Prognostic Value of Preoperative MRI Metrics for Diffuse Lower-Grade Glioma Molecular Subtypes.

BACKGROUND AND PURPOSE: Despite the improved prognostic relevance of the 2016 WHO molecular-based classification of lower-grade gliomas, variability in clinical outcome persists within existing molecular subtypes. Our aim was to determine prognostically significant metrics on preoperative MR imaging for lower-grade gliomas within currently defined molecular categories. MATERIALS AND METHODS: We undertook a retrospective analysis of 306 patients with lower-grade gliomas accrued from an institutional data base and The Cancer Genome Atlas. Two neuroradiologists in consensus analyzed preoperative MRIs of each lower-grade glioma to determine the following: tumor size, tumor location, number of involved lobes, corpus callosum involvement, hydrocephalus, midline shift, eloquent cortex involvement, ependymal extension, margins, contrast enhancement, and necrosis. Adjusted hazard ratios determined the association between MR imaging metrics and overall survival per molecular subtype, after adjustment for patient age, patient sex, World Health Organization grade, and surgical resection status. RESULTS: For isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas, tumor size (hazard ratio, 3.82; 95% CI, 1.94-7.75; P < .001), number of involved lobes (hazard ratio, 1.70; 95% CI, 1.28-2.27; P < .001), hydrocephalus (hazard ratio, 4.43; 95% CI, 1.12-17.54; P = .034), midline shift (hazard ratio, 1.16; 95% CI, 1.03-1.30; P = .013), margins (P = .031), and contrast enhancement (hazard ratio, 0.34; 95% CI, 0.13-0.90; P = .030) were associated with overall survival. For IDH-mutant 1p/19q-codeleted lower-grade gliomas, tumor size (hazard ratio, 2.85; 95% CI, 1.06-7.70; P = .039) and ependymal extension (hazard ratio, 6.34; 95% CI, 1.07-37.59; P = .042) were associated with overall survival. CONCLUSIONS: MR imaging metrics offers prognostic information for patients with lower-grade gliomas within molecularly defined classes, with the greatest prognostic value for IDH wild-type lower-grade gliomas.

Predicting Genotype and Survival in Glioma Using Standard Clinical MR Imaging Apparent Diffusion Coefficient Images: A Pilot Study from The Cancer Genome Atlas.

BACKGROUND AND PURPOSE: Few studies have shown MR imaging features and ADC correlating with molecular markers and survival in patients with glioma. Our purpose was to correlate MR imaging features and ADC with molecular subtyping and survival in adult diffuse gliomas. MATERIALS AND METHODS: Presurgical MRIs and ADC maps of 131 patients with diffuse gliomas and available molecular and survival data from The Cancer Genome Atlas were reviewed. MR imaging features, ADC (obtained by ROIs within the lowest ADC area), and mean relative ADC values were evaluated to predict isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion status, MGMT promoter methylation, and overall survival. RESULTS: IDH wild-type gliomas tended to exhibit enhancement, necrosis, and edema; >50% enhancing area (P < .001); absence of a cystic area (P = .013); and lower mean relative ADC (median, 1.1 versus 1.6; P < .001) than IDH-mutant gliomas. By means of a cutoff value of 1.08 for mean relative ADC, IDH-mutant and IDH wild-type gliomas with lower mean relative ADC (<1.08) had poorer survival than those with higher mean relative ADC (median survival time, 24.2 months; 95% CI, 0.0-54.9 months versus 62.0 months; P = .003; and median survival time, 10.4 months; 95% CI, 4.4-16.4 months versus 17.7 months; 95% CI, 11.6-23.7 months; P = .041, respectively), regardless of World Health Organization grade. Median survival of those with IDH-mutant glioma with low mean relative ADC was not significantly different from that in those with IDH wild-type glioma. Other MR imaging features were not statistically significant predictors of survival. CONCLUSIONS: IDH wild-type glioma showed lower ADC values, which also correlated with poor survival in both IDH-mutant and IDH wild-type gliomas, irrespective of histologic grade. A subgroup with IDH-mutant gliomas with lower ADC had dismal survival similar to that of those with IDH wild-type gliomas.

CSF Pressure Change in Relation to Opening Pressure and CSF Volume Removed.

BACKGROUND AND PURPOSE: Idiopathic intracranial hypertension is a complex neurologic disorder resulting from increased intracranial pressure. Our aim was to determine whether a correlation exists between the CSF pressure-volume relationship, specifically the craniospinal elastance and pressure-volume index, in patients with idiopathic intracranial hypertension and whether opening pressure affects this relationship. MATERIALS AND METHODS: Lumbar punctures performed for suspected idiopathic intracranial hypertension from 2006 to 2017 were identified. Opening and closing pressures, CSF volume removed, and clinical diagnosis of idiopathic intracranial hypertension were obtained from the medical records. The craniospinal elastance (pressure change per milliliter of CSF removed) and pressure-volume index were calculated, and the Pearson correlation coefficients between both the craniospinal elastance and pressure-volume index and opening pressure were determined. Linear regression models of craniospinal elastance and the pressure-volume index and interaction terms with opening pressure were assessed for covariate influence on this association. RESULTS: One hundred sixteen patients were included in the final analysis. The mean craniospinal elastance according to opening pressure group was 0.52 ± 0.18 for <20 cm H2O, 0.57 ± 0.20 for 20-29 cm H2O, 0.91 ± 0.28 for 30-39 cm H2O, and 1.20 ± 0.25 for ≥40 cm H2O. There was a positive linear association between opening pressure and craniospinal elastance with a 0.28 cm H2O/mL increase in craniospinal elastance (standard error = 0.03, P < .001) for every 10 cm H2O increase in opening pressure. Of the covariables analyzed, only age older than 50 years and total volume of CSF removed affected this association. CONCLUSIONS: As opening pressure increases, the craniospinal elastance increases in a linear fashion while the pressure-volume index decreases. Further studies are needed to determine whether these changes relate to the underlying pathophysiology of idiopathic intracranial hypertension or simply represent established CSF volume pressure dynamics.

Deep-Learning Convolutional Neural Networks Accurately Classify Genetic Mutations in Gliomas.

BACKGROUND AND PURPOSE: The World Health Organization has recently placed new emphasis on the integration of genetic information for gliomas. While tissue sampling remains the criterion standard, noninvasive imaging techniques may provide complimentary insight into clinically relevant genetic mutations. Our aim was to train a convolutional neural network to independently predict underlying molecular genetic mutation status in gliomas with high accuracy and identify the most predictive imaging features for each mutation. MATERIALS AND METHODS: MR imaging data and molecular information were retrospectively obtained from The Cancer Imaging Archives for 259 patients with either low- or high-grade gliomas. A convolutional neural network was trained to classify isocitrate dehydrogenase 1 (IDH1) mutation status, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status. Principal component analysis of the final convolutional neural network layer was used to extract the key imaging features critical for successful classification. RESULTS: Classification had high accuracy: IDH1 mutation status, 94%; 1p/19q codeletion, 92%; and MGMT promotor methylation status, 83%. Each genetic category was also associated with distinctive imaging features such as definition of tumor margins, T1 and FLAIR suppression, extent of edema, extent of necrosis, and textural features. CONCLUSIONS: Our results indicate that for The Cancer Imaging Archives dataset, machine-learning approaches allow classification of individual genetic mutations of both low- and high-grade gliomas. We show that relevant MR imaging features acquired from an added dimensionality-reduction technique demonstrate that neural networks are capable of learning key imaging components without prior feature selection or human-directed training.

A Multipronged Comparative Study of the Ultraviolet Photochemistry of 2-, 3-, and 4-Chlorophenol in the Gas Phase.

The S1((1)ππ*) state of the (dominant) syn-conformer of 2-chlorophenol (2-ClPhOH) in the gas phase has a subpicosecond lifetime, whereas the corresponding S1 states of 3- and 4-ClPhOH have lifetimes that are, respectively, ∼2 and ∼3-orders of magnitude longer. A range of experimental techniques-electronic spectroscopy, ultrafast time-resolved photoion and photoelectron spectroscopies, H Rydberg atom photofragment translational spectroscopy, velocity map imaging, and time-resolved Fourier transform infrared emission spectroscopy-as well as electronic structure calculations (of key regions of the multidimensional ground (S0) state potential energy surface (PES) and selected cuts through the first few excited singlet PESs) have been used in the quest to explain these striking differences in excited state lifetime. The intramolecular O-H···Cl hydrogen bond specific to syn-2-ClPhOH is key. It encourages partial charge transfer and preferential stabilization of the diabatic (1)πσ* potential (relative to that of the (1)ππ* state) upon stretching the C-Cl bond, with the result that initial C-Cl bond extension on the adiabatic S1 PES offers an essentially barrierless internal conversion pathway via regions of conical intersection with the S0 PES. Intramolecular hydrogen bonding is thus seen to facilitate the type of heterolytic dissociation more typically encountered in solution studies.

VUV photoionization of gas phase adenine and cytosine: a comparison between oven and aerosol vaporization.

We studied the single photon ionization of gas phase adenine and cytosine by means of vacuum ultraviolet synchrotron radiation coupled to a velocity map imaging electron∕ion coincidence spectrometer. Both in-vacuum temperature-controlled oven and aerosol thermodesorption were successfully applied to promote the intact neutral biological species into the gas phase. The photoion yields are consistent with previous measurements. In addition, we deduced the threshold photoelectron spectra and the slow photoelectron spectra for both species, where the close to zero kinetic energy photoelectrons and the corresponding photoions are measured in coincidence. The photoionization close and above the ionization energies are found to occur mainly via direct processes. Both vaporization techniques lead to similar electronic spectra for the two molecules, which consist of broadbands due to the complex electronic structure of the cationic species and to the possible contribution of several neutral tautomers for cytosine prior to ionization. Accurate ionization energies are measured for adenine and cytosine at, respectively, 8.267 ± 0.005 eV and 8.66 ± 0.01 eV, and we deduce precise thermochemical data for the adenine radical cation. Finally, we performed an evaluation and a comparison of the two vaporization techniques addressing the following criteria: measurement precision, thermal fragmentation, sensitivity, and sample consumption. The aerosol thermodesorption technique appears as a promising alternative to vaporize large thermolabile biological compounds, where extended thermal decomposition or low sensitivity could be encountered when using a simple oven vaporization technique.

Correlation of perfusion parameters with genes related to angiogenesis regulation in glioblastoma: a feasibility study.

BACKGROUND AND PURPOSE: Integration of imaging and genomic data is critical for a better understanding of gliomas, particularly considering the increasing focus on the use of imaging biomarkers for patient survival and treatment response. The purpose of this study was to correlate CBV and PS measured by using PCT with the genes regulating angiogenesis in GBM. MATERIALS AND METHODS: Eighteen patients with WHO grade IV gliomas underwent pretreatment PCT and measurement of CBV and PS values from enhancing tumor. Tumor specimens were analyzed by TCGA by using Human Gene Expression Microarrays and were interrogated for correlation between CBV and PS estimates across the genome. We used the GO biologic process pathways for angiogenesis regulation to select genes of interest. RESULTS: We observed expression levels for 92 angiogenesis-associated genes (332 probes), 19 of which had significant correlation with PS and 9 of which had significant correlation with CBV (P < .05). Proangiogenic genes such as TNFRSF1A (PS = 0.53, P = .024), HIF1A (PS = 0.62, P = .0065), KDR (CBV = 0.60, P = .0084; PS = 0.59, P = .0097), TIE1 (CBV = 0.54, P = .022; PS = 0.49, P = .039), and TIE2/TEK (CBV = 0.58, P = .012) showed a significant positive correlation; whereas antiangiogenic genes such as VASH2 (PS = -0.72, P = .00011) showed a significant inverse correlation. CONCLUSIONS: Our findings are provocative, with some of the proangiogenic genes showing a positive correlation and some of the antiangiogenic genes showing an inverse correlation with tumor perfusion parameters, suggesting a molecular basis for these imaging biomarkers; however, this should be confirmed in a larger patient population.

Sarcoidosis and granuloma genes: a family-based study in African-Americans.

The evidence for a genetic component in the aetiology of sarcoidosis includes familial aggregation, associations with genetic polymorphisms, and linkage to the major histocompatibility complex class region on chromosome 6p. Unfortunately, the majority of genetic associations with sarcoidosis have not been consistently replicated. In the present study, using a family-based study design, which controls for population stratification, the authors attempted to replicate previously reported associations between sarcoidosis and three attractive candidate genes studied primarily in case-control samples. In 225 nuclear families, ascertained through African Americans with a history of sarcoidosis, no evidence was found for an association between sarcoidosis susceptibility and polymorphisms in the angiotensin converting enzyme, vitamin D receptor and tumour necrosis factor-alpha genes. Further analyses of chronic and acute disease phenotypes failed to reveal any notable associations. Assuming an underlying inheritance model with an additive allelic effect on disease risk, the current study had approximately 80-90% statistical power to detect a 3-fold increased risk associated with the putative risk allele of the polymorphisms under study. The present authors conclude that in African-Americans, the angiotensin converting enzyme, vitamin D receptor, and tumour necrosis factor-alpha genes are not significant risk factors for sarcoidosis susceptibility.

RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signalling molecule highly expressed in megakaryocytes.

Myelopoiesis and lymphopoiesis are controlled by haematopoietic growth factors, including cytokines, and chemokines that bind to G-protein-coupled receptors (GPCRs). Regulators of G-protein signalling (RGSs) are a protein family that can act as GTPase-activating proteins for G(alphai)- and G(alphaq)-class proteins. We have identified a new member of the R4 subfamily of RGS proteins, RGS18. RGS18 contains clusters of hydrophobic and basic residues, which are characteristic of an amphipathic helix within its first 33 amino acids. RGS18 mRNA was most highly abundant in megakaryocytes, and was also detected specifically in haematopoietic progenitor and myeloerythroid lineage cells. RGS18 mRNA was not detected in cells of the lymphoid lineage. RGS18 was also highly expressed in mouse embryonic 15-day livers, livers being the principal organ for haematopoiesis at this stage of fetal development. RGS1, RGS2 and RGS16, other members of the R4 subfamily, were expressed in distinct progenitor and mature myeloerythroid and lymphoid lineage blood cells. RGS18 was shown to interact specifically with the G(alphai-3) subunit in membranes from K562 cells. Furthermore, overexpression of RGS18 inhibited mitogen-activated-protein kinase activation in HEK-293/chemokine receptor 2 cells treated with monocyte chemotactic protein-1. In yeast cells, RGS18 overexpression complemented a pheromone-sensitive phenotype caused by mutations in the endogeneous yeast RGS gene, SST2. These data demonstrated that RGS18 was expressed most highly in megakaryocytes, and can modulate GPCR pathways in both mammalian and yeast cells in vitro. Hence RGS18 might have an important role in the regulation of megakaryocyte differentiation and chemotaxis.

Multiple pigmented cutaneous papules associated with a novel canine papillomavirus in an immunosuppressed dog.

Cutaneous papillomavirus infection was diagnosed in a 6-year-old female Boxer dog that was under long-term corticosteroid therapy for atopic dermatitis. Multiple black, rounded papules were present on the ventral skin. Spontaneous regression occurred within 3 weeks after cessation of corticosteroids. Histologically, the lesions consisted of well-demarcated cup-shaped foci of epidermal endophytic hyperplasia with marked parakeratosis. In the upper stratum spinosum and in the stratum granulosum, solitary or small collections of enlarged keratinocytes were observed with basophilic intranuclear inclusion bodies and a single eosinophilic fibrillar cytoplasmic inclusion. Ultrastructurally, viruslike particles (40-45 nm in diameter) were observed within the nucleus, free or aggregated in crystalline arrays. Undulating fibrillar material, thought to be a modified keratin protein, was observed in the cytoplasmic inclusion. Immunohistochemistry, restriction enzyme analysis, and molecular hybridization experiments indicated that these distinctive clinical, histologic, and cytologic features were associated with a novel canine papillomavirus.

Interleukin 2 (IL-2) receptor expression and sensitivity to diphteria fusion toxin DAB389IL-2 in cultured hematopoietic cells.

The high-affinity interleukin 2 (IL-2) receptor is a heterotrimer consisting of alpha, beta, and gamma subunits. We examined the concentration of subunit mRNA for each of the three protein subunits on human hematopoietic cell lines, human peripheral blood mononuclear cells, and murine fibroblasts transfected with cDNAs encoding the human IL-2 receptor subunits. In most cultured hematopoietic cells, there was abundant gamma subunit message. In contrast, there was variable expression of both alpha and beta subunit message. Sensitivity of cells to the diphtheria fusion toxin DAB389IL-2 was not related to expression of any single IL-2 receptor subunit mRNA. Rather, the greatest sensitivity was observed for cells possessing all three subunit mRNAs. Cells displaying beta and gamma subunit mRNA showed a reduced but significant sensitivity to the fusion toxin. In contrast, cells with alpha and gamma subunit mRNA, but missing the beta subunit mRNA, were insensitive to DAB389IL-2. The data correlate with the requirement for an intermediate or a high-affinity receptor for cell intoxication. A critical concentration of the beta subunit may be required for toxin internalization and killing.

Natural killer cell response to regional lymph node metastases.

A determination of natural killer cell activity was performed in 67 individuals with advanced head and neck cancer. The mean activity of 28 patients clinically staged T3 NO or T4 NO was 81 +/- 11 lytic units (LU), significantly higher than 39 patients with palpable lymph node metastases (54 +/- 5 LU). Assessing patients by extent of nodal disease revealed that activity actually increased, though not significantly, with progressive N-staging. A major determinate of increased natural killer cell cytotoxicity in patients with lymph node metastases was extranodal cancer within the neck. The mean activity of nine patients whose tumor was fixed to underlying structures or adherent to skin was 87 +/- 15 LU, significantly higher than the 45 +/- 4 LU mean value of the remaining patients with clinically determined regional nodal disease. The potential clinical implications of these findings are discussed.