Expression of the JAK and STAT superfamilies in human meningiomas.

OBJECT: The goal of this study was to investigate whether the janus kinase/signal transducer and activator of transcription (JAK/STAT) signal transduction pathway is present and active in meningiomas. The results of these investigations are important for all meningioma therapies that, similar to interferon-alpha-2B (IFNalpha-2B), depend on activation of this pathway for their effect. The authors were interested in evaluating the importance, if any, of the JAK/STAT pathway in the biology and therapy for these tumors. METHODS: Total proteins were extracted from 17 meningioma samples and the levels of JAKs and STATs were determined by using Western blot analysis. Levels of these proteins in meningiomas were compared with those found in normal dura. The JAKs and STATs (with the exception of Jak3 and Tyk2) were present both in the dura and in the meningiomas studied. In tumors JAK and STAT levels were always significantly higher than those found in normal dura. Differences in relative levels were found when meningiomas were subdivided according to the current neuropathological criteria and the highest levels were found in transitional meningiomas. The authors also investigated, using tyrosine-phosphorylated Statl and Stat3 antibodies, whether STATs were activated in meningiomas and normal dura in vivo. Their results indicate that both Statl and Stat3 are phosphorylated in vivo in meningiomas and in the dura. Furthermore, in vitro experiments in which two independent short-term cultures obtained from freshly dissected meningioma samples were used indicated that Statl and Stat3 are phosphorylated in response to treatment with IFNalpha-2B. Exposure of meningioma cells to IFNalpha-2B leads to nuclear translocation of tyrosine-phosphorylated Statl and Stat3, as demonstrated by immunocytochemical analysis. CONCLUSIONS: The results of this study indicate that the JAK and STAT families of proteins are important effectors in brain tumors and support the idea that the effects of IFNalpha in vivo are direct and not mediated by the immune system. This suggests a role for modulation of STAT transcription factors in inhibiting meningioma cell proliferation.

Collagen cross-linkage, elastolytic and collagenolytic activities in cerebral aneurysms: a preliminary investigation.

The pathogenesis of aneurysms formation and rupture is not clearly understood and is undoubtedly a multifactorial event. It is generally accepted that the aneurysm arises from an interaction between structural weakness of arterial wall and hemodynamic factors. Previous studies suggested the possible role of collagenolytic and elastolytic activities in aneurysm development, leading to extracellular matrix alteration. The content of collagen 3-hydroxypiridinium cross-links and elastase and collagenase activities were measured in 12 samples of intracranial aneurysms and in control specimens obtained from temporal superficial arteries and from autoptic samples of Willis Circle. Collagen content is significantly lower in aneurysm than in autoptic control samples (p < 0.01). The total amount of cross-links is significantly lower in ruptured aneurysms than in unruptured and autoptic controls (p < 0.01). Collagenase and elastase activities are significantly increased in ruptured cerebral aneurysms versus unruptured aneurysms (p < 0.01). Linear regression shows that an inverse relationship exists between cross-links content and both elastolytic (p = 0.0032) and collagenolytic (p < 0.001) activities in aneurysmal samples. Multiple regression shows that collagenase has a more important statistic impact (p = 0.027) than elastase (p = 0.08). The results of the study supports the hypothesis that an imbalance of protease-antiprotease homeostasis with elevated collagenolytic and elastolytic activities may represent the predisposing condition leading to aneurysms rupture through collagen depauperation and reduced cross-linkage of collagen fibres.

Respiratory complications during artificial barbiturate coma.

Artificial barbiturate coma was induced in 13 patients with disorders of consciousness from traumatic or spontaneous diseases. Early respiratory complications consisting with Adult Respiratory Distress Syndrome (ARDS) were found in 10 out of these 13 patients; on the contrary, only 2 out of 13 patients, treated with routine intensive care therapy without barbiturate, showed analogous respiratory complications. The literature on the subject and the possible pathophysiological mechanism of respiratory distress are discussed.

A cost-effectiveness analysis on different surgical strategies for intracranial aneurysms.

BACKGROUND: Economical studies on surgery of intracranial aneurysms have considered only the significant benefit of surgical approach on unruptured aneurysms and no studies have been performed comparing cost/benefit analysis of early vs delayed surgery. The present study was retrospectively performed in order to verify whether different treatment options in aneurysm surgery have a different cost/benefit ratio. METHODS: We have analysed a series of 137 patients which underwent surgery for intracranial aneurysms (21 unruptured aneurysms, 56 early surgery and 60 delayed surgery). In the analysis we assumed that each state of an operated patient has an assigned quality of life value and an associated medical cost. We expressed the outcome of each patient as the expected length of survival adjusted for quality, and referred to it as "quality-adjusted life years" (QALY). We considered for each patient the direct cost of Hospitalisation (obtained from DRG reimbursement), the Rehabilitation cost and the correction due to QALY adjusted for age and deficit. RESULTS: Significantly higher costs are reported in patients which present as major complication the hydrocephalus and which are treated with nimodipine; moreover, the costs for patients operated for unruptured aneurysms is significantly lower than that of patients which presented with SAH. Meanwhile, the average QALY adjusted for post-operative neurological deficit at three months follow-up is higher in patients operated for unruptured aneurysms than in patients operated after SAH. The cost-effectiveness of different treatment strategies did not significantly differ considering age and neurological deficit adjustment; thus, after SAH, the choice of early or delayed surgery may depend on clinical and logistic conditions related to the neurosurgical department and its organisation, because there is no significant economical advantage leading to recommend early versus delayed surgery. CONCLUSIONS: In conclusion the present data suggest that a decreased length of hospitalisation and a decreased cost for treatment of unruptured aneurysms should justify a more rigorous preventive screening with available non invasive neuroimaging techniques.

Cerebral protection with diphenylhydantoin during disobliterating surgery of the sovra-aortic branches.

Cerebral metabolic protection in patients submitted to carotid tromboendoarterectomy (TEA) can be made by means of drugs, both in the clamping acute intraoperative phase and in the immediate post-operative period. The knowledge that DPH has the property of reducing CMRO2, the lactates production and of increasing the cerebral level of glucose, glycogen and phosphocreatinine, has persuaded us to use this drug instead of barbiturate, as a therapeutic protection to prevent hypoxic damages to the nervous cell. Our series include 12 patients submitted to carotid TEA in whom cerebral metabolic protection has been obtained by means of DPH at the dosage of 15-17 mg/kg body wt. injected intravenously in about 15' just before clamping. Using this type of pharmacologic protection, we have not observed any of the undesired effects in the cardiocirculatory system described in the literature. The prompt awakening, the absence of neurological deficits, the absence of side-effects suggest that DPH can be used to provide a cerebral metabolic protection during TEA.

[Subarachnoid hemorrhage of unknown origin]. / L'emorragia subaracnoidea sine materia.

An analysis upon the incidence of sine materia SAH is done concerning the period before and after the availability of CT-scan. Furthermore, cases of SAH affecting the perimesencephalic cisterns, where the source of bleeding is in the majority not detectable are reported. The evolution of these SAH is generally favourable. Different groups of diffuse SAH, diagnosed sine materia at the first angiographic study, have to be submitted to a further short term angiography. In these cases, high risks to detect aneurysms affecting the anterior or posterior circulation are take into consideration. New technologies, i.e. angio-TC, provided by spiral-TC, or angio-RM may help to achieve a more precise and reliable diagnosis in patients with sine materia SAH.

[Vertebro-medullary lesions: recent therapeutic approaches (author's transl)]. / Vertebro-medulläre Läsionen: Neue Therapieansätze.

Before initiating the treatment of vertebro-medullary lesions, a precise classification of the lesion and stabilization of injured bone structures are necessary. Particular attention should be given to the differential diagnosis between total and partial transverse lesions, which requires an exact neurologic and radiological examination, analysis of liquor cerebrospinalis and, in some cases, myelography. Laminectomy proved to be of little value for 157 patients with total transverse lesions treated at the Department of Neurosurgery at the University of Milan. Better results were obtained with traction and stabilization (plaster jackets). Due to high incidence of trophic and septic complications, patients should be treated exclusively in highly specialized centres.

Effects of vitamin D and retinoic acid on human glioblastoma cell lines.

The biological significance of vitamin D receptors expressed by glioblastoma and other glial tumours is still unclear. In an effort to clarify this issue we studied the effects of increasing concentrations of 25-dihydroxyvitamin D3 and its metabolite 1 alpha,25-dihydroxyvitamin D3 on two human glioblastoma cell lines. Both substances were capable of inducing a significant (> 50%) reduction in growth of the two glioblastoma cell lines at dosages over 5 microM. When the HU 70 cell line was treated by increasing dilutions of 25-dihydroxyvitamin D3 combined with 1 microM all trans-retinoic acid, significant inhibition was apparent even after addition of 25-dihydroxyvitamin D3 in the nanomolar range. Reduction of growth index was mainly due to induced cell death. Our results provide in vitro evidence that vitamin D metabolites alone or in combination with retinoids may be potentially useful agents in the differentiation therapy of human malignant gliomas.

Endoscopic approaches to the cranial base: perspectives and realities.

We describe the development of transnasal endoscopic approaches to the cranial base in an interdisciplinary series of 103 patients, including 13 in the pediatric age group. Our aim was to define, with the aid of different case reports, the possibilities of endoscopic techniques in tumor resection, fistula repair, the treatment of mucoceles and meningoceles, and of combined intracranial and endoscopic approaches. The advantages of these minimally invasive approaches are panoramic visualization, rapidity and reduction of the cosmetic and functional disabilities in comparison with other conventional approaches, and a better capacity for identifying and developing key landmarks for surgery. On the other hand, endoscopic surgery requires an exsanguine operation field, technical improvements in instruments, and specific skills. Interdisciplinary collaboration in endoscopic approaches has proved useful in integrating experiences without overlap between fields, and in broadening possibilities: in our opinion endoscopic approaches will certainly be important in the future of cranial base surgery.

Spiral CT angiography and surgical correlations in the evaluation of intracranial aneurysms.

We investigated the accuracy of spiral computed tomography angiography (CTA) in the detection and study of intracranial aneurysms by comparing CTA with selective angiograms and surgical findings. Twenty-six patients (9 men and 17 women; mean age 53.1 +/- 1.8 years) with suspected intracranial aneurysms were submitted to CTA (1- to 2-mm slices, pitch 1:1, 24 s, RI = 1) after a conventional CT examination showing subarachnoid hemorrhage (SAH) in 19 cases and during neuroradiological investigations performed for other reasons in 7 cases. One hundred twenty to 150 ml iodate contrast agent (0.3-0.4 gI/ml) were injected intravenously at 5 ml/s rate and with 12- to 25-s delay calculated with a preliminary test bolus. Three-dimensional shaded surface display (3D SSD) and maximum intensity projection (MIP) reconstructions were obtained from axial images. Then, within 48 h, all patients were submitted to digital subtraction angiography (DSA), with separate assessment of CTA and DSA findings. Twenty-two aneurysms shown by CTA were confirmed at DSA and surgery (true positives), whereas the vascular lesion was not confirmed at DSA in 2 cases (false positives). The presence of intracranial aneurysms was excluded at both CTA and subsequent DSA in 7 cases (true negatives) and there were no false negatives; sensitivity was 100 %, specificity 77.8 %, and diagnostic accuracy 93.5 %. Computed tomography angiography aneurysm location was confirmed at surgery in all cases, with very high accuracy in assessing the presence of an aneurysm neck (100 %). Computed tomography angiography accurately depicted the aneurysm shape in 20 of 22 cases, but failed to depict its multilobed nature in 2 cases. The mean aneurysm diameter calculated at CTA was 0.99 +/- 0.12 cm vs 1.09 +/- 0.11 cm at surgery (p < 0.01). The present results suggest that the high sensitivity of CTA, if confirmed by further studies, might help in avoiding having to resort to arteriography after negative CTA in SAH patients.