Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate ...the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.
BACKGROUND: Plaque vulnerability plays an important role in determining the risk of subsequent cerebrovascular events in patients with carotid stenosis. Plaque morphology magnetic resonance imaging ...(MRI) can be used to assess plaque vulnerability. We therefore set out to examine the diagnostic accuracy of plaque morphology MRI compared with histopathological findings as gold standard in moderate- to high-grade carotid stenosis at our centre.
A total of 36 patients with moderate- to high-grade carotid stenosis underwent plaque morphology MRI with a multisequence protocol (time of flight sequence, dark blood T1- native and post-gadolinium and T2-weighted sequence with fat suppression). The status of the fibrous cap, calcification, lipid-rich necrotic core (LRNC) and intraplaque haemorrhage (IPH) were assessed by means of qualitative MR analysis of plaque characteristics and compared with the histopathological findings. Detection statistics (sensitivity, specificity), chi-squared test, Cohen's kappa (κ), percentage of agreement and phi coefficient (φ) were determined.
Carotid stenosis was symptomatic (transient ischaemic attack, amaurosis fugax or ischaemic stroke in the territory of the stenosed carotid artery) in 25 patients (69.5%). Twenty-eight patients (77.8%) had a high-grade and eight patients (12.2%) a moderate-grade stenosis. Significant congruence between MRI and histology was found for plaque calcification (89% histology, 75% MRI, κ = 0.364, p = 0.013), for LRNC (89% histology, 53% MRI, κ = 0.245, p = 0.025) and IPH (75% histology, 53% MRI, κ = 0.314, p = 0.035). In a subgroup of patients with symptomatic stenosis, the agreement for LRNC and IPH was slightly better (LRNC κ = 0.390, p = 0.014; IPH κ = 0.386, p = 0.045). Status of the fibrous cap, essentially ulceration, did not show any significant agreement (κ = 0.032, p = 0.842). There was significant correlation between LRNC on MRI and symptomatic carotid stenosis (φ = 0.339, p = 0.042).
Plaque morphology MRI is capable of identifying the main components of atherosclerotic plaques with moderate to good accuracy as compared with histopathological findings as gold standard. LRNC seems to be a useful marker of plaque vulnerability and warrants its use in clinical decision making.  .
Background This study aims to identify robust radiomic features for Magnetic Resonance Imaging (MRI), assess feature selection and machine learning methods for overall survival classification of ...Glioblastoma multiforme patients, and to robustify models trained on single-center data when applied to multi-center data. Methods Tumor regions were automatically segmented on MRI data, and 8327 radiomic features extracted from these regions. Single-center data was perturbed to assess radiomic feature robustness, with over 16 million tests of typical perturbations. Robust features were selected based on the Intraclass Correlation Coefficient to measure agreement across perturbations. Feature selectors and machine learning methods were compared to classify overall survival. Models trained on single-center data (63 patients) were tested on multi-center data (76 patients). Priors using feature robustness and clinical knowledge were evaluated. Results We observed a very large performance drop when applying models trained on single-center on unseen multi-center data, e.g. a decrease of the area under the receiver operating curve (AUC) of 0.56 for the overall survival classification boundary at 1 year. By using robust features alongside priors for two overall survival classes, the AUC drop could be reduced by 21.2%. In contrast, sensitivity was 12.19% lower when applying a prior. Conclusions Our experiments show that it is possible to attain improved levels of robustness and accuracy when models need to be applied to unseen multi-center data. The performance on multi-center data of models trained on single-center data can be increased by using robust features and introducing prior knowledge. For successful model robustification, tailoring perturbations for robustness testing to the target dataset is key. Keywords: Glioblastoma multiforme, MRI radiomics, Overall survival classification, Multi-center, Robustness
Mutations affecting codon 172 of the isocitrate dehydrogenase 2 (IDH2) gene define a subgroup of sinonasal undifferentiated carcinomas (SNUCs) with a relatively favorable prognosis and a globally ...hypermethylated phenotype. They are also recurrent (along with IDH1 mutations) in gliomas, acute myeloid leukemia, and intrahepatic cholangiocarcinoma. Commonly reported mutations, all associated with aberrant IDH2 enzymatic activity, include R172K, R172S, R172T, R172G, and R172M. We present a case of SNUC with a never-before-described IDH2 mutation, R172A. Our report compares the methylation pattern of our sample to other cases from the Gene Expression Omnibus database. Hierarchical clustering suggests a strong association between our sample and other IDH-mutant SNUCs and a clear distinction between sinonasal normal tissues and tumors. Principal component analysis (PCA), using 100 principal components explaining 94.5% of the variance, showed the position of our sample to be within 1.02 standard deviation of the other IDH-mutant SNUCs. A molecular modeling analysis of the IDH2 R172A versus other R172 variants provides a structural explanation to how they affect the protein active site. Our findings thus suggest that the R172A mutation in IDH2 confers a gain of function similar to other R172 mutations in IDH2, resulting in a similar hypermethylated profile.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas ...with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent
CDKN2A/B
deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in
NF1
and
TP53
along with
IDH1/2
and
TERT
promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c)
TERT
promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Background Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low ...sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy. Case presentations. The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3. Conclusions Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Wide-field imaging Mueller polarimetry is a revolutionary, label-free, and non-invasive modality for computer-aided intervention; in neurosurgery, it aims to provide visual feedback of white ...matter fibre bundle orientation from derived parameters. Conventionally, robust polarimetric parameters are estimated after averaging multiple measurements of intensity for each pair of probing and detected polarised light. Long multi-shot averaging, however, is not compatible with real-time in vivo imaging, and the current performance of polarimetric data processing hinders the translation to clinical practice.
Methods
A learning-based denoising framework is tailored for fast, single-shot, noisy acquisitions of polarimetric intensities. Also, performance-optimised image processing tools are devised for the derivation of clinically relevant parameters. The combination recovers accurate polarimetric parameters from fast acquisitions with near-real-time performance, under the assumption of pseudo-Gaussian polarimetric acquisition noise.
Results
The denoising framework is trained, validated, and tested on experimental data comprising tumour-free and diseased human brain samples in different conditions. Accuracy and image quality indices showed significant (
p
<
0.05
) improvements on testing data for a fast single-pass denoising versus the state-of-the-art and high polarimetric image quality standards. The computational time is reported for the end-to-end processing.
Conclusion:
The end-to-end image processing achieved real-time performance for a localised field of view (
≈
6.5
mm
2
). The denoised polarimetric intensities produced visibly clear directional patterns of neuronal fibre tracts in line with reference polarimetric image quality standards; directional disruption was kept in case of neoplastic lesions. The presented advances pave the way towards feasible oncological neurosurgical translations of novel, label-free, interventional feedback.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims
To assess whether in oligoastrocytomas ATRX deficiency, as a surrogate of the alternative lengthening of telomeres (ALT) pathway, has a role in predicting the presence or absence of loss of ...heterozygosity (LOH) of 1p and 19q, the genetic signature of oligodendroglial differentiation and a favourable prognostic marker.
Methods and results
A series of 54 oligoastrocytomas were investigated by immunohistochemistry as well as microsatellite analysis for LOH 1p19q. Genetic findings were correlated with morphological assessment.
Conclusions
ATRX deficiency was mutually exclusive with LOH. Conversely, ATRX‐proficient tumours immunoreactive for R132H‐mutant isocitrate dehydrogenase 1 (IDH1) showed a high rate (85%) of LOH. A more oligodendroglioma‐like morphology was associated with a higher rate of LOH even in the morphologically ambiguous group of oligoastrocytomas. Our findings support the concept that oligoastrocytomas represent a morphological grey zone, rather than a group of truly ‘mixed’ or ‘intermediate’ tumours. More precise classification of diffuse gliomas may also improve grading of borderline cases. We propose an immunohistochemical algorithm for classification of morphologically ambiguous diffuse gliomas.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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