Co-evolution of glioma and immune microenvironment.

Glioma evolution is governed by a multitude of dynamic interactions between tumor cells and heterogenous neighboring, non-cancerous cells. This complex ecosystem, termed the tumor microenvironment (TME), includes diverse immune cell types that have gained increasing attention for their critical and paradoxical roles in tumor control and tumorigenesis. Recent work has revealed that the cellular composition and functional state of immune cells in the TME can evolve extensively depending on the tumor stage and intrinsic features of surrounding glioma cells.

A propensity score-matched cost-effectiveness analysis of magnetic resonance-guided laser interstitial thermal therapy versus craniotomy for brain tumor radiation necrosis.

Objective: Radiation necrosis is becoming an increasingly prevalent complication in patients with brain tumors given the growing utility of stereotactic radiosurgery in modern treatment paradigms. Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a new minimally invasive modality that has exhibited an efficacy comparable to craniotomy in treating radiation necrosis. No studies to date have compared their cost-effectiveness despite the significant additional expenses associated with MRgLITT use.

Timing of diffusion tensor imaging in the management of a ruptured pediatric arteriovenous malformation: illustrative case.

Background: Diffusion tensor imaging (DTI) can characterize eloquent white matter tracts affected by brain arteriovenous malformations (AVMs). However, DTI interpretation can be difficult in ruptured cases due to the presence of blood products. The authors present the case of a ruptured pediatric AVM in the corticospinal tract (CST) and discuss how DTI at different time points informed the treatment.

A combination of protein phosphatase 2A inhibition and checkpoint immunotherapy: a perfect storm.

Immune checkpoint blockade has emerged as a potent new tool in the war on cancer. However, only a subset of cancer patients benefit from this therapeutic modality, sparking a search for combination therapies to increase the fraction of responding patients. We argue here that inhibition of protein phosphatase 2A (PP2A) is a promising approach to increase responses to immune checkpoint blockade and other therapies that rely on the presence of tumor-reactive T cells.

The mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing) promotes glioblastoma tumorigenesis by modulating mitochondrial functions.

Unlabelled: The rapid and sustained proliferation in cancer cells requires accelerated protein synthesis. Accelerated protein synthesis and disordered cell metabolism in cancer cells greatly increase the risk of translation errors. ribosome-associated quality control (RQC) is a recently discovered mechanism for resolving ribosome collisions caused by frequent translation stalls.

Glioma-Immune Cell Crosstalk in Tumor Progression.

Glioma progression is a complex process controlled by molecular factors that coordinate the crosstalk between tumor cells and components of the tumor microenvironment (TME). Among these, immune cells play a critical role in cancer survival and progression. The complex interplay between cancer cells and the immune TME influences the outcome of immunotherapy and other anti-cancer therapies.

Neoadjuvant Chemotherapy with Laser Interstitial Thermal Therapy in Central Nervous System Neuroblastoma: Illustrative Case and Literature Review.

Primitive neuroectodermal tumors of the central nervous system, or CNS neuroblastoma, are rare neoplasms in children. Recently, methylation profiling enabled the discovery of four distinct entities of these tumors. The current treatment paradigm involves surgical resection followed by chemotherapy and radiation.

PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma.

Unlabelled: Glioblastoma (GBM) is an immunologically "cold" tumor that does not respond to current immunotherapy. Here, we demonstrate a fundamental role for the α-isoform of the catalytic subunit of protein phosphatase-2A (PP2Ac) in regulating glioma immunogenicity. Genetic ablation of PP2Ac in glioma cells enhanced double-stranded DNA (dsDNA) production and cGAS-type I IFN signaling, MHC-I expression, and tumor mutational burden.

PP2Ac/STRN4 negatively regulates STING-type I IFN signaling in tumor-associated macrophages.

Stimulator of IFN genes type I (STING-Type I) IFN signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonists as monotherapy have shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in macrophages.

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of Pediatric Medulloblastoma.

Pediatric medulloblastoma (MB) is the most common pediatric brain tumor with varying prognoses depending on the distinct molecular subtype. The four consensus subgroups are WNT, Sonic hedgehog (SHH), Group 3, and Group 4, which underpin the current 2021 WHO classification of MB. While the field of knowledge for treating this disease has significantly advanced over the past decade, a deeper understanding is still required to improve the clinical outcomes for pediatric patients, who are often vulnerable in ways that adult patients are not.

Targeting Mitochondrial Oxidative Phosphorylation in Glioblastoma Therapy.

As a multi-functional cellular organelle, mitochondrial metabolic reprogramming is well recognized as a hallmark of cancer. The center of mitochondrial metabolism is oxidative phosphorylation (OXPHOS), in which cells use enzymes to oxidize nutrients, thereby converting the chemical energy to the biological energy currency ATPs. OXPHOS also creates the mitochondrial membrane potential and serve as the driving force of other mitochondrial metabolic pathways and experiences significant reshape in the different stages of tumor progression.

MRI-guided laser interstitial thermal therapy using the Visualase system and Navigus frameless stereotaxy in an infant: technical case report.

Laser interstitial thermal therapy (LITT) is increasingly used as a surgical option for the treatment of epilepsy. Placement of the laser fibers relies on stereotactic navigation with cranial fixation pins. In addition, the laser fiber is stabilized in the cranium during the ablation using a cranial bolt that assumes maturity of the skull.

Mitochondrial Dysfunction, Macrophage, and Microglia in Brain Cancer.

Glioblastoma (GBM) is the most common malignant brain cancer. Increasing evidence suggests that mitochondrial dysfunction plays a key role in GBM progression as mitochondria is essential in regulating cell metabolism, oxidative stress, and cell death. Meanwhile, the immune microenvironment in GBM is predominated by tumor-associated macrophages and microglia (TAM), which is a heterogenous population of myeloid cells that, in general, create an immunosuppressive milieu to support tumor growth.

Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma.

Purpose: Glioblastoma (GBM) carries a dismal prognosis despite standard multimodal treatment with surgery, chemotherapy and radiation. Immune checkpoint inhibitors, such as PD1 blockade, for treatment of GBM failed to show clinical benefit. Rational combination strategies to overcome resistance of GBM to checkpoint monotherapy are needed to extend the promise of immunotherapy to GBM management.

A comparison of the accuracy of fetal MRI and prenatal ultrasonography at predicting lesion level and perinatal motor outcome in patients with myelomeningocele.

Objective: Prenatal imaging has several critical roles in the diagnosis and management of myelomeningocele, including specific family counseling and the selection of fetal surgery or postnatal repair. In this study, the authors compared the accuracy of fetal MRI and prenatal ultrasonography (US) in predicting the spinal lesion level and assessed the correlation between imaging findings and motor function as independently evaluated by a physical therapist (PT) after birth.

Methods: A retrospective review of demographic and clinical data was performed to identify children who had been treated with postnatal myelomeningocele closure at a single institution between March 2013 and December 2018.

Correction to: Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop.

Following publication of the original article [1], the author reported that an author name, Roberta Zappasodi, was missed in the authorship list.

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop.

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines.

Severe cranial deformity following cerebrospinal fluid diversion in an adolescent with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder that causes bone fragility and deformity. Neurological manifestations, including macrocephaly and hydrocephalus, have been reported. Increased vascular fragility or bleeding diathesis also predisposes OI patients to intracranial hemorrhage.

Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade.

Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model.

LB-100, a novel Protein Phosphatase 2A (PP2A) inhibitor, sensitizes malignant meningioma cells to the therapeutic effects of radiation.

Atypical and anaplastic meningiomas (AAM) represent 20% of all meningiomas. They are associated with poor outcomes due to their tendency to recur. While surgery and radiation (RT) are first line therapy, no effective systemic medical treatment has been identified.

A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors.

The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes-permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors.

PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells.

The protein phosphatase 2A (PP2A) inhibitor, LB100, has been shown in pre-clinical studies to be an effective chemo- and radio-sensitizer for treatment of various cancers. We investigated effects associated with LB100 treatment alone and in combination with cisplatin for medulloblastoma (MB) in vitro and in vivo in an intracranial xenograft model. We demonstrated that LB100 had a potent effect on MB cells.

Viral strategies for studying the brain, including a replication-restricted self-amplifying delta-G vesicular stomatis virus that rapidly expresses transgenes in brain and can generate a multicolor golgi-like expression.

Viruses have substantial value as vehicles for transporting transgenes into neurons. Each virus has its own set of attributes for addressing neuroscience-related questions. Here we review some of the advantages and limitations of herpes, pseudorabies, rabies, adeno-associated, lentivirus, and others to study the brain.