[Glioblastoma treatment in 2010]. / Traitement des glioblastomes à l'aube de 2010.

The treatment of glioblastomas requires a multidisciplinary approach because despite the progresses in surgical and iconographic managements associated with research knowledge this disease presently remains incurable and progresses during the 6 months after its diagnose. Current recommendations are that patients with glioblastoma should undergo maximum surgical resection followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide, followed subsequently by additional adjuvant temozolomide for a period of up to 6 months. Temozolomide mechanism of action is complex and we have recently evidenced a temozolomide-associated anti-angiogenic activity in vitro and in vivo on preclinical human glioblastoma models. We describe in the current review the temozolomide-associated antiangiogenic activity. We also describe here the major signaling pathways that can be constitutively activated in migrating glioma cells, and which render these cells resistant to proapoptotic insults such as conventional chemotherapies. In light of this resistance, we therefore describe the targeted therapies and local drug delivery systems which could be used to complement conventional treatments. We have reviewed more than 400 ongoing clinical trials with respect to these new targeted therapy approaches alone or in combination for glioblastoma therapy and we also emphasize the importance of vaccinotherapy. We conclude our review with a therapeutic model that could be used in the light of the present knowledge.

Present and potential future adjuvant issues in high-grade astrocytic glioma treatment.

Despite major advances in the management of malignant gliomas of which glioblastomas represent the ultimate grade of malignancy, they remain characterized by dismal prognoses. Glioblastoma patients have a median survival expectancy of only 14 months on the current standard treatment of surgical resection to the extent feasible, followed by adjuvant radiotherapy plus temozolomide, given concomitantly with and after radiotherapy. Malignant gliomas are associated with such dismal prognoses because glioma cells can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management. Clinical and experimental data have demonstrated that invasive malignant glioma cells show a decrease in their proliferation rates and a relative resistance to apoptosis (type I programmed cell death) as compared to the highly cellular centre of the tumor, and this may contribute to their resistance to conventional pro-apoptotic chemotherapy and radiotherapy. Resistance to apoptosis results from changes at the genomic, transcriptional and post-transcriptional level of proteins, protein kinases and their transcriptional factor effectors. The PTEN/ PI3K/Akt/mTOR/NF-kappaB and the Ras/Raf/MEK/ERK signaling cascades play critical roles in the regulation of gene expression and prevention of apoptosis. Components of these pathways are mutated or aberrantly expressed in human cancer, notably glioblastomas. Monoclonal antibodies and low molecular-weight kinase inhibitors of these pathways are the most common classes of agents in targeted cancer treatment. However, most clinical trials of these agents as monotherapies have failed to demonstrate survival benefit. Despite resistance to apoptosis being closely linked to tumorigenesis, tumor cells can still be induced to die by non-apoptotic mechanisms such as necrosis, senescence, autophagy (type II programmed cell death) and mitotic catastrophe. Temozolomide brings significant therapeutic benefits in glioblastoma treatment. Part of temozolomide cytotoxic activity is exerted through pro-autophagic processes and also through the induction of late apoptosis. Autophagy, type II programmed cell death, represents an alternative mechanism to overcome, at least partly, the dramatic resistance of many cancers to pro-apoptotic-related therapies. Another way to potentially overcome apoptosis resistance is to decrease the migration of malignant glioma cells in the brain, which then should restore a level of sensitivity to pro-apoptotic drugs. Recent series of studies have supported the concept that malignant gliomas might be seen as an orchestration of cross-talks between cancer cells, microenvironment, vasculature and cancer stem cells. The present chapter focuses on (i) the major signaling pathways making glioblastomas resistant to apoptosis, (ii) the signaling pathways distinctly activated by pro-autophagic drugs as compared to pro-apoptotic ones, (iii) autophagic cell death as an alternative to combat malignant gliomas, (iv) the major scientific data already obtained by researchers to prove that temozolomide is actually a pro-autophagic and pro-apoptotic drug, (v) the molecular and cellular therapies and local drug delivery which could be used to complement conventional treatments, and a review of some of the currently ongoing clinical trials, (vi) the fact that reducing the levels of malignant glioma cell motility can restore pro-apoptotic drug sensitivity, (vii) the observation that inhibiting the sodium pump activity reduces both glioma cell proliferation and migration, (viii) the brain tumor stem cells as a target to complement conventional treatment.

Plasma acrolein levels and their association with delayed ischemic neurological deficits following aneurysmal subarachnoid haemorrhage: a pilot study.

BACKGROUND: The molecular mechanisms of cerebral vasospasm following aneurysmal subarachnoid haemorrhage (aSAH) remain unclear. Acrolein, a reactive metabolite produced in many models of mechanical and ischemic injury, has been shown to cause vasospasm in coronary artery and aorta models. These traits suggest it may play a role in post-aSAH cerebral vasospasm. This pilot study was designed as a preliminary investigation to determine if acrolein levels could be used as a clinical tool to predict the presence of vasospasm. METHODS: Eleven patients with aSAH and Hunt and Hess admission grades of III-V were prospectively enrolled. Patients were stratified according to the presence or absence of vasospasm, defined as a delayed ischaemic neurological deficit in which all other possible causes have been excluded. Soluble acrolein levels were determined at two times points: early (day 1-3 post-SAH) and late (day 8-12 post-SAH) and the change in acrolein levels over this period was computed using a Mann-Whitney test. RESULTS: The change in acrolein levels over this period between the vasospasm and non-vasospasm group trended toward but did not achieve statistical significance (means: 5.68 versus -5.54; medians: 5.27 versus -3.99; range: -8.067 to 22.904 versus -13.83 to 5.199 p=0.13). Five out of six vasospasm patients showed an increase in acrolein levels over the vasospasm period. Three out of four non-vasospasm patients showed a decrease over the vasospasm period. CONCLUSIONS: The results of this pilot study suggest that acrolein levels increase in patients undergoing vasospasm during the vasospasm window. This suggests that acrolein may play a role in the pathways leading up to or following vasospasm. There is a need for larger more definitive studies.

Surgical anatomy of anterior petrosectomy.

Neurosurgical procedures in the region of the petroclival region of the skull base require unique knowledge of the local anatomy. The measurements of this region considering the visible anatomical landmarks are helpful both during surgery and while planning the general schemes for the approach. We have evaluated the anatomy of the anterior surface of the petrous bone and of the middle fossa taking into consideration the surgical removal of part of the petrous bone--the anterior petrosectomy. We have measured the distances and angles between the chosen structures in this region. The measurements were taken on 10 skulls, on both sides. The results enrich the algorithm of the anterior petrosectomy.

Alterations in respiratory status: early signs of severe necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) presents with well-recognized signs of intestinal inflammation such as bilious vomiting, bloody stool, abdominal distension, and tenderness. The authors observed otherwise unexplained changes in the respiratory status requiring increased respiratory support during the 24 hours before direct evidence of the intestinal disorder in patients with severe NEC. METHODS: To study this observation the authors collected data on 10 consecutive patients in whom NEC required an operation. RESULTS: Eight of these patients were recovering from respiratory distress syndrome (RDS). During the 24 hours before any direct sign of intestinal dysfunction seven of these eight had a respiratory prodrome needing increased respiratory support. Two patients required intubation and mechanical ventilation. Five needed increased supplemental oxygen. This prodrome included decreased oxygenation in seven, increased respiratory rate in five, and increased PCO2 in five, preceded by hypocarbia in three. CONCLUSIONS: These changes in the respiratory condition revisit the concept of high output respiratory failure. This term was introduced to describe the respiratory failure in adult patients who suffer acute intestinal illness. Increased metabolic demand from the intestinal illness was thought to stress the ability of the patient to delivery oxygen and remove carbon dioxide. The ability of the respiratory system to meet the increased demands is limited by the intestinal dysfunction itself (abdominal pain and distension). In our patients recovering from RDS the pulmonary reserve is inherently limited. Because they are carefully monitored, it is easy to retrieve evidence of respiratory changes that precede the direct signs of intestinal disease. In the earliest stages of intestinal illness before the direct signs of intestinal dysfunction, these patients often manifest unexplained signs of respiratory compensation and decompensation and require increased respiratory support. Regardless of the pathophysiology, these alterations in respiratory status represent an early warning sign of NEC.