Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone

Background: The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers. Methods: mRNA microarray data of a discovery set (n = 36 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCore™ workflow. Differential gene expression was confirmed by qPCR in a validation set of 142 IDH1 wild-type GBMs that was also used for survival analysis. Results: Microarray analysis revealed a transcriptome distinctive of SVZ+ GBM that was enriched for genes associated with Notch signaling. No overlap was found to The Cancer Genome Atlas’s molecular subtypes. Independent validation of SVZ-dependent expression confirmed four genes with simultaneous prognostic impact: overexpression of HES4 (p = 0.034; HR 1.55) and DLL3 (p = 0.017; HR 1.61) predicted inferior, and overexpression of NTRK2 (p = 0.049; HR 0.66) and PIR (p = 0.025; HR 0.62) superior overall survival (OS). Additionally, overexpression of DLL3 was predictive of shorter progression-free survival (PFS) (p = 0.043; HR 1.64). Multivariate analysis revealed overexpression of HES4 to be independently associated with inferior OS (p = 0.033; HR 2.03), and overexpression of DLL3 with inferior PFS (p = 0.046; HR 1.65). Conclusions: We identified four genes with SVZ-dependent expression and prognostic significance, among those HES4 and DLL3 as part of Notch signaling, suggesting further evaluation of location-tailored targeted therapies

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

Prognostic relevance of elevated pulmonary arterial pressure assessed non-invasively: Analysis in a large patient cohort with invasive measurements in near temporal proximity.

The clinical relevance of non-invasively derived pulmonary arterial pressure (PAP) by Doppler echocardiography (DE) has been questioned in the past. However, transthoracic echocardiography is used as a cornerstone examination for patients with dyspnea and suspected pulmonary hypertension (PH). This study aimed to evaluate the prognostic value of non-invasive assessed PAP in a large population of patients with known or suspected cardiopulmonary disease.The analyses are based on data of patients of a tertiary cardiology center that received right heart catheterization (RHC) as well as non-invasively assessed PAP by DE within five days, and includes serological and clinical parameters in a retrospective follow-up for up to eight years.Of 1,237 patients, clinical follow-up was possible in 1,038 patients who were included in the statistical analysis. The mean-follow up time was 1,002 days. The composite endpoint of heart transplantation (HTx) or death occurred in n = 308 patients. Elevated PAP measured non-invasively as well as invasively had significant prognostic impact (hazard ratio (HR) 2.32; 95% confidence interval (CI) 1.78-3.04; χ2 = 37.9; p<0.001 versus HR 2.84; 95%CI 2.11-3.82; χ2 = 51.9; p<0.001, respectively). By multivariate analysis, NYHA functional class, N-terminal pro-brain natriuretic peptide, cardiac troponin T, left ventricular ejection fraction, and right ventricular dysfunction remained independently predictive. Incremental prognostic information in a multimodal approach was highly relevant.In this comprehensive study, elevated pulmonary arterial pressure measured by DE offers similar prognostic information on survival or need for HTx as right heart catheterization. Furthermore, the addition of functional capacity and serological biomarkers delivered incremental prognostic information

Survival of patients with or without PH as suggested by Doppler echocardiography visualized by Kaplan-Meier curves.

<p><b>Abbreviations:</b> PH pulmonary hypertension, sPAP systolic pulmonary arterial pressure, HR hazard ratio, 95%CI 95% confidence interval.</p

Prognostic relevance of elevated pulmonary arterial pressure assessed non-invasively: Analysis in a large patient cohort with invasive measurements in near temporal proximity - Fig 4

<p><b>Outcome differentiated by PAP for subgroup of patients:</b> left ventricular cardiomyopathy (CMP):A,B; valvular heart disease: C,D; ischemic heart disease (IHD): E,F and rare cardiac diseases: G;H. Invasive measurements by RHC (A,C,E,G) are compared to non-invasively assessment by DE (B,D,F,G). <b>Abbreviations:</b> m/sPAP mean/systolic pulmonary arterial pressure, HR hazard ratio, 95%CI 95% confidence interval, ns not significant.</p

Incremental predictive information for survival of multimodal clinical settings based on complete-case data (n = 395).

<p><b>Abbreviations:</b> Clin: clinical assessment (age, sex, NYHA functional class), Clin+Echo: clinical assessment and transthoracic (Doppler) echocardiography (LV-EF, RV dysfunction, sPAP, RAP), Clin+Sero: clinical assessment and cardiac serological parameters (NT-proBNP, cTnT); Clin+Sero+Echo: clinical assessment, cardiac serological parameters and transthoracic echocardiography combined; Clin+Sero+Echo+RHC: Non-invasive diagnostics and RHC (CI, mPAP, RAP) combined; Clin+RHC: clinical assessment and RHC (CI, mPAP, RAP) combined. <b>**</b>p<0.001. NYHA New York Heart Association, LV-EF left ventricular ejection fraction, sPAP systolic pulmonary arterial pressure, RAP right atrial pressure, NT-proBNP N-terminal pro brain natriuretic peptide, cTnT cardiac troponin T, CI cardiac index, mPAP mean pulmonary arterial pressure, RHC right heart catheterization.</p

Multivariate analysis for independent predictive parameters.

<p>Multivariate analysis for independent predictive parameters.</p

Hemodynamic characteristics of the study population.

<p>Hemodynamic characteristics of the study population.</p

Study protocol.

<p>Flow chart with inclusion criteria from catheter and echocardiography databases, identification of individual patients, and exclusion due to loss of clinical follow-up. <b>Abbreviation:</b> RHC right heart catheterization.</p