Giovanni Sabatino

Stem Cell Marker Nestin and c-Jun NH2-Terminal Kinases in Tumor and Peritumor Areas of Glioblastoma Multiforme: Possible Prognostic Implications

Purpose: It has been hypothesized that brain tumors are derived from stem cell or transiently dividing precursor transformation. Furthermore, c-Jun NH2-terminal kinases (JNKs) have been involved in gliomagenesis. This study analyzes stem cell marker nestin and JNK expression in glioblastoma multiforme (GBM) and peritumor tissue and assesses their possible prognostic implications. Experimental Design: Nestin and both total JNK (tJNK) and phosphorylated JNK (pJNK) expression was investigated by immunohistochemistry in 20 GBMs. Samples were derived from tumors (first area), from tissues at a distance <1 cm (second area), and between 1 and 3.5 cm (third area) from the macroscopic tumor border. The relationships between patients age, Karnofsky performance status, gender, protein expression, and survival were analyzed. Results: Nestin cytoplasmic immunoreactivity was observed in the majority of cells in tumor but infrequently in peritumor areas. tJNK, observed in the nucleus and cytoplasm, was widely expressed in the three areas; pJNK, mostly located in the nuclei, was found in a variable percentage of cells in the tumor and peritumor tissue. Nestin and JNK expression in peritumor areas was independent of the presence of neoplastic cells. Univariate analysis indicated that survival was longer (19 versus 12 months; P = 0.01) for patients whose pJNK/nestin and (pJNK/tJNK)/nestin ratios in the second area were ≥2.619 and ≥0.026, respectively. The same variables showed an independent prognostic value in multivariate analysis. Conclusions: Nestin and JNK expression indicates that peritumor tissue, independently of the presence of neoplastic cells, may present signs of transformation. Moreover, pJNK/nestin and (pJNK/tJNK)/nestin ratios in that tissue seem to have some prognostic implications in GBM patients.

Rosette-forming glioneuronal tumour of the fourth ventricle: report of a case with clinical and surgical implications

A 32-year-old woman presented with a 2-month history of episodic headache, cervical pain and neck rigidity. Neurological examination showed a moderate dysmetria. Magnetic resonance imaging (MRI) revealed a mass occupying the fourth ventricle. The patient underwent median sub-occipital craniotomy with total excision of the lesion well demarcated except for a portion infiltrating the right side of the IV ventricle wall. In the post-operative course the patient developed VI and VII right cranial nerves palsy and worsening of dysmetria. MRI confirmed the complete removal of the tumour without signs of recurrence. The pathological diagnosis was rosette forming glio-neuronal tumour (RGNT). At present this is the 13th RGNT reported in literature. These lesions are considered low-grade tumours (WHO I). Nevertheless, the case here reported, like in 6 of the 12 cases in literature, developed disabling post-operative deficits. To establish the therapeutic choice long-term follow-up studies are needed.

Glioblastoma Multiforme in the Elderly: A Therapeutic Challenge

SummaryIntroduction: Elderly patients with glioblastoma multiforme (GBM) are frequently excluded from cancer therapy trials, treated suboptimally or not treated at all. The average survival in elderly patients is 4–8 months. The goal of the present study was to evaluate the efficacy of different treatment options in terms of survival in an elderly population affected with GBM.n Materials and methods: About 34 Patients with primary supratentorial GBM aged 65 or higher were included in this study. All patients underwent craniotomy and tumor mass resection. After surgery they received radiation therapy, chemotherapy and radioimmunotherapy in different combinations.n Results: Overall median survival was 10.5 months with one patient still alive at 35 months. Survival was longer for patients who underwent total resection instead of partial (13 months vs 4 months, P = 0.006). If total en-bloc resection was used a further survival advantage was obtained (16months for en-bloc resection, 9months for inside-out resection, P = 0.008). Where a second surgical intervention was performed median survival was 21 months (P = 0.05). Survival according to adjuvant therapy has been 21 months (radiotherapy, chemotherapy, radioimmunotheraphy), 18 months (radiotherapy, chemotherapy) and 7 months (radiotherapy) (P = 0.0001).n Conclusions: We think that single prognostic factor such as age should be not a reason for undertreatment.

Clivus metastases: report of seven patients and literature review.

BackgroundTumours of the clivus are rare and metastases involving this area have been previously described only as single case reports or included in series with other skull base tumours. Here, we describe seven such examples and review the pertinent literature.MethodClinical, radiological and follow-up data of patients who had undergone surgery for clivus tumours at our Institution between January 1995 and December 2007 were retrospectively collected. A literature review was performed using PubMed.FindingsOf 46 patients who underwent surgery for clivus bone tumours, seven proved to harbour a metastasis. This figure represents 0.18% and 0.42% respectively of intracranial and skull base tumours which were treated in our Institution in the study period. The primary tumours associated were lung adenocarcinoma (nu2009=u20092), prostate carcinoma (nu2009=u20092), skin melanoma (nu2009=u20091), hepatocarcinoma (nu2009=u20091) and lung squamous cell carcinoma (nu2009=u20091). All patients presented with a sixth nerve palsy as the symptom. Histopathology was obtained via a trans-sphenoidal biopsy. In spite of radiotherapy and chemotherapy, the mean survival was 12xa0months. On literature review, 27 examples of metastases located in the clival bone were found. Including our series, the most common primary tumours were prostate cancer (26.4%), thyroid carcinoma (11.7%) and hepatocarcinoma (11.7%).ConclusionThough exceedingly rare, metastases involving the clivus should be considered in the differential diagnosis with clivus chordoma. The metastatic lesion might be a late and single expression of the primary tumour. The trans-sphenoidal approach is the ideal procedure to establish a histopathological diagnosis. Prognosis is poor.

Gene Expression Profile of Glioblastoma Peritumoral Tissue: An Ex Vivo Study

The gene expression pattern of glioblastoma (GBM) is well documented but the expression profile of brain adjacent to tumor is not yet analysed. This may help to understand the oncogenic pathway of GBM development. We have established the genome-wide expression profiles of samples isolated from GBM tumor mass, white matter adjacent to tumor (apparently free of tumor cells), and white matter controls by using the Affymetrix HG-U133 arrays. Array-CGH (aCGH) was also performed to detect genomic alterations. Among genes dysregulated in peritumoral white matter, 15 were over-expressed, while 42 were down-regulated when compared to white matter controls. A similar expression profile was detected in GBM cells. Growth, proliferation and cell motility/adhesion-associated genes were up-regulated while genes involved in neurogenesis were down-regulated. Furthermore, several tumor suppressor genes along with the KLRC1 (a member of natural killer receptor) were also down-regulated in the peritumoral brain tissue. Several mosaic genomic lesions were detected by aCGH, mostly in tumor samples and several GBM-associated mosaic genomic lesions were also present in the peritumoral brain tissue, with a similar mosaicism pattern. Our data could be explained by a dilution of genes expressed from tumor cells infiltrating the peritumour tissue. Alternatively, these findings could be substained by a relevant amount of “apparently normal” cells presenting a gene profile compatible with a precancerous state or even “quiescent” cancer cells. Otherwise, the recurrent tumor may arise from both infiltrating tumor cells and from an interaction and recruitment of apparently normal cells in the peritumor tissue by infiltrating tumor cells.

Antibiotic-impregnated ventriculo-peritoneal shunts in patients at high risk of infection.

PurposeTo determine the efficacy of antibiotic impregnated shunts (AIS) in reducing shunt infections in a population at high risk of shunt infection.MethodsFrom October 2005 to October 2007, patients at high risk of infection (severely disabled, not able to take care of themselves, frequent nosocomial infections) were selected from the 198 adults who underwent shunt placement.ResultsEighteen adults were identified (mean age 61.8xa0years). Six patients had AISs, and 12 patients had non-AISs. Groups did not differ in age, sex, type of hydrocephalus or hospital stay before shunting. Shunt infection occurred in 7/12 cases of the non-AIS group (58.3%) versus no infections in the AIS group. In six of seven cases, infection occurred within the first 6 months after surgery. A prevalence of S. epidermidis was detected.ConclusionsWe believe that in these patients AIS could be effective. Larger, prospective studies are needed in order to definitely address this issue.

Diagnosis and management of dural arteriovenous fistulas: A 10 years single-center experience

OBJECTIVESnDural arteriovenous fistulas (DAVFs) are a challenging condition in vascular neurosurgery. Disease natural history and its management is still debated. In the present paper we report our center series on DAVFs over a period of 10 years. Our data were compared with relevant literature.nnnPATIENT AND METHODSnOur series includes 45 cases: 14 cavernous sinus, 11 transverse-sigmoid, 8 patients tentorial, 6 anterior cranial fossa, 5 patients spinal, 1 patient foramen magnum.nnnRESULTS AND CONCLUSIONSnDVAFs distribution, clinical presentation and hemorrhagic risk are discussed. Cavernous sinus DAVFs are the most common site in our series. Other locations in order of frequency are transverse-sigmoid sinus, tentorial, anterior cranial fossa, spinal and foramen magnum. The majority of patients presented with non-aggressive symptoms. 18% presented with intracranial hemorrhage: all the hemorrhages occurred in high-grade DAVFs. For most patients, endovascular treatment, transarterial or transvenous, was the first option. Surgery was performed for the anterior cranial fossa DAVFs and other complex lesions draining mostly transverse-sigmoid sinus and tentorium. In 7% of cases a combination of endovascular+surgical treatment was used. Our series has been carefully analyzed in comparison side by side with most relevant literature on DVAFs, focusing particularly on management strategies, therapeutic options and risks related to treatment.

Indocyanine green video-angiography in neurosurgery: A glance beyond vascular applications

OBJECTIVEnIndocyanine green video angiography (ICG-VA) is a non invasive, easy to use and a very useful tool for various neurosurgical procedures. Initially introduced in vascular neurosurgery since 2003, its applications have broadened over time, both in vascular applications and in other neurosurgical fields. The objective of our study is to review all published literature about ICG-VA, cataloguing its different applications.nnnMETHODSnA systematic review of all pertinent literature articles published from January 2003 to May 2014 using Pubmed access was performed using pertinent keywords; cross check of references of selected articles was performed in order to complete bibliographical research. Results of research were grouped by pathology.nnnRESULTS AND CONCLUSIONSnThe paper systematically analyses ICG-VA different applications in neurosurgery, from vascular neurosurgery to tumor resection and endoscopic applications, focusing on reported advantages and disadvantages, and discussing future perspectives.

Intratumoral vs systemic administration of meta-tetrahydroxyphenylchlorin for photodynamic therapy of malignant gliomas: assessment of uptake and spatial distribution in C6 rat glioma model.

Malignant gliomas, with an incidence of 5 cases per 100,000 population per year, represent the most common primary brain tumour. They have an overall survival length of less than 2 years. Many different adjuvant therapies have been developed. Among them, Photodynamic Therapy (PDT), that is based on photochemical reactions between light and tumoral tissue selectively labelled with exogenous photosensitizing agents. Among photosensitizers, m-THPC (Temoporfin), seems to be the most promising one for the treatment of brain tumors, but, unfortunately, it causes problems of high skin photosensitivity. To by-pass this problem, we devised an intratumoral route of administration of this photosensitizer. The aim of this study is to investigate and compare the uptake of m-THPC in brain tumor and normal tissue after systemic and intratumoral administration of the drug. 30 female Wistar rats received m-THPC 12 days after C6 tumor implantation. Temoporfin was administered intratumorally in 24 rats at two different concentrations. 6 rats constituted the control group and received m-THPC by means of an intraperitoneal injection. The brains were extracted at 4 h, 24 h and 96 h after Temoporfin injection. The samples were examined with a confocal laser scanning microscope. All samples showed high fluorescence emission exclusively in the tumour area, without appreciable differences between the samples taken at the different times of sacrifice and the two routes of administration. No fluorescence whatsoever was detected among normal brain tissue surrounding the tumour. The intratumoral route appears to give comparable results to the systemic one, regarding intracellular uptake efficiency and tumour - normal tissue ratio, with the advantage of a much shorter time needed to reach optimal intratumoural concentration - that is just four hours from m-THPC injection.

Neonatal diagnosis of tuberous sclerosis

Intracranial tumors are rare in the neonatal period, and generally the most common histological types are astrocytoma, medulloblastoma, choroid plexus papilloma and neuroectodermal tumors. The early diagnosis of these tumors is often very difficult. The authors report a case of a full-term newborn who presented with opisthotonus. A subependymal mass was detected by cerebral ultrasonography, and when the child was 1 month of age depigmentations appeared on the trunk and on the right leg, confirming the suspicion of tuberous sclerosis. At 3 months of age the child suffered infantile spasm with hypsarrhythmia. The developmental delay, the marked progressive neurological deterioration and the daily seizures suggested surgical resection. Histologic studies showed a subependymal giant cell astrocytoma such as typically occurs in tuberous sclerosis.