R. Agati

Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status.

A recent randomized study conducted on newly diagnosed glioblastoma (GBM) patients demonstrated that concomitant and adjuvant temozolomide added to standard radiotherapy had a survival advantage compared with radiotherapy alone. The overall survival benefit of this aggressive treatment, however, was attenuated in older or poor performance status patients. The aim of the present study was to verify the activity and the toxicity of temozolomide administration concurrent and adjuvant to radiotherapy as first‐line treatment for elderly GBM patients, and to explore correlations between clinical outcome and O6 methylguanine‐DNA methyltransferase (MGMT) promoter methylation status.

O6-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: clinical implications

O(6)-methylguanine DNA-methyltransferase (MGMT) promoter methylation status is a prognostic factor in newly diagnosed glioblastoma patients. However, it is not yet clear whether, and if so how, MGMT methylation status may change. Moreover, it is unknown whether the prognostic role of this epigenetic feature is retained during the disease course. A retrospective analysis was made using a database of 614 glioblastoma patients treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age > or = 18 years; performance status 0-2; histological diagnosis of glioblastoma at both first and second surgery for recurrence; postoperative treatment consisting of: (i) radiotherapy (RT) followed by adjuvant temozolomide (TMZ) until 2005 and (ii) TMZ concurrent with and adjuvant to RT after 2005; a time interval > or = 3 months between first and second surgery. MGMT status was evaluated at first and second surgery in all 44 patients (M:F 32:12, median age: 49 years, range: 27-67 years). In 38 patients (86.4%), MGMT promoter status was assessable at both first and second surgery. MGMT methylation status, changed in 14 patients (37%) of second surgery samples and more frequently in methylated than in unmethylated patients (61.5% vs 24%, P = .03). The median survival was significantly influenced only by MGMT methylation status determined at first surgery (P = .04). Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. MGMT methylation status determined at first surgery appears to be of prognostic value; however, it is not predictive of outcome following second surgery.

Quantitative proton magnetic resonance spectroscopy of the human cervical spinal cord at 3 tesla

Cervical spinal cord spectroscopy has the potential to add metabolic information to spinal cord MRI and improve the clinical evaluation and research investigation of spinal cord diseases, such as multiple sclerosis (MS) and intraspinal tumors. However, in vivo proton MR spectroscopy (1H‐MRS) of the spinal cord is difficult to perform due to magnetic field inhomogeneities, physiological movements, and the size of the anatomical region of interest (ROI). For these reasons, few spinal cord 1H‐MRS studies have been undertaken and two preliminary studies on a 3T system were only recently presented as abstracts. In this work we demonstrate the feasibility of cervical spinal cord quantitative 1H‐MRS on a clinical 3T system, propose a study protocol, and report quantification results obtained from healthy volunteers. The main metabolite concentration ratios obtained in 10 healthy subjects, as provided by LCModel, were as follows: total N‐acetyl aspartate/creatine (tNAA/Cr) 1.4 ± 0.3, choline/creatine (Cho/Cr) 0.5 ± 0.1, and myoinositol/creatine (mI/Cr) 1.7 ± 0.2. A significant difference was found between spinal cord tNAA, Cr, Cho, and mI concentration ratios and brainstem concentrations previously acquired on the same system. Magn Reson Med 57:160–163, 2007.

Treatment of Intracranial Aneurysms Using Flow-Diverting Silk Stents (BALT): a Single Centre Experience

The Silk stent (Balt, Montmorency, France) is a retractable device designed to achieve curative reconstruction of the parent artery associated with an intracranial aneurysm. We present our initial experience with the Silk flow-diverting stent in the management and follow-up of 25 patients presenting with intracranial aneurysms. Twenty-five patients (age range, 34–81 years; 24 female) were treated with the Silk flow-diverting device. Aneurysms ranged in size from small (5), large (10) and giant (10) and included wide-necked aneurysms, multiple, nonsaccular, and recurrent intracranial aneurysms. Nine aneurysms were treated for headache, 14 for mass effect. None presented with haemorrhage. All patients were pretreated with dual antiplatelet medications for at least 72 hours before surgery and continued taking both agents for at least three months after treatment. A total of 25 Silk stents were used. Control MR angiography and/or CT angiography was typically performed prior to discharge and at one, three, six and 12 months post treatment. A follow-up digital subtraction angiogram was performed between six and 19 months post treatment. Complete angiographic occlusion or subtotal occlusion was achieved in 15 patients in a time frame from three days to 12 months. Three deaths and one major complication were encountered during the study period. Two patients, all with cavernous giant aneurysms, experienced transient exacerbations of preexisting cranial neuropathies and headache after the Silk treatment. Both were treated with corticosteroids, and symptoms resolved completely within a month. In our experience the Silk stent has proven to be a valuable tool in the endovascular treatment of intracranial giant partially thrombosed aneurysms and aneurysms of the internal carotid artery cavernous segment presenting with mass effect. The time of complete occlusion of the aneurysms and the risk of the bleeding is currently not predictable.

Metabolic findings on 3T 1H-MR spectroscopy in peritumoral brain edema.

BACKGROUND AND PURPOSE: Little is known about the metabolic properties of brain edema associated with tumors. This work was conducted on the basis of the assumption that, in the presence of intra-axial and extra-axial brain tumors, the white matter involved by the edema is a site of metabolic change that involves the structure of the myelin sheath. MATERIALS AND METHODS: Thirteen patients comprised our cohort affected by intra-axial and extra-axial cerebral tumors with a peritumoral T2-weighted MR signal hyperintensity as a result of edema, where MR spectroscopy showed no increase in choline-containing compounds. Measurements on proton MR spectroscopy (1H-MR spectroscopy) were performed with a 3T whole-body scanner with use of a point-resolved spectroscopy sequence for localization (TR, 2000 ms; TE, 35 ms), and the metabolites were quantified with the SAGE method. Peak intensities of the main metabolites were expressed as ratios of one another and were compared with values obtained in the white matter of the left frontal region in a control group of 16 healthy volunteers. RESULTS: Choline-to-creatine (Cho/Cr) and myo-inositol-to-creatine (mIns/Cr) signal intensity ratios were normal in all patients. N-acetylaspartate-to-creatine (NAA/Cr) and N-acetylaspartate-to-choline (NAA/Cho) ratios decreased in 4 patients. Glutamate plus glutamine-to-creatine (Glx/Cr) was increased in 10 patients. A resonance peak at 3.44 ppm, strongly suggesting the presence of glucose, was detected in all but 1 patient. Lactate was detected in 12 patients and lipids in 5. Moreover, the resonances that pertained to the aliphatic amino acids valine, leucine, and isoleucine were present in 12 patients. CONCLUSIONS: Our findings on MR spectroscopy confirmed the hypothesis that in the edema surrounding brain tumors, an energy-linked metabolic alteration was associated with injury to the myelin sheath.

A classification tree approach for pituitary adenomas

It is difficult to evaluate the recurrence and progression potential of pituitary adenomas at presentation. The World Health Organization classification of endocrine tumors suggests that invasion of the surrounding structures, size at presentation, an elevated mitotic index, a Ki-67 labeling index higher than 3%, and extensive p53 expression are indicators of aggressive behavior. Nevertheless, Ki-67 and p53 labeling index evaluation is subject to interobserver variability, and their cutoff values are controversial. In the present study, the prognostic value of Ki-67 and p53 protein labeling indices and their correlation with clinical and radiologic parameters were evaluated using digital image analysis in a series of 166 pituitary adenomas in patients having undergone a follow-up of at least 6 years to evaluate the impact on the recurrence and progression potential of pituitary adenomas. The data were analyzed using the receiver operating characteristic curve and classification and regression tree analysis. The results showed that, in the unstratified data set, the commonly used threshold of the Ki-67 index of 3% has a high specificity (89.5%) but a low sensitivity (53.8%). Unsatisfactory performance results were obtained by performing receiver operating characteristic curve analysis on the p53 labeling index. On the contrary, the classification and regression tree analysis-derived tree demonstrated that each pituitary adenoma subtype has specific prognostic factors. Specifically, the Ki-67 labeling index is a useful prognostic factor in nonfunctioning, adrenocorticotropin, and prolactin adenomas, but with different thresholds. In conclusion, our study emphasizes that the term pituitary adenomas includes different types of tumors, each one having specific prognostic factors.

Quantitative Cervical Spinal Cord 3T Proton MR Spectroscopy in Multiple Sclerosis

BACKGROUND AND PURPOSE: Brain proton MR spectroscopy (1H-MR spectroscopy) is a useful technique for evaluating neuronal/axonal damage and demyelization in multiple sclerosis (MS). Because MS disability is frequently related to spinal cord lesions, potential markers for MS stage differentiation and severity would require in vivo quantification of spinal integrity. However, few spectroscopy studies have investigated cervical disease due to technical difficulties. The present study used 3T 1H-MR spectroscopy to measure the main metabolites in cervical spinal cord plaques of a group in patients with relapsing-remitting MS (RRMS) and compared them with metabolite measurements in healthy volunteers. MATERIALS AND METHODS: A 1H-MR point-resolved spectroscopy sequence volume of interest was prescribed along the main axis of the cord between C2 and C3 levels on a plaque in a group of 15 patients with RRMS for a total acquisition time of approximately 14 minutes. MR spectroscopy data were analyzed by the user-independent fitting routine LCModel, and relative metabolite concentrations were expressed by the absolute concentration ratios. A Student t test was used to evaluate the difference compared with the healthy metabolite content previously published. RESULTS: We found a significant decrease of total N-acetylaspartate/choline and an increase in choline/creatine and myo-inositol/creatine content on MS plaques in comparison with healthy cervical spine tissue. CONCLUSIONS: In vivo 1H-MR spectroscopy, if confirmed by other similar studies, should be as reliable for clinical studies as it is in brain imaging. Moreover, 1H-MR spectroscopy allows examination of spinal cord integrity at a biochemical level and may be sensitive to subtle changes occurring during the course of MS disease.

Galectin-3 expression in pituitary adenomas as a marker of aggressive behavior

The purpose of this retrospective study was to investigate the role of galectin-3 (LGALS3) expression in predicting the recurrence and the progression potential of prolactin (PRL) and adrenocorticotropic hormone (ACTH)-producing pituitary adenomas and its correlation with the RUNX1 and RUNX2 transcription factors involved in the regulation mechanism of LGALS3 expression. Clinical, neuroradiologic, and follow-up data from 92 pituitary adenomas, including 59 PRL cell adenomas and 33 ACTH-functioning pituitary adenomas, were collected. The LGALS3 expression was analyzed by both immunohistochemistry and quantitative real time-polymerase chain reaction, whereas RUNX1 and RUNX2 were analyzed by quantitative real time-polymerase chain reaction only. The data obtained indicated that invasive growth with suprasellar extension, Ki-67 labeling index, and LGALS3 immunohistochemical and/or LGALS3 messenger RNA levels are the most important histologic features for assessing a high risk of progression or recurrence of PRL- and ACTH-functioning pituitary adenomas. Multivariate Cox regression analysis assessed LGALS3 immunohistochemical positivity in at least 30% of neoplastic cells and/or LGALS3 messenger RNA positivity (P < .001) as strong predictive factors of recurrence/tumor progression followed by a Ki-67 labeling index greater than 3% (P = .019) in the 81 cases in which follow-up data were available. In addition, a significant correlation between LGALS3 and RUNX1 expression levels (P = .0435) was found. This retrospective immunohistochemical and molecular study demonstrated that LGALS3 expression appeared to be a predictive factor of the aggressive behavior of PRL- and ACTH-functioning pituitary adenomas, and its expression was correlated with RUNX1 expression levels.

Brain functional changes in patients with ulcerative colitis: A functional magnetic resonance imaging study on emotional processing

Background: Ulcerative colitis (UC) is associated with psychological stress and poor emotional functioning. The neural emotional processing involves the complex integration of several cortical and subcortical brain structures. The amygdala plays a fundamental role in the neural processing of emotional stimuli and is a core structure of the brain–gut axis (BGA) that represents the anatomo‐functional substrate for the bidirectional influences between emotions and gastrointestinal functions. The aim of this study was to investigate the brain emotional processing in UC patients compared to healthy people. Methods: Ten UC patients in remission and 10 matched healthy controls underwent a functional magnetic resonance imaging (fMRI) scan while performing a task involving emotional visual stimuli. A set of negative, positive, and neutral pictures were used to study brain‐related emotional responses. Results: A significantly reduced blood oxygen level‐dependent (BOLD) signal in UC patients relative to controls was found in the amygdala, thalamic regions, and cerebellar areas (P < 0.05 corrected for multiple comparisons). The group‐related differences were detected in the brain activity in response to positive emotional stimuli. Conclusions: UC is associated with an emotional dysfunction characterized by decreased sensitivity to emotions with a positive content. The previous intestinal inflammatory activity in UC patients might have contributed to determine the functional changes of the amygdala that we found. On the other hand, the dysfunction of the amygdala may influence the course of the disease. (Inflamm Bowel Dis 2010;)

Complications in the Treatment of Intracranial Aneurysms with Silk Stents: an Analysis of 30 Consecutive Patients

Flow-diverting stents (Silk and PED) have radically changed the approach to intracranial aneurysm treatment from the use of endosaccular materials to use of an extraaneurysmal endoluminal device. However, much debate surrounds the most appropriate indications for the use of FD stents and the problems raised by several possible complications. We analysed our technical difficulties and the early (less than ten days after treatment) and late complications encountered in 30 aneurysms treated comprising 13 giant lesions, 12 large, five with maximum diameters <10 mm and one blister-like aneurysm. In our experience the primary indications for the use of FD stents can be the symptomatic intracavernous giant aneurysms. Although the extracavernous carotid siphon aneurysms have major risk of bleeding, FD stents are indicated clearly explaining the risks to the patient in case of severe mass effect. There is a very complex assessment for aneurysms of the vertebrobasilar circulation.