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Biomedical subjects

R Fahlbusch

Publications and source records attributed to R Fahlbusch.

At least 109 records · Page 6Linked to original sources
PubMed1997

Relationship between invasiveness of pituitary somatotrophinomas and structural abnormalities of protein kinase C gene in human.

The potential role of the protein kinase C (PKC) transduction system in controlling proliferation of human pituitary somatotrophinomas was investigated. Twenty somatotrophinomas were studied using PCR and direct sequencing methods. No point mutation within the alpha PKC gene, previously thought to be associated with invasive pituitary tumors, was found in any of the 20 somatotrophinomas. It is concluded that PKC transduction system may play an important role in controlling pituitary somatotrophinoma proliferation, but there is no correlation between invasiveness and the previously reported alpha PKC gene mutation.

Adenoma↗
PubMed1997

Relationship between GHRP-6 and TPA in the regulation of growth hormone secretion by human pituitary somatotrophinomas.

Growth hormone releasing peptide (GHRP-6) is a synthetic hexapeptide which specifically stimulates secretion of growth hormone (GH) by pituitary somatotrophs. Phorbel ester, 1, 2 tetradecanoylphorbol 13 acetate (TPA) can also stimulate releasing of GH. The precise intracellular mechanism has not been entirely deciphered. We used cell cultures of human pituitary somatotrophinomas to investigate the relation between GHRP-6 and TPA on membrane phosphatidylinositol (PI) turnover and GH secretion. The results showed that the working mechanisms of GHRP-6 and TPA are not identical, although they all can stimulate GH secretion in human pituitary somatotrophinomas. This indicates that PI-PKC signal transduction system may play a crucial role in the regulation of GH secretion.

Adenoma↗
PubMed1997

Human meningiomas possess muscarinic acetylcholine receptors: stimulation of phosphatidylinositol turnover by carbachol.

The effect of carbachol, an acetylcholine receptor agonist, on rate of phosphatidylinositol (PI) turnover in cultured human meningioma cells was investigated. Exposure of meningioma cells for 2 h to carbachol (3.12-200 mumol/L) resulted in a dose-dependent stimulation of PI turnover to a maximum of 5.5-fold over basal controls. A time course study showed stimulation of IP3 formation after 30 s followed by increases in IP1 and IP2. The stimulatory effect of carbachol on PI turnover was completely abolished by the muscarinic receptor antagonist, atropine, but was unaltered by the nicotinic antagonist, hexamethonium. Reverse-transcription of meningioma-derived RNA into cDNA followed by amplification by the polymerase chain reaction using specific primers revealed presence of ml type muscarinic receptor mRNA. These results provide evidence that human meningioma cells possess muscarinic acetylcholine receptors the activation of which leads to PI hydrolysis.

Atropine↗
PubMed1997

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.

Adolescent↗
PubMed1997

Magnetic source imaging combined with image-guided frameless stereotaxy: a new method in surgery around the motor strip.

OBJECTIVE: In this study, information about the localization of the central sulcus obtained by magnetic source imaging (MSI) was intraoperatively translated to the brain, using frameless image-guided stereotaxy. In the past, the MSI results could be translated to the surgical space only by indirect methods (e.g., the comparison of the MSI results, displayed in surface renderings, with bony landmarks or blood vessels on the exposed brain surface). METHODS: Somatosensory evoked fields were recorded with a MAGNES II biomagnetometer (Biomagnetic Technologies Inc., San Diego, CA). Using the single equivalent current dipole model, the localization of the somatosensory cortex was superimposed on magnetic resonance imaging with a self-developed contour fit program. The magnetic resonance image set containing the magnetoencephalographic dipole was then transferred to a frameless image-guided stereotactic system. Intraoperatively, the gyrus containing the dipole was identified as the postcentral gyrus, using neuronavigation, and the next anterior sulcus was regarded as the central sulcus. With intraoperative cortical recording of somatosensory evoked potentials, this assumption was verified in each case. RESULTS: In all cases, the preoperatively assumed localization of the central sulcus and motor cortex with MSI agreed with the intraoperative identification of the central sulcus using the phase reversal technique. CONCLUSION: The combined use of MSI and a frameless stereotactic system allows a fast orientation of eloquent brain areas during surgery. This may contribute to a safer and more radical surgery in lesions adjacent to the motor cortex.

Aged↗
PubMed1997

Progesterone receptor gene expression in craniopharyngiomas and evidence for biological activity.

OBJECTIVE: Previous studies have demonstrated the presence of estrogen receptors in human craniopharyngiomas, raising the possibility that these lesions can be influenced by steroids. To complement these earlier findings, we examined for the presence of progesterone receptor (PR) messenger RNA in surgically removed craniopharyngiomas and performed some studies to determine whether progestogens can exert biological effects on these tumors in vitro. METHODS: Total RNA was extracted from fresh surgically removed craniopharyngiomas and reverse-transcribed into cDNA. The polymerase chain reaction was applied to this craniopharyngioma-derived cDNA using amplimers complementary to exons 4 and 7 of the PR gene. Additionally, craniopharyngioma cell cultures were established, and the in vitro effects of progesterone and 6 alpha-methyl-17 alpha-hydroxyprogesterone acetate on [3H]thymidine uptake and 17 beta-estradiol oxidoreductase activity were determined. RESULTS: Reversed-transcribed polymerase chain reaction of craniopharyngioma-derived RNA yielded bands of predicted size (389 base pairs) in six of seven tumors studied. Hinfl digestion and direct sequencing of the bands confirmed that the polymerase chain reaction DNA was representative of PR messenger RNA. Treatment of craniopharyngioma cell cultures with progesterone resulted in reduced [3H]thymidine uptake. Both progesterone and 6 alpha-methyl-17 alpha-hydroxyprogesterone acetate powerfully increased oxidative 17 beta-estradiol oxidoreductase activity. CONCLUSION: These results provide evidence that PR messenger RNA can be produced by at least some human craniopharyngiomas and indirectly show that this is translated into biologically active receptor protein.

Adolescent↗
PubMed1997

Technical accuracy of a neuronavigation system measured with a high-precision mechanical micromanipulator.

OBJECTIVE: This study was designed to determine and evaluate the different system-inherent sources of erroneous target localization of a light-emitting diode (LED)-based neuronavigation system (StealthStation, Stealth Technologies, Boulder, CO). METHODS: The localization accuracy was estimated by applying a high-precision mechanical micromanipulator to move and exactly locate (+/- 0.1 micron) the pointer at multiple positions in the physical three-dimensional space. The localization error was evaluated by calculating the spatial distance between the (known) LED positions and the LED coordinates measured by the neuronavigator. The results are based on a study of approximately 280,000 independent coordinate measurements. RESULTS: The maximum localization error detected was 0.55 +/- 0.29 mm, with the z direction (distance to the camera array) being the most erroneous coordinate. Minimum localization error was found at a distance of 1400 mm from the central camera (optimal measurement position). Additional error due to 1) mechanical vibrations of the camera tripod (+/- 0.15 mm) and the reference frame (+/- 0.08 mm) and 2) extrapolation of the pointer tip position from the LED coordinates of at least +/- 0.12 mm were detected, leading to a total technical error of 0.55 +/- 0.64 mm. CONCLUSIONS: Based on this technical accuracy analysis, a set of handling recommendations is proposed, leading to an improved localization accuracy. The localization error could be reduced by 0.3 +/- 0.15 mm by correct camera positioning (1400 mm distance) plus 0.15 mm by vibration-eliminating fixation of the camera. Correct handling of the probe during the operation may improve the accuracy by up to 0.1 mm.

Evaluation Studies as Topic↗
PubMed1997

Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly.

BACKGROUND AND PURPOSE: Autosomal dominant hypertension with brachydactyly features severe hypertension that causes stroke usually before the age of 50 years. We recently characterized the hypertension as featuring normal renin, aldosterone, and catecholamine responses and mapped the gene responsible to chromosome 12p. Since angiography in an affected subject had earlier shown tortuous vessels, we performed magnetic resonance tomography (MRT) angiography to look for possible neurovascular anomalies (NVA), which have been previously associated with hypertension. NVA can be caused by a looping posterior inferior cerebellar or vertebral artery. Experimental and clinical evidence suggests that NVA may cause hypertension by a compression of the ventrolateral medulla. METHODS: We performed MRT in 15 hypertensive affected (aged 14 to 57 years) and 12 normotensive nonaffected (aged 12 to 59 years) family members. We then tested for linkage between the hypertension-brachydactyly phenotypes and the presence of NVA. RESULTS: All 15 affected persons had MRT evidence for NVA. All had left-sided posterior inferior cerebellar artery or vertebral artery loops, while 6 had bilateral NVA. None of the nonaffected family members had NVA. The phenotypes were linked with an LOD score of 9.2 given a penetrance of 99%. CONCLUSIONS: Autosomal dominant hypertension and brachydactyly regularly feature NVA, which is frequently bilateral. The early age at which NVA was identified suggests that the condition is primary. We suggest that NVA may be involved in the pathogenesis of this form of hypertension and perhaps essential hypertension as well. Further studies are necessary to address the question of causation.

Abnormalities, Multiple↗
PubMed1997

Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors.

The molecular basis of Cushing's disease is not known. One of the most characteristic features of such tumors is their resistance to corticosteroid feedback at the pituitary level. We have hypothesized that abnormalities of the glucocorticoid receptor (GR) gene might play a role in the development of Cushing's disease via an increase in the relative production of the nonligand-binding splice variant of the GR, GR beta, known to exert dominant negative effects over the ligand-binding isoform, GR alpha. Alternatively, a change in overall GR expression, or mutations of some functional domains of the GR gene, might be involved in the pathogenesis of corticotroph tumors. We studied 22 tumors (17 pituitary ACTH-secreting tumors, 2 ectopic ACTH-producing tumors, 2 prolactinomas, and 1 nonfunctioning adenoma) and three normal pituitaries. RT-PCR was performed with primers specific to GR alpha and GR beta complementary DNA, followed by Southern blotting using an internal probe, and the ratio of the two bands quantitated by densitometry. We also assessed the overall expression of GR relative to the message of both the POMC gene and a housekeeping gene. Single-strand conformation polymorphism analysis of the DNA-binding domain and splice junction region of the gene was also performed. GR alpha messenger RNA was expressed at 37.3-fold +/- 5.7 (range, 32 to 46) excess, as compared with the GR beta subform. This pattern was observed both in the tumor samples and in the normal pituitaries used as controls. A majority of the ACTH-secreting tumors (16/19), including the ectopic secretors, showed variable but increased overall GR expression, whereas 3 tumors showed an expression approximately equivalent to the normal controls; however, no correlation was found between these two groups and the response to the high-dose dexamethasone test, nor was there any correlation with tumor histology. No mutations were found in any of the tumors by PCR-single-strand conformation polymorphism analysis. In conclusion, although both pituitary and ectopic ACTH-secreting tumors are at least partially glucocorticoid-resistant, no significant abnormalities in the relative expression of the two main GR subforms were observed in a series of such tumors. Additionally, mutations of regions critical to normal function of the receptor do not seem to be a frequent event in these tumors.

ACTH Syndrome, Ectopic↗
PubMed1997

Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea.

In this paper the authors present the first evidence that meningiomas respond to treatment with hydroxyurea. Hydroxyurea was administered as an adjunct chemotherapeutic treatment in patients with recurrent and unresectable meningiomas. Hydroxyurea was used because experimental data demonstrated that it inhibits growth of cultured human meningioma cells and meningioma transplants in nude mice by inducing apoptosis. The authors therefore treated four selected patients with hydroxyurea. All patients had undergone multiple gross resections and all except one received radiotherapy. Three patients with recurrent Grade I meningiomas assessed according to World Health Organization (WHO) guidelines received hydroxyurea because of an increased tumor growth rate, documented by magnetic resonance (MR) imaging, within a 6- or 12-month interval. A fourth patient with a malignant meningioma (WHO Grade III) began a course of treatment with hydroxyurea immediately after his sixth palliative operation without waiting for another relapse to be demonstrated on MR imaging. Because of their location and invasive growth behavior none of the meningiomas could have been removed completely by surgical intervention. All patients received hydroxyurea at a dosage level of 1000 to 1500 mg/day (approximately 20 mg/kg/day). In a man with a large sphenoid wing meningioma invading the right cavernous sinus and the temporal base, the intracranial tumor mass was reduced by 60% during 6 months of treatment. A woman with a large ball-shaped meningioma of the right sphenoid wing invading the cavernous sinus exhibited a 74% decrease of the initial tumor volume in 10 months of treatment with oral hydroxyurea. Serial MR images obtained monthly revealed that the process of size reduction was continuous and proportionate. The shrinkage of the tumor was accompanied by a complete remission of symptomatic trigeminal neuralgia after 2 months and by improved abducent paresis after 5 months. The third patient had a slowly growing meningioma that exhibited a 15% reduction in mass when reassessed after 5 months of hydroxyurea treatment. The fourth patient with the malignant meningioma in the left cerebellopontine angle has had no recurrence for 24 months. Long-term treatment with hydroxyurea may result in full remission of tumors in meningioma patients. The preliminary data indicate that hydroxyurea provides true medical treatment in patients with unresectable and recurrent meningiomas, replacing palliative surgery and radiotherapy in the management of this disease.

Adult↗
PubMed1997

Hydroxyurea for treatment of unresectable and recurrent meningiomas. I. Inhibition of primary human meningioma cells in culture and in meningioma transplants by induction of the apoptotic pathway.

Meningiomas, which invade intracranial bone structures and the adjacent connective tissue, are frequently unresectable because of their aggressive and recalcitrant growth behavior. They have a high recurrence rate, and in approximately 10% of these tumors there is an increased risk of malignancy. Significant morbidity and mortality rates associated with recurrent meningiomas demand nonsurgical approaches. To date, adjuvant hormonal treatment has not proven beneficial. The anticancer drug hydroxyurea was therefore tested for its potential use in the treatment of meningiomas. Early-passaged cell cultures were established from 20 different meningiomas. The addition of 5 x 10(-4) and 10(-3) M hydroxyurea over a period of 5 to 9 days resulted in a remarkable decrease in cell proliferation and even blocked tumor cell growth when compared with untreated cells. A significant arrest of meningioma cell growth in the S phase of the cell cycle was revealed on DNA flow cytometry. Electron micrographs of hydroxyurea-treated tumor cells showed ultrastructural features consistent with apoptosis, and light microscopy demonstrated DNA fragmentation by in situ DNA strand break labeling. Short-term treatment of meningioma cell cultures with hydroxyurea for 24 to 48 hours resulted in discrete oligonucleosomal fragments (DNA ladder), another characteristic sign of apoptosis. In addition to the in vitro studies, tissue from five different meningiomas was transplanted into nude mice followed by treatment with 0.5 mg/g body weight hydroxyurea over 15 days. In situ DNA strand break labeling demonstrated DNA fragmentation in distinct regions with different tumor cell densities in all hydroxyurea-treated meningioma transplants. These data provide evidence that hydroxyurea is a powerful inhibitor of meningioma cell growth, most likely by causing apoptosis in the tumor cells. Thus, hydroxyurea may be a suitable chemotherapeutic agent for the long-term treatment of unresectable or semi- to malignant meningiomas, or for preventing recurrent growth of meningiomas after resection.

Animals↗
PubMed1997

Pericollicular surgical approaches to the rhomboid fossa. Part I. Anatomical basis.

A safe paramedian approach to the rhomboid fossa for surgical treatment of intrinsic brainstem lesions is based on detailed knowledge of the morphometric anatomy of superficially located motor structures. The morphometry of the rhomboid fossa is described in this report on the basis of histological studies conducted in six human brainstem specimens, with special emphasis on the colliculus facialis and the trigona nervi hypoglossi and vagi. Morphometric data include analysis of shrinkage factors in each specimen. The colliculus is a landmark for the nervus facialis, oculomotor nuclei, and the paramedian pontine reticular formation. In the surgeon's view from the posterior approach, the colliculus covers an area of 5.7 mm in the mediolateral and 6.8 mm in the craniocaudal direction and is located 0.6 mm lateral to the median sulcus. The fibers of the nervus facialis come as close as 0.2 mm to the surface of the fourth ventricle. The colliculus is located 15.7 mm above the obex. The trigona nervi hypoglossi and vagi cover a rectangular area measuring 3.1 by 6.5 mm and serve as a landmark for lower cranial nerve nuclei. These nuclei are located 0.3 mm lateral to the midline. An area with a maximum extension of 0.9 cm between the colliculus and trigona can be used for an infracollicular paramedian approach. The same applies to a supracollicular approach cranial to the colliculus and caudal to the fibers of the nervus trochlearis within the medullary velum, with a craniocaudal extension of 4 mm. Superficial motor nuclei and fibers can be identified by neurophysiological mapping, which helps to define safe surgical corridors into the rhomboid fossa, thus reducing functional morbidity caused by the operative approach in intrinsic pontine and pontomedullary lesions.

Abducens Nerve↗
PubMed1997

Anatomical aspects for surgery within the floor of the IVth ventricle.

Successful removal of brainstem lesions is among other factors dependent on a safe surgical approach into the brainstem avoiding functional morbidity of superficially located nervous structures. Most midline pontine and pontomedullary lesions can be reached via a transvermian approach through the rhomboid fossa. This review describes the anatomical basis for the pericollicular paramedian surgical approaches into the rhomboid fossa with special emphasis on the microscopic anatomy.

Biopsy↗
PubMed1997

Evidence supporting surgery as treatment of choice for acromegaly.

Within a period of fourteen years 531 operations for growth hormone (GH)-secreting adenomas were carried out. In this consecutive series 73% of the 396 patients who underwent primary transsphenoidal surgery achieved basal GH levels below 5 micrograms/l, and 58% also had an adequate suppression following an oral glucose tolerance test (OGTT). Slightly less favourable results were found in patients requiring surgery following an initial therapy. However, 41% of 121 such patients, who had either been operated upon previously or who had received external or internal irradiation, nevertheless achieved basal GH levels below 5 micrograms/l after the surgical reintervention. Normal suppression of serum GH during an OGTT was observed in 23% of these patients. The overall complication rate was low and tumour recurrences were very rare. To facilitate easier tumour removal, octreotide was preoperatively administered in 53 patients undergoing primary surgery of large adenomas. Recurrences were documented in a few exceptional cases. These data support our previous experience that once a normal suppression of growth hormone has been documented following surgery of pituitary adenomas, the long-term outcome is favourable.

Acromegaly↗
PubMed1996

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.

Brain↗
PubMed1996

Molecular biology of growth-hormone-secreting human pituitary tumours: biochemical consequences and potential clinical significance.

Molecular biological studies have revealed that 30-40% of GH-secreting human pituitary tumours, associated with acromegaly, harbour single-base missense mutations within the Gs alpha gene, termed gsp oncogenes. In addition, a large proportion of GH-secreting tumours inappropriately express the GH-releasing factor (GRF) gene. Gsp-oncogenes result in elevated adenylyl cyclase activity with consequent abnormally high cAMP production. In culture, GH-secreting tumours expressing gsp oncogenes respond more efficiently to the somatostatin analogue, octreotide (SMS), raising the possibility that acromegalics harbouring gsp-positive tumours may be those who optimally benefit from SMS therapy. Inappropriate expression of GRF may result in abnormal presence of a positive autocrine feedback loop, in which secreted GRF acts on the same cells to promote cellular proliferation and GH secretion. Blockade of GRF mRNA translation by means of anti-sense oligonucleotide approaches may prove to be of value in inhibiting tumour function.

Acromegaly↗
PubMed1996

Proliferation parameters for pituitary adenomas.

In this review, the value of assessing proliferation parameters in surgically resected pituitary tumour tissue is analyzed. Histological examination of basal dura biopsies identifies invasive growth even when intraoperatively not apparent to the surgeon. Determination of DNA-polymerase activity, Ki-67 immunohistochemistry and DNA-flow-cytometry shows a clear difference in the proliferative potential of enclosed and invasive pituitary adenomas. Among the various endocrinologically differentiated groups ACTH-secreting adenomas associated with Nelson's syndrome and thyrotropinomas were the most rapidly proliferating. At present, however, our results reveal that the prognosis of an individual patient cannot be reliably predicted on the basis of such studies.

Adenoma↗