Characterization of system-related geometric distortions in MR images employed in Gamma Knife radiosurgery applications.

This work provides characterization of system-related geometric distortions present in MRIs used in Gamma Knife (GK) stereotactic radiosurgery (SRS) treatment planning. A custom-made phantom, compatible with the Leksell stereotactic frame model G and encompassing 947 control points (CPs), was utilized. MR images were obtained with and without the frame, thus allowing discrimination of frame-induced distortions. In the absence of the frame and following compensation for field inhomogeneities, measured average CP disposition owing to gradient nonlinearities was 0.53 mm. In presence of the frame, contrarily, detected distortion was greatly increased (up to about 5 mm) in the vicinity of the frame base due to eddy currents induced in the closed loop of its aluminum material. Frame-related distortion was obliterated at approximately 90 mm from the frame base. Although the region with the maximum observed distortion may not lie within the GK treatable volume, the presence of the frame results in distortion of the order of 1.5 mm at a 7 cm distance from the center of the Leksell space. Additionally, severe distortions observed outside the treatable volume could possibly impinge on the delivery accuracy mainly by adversely affecting the registration process (e.g. the position of the lower part of the N-shaped fiducials used to define the stereotactic space may be miss-registered). Images acquired with a modified version of the frame developed by replacing its front side with an acrylic bar, thus interrupting the closed aluminum loop and reducing the induced eddy currents, were shown to benefit from relatively reduced distortion. System-related distortion was also identified in patient MR images. Using corresponding CT angiography images as a reference, an offset of 1.1 mm was detected for two vessels lying in close proximity to the frame base, while excellent spatial agreement was observed for a vessel far apart from the frame base.

Hypophysitis superimposed on a non-functioning pituitary adenoma: diagnostic clinical, endocrine, and radiologic features.

Pituitary adenomas are common neoplasms requiring medical and/or surgical treatment when associated with hormonal hypersecretion. Treatment of non-functioning pituitary adenomas is necessary when symptoms of mass effect or hormonal deficits occur. However, therapeutic options, including surgical resection and/or radiotherapy, can be associated with significant complications. Hence, it is important to consider disorders that could present in a similar manner to pituitary adenomas, for which surgery is not the indicated therapeutic approach. We describe herein a 38-yr-old woman who presented with a pituitary lesion that was considered to be a non-functioning pituitary adenoma. Due to lack of hormonal deficits and/or compression of adjacent structures, we opted for conservative management and followup with consecutive magnetic resonance imaging. Fifteen months after initial diagnosis, considerable enlargement of the lesion was noted, extending mainly superiorly and indenting the optic chiasm. Repeated endocrine investigation revealed partial anterior pituitary insufficiency. The patient underwent trans-sphenoidal resection of the pituitary lesion; histology revealed a null cell pituitary adenoma and lymphocytic hypophysitis (LYH) of the non-neoplastic adenohypophysial gland. Post-operatively, complete anterior and partial posterior pituitary insufficiency developed. This case illustrates the effects of new-onset LYH in a patient with a pre-existing non-functioning pituitary adenoma. Being aware of this rare possibility is important, as enlargement of the pituitary lesion may not be caused by expansion of the preexisting tumor, but by the onset of LYH of the nonneoplastic pituitary tissue.

DNA-flow cytometry of 207 pituitary adenomas: ploidy, proliferation, and prognosis.

The principal factors involved in pituitary adenoma formation are unknown. DNA-flow cytometry is a useful study providing an estimation of a tumor proliferative rate. In this study, DNA-flow cytometry was performed to evaluate its capability to both assess prognosis and predict recurrence. Two hundred and seven fresh pituitary adenoma specimens were assessed by flow cytometry. Pre-operative endocrine function, previous medical treatment, radiographic appearance, surgical findings and immunohistochemistry were recorded for each patient. Patient outcomes were assessed at a mean follow-up of 5.3 +/- 3.1 yr. Endocrinologically inactive pituitary adenomas were predominantly euploids (50.8%). The highest proliferation rates occurred in Nelson's syndrome and the lowest in Cushing's disease. A significant difference in proliferation was observed with prolactinomas and acromegaly when a medical treatment was performed before primary surgery. Massive histological invasiveness was directly associated with a significant increase in proliferation rate. Radiotherapy did not affect the recurrence rate (4.4%) statistically. In conclusion, DNA-flow cytometry was found to be useful for determining ploidy and obtaining an overview of cell cycle status. It was helpful in identifying patients requiring closer follow-up, such as those with invasive adenomas and Nelson's syndrome. No single parameter revealed by DNA-flow cytometry could predict tumor prognosis or recurrence in the follow-up of 7.5 +/- 1.3 yr.

Analysis of secretory, immunostaining and clinical characteristics of human "functionless" pituitary adenomas: transdifferentiation or gonadotropinomas?

In this study, the central technique of in vitro culture has been used to further investigate whether LH/FSH-expressing, but clinically "functionless" pituitary adenomas are gonadotropinomas or whether their hormone secretion is due to transdifferentiation events. 664 "functionless" pituitary adenomas were examined for hormone secretion by in vitro culture and for hormone content by immunostaining. The results were correlated with the clinical findings. 40 % of the tumours (n = 263) secreted at least one of the gonadotropins alone, 8 % (n = 53) exhibited various patterns of anterior pituitary hormones, whilst the remaining 52 % of tumours were not associated with any hormone. In the secretory tumours, immunostaining revealed only a few scattered hormone-containing cells (5 to 15 %). Mild hyperprolactinaemia was observed in some cases, presumably because of pressure effects of the tumours. The majority of the patients suffered clear cut hypopituitarism (p < 0.05). Pre-operatively, gonadotropin hypersecretion was observed in 3 cases, but only one of these secreted hormones in culture. Interestingly, a higher proportion of tumours removed from patients with hypopituitarism showed secretory activity in vitro than those tumours removed from patients showing no hormonal dysfunction or hyperprolactinaemia. We conclude that the term "gonadotropinoma" to describe functionless pituitary tumours associated with LH and/or FSH secretion is a misnomer, because the presence of LH and/or FSH confirmed by in vitro methods in the present series is a result of only a few scattered cells. We suggest that primary pituitary tumour cells differentiate into a secretory type (transdifferentiation), possibly in response to altered serum hormone levels such as decreased steroids. Further work is required to identify the factors which trigger the altered cells' characteristics.

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

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.

Chondrosarcoma of the larynx: treatment with radiotherapy.

The case of a 50-year-old man with chondrosarcoma of the larynx treated with radiotherapy is reported. The patient presented with hoarseness and dyspnea. He underwent computed tomography (CT), which demonstrated a soft tissue mass of the larynx. Direct laryngoscopy with biopsy established the diagnosis of chondrosarcoma. Although experience with radiotherapy in these cases has been lacking in the literature, it was considered and eventually used, as radical surgery would result in severe cosmetic and functional impairment. Radiation therapy alone resulted in long-term remission of the tumour for more than 3 years. The patient has been followed up using CT and direct laryngoscopy for early detection of recurrence or metastases.

Gene expression of adrenomedullin, leptin, their receptors and neuropeptide Y in hormone-secreting and non-functioning pituitary adenomas, meningiomas and malignant intracranial tumours in humans.

The aim of this study was to assess human intracranial tumours for their gene expression pattern of the vasoactive peptide adrenomedullin (AM), its receptor (AM-R) and leptin, which exerts multiple biological effects including proliferation and angiogenesis via the leptin receptor (OB-Rb). Gene activity of neuropeptide Y (NPY) was monitored additionally. We investigated whether there was a characteristic gene expression pattern of AM and leptin in different intracranial tumours, depending on their proliferation activity and biological behaviour. We investigated 35 non-functioning pituitary adenomas (including eight null cell, four silent plurihormonal, 23 silent gonadotroph adenomas), seven somatotropinomas, seven prolactinomas, eight meningiomas, five astrocytomas, two glioblastoma multiformes and unaffected temporal lobe (n = 8). Quantitative reverse transcriptase-polymerase chain reaction (TaqMan RT-PCR) was performed. AM mRNA was detectable in all tumour specimens. AM/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) ratio was significantly higher in somatotropinomas, as was AM/CD31 ratio in prolactinomas, compared with inactive adenomas (P < 0.05). AM-R mRNA was found in all tumour subgroups in small quantities but, in general, higher in tumours than in temporal lobe tissue, respectively. AM-R/CD31 ratio was significantly higher in prolactinomas than in inactive adenomas (P < 0.05). Leptin was detectable in very low quantities in each subgroup. OB-Rb gene expression was found in all tumour subgroups, OB-Rb/GAPDH ratio was highest for meningiomas (P < 0.0001, compared with temporal lobe). NPY mRNA was detectable in temporal lobe in higher quantities than in tumours (P < 0.0001), and almost undetectable in prolactinomas and astrocytomas. Our data demonstrate that AM and AM-R, NPY, as well as leptin and OB-Rb, are expressed in various intracranial tumours in humans but their particular function has to be elucidated further. At present, there is no evidence for a cross-talk on transcriptional level between the peptidergic vasodilative system AM and the putative angiogenic and proliferation affecting factor leptin.

A neurilemmoma of the parotid gland: report of a case.

Benign primary tumors of the facial nerve are frequently misdiagnosed because of the variety of their clinical manifestations. Much attention has been paid to neurilemmomas in the recent otolaryngologic literature, but far less has been focused on intraparotid facial nerve neurilemmomas. In this article, we describe a new case of this truly rare tumor, and we review its diagnosis, pathology, and treatment.

Spinal-thoracic dumbbell meningioma: a case report.

STUDY DESIGN: Total excision of a large dumbbell cervicothoracic intra- and extraspinal meningioma that had grown into the posterior mediastinum is described. This excision involved a two-step neurosurgical-thoracosurgical procedure within a short interval. OBJECTIVES: To document that the described laminectomy and thoracotomy techniques are adequate, safe, and effective for the treatment of this intra- and extraspinal meningioma lesion. SUMMARY OF BACKGROUND DATA: The management of intra- and extraspinal dumbbell tumors is based on anecdotal reports of mostly neurinomas, and thus remains a controversial issue. Even large series of spinal meningiomas lack adequate information on how best to treat large cervicothoracic meningiomas. METHODS: The authors have modified standard techniques used for resection of spinal and mediastinal tumors, respectively, adapting them for a large, invasive dumbbell meningioma in a 72-year-old lady. The patient initially underwent laminectomy and microsurgical excision of the intraspinal tumor portions encasing vascular structures. A week thereafter, a thoracotomy was performed, and the mediastinal tumor portions were removed completely. RESULTS: Restitution was remarkably good. The patient, who had been unable to walk on her own, regained some mobility. At this writing, she was able to walk considerable distances without support. There was no evidence of tumor recurrence during a follow-up interval of 3 years. CONCLUSIONS: The authors recommend a two-staged procedure for complete excision of a large spinal-thoracic meningioma. Even in elderly patients with major neurologic deficits, an impressive recovery can be achieved with such lesions.

Smoking and alcohol in the etiology of oral cancer: gender-specific risk profiles in the south of Greece.

Oral and pharyngeal cancer (OC) mortality is very low in Greece, especially among men, compared to other European countries. We conducted a case-control study of OC in Athens, and obtained information on tobacco, alcohol use and other potential risk factors and confounding variables for 110 incident cases and 115 hospital-based controls. We used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Tobacco smoking (pack years, P(trend)=0.01) and alcohol use (drinks/week, P(trend)=0.07) were independent risk factors, with a multiplicative effect for combined exposures (OR, 8.3; 95% CI, 2.4-29.1, for >28 alcohol drinks/week and >50 pack years of cigarette smoking). The type of alcoholic beverage also seemed important: drinking ouzo and tsipouro (liquors of high ethanol concentration) was associated with greater increased OC risk than drinking comparable amounts of wine, beer or dark spirits. While alcohol drinking is more common for male cases versus controls, few men reported regularly consuming large quantities of ethanol associated with highest risk of OC in other studies. This may partially explain the low rates of male OC mortality in Greece. Among the 38% of our cases who were women, however, neither smoking nor alcohol drinking frequencies were significantly elevated compared to controls, and so the etiology of OC risk in females requires further investigation.

Current management of prolactinomas.

Prolactinomas constitute the largest group of pituitary adenomas in autopsy series. However, their relative incidence in recent surgical series is much less impressive since medical treatment with dopamine agonists is routinely employed, which in many cases leads to tumor shrinkage and normalization of prolactin levels. The clinical symptoms of hyperprolactinemia are menstrual dysfunction and galactorrhea in women and loss of libido and potency in men. Prolactinomas may present also as space occupying sellar mass lesions impinging on the adjacent structures like the pituitary gland, cavernous sinus and optic nerves. The standard primary treatment is medical by dopamine agonists. Prolactinomas are the prototype of tumors, the growth of which can be reliably and safely inhibited by specific drugs other than cytostatic chemotherapy. These unfortunately have side effects, like orthostatic hypotension, nausea and vomiting. The effects induced by dopamine agonists are suppressive but not tumoricidal. Thus, the therapeutic effect is only maintained as long as the drug is administered. Consequently. in most cases, treatment has to be continued life-long with a few exceptions, in whom normoprolactinemia persists even after discontinuation of dopamine agonists. Main indications of surgery in prolactinomas are intolerance of the medication, and tumors not responding to dopamine agonists. Occasionally, these may ultimately require radiation therapy. Remission rates in large series of surgically treated prolactinomas vary between 54% and 86%. In our consecutive series of 540 surgically treated prolactinomas, the normalization rate after transsphenoidal surgery basically depended on the preoperative prolactin levels, tumor size and extension. The remission rate of 82% in microprolactinomas with initial prolactin levels <200 ng/ml would even in small adenomas make one consider surgical treatment as an interesting alternative to long-term medical treatment.

Intra- and suprasellar colloid cysts.

During the past 11 years 69 patients underwent transsphenoidal surgery for symptomatic intra- and suprasellar non-neoplastic cysts in our department. Eighteen of them harbored intra- and suprasellar colloid cysts. The most frequent presenting symptoms were oligomenorrhea, galactorrhea, and headaches. One patient presented with polydipsia. One male patient complained about mild hypogonadism and oligospermia. Two male patients presented with symptoms of panhypopituitarism. Endocrine assessment revealed hyperprolactinaemia in 72% of the female patients. Hypogonadism was found in 72%. Panhypopituitarism was found in two cases. During transsphenoidal surgery, a circumscribed collection of colloid material was removed in each case. Additional tumorous tissue was encountered in three cases that harbored a concomitant pituitary adenoma. Biopsies confirmed the surrounding tissue to be normal pituitary tissue. Postoperatively, regular menstrual cycles were found in 82% of the female patients with oligomenorrhea and headaches improved in 80%. Serum prolactin levels were restored in 92%, galactorrhea ceased in 89%. Only in one case deterioration of pituitary function occurred (diabetes insipidus). Symptomatic SIADH occurred in another one. There were no other post-operative complications. We conclude, that transsphenoidal surgery is a safe therapy for treating symptomatic intra- and suprasellar colloid cysts. Surgery is mainly indicated for female patients in childbearing age to restore fertility and to prevent further deterioration of pituitary function. The differential diagnosis is often unclear preoperatively, but a non-enhancing mass on MRI between anterior and posterior lobe may suggest the presence of an intra- and suprasellar colloid cyst.

Xanthomatous Hypophysitis: A Novel Entity of Obscure Etiology.

We report a case of xanthomatous hypophysitis, a recently described entity of obscure etiology affecting the pituitary gland, in a 43-yr-old woman, Histologically it is characterized by infiltration of the anterior pituitary by foamy histiocytes which are strongly immunoreactive for CD68 (histiocytic marker) and are immunonegative for 5100 and CD 1 a. Electron microscopy revealed histiocytes with abundant cytopasmic lipid droplets and membrane bound vacuoles. Fragments of intact anterior pituitary with preserved vascw lar and reticulin networks are seen. Xanthomatous hypophysitis resembles neoplasm on clinical and radiologic grounds.

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.

Dopamine D1, dopamine D2, and prolactin receptor messenger ribonucleic acid expression by the polymerase chain reaction in human meningiomas.

Previous studies have suggested the presence of high-affinity dopamine D1 receptors and prolactin receptors in human cerebral meningiomas. In this study, using the polymerase chain reaction, we report the presence of the messenger ribonucleic acid (mRNA) for the dopamine D1 and D2 receptors and the prolactin receptor in meningioma tissue specimens and cell cultures derived from meningioma tissue. Dopamine D1 receptor mRNA was present in a majority of female tissue specimens and in all male tissue specimens. D2 receptor mRNA was detected in all specimens examined. Prolactin receptor mRNA was present in a little more than half of the female and male meningioma tumor specimens. The polymerase chain reaction products were directly sequenced to confirm the identity of these receptors in meningiomas and cell cultures. Ligand binding studies confirmed the presence of the dopamine D1 receptor in meningioma tissue specimens. In contrast, receptor studies with the dopamine D2 ligand [125I]4-iodospiperone failed to detect D2 binding in meningioma membrane preparations. These results suggest the existence of active dopamine D1 receptors in cerebral meningiomas.

Hormonal dependency of cerebral meningiomas.

Though meningiomas are benign intracranial tumors, a minor group invades the skull base and the connective tissue of the sinus cavernous inducing neurological deficits. These patients can not be cured by surgical treatment. Therefore, the development of an adjuvant medical therapy has been the goal during the last decade. We report here on different medical concepts which are based on steroids, amines, growth factor antagonists and cytokines. In addition, our data give evidence that the growth of intracranial meningiomas is under multifactorial proliferative control.

A new miniature x-ray source for interstitial radiosurgery: device description.

A device that generates low-energy x rays at the tip of a needle-like probe was developed for stereotactic interstitial radiosurgery. Electrons from a small thermionic gun are accelerated to a final energy of up to 40 keV and directed along a 3 mm outside diameter drift tube to a thin Au target, where the beam size is approximately 0.3 mm. All high-voltage electronics are in the probe housing, connected by low-voltage cable to a battery-operated control box. X-ray output, which is nearly isotropic, consists of a bremsstrahlung spectrum and several lines between 7 and 14 keV, with characteristic radiation contributing 15% of the total energy output. To date, 14 patients with metastatic brain tumors have been treated with this device.

Presence of dopamine D1 receptors and absence of dopamine D2 receptors in human cerebral meningioma tissue.

Preliminary studies have shown that the dopamine D1 receptor is expressed in cerebral meningioma tissue. The current study presents evidence that the iodinated dopamine D1 antagonist [125I]SCH-23982 bound to dopamine binding sites in 33 of the 45 human cerebral meningiomas examined for this. Saturation curves and the linearity of the Scatchard analysis indicate that [125]SCH-23982 binds to a homogeneous population of binding sites. Competition curves reveal the presence of a dopamine D1 receptor by rank order of various dopaminergic and nondopaminergic antagonists ((+)-SCH-23390 greater than (+/-)-SKF-83566 greater than (cis)-flupentixol greater than (+)-butaclamol greater than chlorpromazine greater than 1-sulpiride greater than mianserin greater than (-)-butaclamol). Stereoselectivity was evaluated by (+)- and (-)-butaclamol. The mean (+/- standard deviation) dissociation rate constant was 369 +/- 196 pM with a density of 31.9 +/- 12.5 fmol/mg membrane protein among 33 meningiomas. The dopamine D2 receptor was not present in the 30 meningiomas examined for this. These findings indicate that the dopamine D1 receptor identified is expressed alone and is therefore regulated independent of a D2 receptor in cerebral meningioma tissue. Although the function of the dopamine D1 receptor in cerebral meningiomas has not so far been defined, previous studies have suggested that the D1 receptor might be involved in the control of proliferative growth of meningiomatous tissue.

Growth of cultured human cerebral meningiomas is inhibited by dopaminergic agents. Presence of high affinity dopamine-D1 receptors.

We have found that microM concentrations of the dopamine agonist bromocriptine significantly decrease the proliferation rate of human meningioma cells in culture (25-56% inhibition). This effect was also seen with direct application of dopamine, as well as the dopamine-D1 agonist (+)-SKF-38393 (both applied in microM concentrations) to meningioma cell cultures. Receptor studies with the dopamine-D1 ligand (125I)SCH-23982 (dopamine-D1 antagonist) indicated that dopamine-D1 binding sites were present in the membranes of meningioma tissue. The mean dissociation constant (Kd) was 325 ( +/- 74.5 SEM) pM and the receptor density (Bmax) was 25.4 ( +/- 1.5 SEM) fmol/mg pellet protein in 5 human meningiomas. The pharmacological specificity was proven by (+)-SKF-38393, ( +/-SKF-83566 or (+)-butaclamol and their inactive isomers (-)-SKF-38393 and (-)-butaclamol in a 1000 fold excess. These results provide evidence that human meningiomas possess high affinity dopamine-D1 receptors and that dopamine agonists have an antiproliferative effect on these tumors in culture. We conclude that the proliferation of cerebral meningiomas may be under dopaminergic control and that dopamine agonists may have a role in the medical treatment of patients with meningiomas.