Surgery for brain metastases: radiooncology scores predict survival-score index for radiosurgery, graded prognostic assessment, recursive partitioning analysis

BACKGROUND: Radiooncological scores are used to stratify patients for radiation therapy. We assessed their ability to predict overall survival (OS) in patients undergoing surgery for metastatic brain disease. METHODS: We performed a post-hoc single-center analysis of 175 patients, prospectively enrolled in the MetastaSys study data. Score index of radiosurgery (SIR), graded prognostic assessment (GPA), and recursive partitioning analysis (RPA) were assessed. All scores consider age, systemic disease, and performance status prior to surgery. Furthermore, GPA and SIR include the number of intracranial lesions while SIR additionally requires metastatic lesion volume. Predictive values for case fatality at 1 year after surgery were compared among scoring systems. RESULTS: All scores produced accurate reflections on OS after surgery (p ≤ 0.003). Median survival was 21–24 weeks in patients scored in the unfavorable cohorts, respectively. In cohorts with favorable scores, median survival ranged from 42 to 60 weeks. Favorable SIR was associated with a hazard ratio (HR) of 0.44 [0.29, 0.66] for death within 1 year. For GPA, the HR amounted to 0.44 [0.25, 0.75], while RPA had a HR of 0.30 [0.14, 0.63]. Overall test performance was highest for the SIR. CONCLUSIONS: All scores proved useful in predicting OS. Considering our data, we recommend using the SIR for preoperative prognostic evaluation and counseling

The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease

<p>Abstract</p> <p>Background</p> <p>Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD). In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD.</p> <p>Results</p> <p>Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels.</p> <p>Conclusions</p> <p>Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.</p

Huntingtin cleavage product A forms in neurons and is reduced by gamma-secretase inhibitors

BACKGROUND: The mutation in Huntington\u27s disease is a polyglutamine expansion near the N-terminus of huntingtin. Huntingtin expressed in immortalized neurons is cleaved near the N-terminus to form N-terminal polypeptides known as cleavage products A and B (cpA and cpB). CpA and cpB with polyglutamine expansion form inclusions in the nucleus and cytoplasm, respectively. The formation of cpA and cpB in primary neurons has not been established and the proteases involved in the formation of these fragments are unknown. RESULTS: Delivery of htt cDNA into the mouse striatum using adeno-associated virus or into primary cortical neurons using lentivirus generated cpA and cpB, indicating that neurons in brain and in vitro can form these fragments. A screen of small molecule protease inhibitors introduced to clonal striatal X57 cells and HeLa cells identified compounds that reduced levels of cpA and are inhibitors of the aspartyl proteases cathepsin D and cathepsin E. The most effective compound, P1-N031, is a transition state mimetic for aspartyl proteases. By western blot analysis, cathepsin D was easily detected in clonal striatal X57 cells, mouse brain and primary neurons, whereas cathepsin E was only detectible in clonal striatal X57 cells. In primary neurons, levels of cleavage product A were not changed by the same compounds that were effective in clonal striatal cells or by mRNA silencing to partially reduce levels of cathepsin D. Instead, treating primary neurons with compounds that are known to inhibit gamma secretase activity either indirectly (Imatinib mesylate, Gleevec) or selectively (LY-411,575 or DAPT) reduced levels of cpA. LY-411,575 or DAPT also increased survival of primary neurons expressing endogenous full-length mutant huntingtin. CONCLUSION: We show that cpA and cpB are produced from a larger huntingtin fragment in vivo in mouse brain and in primary neuron cultures. The aspartyl protease involved in forming cpA has cathepsin-D like properties in immortalized neurons and gamma secretase-like properties in primary neurons, suggesting that cell type may be a critical factor that specifies the aspartyl protease responsible for cpA. Since gamma secretase inhibitors were also protective in primary neurons, further study of the role of gamma-secretase activity in HD neurons is justified

A high-throughput compatible quantitative homogenous assay for Fragile X Mental Retardation 1 Protein

Hypermethylation of the FMR1 gene results in decreased expression of FMRP protein which is the underlying cause of Fragile X Syndrome, an incurable neurological disorder characterized by mental retardation, anxiety, epileptic episodes and autism. Disease modifying therapies for Fragile X are thus aimed at treatments increasing FMRP expression levels in the brain. Here we describe the development and characterization of two homogenous immunoassays for quantitative detection of FMRP protein using time-resolved FRET. The assays display high stability and reproducibility and can be used to quantify endogenous FMRP in human fibroblast. Importantly, due to the simplicity of the assay protocol, the method is well suited to be used in high-throughput screening applications to identify compounds or genetic interventions that result in increased FMRP levels in human cells

Transgenic expression of beta 1 antibody in brain neurons impairs age-dependent amyloid deposition in APP23 mice

Heterologous expression of the functional amyloid beta (A beta) antibody beta 1 in the central nervous system was engineered to maximize antibody exposure in the brain and assess the effects on A beta production and accumulation in these conditions. A single open reading frame encoding the heavy and light chains of beta 1 linked by the mouth and foot virus peptide 2A was expressed in brain neurons of transgenic mice. Two of the resulting BIN66 transgenic lines were crossed with APP23 mice, which develop severe central amyloidosis. Brain concentrations at steady-state 5 times greater than those found after peripheral beta 1 administration were obtained. Similar brain and plasma beta 1 concentrations indicated robust antibody efflux from the brain. In preplaque mice, beta 1 formed a complex with A beta that caused a modest A beta increase in brain and plasma. At 11 months of age, beta 1 expression reduced amyloid by 97% compared with age-matched APP23 mice. Interference of beta 1 with beta-secretase cleavage of amyloid precursor protein was relatively small. Our data suggest that severely impaired amyloid formation was primarily mediated by a complex of beta 1 with soluble A beta, which might have prevented A beta aggregation or favored transport out of the brain. (C) 2013 Elsevier Inc. All rights reserved

Cerebral metastases: do size, peritumoral edema, or multiplicity predict infiltration into brain parenchyma?

BackgroundBrain metastases (BMs) are the most frequent malignancy of the central nervous system. Previous research suggested that some metastases show infiltrative behavior rather than sharp demarcation. We hypothesized that three magnetic resonance (MR) imaging parameters(a) tumor size, (b) extent of peritumoral edema, and (c) presence of multiple BMsare predictors of cellular invasion beyond the surgically identifiable tumor margins.MethodsWe performed a post hoc analysis on prospectively collected data of patients with BMs. Biopsies beyond the resection margin and immunohistochemistry were performed to assess infiltration status. The three MR imaging parameters were dichotomized into diameters 30mm (small) and >30mm (large), amount of peritumoral edema extended and limited, and multiple BMs and single BMs, respectively. The association between infiltration status and imaging parameters was calculated using chi-square test.ResultsBiopsy beyond the resection margin was performed in 77 patients; 49 (63.6%) had supramarginal infiltration and 28 patients (36.4%) showed no infiltration. Histological evidence of tumor infiltration was found in 25/41 patients with smaller lesions (61%) and in 24/36 with larger lesions (66.7%, p=0.64), in 28/44 patients with limited (63.6%) and in 21/33 patients with extended edema (63.6%, p=1.0), in 28/45 patients (62.2%) with single BM and in 21/32 patients (65.6%) with multiple BMs (p=0.81).ConclusionsBased on the post hoc analysis of our prospective trial data, we could not confirm the hypothesis that infiltration of brain parenchyma beyond the glial pseudocapsule is associated with the MR imaging parameters tumor size, extent of edema, or multiplicity of metastases

Microenvironmental stromal cells abrogate NF-κB inhibitor-induced apoptosis in chronic lymphocytic leukemia

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease