Therefore, the use of PARP and other DDR inhibitors to render GBM cells more vulnerable to conventional treatments is an area of intense investigation. In this review, we highlight the growing body of data behind DDR inhibitors in GBM, with a focus on putative predictive biomarkers of response. We also discuss the challenges involved in the successful development of DDR inhibitors for GBM, including the intracranial location and predicted overlapping toxicities of DDR agents with current standards of care, and propose promising strategies to overcome these hurdles.
  Meningiomas express high levels of somatostatin receptor 2 (SSTR2). SSTR2-targeted PET imaging with [
  Ga]-DOTATATE can aid with distinguishing residual meningioma from reactive changes in the postoperative setting. We present initial dosimetric analyses, acute events, and local control data utilizing [
  Ga]-DOTATATE PET/MRI-assisted target delineation for prospectively-treated intermediate-risk meningiomas.
 
  Twenty-nine patients underwent DOTATATE PET/MRI meningioma evaluation in 2019. Eight patients with 9 postoperative meningiomas met RTOG 0539 intermediate-risk criteria (recurrent WHO grade I, 1/9; WHO grade II, 8/9). Target volumes were created using DOTATATE PET/MRI to determine residual disease and received a nominal dose of 35.0 Gy over 5 fractions. For comparison, cases were recontoured and planned with MRI alone per RTOG 0539 guidelines. Mean and maximum equivalent 2 Gy doses were generated for target volumes and organs at risk (OAR) within 1 cm of the PTV and compared using Wilcoxon matched pairostoperative meningiomas.
  Breast cancer is the second most common cancer associated with brain metastases. The purpose of this study was to identify factors that impact the time to brain metastases in breast cancer patients at a single institution.
 
  Single institution retrospective study that captured all consecutive stage 2 and stage 3 breast cancer patients from 2003 to 2010. Patient characteristics analyzed included age, hormone status, HER2 receptor status, grade, stage, and time from breast cancer diagnosis to brain metastasis.
 
  A total of 1218 patients were eligible for the final analysis. 849 (69.7%) patients were ER+/HER2-, 90 (7.4%) were HER2+, and 279 (22.9%) were triple-negative (TN). Overall, 74 patients (6.1%) developed brain metastases over a median follow up time of 92 months. Median times to brain metastases for HER2+, TN, and ER+/HER2- patients were 20, 26, and 57 months, respectively. Multivariate analysis demonstrated that TN disease (HR = 2.043, 
  = .015), grade (HR = 1.667, 
  = .024) and stage (HR = 3.851, 
  < .001) were independent risk factors for earlier brain metastases. Median times to brain metastases were 34 and 52 months for stage 3 and 2 patients, and 30, 49, and 71 months for grade 3, 2, and 1 tumors, respectively.
 
  This single-institutional case series demonstrates that TN breast cancer, higher stage, and higher histologic grade are associated with earlier brain metastases in multivariate analysis. Additional prospective studies are warranted to investigate the impact of brain metastases screening on survival outcome in this high-risk defined group.
 This single-institutional case series demonstrates that TN breast cancer, higher stage, and higher histologic grade are associated with earlier brain metastases in multivariate analysis. Additional prospective studies are warranted to investigate the impact of brain metastases screening on survival outcome in this high-risk defined group.Brain somatic mutations are an increasingly recognized cause of epilepsy, brain malformations and autism spectrum disorders and may be a hidden cause of other neurodevelopmental and neurodegenerative disorders. At present, brain mosaicism can be detected only in the rare situations of autopsy or brain biopsy. Liquid biopsy using cell-free DNA derived from cerebrospinal fluid has detected somatic mutations in malignant brain tumours. Here, we asked if cerebrospinal fluid liquid biopsy can be used to detect somatic mosaicism in non-malignant brain diseases. First, we reliably quantified cerebrospinal fluid cell-free DNA in 28 patients with focal epilepsy and 28 controls using droplet digital PCR. Then, in three patients we identified somatic mutations in cerebrospinal fluid in one patient with subcortical band heterotopia the LIS1 p. Lys64* variant at 9.4% frequency; in a second patient with focal cortical dysplasia the TSC1 p. Phe581His*6 variant at 7.8% frequency; and in a third patient with ganglioglioma the BRAF p. Val600Glu variant at 3.2% frequency. To determine if cerebrospinal fluid cell-free DNA was brain-derived, whole-genome bisulphite sequencing was performed and brain-specific DNA methylation patterns were found to be significantly enriched (P = 0.03). Our proof of principle study shows that cerebrospinal fluid liquid biopsy is valuable in investigating mosaic neurological disorders where brain tissue is unavailable.Acetyl-dl-leucine is a derivative of the branched chain amino acid leucine.  https://www.selleckchem.com/products/cbl0137-cbl-0137.html  In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic Npc1-/- mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1-/- mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders.