Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy.

BACKGROUND: Intratumoral heterogeneity at the cellular and molecular level is a hallmark of glioblastoma (GB) that contributes to treatment resistance and poor clinical outcome. Little is known regarding epigenetic heterogeneity and intratumoral phylogeny and their implication for molecular classification and targeted therapies. PATIENTS AND METHODS: Multiple tissue biopsies (238 in total) were sampled from 56 newly-diagnosed, treatment-naive GB patients from a prospective in-house cohort and publicly available data and profiled for DNA methylation using the Illumina MethylationEPIC array. Methylation-based classification using the glioma classifier developed by Ceccarelli et al. and estimation of the MGMT promoter methylation status via the MGMT-STP27 model were carried out. In addition, copy number variations (CNVs) and phylogeny were analyzed. RESULTS: Almost half of the patients (22/56, 39%) harbored tumors composed of heterogeneous methylation subtypes. We found two predominant subtype combinations: classic-/mesenchymal-like, and mesenchymal-/pilocytic astrocytoma-like. Nine patients (16%) had tumors composed of subvolumes with and without MGMT promoter methylation, whereas 20 patients (36%) were homogeneously methylated, and 27 patients (48%) were homogeneously unmethylated. CNV analysis revealed high variations in many genes, including CDKN2A/B, EGFR, and PTEN. Phylogenetic analysis correspondingly showed a general pattern of CDKN2A/B loss and gain of EGFR, PDGFRA, and CDK4 during early stages of tumor development. CONCLUSIONS: (Epi)genetic intratumoral heterogeneity is a hallmark of GB, both at DNA methylation and CNV level. This intratumoral heterogeneity is of utmost importance for molecular classification as well as for defining therapeutic targets in this disease, as single biopsies might underestimate the true molecular diversity in a tumor.

[Spinal column: implants and revisions]. / Wirbelsäule: Implantate und Revisionen.

Non-fusion spinal implants are designed to reduce the commonly occurring risks and complications of spinal fusion surgery, e.g. long duration of surgery, high blood loss, screw loosening and adjacent segment disease, by dynamic or movement preserving approaches. This principle could be shown for interspinous spacers, cervical and lumbar total disc replacement and dynamic stabilization; however, due to the continuing high rate of revision surgery, the indications for surgery require as much attention and evidence as comparative data on the surgical technique itself.

Synaptic Conductance Estimates of the Connection Between Local Inhibitor Interneurons and Pyramidal Neurons in Layer 2/3 of a Cortical Column.

Stimulation of a principal whisker yields sparse action potential (AP) spiking in layer 2/3 (L2/3) pyramidal neurons in a cortical column of rat barrel cortex. The low AP rates in pyramidal neurons could be explained by activation of interneurons in L2/3 providing inhibition onto L2/3 pyramidal neurons. L2/3 interneurons classified as local inhibitors based on their axonal projection in the same column were reported to receive strong excitatory input from spiny neurons in L4, which are also the main source of the excitatory input to L2/3 pyramidal neurons. Here, we investigated the remaining synaptic connection in this intracolumnar microcircuit. We found strong and reliable inhibitory synaptic transmission between intracolumnar L2/3 local-inhibitor-to-L2/3 pyramidal neuron pairs [inhibitory postsynaptic potential (IPSP) amplitude -0.88 ± 0.67 mV]. On average, 6.2 ± 2 synaptic contacts were made by L2/3 local inhibitors onto L2/3 pyramidal neurons at 107 ± 64 µm path distance from the pyramidal neuron soma, thus overlapping with the distribution of synaptic contacts from L4 spiny neurons onto L2/3 pyramidal neurons (67 ± 34 µm). Finally, using compartmental simulations, we determined the synaptic conductance per synaptic contact to be 0.77 ± 0.4 nS. We conclude that the synaptic circuit from L4 to L2/3 can provide efficient shunting inhibition that is temporally and spatially aligned with the excitatory input from L4 to L2/3.

[Consumer participation in the shaping of clinical quality assurance. A handling-oriented study of patient satisfaction]. / Brukermedvirkning i utformingen av klinisk kvalitetssikring. En handlingsorientert undersøkelse av pasienttilfredshet.

Health care in a department of rheumatology was evaluated by interviewing 15 patients by a person not associated with the department. The patients' evaluation of the health care was then further evaluated by 264 former patients and the staff. There was a considerable mismatch between the patients' and staff's rating of the problems. The patients' feedback was then used systematically to choose between alternative methods of organising and providing the health care, and the effect of this was then re-evaluated by the patients.