ReFaey, Karim

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.

Abstract High grade gliomas (HGGs) are aggressive brain tumors that are difficult to remove completely, leading to poor survival rates. Contrast enhancement on T1Gd magnetic resonance imaging (MRI) has traditionally been used to guide resection, however it often underestimates true tumor burden, adding a layer of uncertainty for surgeons during pre-operative planning. Fluorescence guided surgery using 5-aminolevulinic acid (5-ALA) has emerged as an intraoperative solution and understanding it in conjunction with MRI features can address the limitations of routine T1Gd imaging during surgical planning. Here we investigate sex-specific patterns in HGGs using 5-ALA fluorescence and imaging features. We analyzed a patient dataset of 202 multiregional MRI-localized biopsies from 42 HGG patients (20 male and 22 female). Data included patient demographics, 5-ALA status (positive or negative), MRI annotations (CE = contrast enhancement, NE = non-enhancement, BAT = brain around tumor non-enhancement), and survival outcomes. Statistical analyses included Wilcoxon rank-sum tests, Kruskal-Wallis tests, and chi-squared tests to assess differences in imaging annotations and 5-ALA positive vs negative status among sex cohorts. Among all samples, CE and BAT were associated with higher 5-ALA positivity, while NE was associated with higher 5-ALA negativity (p = 0.02119). Female patients were less likely to have detectable 5-ALA in their multiregional biopsy samples than males (p < 0.0001). CE at the biopsy location was more likely to be indicative of 5-ALA positivity in males than females (p = 0.001927); whereas NE was associated with higher 5-ALA negativity in females than males (p = 0.03426). BAT was associated with higher 5-ALA positivity in males than females (p = 0.03895). Our study reveals sex-specific patterns in 5-ALA fluorescence and image features among HGG patients. These unique features may serve as potential pre-surgical markers for tumor regions that are more likely to benefit from 5-ALA-guided resection.

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor in adults with a median survival of 8-14 months and 5-year survival rate of 6.9%. Its aggressive nature arises mostly from molecular heterogeneity and resistance to standard of care (SOC), including radiation and temozolomide (TMZ). Recurrence is nearly inevitable, driven by highly invasive brain tumor initiating cells (BTICs). Our previous studies revealed that exposing BTICs to cerebrospinal fluid (CSF) from GBM patients increases cell migration and proliferation compared to non-cancer CSF. Transcriptomic analysis identified the upregulation of the SERPINA3 gene, which encodes alpha-1-antichymotrypsin (ACT). Silencing of SERPINA3 reduces BTIC migration and proliferation and abolishes the promigratory response to GBM-derived CSF, highlighting SERPINA3 as a potential therapeutic target. ACT has been reported to bind to DNA, although the implications of this interaction are unknown. We have previously observed higher levels of intranuclear ACT in human GBM compared to non-cancer brain tissues. We hypothesize that the nuclear localization of SERPINA3 in GBM contributes to increased malignancy, opening the possibility of therapeutically targeting its intranuclear transport. Here, we determined the intracellular localization of ACT in BTICs and GBM and compared it to non-cancer tissues. Additionally, we evaluated whether SOC affected intranuclear localization of ACT. Patient-derived BTICs were treated with TMZ, radiation, and a combination of both, to assess changes in ACT expression via Western Blot, PCR, and ICC. A decrease in cell confluency was correlated with a significant decrease (p<0.05) in SERPINA3 mRNA and overall protein expression when BTICs were treated with TMZ alone or in combination. Interestingly, confocal microscopy revealed a significant increase (p<0.05) in its nuclear localization, particularly with TMZ treatment, indicating a change in its intracellular distribution. Overall, nuclear translocation of SERPINA3 increases in response to SOC with potential implications as a treatment resistance mechanism.

BACKGROUND AND OBJECTIVES: Awake minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) generates minimal surrounding tissue damage and has been shown to be a safe, time-effective, and cost-reductive technique in single-level procedures. The purpose of this study was to advocate for the utilization of multilevel MIS-TLIF even in challenging cases as it has demonstrated positive outcomes. METHODS: Chart review was conducted for consecutive patients undergoing awake multilevel MIS-TLIF from 2020 to 2023. Various demographic, preoperative, and postoperative variables were collected and descriptively analyzed. RESULTS: Sixteen patients underwent multilevel awake MIS-TLIF at our institution during the specified period. Among them, 87.5% underwent a two-level procedure and 12.5% a three-level procedure. The median age ± IQR was 69.5 ± 11 years, with a slight male predominance (56.25%). Common comorbidities included hypertension (56.25%), obesity (37.5%), sleep apnea (25%), and type 2 diabetes (18.75%). The American Society of Anesthesiologists risk was 2 in 43.75% of patients and 3 in 56.25%. All patients presented pain, and 12.5% showed motor deficit. Intraoperative data showed a median of 196 minutes in the operating room where 156 ± 27.75 minutes corresponded to actual procedure time. The median estimated blood loss was 50 ± 70 cc. In the immediate postoperative period, 1 patient had nausea and emesis, and 1 reported fatigue. The median pain score during this period was 4.6 ± 2.03. Pain control medications were required for various patients, with methocarbamol (50%), hydromorphone (37.5%), and oxycodone (25%) being the most commonly prescribed in the postanesthesia care unit. No patient had new neurological deficits after the surgical intervention. The median length of stay was 2 days ±1.25. All patients were discharged with no complications. CONCLUSION: Multilevel awake MIS-TLIF emerges as a safe and effective technique for complex cases, enhancing patient quality of life with minimal blood loss and postoperative pain.