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Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) ranks among the most lethal of human malignancies with GBM stem cells (GSCs) that contribute to tumor growth and therapeutic resistance. Identification and isolation of GSCs continue to be a challenge, as definitive methods to purify these cells for study or targeting are lacking. Here, we leveraged orthogonal in vitro and in vivo phage display biopanning strategies to isolate a single peptide with GSC-specific binding properties. In silico analysis of this peptide led to the isolation of EYA1 (Eyes Absent 1), a tyrosine phosphatase and transcriptional coactivator. Validating the phage discovery methods, EYA1 was preferentially expressed in GSCs compared to differentiated tumor progeny. MYC is a central mediator of GSC maintenance but has been resistant to direct targeting strategies. Based on correlation and colocalization of EYA1 and MYC, we interrogated a possible interaction, revealing binding of EYA1 to MYC and loss of MYC expression upon targeting EYA1. Supporting a functional role for EYA1, targeting EYA1 expression decreased GSC proliferation, migration, and self-renewal in vitro and tumor growth in vivo. Collectively, our results suggest that phage display can identify novel therapeutic targets in stem-like tumor cells and that an EYA1-MYC axis represents a potential therapeutic paradigm for GBM., (©AlphaMed Press 2021.)

Solitary brain metastasis is defined by a single metastatic brain lesion as the only site of metastasis. The initial approach to this condition consists of radiographical evaluation to establish diagnosis, followed by assessment of functional and prognostic status. Neurologic symptom management consists of using dexamethasone and antiepileptic medications. Treatment consists of a combination of surgical and radiation therapy. Surgical treatment is indicated where there is a need for tissue diagnosis or immediate alleviation of neurologic symptoms and mass effect. Stereotactic radiosurgery has become an effective treatment modality. Whole-brain radiation therapy may have a role as an adjunctive therapy., Competing Interests: Disclosure Novocure, advisory board. BMS, scientific grant funding., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Spinal subdural hematomas (SDHs) have been reported secondary to direct trauma or iatrogenic causes associated with coagulopathies. Spinal SDHs found after the development of acute intracranial SDHs, without any evidence of trauma to the spine, are extremely rare. In addition to this rare presentation, there is a lack of consensus regarding whether surgical decompression is the ideal treatment strategy. Depending on the extent of SDH within the spinal canal, surgical decompression may be difficult where diffuse hematoma within the intradural space requires multilevel decompression for treatment., Case Description: A 46-year-old man initially presented with an acute cranial SDH following isolated head trauma. After a period of full recovery, he developed delayed lower extremity paraparesis secondary to the formation of a thoracolumbar SDH. This hematoma coincided with resolution of the cranial SDH and likely was due to redistribution of blood from the cranial subdural space into the spinal canal. Given the diffuse multilevel nature of the spread of hematoma and lack of a focal area of compression, he was managed conservatively. He demonstrated small signs of neurologic improvement over several days and regained considerable strength over the following several weeks., Conclusions: This report demonstrates a very rare occurrence of a traumatic intracranial SDH migrating into the thoracic and lumbar spine. This case also highlights that despite acute neurologic deficits, conservative management may be a feasible strategy that can result in recovery of neurologic function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Intracranial hypotension from cerebrospinal fluid (CSF) hypovolemia resulting in cerebral herniation is a rare but known complication that can occur after neurosurgical procedures, usually encountered in correlation with perioperative placement of a lumbar subarachnoid drain. Decrease in CSF volume resulting in loss of buoyancy results in downward herniation of the brain without contributing mass effect, causing a phenomenon known as brain sag. Unreported previously is brain sag occurring without concomitant occult CSF leak or lumbar drainage., Case Description: This case report describes a patient who underwent bilateral craniotomies for subacute on chronic subdural hematoma with successful decompression but experienced acute neurologic deterioration secondary to brain sag. Despite an initial improvement in neurologic function, he subsequently experienced progressive neurologic deterioration with evidence of cerebral herniation on neuroimaging, without evidence of continued mass effect on the brain parenchyma. After a diagnosis of brain sag was determined based on imaging criteria, the patient was placed in a flat position, which resulted in rapid improvement in his neurologic function without any further intervention., Conclusions: This case is unique in comparison with previous reports of intracranial hypotension after craniotomy in that the symptoms were completely reversed with positioning alone, without any evidence of active or occult CSF drainage. This report emphasizes that the diagnosis of brain sag should be taken into consideration when there is an unknown reason for neurologic decline after craniotomy, particularly bilateral craniotomies, if the imaging indicates herniation with imaging findings consistent with intracranial hypotension, without evidence of overlying mass effect., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Oculoleptomeningeal amyloidosis (OLMA) is a variant of familial amyloidosis that results in amyloid deposition in the vitreous and leptomeninges. A 60-year-old woman with a history of OLMA presented to the emergency department for obtundation secondary to apparent shunt malfunction and lower extremity weakness. CT imaging of her spinal axis showed high attenuation material present intradurally from the mid cervical level extending through the thoracic and lumbar spine in the extramedullary space. MRI demonstrated circumferential signal enhancement surrounding the entire spinal cord. The patient underwent open biopsy at L3-L5. Upon opening the dura, a homogenous intradural ossification encasing the nerve roots was seen. Given the extent of the ossification, no further attempt at decompression was performed. Microscopic review of the biopsy sample revealed sclerotic bone with focal amorphous material consistent with amyloid. To our knowledge this is the first case report of a patient with OLMA presenting with extensive circumferential intrathecal ossification from amyloid deposition. Despite examples of leptomeningeal enhancement in patients with OLMA, extensive intradural ossification is a finding that has not been previously reported radiographically or post mortem., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Treatment options for metastatic and primary spinal tumors have expanded in recent years, in part due to the advances made in stereotactic radiosurgery. For metastatic spinal tumors, our institution utilizes the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework, which provides a treatment paradigm based on the neurologic, oncologic, mechanical and systemic status of the patient. Radiosurgery as a supplement to surgical decompression has allowed for less-invasive surgical procedures carrying minimal morbidity while still providing effective local tumor control. Although wide en bloc excision has traditionally been the goal for the treatment of high-grade primary spine tumors, recent studies have shown promise for radiosurgery in providing control in tumors such as chordomas and high-grade sarcomas. Despite advances in radiosurgery, there continues to be limitations in providing effective conformational doses with minimal toxicity to critical structures. One of the ways to circumvent this and supplement external beam radiation is through the use of brachytherapy delivered by radioactive plaque or seeds.