Mapping actionable pathways and mutations in brain tumours using targeted RNA next generation sequencing.

Many biology-based precision drugs are available that neutralize aberrant molecular pathways in cancer. Molecular heterogeneity and the lack of reliable companion diagnostic biomarkers for many drugs makes targeted treatment of cancer inaccurate for many individuals. Identifying actionable hyperactive biological pathways in individual cancers may improve this situation.To achieve this we applied a novel targeted RNA next generation sequencing (t/RNA-NGS) technique to surgically obtained glioma tissues. The test combines mutation detection with analysis of biological pathway activities that are involved in tumour behavior in many cancer types (e.g. tyrosine kinase signaling, angiogenesis signaling, immune response, metabolism), via quantitative measurement of transcript levels and splice variants of hundreds of genes. We here present proof of concept that the technique, which uses molecular inversion probes, generates a histology-independent molecular diagnosis and identifies classifiers that are strongly associated with conventional histopathology diagnoses and even with patient prognosis. The test not only confirmed known glioma-associated molecular aberrations but also identified aberrant expression levels of actionable genes and mutations that have so far been considered not to be associated with glioma, opening up the possibility of drug repurposing for individual patients. Its cost-effectiveness makes t/RNA-NGS to an attractive instrument to aid oncologists in therapy decision making.

The diagnostic accuracy of brain microdialysis during surgery: a qualitative systematic review.

BACKGROUND: Monitoring of brain function and metabolism during surgery may be of benefit for patient outcome. Microdialysis is the only sampling technique to date that allows continuous monitoring of drug or metabolite concentrations in the extracellular fluid of multiple tissues in the brain. This qualitative systematic review aimed to determine whether microdialysis is a valid tool for detecting changes in tissue composition as would be expected upon changes in (induced) tissue metabolic composition during brain surgery. METHODS: A systematic review was conducted by performing a MEDLINE search using the terms "Intraoperative Period" (Medical Subject Heading [MeSH]) OR "Surgery" [Subheading] OR "Monitoring, Intraoperative" [MeSH] AND "Microdialysis" [MeSH] AND "Brain" [MeSH]. Two reviewers independently assessed the methodological quality of the studies. For each study the grades of recommendation were determined. RESULTS: The search strategy yielded 46 publications in Medline. Data extraction was performed on 16 studies. The methodological quality of studies was low, with overall scores of 4 or 5. A quantitative analysis could not be performed because of lack of sufficient data. A qualitative analysis was positive with regard to the detection of different states of tissue composition by microdialysis. However, the levels of recommendation on the outcome statements were low, resulting in a grade D level of recommendation on all statements. CONCLUSIONS: The available evidence for the validity of cerebral microdialysis as a diagnostic tool during brain surgery is of low scientific quality. In order to develop cerebral microdialysis as a valid instrument for monitoring of brain metabolism during surgery, standardised clinical prospective studies in homogeneous patient populations are required.

Distribution of signs and symptoms of complex regional pain syndrome type I in patients meeting the diagnostic criteria of the International Association for the Study of Pain.

The aim of the present study was to describe the occurrence of signs and symptoms in CRPS I patients meeting the IASP (Orlando) criteria, assess the occurrence of signs and symptoms in relation to disease duration and compare these to historical data based on a different diagnostic criteria set. Six hundred and ninety-two ambulatory patients meeting the IASP criteria for CRPS I referred to the outpatient clinics of five participating centers were included in this cross-sectional study. Characteristics were recorded in a standardized fashion and categorized according to the factor structure proposed by Bruehl/Harden. Subgroups were classified according to the duration of complaints and compared to historical data as described by Veldman et al. The Chi-square test corrected for multiple comparisons was used for statistical analysis. The prevalence of sensory signs was higher in patients with longer disease duration, especially for the allodynia's and hyperalgesia (all p<0.001). Signs in vasomotor (color difference; p=0.0007) and sudomotor (edema; p<0.0001) subgroups were less frequently present in patients with longer disease duration (i.e. >6 months). Prevalences of signs in the motor subgroup were all higher (p<0.0001) in patients with longer disease duration, except for limited range of motion. Occurrence of signs was significantly lower (<0.001) than those reported by Veldman et al., except for hyperesthesia and dystonia. Occurrence rates may vary at different time points after onset of CRPS, which may be of influence for diagnosing patients with novel derived diagnostic criteria. We argue for a mechanism based description of CRPS I based on one set of uniform generally accepted diagnostic criteria in future studies.