed. CONCLUSIONS: Symptomatic IIH is rare in adult patients but can be severe and result in permanent vision loss. A high index of suspicion should be maintained and a fundus examination is necessary to exclude papilledema, whenever there are suggestive symptoms that initially may overlap with AI. It is possible that some cases of mild IIH are misdiagnosed as GC withdrawal or AI; however, further studies are needed. Treatment consists of reinitiation of higher steroid doses together with acetazolamide with or without cerebrospinal fluid diversion and the priority is to preserve vision and reverse any visual loss.

Macroadenoma de hipófisis: informe de un caso / Pituitary adenoma: case report

Los adenomas de hipófisis constituyen la tumoración intracraneal que con mayor frecuencia afecta el sistema visual, acorde a lo que demuestran los estudios psicofísicos y neurofisiológicos, de ahí, la importancia de un seguimiento adecuado y oportuno en consultas de Neuroftamología. En este estudio se describe el caso de una paciente atendida en nuestro servicio con palidez temporal de discos ópticos y defectos campimétricos importantes, con diagnóstico de macroadenoma de hipófisis al realizarle estudios de imagen (AU)

Pituitary adenomas are the intracranial tumor that most often affects the visual system, according to what show psychophysical and neurophysiological studies, hence, the importance of proper monitoring and timely Neuro and ophthalmologic consultations. This study describes the case of a patient treated in our department with optical disc temporal pallor and significant visual field defects, diagnosed with pituitary adenoma by x-ray tests (AU)

Tratamiento de la enfermedad de Cushing con ketoconazol / Treatment of Cushing's disease with ketoconazole

La enfermedad de Cushing (EC), debida fundamentalmente a un microadenoma hipofisario, es un cuadro clínico poco frecuente en la edad pediátrica y se asocia a una significativa morbilidad. La principal indicación terapéutica es la cirugía transesfenoidal, aunque se reserva el ketoconazol como alternativa terapéutica temporal durante el período de espera previo, a fin de controlar el hipercortisolismo. A continuación se presenta el caso de una niña de 13 años y 8 meses con EC. Sus manifestaciones clínicas eran obesidad, disminución de la velocidad del crecimiento, fenotipo cushingoide, cefaleas e hipertensión arterial. Las determinaciones hormonales pusieron de manifiesto valores elevados de cortisol libre urinario y de corticotropina (ACTH). El ritmo de cortisol y de ACTH así como el test corto y largo de dexametasona confirmaron un hipercortisolismo dependiente de ACTH. La resonancia magnética craneal con gadolinio mostró la presencia de microadenoma en hemiadenohipófisis derecha. El diagnóstico se confirmó tras realizar un cateterismo selectivo de senos petrosos inferiores con estímulo de corticoliberina. En espera de cirugía transesfenoidal, el tratamiento con ketoconazol (200mg/24h) durante 6 meses controló el cuadro de hipercortisolismo. Tras la adenomectomía transesfenoidal, recibió tratamiento sustitutivo con hidrocortisona durante un mes. En la actualidad, la niña lleva 2 años y medio en remisión clínica y hormonal sin cumplir los criterios iniciales posquirúrgicos de curación (AU)

Cushing’s disease (CD), which is caused fundamentally by a pituitary microadenoma, is a rare endocrine disease in the paediatric age and which is associated with significant morbidity. The current treatment of choice for CD is trans-sphenoidal selective adenomectomy resulting in long-term remission rates. Pharmacological management of CD is directed at decreasing adrenal steroid secretion. Ketoconazole inhibits adrenal enzyme activity and decreases cortisol secretion. Our patient is a girl of 13 years and eight months of age with CD. The clinical manifestations were obesity, decrease in growth rate, Cushingoid phenotype, headache and arterial hypertension. The hormone determinations showed elevated values of UFC and ACTH. The circadian rhythm cortisol and ACTH and the short and long dexamethasone tests of provide definitive diagnosis of CD. The cranial MRI with gadolinium suggests the presence of microadenoma in the right pituitary lobe. The diagnosis is confirmed after performing a selective catheterisation of the inferior petrosal sinuses with CRH stimulus. While waiting for trans-sphenoidal surgery, the treatment with ketoconazole (200mg/24h) controlled the hypercortisolism. After the surgical procedure, the patient received replacement therapy with hydrocortisone for 1 month. At the present time, the patient, without fulfilling the post surgery cure criteria, has been 2 and a half years in clinical and hormonal remission (AU)

Cushing's disease in a 5-month infant due to a basophilic microadenoma of the pituitary gland.

We report a female patient who developed severe Cushing's disease during the fifth month of life due to a basophilic pituitary adenoma Histological findings showed a basophilic microadenoma of the pituitary gland, leading to the diagnosis of Cushing's disease. The infant died because of untreatable septic shock. The importance of the present report resides in the age of the child at diagnosis, and that it was the necropsy finding of microadenoma which clarified the cause of the Cushing's syndrome, since it was not diagnosed during life. Cushing's disease is most often diagnosed in children older than 7 years, and our patient was only 5 months old when we detected the pituitary adenoma, the earliest case diagnosed so far. Cushing's syndrome in pediatric patients has been rarely reported and most cases are due to functioning adrenal tumors, usually a malignant carcinoma but occasionally a benign adenoma. The present case shows that the pituitary of these patients should be investigated with important implications in terms of therapeutic approaches, such as pituitary radiotherapy, which can cure the patient when treatment is started very soon.

Clinical characteristics of silent corticotrophic adenomas and creation of an internet-accessible database to facilitate their multi-institutional study.

OBJECTIVE: Silent corticotrophic adenomas (SCAs) of the pituitary gland present as clinically nonfunctioning sellar lesions, with normal serum and urine hormone testing results, but stain positively for adrenocorticotropic hormone in immunohistochemical analyses. These tumors are now more readily recognized, but determination of their natural history and responses to treatment is difficult because of their rarity. We report the diagnoses and outcomes for a series of patients with SCAs, and we describe the creation of an Internet-accessible database (www.hsc.virginia.edu/neuro/neurosurgery/pituitary.html) for collection of multi-institutional data on these lesions. METHODS: The medical records of patients with documented SCAs who were treated at the University of Virginia between 1991 and 2002 were reviewed. A comprehensive data collection form was then created and posted online. RESULTS: Twenty-seven patients with SCAs were identified, with a female predominance (70%, P = 0.04). Headache was the most common presenting symptom (70%), followed by visual field deficits (52%), acute or subacute pituitary apoplexy (33%), cavernous sinus syndrome (18.5%), and hypopituitarism (11.1%). Extrasellar extension was noted for 92.6% of patients on preoperative magnetic resonance imaging scans. Transsphenoidal surgery was performed for all patients. Follow-up information was available for all patients (median, 60 mo; range, 3-254 mo). Postoperatively, 33% of patients received radiotherapy. Recurrence was noted for 37% of all patients and 41.7% of patients who did not receive postoperative radiotherapy. CONCLUSION: SCAs, although clinically nonfunctioning, may behave like aggressive adrenocorticotropic hormone-secreting adenomas and therefore should receive vigorous follow-up monitoring, with consideration being given to the recommendation of radiotherapy in cases with residual tumor.

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.

An R201H activating mutation of the GNAS1 (Gsalpha) gene in a corticotroph pituitary adenoma.

In the pituitary gland, activating mutations of the GNAS1 (Gsalpha) gene at Gln227 have been identified in adrenocorticotrophin secreting, growth hormone secreting, and prolactin secreting adenomas. To date, mutations at the codon encoding R201, typically underlying the McCune-Albright syndrome and isolated fibrous dysplasia of bone, have been demonstrated only in growth hormone secreting pituitary adenomas. In this study, a polymerase chain reaction amplified target sequence in exon 8 of the GNAS1 gene was sequenced, identifying the first R201 mutation seen in an isolated basophilic adenoma which generated Cushing's disease in a child. This case adds Cushing's disease to the range of human diseases caused by R201 mutations of the GNAS1 gene.

[Neurosurgery and pituitary tumors: etio-pathogenic considerations]. / La neurochirurgie et les tumeurs hypophysaires. Considérations étio-pathogéniques.

PITUITARY ADENOMA: Based on the experience of nearly 5000 cases of surgically treated pituitary tumors at the neurosurgery department of the Foch Hospital, the pituitary adenoma is the most frequent pituitary tumor. Secreting tumors lead to a clinical syndrome depending on the level of hormone overproduction. Gonadotrop or non-functioning pituitary adenomas are mainly macroadenomas presenting with visual symptoms, hypopituitarism or as an incidentaloma. Anatomical features dictate the surgical approach. OTHER TUMORS: The other types of hypophyseal tumors, such as craniopharyngioma, Rathke's cleft cyst or others are usually surgical tumors because medical treatment is ineffective. Malignant pituitary tumors are unusual.

Gamma Knife radiosurgery as a primary surgical treatment for hypersecreting pituitary adenomas.

OBJECT: To estimate the efficacy of Gamma Knife radiosurgery (GKR) especially as a primary surgical treatment for hypersecreting pituitary adenomas. METHODS: 274 patients were treated with GKR. The mean tumor volume was 1.86 cm(3). The mean peripheral dose was 28.7 Gy. RESULTS: 223 patients were followed up for an average of 31.6 months. The dose related to the tumor growth control and endocrinological normalization was detailed and statistical analysis of the data was performed. CONCLUSION: GKR as a primary surgical treatment for hypersecreting pituitary adenomas may be safe and effective.

Triple pituitary adenoma in Cushing's disease: case report.

A case of a triple pituitary adenoma identified in a surgically removed pituitary gland from a 52-year-old woman operated on for Cushing's disease is presented. The histology revealed 3 distinctly separate microadenomas, 1 corticotroph and 2 immunoreactive for prolactin (PRL). The latter were apparently silent, since the serum PRL levels were within normal range. The problems associated with the inability to identify multiple adenomas pre-operatively and the possible failure of selective transsphenoidal adenomectomy in case of multiple adenomas are emphasised.

[Cushing disease in children and in adolescents. Therapeutic results]. / Maladie de Cushing de l'enfant et de l'adolescent. Résultats thérapeutiques.

BACKGROUND: Trans-sphenoidal surgery is currently the treatment of choice for Cushing's disease in children. PATIENTS AND METHODS: The results obtained in 20 consecutive patients referred to the Pediatric Endocrinology Department of hôpital Saint-Vincent-de-Paul are reported. RESULTS: A remission of Cushing's disease was observed in 12/16 (75%) patients in whom surgery was the first treatment. Among these 12 patients, three relapsed (25%) 21 to 80 months after surgery. Four patients were initially treated with steroid synthesis inhibitors: three of those patients were subsequently operated on and their disease remitted. Among the seven patients in whom surgery failed (primary failure or relapse), two were reoperated and also remitted. Taken together, 21 operations were performed and resulted in four immediate failures (19%), three relapses (14%) and 14 long-term remissions (67%, follow-up 40 +/- 35 months). None of the biological, radiological or operative criteria were predictive of the therapeutic results. CONCLUSION: Our results illustrate the efficacy and limits of trans-sphenoidal surgery for Cushing's disease of children and emphasize the need for a very long follow-up of these patients. Treatment of patients in whom surgery has failed (initially or secondarily) is particularly difficult and requires a multidisciplinary approach.

[Cushing's disease]. / Maladie de Cushing.

Patients with Cushing's disease usually present typical clinical and biological features easily leading to the diagnosis. However very atypical presentations of the disease do exist especially in the intermittent forms and several investigations are often necessary to detect pituitary microadenoma wich sometimes is inconspicuous. The course of the disease can be serious and might responsible of definitive sequellas wich can threaten patient's life. Therefore rapid treatment is recommended. Pituitary surgery should be considered as the major therapeutic approach; however, in severe cases or when pituitary-directed treatments or OP'DDD have failed, total bilateral adrenalectomy should be proposed.

Coexistence of primary empty sella and silent corticotrophic adenoma.

Primary empty sellae are rarely associated with an intact pituitary adenoma. Most of such cases are documented clinically and radiographically. This paper reports a case of coexistence of primary empty sella and a silent corticotrophic adenoma in a 61-year-old woman. The en bloc preparation of the sella turcica demonstrates the anatomical relationship of the empty sella and the flattened pituitary gland and the adenoma. The immunostain shows the presence of all five cell types of the adenohypophysis.