Pasquale De Bonis

The EphA2 Receptor Drives Self-Renewal and Tumorigenicity in Stem-Like Tumor-Propagating Cells from Human Glioblastomas

In human glioblastomas (hGBMs), tumor-propagating cells with stem-like characteristics (TPCs) represent a key therapeutic target. We found that the EphA2 receptor tyrosine kinase is overexpressed in hGBM TPCs. Cytofluorimetric sorting into EphA2(High) and EphA2(Low) populations demonstrated that EphA2 expression correlates with the size and tumor-propagating ability of the TPC pool in hGBMs. Both ephrinA1-Fc, which caused EphA2 downregulation in TPCs, and siRNA-mediated knockdown of EPHA2 expression suppressed TPCs self-renewal ex vivo and intracranial tumorigenicity, pointing to EphA2 downregulation as a causal event in the loss of TPCs tumorigenicity. Infusion of ephrinA1-Fc into intracranial xenografts elicited strong tumor-suppressing effects, suggestive of therapeutic applications.

Post-Traumatic Hydrocephalus after Decompressive Craniectomy: An Underestimated Risk Factor

The incidence of post-traumatic hydrocephalus (PTH) has been reported to be 0.7-51.4%, and we have frequently observed the development of PTH in patients undergoing decompressive craniectomy (DC). For this reason we performed a retrospective review of a consecutive series of patients undergoing DC after traumatic brain injury (TBI). From January 2006 to December 2009, 41 patients underwent DC after closed head injury. Study outcomes focused specifically on the development of hydrocephalus after DC. Variables described by other authors to be associated with PTH were studied, including advanced age, the timing of cranioplasty, higher score on the Fisher grading system, low post-resuscitation Glasgow Coma Scale (GCS) score, and cerebrospinal fluid (CSF) infection. We also analyzed the influence of the area of craniotomy and the distance of craniotomy from the midline. Logistic regression was used with hydrocephalus as the primary outcome measure. Of the nine patients who developed hydrocephalus, eight patients (89%) had undergone craniotomy with the superior limit <25 mm from the midline. This association was statistically significant (p = 0.01 - Fishers exact test). Logistic regression analysis showed that the only factor independently associated with the development of hydrocephalus was the distance from the midline. Patients with craniotomy whose superior limit was <25 mm from the midline had a markedly increased risk of developing hydrocephalus (OR = 17). Craniectomy with a superior limit too close to the midline can predispose patients undergoing DC to the development of hydrocephalus. We therefore suggest performing wide DCs with the superior limit >25 mm from the midline.

Cranial repair: how complicated is filling a "hole"?

In general, cranioplasty is viewed as a straightforward surgical procedure, and for many years the complications associated with the procedure have been underestimated. We reviewed our 5-year experience consisting of 218 cranioplasties. Study outcomes focused specifically on the occurrence of complications after cranioplasty. Autologous bone-assisted and prosthetic cranioplasties were considered. Variables described by other authors to be associated with complications were studied, including history of previous cranioplasty, wider craniectomy size, bifrontal craniectomy, and delayed cranioplasty. We also analyzed the influence of material used for craniectomy on the occurrence of complications. The overall complication rate was 19.7%. Nineteen cases of infection (8.7%), 5 cases of postoperative wound dehiscence (2.3%), 6 cases of epidural hemorrhage (2.8%), and 13 cases of cranioplasty dislocation (5.9%) were observed. Bifrontal cranioplasties were more frequently associated with complications (p=0.01; Fishers exact test) and infection (p<0.0001; Fishers exact test). Postoperative wound dehiscence was more frequently observed with hand-made or custom-made cranioplasties compared with autologous cranioplasties (p=0.02). Early cranioplasty (<3 months from craniectomy) was significantly associated with cranioplasty dislocation (p=0.03). Logistical regression analysis showed that the only factor independently associated with complication was the site of cranioplasty (p=0.01). In particular, patients with a bifrontal cranioplasty had a 2-fold increased risk of complication (CI 95 1.1-3.6, p=0.017) and a 2.5-fold increased risk of developing infection (CI 95 1.3-4.9, p=0.009) compared with hemispheric/bihemispheric cranioplasty. Our analysis confirms that cranioplasty is burdened by a significant complication rate. In this context, bifrontal cranioplasty is related to a higher risk of complication and, in particular, infection.

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma

BackgroundCombining Gliadel wafers and radiochemotherapy with TMZ may carry the risk of increased adverse events (AE). We analyzed the efficacy and safety in patients with glioblastoma who underwent multimodal treatment with implantation of Gliadel wafers.MethodsOne hundred sixty-five consecutive patients with newly diagnosed (77 patients) or recurrent (88 patients) glioblastoma were studied. Forty-seven patients underwent surgery + Gliadel. The impact of age (≥65 vs. <65), resection extent (gross total vs. partial), use of Gliadel and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on overall survival (OS, for patients with newly diagnosed glioblastoma) and on recurrence-survival (for patients with recurrent glioblastoma) was analyzed with Cox regression. The impact of age, history (newly diagnosed vs. recurrent glioblastoma), number of Gliadel wafers implanted (0 vs. <8 vs. 8), resection extent (gross-total vs. partial) and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on the occurrence of AE and on the occurrence of implantation site-related AE (ISAE) was analyzed with the logistic regression model. Significance was set at p < 0.05.ResultsMultivariate analysis showed the only factor associated with longer survival, both for newly diagnosed and for recurrent GBM, was resection extent. Both patients with a higher number of wafers implanted and patients with recurrent tumors were significantly at risk for AE and ISAE. Patients with eight Gliadel wafers implanted had a 3-fold increased risk of AE and a 5.6-fold increased risk of ISAE, and patients with recurrent tumor had a 2.8-fold increased risk of AE and a 9.3-fold increased risk of ISAE.ConclusionsAdding Gliadel to standard treatment did not significantly improve the outcome. The toxicity after Gliadel use was significantly higher, both for patients with newly diagnosed and patients with recurrent glioblastoma.

Invasive tumor cells and prognosis in a selected population of patients with glioblastoma multiforme

After surgical resection, the residual, invasive glioblastoma (GBM) cells give rise to a recurrent tumor, which, in 96% of patients, arises adjacent to the resection margin.

Single-Arm Phase II Study of Conformal Radiation Therapy and Temozolomide plus Fractionated Stereotactic Conformal Boost in High-Grade Gliomas

Purpose:To assess survival, local control and toxicity using fractionated stereotactic conformal radiotherapy (FSCRT) boost and temozolomide in high-grade gliomas (HGGs).Patients and Methods:Patients affected by HGG, with a CTV1(clinical target volume, representing tumor bed ± residual tumor + a margin of 5 mm) ≤ 8 cm were enrolled into this phase II study. Radiotherapy (RT, total dose 6,940 cGy) was administered using a combination of two different techniques: three-dimensional conformal radiotherapy (3D-CRT, to achieve a dose of 5,040 or 5,940 cGy) and FSCRT boost (19 or 10 Gy) tailored by CTV1diameter (≤ 6 cm and > 6 cm, respectively). Temozolomide (75 mg/m2) was administered during the first 2 or 4 weeks of RT. After the end of RT, temozolomide (150–200 mg/m2) was administered for at least six cycles. The sample size of 41 patients was assessed by the single proportion–powered analysis.Results:41 patients (36 with glioblastoma multiforme [GBM] and five with anaplastic astrocytoma [AA]) were enrolled; RTOG neurological toxicities G1–2 and G3 were 12% and 3%, respectively. Two cases of radionecrosis were observed. At a median follow-up of 44 months (range 6–56 months), global and GBM median overall survival (OS) were 30 and 28 months. The 2-year survival rate was significantly better compared to the standard treatment (63% vs. 26.5%; p < 0.00001). Median progression-free survival (PFS) was 11 months, in GBM patients 10 months.Conclusion:FSCRT boost plus temozolomide is well tolerated and seems to increase survival compared to the standard treatment in patients with HGG.ZusammenfassungZiel:Untersuchung von Uberleben, lokaler Tumorkontrolle und Toxizitat einer fraktionierten stereotaktischen konformalen Strahlentherapie (FSCRT) mit Boostbestrahlung in Kombination mit Temozolomid bei hochmalignen Gliomen (HMG).Patienten und Methodik:Patienten mit HMG und einem CTV1(klinisches Zielvolumen, d. h. Tumorbett ± Resttumor + einem Sicherheitsabstand von 5 mm) ≤ 8 cm wurden in diese Phase-II-Studie eingeschlossen. Die Strahlentherapie (Gesamtdosis 6 940 cGy) wurde als Kombination aus zwei unterschiedlichen Techniken appliziert: dreidimensionale konformale Strahlentherapie (3D-CRT, um eine Strahlendosis von 5 040 oder 5 940 cGy zu erreichen) und lokale Dosisaufsattigung mit FSCRT-Boost (19 oder 10 Gy), die auf den CTV1-Durchmesser (≤ 6 cm bzw. > 6 cm) zugeschnitten war. Temozolomid (75 mg/m2) wurde wahrend der ersten 2 oder 4 Wochen der Strahlentherapie verabreicht. Nach dem Ende der Strahlentherapie erhielten die Patienten Temozolomid (150–200 mg/m2) fur wenigstens sechs Zyklen. Die Fallzahl wurde mit Hilfe eines einfach-proportionalen Testverfahrens („single proportion-powered analysis“) bei 41 Patienten bestimmt.Ergebnisse:41 Patienten (36 mit Glioblastoma multiforme [GBM] und funf mit anaplastischem Astrozytom [AA]) wurden behandelt; Neurotoxizitat gemas RTOG-Skala G1–2 bzw. G3 wurde in 12% bzw. 3% der Patienten beobachtet. Zwei Falle von Radionekrose traten auf. Bei einer mittleren Beobachtungszeit von 44 Monaten (Range 6–56 Monate) lagen die mittlere Gesamt- und die GBM-spezifische Uberlebenszeit (OS) bei 30 und 28 Monaten. Die 2-Jahres-Uberlebensrate war signifikant besser im Vergleich zur Standardbehandlung (63% vs. 26,5%; p < 0.00001). Die mittlere progressionsfreie Uberlebenszeit (PFS) betrug 11 Monate, bei GBM-Patienten 10 Monate.Schlussfolgerung:FSCRT-Boostbestrahlung plus Temozolomid wird gut toleriert und scheint im Vergleich zur Standardbehandlung die Uberlebenszeit von Patienten mit HMG zu verbessern.

Glioblastoma therapy: going beyond Hercules Columns

Glioblastoma multiforme is the most common primary brain tumor in adults. Median survival from the time of diagnosis is 14 months, with less than 5% of patients surviving 5 years. Despite advances in deciphering the complex biology of these tumors, the overall prognosis has only slightly improved in the past three decades. The clinical failure of many therapeutic approaches can be explained by the following considerations: the location of tumors within the brain presents a special set of challenges, including ability of drugs to cross the BBB; cancer cells have unstable genetic structures, very susceptible to mutations; cancer cells have an amalgam of different genetic defects that respond in different ways to any given treatment agent; and, infiltrating and apparently normal but ‘activated’ cells are evident in the brain surrounding the main tumor. In this way, the biologic phenomena of the ‘normal brain’ adjacent to the enhanced tumor could allow us to understand the first steps of cancerogenesis and, consequently, to interfere with the pathways responsible for tumor growth and recurrence.

Antiplatelet/Anticoagulant Agents and Chronic Subdural Hematoma in the Elderly

Background and Purpose In the last decade there has been an increasing use of antiplatelet/anticoagulant agents in the elderly. The aim of the study was to evaluate the association between exposure to anticoagulant/antiplatelet therapy and chronic subdural haematoma-CSDH. Methods Single institution case-control study involving 138786 patients older than 60 years who visited our academic tertiary care Emergency Department from January 1st 2001 to December 31st 2010. 345 patients with CSDH (cases) were identified by review of ICD-9 codes 432.1 and 852.2x. Case and controls were matched with a 1∶3 ratio for gender, age (±5 years), year of admission and recent trauma. A conditional logistic model was built. A stratified analysis was performed with respect to the presence (842 patients) or absence (536 patients) of recent trauma. Results There were 345 cases and 1035 controls. Both anticoagulant and antiplatelet agents were associated with an increased risk of CSDH with an OR of 2.46 (CI 95% 1.66–3.64) and 1.42 (CI 95% 1.07–1.89), respectively. OR was 2.70 (CI 95% 1.75–4.15), 1.90 (CI 95% 1.13–3.20), and 1.37(CI 95% 0.99–1.90) for patients receiving oral anticoagulants, ADP-antagonists, or Cox-inhibitors, respectively. History of recent trauma was an effect modifier of the association between anticoagulants and CSDH, with an OR 1.71 (CI 95% 0.99–2.96) for patients with history of trauma and 4.30 (CI 95% 2.23–8.32) for patients without history of trauma. Conclusions Anticoagulant and antiplatelet therapy have a significant association with an increased risk of CSDH. This association, for patients under anticoagulant therapy, appears even stronger in those patients who develop a CSDH in the absence of a recent trauma.

Decompressive craniectomy for elderly patients with traumatic brain injury: it's probably not worth the while

Decompressive craniectomy (DC) has been regarded as an ultima ratio measure in the treatment of refractory intracranial hypertension after brain injury. Most discussion about its benefits is based on studies performed in patients who are <65 years of age. The aim of this study was to identify patients aged ≥66 years who underwent DC after traumatic brain injury (TBI), in order to assess patient outcome and to correlate the values of potential predictors of survival on prognosis. From January 2002 to December 2009, 44 patients aged ≥66 underwent DC (follow-up, 12-102 months). Potential predictors of outcome were analyzed, including age, post-resuscitation Glasgow Coma Scale (GCS) score, presence of mass lesion, Simplified Acute Physiology Score (SAPS) II, Injury Severity Score (ISS), and timing of surgical decompression. Mortality was 48% at discharge from the intensive care unit (ICU), 57% at hospital discharge, and 77% at 1-year follow-up and at last follow-up. A bad outcome Glasgow Outcome Scale Dead-Vegetative State-Severely Disabled (GOS D-VS-SD) was observed in 36/44 patients both at hospital discharge and at 1-year follow-up. Mean SAPS II was 45.2 for patients who survived and 57.3 for patients who had died (p=0.0022). Patients who survived had a higher mean post-resuscitation GCS score (p=0.02). Logistical regression analysis indicated post-resuscitation GCS score as the only independent predictive factor for outcome. None of the 22 patients with a post-resuscitation GCS score of 3-5 had a good outcome, 2/10 (20%) patients with a post-resuscitation GCS score of 6-8 and 6/12 patients (50%) with a post-resuscitation GCS score ≥9 had a good outcome.

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.