Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas.

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations

Hospital-based intervention to reduce tPA administration time

Objective: Ischemic strokes cause significant morbidity and mortality. Treatment with tissue plasminogen activator (tPA) is an important step to achieve reperfusion and minimize neuronal loss for those patients that qualify. Multiple studies have shown that there is a direct correlation between the timeliness of tPA administration after infarction has begun and improved health outcomes. Hospital process related barriers to tPA administration increase the time from the onset of stroke to treatment, leading to worse outcomes. Patients and methods: This retrospective review from a single stroke center looked at stroke patients across three years (July 2014–May 2017) and examined the temporal delay to treatment that potentially stemmed from the fact that tPA was given after transfer from the radiology suite (post-CT scan) back to the emergency department. This order of events is commonplace in stroke centers across the US. Results: Our results indicate there is a significant 26 minute delay with the commonly used protocol where tPA is given, not in the CT scanner, but rather after the scan when patients return to the emergency room. Conclusion: Our results imply that a change in the protocol (direct administration of tPA in the radiology suite) could improve health outcomes by decreasing the delay in tPA administration. Keywords: Stroke, tPA, Barriers to treatment, Vascular neurology, Quality improvement, Vascular neurosurger

Genomic characterization of an esthesioneuroblastoma with spinal metastases: illustrative case.

BACKGROUND: Esthesioneuroblastoma (ENB) is a rare neoplasm of the sinonasal tract. Currently, the optimal treatment includes maximal resection combined with radiotherapy and/or chemotherapy. Although ENBs often recur and have an aggressive clinical course, spinal metastases are extremely rare and the underlying molecular mechanisms are poorly understood. OBSERVATIONS: Here, the authors describe a 50-year-old male with an aggressive ENB, initially treated with resection and chemotherapy/radiation, who developed multiple thoracic and lumbar spinal metastases. The authors performed targeted exome sequencing on both the resected primary tumor and biopsied spinal metastases, which revealed 12 total variants of unknown clinical significance in genes associated with the PI3K/AKT/mTOR pathway, chromatin remodeling, DNA repair, and cell proliferation. Six of these variants were restricted to the metastatic lesion and included missense mutations with predicted functional effects in GRM3, DNMT3B, PLCG2, and SPEN. LESSONS: This report discusses the potential impact of these variants on tumor progression and metastasis, as well as the implications for identifying potential new biomarkers and therapies

Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas.

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations

Box and whisker plots showing antigen concentration distributions among symptomatic cases and oligo/asymptomatic cases among the close contacts in anterior nares swab (ANS), nasopharyngeal swab (NPS), and saliva specimens.

The number (n) of specimens per category is listed above each category.</p

Summary of SARS-CoV-2 cases, associated specimens, and number of antigen results.

Result totals are shown for the study participants for index cases, household contacts, and non-household contacts. The proportion of samples selected and run for antigen testing from each participant is shown for nasopharyngeal swab (NPS), anterior nares swab (ANS), and saliva. The lysis buffer for the STANDARD Q ANS specimen was used for antigen concentration determination in the ANS specimen. Because the 64 household contacts had multiple timepoints per individual, test results are reported for the combined individual and timepoint together for a total of 224 samplings). Positive and negative classifications correspond to available test results from laboratory PCR results, SalivaDirect, STANDARD Q Saliva, LumiraDx, and STANDARD Q point-of-care (anterior nasal) and exclude antigen concentration measurement results. Totals are listed with breakdowns from those totals of number of Sympomatic (S), Oligosymptomatic (O), Asymptomatic (A). (DOCX)</p

Probability of positivity for the rapid antigen tests as a function of antigen concentration on their cognate specimen.

Points plot test results (1 = positive, 0 = negative) versus concentration of N antigen in sample. Lines represent fits to data points to model probability of positivity. Panel (A): Probability for positive test result for Lumira (blue) and the STANDARD Q test (magenta) conducted on the ANS specimen as a function of the antigen concentration in the ANS specimen, and the STANDARD Q test (green) conducted on the saliva specimen as a function of the antigen concentration in the saliva specimen. Panel (B): Probability of positive test for the same three tests as a function of viral load in NPS specimens. The antigen concentration or viral load at which there is greater than 90% probability of a positive test result is indicated. The shaded areas show the 95% credible intervals for the probability functions.</p

Case definitions for the study.

Descriptions are of participant symptoms, regardless of test positivity. (DOCX)</p