Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction of glutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 in regulating synapse maturation and neuronal process formation has not been extensively examined. Here we demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitory postsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number of presynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynaptic inputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutant constructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain, whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4 signaling differentially regulates synapse maturation and dendritic morphology via two distinct mechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively.Although central nervous system synapses utilize a variety of brain-specific molecules to mediate contact formation and maturation, some of the proteins implicated in this process are also major players in neuromuscular junction development. Among these shared molecules are NRG1 3 and its receptor, ErbB4, which are expressed in both the developing and adult brain. Neuregulins comprise a family of four related genes (nrg1-4), each producing a large number of isoforms via differential promoter usage and alternative splicing (1, 2). NRGs contain EGF-like repeats, which enable them to bind to and activate EGF family receptors (ErbB2-4). Previous studies showed that NRG1 is initially synthesized as a transmembrane protein, which then undergoes proteolytic processing, whereby the extracellular EGF-containing fragment is released into the extracellular environment. The remaining intracellular fragment has been shown to translocate into the nucleus, where it regulates neuronal survival and transcription of PSD-95 (3, 4). Proteolytic processing of NRG1 is also regulated by neuronal activity and by interaction with ErbB receptors (3, 5). NRG1 is widely expressed throughout development and adulthood, with the highest expression in nervous tissue (6) and is essential for survival. In the central nervous system NRG1 is also required for differentiation, migration, and development of neurons and glia as well as for axonal myelination and pathfinding, dendritic development, and neurotransmitter receptor maintenance. During development, NRG1-ErbB signaling mediates radial glia maintenance and elonga...
The goal of glioma surgery is maximal safe resection. These intrinsic brain neoplasms, however, lack a clear margin and frequently infiltrate eloquent areas of the brain thus making their surgical resection challenging. This review first focuses on discussion of preoperative investigations that aid in anatomical and functional tumor characterization that help define tumor extent and determine the feasibility of complete resection. The second part of this review outlines intraoperative adjuncts that help identify tumor infiltrated tissues during surgery to maximize the extent of resection. In addition, we discuss the principles of intraoperative functional cortical and subcortical mapping and monitoring that enable maximal tumor resection while minimizing the risk of postoperative neurological deficit. Combined use of different modalities before and during surgery is encouraged to meet surgical goals and to ensure best patient outcome.
Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been extended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients that receive sub-therapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements, and by determining intra-tumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood-brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this manuscript, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0-like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include 1) only patients in whom a resection of the tumor is planned, 2) use of clinical doses of an investigational agent, 3) tissue sampling from enhancing and non-enhancing portions of the tumor, and 4) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.
C erebellar liponeurocytomas are typically lowgrade tumors that arise in the cerebellar hemispheres or vermis and contain cells of neuronal, astrocytic, and lipomatous differentiation. 17 The biology and long-term outcomes of these tumors are undefined, and to our knowledge, familial occurrences have not been described. We present here the case of a young woman with a cerebellar liponeurocytoma and multiple immediate family members, including her mother, with similar lesions. This report describes the tumors from the patient and her mother and provides a brief overview of the histopathology and genetic changes associated with this disease. case report Clinical PresentationA 37-year-old woman presented with a 2-year history of worsening morning and daytime headaches in the occipital area that radiated over the cranium. She also described intermittent paresthesia in her hands and feet, which was of variable distribution and duration. The patient was otherwise healthy with a grossly normal neurological examination. She smoked cigarettes but had no other known medical problems. CT and MRI of the head and spine revealed a solitary fat-containing tumor arising from the region of the superior cerebellar hemisphere and vermis. The heterogeneous lesion had numerous ill-defined septations with patchy enhancement and measured 4.4 × 4.1 × 4.3 cm in the anterior-posterior, medial-lateral, and superior-inferior dimensions, respectively. It extended through the incisura and involved the tectal plate and several deep veins, including the left basal vein of Rosenthal. There was complete effacement of the fourth ventricle and compensated dilation of the third and lateral ventricles. There was displacement of the cerebellar tonsils through the foramen magnum, with compression of the cervicomedullary junction ( Fig. 1A and B).abbreviatioNs GFAP = glial fibrillary acidic protein; IDH1 = isocitrate dehydrogenase 1; MAP-2 = microtubule-associated protein 2; MIB-1 = monoclonal antihuman Ki 67. The biological origin of cerebellar liponeurocytomas is unknown, and hereditary forms of this disease have not been described. Here, the authors present clinical and histopathological findings of a young patient with a cerebellar liponeurocytoma who had multiple immediate family members who harbored similar intracranial tumors. A 37-year-old otherwise healthy woman presented with a history of progressive headaches. Lipomatous medulloblastoma had been diagnosed previously in her mother and maternal grandfather, and her maternal uncle had a supratentorial liponeurocytoma. MRI revealed a large, poorly enhancing, lipomatous mass emanating from the superior vermis that produced marked compression of posterior fossa structures. An uncomplicated supracerebellar infratentorial approach was used to resect the lesion. Genetic and histopathological analyses of the lesion revealed neuronal, glial, and lipomatous differentiation and confirmed the diagnosis of cerebellar liponeurocytoma. A comparison of the tumors resected from the patient and, 22 years previo...
Acute subdural hematoma (aSDH) is associated with a 60-80% mortality rate and is considered a neurosurgical emergency. Although it is most often treated with emergent surgical decompression, patients may be managed conservatively when they are neurologically intact or the hematoma is small. Typical progression of aSDH resolution occurs over weeks, and is characterized by corresponding changes on radiographic imaging where bright aSDH becomes first isointense at about two weeks and then hypointense on noncontrast computed tomogram (CT) head imaging. If there is continued bleeding acutely, however, the SDH may increase in size leading to transtentorial herniation and subsequent clinical deterioration of the patient.Interestingly, there are a number of case reports in the literature describing the event of spontaneous aSDH resolution. Several hypotheses have been put forward to explain this phenomenon including redistribution of subdural blood and dilution by cerebral spinal fluid (CSF) 1 . Cerebral atrophy, as well as cerebral swelling were both identified to facilitate aSDH resolution 2,3 . Here we describe a patient with an unexpected resolution of an acute SDH in the setting of a bleeding diathesis, and propose that in this patient, coagulopathy contributed to the spontaneous resolution of the hematoma. CASE PRESENTATIONOur patient is a 73-year-old gentleman who had acute onset of left-sided weakness. His strength was 4-/5 in the left upper and lower extremities. He was alert and oriented, with stable vital signs. His past medical history was significant for myelodysplastic syndrome with chronic pancytopenia, and atrial fibrillation on warfarin therapy.On admission, significant findings on bloodwork included platelet count of 17 x 10 9 /L and an international normalized ratio (INR) of 1.6. Non-contrast CT head scan performed at the initial evaluation demonstrated a moderate-sized acute subdural hemorrhage over the right convexity ( Figure 1A). He received vitamin K and platelets, and was admitted for observation. Five hours later, his level of consciousness decreased, and he required intubation. A follow-up non-contrast CT head demonstrated dramatic enlargement of the acute SDH with uncal herniation ( Figure 1B). He received a platelet transfusion and the prothrombin complex concentrate on formulary, Octaplex, in anticipation of emergent surgical evacuation. However, the patient's family instead opted for comfort measures.Over
Introduction Preserving the integrity of the corticospinal tract (CST) while maximizing the extent of tumor resection is one of the key principles of brain tumor surgery to prevent new neurologic deficits. Our goal was to determine the impact of the use of perioperative diffusion tensor imaging (DTI) fiber-tracking protocols for location of the CSTs, in conjunction with intraoperative direct electrical stimulation (DES) on patient neurologic outcomes. The role of combining DES and CST shift in intraoperative magnetic resonance imaging (iMRI) to enhance extent of resection (EOR) has not been studied previously. Methods A total of 53 patients underwent resection of tumors adjacent to the motor gyrus and the underlying CST between June 5, 2009, and April 16, 2013. All cases were performed in the iMRI (BrainSuite 1.5 T). Preoperative DTI mapping and intraoperative cortical and subcortical DES including postoperative DTI mapping were performed in all patients. There were 32 men and 21 women with 40 high-grade gliomas (76%), 4 low-grade gliomas (8%), and 9 (17%) metastases. Thirty-four patients (64%) were newly diagnosed, and 19 (36%) had a previous resection. There were 31 (59%) right-sided and 22 (42%) left-sided tumors. Eighteen patients (34%) had a re-resection after the first intraoperative scan. Most patients had motor-only mapping, and one patient had both speech and motor mapping. Relative to the resection margin, the CST after the first iMRI was designated as having an outward shift (OS), inward shift (IS), or no shift (NS). Results A gross total resection (GTR) was achieved in 41 patients (77%), subtotal resection in 4 (7.5%), and a partial resection in 8 (15%). Eighteen patients had a re-resection, and the mean EOR increased from 84% to 95% (p = 0.002). Of the 18 patients, 7 had an IS, 8 an OS, and in 3 NS was noted. More patients in the OS group had a GTR compared with the IS or NS groups (p = 0.004). Patients were divided into four groups based on the proximity of the tumor to the CST as measured from the preoperative scan. Group 1 (32%) included patients whose tumors were 0 to 5 mm from the CST based on preoperative scans; group 2 (28%), 6 to 10 mm; group 3 (13%), 11 to 15 mm; and group 4 (26%), 16 to 20 mm, respectively. Patients in group 4 had fewer neurologic complications compared with other groups at 1 and 3 months postoperatively (p = 0.001 and p = 0.007, respectively) despite achieving a similar degree of resection (p = 0.61). Furthermore, the current of intraoperative DES was correlated to the distance of the tumor to the CST, and the regression equation showed a close linear relationship between the two parameters. Conclusions Combining information about intraoperative CST and DES in the iMRI can enhance resection in brain tumors (77% had a GTR). The relative relationship between the positions of the CST to the resection cavity can be a dynamic process that could further influence the surgeon's decision about the stimulation parameters and EOR. Also, the patients with an OS of the CST relative to the resection cavity had a GTR comparable with the other groups.
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