Disrupting glioblastoma networks with tumor treating fields (TTFields) in in vitro models.

Purpose: This study investigates the biological effect of Tumor Treating Fields (TTFields) on key drivers of glioblastoma's malignancy-tumor microtube (TM) formation-and on the function and overall integrity of the tumor cell network.

Method: Using a two-dimensional monoculture GB cell network model (2DTM) of primary glioblastoma cell (GBC) cultures (S24, BG5 or T269), we evaluated the effects of TTFields on cell density, interconnectivity and structural integrity of the tumor network. We also analyzed calcium (Ca) transient dynamics and network morphology, validating findings in patient-derived tumoroids and brain tumor organoids.

Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy.

The identification of patient-derived, tumor-reactive T cell receptors (TCRs) as a basis for personalized transgenic T cell therapies remains a time- and cost-intensive endeavor. Current approaches to identify tumor-reactive TCRs analyze tumor mutations to predict T cell activating (neo)antigens and use these to either enrich tumor infiltrating lymphocyte (TIL) cultures or validate individual TCRs for transgenic autologous therapies. Here we combined high-throughput TCR cloning and reactivity validation to train predicTCR, a machine learning classifier that identifies individual tumor-reactive TILs in an antigen-agnostic manner based on single-TIL RNA sequencing.

A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1.

Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging and the impact on patient survival unresolved. Here, we establish a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells using a dye uptake methodology, and validate it with recording of cellular calcium epochs and clinical correlations.

PerSurge (NOA-30) phase II trial of perampanel treatment around surgery in patients with progressive glioblastoma.

Background: Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been discovered that excitatory synapses of the AMPA-receptor subtype form between non-malignant brain neurons and tumor cells. This neuron-tumor network connectivity contributed to glioma progression and could be efficiently targeted with the EMA/FDA approved antiepileptic AMPA receptor inhibitor perampanel in preclinical studies.

Fluorescein-stained confocal laser endomicroscopy versus conventional frozen section for intraoperative histopathological assessment of intracranial tumors.

Background: The aim of this clinical trial was to compare Fluorescein-stained intraoperative confocal laser endomicroscopy (CLE) of intracranial lesions and evaluation by a neuropathologist with routine intraoperative frozen section (FS) assessment by neuropathology.

Methods: In this phase II noninferiority, prospective, multicenter, nonrandomized, off-label clinical trial (EudraCT: 2019-004512-58), patients above the age of 18 years with any intracranial lesion scheduled for elective resection were included. The diagnostic accuracies of both CLE and FS referenced with the final histopathological diagnosis were statistically compared in a noninferiority analysis, representing the primary endpoint.

Infective Endocarditis Complicated With a Large Left Coronary Cusp Aneurysm: A Condition With Undefined Natural History and Treatment.

The natural history and treatment of an aortic cusp aneurysm with or without rupture because of native aortic valve infective endocarditis (NAV-IE) have not been well defined. This may explain why current guidelines for the management of valvular heart disease do not include this complication as an indication for surgical aortic valve replacement or repair or transcatheter aortic valve replacement (TAVR). We describe herein the first case of a man aged 76 years with multiple co-morbidities with a NAV-IE associated large left coronary cusp aneurysm with subsequent rupture and consequent severe aortic regurgitation and heart failure for which he underwent an off-label successful TAVR.

Concurrent gliomas in patients with multiple sclerosis.

Background: Concurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives.

Methods: A multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients.

Results: MS neither predisposes nor protects from the development of gliomas.

Side-by-Side Comparison of Compensation Beads Used in Polychromatic Flow Cytometry.

Compensation or unmixing is essential in analyzing multiparameter flow cytometry data. Errors in data correction, either by compensation or unmixing, can completely change the outcome or mislead the researchers. Owing to limited cell numbers, researchers often use synthetic beads to generate the required single stains for the necessary calculation.

How Do Survivor and Mandatory Reporter Status Correlate with Program Outcomes for an Adult-Focused Child Sexual Abuse Prevention Program?

This exploratory study investigated group differences and pre-post changes in knowledge, beliefs, and behavior by mandatory reporters and Child Sexual Abuse (CSA) survivor status for a CSA prevention training designed for the general public. Of the 8,114 study participants, 32% identified as having experienced CSA, and 77% indicated they were mandatory reporters for child abuse and neglect. Mandatory reporters had higher baseline knowledge about CSA than those who were not mandatory reporters and reported more CSA preventative behaviors.

NLGN4X TCR transgenic T cells to treat gliomas.

Background: Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumor-associated antigen, overexpressed in human gliomas, that was found to induce specific cytotoxic T cell responses following multi-peptide vaccination in patients with newly diagnosed glioblastoma.

Methods: T cell receptor (TCR) discovery was performed using droplet-based single-cell TCR sequencing of NLGN4X-tetramer-sorted T cells postvaccination. The identified TCR was delivered to Jurkat T cells and primary human T cells (NLGN4X-TCR-T).

Misclassification of Loss to Care Among Persons With Human Immunodeficiency Virus: Improved Capture of Silent Transfers Through Surveillance Linkage Using Statewide Mandatorily Reported Laboratory Measures.

Human Immunodeficiency Virus (HIV)-positive individuals lost to follow-up from particular clinics may not be lost to care (LTC). After linking Vanderbilt's Comprehensive Care Clinic cohort to Tennessee's statewide HIV surveillance database, LTC decreased from 48.4% to 35.

Individual glioblastoma cells harbor both proliferative and invasive capabilities during tumor progression.

Background: Glioblastomas are characterized by aggressive and infiltrative growth, and by striking heterogeneity. The aim of this study was to investigate whether tumor cell proliferation and invasion are interrelated, or rather distinct features of different cell populations.

Methods: Tumor cell invasion and proliferation were longitudinally determined in real-time using 3D in vivo 2-photon laser scanning microscopy over weeks.

Depression in brain tumor patients-early detection and screening.

Background: Depres sion is reported in up to 90% of cancer patients but to this date, a standardized screening tool for depression specifically modified for patients diagnosed with brain tumors is lacking. Thus, this study aims to develop an adapted screening tool and identify a suitable time slot for screening.

Methods: Sixty-one patients with brain lesions were interviewed prior to neurosurgical resection.

Perceptions of mindfulness practices as a support for individuals managing caregiving responsibilities and chronic disease: A qualitative study.

Objectives: Explore the lived experience of individuals managing and/or caregiving for someone with a chronic disease and their perceptions of developing a mindfulness program for stress reduction.

Methods: Sixteen participants with chronic disease and/or caregivers participated. Participants completed eligibility screening, demographic questionnaires, and semi-structured interviews (30-60 min each) online or by phone.

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors.

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME.

Autonomous rhythmic activity in glioma networks drives brain tumour growth.

Diffuse gliomas, particularly glioblastomas, are incurable brain tumours. They are characterized by networks of interconnected brain tumour cells that communicate via Ca transients. However, the networks' architecture and communication strategy and how these influence tumour biology remain unknown.

T cell receptor dynamic and transcriptional determinants of T cell expansion in glioma-infiltrating T cells.

Background: Glioblastoma (GBM) is characterized by low numbers of glioma-infiltrating lymphocytes (GIL) with a dysfunctional phenotype. Whether this dysfunctional phenotype is fixed or can be reversed upon culturing is poorly understood. The aim of this study was to assess T cell receptor (TCR)-dynamics and -specificities as well as determinants of GIL expansion by sequencing-based technologies and functional assays to explore the use of GIL for cell therapy.

Glioblastoma hijacks neuronal mechanisms for brain invasion.

Glioblastomas are incurable tumors infiltrating the brain. A subpopulation of glioblastoma cells forms a functional and therapy-resistant tumor cell network interconnected by tumor microtubes (TMs). Other subpopulations appear unconnected, and their biological role remains unclear.

Patient-Derived Tumor Organoids for Guidance of Personalized Drug Therapies in Recurrent Glioblastoma.

An obstacle to effective uniform treatment of glioblastoma, especially at recurrence, is genetic and cellular intertumoral heterogeneity. Hence, personalized strategies are necessary, as are means to stratify potential targeted therapies in a clinically relevant timeframe. Functional profiling of drug candidates against patient-derived glioblastoma organoids (PD-GBO) holds promise as an empirical method to preclinically discover potentially effective treatments of individual tumors.

Progression Patterns in Non-Contrast-Enhancing Gliomas Support Brain Tumor Responsiveness to Surgical Lesions.

The overall benefit of surgical treatments for patients with glioma is undisputed. We have shown preclinically that brain tumor cells form a network that is capable of detecting damage to the tumor, and repair itself. The aim of this study was to determine whether a similar mechanism might contribute to local recurrence in the clinical setting.

Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.

The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response.

A gain and dynamic range independent index to quantify spillover spread to aid panel design in flow cytometry.

In conventional flowcytometry one detector (primary) is dedicated for one fluorochrome. However, photons usually end up in other detectors too (fluorescence spillover). 'Compensation' is a process that corrects the spillover signal from all detectors except the primary detector.