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Histone deacetylase inhibitors (HDACis) are drugs that target the epigenetic state of cells by modifying the compaction of chromatin through effects on histone acetylation. Gliomas often harbor a mutation of isocitrate dehydrogenase (IDH) 1 or 2 that leads to changes in their epigenetic state presenting a hypermethylator phenotype. We postulated that glioma cells with IDH mutation, due to the presence of epigenetic changes, will show increased sensitivity to HDACis. This hypothesis was tested by expressing mutant IDH1 with a point alteration—converting arginine 132 to histidine—within glioma cell lines that contain wild-type IDH1. Glioma cells engineered to express mutant IDH1 produced D-2-hydroxyglutarate as expected. When assessed for response to the pan-HDACi drug belinostat, mutant IDH1-expressing glioma cells were subjected to more potent inhibition of growth than the corresponding control cells. Increased sensitivity to belinostat correlated with the increased induction of apoptosis. Finally, a phase I trial assessing the addition of belinostat to standard-of-care therapy for newly diagnosed glioblastoma patients included one patient with a mutant IDH1 tumor. This mutant IDH1 tumor appeared to display greater sensitivity to the addition of belinostat than the other cases with wild-type IDH tumors based on both standard magnetic resonance imaging (MRI) and advanced spectroscopic MRI criteria. These data together suggest that IDH mutation status within gliomas may serve as a biomarker of response to HDACis.

Radiation therapy (RT) is a critical part of definitive therapy for pediatric high-grade glioma (pHGG). RT is designed to treat residual tumor defined on conventional MRI (cMRI), though pHGG lesions may be ill-characterized on standard imaging. Spectroscopic MRI (sMRI) measures endogenous metabolite concentrations in the brain, and Choline (Cho)/N-acetylaspartate (NAA) ratio is a highly sensitive biomarker for metabolically active tumor. We provide a preliminary report of our study introducing a novel treatment approach of whole brain sMRI-guided proton therapy for pHGG. An observational cohort (c1 = 10 patients) receives standard of care RT; a therapeutic cohort (c2 = 15 patients) receives sMRI-guided proton RT. All patients undergo cMRI and sMRI, a high-resolution 3D whole-brain echo-planar spectroscopic imaging (EPSI) sequence (interpolated resolution of 12 µL) prior to RT and at several follow-up timepoints integrated into diagnostic scans. Treatment volumes are defined by cMRI for c1 and by cMRI and Cho/NAA ≥ 2x for c2. A longitudinal imaging database is used to quantify changes in lesion and metabolite volumes. Four subjects have been enrolled (c1 = 1/c2 = 3) with sMRI imaging follow-up of 4–18 months. Preliminary data suggest sMRI improves identification of pHGG infiltration based on abnormal metabolic activity, and using proton therapy to target sMRI-defined high-risk regions is safe and feasible.

Glioblastoma (GBM) is a fatal disease, with poor prognosis exacerbated by difficulty in assessing tumor extent with imaging. Spectroscopic MRI (sMRI) is a non-contrast imaging technique measuring endogenous metabolite levels of the brain that can serve as biomarkers for tumor extension. We completed a three-site study to assess survival benefits of GBM patients when treated with escalated radiation dose guided by metabolic abnormalities in sMRI. Escalated radiation led to complex post-treatment imaging, requiring unique approaches to discern tumor progression from radiation-related treatment effect through our quantitative imaging platform. The purpose of this study is to determine true tumor recurrence timepoints for patients in our dose-escalation multisite study using novel methodology and to report on median progression-free survival (PFS). Follow-up imaging for all 30 trial patients were collected, lesion volumes segmented and graphed, and imaging uploaded to our platform for visual interpretation. Eighteen months post-enrollment, the median PFS was 16.6 months with a median time to follow-up of 20.3 months. With this new treatment paradigm, incidence rate of tumor recurrence one year from treatment is 30% compared to 60–70% failure under standard care. Based on the delayed tumor progression and improved survival, a randomized phase II trial is under development (EAF211).

PurposeGlioblastoma (GBM) is highly aggressive with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability, anti-GBM activity, and potential to enhance chemoradiation. The purpose of this clinical trial was to assess the clinical efficacy of combining belinostat with standard-of-care therapy for GBMs. Methods13 patients were enrolled in each of the control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mg/m2 1x/day x 5 days) every 3 weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5-10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Patient outcomes included progression-free survival, overall survival (OS), and recurrence pattern analysis of enhancing tumor (rGTV). ResultsMedian OS was 15.8 months for the control cohort and 18.5 months for the belinostat cohort (p=0.53). The rGTVs in the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-the field recurrence, tumors were detectable by spectroscopic MRI before RT. ConclusionThe median OS was slightly longer for the belinostat cohort than the control cohort but not statistically significant. Recurrence analysis suggests better in-field control with belinostat, suggesting a radio-sensitizing effect. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM treatment. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided radiation therapy.

2018 Background: Glioblastoma (GBM) is the most common adult primary malignant brain tumor. These pts have poor outcomes [median overall survival (OS) ̃ 16 months] despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Magnetic resonance spectroscopy (MRS) measures levels of specific metabolites in the brain including choline (Cho) and N-acetyl aspartate (NAA). Previously, we found that high Cho/NAA ratios can aid in localizing regions of brain at high risk for GBM recurrence that may not be appreciated on standard contrast-enhanced (CE) MRI. Based on this finding, we conducted a clinical trial to assess the feasibility and safety of using an advanced volumetric MRS technique termed spectroscopic MRI (sMRI) to guide RT dose escalation for newly-diagnosed GBMs. Methods: Our clinical trial (NCT03137888) funded by the NCI (RO1CA214557) enrolled pts at 3 institutions (Emory U, U Miami, Johns Hopkins U) from 5/2017 to 4/2019. This study was approved by the IRB at each respective institution. Eligibility criteria included newly-diagnosed GBM pts ≥ 18 years of age with a tumor site that could be adequately imaged by sMRI. Cho/NAA ratio was normalized to the contralateral normal appearing white matter (NAWM). For RT planning, standard gross tumor volumes (GTV1 & 2) were defined based on T2-FLAIR and T1 CE MRIs and 5 mm margins were added to generate clinical tumor volumes (CTV1 & 2). GTV3 ( = CTV3, sMRI-defined) was generated by the union of residual CE tumor and Cho/NAA ≥ 2x NAWM. To remain eligible, CTV3 was required to be ≤ 65 cc. Planning target volumes (PTVs) were generated by applying a 3 mm margin around CTVs. 50.1, 60 and 75 Gy in 30 fractions were prescribed to PTV1, PTV2 and PTV3, respectively. All pts received standard concurrent/adjuvant TMZ. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. Results: 30 pts met eligibility and were treated on study. Mean/median ages were 56.4/58.9 years. 9 pts (30%) were MGMT methylated; 2 pts (6.7%) harbored an IDH1 mutation. With median followup of 21.4 months in censored pts, median OS was 23.0 months. 11 of 30 pts were documented to have experienced grade 3 or greater toxicities that were at least possibly due to their treatment. Of the 7 pts who experienced these by 9 months post-RT, most were attributable to TMZ (thrombocytopenia x 4, thrombocytopenia/neutropenia x 1, transaminitis x 1) and only one case (headaches/fatigue x 1) could potentially be ascribed to RT. Increased risk of pseudoprogression or radiation necrosis, especially beyond 3 months post-RT, was noted but these were clinically manageable and did not result in toxicity ≥ grade 3. Conclusions: Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for pts with newly-diagnosed GBMs. OS outcome is also quite promising and warrants additional testing. Based on these results, a phase II randomized trial is planned at ECOG-ACRIN (EAF211). Clinical trial information: NCT03137888.

Contraversive Lateropulsion, also referred to as contraversive pushing, pusher behavior, and pusher syndrome, can be associated with increased hospital length of stay, increased health care costs, and delayed outcomes in persons with stroke. The purpose of this updated systematic review was to identify scales used to classify contraversive lateropulsion, investigate literature that addresses their clinimetric properties, and create a resource for clinicians recommending use in clinical practice.Three databases were searched for articles from inception to March 2017. The search strategy followed Cochrane Collaboration guidelines. The Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was applied to evaluate methodological quality.Four hundred three records were screened. Seven studies met inclusion criteria. Four scales were identified: the Scale for Contraversive Pushing (SCP), the Modified Scale for Contraversive Pushing (M-SCP), the Burke Lateropulsion Scale (BLS), and the Swedish Scale for Contraversive Pushing (S-SCP). Psychometric property investigation was most robust for the SCP and the BLS. Cross-cultural validity has not been fully investigated in scales used outside of their country of origin.The BLS is recommended for identifying contraversive lateropulsion. The scale assesses the presence of contraversive lateropulsion across several functional tasks, from rolling to walking, and is the only scale originally written in English. The BLS is the only tool to receive ratings greater than poor for reliability and responsiveness. The BLS should be implemented as soon as contraversive lateropulsion is suspected to guide frontline clinicians' initial plan of care, allow objective identification of change over time, and facilitate easier investigation of interventional efficacy.Video Abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A177).

© 2016, Springer-Verlag Berlin Heidelberg. Acetoclastic methanogenesis is a key metabolic process in anaerobic digestion, a technology with broad applications in biogas production and waste treatment. Acetoclastic methanogenesis is known to be performed by two archaeal genera, Methanosaeta and Methanosarcina. The conventional model posits that Methanosaeta populations are more competitive at low acetate levels (

This paper presents a study in which the feasibility of utilizing two industrial wastes, a heavy clay material from the automotive industry and a waste foundry sand from the metallurgical industry, as construction materials was evaluated through laboratory experiments. The laboratory study blended two industrial wastes at different proportions and stabilized the blend with varying amounts of cement. The engineering properties of the blends were evaluated through the Atterberg limits, Proctor compaction test, direct shear, and unconfined compressive strength tests. The results from this study indicate that blending foundry sand into waste heavy clay significantly reduced its plasticity and cohesion and hence made it possible to be further stabilized with cement. In addition, it is observed that the blended materials had other improved properties such as increased maximum dry unit weight, friction angle, and compressive strength. However, the increase in compaction and strength properties became less significant with the increase of foundry sand content. An optimum blending ratio was recommended through this laboratory study.