Aberrant DNA methylation of alternative promoter of DLC1 isoform 1 in meningiomas.

DLC1 encodes GTPase-activating protein with a well-documented tumor suppressor activity. This gene is downregulated in various tumors through aberrant promoter hypermethylation. Five different DLC1 isoforms can be transcribed from alternative promoters. Tumor-related DNA methylation of the DLC1 isoform 1 alternative promoter was identified as being hypermethylated in meningiomas in genome-wide DNA methylation profiling. We determined the methylation pattern of this region in 50 meningioma FFPE samples and sections of 6 normal meninges, with targeted bisulfite sequencing. All histopathological subtypes of meningiomas showed similar and significant increase of DNA methylation levels. High DNA methylation was associated with lack of DLC1 protein expression in meningiomas as determined by immunohistochemistry. mRNA expression levels of 5 isoforms of DLC1 transcript were measured in an additional series of meningiomas and normal meninges. The DLC1 isoform 1 was found as the most expressed in normal control tissue and was significantly downregulated in meningiomas. Transfection of KT21 meningioma cell line with shRNA targeting DLC1 isoform 1 resulted in increased activation of RHO-GTPases assessed with pull-down assay, enhanced cell migration observed in scratch assay as well as slight increase of cell metabolism determind by MTT test. Results indicate that isoform 1 represents the main pool of DLC1 protein in meninges and its downregulation in meningiomas is associated with hypermethylation of CpG dinucleotides within the corresponding promoter region. This isoform is functional GAP protein and tumor suppressor and targeting of its expression results in the increase of DLC1 related cell processes: RHO activation and cell migration.

Necrotic rhabdoid meningiomas with aggressive clinical behavior.

Rhabdoid meningioma (RM) is a rare, aggressive variant of meningioma classified as a WHO Grade III malignancy. RM exhibits a striking histological resemblance to other rhabdoid tumors and strong tendency towards local recurrences, CSF dissemination, and/or remote metastasis. The majority of reported cases are of secondary rhabdoid transformation in recurrent meningiomas. We present two unusual cases of rhabdoid meningiomas diagnosed as a primary intracranial lesion in adults that were associated with extensive necrosis and an aggressive clinical course. On histological examination, the majority of the tumor mass was composed of necrotic tissue with focal clusters of neoplastic cells, often localized around blood vessels. Most tumor cells exhibited typical rhabdoid morphology with large, vesicular, often eccentrically located nuclei with distinct nucleoli and abundant cytoplasm containing eosinophilic hyaline inclusions. Classical meningothelial features with focal whorl formation were scarce and seen only in one case; in the second case the tumor was entirely rhabdoid. The differential diagnosis with atypical teratoid/rhabdoid tumors (AT/RTs) and other neoplasms, particularly metastatic carcinoma, was considered. Immunohistochemical and electron microscopic study were critical for the accurate diagnosis of the rhabdoid subtype of meningiomas. Rhabdoid cells stained diffusely positive for vimentin and S-100 protein and showed focal but strong expression of epithelial membrane antigen and cytokeratins. The rhabdoid areas of the tumors exhibited high mitotic activity with a MIB-1 labeling index of 80 - 90%. The diagnosis of rhabdoid meningioma was supported by evidence of SNF5 (INI1) protein expression. Ultrastructural examination demonstrated the presence of interdigitating cell processes joined by numerous desmosomes and paranuclear whorls of intermediate filaments typical of the rhabdoid phenotype. Our two cases of rhabdoid meningiomas were associated with lethal outcome within a few months of initial diagnosis. Extensive necrosis in rhabdoid meningioma might be considered an additional predictor of aggressive clinical behavior.

Nelson's syndrome -- 46 years later: clinical experience with 37 patients.

OBJECTIVE: Pituitary tumours occurring after bilateral adrenalectomy for Cushing's disease (Nelson's syndrome) are frequently aggressive, so an early diagnosis and careful management are of prime importance. For a new insight into this entity it is necessary to analyse the factors predisposing to its development and the course of the disease, as well as the methods of diagnosis and modalities of treatment. PATIENTS AND METHODS: Thirty-seven patients with Nelson's syndrome were observed, 32 women and 5 men, aged 16 to 61 years at the time of pituitary tumour detection (at present, 27 to 82 years old). The diagnostic methods included clinical observation, imaging examinations (X-ray studies, CT, MRI), hormonal evaluation (especially ACTH and cortisol levels during replacement therapy) and ophthalmologic investigations. Neurosurgery was the main method of treatment. RESULTS: The clinical analysis indicated that young age at the time of adrenalectomy, pregnancy, insufficient replacement therapy and fulminant course of Cushing's disease were the main factors predisposing to Nelson's syndrome. MRI appeared to be the most valuable imaging method, as this detected Nelson's tumours in the microadenoma stage in 7 patients. Plasma ACTH levels varied between 32.6 pmol/l in an early phase to 2 000 pmol/l in the full-blown syndrome. Absolute temporal scotomas found in ophthalmologic examinations were an early abnormality. The best results after therapy were obtained in patients treated by neurosurgery using a transsphenoidal approach in an early stage. CONCLUSIONS: MRI, ophthalmologic examination and plasma ACTH determination were the most valuable investigations for early diagnosis of Nelson's syndrome. Early neurosurgery offered the best outcome in our group of patients.

[The value of structural neuroimaging in the selection of patients for epileptic surgery]. / Znaczenie strukturalnych badan neuroobrazujacych, w kwalifikacji chorych do leczenia operacyjnego padaczki.

UNLABELLED: The aim of this study was to investigate the value of structural neuroimaging with MRI in the selection of patients for epilepsy surgery. We sought to determine whether MRI influenced decision concerning resective surgery and whether MRI provided much more useful information than enhanced CT. MATERIALS AND METHODS: Neuroimaging studies, MRI and CT, of 300 patients; 265 with partial and 35 with primary generalized seizures, evaluated for surgical treatment of epilepsy were analysed. The MRIs and CTs were interpreted using visual diagnostic criteria and findings were correlated with the EEG changes and clinical semiology. RESULTS: MRIs identified structural lesions in 142, CTs in 96 of all patients. The clinical semiology (partial seizures), MRI, CT and EEG focal findings were concordant in 72 cases. The group of 34 patients had resective surgery. The 7 patients were also operated with MRI and CT focal abnormalities discordant with EEG changes. Also one patient with primary generalized epilepsy and temporal lobe lesion (glioma) had resective surgery. MRI studies revealed structural lesions in 48 patients with normal CT studies. The 43 patients with partial epilepsy had normal CTs and lesions in MRIs; the 34 cases revealed correlation with the EEG findings in 29 temporal and 5 extratemporal regions. Surgery were performed in 23 cases. Also one with partial seizures and MRI detected hippocampal atrophy was operated, despite of generalized EEG patterns. In contrast CT revealed two patients with normal MRI and focal changes. The patients with partial seizures and only CT abnormalities (focal calcifications) were not operated due to discordant EEG findings. In group of 132 patients with normal neuroimaging studies and EEG identified seizure focus only 27 had anterior temporal lobectomy. CONCLUSION: MRI studies gave additional information in case of 16% patients with intractable epilepsy in comparison with CT findings. Resective epilepsy surgery was almost twice as often performed when MRIs revealed structural abnormality. In operated patients, diagnostic sensitivity of structural MRI, CT and EEG to neurophatology were 70.6%, 46.7 and 92.4% respectively.

MRI versus CT in the diagnosis of Nelson's syndrome.

The purpose of the study was to evaluate the utility of MRI and CT in the diagnosis of Nelson's syndrome, i. e. pituitary tumours in patients bilaterally adrenalectomized for Cushing's disease. Thirteen patients, followed up for 5-29 years after adrenalectomy, were studied. In 6 of them CT and MRI revealed no changes in the pituitary gland. In the remaining 7 patients only three CT scans were suggestive of a pituitary adenoma. MRI studies with administration of gadodiamide confirmed the CT diagnosis of Nelson's tumour in 3 patients and disclosed microadenomas in a further 4 patients. Neurosurgical treatment in 4 patients confirmed the MRI findings. Additionally CT and MRI examinations were performed in 5 patients suspected of a recurrent Nelson's tumour 3-11 years after neurosurgery. MRI visualized recurrent adenomas in 3 patients that were not well seen by CT scans. In our experience MRI was more effective than CT in the diagnosis of Nelson's syndrome.

[Relationship between fasting glycemia, serum peptide C, insulin, growth hormone and plasma glucagon in acromegaly]. / Zaleznosci glikemii, stezen peptydu C, insuliny, hormonu wzrostu w surowicy i glukagonu w osoczu na czczo u ludzi z akromegalia.

UNLABELLED: The aim of this study was to investigate interrelations among fasting glycaemia, serum C-peptide, insulin, growth hormone and plasma glucagon concentration in people with acromegaly. 22 patients with active acromegaly, 11 women and 11 men (group A) and 19 healthy people (group K) participated in the study. The oral glucose tolerance test was carried out in all participants. Blood glucose, serum C-peptide, growth hormone and plasma glucagon concentration was measured. 13 patients with acromegaly had normal glucose tolerance (group AT) and 9 had impaired glucose tolerance (group AN). Statistical analysis was performed using Student's test and regression analysis. The comparison of patients from group A and K showed, that serum growth hormone, C-peptide, insulin, blood glucose concentration in fasting state was higher in acromegaly. There were no differences in fasting plasma glucagon concentration between both groups. Fasting glycaemia was similar in patients AT and controls, but there were also higher fasting serum C-peptide and insulin concentrations in the AT group. Fasting blood glucose, serum C-peptide and insulin concentration was higher in AN group than in controls. There were no significant differences in the above parameters between AT and AN group. Analysis of regression showed the negative correlation of fasting serum growth hormone and blood glucose concentration in the group A and AT. However there was no correlation between other parameters and fasting glycaemia, in particular between fasting glycaemia and insulin concentration. Fasting glycaemia positively correlated with fasting serum insulin concentration in healthy men. The comparison of glycaemia and fasting concentration of some hormones in patients with acromegaly regarding their glucose tolerance, did not answer the question, which hormonal abnormality is the most specific for disturbances of carbohydrate metabolism in acromegaly. Therefore groups of patients with markedly high of hormones in fasting state concentrations were distinguished. There was no difference in fasting glycaemia in this people compared to patients with normal or moderately elevated concentrations of hormones studied. CONCLUSIONS: There is higher fasting glycaemia in patients with acromegaly compared to healthy men. Among them one can see subjects with normal glucose tolerance that is accompanied with high serum C-peptide and insulin concentration. Disturbances of glucose-insulin interregulation occur in these people.

Early diagnosis of Nelson's syndrome.

Nelson's syndrome is a specific form of Cushing's disease treated by bilateral adrenalectomy, presenting with a deep hyperpigmentation caused by a pituitary adenoma (corticotropinoma). These ACTH-secreting tumors are frequently aggressive, so early diagnosis is of prime importance. We have studied 33 patients with Nelson's syndrome, 28 women and 5 men, aged 14-56 yr at the time of adrenalectomy and 16-58 yr at the time of Nelson's syndrome diagnosis (observed for 5-32 yr). Methods of examination included simultaneous adrenocorticotropic hormone (ACTH) and cortisol measurements during routine hydrocortisone replacement therapy, computed tomography (CT), pituitary magnetic resonance imaging (MRI), and visual field examination. The results obtained in a group of six patients diagnosed in the last 3 yr were compared with those obtained in a group of 27 patients examined before 1992. High plasma ACTH levels accompanied by normal serum cortisol concentration were characteristic for a late stage of the disease. Absolute temporal scotomas were an early finding. MRI, especially with the gadolinium enhancement, was superior to CT in demonstrating pituitary microadenomas in Nelson's syndrome. Thus, MRI diagnosis allowed for an early neurosurgical treatment of the patients with Nelson's tumors.

[Diagnosis and treatment of Cushing's disease]. / Diagnostyka i leczenie choroby Cushinga.

Authors present the results of surgical treatment of 63 patients with Cushing's disease. They evaluate various diagnostic procedures, applied to define the aetiology of endogenous hypercortisol. The petrosal sinus sampling for ACTH level is described. In the series in only 32% of patients; radiological examinations (including CT and MRI) showed the pituitary adenoma. Among 63 operated persons--43 were subjected to surgery based on endocrinological data alone. All the patients were operated by transsphenoidal route. Good result--endocrinological recovery in the treatment of Cushing's disease was achieved in 80% of patients.

[Importance of catheterization of inferior petrous sinuses in surgical treatment of Cushing's in children and adolescents]. / Znaczenie cewnikowania zatok skalistych dolnych w leczeniu operacyjnym choroby Cushinga u dzieci i mlodziezy.

The authors present 12 cases of Cushing disease in children and adolescents. In childhood the course of this disease differs from that in adulthood. The predominating initial signs in children are growth stunting and arrest of sexual maturation. Radiological methods (sella X-ray, CT, NMR) are normal initially in most cases and the diagnosis is confirmed exclusively by hormonal investigations. ACTH determination of venous blood samples obtained by catheterization of the inferior petrous sinuses is essential not only for the diagnosis of pituitary adenoma but also for choice of proper surgical treatment. The optimal method is selective removal of the adenoma. In case of impossibility of this removal (anterior lobe hyperplasia) hemiphysectomy is suggested (with removal of the lateral part of the anterior lobe on the side of greater secretion of ACTH into the inferior petrous sinus. This method is possible only if before the operation catheterization of these sinuses was done and a significant difference of ACTH level was found between the right and the left sinus. This is the reason why this test is essential for selection of proper treatment. Anterior lobe hypophysectomy, bilateral adrenalectomy, X-ray hypophysis irradiation are unacceptable for children because of their maiming character making impossible further somatic development and sexual maturation of children.

[Technical difficulties in surgical treatment of Cushing disease in children and adolescents]. / Trudnosci techniczne w leczeniu operacyjnym choroby Cushinga u dzieci i mlodziezy.

Cushing disease in children and adolescents is connected with many technical difficulties in operations for removal of pituitary adenoma from the approach through the sphenoid bone which is connected with anatomical conditions specific for that age group. The greatest difficulty is related to incomplete development of the sphenoidal sinus, which is sometimes spongy or presellar. Besides that, the size of the sphenoidal sinus and sella is small. The surgical methods are analysed which make possible overcoming of these difficulties.

[Cerebrospinal fluid rhinorrhea as a postoperative complication of pituitary tumor surgery. Corrective surgery of sella turcica by own methods]. / Plynotok nosowy jako powiklanie przezklinowej operacji guzów przysadki. Operacja naprawcza wlasna metoda plastyki dna siodla tureckiego.

A relatively simple technically and effective own method of corrective operation of sella floor in cases of cerebrospinal fluid rhinorrhoea after transsphenoid operations for pituitary tumours is presented. This complication developed in 12 cases in a group of 720 patients operated on in the years 1973-1990. The described method was applied in 9 cases.

[Caudal tumors as a rare cause of subarachnoid hemorrhage]. / Guz ogona konskiego--rzadka przyczyna krwawienia podpajeczynówkowego.

A case of cauda tumour (neurolemmona) is reported in which the presenting symptom was subarachnoid haemorrhage. The investigations for suspected cerebral vascular malformation brought no results. Only after appearance of clinical signs of cauda damage vertebral canal investigations made possible the correct diagnosis and proper treatment.

Pituitary apoplexy: endocrine, surgical and oncological emergency. Incidence, clinical course and treatment with reference to 799 cases of pituitary adenomas.

Authors analyzed retrospectively the incidence of pituitary apoplexy in a series of 799 pituitary adenomas with respect to the long term follow-up of the patients. Focal vascular abnormalities in histological specimens of tumours, regarded as morphological suggestion of past apoplexy (haemorrhage, ischaemic infarction or necrosis), were established in 113 out of 783 surgical cases (14.4%). Acute clinical onset, justifying the clinical diagnosis of pituitary apoplexy, occurred in 39 patients only (5% of the whole series), 19 of them were subjected to urgent surgical decompression due to severe neurological deficit. The haemorrhagic character of apoplexy was established in most cases requiring immediate surgery. The detailed clinical picture of this condition and its management are discussed with respect to the long term prognosis. On this basis the authors suggest the necessity of surgical treatment in every case of pituitary apoplexy, taking into account not only neurological recovery, but also endocrine and oncological aspects of the disease. The observation that pituitary apoplexy may be a "marker" of tumour invasiveness (even in small, "enclosed" adenomas) is highlighted.

[Evaluation of a method for determining ACTH concentration in samples of serum obtained by catheterization of inferior petrosal sinuses in diagnosis of Cushing's disease]. / Wartosc metody oznaczania poziomu hormonu ACTH w próbkach krwi uzyskanych poprzez cewnikowanie zatok skalistych dolnych w diagnostyce choroby Cushinga.

A method consisting in the catheterization of lower petrosal sinuses aimed at obtaining blood samples for the determination of ACTH concentration has been applied in diagnostically difficult cases of Cushing's disease. The appearance of ACTH concentration gradient between the blood originating from the immediate vicinity of pituitary and the peripheral venous blood confirmed the hypophyseal etiology of hypercortisolemia. The gradient of ACTH concentration between the two petrosal sinuses made possible the localization of a microadenoma in the anterior lobe of pituitary. The diagnostic conclusions obtained by the above method have been confirmed during the surgery.

[A method of bilateral craniofacial approach in the surgical treatment of cancer of the nose and paranasal sinuses]. / Metoda dwustronnego dostepu czaszkowo-twarzowego w leczeniu chirurgicznym nowotworów nosa i zatok przynosowych.

The authors presented the two sides craniofacial method in surgical intervention of nasal and paranasal sinus cancers. The detailed indication, technique and complications of this method were also described as well as the own case as an example.

[Spasm in angiographic image and the development of the symptoms of ischemic stroke in patients after subarachnoid hemorrhage from supratentorial ruptured aneurysm]. / Skurcz w obrazie angiograficznym a wystepowanie objawów udaru niedokrwiennego mózgu u chorych po krwawieniu podpajeczynówkowym z peknietego tetniaka w obszarze nadnamiotowym.

The results of angiographic examinations are presented in relation to the development of ischaemic stroke in 219 patients. In the selection of the patients cases were ruled out with coexistent intracranial haematomas, and the patients treated surgically were ruled out in whom the course of the operation suggested a possible influence of additional factors which might have changed the condition of the patient independently of the main disease. Depending on the results of angiography three groups of patients were isolated with different likelihood of ischaemic stroke development: patients without vasospasm or with segmental vasospasm-stroke developed in 15%-9% of cases; patients with unilateral or bilateral diffuse vasospasm of low or medium intensity-stroke in 34%; patients with high-grade diffuse intensity-stroke in 73% of cases. The frequency of stroke in these groups is analysed in relation to the condition of the patient at the time of angiographic examination.

[Location of cerebral aneurysms and arteriospasm after subarachnoid hemorrhage]. / Umiejscowienie tetniaków a skurcz tetnic u chorych po krwawieniu podpajeczynówkowym.

On the basis of an analysis of 314 patients with aneurysms situated supratentorially the authors tried to establish a possible correlation between the location of the aneurysm and the frequency, intensity and extent of this spasm. Similarly as in the reports of other authors it was not possible to find a correlation between the location of the aneurysm and arteriospasm. Only the group of 28 patients with multiple aneurysms showed the highest percent of most intense and most extensive arteriospasm, which was particularly evident within the first three days after haemorrhage. In the period from the 4th to the 6th days after the last subarachnoid haemorrhage the lowest proportion of angiograms with arteriospasm was noted in patients with aneurysms of the anterior communicating artery. In this group diffuse bilateral arteriospasm was significantly more frequent than in the remaining groups.

Ruptured intracranial aneurysm associated with spontaneous occlusion of internal carotid artery. Experience with 5 cases.

Out of 921 patients diagnosed and treated for intracranial aneurysm in 5 cases (0.5%) the co-existence of ruptured aneurysm and occlusion of the internal carotid artery was found. 4 patients were treated surgically--aneurysm clipping--without serious post-operative complications and 6 months follow-up showed satisfactory results. In 4 of 5 cases the aneurysm was located on the anterior communicating artery (ACA); this fact may support the hypothesis concerning a possible role of enhanced blood flow in aneurysm formation and rupture. In cases with good collateral blood flow extra-/intracranial bypass before aneurysm occlusion seems not to be necessary. The risk of operation in those patients is not as high, as might be expected.