Chemoresistance of glioblastoma cancer stem cells - much more complex than expected

Glioblastomas (GBM) are a paradigm for the investigation of cancer stem cells (CSC) in solid malignancies. The susceptibility of GBM CSC to standard chemotherapeutic drugs is controversial as the existing literature presents conflicting experimental data. Here, we summarize the experimental evidence on the resistance of GBM CSC to alkylating chemotherapeutic agents, with a special focus on temozolomide (TMZ). The data suggests that CSC are neither resistant nor susceptible to chemotherapy per se. Detoxifying proteins such as O6-methylguanine-DNA-methyltransferase (MGMT) confer a strong intrinsic resistance to CSC in all studies. Extrinsic factors may also contribute to the resistance of CSC to TMZ. These may include TMZ concentrations in the brain parenchyma, TMZ dosing schemes, hypoxic microenvironments, niche factors, and the re-acquisition of stem cell properties by non-stem cells. Thus, the interaction of CSC and chemotherapy is more complex than may be expected and it is necessary to consider these factors in order to overcome chemoresistance in the patient

Co-enzyme Q(10) and idebenone use in Friedreich's ataxia

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Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

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Grading of proximal internal carotid artery (ICA) stenosis by Doppler/duplex ultrasound (DUS) and computed tomographic angiography (CTA): correlation and interrater reliability in real-life practice

Doppler/duplex ultrasound (DUS) and computed tomographic angiography (CTA) are frequently applied methods to assess the degree of proximal internal carotid artery (ICA) stenoses in patients with acute ischemic stroke. This study evaluated the agreement and interrater reliability (IR) of both methods using a revised DUS grading system as well as different criteria (ECST/NASCET) under real-life conditions. CTA and DUS data of 281 proximal ICA stenoses [143 patients; 65.7 % male; age (mean (years) +/- SD, range) 72.2 +/- 11.1, 40-99] were retrospectively analyzed. For both methods, two independent raters estimated the degree of stenosis according to NASCET and ECST criteria. DUS raters applied revised German DUS criteria. For agreement and IR assessment, the linear weighted Kappa statistic was used. Correlation between DUS and CTA was substantial irrespective of the applied classification [weighted Kappa: 0.77 (NASCET)/0.79 (ECST)]. IR for DUS was almost perfect (weighted Kappa: 0.94) and better than for CTA [weighted Kappa: 0.78 (NASCET)/0.78 (ECST)]. In a real-life setting, CTA and DUS assessments of the degree of proximal ICA stenoses agreed substantially irrespective of the criteria applied (ECST/NASCET). For DUS, IR was better than for CTA