Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease.In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia.For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group.Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).
Background: Gliomas account for 42% of all primary CNS neoplasms and 77% of all malignant primary CNS neoplasms. Unfortunately the high-grade variant of gliomas, glioblastoma multiforme (GBM), is difficult to treat and generally considered incurable. Survival rates are generally poor, and neurological morbidity in the setting of disease progression is high. Fortunately, significant progress has been achieved in the past decade in our understanding of the molecular biology of this aggressive tumour histology and, as a consequence, there is renewed clinical trial activity in this area focused on improving quality of life, treatment-related morbidity and outcomes.Methods: A review of literature from June 2005 to June 2008 was conducted on multimodal treatment of malignant glioma (MG) patients, using specific search criteria in Medline, EMBASE, and BIOSIS. Abstracts from relevant US and European medical (cancer) meetings were also evaluated.Results: The established therapies for MG include surgery, radiotherapy (RT), and local or systemic chemotherapy. However, over the last 10 years only two chemotherapeutic agents have received regulatory approval for treatment of MG: polifeprosan 20 with carmustine (BCNU implant) and temozolomide (TMZ), an imidazotetrazine derivative of dacarbazine. More recent advances in the treatment of brain tumours have been in the development of multimodal approaches. Specific interest in the combination of BCNU implant and TMZ has arisen due to the demonstrable depletion by TMZ of the DNA repair enzyme responsible for resistance to a nitrosourea such as BCNU. Further interest in this combination stems from the observation that there is a difference in the time to peak effect for each agent. Additional emerging data suggest that multimodal therapy with maximal resection and BCNU implants, followed by adjuvant therapy with radiation and TMZ, is effective and well-tolerated in patients with initial high-grade, resectable MG.Conclusions: The increasing body of efficacy data suggests that this combination of BCNU implants and TMZ within a multimodal treatment strategy including surgery and RT may provide an enhanced benefit compared with the use of either of these agents alone in select patients with high-grade glioma.
Spinal cord injury (SCI) often results in intractable chronic central pain syndromes. Recently chemokines such as CCL2 were identified as possible key integrators of neuropathic pain and inflammation after peripheral nerve lesion. The focus of the current study was the investigation of time-dependent CCL2 and CCR2 expression in relation to central neuropathic pain development after spinal cord impact lesions of 100, 150, or 200 kdyn force on spinal cord level T9 in adult rats. Below-level pain was monitored with weekly sensory testing for 42 days after SCI. In parallel expression of CCL2/CCR2 on cervical, thoracic, and lumbar levels was investigated by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry early (7 days [7d]), intermediate (15d), and late (42d) after lesion. Cellular source and anatomical pain related expression was determined by double-immunohistochemistry. Force-defined SCI led to acute mechanical hypersensitivity in all lesion groups, and to persistent below-level pain in severely injured animals. While in the early post-operative time course, CCL2 and CCR2 were expressed in astroglia and granulocytes only on level T9; there was additional astroglial CCL2 expression in dorsal columns and dorsal horns above and below T9 of severely injured animals 42d after lesion. In dorsal horns (level L3-L5) of animals exhibiting chronic below-level pain CCL2 was co-expressed with transmitters and receptors that are involved in nociceptive processing like calcitonin gene-related peptide (CGRP), Substance-P, vanilloid-receptor-1, and its activated phosphorylated form. These data demonstrate lesion grade dependence of below-level pain development and suggest chemokines as potential candidates for integrating inflammation and central neuropathic pain after SCI.
Patients with highly malignant glioblastomas have a short median survival time mainly due to aggressive relapses after therapeutic treatment. Beside others, they achieve their progressive character via epithelial-to-mesenchymal transition (EMT). However, comprehensive investigations on EMT in paired primary-recurrent glioblastoma pairs are presently not available. Thus, in our present study we examined the expression profile of different EMT-markers in 17 matched primary and recurrent glioblastomas by qPCR and double-immunofluorescence stainings to identify EMT marker expressing cell types. Additionally, we analyzed the influence of temozolomide on EMT marker expression in vitro. In comparison to primary tumors, expression of β-catenin (p<0.05), Snail1 (p<0.05), Snail2/Slug (p<0.05), biglycan (p<0.05) and Twist1 (p<0.01) was downregulated in recurrence whereas L1CAM showed upregulation (p<0.05; qPCR). Expression of desmoplakin, vimentin, fibronectin and TGF-β1 with its receptors TGF-βR1 and TGF-βR2 was almost unchanged. Comparing each individual pair, five different 'EMT groups' within our glioblastoma collective were identified according to the regulation of mRNA expression of GFAP, desmoplakin, Snail1, Snail2, Twist1 and vimentin. Additionally, double-stainings of EMT markers in combination with cell specific markers (glial fibrillary acidic protein, CD11b, von Willebrand factor) revealed that EMT markers were expressed in a complex pattern with all three cellular types as possible sources. Temozolomide treatment significantly induced mRNA expression of nearly all investigated EMT markers in T98G glioma cells. Thus, EMT seems to be involved in glioma progression in a complex way requiring an individualized analysis, and is influenced by commonly used therapeutic options in glioma therapy.
