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Cells Jul 2023The most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. This implies the extraction and analysis of non-solid biological tissues... (Review)
Review
The most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. This implies the extraction and analysis of non-solid biological tissues (serum, plasma, saliva, urine, and cerebrospinal fluid) without undergoing invasive procedures to determine disease prognosis. Liquid biopsy can be used for the screening of several components, such as extracellular vesicles, microRNAs, cell-free DNA, cell-free mitochondrial and nuclear DNA, circulating tumour cells, circulating tumour DNA, transfer RNA, and circular DNA or RNA derived from body fluids. Its application includes early disease diagnosis, the surveillance of disease activity, and treatment response monitoring, with growing evidence for validating this methodology in cancer, liver disease, and central nervous system (CNS) disorders. This review will provide an overview of mentioned liquid biopsy components, which could serve as valuable biomarkers for the evaluation of complex neurological conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, traumatic brain injury, CNS tumours, and neuroinfectious diseases. Furthermore, this review highlights the future directions and potential limitations associated with liquid biopsy.
Topics: Humans; Liquid Biopsy; Cell-Free Nucleic Acids; MicroRNAs; Central Nervous System Neoplasms; Biomarkers
PubMed: 37508574
DOI: 10.3390/cells12141911 -
Nature Oct 2023Central nervous system tumours represent one of the most lethal cancer types, particularly among children. Primary treatment includes neurosurgical resection of the...
Central nervous system tumours represent one of the most lethal cancer types, particularly among children. Primary treatment includes neurosurgical resection of the tumour, in which a delicate balance must be struck between maximizing the extent of resection and minimizing risk of neurological damage and comorbidity. However, surgeons have limited knowledge of the precise tumour type prior to surgery. Current standard practice relies on preoperative imaging and intraoperative histological analysis, but these are not always conclusive and occasionally wrong. Using rapid nanopore sequencing, a sparse methylation profile can be obtained during surgery. Here we developed Sturgeon, a patient-agnostic transfer-learned neural network, to enable molecular subclassification of central nervous system tumours based on such sparse profiles. Sturgeon delivered an accurate diagnosis within 40 minutes after starting sequencing in 45 out of 50 retrospectively sequenced samples (abstaining from diagnosis of the other 5 samples). Furthermore, we demonstrated its applicability in real time during 25 surgeries, achieving a diagnostic turnaround time of less than 90 min. Of these, 18 (72%) diagnoses were correct and 7 did not reach the required confidence threshold. We conclude that machine-learned diagnosis based on low-cost intraoperative sequencing can assist neurosurgical decision-making, potentially preventing neurological comorbidity and avoiding additional surgeries.
Topics: Child; Humans; Central Nervous System Neoplasms; Clinical Decision-Making; Deep Learning; Intraoperative Care; Methylation; Retrospective Studies; Sequence Analysis, DNA; Time Factors
PubMed: 37821699
DOI: 10.1038/s41586-023-06615-2 -
Cancer Cell Nov 2023Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain...
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory. This antitumor effect is driven by the direct effect of TIM-3 inhibition in tumor cells, the coordinated action of several immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. This work uncovers TIM-3 as a bona fide target in DIPG and supports its clinical translation.
Topics: Humans; Child; Diffuse Intrinsic Pontine Glioma; Glioma; Immunologic Memory; Hepatitis A Virus Cellular Receptor 2; Brain Stem Neoplasms; Tumor Microenvironment
PubMed: 37802053
DOI: 10.1016/j.ccell.2023.09.001 -
Current Oncology (Toronto, Ont.) Jun 2023The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer... (Review)
Review
The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer types. For our purposes, the focused metastatic malignancies include breast cancer, lung cancer, melanoma, primary central nervous system tumors, and hematologic cancers (lymphoma, leukemia, and multiple myeloma). Of note, our discussion was limited to cancer-specific leptomeningeal metastases secondary to the aforementioned primary cancers. LMD mechanisms secondary to non-cancerous pathologies, such as infection or inflammation of the leptomeningeal layer, were excluded from our scope of review. Furthermore, we intended to characterize general leptomeningeal disease, including the specific anatomical infiltration process/area, CSF dissemination, manifesting clinical symptoms in patients afflicted with the disease, detection mechanisms, imaging modalities, and treatment therapies (both preclinical and clinical). Of these parameters, leptomeningeal disease across different primary cancers shares several features. Pathophysiology regarding the development of CNS involvement within the mentioned cancer subtypes is similar in nature and progression of disease. Consequently, detection of leptomeningeal disease, regardless of cancer type, employs several of the same techniques. Cerebrospinal fluid analysis in combination with varied imaging (CT, MRI, and PET-CT) has been noted in the current literature as the gold standard in the diagnosis of leptomeningeal metastasis. Treatment options for the disease are both varied and currently in development, given the rarity of these cases. Our review details the differences in leptomeningeal disease as they pertain through the lens of several different cancer subtypes in an effort to highlight the current state of targeted therapy, the potential shortcomings in treatment, and the direction of preclinical and clinical treatments in the future. As there is a lack of comprehensive reviews that seek to characterize leptomeningeal metastasis from various solid and hematologic cancers altogether, the authors intended to highlight not only the overlapping mechanisms but also the distinct patterning of disease detection and progression as a means to uniquely treat each metastasis type. The scarcity of LMD cases poses a barrier to more robust evaluations of this pathology. However, as treatments for primary cancers have improved over time, so has the incidence of LMD. The increase in diagnosed cases only represents a small fraction of LMD-afflicted patients. More often than not, LMD is determined upon autopsy. The motivation behind this review stems from the increased capacity to study LMD in spite of scarcity or poor patient prognosis. In vitro analysis of leptomeningeal cancer cells has allowed researchers to approach this disease at the level of cancer subtypes and markers. We ultimately hope to facilitate the clinical translation of LMD research through our discourse.
Topics: Humans; Female; Positron Emission Tomography Computed Tomography; Meningeal Carcinomatosis; Breast Neoplasms; Magnetic Resonance Imaging; Hematologic Neoplasms
PubMed: 37366925
DOI: 10.3390/curroncol30060442 -
Cells Apr 2024Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently... (Review)
Review
Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they come. In this work, the possibility of using MSCs to deliver therapeutic genes, oncolytic viruses, and miRNA is presented, as well as strategies that can improve their therapeutic efficacy against glioblastoma, such as CAR-T cells, nanoparticles, and exosomes.
Topics: Humans; Glioblastoma; Mesenchymal Stem Cell Transplantation; Glioma; Brain Neoplasms; Mesenchymal Stem Cells
PubMed: 38607056
DOI: 10.3390/cells13070617 -
Current Opinion in Oncology Sep 2023Primary central nervous system lymphoma (PCNSL) is a rare central nervous system (CNS) malignancy, which represents a heterogenous group of tumors. Among PCNSL, diffuse... (Review)
Review
PURPOSE OF REVIEW
Primary central nervous system lymphoma (PCNSL) is a rare central nervous system (CNS) malignancy, which represents a heterogenous group of tumors. Among PCNSL, diffuse large B-cell lymphoma of the CNS (CNS-DLBCL) represents the most common tumor type. Multiomics studies have recently revealed the complex genomic landscape of these rare diseases. These findings lead to a potential new molecular and epigenetic classification.
RECENT FINDINGS
Our review is focused on CNS-DLBCL in immunocompetent patients. CNS-DLBCL are derived from self-reactive/polyreactive precursor cells. An early molecular event such as MYD88 mutation leads to escape elimination of precursor cells, which, by a dysregulated GC reaction, acquire auto-/polyreactivity of the B-cell tumoral cells for antigens physiologically expressed in the CNS. Most of CNS-DLBCL tumor cells harbor a non-GCB, ABC-like immunophenotype associated with a late GC (exit) B-cells genotype by gene expression profiling. Various mechanisms of genetic alterations are involved in the pathogenesis of PCNSL, including point mutations [nonsomatic hypermutation (SHM), aberrant SHM (aSHM)], SHM/aSHM, chromosome copy gains or losses, and DNA hypermethylation. Constitutive NFκB activation plays a key role in lymphoma cell proliferation and survival by dysregulation of toll-like receptor (mutations of CARD11 and MYD88 ), BCR ( CD79B ), JAK-STAT, and NFκB signaling pathways.
SUMMARY
Multiomics approaches have succeeded to substantially improve the understanding of the pathogenesis, as well as the molecular and epigenetic events in PCNSL. Challenges remain due to the obvious heterogeneity of CNS-DLBCL, and improvement is needed for their classification.
Topics: Humans; Myeloid Differentiation Factor 88; Lymphoma, Large B-Cell, Diffuse; Mutation; Signal Transduction; Central Nervous System; Central Nervous System Neoplasms
PubMed: 37439536
DOI: 10.1097/CCO.0000000000000978 -
Der Nervenarzt Feb 2024Gliomas represent the most frequent malignant primary brain tumors in adults. Despite multimodal treatment concepts involving surgery, irradiation and chemotherapy, the... (Review)
Review
BACKGROUND
Gliomas represent the most frequent malignant primary brain tumors in adults. Despite multimodal treatment concepts involving surgery, irradiation and chemotherapy, the prognosis remains poor and they are incurable. Recent insights into the interactions between the immune system and the central nervous system as well as breakthroughs in the results of other cancer types have led to the fact that various immunotherapeutic approaches against gliomas have also been investigated and in some cases specifically developed.
OBJECTIVE
This article provides an overview of the current status of different immunotherapeutic concepts against gliomas, highlighting the advantages, disadvantages, and challenges. Additionally, it provides an overview of currently ongoing immunotherapeutic clinical trials in Germany and neighboring countries.
RESULTS
Previous randomized studies on antibodies against programmed cell death protein 1 (anti-PD1) immune checkpoint inhibition, viral treatment and peptide vaccination targeting the variant III of the epidermal growth factor receptor (EGFRvIII) in glioblastomas were negative with respect to survival benefits. Conversely, other immunotherapeutic approaches, such as multivalent or driver mutation-based vaccinations, cytokine-based therapy and cell therapy, demonstrated a robust scientific foundation, with at least early studies showing promising safety and pharmacodynamic effects on the tumors.
DISCUSSION
Currently, immunotherapies against gliomas should only be applied within the framework of well-designed clinical studies. There are still many knowledge gaps regarding the mechanisms of action and resistance of various immunotherapies. Accompanying translational research is essential to address these gaps and develop more effective therapies.
Topics: Adult; Humans; Cancer Vaccines; Vaccines, Subunit; Glioma; Brain Neoplasms; Immunotherapy
PubMed: 38169045
DOI: 10.1007/s00115-023-01590-5 -
Cell Communication and Signaling : CCS Sep 2023Gliomas are the most common brain tumors characterized by complicated heterogeneity. The genetic, molecular, and histological pathology of gliomas is characterized by... (Review)
Review
Gliomas are the most common brain tumors characterized by complicated heterogeneity. The genetic, molecular, and histological pathology of gliomas is characterized by high neuro-inflammation. The inflammatory microenvironment in the central nervous system (CNS) has been closely linked with inflammasomes that control the inflammatory response and coordinate innate host defenses. Dysregulation of the inflammasome causes an abnormal inflammatory response, leading to carcinogenesis in glioma. Because of the clinical importance of the various physiological properties of the inflammasome in glioma, the inflammasome has been suggested as a promising treatment target for glioma management. Here, we summarize the current knowledge on the contribution of the inflammasomes in glioma and therapeutic insights. Video Abstract.
Topics: Humans; Inflammasomes; Glioma; Brain Neoplasms; Carcinogenesis; Clinical Relevance; Tumor Microenvironment
PubMed: 37723542
DOI: 10.1186/s12964-023-01255-5 -
Cancer Biology & Therapy Dec 2024Gliomas are the most common type of primary brain tumor. Despite advances in treatment, it remains one of the most aggressive and deadly tumor of the central nervous... (Review)
Review
Gliomas are the most common type of primary brain tumor. Despite advances in treatment, it remains one of the most aggressive and deadly tumor of the central nervous system (CNS). Gliomas are characterized by high malignancy, heterogeneity, invasiveness, and high resistance to radiotherapy and chemotherapy. It is urgent to find potential new molecular targets for glioma. The TRPM channels consist of TRPM1-TPRM8 and play a role in many cellular functions, including proliferation, migration, invasion, angiogenesis, etc. More and more studies have shown that TRPM channels can be used as new therapeutic targets for glioma. In this review, we first introduce the structure, activation patterns, and physiological functions of TRPM channels. Additionally, the pathological mechanism of glioma mediated by TRPM2, 3, 7, and 8 and the related signaling pathways are described. Finally, we discuss the therapeutic potential of targeting TRPM for glioma.
Topics: Humans; Glioma; TRPM Cation Channels; Brain Neoplasms; Signal Transduction; Animals
PubMed: 38680092
DOI: 10.1080/15384047.2024.2338955 -
Frontiers in Immunology 2023Midkine (MDK) is a neurotrophic growth factor highly expressed during embryogenesis with important functions related to growth, proliferation, survival, migration,... (Review)
Review
Midkine (MDK) is a neurotrophic growth factor highly expressed during embryogenesis with important functions related to growth, proliferation, survival, migration, angiogenesis, reproduction, and repair. Recent research has indicated that MDK functions as a key player in autoimmune disorders of the central nervous system (CNS), such as Multiple Sclerosis (MS) and is a promising therapeutic target for the treatment of brain tumors, acute injuries, and other CNS disorders. This review summarizes the modes of action and immunological functions of MDK both in the peripheral immune compartment and in the CNS, particularly in the context of traumatic brain injury, brain tumors, neuroinflammation, and neurodegeneration. Moreover, we discuss the role of MDK as a central mediator of neuro-immune crosstalk, focusing on the interactions between CNS-infiltrating and -resident cells such as astrocytes, microglia, and oligodendrocytes. Finally, we highlight the therapeutic potential of MDK and discuss potential therapeutic approaches for the treatment of neurological disorders.
Topics: Humans; Midkine; Central Nervous System; Brain Injuries, Traumatic; Astrocytes; Brain Neoplasms
PubMed: 38098484
DOI: 10.3389/fimmu.2023.1310094