Pasquale Gallina

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

Recent studies have led to considerable advancement in our understanding of the molecular mechanisms that underlie the relentless cell growth and invasiveness of human gliomas. Partial understanding of these mechanisms has (1) improved the classification for gliomas, by identifying prognostic subgroups, and (2) pointed to novel potential therapeutic targets. Some classes of ion channels have turned out to be involved in the pathogenesis and malignancy of gliomas. We studied the expression and properties of K+ channels in primary cultures obtained from surgical specimens: human ether a gò-gò related (hERG)1 voltage-dependent K+ channels, which have been found to be overexpressed in various human cancers, and human ether a gò-gò-like 2 channels, that share many of hERG1s biophysical features. The expression pattern of these two channels was compared to that of the classical inward rectifying K+ channels, IRK, that are widely expressed in astrocytic cells and classically considered a marker of astrocytic differentiation. In our study, hERG1 was found to be specifically overexpressed in high-grade astrocytomas, that is, glioblastoma multiforme (GBM). In addition, we present evidence that, in GBM cell lines, hERG1 channel activity actively contributes to malignancy by promoting vascular endothelial growth factor secretion, thus stimulating the neoangiogenesis typical of high-grade gliomas. Our data provide important confirmation for studies proposing the hERG1 channel as a molecular marker of tumour progression and a possible target for novel anticancer therapies.

Failure in Radiosurgery Treatment of Cerebral Arteriovenous Malformations

OBJECTIVE The aim of this study was to retrospectively analyze the reasons for the failure of radiosurgical treatment of cerebral arteriovenous malformations (AVMs). METHODS Seventeen cases of noncured AVMs were reviewed 3 years after radiosurgical treatment. Follow-up ranged from 33 to 54 months (mean, 44.3 mo). Lesion dimensions varied from 9 to 55 mm (mean, 29.2 mm). The lesions were located in critical or near-critical brain regions. Angiography was performed under Talairachs stereotactic conditions. Two large AVMs bled 36 and 39 months after receiving irradiation, respectively. These two AVMs had been incompletely irradiated. RESULTS Retrospectively, in four cases (23.5%) we observed errors in determining AVM target shape and size because of inaccurate definition of the nidus and/or because of stereoangiographic incompleteness (absence of external carotid artery injections). In five large and/or irregularly shaped AVMs (29.4%), a strategy of partial volume irradiation had been used. In one patient (5.8%), we observed the recanalization of previously embolized AVMs. In another case (5.8%), the target had been partially missed. The AVMs in one case (5.8%) had been treated with an ineffective peripheral dose. In one (5.8%), the failure occurred because of the lesion angio-architecture. In four cases (23.5%), no evident reasons for failure were determined. CONCLUSION The results of this study suggest the necessity of complete irradiation of the nidus. The strategy of partial volume irradiation might be avoided, even if it necessitates lowering the doses to treat large AVMs. Accuracy in the target determination is required, and complete stereoangiography is necessary.

Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation.

Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntingtons disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.

Evaluation of the anterior pituitary function in the acute phase after spontaneous subarachnoid hemorrhage

Background: Subarachnoid hemorrhage (SAH) is a potential cause of hypopituitarism. Most of the studies regarding the relationship between SAH and anterior pituitary function were retrospective and hormonal assessment was performed several months after SAH. Aim: To prospectively evaluate the prevalence of anterior pituitary hormone deficiencies in the acute phase after spontaneous SAH and their possible correlation with clinical and radiological parameters. Methods: Pituitary function was tested in 60 patients within 72 h after spontaneous SAH. Results: 56.9% of the patients showed at least one anterior pituitary hormone deficiency: gonadotropin and GH secretion failure represented the most prevalent hormonal deficiencies (33.3 and 22.0%, respectively), whereas ACTH and TSH deficiency was less frequent (7.1 and 1.8%, respectively). With the exception of secondary hypogonadism, the prevalence of other pituitary hormone deficiencies is in agreement with previous studies, which evaluated pituitary function on long-term follow up after SAH. No correlation was found between hypopituitarism and clinical status, as assessed with Hunt-Hess and Glascow Coma Scales. Moreover, no correlation was found between hypopituitarism and bleeding severity evaluated with Fisher’s scale. Conclusions: We demonstrated a high prevalence of anterior pituitary hormone deficiencies acutely after SAH. Although part of GH and gonadotropin deficiencies might be a consequence of functional alteration due to SAH itself, the finding of low cortisol levels in this stressful condition strongly suggests the presence of true hypocortisolism. Therefore, an evaluation of pituitary function shortly after SAH might be useful to identify a subset of patients who deserve a more accurate follow-up.

Neuronavigation accuracy dependence on CT and MR imaging parameters: a phantom-based study

Clinical benefits from neuronavigation are well established. However, the complexity of its technical environment requires a careful evaluation of different types of errors. In this work, a detailed phantom study which investigates the accuracy in a neuronavigation procedure is presented. The dependence on many different imaging parameters, such as field of view, slice thickness and different kind of sequences (sequential and spiral for CT, T1-weighted and T2-weighted for MRI), is quantified. Moreover, data based on CT images are compared to those based on MR images, taking into account MRI distortion. Finally, the contributions to global accuracy coming from image acquisition, registration and navigation itself are discussed. Results demonstrate the importance of imaging accuracy. Procedures based on CT proved to be more accurate than procedures based on MRI. In the former, values from 2 to 2.5 mm are obtained for 95% fractiles of cumulative distribution of Euclidean distances between the intended target and the reached one while, in the latter, the measured values range from 3 to 4 mm. The absence of imaging distortion proved to be crucial for registration accuracy in MR-based procedures.

Fetal striatal grafting slows motor and cognitive decline of Huntington's disease

Objective To assess the clinical effect of caudate-putaminal transplantation of fetal striatal tissue in Huntingtons disease (HD). Methods We carried out a follow-up study on 10 HD transplanted patients and 16 HD not-transplanted patients. All patients were evaluated with the Unified HD Rating Scale (UHDRS) whose change in motor, cognitive, behavioural and functional capacity total scores were considered as outcome measures. Grafted patients also received morphological and molecular neuroimaging. Results Patients were followed-up from disease onset for a total of 309.3 person-years (minimum 5.3, median 11.2 years, maximum 21.6 years). UHDRS scores have been available since 2004 (median time of 5.7 years since onset, minimum zero, maximum 17.2 years). Median post-transplantation follow-up was 4.3 years, minimum 2.8, maximum 5.1 years. Adjusted post-transplantation motor score deterioration rate was reduced compared to the pretransplantation period, and to that of not-transplanted patients by 0.9 unit/years (95% CI 0.2 to 1.6). Cognitive score deterioration was reduced of 2.7 unit/years (95% CI 0.1 to 5.3). For grafted patients the 2-year post-transplantation [18F]fluorodeoxyglucose positron emission tomography (PET) showed striatal/cortical metabolic increase compared to the presurgical evaluation; 4-year post-transplantation PET values were slightly decreased, but remained higher than preoperatively. [123I]iodobenzamide single photon emission CT demonstrated an increase in striatal D2-receptor density during postgrafting follow-up. Conclusions Grafted patients experienced a milder clinical course with less pronounced motor/cognitive decline and associated brain metabolism improvement. Life-time follow-up may ultimately clarify whether transplantation permanently modifies the natural course of the disease, allowing longer sojourn time at less severe clinical stage, and improvement of overall survival.

Cerebellar liponeurocytoma : Morphological, immunohistochemical, and ultrastructural study of a relapsed case

Cerebellar liponeurocytoma is a rare and newly identified neoplasm  found  in  adults  which  is  reputed  to  be benign. Its salient morphological characteristics are advanced neuronal/neurocytic differentiation, the presence of lipomatous areas, low mitotic rate, and the absence of necrosis, pleomorphism and vascular hyperplasia. Reported is a case of relapsing liponeurocytoma which occurred 3 and a half years after the radical excision of the primary lesion. Histopathological aggressive features (mitoses and a high proliferation index as evaluated by MIB‐1) were shown in the primary lesion and recurrence of the tumor. We suggest that liponeurocytoma is an uncertain malignant potential lesion when mitoses are present and the MIB‐1 positive cells are more than 10%.

Changes in Aqueductal CSF Stroke Volume in Shunted Patients with Idiopathic Normal-Pressure Hydrocephalus

BACKGROUND AND PURPOSE: Aqueductal CSF stroke volume (ACSV) measured by phase-contrast MR imaging is a tool for selection of surgical patients with idiopathic normal-pressure hydrocephalus (iNPH). The aim of the present study was to investigate whether there is a relationship between clinical outcome and changes in ACSV in patients with iNPH who have been shunted. MATERIALS AND METHODS: Sixty-five shunted patients with iNPH underwent clinical evaluation and ACSV measurements 7–30 days before and 1, 3, 6, and 12 months after surgery. RESULTS: Two patients were excluded from the study for the occurrence of a perioperative complication. In a group of 35 clinically improved patients, the mean preoperative ACSV (157.01 μL) decreased to 18% one month after ventriculoperitoneal shunt (VPS) and ≤49% at 12 months post-VPS. In a group of 15 unimproved patients, the lower mean preoperative ACSV (84.2 μL) decreased to 14.3% one month post-VPS and ≤34% at 12 months post-VPS. In the other 8 improved patients who developed a subdural fluid collection (SDFC), ACSV values decreased by 43%–75% in the 3 months post-VPS. A postoperative ACSV increase was noted in 6 patients with a shunt system malfunction. One patient experienced both SDCF and shunt malfunction. CONCLUSIONS: ACSV decreases in all patients in whom the VPS system works properly, with the rate of ACSV decrease being higher in the patients who show clinical improvement. Postoperative ACSV increase suggests shunt malfunction. A precipitous drop of ACSV values after VPS may be the consequence of increased drainage and herald the occurrence of SDFC.

Cyclooxygenase-2 in oligodendroglioma: Possible prognostic significance

Cyclooxygenase‐2 (COX‐2) is the inducible form of the enzyme involved in the first two steps of the prostaglandins and thromboxane synthesis. Up‐regulation of COX‐2 is demonstrated in tumors where it can modulate tumoral progression, metastasis, multidrug resistance and angiogenesis. Selective COX‐2 inhibitors are seen with growing interest in the tumors treatment. This present study reviews the COX‐2 expression in 32 primary oligodendrogliomas (24 WHO II; eight WHO III) and two glioblastomas with prominent oligodendroglial features (WHO IV). Immunohistochemical results were compared with survival in order to verify the COX‐2 prognostic significance. COX‐2 positivity was found in 44% tumors. Median survival of the patients with a COX‐2 positive lesion was 37 months; median survival of the patients with a COX‐2 negative lesion was 93 months (P = 0.010). Twenty‐nine percent WHO grade II tumors, 87% WHO grade III, 50% WHO grade IV resulted COX‐2 positive (P = 0.016). In patients affected by WHO grade II oligodendroglioma, median survival was 24 and 96 months, respectively, in COX‐2 positive and negative lesions (P = 0.012). In conclusion, even if further studies on different, homogeneous and larger series in vivo are certainly necessary, it is believed that COX‐2 could really have a prognostic value and can be considered as a possible therapeutic opportunity.

Multifaceted roles of BDNF and FGF2 in human striatal primordium development. An in vitro study.

Grafting fetal striatal cells into the brain of Huntingtons disease (HD) patients has raised certain expectations in the past decade as an effective cell-based-therapy for this devastating condition. We argue that the first requirement for successful transplantation is defining the window of plasticity for the striatum during development when the progenitor cells, isolated from their environment, are able to maintain regional-specific-identity and to respond appropriately to cues. The primary cell culture from human fetal striatal primordium described here consists of a mixed population of neural stem cells, neuronal-restricted progenitors and striatal neurons. These cells express trophic factors, such as BDNF and FGF2. We show that these neurotrophins maintain cell plasticity, inducing the expression of neuronal precursor markers and cell adhesion molecules, as well as promoting neurogenesis, migration and survival. We propose that BDNF and FGF2 play an important autocrine-paracrine role during early striatum development in vivo and that their release by fetal striatal grafts may be relevant in the setting of HD cell therapy.