Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and ...radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.
Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.
Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.
The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
Purpose:
One of the important challenges in the field of medical imaging is finding real clinical images with which to validate new image processing algorithms. This is particularly true for tracked ...3D ultrasound images of the brain.
Methods:
In 2010, pre- and postoperative magnetic resonance and intraoperative ultrasound images were acquired from brain tumor patients involved in the authors’ imaging study at the Montreal Neurological Institute.
Results:
These data are available online at the Montreal Neurological Institute’s Brain Images of Tumors for Evaluation database, termed here the MNI BITE database. It contains ultrasound and magnetic resonance images from 14 patients. Each patient underwent a preoperative and a postoperative T1-weighted magnetic resonance scan with gadolinium enhancement, and multiple intraoperative B-mode images were acquired before and after resection. Corresponding features were manually selected in some image pairs for validation. All images are in MINC format, the file format used at the authors’ institute for image processing. The MINC tools are available for free download at packages.bic.mni.mcgill.ca.
Conclusions:
This is the first online database of its kind. These images can be used by image processing scientists as well as clinicians wishing to compare findings from magnetic resonance and ultrasound imaging.
Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human ...OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte‐lineage cells with stage‐specific functional properties. Cells were isolated from surgical tissue samples of second‐trimester fetal, 2‐year‐old pediatric, 13‐year‐old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet‐based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e‐OPC) group, a late OPC group (l‐OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e‐OPCs included cell cycle and development, for l‐OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e‐OPCs were mostly confined to the premyelinating fetal group, and the l‐OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l‐OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL‐lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.
Human scRNA‐seq based OL‐lineage cell data was derived from immediately ex vivo surgically resected specimens covering a wide age range.
Transcriptomic signatures were characterized across distinct stages of OL development, with links to specific biological processes.
Significance: Raman spectroscopy has been developed for surgical guidance applications interrogating live tissue during tumor resection procedures to detect molecular contrast consistent with cancer ...pathophysiological changes. To date, the vibrational spectroscopy systems developed for medical applications include single-point measurement probes and intraoperative microscopes. There is a need to develop systems with larger fields of view (FOVs) for rapid intraoperative cancer margin detection during surgery.
Aim: We design a handheld macroscopic Raman imaging system for in vivo tissue margin characterization and test its performance in a model system.
Approach: The system is made of a sterilizable line scanner employing a coherent fiber bundle for relaying excitation light from a 785-nm laser to the tissue. A second coherent fiber bundle is used for hyperspectral detection of the fingerprint Raman signal over an area of 1 cm2. Machine learning classifiers were trained and validated on porcine adipose and muscle tissue.
Results: Porcine adipose versus muscle margin detection was validated ex vivo with an accuracy of 99% over the FOV of 95 mm2 in ∼3 min using a support vector machine.
Conclusions: This system is the first large FOV Raman imaging system designed to be integrated in the workflow of surgical cancer resection. It will be further improved with the aim of discriminating brain cancer in a clinically acceptable timeframe during glioma surgery.
Abstract Here we introduce a Raman spectroscopy approach combining multi‐spectral imaging and a new fluorescence background subtraction technique to image individual Raman peaks in less than 5 ...seconds over a square field‐of‐view of 1‐centimeter sides with 350 micrometers resolution. First, human data is presented supporting the feasibility of achieving cancer detection with high sensitivity and specificity – in brain, breast, lung, and ovarian/endometrium tissue – using no more than three biochemically interpretable biomarkers associated with the inelastic scattering signal from specific Raman peaks. Second, a proof‐of‐principle study in biological tissue is presented demonstrating the feasibility of detecting a single Raman band – here the CH 2 /CH 3 deformation bands from proteins and lipids – using a conventional multi‐spectral imaging system in combination with the new background removal method. This study paves the way for the development of a new Raman imaging technique that is rapid, label‐free, and wide field.
Abstract
BACKGROUND
The median time to recurrence of glioblastoma (GB) following multimodal treatment is ∼7 mo. Nearly all cancers recur locally, suggesting that augmenting local treatments may ...improve outcomes.
OBJECTIVE
To investigate whether intraoperative radiotherapy (IORT) to the resection cavity is safe and effective.
METHODS
INTRAGO was a phase I/II trial to evaluate the safety and tolerability of IORT with 20 to 40 Gy of low-energy photons in addition to standard radiochemotherapy (ClinicalTrials.gov ID, NCT02685605). The primary endpoint was safety as per occurrence of dose-limiting toxicities. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also performed an exploratory analysis of the local PFS (L-PFS), defined as recurrence within 1 cm of the treated margin.
RESULTS
Fifteen patients were treated at 3 dose levels. Of these, 13 underwent incomplete resection, 6 had unresected satellites, and 3 did not receive per-protocol treatment (PPT). The MGMT promoter was unmethylated in 10 patients. The median follow-up was 13.8 mo. The majority of grade 3 to 5 adverse events were deemed unrelated to IORT. Five cases of radionecrosis were observed, 2 were classified as grade 3 events. Other grade 3 events judged related to radiotherapy (external-beam radiotherapy and/or IORT) were wound dehiscence (n = 1), CSF leakage (n = 1), cyst formation (n = 1). No IORT-related deaths occurred. The median PFS was 11.2 mo (95% confidence interval CI: 5.4-17.0) for all patients and 11.3 mo (95% CI: 10.9-11.6) for those receiving PPT. The median L-PFS was 14.3 mo (95% CI: 8.4-20.2) for all patients and 17.8 mo (95% CI: 9.7-25.9) for those receiving PPT. The median OS was 16.2 mo (95% CI: 11.1-21.4) for all patients and 17.8 mo (95% CI: 13.9-21.7) for those receiving PPT.
CONCLUSION
These data suggest that IORT is associated with manageable toxicity. Considering the limitations of a 15-patient phase I/II trial, further studies aimed at assessing an outcome benefit are warranted.
Abstract
Driver mutations in IDH1 and IDH2 characterize a substantial proportion of diffuse gliomas. These tumors are typically of lower grade at diagnosis, but many eventually transform to more ...aggressive disease. Furthermore, there is a lack of effective curative treatments. Mutated IDH molecules acquire neomorphic enzymatic activity, favoring the synthesis of D-2-hydroxyglutarate (D-2-HG). Accumulation of this metabolite perturbs many cellular functions and drives gliomagenesis through incompletely understood mechanisms. IDH mutations are early events in gliomagenesis, but the identity of the initiating cell type has been debated. Here, using genetically engineered mice, we found that combining Idh1R132H and Trp53 loss in oligodendrocyte progenitors leads to fully penetrant development of diffuse gliomas. The tumors recapitulate the cardinal features of the corresponding human disease. While heterogeneous, the mouse Idh1R132H and Idh1WT tumors show distinct patterns of transcriptional alterations and oncogenic copy number variants. Mutant IDH itself is an attractive drug target, as it is clonally expressed and usually retained during tumor evolution, even though its relevance for disease progression has been questioned. Nevertheless, recent clinical trials have demonstrated clear, but variable, anti-tumor effects of mutant IDH inhibitors in patients. To better understand the mechanistic basis for heterogeneous responses to mutant IDH inhibition, we performed CRISPR/Cas9 functional genomic screens in cell lines derived from the mouse Idh1R132H;Trp53MUT tumors. These revealed interactions between the mutant IDH inhibitor vorasidenib and molecules related to astrocytic differentiation, Notch signaling, and cell growth and metabolism. The translational relevance of these findings was supported by molecular data from human tumors, patients treated with IDH inhibitors, and human-derived cell models. Overall, these studies nominate oligodendrocyte progenitors as candidate cells of origin for IDH mutated gliomas, and point to strategies that may enhance the efficacy of IDH inhibitors.
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