Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas

Purpose: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non–xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011). Conclusion: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients.Koch Institute Dana Farber/Harvard Cancer Center Bridge Projec

Rapid Intraoperative Molecular Characterization of Glioma

IMPORTANCE: Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS: This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%–99%) and 100% specificity (95% CI, 95%–100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE: The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations

Verzerrung durch Erinnerungen in der Methode des Ecological Momentary Assessments - eine Pilotstudie

Ecological Momentary Assessment (EMA) enables the evaluation of current hearing situations in real time. This can be useful for hearing aid fitting by querying as many everyday situations as possible and fine-tuning the hearing aids based on the individual assessments. However, since not all situations can always be assessed in the moment because safety is not guaranteed or politeness prohibits it, it should also be possible to assess situations retrospectively. This study addresses the question of the extent to which a retrospective assessment of events provides a valid reflection of the situation being assessed. For this purpose, ten participants were fitted with hearing aids and an EMA device for two weeks. The task was to assess various situations in real time and again with a delay of 30 and 60 minutes. In summary, it can be said that situations should be assessed as soon as possible. If this is not possible, the time frame should not exceed 30 minutes, as rare situations particularly benefit from a short delay. When the delay was shortened from 60 to 30 minutes, the deviation in responses was reduced by 8 percentage points. In addition, mood and stress could be more related to the assessment after a delay of 60 minutes. The self-assessment of how well the event could be recalled correlates with the reliability of the responses given.Ecological Momentary Assessment (EMA) ermöglicht die Bewertung aktueller Hörsituationen in Echtzeit. Dies kann für die Hörsystemanpassung von Nutzen sein, indem möglichst viele alltägliche Situationen abgefragt werden und die Hörsysteme aufgrund der individuellen Bewertungen feiner eingestellt werden. Da jedoch nicht alle Situationen immer in dem Moment beurteilt werden können, weil die Sicherheit nicht gewährleistet ist oder es die Höflichkeit verbietet, sollten Situationen auch rückblickend bewertet werden können. Diese Studie befasst sich mit der Frage, inwieweit eine retrospektive Beurteilung von Ereignissen die zu beurteilende Situation valide wiedergibt. Zu diesem Zweck wurden zehn Teilnehmende mit Hörgeräten und einem EMA-System für zwei Wochen ausgestattet. Aufgabe war es, verschiedene Situationen zeitnah und nochmals verzögert nach 30 bzw. 60 Minuten zu bewerten. Zusammenfassend kann festgestellt werden, dass Situationen möglichst zeitnah bewertet werden sollten. Wenn dies nicht möglich ist, dann sollte der Zeitrahmen 30 Minuten nicht überschreiten, da seltene Situationen besonders von einer kurzen Verzögerung profitieren. Bei der Verkürzung der Verzögerung von 60 auf 30 Minuten reduzierte sich die Abweichung der Antworten um 8%-Punkte. Zudem könnten Stimmung und Stress einen größeren Zusammenhang zur Bewertung nach einer Verzögerung von 60 Minuten aufweisen. Die Selbsteinschätzung, wie gut das Ereignis abgerufen werden konnte, korreliert mit der Zuverlässigkeit der getätigten Antworten