Glioma is the most common and lethal intrinsic primary tumor of the brain. Its controversial origins may contribute to its heterogeneity, creating challenges and difficulties in the development of therapies. Among the components constituting tumors, glioma stem cells are highly plastic subpopulations that are thought to be the site of tumor initiation. Neural stem cells/progenitor cells and oligodendrocyte progenitor cells are possible lineage groups populating the bulk of the tumor, in which gene mutations related to cell-cycle or metabolic enzymes dramatically affect this transformation. Novel approaches have revealed the tumor-promoting properties of distinct tumor cell states, glial, neural, and immune cell populations in the tumor microenvironment. Communication between tumor cells and other normal cells manipulate tumor progression and influence sensitivity to therapy. Here, we discuss the heterogeneity and relevant functions of tumor cell state, microglia, monocyte-derived macrophages, and neurons in glioma, highlighting their bilateral effects on tumors. Finally, we describe potential therapeutic approaches and targets beyond standard treatments.
Humans ; Glioma/metabolism* ; Neuroglia/metabolism* ; Carcinogenesis/pathology* ; Neural Stem Cells/metabolism* ; Microglia/metabolism* ; Brain Neoplasms/metabolism* ; Tumor Microenvironment

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.
Humans ; Brain Neoplasms/pathology* ; Neoplasm Recurrence, Local/metabolism* ; Glioma/pathology* ; Neural Stem Cells/pathology* ; Oligodendrocyte Precursor Cells/pathology* ; Tumor Microenvironment

A 74-year-old woman presented with a month-long nausea and vomiting, then she could not take a meal. She had found an asymptomatic 4th ventricular mass 6 year ago as a preoperative work-up for ovarian cancer. And during the yearly follow-up, the mass had grown continuously over 6 years, and caused symptoms in the seventh year. MRI revealed a large ovoid extra-axial mass in the fourth ventricle compressing adjacent medulla and cerebellum. Surgery achieved near total resection since the tumor tightly adhered to the brain stem of 4th ventricle floor. The histological diagnosis was ependymoma (WHO grade II). She transferred rehabilitation facility for mild gait disturbance, hoarseness and swallowing difficulty. Fourth ventricle ependymoma in the elderly is extremely rare and the growth rate has not been reported. Here, we present a rare care of 4th ventricle ependymoma found asymptomatic at elderly but continuously grow to cause local pressure symptoms.
Aged ; Brain Stem ; Cerebellum ; Deglutition ; Diagnosis ; Ependymoma ; Female ; Follow-Up Studies ; Fourth Ventricle ; Gait ; Hoarseness ; Humans ; Magnetic Resonance Imaging ; Meals ; Nausea ; Ovarian Neoplasms ; Rehabilitation ; Vomiting

Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumor-related death among children. Until now, there is still a lack of effective therapy with prolonged overall survival for this disease. A typical strategy for preclinical cancer research is to find out the molecular differences between tumor tissue and para-tumor normal tissue, in order to identify potential therapeutic targets. Unfortunately, it is impossible to obtain normal tissue for DIPG because of the vital functions of the pons. Here we report the human fetal hindbrain-derived neural progenitor cells (pontine progenitor cells, PPCs) as normal control cells for DIPG. The PPCs not only harbored similar cell biological and molecular signatures as DIPG glioma stem cells, but also had the potential to be immortalized by the DIPG-specific mutation H3K27M in vitro. These findings provide researchers with a candidate normal control and a potential medicine carrier for preclinical research on DIPG.
Animals ; Brain Stem Neoplasms ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Cellular Senescence ; Female ; Glioma ; genetics ; metabolism ; pathology ; Histones ; genetics ; Humans ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Transplantation ; Neoplastic Stem Cells ; drug effects ; metabolism ; pathology ; Neural Stem Cells ; drug effects ; metabolism ; pathology ; Pons ; embryology ; metabolism ; pathology ; Primary Cell Culture

PURPOSE: The aim is to study the dependence of deformable based auto-segmentation of head and neck organs-at-risks (OAR) on anatomy matching for a single atlas based system and generate an acceptable set of contours. METHODS: A sample of ten patients in neutral neck position and three atlas sets consisting of ten patients each in different head and neck positions were utilized to generate three scenarios representing poor, average and perfect anatomy matching respectively and auto-segmentation was carried out for each scenario. Brainstem, larynx, mandible, cervical oesophagus, oral cavity, pharyngeal muscles, parotids, spinal cord, and trachea were the structures selected for the study. Automatic and oncologist reference contours were compared using the dice similarity index (DSI), Hausdroff distance and variation in the centre of mass (COM). RESULTS: The mean DSI scores for brainstem was good irrespective of the anatomy matching scenarios. The scores for mandible, oral cavity, larynx, parotids, spinal cord, and trachea were unacceptable with poor matching but improved with enhanced bony matching whereas cervical oesophagus and pharyngeal muscles had less than acceptable scores for even perfect matching scenario. HD value and variation in COM decreased with better matching for all the structures. CONCLUSION: Improved anatomy matching resulted in better segmentation. At least a similar setup can help generate an acceptable set of automatic contours in systems employing single atlas method. Automatic contours from average matching scenario were acceptable for most structures. Importance should be given to head and neck position during atlas generation for a single atlas based system.
Brain Stem ; Head and Neck Neoplasms ; Head ; Humans ; Larynx ; Mandible ; Methods ; Mouth ; Neck ; Organs at Risk ; Pharyngeal Muscles ; Radiotherapy ; Spinal Cord ; Trachea

Anti-Ma2-associated encephalitis is one of the paraneoplastic limbic and brainstem encephalitis characterized by decreased consciousness, parkinsonism and the limitation of vertical eye movement. It is usually associated with non-small cell lung cancer in male and female or germ cell tumor in male. Herein, we report a case of atypical anti-Ma2-associated encephalitis which presented with axonal sensorimotor polyneuropathy.
Autoantibodies ; Axons ; Brain Stem ; Carcinoma, Non-Small-Cell Lung ; Consciousness ; Encephalitis ; Eye Movements ; Female ; Humans ; Limbic Encephalitis ; Male ; Neoplasms, Germ Cell and Embryonal ; Paraneoplastic Syndromes ; Parkinsonian Disorders ; Polyneuropathies

This study aimed at identifying the frequency and final diagnoses of stroke mimics (SMs) among suspected stroke cases, and seeking differences in clinical & imaging features between SMs and true strokes. It was retrospective with data taken from an ongoing stroke registry for patients admitted to a Stroke Unit between 1 May and 31 October 2011. Baseline characteristics, clinical & imaging features, complications, and outcomes of SMs were compared to those with true strokes by appropriate statistical tests. The total number of cases admitted was 537. Only 232 (43.2%) of them presented during the critical time thrombolytic intervention. SMs comprised 15.9% of all suspected stroke cases. The commonest mimics were psychiatric disorders (43.2%), migraines (16.2%), seizures (8.1%), brain tumors (5.4%), and systemic infections (5.4%). SMs were younger, more common in females, with less evidence of preexisting hypertension (43.2% vs. 56.9% for true strokes). Hemianopia (p = 0.001), sensory inattention, neglect or both (p < 0.001) were more associated with true strokes, while cerebellar, brainstem signs or both (p = 0.045) excluding dysarthria were linked only to SMs. Acute ischemic signs in imaging scans were found linked to true strokes. Some clinical and imaging characteristics were found to differentiate to some extent between SMs and true strokes.
Brain Neoplasms ; Brain Stem ; Diagnosis ; Diagnosis, Differential ; Dysarthria ; Female ; Hemianopsia ; Humans ; Hypertension ; Migraine Disorders ; Retrospective Studies ; Seizures ; Stroke* ; Thrombolytic Therapy

The prognosis of brain tumors in children has improved for last a few decades. However, the prognosis remains dismal in patients with recurrent brain tumors. The outcome for infants and young children in whom the use of radiotherapy (RT) is very limited because of unacceptable long-term adverse effect of RT remains poor. The prognosis is also not satisfactory when a large residual tumor remains after surgery or when leptomeningeal seeding is present at diagnosis. In this context, a strategy using high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) has been explored to improve the prognosis of recurrent or high-risk brain tumors. This strategy is based on the hypothesis that chemotherapy dose escalation might result in improvement in survival rates. Recently, the efficacy of tandem HDCT/auto-SCT has been evaluated in further improving the outcome. This strategy is based on the hypothesis that further dose escalation might result in further improvement in survival rates. At present, the number of studies employing tandem HDCT/auto-SCT for brain tumors is limited. However, results of these pilot studies suggest that tandem HDCT/auto-SCT may further improve the outcome. In this review, we will summarize our single center experience with tandem HDCT/auto-SCT for recurrent or high-risk brain tumors.
Brain Neoplasms ; Brain ; Child ; Diagnosis ; Drug Therapy ; Humans ; Infant ; Neoplasm, Residual ; Pilot Projects ; Prognosis ; Radiotherapy ; Stem Cell Transplantation ; Stem Cells ; Survival Rate

Intraoperative monitoring (IOM) utilizes electrophysiological techniques as a surrogate test and evaluation of nervous function while a patient is under general anesthesia. They are increasingly used for procedures, both surgical and endovascular, to avoid injury during an operation, examine neurological tissue to guide the surgery, or to test electrophysiological function to allow for more complete resection or corrections. The application of IOM during pediatric brain tumor resections encompasses a unique set of technical issues. First, obtaining stable and reliable responses in children of different ages requires detailed understanding of normal ageadjusted brain-spine development. Neurophysiology, anatomy, and anthropometry of children are different from those of adults. Second, monitoring of the brain may include risk to eloquent functions and cranial nerve functions that are difficult with the usual neurophysiological techniques. Third, interpretation of signal change requires unique sets of normative values specific for children of that age. Fourth, tumor resection involves multiple considerations including defining tumor type, size, location, pathophysiology that might require maximal removal of lesion or minimal intervention. IOM techniques can be divided into monitoring and mapping. Mapping involves identification of specific neural structures to avoid or minimize injury. Monitoring is continuous acquisition of neural signals to determine the integrity of the full longitudinal path of the neural system of interest. Motor evoked potentials and somatosensory evoked potentials are representative methodologies for monitoring. Free-running electromyography is also used to monitor irritation or damage to the motor nerves in the lower motor neuron level : cranial nerves, roots, and peripheral nerves. For the surgery of infratentorial tumors, in addition to free-running electromyography of the bulbar muscles, brainstem auditory evoked potentials or corticobulbar motor evoked potentials could be combined to prevent injury of the cranial nerves or nucleus. IOM for cerebral tumors can adopt direct cortical stimulation or direct subcortical stimulation to map the corticospinal pathways in the vicinity of lesion. IOM is a diagnostic as well as interventional tool for neurosurgery. To prove clinical evidence of it is not simple. Randomized controlled prospective studies may not be possible due to ethical reasons. However, prospective longitudinal studies confirming prognostic value of IOM are available. Furthermore, oncological outcome has also been shown to be superior in some brain tumors, with IOM. New methodologies of IOM are being developed and clinically applied. This review establishes a composite view of techniques used today, noting differences between adult and pediatric monitoring.
Adult ; Anesthesia, General ; Anthropometry ; Brain Neoplasms ; Brain ; Child ; Cranial Nerves ; Electromyography ; Evoked Potentials, Auditory, Brain Stem ; Evoked Potentials, Motor ; Evoked Potentials, Somatosensory ; Humans ; Infratentorial Neoplasms ; Intraoperative Neurophysiological Monitoring ; Longitudinal Studies ; Monitoring, Intraoperative ; Motor Neurons ; Muscles ; Neurophysiology ; Neurosurgery ; Peripheral Nerves ; Prospective Studies

Diffuse intrinsic pontine glioma (DIPG) is a deadly paediatric brain cancer. Transient response to radiation, ineffective chemotherapeutic agents and aggressive biology result in rapid progression of symptoms and a dismal prognosis. Increased availability of tumour tissue has enabled the identification of histone gene aberrations, genetic driver mutations and methylation changes, which have resulted in molecular and phenotypic subgrouping. However, many of the underlying mechanisms of DIPG oncogenesis remain unexplained. It is hoped that more representative in vitro and preclinical models–using both xenografted material and genetically engineered mice–will enable the development of novel chemotherapeutic agents and strategies for targeted drug delivery. This review provides a clinical overview of DIPG, the barriers to progress in developing effective treatment, updates on drug development and preclinical models, and an introduction to new technologies aimed at enhancing drug delivery.
Biology ; Brain Neoplasms ; Brain Stem Neoplasms ; Carcinogenesis ; Glioma ; Heterografts ; Histones ; Hope ; In Vitro Techniques ; Methylation ; Molecular Biology ; Prognosis