Henry Brem

Glioma is one of the most common primary malignant brain tumors. Despite progress in therapeutic approaches, the median survival of patients with glioma remains less than 2 years, generating the need for new therapeutic approaches. Ultrasound (US) is widely used in medical fields and is used as a therapeutic tool mainly for improving the performance of therapeutic entities. In this study, we examined a novel approach using low frequency US (20 kHz) (LFUS) as an independent treatment tool for malignant glioma, since primary studies showed that cancer cells are more susceptible to LFUS than healthy cells. LFUS safety and efficacy were examined in a 9L gliosarcoma‐bearing female Fischer 344 rats. Two LFUS protocols were examined: a one‐time treatment (US1X), and two treatments 24 h apart (US2X). For safety evaluation, rats were monitored for weight change and pain measurements. For efficacy …

METHODS:A retrospective single-center study evaluated adults with pathologically confirmed IDH-mutant and 1p/19q co-deleted oligodendrogliomas that underwent surgery between 2005 and 2021. Genetic data from formalin-fixed, paraffin-embedded specimens were analyzed with the NGS Solid Tumor Panel at the Johns Hopkins Medical Laboratories, which tested over 400 genes. Kaplan-Meier curves and log-rank tests were used to compare progression-free survival (PFS) and overall survival (OS). Chi-squared tests compared clinical characteristics between mutation status in the ten most frequently mutated genes.RESULTS:From 277 patients with IDH-mutated, 1p/19q co-deleted oligodendrogliomas, 95 patients with NGS were included. Ten genes had 9 or more patients with a mutation, with CIC and FUBP1 being the most frequently mutated genes (n= 60 and n= 23, respectively). Kaplan-Meier curves …

Glioblastoma (GB) is an aggressive type of brain cancer with a high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells that have been shown to facilitate GB cell invasion and immune suppression. The mechanism by which GB cells alter microglia behavior is yet to be fully understood. One proposed mechanism involves adhesion molecules such as the Selectins family of proteins which are expressed on the surface of endothelial and immune cells and are involved in immune modulation and cancer immunity. We have previously shown that one member of the Selectin family, P-Selectin (SELP), is expressed by GB cells. Here, we investigated the functional role of SELP in GB-microglia interactions. First, we found that microglia cells facilitate the expression and …

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher …

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and …

BackgroundGlioblastoma multiforme (GBM) stands as a formidable challenge in oncology because of its aggressive nature and severely limited treatment options. Despite decades of research, the survival rates for GBM remain effectively stagnant. A defining hallmark of GBM is a highly acidic tumor microenvironment, which is thought to activate pro-tumorigenic pathways. This acidification is the result of altered tumor metabolism favoring aerobic glycolysis, a phenomenon known as the Warburg effect. Low extracellular pH confers radioresistant tumors to glial cells. Notably GPR68, an acid sensing GPCR, is upregulated in radioresistant GBM. Usage of Lorazepam, which has off target agonism of GPR68, is linked to worse clinical outcomes for a variety of cancers. However, the role of tumor microenvironment acidification in GPR68 activation has not been assessed in cancer. Here we interrogate the role of GPR68 …

PurposeThere is limited literature describing care coordination for patients with glioblastoma (GBM). We aimed to investigate the impact of primary care and electronic health information exchange (HIE) between neurosurgeons, oncologists, and primary care providers (PCP) on GBM treatment patterns, postoperative outcomes, and survival.MethodsWe identified adult GBM patients undergoing primary resection at our institution (2007–2020). HIE was defined as shared electronic medical information between PCPs, oncologists, and neurosurgeons. Multivariate logistic regression analyses were used to determine the effect of PCPs and HIE upon initiation and completion of adjuvant therapy. Kaplan-Meier and multivariate Cox regression models were used to evaluate overall survival (OS).ResultsAmong 374 patients (mean age±SD: 57.7±13.5, 39.0% female), 81.0% had a PCP and 62.4% had electronic HIE. In …

ObjectiveThe Hospital Frailty Risk Score (HFRS) is a tool for quantifying patient frailty using International Classification of Diseases, Tenth Revision codes. This study aimed to determine the utility of the HFRS in predicting surgical outcomes after resection of glioblastoma (GBM) and compare its prognostic ability with other validated indices such as American Society of Anesthesiologists score and Charlson Comorbidity Index.MethodsA retrospective analysis was conducted using a GBM patient database (2017–2019) at a single institution. HFRS was calculated using International Classification of Diseases, Tenth Revision codes. Bivariate logistic regression was used to model prognostic ability of each frailty index, and model discrimination was assessed using area under the receiver operating characteristic curve. Multivariate linear and logistic regression models were used to assess for significant associations …

A drug delivery device comprising: a first layer comprising a first coaxially electrospun nanofiber membrane; a second layer comprising a second coaxially electrospun nanofiber membrane; a first therapeutic agent integrated into the first coaxially electrospun nanofiber membrane; and a second

METHODS:A systematic review of the PubMed database was performed following PRISMA guidelines from database inception through August 2021. Included studies were published in peer-reviewed journals, in English, and described outcomes for patients undergoing elective craniotomies without post-operative ICU care. Data regarding study design, patient characteristics, and post-operative care pathways was extracted independently by two authors. Quality and risk of bias were evaluated using the Oxford Centre for Evidence-Based Medicine Levels of Evidence tool and Risk Of Bias In Non-Randomized Studies—of Interventions tool, respectively.RESULTS:In total, 1,131 unique papers were identified through the database search, with 27 meeting inclusion criteria. Included articles were published from 2001-2021 and included non-ICU inpatient care and same-day discharge pathways. Overall, the studies …

While the central nervous system (CNS) tumor classification has increasingly incorporated molecular parameters, there is a paucity of literature reporting molecular alterations found in intraventricular glioblastoma (IVGBM), which are rare. We present a case series of nine IVGBMs, including molecular alterations found in standardized next-generation sequencing (NGS). We queried the clinical charts, operative notes, pathology reports, and radiographic images of nine patients with histologically confirmed IVGBM treated at our institution (1995–2021). Routine NGS was performed on resected tumor tissue of two patients. In this retrospective case series of nine patients (22% female, median (range) age: 64.3 (36–85) years), the most common tumor locations were the atrium of the right lateral ventricle (33%) and the septum pellucidum (33%). Five patients had preoperative hydrocephalus, which was managed with intraoperative external ventricular drains in three patients and ventriculoperitoneal shunts in one patient. Hydrocephalus was managed with subtotal resection of a fourth ventricular IVGBM in one patient. The most common surgical approach was transcortical intraventricular (56%). Gross total resection was achieved in two patients, subtotal resection was achieved in six patients, and one patient received a biopsy only. Immunohistochemistry for IDH1 R132H mutant protein was performed in four cases and was negative in all four. Genetic alterations common in glioblastoma, IDH-wildtype, were seen in two cases with available NGS data, including EGFR gene amplification, TERT promoter mutation, PTEN mutation, trisomy of chromosome 7 …

Background: Brain metastases (BM) constitute a significant cause of oncological mortality. Statistics on the incidence of BM are scarce because of the limited systematic worldwide reporting. We report the incidence of synchronous brain metastases (sBM), defined as BM identified at the time of primary cancer diagnosis from 2015-2019 using the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program database of the United States.Methods: We identified 1,872,057 patients with malignancies between 2015-2019 from the SEER 17 Registries, including 35,986 (1.9%) patients with sBM. Age-adjusted incidence rates were examined using the NCI Joinpoint software. Survival was evaluated with Kaplan-Meier curves and multivariate Cox regression.Results: The incidence rate of sBM from 2015 to 2019 was 7.1 persons per 100,000. Lung and bronchus cancers had the highest …

OBJECTIVES/GOALS: Surgical training is constrained by duty hour limits, bias, and a trial-and-error learning process. Surgeon skill variation is a healthcare system disparity that can impact patient outcomes. Incorporating validated, standardized assessment tools and machine learning (ML) algorithms may help to standardize and reduce bias in surgeon education. METHODS/STUDY POPULATION: To support assessment tool and ML algorithm development, we are curating an annotated video registry of neurosurgical procedures. Point-of-view video of resident and attending neurosurgeons performing craniotomies is recorded via an eye-tracking headset. A Delphi panel of neurosurgeons will review the video and determine which represent expert versus trainee performance. Neurosurgery attendings will be interviewed to provide descriptions of craniotomies which will be used to develop an assessment rubric. A …

Glioblastoma (GB) is the most aggressive neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness and drug resistance. Only a small fraction of GB patients survives longer than 24 months from the time of diagnosis (ie, long‐term survivors [LTS]). In our study, we aimed to identify molecular markers associated with favorable GB prognosis as a basis to develop therapeutic applications to improve patients' outcome. We have recently assembled a proteogenomic dataset of 87 GB clinical samples of varying survival rates. Following RNA‐seq and mass spectrometry (MS)‐based proteomics analysis, we identified several differentially expressed genes and proteins, including some known cancer‐related pathways and some less established that showed higher expression in short‐term (<6 months) survivors (STS) compared to LTS. One such target found was deoxyhypusine …

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METHODS:We conducted a single-center retrospective cohort study. We identified patients from 1/12/2017-6/1/2021 who sustained a PSI 04-attributed complication (pneumonia, deep venous thrombosis/pulmonary embolism (DVT/PE), sepsis, shock/cardiac arrest, or gastrointestinal (GI) hemorrhage/acute ulcer), underwent a neurosurgical procedure, and had inpatient mortality. The primary outcome was whether the attributed PSI 04 designation was the primary driver of mortality.RESULTS:We identified 67 patients who met PSI 04 criteria (median age, 61; female sex, 43.4%). Nearly 20% of patients met the PSI complication criteria prior to admission. Patients who underwent emergent bedside procedures were more likely to present with poor GCS (P= 0.016), more likely to be intubated prior to admission (P= 0.016), and less likely to have mortality due to a PSI 04-related complication (P= 0.002). PSI 04-related …

BackgroundEvaluation after posterior fossa decompression for Chiari malformation can require repeated imaging, particularly with persistent symptoms. Typically, CT or MRI is used. However, CT carries radiation risk and MRI is costly. Ultrasound is an inexpensive, radiation-free, point-of-care modality that has, thus far, been limited by intact skull and traditional cranioplasty materials. Ultrasound also allows for imaging in different head positions and body postures, which may lend insight into cause for persistent symptoms despite adequate decompression on traditional neutral static CT or MRI. We evaluate safety and feasibility of ultrasound as a post-operative imaging modality in patients reconstructed with sonolucent cranioplasty during posterior fossa decompression for Chiari malformation.MethodsOutcomes were analyzed for 26 consecutive patients treated with a Chiari-specific sonolucent cranioplasty. This …

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Methods: The robotic platform used in this study is a third-generation, cooperative-control robot consisting of a gantry arm with five actuated degrees of freedom developed by Galen Robotics. The robot is currently being evaluated by the US FDA and can only be used for investigational (ie, non-human) uses. The robot allows manipulation of conventional surgical instruments with tremor dampening and heightened precision. For this study, we utilized a Karl Storz Image 1 Hub HD Video Camera fitted with a 0-degree rigid endoscope to operate on a fresh-frozen cadaver head. Functional endoscopic sinus surgery was performed by the skull base otolaryngology and neurosurgery team with the endoscope held by the robot arm. The team then proceeded to the sphenoid sinus for exposure of the sella using two-handed technique with the endoscope held by the robot arm. We qualitatively evaluated safety, feasibility of …

The unique cancer-associated immunosuppression in brain, combined with a paucity of infiltrating T cells, contributes to the low response rate and poor treatment outcomes of T cell-based immunotherapy for patients diagnosed with glioblastoma multiforme (GBM). Here, we report on a self-assembling paclitaxel (PTX) filament (PF) hydrogel that stimulates macrophage-mediated immune response for local treatment of recurrent glioblastoma. Our results suggest that aqueous PF solutions containing aCD47 can be directly deposited into the tumor resection cavity, enabling seamless hydrogel filling of the cavity and long-term release of both therapeutics. The PTX PFs elicit an immune-stimulating tumor microenvironment (TME) and thus sensitizes tumor to the aCD47-mediated blockade of the antiphagocytic “don’t eat me” signal, which subsequently promotes tumor cell phagocytosis by macrophages and also triggers …