Michael Buchfelder

Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

OBJECTIVE Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushings syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushings syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushings disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushings disease, and 5) management of ectopic ACTH syndrome, Nelsons syndrome, and special patient populations. EVIDENCE Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS ACTH-dependent Cushings syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushings syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushings disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushings syndrome, early diagnosis and prompt therapy are warranted.

Lymphocytic and granulomatous hypophysitis: experience with nine cases.

OBJECTIVE Lymphocytic hypophysitis and granulomatous hypophysitis are rarely encountered. The aim of this study was to demonstrate their clinical peculiarities among pituitary disorders and to provide an approach for their clinical management. METHODS In a retrospective study, we reviewed our surgical experience with nine patients harboring hypophysitis. The series included six cases of lymphocytic hypophysitis, two cases of granulomatous hypophysitis, and one case with evidence of coexisting lymphocytic and granulomatous hypophysitis. RESULTS A striking similarity of clinical signs was found for our nine patients. Headache or aseptic meningitis, thickening of the sphenoid sinus mucosa, pituitary stalk enlargement, and tongue-shaped extension of the lesion along the basal hypothalamus were characteristic signs. Lymphocytic hypophysitis was not associated with pregnancy in any of the seven cases. No recurrence has been observed in six cases with total removal of the inflammatory tissue. CONCLUSION Lymphocytic hypophysitis and granulomatous hypophysitis represent related inflammatory disorders. Their conspicuous clinical features frequently allow preoperative diagnosis of hypophysitis. In view of their sometimes insidious clinical course, early surgical exploration is justified.

Mutations in the deubiquitinase gene USP8 cause Cushing's disease

Cushings disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushings disease via activation of EGF receptor signaling.

Correlation of the extent of tumor volume resection and patient survival in surgery of glioblastoma multiforme with high-field intraoperative MRI guidance

Extent of resection (EOR) still remains controversial in therapy of glioblastoma multiforme (GBM). However, an increasing number of studies favor maximum EOR as being associated with longer patient survival. One hundred thirty-five GBM patients underwent tumor resection aided by 1.5T intraoperative MRI (iMRI) and integrated multimodal navigation. Tumor volume was quantified by manual segmentation. The influences of EOR, patient age, recurrent tumor, tumor localization, and gender on survival time were examined. Intraoperative MRI detected residual tumor volume in 88 patients. In 19 patients surgery was continued; further resection resulted in final gross total resection (GTR) for 9 patients (GTR increased from 47 [34.80%] to 56 [41.49%] patients). Tumor volumes were significantly reduced from 34.25 ± 23.68% (first iMRI) to 1.22 ± 16.24% (final iMRI). According to Kaplan-Meier estimates, median survival was 14 months (95% confidence interval [CI]: 11.7-16.2) for EOR ≥ 98% and 9 months (95% CI: 7.4-10.5) for EOR <98% (P< .0001); it was 9 months (95% CI: 7.3-10.7) for patients ≥ 65 years and 12 months (95% CI: 8.4-15.6) for patients <65 years (P < .05). Multivariate analysis showed a hazard ratio of 0.39 (95% CI: 0.24-0.63; P = .001) for EOR ≥ 98% and 0.61 (95% CI: 0.38-0.97; P < .05) for patient age <65 years. To our knowledge, this is the largest study including correlation of iMRI, tumor volumetry, and survival time. We demonstrate that navigation guidance and iMRI significantly contribute to optimal EOR with low postoperative morbidity, where EOR ≥ 98% and patient age <65 years are associated with significant survival advantages. Thus, maximum EOR should be the surgical goal in GBM surgery while preserving neurological function.

Intraoperative visualization for resection of gliomas: the role of functional neuronavigation and intraoperative 1.5 T MRI

Abstract Objective: To investigate how functional neuronavigation and intraoperative high-field magnetic resonance imaging (MRI) influence glioma resection. Methods: One hundred and thirty-seven patients [World Health Organization (WHO) grade I: 20; II: 19; III: 41; IV: 57] underwent resection for supratentorial gliomas in an operative suite equipped with intraoperative high-field MRI and microscope-based neuronavigation. Besides standard anatomical image data including T1- and T2-weighted sequences, various functional data from magnetoencephalography (n=37), functional MRI (n=65), positron emission tomography (n=8), MR spectroscopy (n=28) and diffusion tensor imaging (n=55) were integrated in the navigational setup. Results: Intraoperative MRI showed primary complete resection in 27% of all patients (I: 50%; II: 53%; III: 2%; IV: 28%). In 41% of all patients (I: 40%; II: 26%; III: 66%; IV: 28%) the resection was extended owing to intraoperative MRI increasing the percentage of complete resections to 40% (I: 70%; II: 58%; III: 17%; IV: 40%). Integrated application of functional navigation resulted in low post-operative morbidity with a transient new neurological deficit in 10.2% (paresis: 8.8% and speech disturbance: 1.4%) decreasing to a permanent deficit in 2.9% (four of 137 patients with a new or increased paresis). Conclusions: The combination of intraoperative MRI and functional navigation allows safe extended resections in glioma surgery. However, despite extended resections, still in the majority of the grade III and IV gliomas no gross total resection could be achieved owing to the extension of the tumor into eloquent brain areas. Intraoperative MRI data can be used to localize the tumor remnants reliably and compensate for the effects of brain shift.

Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY.

CONTEXT Pegvisomant is a GH receptor antagonist. The ACROSTUDY is a global safety surveillance study of long-term treatment of acromegaly with pegvisomant. OBJECTIVE The objective of the study was to monitor long-term safety and treatment outcomes. DESIGN ACROSTUDY is open to all patients with acromegaly who are treated with pegvisomant. We report an interim analysis of data captured from 1288 subjects enrolled before a database freeze of December 31, 2009. SETTING This was a global noninterventional surveillance study. MAIN OUTCOME MEASURE(S) Long-term monitoring of safety, including central magnetic resonance imaging (MRI) reading and treatment outcomes, was measured. RESULTS Subjects (n = 1288) were treated with pegvisomant for a mean of 3.7 yr and followed up in ACROSTUDY for a mean of 2.1 yr. A total of 1147 adverse events (AE) were recorded in 477 subjects (37%), among which 192 AE in 124 subjects (9.6%) were considered to be related to pegvisomant. Serious AE were recorded in 159 subjects (12.3%), whereas pegvisomant-related Serious AE were recorded in 26 subjects (2%). No deaths (15 subjects; 1.2%) were attributed to pegvisomant use. The incidence of increase in pituitary tumor size in the subset with confirmed MRI increases on central reading represented 3.2% of the overall cohort with at least two available MRI (n = 936). Injection-site reactions were reported in 28 cases (2.2%). In 30 patients (2.5%), an elevated aspartate aminotransferase or alanine aminotransferase of more than 3 times the upper level of normality was reported. There were no reports of liver failure. After 5 yr of pegvisomant treatment, 63.2% of subjects had normal IGF-I levels at a mean dose of 18 mg/d. CONCLUSIONS Data entered and evaluated in ACROSTUDY indicate that pegvisomant is an effective and safe medical treatment in patients with acromegaly. The reported low incidence of pituitary tumor size increase, liver enzyme elevations, and lipodystrophy at the injection site are reassuring.

Impact of primary surgery on pituitary function in patients with non-functioning pituitary adenomas – a study on 721 patients

Summary¶Introduction. The aim of this study was to define the impact of surgery on pituitary function in a large consecutive series of patients harbouring non-functioning pituitary adenomas. Materials and method. Between December 1982 and December 2000, a total of 822 patients underwent primary surgery in the authors’ department. In 721 cases a complete set of endocrinological data was available. Functions of the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes were assessed immediately before surgery and again one week, 3 months and 1 year after the operation, utilizing standardized tests and commercially available assays. Results. There was some degree of pre-operative hypopituitarism in 561 (85%) and 53 (86.3%) of the patients belonging to the transsphenoidal and the transcranial groups, respectively. Prior to transsphenoidal [transcranial] surgery, 163 (31%) [34 (55.7%)] of the patients had secondary adrenal deficiency, 463 (76.6%) [49 (89%)] had hypogonadism and 105 (19.1%) [14 (25.4%)] were hypothyroid. Preoperatively, prolactin levels were mildly elevated in 167 patients (25.3%), whereas 1 year after surgery, levels were elevated in only 5 patients. Permanent diabetes insipidus occurred in 4 patients, 2 from the transsphenoidal group (0.3%) and 2 from the transcranial group (3.2%). Following transsphenoidal surgery 110 (19.6%) of patients had normal pituitary function [versus 0% after transcranial surgery], 169 (30.1%) [6 (11.3%)] showed improvement, 274 (48.9%) [49 (73.7%)] had persistent deficits and 8 (1.4%) [8 (15%)] showed deterioration of pituitary function. Discussion. These data indicate that transsphenoidal surgery for non-functioning pituitary adenomas in expert hands is, relatively, far less detrimental to patients compared with transcranial surgery. The latter carries a much greater risk of post-operative deterioration in pituitary function.

Transsphenoidal surgery for Cushing's disease.

A series of 101 patients with Cushings disease underwent transsphenoidal surgery. Diagnosis was fundamentally based on dynamic testing, mainly on the dosage-dependent suppression of cortisol after dexamethasone. The effect of surgery was monitored by intraoperative ACTH measurements. In 96 out of 101 patients a microadenoma of the pituitary was identified and removed selectively. In 74% of patients there was a clinical and endocrinological remission of Cushings disease. Four ‘operative failures’ after selective adenomectomy underwent hypophysectomy in a second operation and each remitted. Thus the overall remission rate was 77%. In general, bilateral adrenalectomy was performed in patients who had failed to remit after selective adenomectomy. Although there is a considerable mortality and morbidity in patients with Cushings syndrome, complications attributed to surgery were low. Two patients died postoperatively. In general, an improvement of disturbed pituitary function was noted after selective adenomectomy.

Prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after transsphenoidal surgery for pituitary adenomas

Disturbances of osmoregulation, leading to diabetes insipidus and hyponatraemia are well known complications after surgery in the sella region. This study was performed to examine the prevalence and predictors of polyuria and hyponatraemia after a complete and selective removal of pituitary adenomas was attempted via the transnasal–transsphenoidal approach.

Transsphenoidal surgery of parasellar pituitary adenomas

SummaryA series of 147 transsphenoidal operations for parasellar pituitary adenomas performed in a 4.5 year period is presented. The clinical and radiological features of the tumours are described and a new practical classification for the neurosurgeon is introduced. The results of surgery are analyzed with special attention to normalization rates in endocrinologically active adenomas and to the recovery rate of optomotoric nerve lesions in 10 of these cases. While in intraand parasellar microadenomas the surgical normalization rates are comparable to those not extending beyond the confines of the sella, correction of hormonal oversecretion is only exceptionally observed in invasive parasellar macroadenomas. The prognosis for extraocular nerve palsies was found to be favourable, irrespective of the duration of the palsies before surgical intervention. It is to be stressed that even adenomas invading the cavernous sinus can be totally removed via the transsphenoidal approach.