Alexander Brawanski

Bio: Alexander Brawanski is an academic researcher from University of Regensburg. The author has contributed to research in topics: Subarachnoid hemorrhage & Cerebral blood flow. The author has an hindex of 43, co-authored 232 publications receiving 7022 citations. Previous affiliations of Alexander Brawanski include University of Würzburg & University Hospital Regensburg.

CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles.

Abstract: Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth and differentiation properties vary considerably between individual cases. To investigate whether different subtypes of glioblastomas might originate from different cells of origin, we cultured tumor cells from 22 glioblastomas under medium conditions favoring the growth of neural and cancer stem cells (CSC). Secondary glioblastoma (n = 7)-derived cells did not show any growth in the medium used, suggesting the absence of neural stem cell-like tumor cells. In contrast, 11/15 primary glioblastomas contained a significant CD133(+) subpopulation that displayed neurosphere-like, nonadherent growth and asymmetrical cell divisions yielding cells expressing markers characteristic for all three neural lineages. Four of 15 cell lines derived from primary glioblastomas grew adherently in vitro and were driven by CD133(-) tumor cells that fulfilled stem cell criteria. Both subtypes were similarly tumorigenic in nude mice in vivo. Clinically, CD133(-) glioblastomas were characterized by a lower proliferation index, whereas glial fibrillary acidic protein staining was similar. GeneArray analysis revealed 117 genes to be differentially expressed by these two subtypes. Together, our data provide first evidence that CD133(+) CSC maintain only a subset of primary glioblastomas. The remainder stems from previously unknown CD133(-) tumor cells with apparent stem cell-like properties but distinct molecular profiles and growth characteristics in vitro and in vivo.

Temozolomide preferentially depletes cancer stem cells in glioblastoma.

Abstract: The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells (CSC) maintaining these tumors persist. We have therefore investigated the effect of temozolomide on CD133(+) and CD133(-) GBM CSC lines. Although differentiated tumor cells constituting the bulk of all tumor cells were resistant to the cytotoxic effects of the substance, temozolomide induced a dose- and time-dependent decline of the stem cell subpopulation. Incubation with sublethal concentrations of temozolomide for 2 days completely depleted clonogenic tumor cells in vitro and substantially reduced tumorigenicity in vivo. In O(6)-methylguanine-DNA-methyltransferase (MGMT)-expressing CSC lines, this effect occurred at 10-fold higher doses compared with MGMT-negative CSC lines. Thus, temozolomide concentrations that are reached in patients were only sufficient to completely eliminate CSC in vitro from MGMT-negative but not from MGMT-positive tumors. Accordingly, our data strongly suggest that optimized temozolomide-based chemotherapeutic protocols might substantially improve the elimination of GBM stem cells and consequently prolong the survival of patients.

Moderate hypothermia in patients with severe head injury: cerebral and extracerebral effects

Abstract: Cerebral and extracerebral effects of moderate hypothermia (core temperature 32.5 degrees C-33.0 degrees C) were prospectively studied in 10 patients with severe closed head injury (Glasgow Coma Scale score < 7) in the intensive care unit of a university hospital. Hypothermia was induced by cooling the patient's body surface with water-circulating blankets. Before cooling, a conventional intracranial pressure (ICP) reduction therapy was applied, which remained unchanged throughout the study. Cerebral blood flow (CBF), cerebral metabolic rates for oxygen (CMRO2) and lactate (CMRL), and ICP were simultaneously measured prior to inducing hypothermia, after obtaining hypothermia, after 24 hours of hypothermia, and after rewarming. With respect to extracerebral effects, supplemental investigations were conducted 24 and 72 hours after rewarming. The median delay between injury and induction of hypothermia was 16 hours. Hypothermia reduced CMRO2 by 45% (p < 0.01), whereas CBF did not change significantly. Before cooling, six patients had elevated CMRL indicating cerebral ischemia. Cooling normalized CMRL in all patients (p < 0.01). The intracranial hypertension present prior to cooling declined markedly during hypothermia (p < 0.01) without significant rebound effects after rewarming. Cardiac index decreased by 18% after hypothermia was reached (p < 0.05), recovered at 24 hours of hypothermia, and surpassed baseline values after rewarming. Platelet counts dropped continuously up to 24 hours after rewarming (p < 0.01). Plasma coagulation tests did not show significant worsening. Creatinine clearance decreased during cooling (p < 0.01) and recovered by 24 hours after rewarming. Twenty-four hours after cooling had begun, eight patients had elevated serum lipase activity (p < 0.01) and four of them acquired pancreatitis. Rewarming normalized both pancreatic alterations. Seven patients made a good recovery; one survived severely disabled; and two patients died. Moderate hypothermia is effective in preventing secondary brain damage while reducing cerebral ischemia. However, there are potentially hazardous side effects that require additional monitoring.

Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.

Abstract: Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.

Comparison of serial S-100 and NSE serum measurements after severe head injury.

Abstract: We investigated the time course of neuron specific enolase (NSE) and S-100 protein after severe head injury in correlation to outcome. We included 30 patients (GCS<9), who had been admitted within 5 hours after injury, in a prospective study. Blood samples were taken on admission, 6, 12. and 24 hours and every 24 hours up to the fifth day after injury. The outcome was estimated on discharge using the Glasgow Outcome Scale. 70% reached a good outcome. All concentrations of NSE and 83% of the S-100 samples were elevated concerning the first probe (30.2 μg/l NSE mean and 2.6 μg/l S-100 mean). Patients with bad outcome had an NSE concentration of 38 μg/l (mean) compared with 26.9 μg/l (mean) in patients with good outcome. Patients with bad outcome had an S-100 concentration of 4.9 μg/l (mean) compared with 1.7 μg/l (mean) in patients with good outcome (p<0.05). The mean values of NSE and S-100 decreased during the first 5 days. Four patients with increasing intracranial pressure showed a quick increasing concentration of NSE, in two patients the S-100 level showed a slower rise. The NSE serum levels did not correlate with intracranial pressure values. Our results show that the first serum concentration of S-100 seems to be predictive for outcome after severe head injury.

Ensemble empirical mode decomposition: a noise-assisted data analysis method

Abstract: A new Ensemble Empirical Mode Decomposition (EEMD) is presented. This new approach consists of sifting an ensemble of white noise-added signal (data) and treats the mean as the final true result. Finite, not infinitesimal, amplitude white noise is necessary to force the ensemble to exhaust all possible solutions in the sifting process, thus making the different scale signals to collate in the proper intrinsic mode functions (IMF) dictated by the dyadic filter banks. As EEMD is a time–space analysis method, the added white noise is averaged out with sufficient number of trials; the only persistent part that survives the averaging process is the component of the signal (original data), which is then treated as the true and more physical meaningful answer. The effect of the added white noise is to provide a uniform reference frame in the time–frequency space; therefore, the added noise collates the portion of the signal of comparable scale in one IMF. With this ensemble mean, one can separate scales naturall...

Malignant Gliomas in Adults

Abstract: Approximately 5% of patients with malignant gliomas have a family history of gliomas. Some of these familial cases are associated with rare genetic syndromes, such as neurofibromatosis types 1 and 2, the Li−Fraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcot’s syndrome (intestinal polyposis and brain tumors). 10 However, most familial cases have

Cancer stem cells in solid tumours: accumulating evidence and unresolved questions

Abstract: Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.

Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Abstract: Purpose—The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods—A formal literature s...

Malignant astrocytic glioma: genetics, biology, and paths to treatment.

Abstract: Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.