Transient Lymphatic Remodeling Follows Sub-Ablative High-Frequency Irreversible Electroporation Therapy in a 4T1 Murine Model.

High-frequency irreversible electroporation (H-FIRE) is a minimally invasive local ablation therapy known to activate the adaptive immune system and reprogram the tumor microenvironment. Its predecessor, irreversible electroporation (IRE), transiently increases microvascular density and immune cell infiltration within the surviving non-ablated and non-necrotic tumor region, also known as the viable tumor region. However, the impact of pulse electric field therapies on lymphatic vessels, crucial for T-cell fate and maturation, remains unclear.

3D models of glioblastoma interaction with cortical cells.

Glioblastoma (GBM) invasiveness and ability to infiltrate deep into the brain tissue is a major reason for the poor patient prognosis for this type of brain cancer. Behavior of glioblastoma cells, including their motility, and expression of invasion-promoting genes such as matrix metalloprotease-2 (MMP2), are strongly influenced by normal cells found in the brain parenchyma. Cells such as neurons may also be influenced by the tumor, as many glioblastoma patients develop epilepsy.

[89Zr]ZrDFO-CR011 PET Correlates with Response to Glycoprotein Nonmetastatic Melanoma B-targeted Therapy in Triple-negative Breast Cancer.

There is a need for prognostic markers to select patients most likely to benefit from antibody-drug conjugate (ADC) therapy. We quantified the relationship between pretreatment PET imaging of glycoprotein nonmetastatic melanoma B (gpNMB) with 89Zr-labeled anti-gpNMB antibody ([89Zr]ZrDFO-CR011) and response to ADC therapy (CDX-011) in triple-negative breast cancer. First, we compared different PET imaging metrics and found that standardized uptake values (SUV) and tumor-to-heart SUV ratios were sufficient to delineate differences in radiotracer uptake in the tumor of four different cell- and patient-derived tumor models and achieved high standardized effect sizes.

Role of novel cancer gene SLITRK3 to activate NTRK3 in squamous cell lung cancer.

The development of targeted therapies that inhibit cancer-driving oncogenes has improved outcomes of patients diagnosed with lung adenocarcinoma (LUAD). In contrast, patients diagnosed with lung squamous cell carcinoma (LUSC) suffer worse survival outcomes and lack effective targeted treatment options. Identification of molecular drivers of LUSC to support development of targeted treatments is urgently needed.

Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling.

Background: Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level.

Dopamine is an aryl hydrocarbon receptor agonist.

Tryptophan metabolites exhibit aryl hydrocarbon receptor (AhR) agonist activity and recent studies show that the phenylalanine metabolites serotonin and carbidopa, a drug used in treating Parkinson's disease, activated the AhR. In this study, we identified the neuroactive hormone dopamine as an inducer of drug-metabolizing enzymes CYP1A1, CYP1B1, and UGT1A1 in colon and glioblastoma cells and similar results were observed for carbidopa. In contrast, carbidopa but not dopamine exhibited AhR activity in BxPC3 pancreatic cancer cells whereas minimal activity was observed for both compounds in Panc1 pancreatic cancer cells.

Depression and tryptophan metabolism in patients with primary brain tumors: Clinical and molecular imaging correlates.

Patients with brain tumors have an increased risk for depression, whose underlying pathomechanism may involve dysregulated tryptophan/kynurenine metabolism. In this study, we analyzed the relation of depressive symptoms to clinical and tumor characteristics as well as cerebral and systemic tryptophan metabolism in patients with primary brain tumors. Sixty patients with newly-diagnosed or recurrent primary brain tumor underwent testing with the Beck Depression Inventory-II (BDI-II), and 34 patients also had positron emission tomography (PET) imaging with alpha-[C]methyl-L-tryptophan (AMT).

Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth.

: The aryl hydrocarbon receptor (AhR) is expressed in gliomas and the highest staining is observed in glioblastomas. A recent study showed that the AhR exhibited tumor suppressor-like activity in established and patient-derived glioblastoma cells and genomic analysis showed that this was due, in part, to suppression of CXCL12, CXCR4 and MMP9. : Selective AhR modulators (SAhRMs) including AhR-active pharmaceuticals were screened for their inhibition of invasion using a spheroid invasion assay in patient-derived AhR-expressing 15-037 glioblastoma cells and in AhR-silenced 15-037 cells.

Nuclear receptor 4A2 (NR4A2) is a druggable target for glioblastomas.

Introduction: The orphan nuclear receptor 4A2 (NR4A2) has been extensively characterized in subcellular regions of the brain and is necessary for the function of dopaminergic neurons. The NR4A2 ligand, 1,1-bis (3-indoly1)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) inhibits markers of neuroinflammation and degeneration in mouse models and in this study we investigated expression and function of NR4A2 in glioblastoma (GBM).

Methods: Established and patient-derived cell lines were used as models and the expression and functions of NR4A2 were determined by western blots and NR4A2 gene silencing by antisense oligonucleotides respectively.

Alternative Splicing of RAD6B and Not RAD6A is Selectively Increased in Melanoma: Identification and Functional Characterization.

Rad6B, a principal component of the translesion synthesis pathway, and activator of canonical Wnt signaling, plays an essential role in cutaneous melanoma development and progression. As Rad6 is encoded by two genes, namely, () and (), in humans, we compared their expressions in melanomas and normal melanocytes. While both genes are weakly expressed in normal melanocytes, Rad6B is more robustly expressed in melanoma lines and patient-derived metastatic melanomas than RAD6A.

The aryl hydrocarbon receptor is a tumor suppressor-like gene in glioblastoma.

The aryl hydrocarbon receptor (AhR) plays an important role in maintaining cellular homeostasis and also in pathophysiology. For example, the interplay between the gut microbiome and microbially derived AhR ligands protects against inflammation along the gut-brain axis. The AhR and its ligands also inhibit colon carcinogenesis, but it has been reported that the AhR and its ligand kynurenine enhance glioblastoma (GBM).

Multimodal imaging-defined subregions in newly diagnosed glioblastoma: impact on overall survival.

Background: Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value.

Methods: Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma.

Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors.

Introduction: There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment.

Amino Acid PET Imaging of the Early Metabolic Response During Tumor-Treating Fields (TTFields) Therapy in Recurrent Glioblastoma.

Tumor-treating fields (TTFields) therapy is a relatively new treatment approach for malignant gliomas. We evaluated if amino acid PET can detect an objective metabolic response to TTFields therapy in recurrent glioblastomas. PET scanning with alpha[C-11]-methyl-L-tryptophan (AMT) before and 2 to 3 months after the start of TTFields treatment showed an interval decrease of tryptophan uptake in the whole tumor (2 patients) or in a portion of the tumor (1 patient).

GNAQ Mutation in the Venous Vascular Malformation and Underlying Brain Tissue in Sturge-Weber Syndrome.

The recent identification of the somatic mutation (c.548G > A) provides insight into the pathogenesis of Sturge–Weber syndrome (SWS). Although the primary SWS brain pathology is the leptomeningeal angiomatosis (LMA), cerebral cortical and white matter abnormalities play a prominent role in the disease manifestations.

Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies.

OBJECTIVE Treatment for glioblastoma (GBM) remains largely unsuccessful, even with aggressive combined treatment via surgery, radiotherapy, and chemotherapy. Tumor treating fields (TTFs) are low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties in vitro and in vivo. The authors provide an up-to-date review of the mechanism of action as well as preclinical and clinical data on TTFs.

Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma.

Purpose: Several molecular glioma markers (including isocitrate dehydrogenase 1 [IDH1] mutation, amplification of the epidermal growth factor receptor [EGFR], and methylation of the O6-methylguanine-DNA methyltransferase [MGMT] promoter) have been associated with glioblastoma survival. In this study, we examined the association between tumoral amino acid uptake, molecular markers, and overall survival in patients with IDH1 wild-type (primary) glioblastoma.

Patients And Methods: Twenty-one patients with newly diagnosed IDH1 wild-type glioblastomas underwent presurgical MRI and PET scanning with alpha[C-11]-L-methyl-tryptophan (AMT).

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts.

Unlabelled: Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. α-C-methyl-l-tryptophan (C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-F-fluoroethyl)-l-tryptophan (F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway.

Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma.

Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM).

Preferential expression of functional IL-17R in glioma stem cells: potential role in self-renewal.

Gliomas are the most common primary brain tumor and one of the most lethal solid tumors. Mechanistic studies into identification of novel biomarkers are needed to develop new therapeutic strategies for this deadly disease. The objective for this study was to explore the potential direct impact of IL-17-IL-17R interaction in gliomas.

Whole genome sequence analysis links chromothripsis to EGFR, MDM2, MDM4, and CDK4 amplification in glioblastoma.

Background: Findings based on recent advances in next-generation sequence analysis suggest that, in some tumors, a single catastrophic event, termed chromothripsis, results in several simultaneous tumorigenic alterations. Previous studies have suggested that glioblastoma (GBM) may exhibit chromothripsis at a higher rate (39%) than other tumors (9%). Primary glioblastoma is an aggressive form of brain cancer that typically appears suddenly in older adults.

Acute or chronic use of lacosamide does not alter its distribution between serum and cerebrospinal fluid.

Objective: The site of action for antiepileptic drugs (AEDs) is within the brain; however, cerebrospinal fluid (CSF) concentration is highly variable. Lacosamide (LCM) is approved by the U.S.

Development of patient-derived xenograft models from a spontaneously immortal low-grade meningioma cell line, KCI-MENG1.

Background: There is a paucity of effective therapies for recurrent/aggressive meningiomas. Establishment of improved in vitro and in vivo meningioma models will facilitate development and testing of novel therapeutic approaches.

Methods: A primary meningioma cell line was generated from a patient with an olfactory groove meningioma.

Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas.

Background: Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas. However, details of tryptophan metabolism in meningiomas have not been elucidated. In this study, we evaluated in vivo tryptophan metabolism in meningiomas and compared it with gliomas using α-[(11)C]-methyl-L-tryptophan (AMT)-PET.