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

Global retrieval of stratospheric and tropospheric BrO columns from the Ozone Mapping and Profiler Suite Nadir Mapper (OMPS-NM) on board the Suomi-NPP satellite

Quantifying the global bromine monoxide (BrO) budget is essential to understand ozone chemistry better. In particular, the tropospheric BrO budget has not been well characterized. Here, we retrieve nearly a decade (February 2012–July 2021) of stratospheric and tropospheric BrO vertical columns from the Ozone Mapping and Profiling Suite Nadir Mapper (OMPS-NM) on board the Suomi National Polar-orbiting Partnership (Suomi-NPP) satellite. In quantifying tropospheric BrO enhancements from total slant columns, the key aspects involve segregating them from stratospheric enhancements and applying appropriate air mass factors. To address this concern and improve upon the existing methods, our study proposes an approach that applies distinct BrO vertical profiles based on the presence or absence of tropospheric BrO enhancement at each pixel, identifying it dynamically using a satellite-derived stratospheric-ozone–BrO relationship. We demonstrate good agreement for both stratosphere (r = 0.81–0.83) and troposphere (r = 0.50–0.70) by comparing monthly mean BrO vertical columns from OMPS-NM with ground-based observations from three stations (Lauder, Utqiaġvik, and Harestua). Although algorithm performance is primarily assessed at high latitudes, the OMPS-NM BrO retrievals successfully capture tropospheric enhancements not only in polar regions but also in extrapolar areas, such as the Rann of Kutch and the Great Salt Lake. We also estimate random uncertainties in the retrievals pixel by pixel, which can assist in quantitative applications of the OMPS-NM BrO dataset. Our BrO retrieval algorithm is designed for cross-sensor applications and can be adapted to other space-borne ultraviolet spectrometers, contributing to the creation of continuous long-term satellite BrO observation records.</p

Evaluation of Diffusion-Tensor Imaging-Based Global Search and Tractography for Tumor Surgery Close to the Language System

Pre-operative planning and intra-operative guidance in neurosurgery require detailed information about the location of functional areas and their anatomo-functional connectivity. In particular, regarding the language system, post-operative deficits such as aphasia can be avoided. By combining functional magnetic resonance imaging and diffusion tensor imaging, the connectivity between functional areas can be reconstructed by tractography techniques that need to cope with limitations such as limited resolution and low anisotropic diffusion close to functional areas. Tumors pose particular challenges because of edema, displacement effects on brain tissue and infiltration of white matter. Under these conditions, standard fiber tracking methods reconstruct pathways of insufficient quality. Therefore, robust global or probabilistic approaches are required. In this study, two commonly used standard fiber tracking algorithms, streamline propagation and tensor deflection, were compared with a previously published global search, Gibbs tracking and a connection-oriented probabilistic tractography approach. All methods were applied to reconstruct neuronal pathways of the language system of patients undergoing brain tumor surgery, and control subjects. Connections between Broca and Wernicke areas via the arcuate fasciculus (AF) and the inferior fronto-occipital fasciculus (IFOF) were validated by a clinical expert to ensure anatomical feasibility, and compared using distance- and diffusion-based similarity metrics to evaluate their agreement on pathway locations. For both patients and controls, a strong agreement between all methods was observed regarding the location of the AF. In case of the IFOF however, standard fiber tracking and Gibbs tracking predominantly identified the inferior longitudinal fasciculus that plays a secondary role in semantic language processing. In contrast, global search resolved connections in almost every case via the IFOF which could be confirmed by probabilistic fiber tracking. The results show that regarding the language system, our global search is superior to clinically applied conventional fiber tracking strategies with results similar to time-consuming global or probabilistic approaches

Forward Look Bericht des EMRC: "Implementation of Medical Research in Clinical practice"

Bei der European Science Foundation (ESF) ist der 'Forward Look'-Bericht "Implementation of Medical Research in Clinical practice" erschienen - wir dokumentieren den Original-Bericht und die deutsche Übersetzung der Zusammenfassung auf der AWMF-Website

Olfactory bulb volume changes associated with trans-sphenoidal pituitary surgery.

ObjectiveThe trans-sphenoidal approach is most frequently used for pituitary adenoma (PA) enucleation. However, effects of this surgery on neighboring structures have received little attention so far. In particular, no investigations on olfactory bulb (OB) anatomy after trans-sphenoidal surgery have been reported. Because impairment of olfaction has been shown in small groups following trans-sphenoidal surgery we hypothesized that the transnasal approach is likely to alter OB volume which is associated with changes of olfactory function.MethodsThe study comprised 33 patients with pituitary adenoma (14 women and 19 men, mean age 50 years). Comprehensive assessment of olfactory function was conducted with the "Sniffin' Sticks" test kit. Based on magnetic resonance imaging scans OBs were measured before and approximately one year after trans-sphenoidal PA enucleation.ResultsOwing to postoperative non-compliance and MRI artifacts partly due to drill friction complete evaluation of "Sniffin' Sticks" in term of obtaining the TDI score was possible pre- and postoperatively in 21 patients whereas OB volumes were available in 32 patients. Approximately one year after surgery olfactory function was not significantly different from baseline. However, left- and right-sided OB volume in patients treated via trans-sphenoidal surgery decreased (p = 0.001). The side of the surgical approach did not affect OB volume in a side-specific manner. Changes in odor threshold were significantly correlated to changes in right-sided OB volume (r = 0.45, p = 0.024).ConclusionOverall olfactory performance one year after surgery was not significantly different from baseline. However, changes in OB volume are associated with changes in olfactory performance and OB volumes decreased in patients

Patient (male, 29 years) with diffuse left post-central astrocytoma (WHO grade II).

<p>Patient (male, 29 years) with diffuse left post-central astrocytoma (WHO grade II).</p

Patient (female, 36 years) with left temporal astrocytoma (WHO grade II).

<p>Patient (female, 36 years) with left temporal astrocytoma (WHO grade II).</p

Patient (female, 48 years) with left frontal anaplastic astrocytoma (WHO grade III).

<p>Patient (female, 48 years) with left frontal anaplastic astrocytoma (WHO grade III).</p

Barplots showing the average fractional anisotropy () of the resulting fiber tracts of each compared pair of methods for the AF (left) and IFOF (right) in the patient and control group.

<p>The numbers N of matching fiber tract pairs are provided in parenthesis. For an explanation of the reduced numbers see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050132#pone-0050132-g005" target="_blank">Figure 5</a>.</p