Expression and activity of the calcitonin receptor family in a sample of primary human high-grade gliomas.

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer. With median survival of less than 15 months, identification and validation of new GBM therapeutic targets is of critical importance. RESULTS: In this study we tested expression and performed pharmacological characterization of the calcitonin receptor (CTR) as well as other members of the calcitonin family of receptors in high-grade glioma (HGG) cell lines derived from individual patient tumours, cultured in defined conditions. Previous immunohistochemical data demonstrated CTR expression in GBM biopsies and we were able to confirm CALCR (gene encoding CTR) expression. However, as assessed by cAMP accumulation assay, only one of the studied cell lines expressed functional CTR, while the other cell lines have functional CGRP (CLR/RAMP1) receptors. The only CTR-expressing cell line (SB2b) showed modest coupling to the cAMP pathway and no activation of other known CTR signaling pathways, including ERK1/2 and p38 MAP kinases, and Ca2+ mobilization, supportive of low cell surface receptor expression. Exome sequencing data failed to account for the discrepancy between functional data and expression on the cell lines that do not respond to calcitonin(s) with no deleterious non-synonymous polymorphisms detected, suggesting that other factors may be at play, such as alternative splicing or rapid constitutive receptor internalisation. CONCLUSIONS: This study shows that GPCR signaling can display significant variation depending on cellular system used, and effects seen in model recombinant cell lines or tumour cell lines are not always reproduced in a more physiologically relevant system and vice versa.

Long-term significance of postictal psychotic episodes I. Are they predictive of bilateral ictal foci?

OBJECTIVE: The aim of this study was to determine the degree to which postictal psychotic episodes (PIPE) are predictive of bilateral independent ictal foci. METHODS: This was a retrospective study of 18 consecutive adults with a partial seizure disorder and PIPE (study group) and 36 patients with a partial seizure disorder but without PIPE (control group). The two groups were compared with respect to the number and location of ictal foci identified with video/EEG monitoring, seizure type, etiology, age at seizure onset, duration of seizure disorder, MRI abnormalities, and psychiatric history prior to the index video/EEG monitoring (other than PIPE). Statistical analyses consisted of logistic regression models, one to identify the variables predictive of bilateral ictal foci and the other to identify the variables predictive of PIPE. RESULTS: The occurrence of PIPE (P<0.0001) and cryptogenic partial epilepsy (P=0.004) was predictive of bilateral independent ictal foci in univariate analyses. In multivariate analyses, cryptogenic partial epilepsy was the only significant variable (P=0.03). Conversely, bilateral independent ictal foci on video/EEG monitoring (P<0.0001) and having secondarily generalized tonic-clonic seizures (P=0.035) were independent predictors of the development of PIPE in univariate and multivariate analyses. Surgery was performed in 20 controls and 3 patients with PIPE; 17 controls and 2 patients with PIPE became seizure-free. CONCLUSIONS: The presence of PIPE appears to be a predictor of bilateral ictal foci.

Long-term significance of postictal psychotic episodes II. Are they predictive of interictal psychotic episodes?

OBJECTIVE: The aim of this study was to determine whether postictal psychotic episodes (PIPE) are predictive of the development of interictal psychotic episodes (IPE). METHODS: This was a retrospective study of 18 consecutive adults with a partial seizure disorder and PIPE (study group) and 36 patients with a partial seizure disorder but without PIPE (control group). These two groups were compared with respect to the likelihood of developing IPE over an 8-year follow-up period and the variables operant in the development of IPE. Statistical analyses consisted of logistic regression models to identify the variables predictive of the development of IPE. Predictors included: number and location of ictal foci, seizure type, etiology, age at seizure onset, duration of seizure disorder, MRI abnormalities, and psychiatric history prior to the index video/EEG monitoring (other than PIPE). RESULTS: Seven patients with PIPE and one control patient went on to develop an IPE. Predictors of IPE in univariate logistic regression analyses included a history of PIPE (P=0.006), male gender (P=0.028), and having bilateral ictal foci (P=0.048). Significance disappeared for all of these variables when they were entered into a multivariate analysis. CONCLUSIONS: A history of PIPE may be a risk factor for the development of IPE. Yet, the disappearance of significance on multivariate analysis indicates that it is not an independent predictor.