TERT Promoter Mutation Detection in Cell-Free Tumor-Derived DNA in Patients with IDH Wild-Type Glioblastomas: A Pilot Prospective Study

Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)–mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients. Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp mutation in the CSF-tDNA was correlated with tumor features and patients’ outcome. Results: Thirty-eight patients had TERTp-mutant/IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6–100%) and 92.1% sensitivity (95% CI, 78.6–98.3%) (n = 35/38). In contrast, the sensitivity in the plasma-tDNA was far lower [n = 3/38, 7.9% (95% CI, 1.6–21.4%)]. We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared with patients with high VAF, irrespective of using the lower quartile VAF [11.45%; 14.0 mo. (95% confidence interval, CI, 10.3–17.6) vs. 8.6 mo. (95% CI, 4.1–13.2), P = 0.035], the lower third VAF [13%; 15.4 mo. (95% CI, 11.6–19.2) vs. 8.3 mo. (95% CI, 2.3–14.4), P = 0.008], or the median VAF [20.3%; 14.0 mo. (95% CI, 9.2–18.7) vs. 8.6 mo. (95% CI, 7.5–9.8), P = 0.062] to dichotomize the patients. Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients. Further studies are needed to complement the findings of our exploratory analysis

Low Diagnostic Yield of Routine Cerebrospinal Fluid Analysis in Juvenile Stroke

Background: The diagnostic value of cerebrospinal fluid (CSF) analysis in juvenile stroke, i.e., stroke in young adult patients, is not well studied. We sought to determine the therapeutic impact of routine CSF-analysis in young adults with acute ischemic stroke or transient ischemic attack (TIA).Methods: We abstracted data from patients with acute cerebral ischemia aged 18–45 years who were consecutively admitted to our stroke center between 01/2008 and 12/2015. We routinely performed CSF-analysis in patients with hitherto unknown stroke etiology after complete diagnostic work up. We assessed the frequency and underlying causes of abnormal CSF-findings and their impact on secondary stroke prevention therapy.Results: Among 379 patients (median [IQR:IQR3-IQR1] age 39 [10:43-33] years, 48% female) with acute ischemic stroke (n = 306) or TIA (n = 73), CSF analysis was performed in 201 patients (53%). Of these, 25 patients (12.4 %) had CSF pleocytosis (leucocyte cell count ≥ 5 Mpt/L), that was rated as non-specific (e.g., traumatic lumbar puncture, reactive pleocytosis) in 22 patients. Only 3 patients (1.5% of all patients who underwent CSF-analysis) with CSF-pleocytosis had specific CSF-findings that were related to stroke etiology and affected secondary stroke prevention therapy. Imaging findings had already suggested cerebral vasculitis in two of these patients.Conclusions: The diagnostic yield of routine CSF-analysis in juvenile stroke was remarkably low in our study. Our data suggest that CSF-analysis should only be performed if further findings raise the suspicion of cerebral vasculitis

Hibernoma – two patients with a rare lipoid soft-tissue tumour

Background: Hibernomas are rare benign soft-tissue tumours arising from brown fat tissue. Although imaging characteristics are not specific certain imaging features, common locations and patient demographics may suggest hibernoma as a differential diagnosis. Case presentation: We report on two 48-year-old male patients with hibernoma. The tumour presented with local swelling of the inguinal region in the first patient and was an incidental imaging finding in the second patient. Imaging included magnetic resonance imaging in both patients and computed tomography as well as 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in the second patient. In both cases histological diagnosis was initially based on excisional and needle core biopsy, respectively. Complete surgical resection confirmed the diagnosis of hibernoma thereafter. Conclusion: In soft tissue tumours with fatty components hibernoma may be included into the differential diagnosis. Because of the risk of sampling errors in hibernoma-like tissue components of myxoid and well-differentiated liposarcoma, complete resection is mandatory. This article also reviews the current imaging literature of hibernomas

Safety and Effectiveness of BisChloroethylnitrosourea Wafer Chemotherapy in Elderly Patients with Recurrent Glioblastoma

Objective: To assess the safety and effectiveness of bis-chloroethylnitrosourea (BCNU) wafers in elderly patients with recurrent glioblastoma (GBM). Methods: Patients with recurrent GBM operated on between 2007 and 2014 were divided into 3 groups: >65 years with BCNU wafer implantation, >65 years without BCNU wafer implantation, and ≤ 65 years with BCNU wafer implantation. We compared survival and complications. Results: A total of 79 patients were identified: 24 in the older BCNU group (median age 68.2 years, 33.3% with a methylated MGMT promoter), 16 in the older non-BCNU group (median age 68.6 years, 31.3% with a methylated MGMT promoter), and 39 in the younger BCNU group (median age 56.8 years). Survival after progression was 9.2 months in the elderly BCNU group and 7.6 months in the elderly non-BCNU group ( p = 0.34); overall survival was 17.2 and 15.9 months, respectively ( p = 0.35). We found a tendency toward a higher rate of seizures and pneumonia in the older BCNU group. Conclusion: BCNU wafer implantation after resection of recurrent GBM is a reasonably safe treatment in patients aged >65 years. Seizures and systemic infections may occur more frequently, but the trade-off is still favorable as survival may be influenced positively. Higher age should not be regarded as a contraindication for BCNU wafers

Glioblastoma multiforme presenting as postpartum depression: a case report

Background Alterations of mental status are characteristic of psychiatric disorders but may also result from a multitude of organic causes. Generally, physical examination and blood analysis are a part of basic psychiatric differential diagnostics, whereas more sophisticated procedures (for example, brain imaging) are applied only in cases with pathologic diagnostic findings. Our report challenges this approach by describing a case of glioblastoma multiforme presenting as postpartum depression without abnormalities in basic differential diagnostics. Case presentation A 28-year-old white woman who had been in outpatient treatment for postpartum depression was taken to the psychiatric emergency room. The psychopathological assessment, however, showed mild disorientation and severe deficits of long-term memory. Moreover, she complained of stabbing, bilateral headaches, but results of her physical examination and blood analysis were unremarkable. Magnetic resonance imaging of the brain was performed, which showed a contrast-enhanced mass lesion in the left frontal lobe. The patient underwent urgent tumor resection, and histologic results revealed an IDH-mutant glioblastoma multiforme. The patient was discharged with a substantially improved psychopathology and without neurological deficits. Conclusions This report adds to the evidence that postpartum depression may have organic causes in some cases, a fact that needs to be considered in the clinical setting. Atypical neurocognitive findings in a psychiatric interview may alone justify brain imaging, despite normal physical examination and blood analysis results

Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas

Background: Recent studies have reported mutations in the telomerase reverse transcriptase promoter (TERTp) in meningiomas. We sought to determine the frequency, clonality and clinical significance of telomere gene alterations in a cohort of patients with progressive/higher-grade meningiomas. Methods: We characterized 64 temporally- and regionally-distinct specimens from 26 WHO grade III meningioma patients. On initial diagnoses, the meningiomas spanned all WHO grades (3 grade I, 13 grade II and 10 grade III). The tumor samples were screened for TERTp and ATRX/DAXX mutations, and TERT rearrangements. Additionally, TERTp was sequenced in a separate cohort of 19 patients with radiation-associated meningiomas. We examined the impact of mutational status on patients’ progression and overall survival. Results: Somatic TERTp mutations were detected in six patients (6/26 = 23%). Regional intratumoral heterogeneity in TERTp mutation status was noted. In 4 patients, TERTp mutations were detected in recurrent specimens but not in the available specimens of the first surgery. Additionally, a TERT gene fusion (LPCAT1-TERT) was found in one sample. In contrary, none of the investigated samples harbored an ATRX or DAXX mutation. In the cohort of radiation-induced meningiomas, TERTp mutation was detected in two patients (10.5%). Importantly, we found that patients with emergence of TERTp mutations had a substantially shorter OS than their TERTp wild-type counterparts (2.7 years, 95% CI 0.9 – 4.5 years versus 10.8 years, 95% CI 7.8 -12.8 years, p=0.003). Conclusions: In progressive/higher-grade meningiomas,TERTp mutations are associated with poor survival, supporting a model in which selection of this alteration is a harbinger of aggressive tumor development. In addition, we observe spatial intratumoral heterogeneity of TERTp mutation status, consistent with this model of late emergence in tumor evolution. Thus, early detection of TERTp mutations may define patients with more aggressive meningiomas. Stratification for TERT alterations should be adopted in future clinical trials of progressive/higher-grade meningiomas