Browsing by Author "Saratsis, Amanda"

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    Combinatorial Inhibition of Epigenetic Regulators to Treat Glioblastoma
    (2022-07-29) Burket, Noah; Koenig, Jenna; Saratsis, Amanda
    Glioblastoma (GBM) is a deadly primary brain cancer that affects 12,000 patients in the US annually with a median survival time of 15 months. Temozolomide is the standard-of-care chemotherapy for GBM; however, many tumors are resistant, necessitating the expansion of therapeutic options. EZH2 and JMJD3 are two proteins responsible for epigenetic regulation of the genome via histone methylation, with EZH2 also affecting non-histone targets. Prior studies showed that inhibition of these proteins decreased cell counts and induced radiosensitivity in GBM cells. Thus, we investigated combined use of EZH2 inhibitor, EPZ6438, and JMJD3 inhibitor, GSK-J4, in the treatment of temozolomide-resistant GBM10 cells. Non-irradiated cells were treated with both drugs singly and combined, and counted at 24-, 48-, and 72-hour intervals. Irradiated cells were pre-treated with each drug and combination therapy for three days, irradiated, and then counted at 24-, 48-, and 72-hour intervals. Western blot was used to investigate dsDNA damage biomarker y-H2AX, gene-silencing modification H3K27me3, tumor suppressor p53, EZH2, and JMJD3 expression in non-irradiated and irradiated cells following drug treatment. Single EPZ-6438 and GSK-J4 treatments reduced cell counts with increasing concentration and time. GSK-J4 appears to reduce cell counts more than EPZ-6438 alone, and combinatorial use reduces this further. Western blot reveals increased H3K27me3 expression with GSK-J4 treatment following radiation, but not with EPZ-6438. y-H2AX expression is increased after EPZ-6438 treatment but is not further increased with radiation. Meanwhile, GSK-J4 increased y-H2AX, but only after irradiation. Reduced cell counts following treatment with GSK-J4 may be due to its effects on gene silencing from inhibition of H3K27 demethylation. Additionally, increased dsDNA breaks seen in EPZ-6438 and GSK-J4 supports their roles in radiosensitizing GBM cells. This study highlights the importance of further investigation into GSK-J4 and EPZ-6438 combination therapy in temozolomide-resistant GBM tumors.
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    Patient and operative factors associated with unanticipated intensive care admission and outcomes following posterior fossa decompressions in children: A retrospective study
    (Wiley, 2022) Benzon, Hubert A.; Tantoco, Anthony; Longhini, Anthony; Hajduk, John; Saratsis, Amanda; Suresh, Santhanam; McCarthy, Robert J.; Jagannathan, Narasimhan; Neurological Surgery, School of Medicine
    Introduction: Posterior fossa decompression for Chiari I Malformation is a common pediatric neurosurgical procedure. We sought to identify the impact of anesthesia-related intraoperative complications on unanticipated admission to the intensive care unit and outcomes following posterior fossa decompression. Methods: Medical records of all patients <18 years who underwent surgery for Chiari I malformation between 1/1/09 and 1/31/21 at the Ann & Robert H. Lurie Children's Hospital of Chicago were included. Records were reviewed for patient characteristics, anesthesia-related intraoperative complications, postoperative complications, and surgical outcomes. The primary outcome was the incidence of unanticipated admission to the intensive care unit, and the primary variable of interest was an anesthesia-related intraoperative complication. Patient, surgical characteristics, and year of surgery were also compared between patients with and without an unanticipated admission to the intensive care unit, and a multi-variable adjusted estimate of odds of unanticipated admission to the intensive care unit admission following an anesthesia-related intraoperative complication was performed. Secondary outcomes included anesthesia factors associated with an anesthesia-related intraoperative event, and postoperative complications and surgical outcomes between patients admitted to the intensive care unit and those who were not. Results: Two hundred ninety-six patients with Chiari I Malformation were identified. Clinical characteristics associated with an unanticipated admission to the intensive care unit were younger age, American Society of Anesthesiologist (ASA) physical status >2 and an anesthesia-related intraoperative complication. 29 anesthesia-related intraoperative complications were observed in 25 patients (8.4%). Two of 25 patients (8%) with an anesthesia-related intraoperative complication compared with 3 of 271 (1%) patients without anesthesia-related intraoperative complication had an unanticipated admission to the intensive care unit, odds ratio 7.8 (95% CI 1.2-48.8, p = .010). When adjusted for age, sex, ASA physical status, presenting symptoms, concomitant syringomyelia, previous decompression surgery and year of surgery, the odds ratio for an unanticipated admission to the intensive care unit following an anesthesia-related intraoperative complication was 5.9 (95% CI 0.51-59.6, p = .149). There were no differences in surgical outcomes between patients with or without an unanticipated admission to the intensive care unit. Conclusion: Our study demonstrates that although anesthesia-related intraoperative complications during posterior fossa decompression are infrequent, they are associated with an increased risk of an unanticipated admission to the intensive care unit.