Higgins, Dominique

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.

OBJECTIVE High-grade spinal glioma (HGSG) is a rare but aggressive tumor that occurs in both adults and children. Histone H3 K27M mutation correlates with poor prognosis in children with diffuse midline glioma. However, the role of H3 K27M mutation in the prognosis of adults with HGSG remains unclear owing to the rarity of this mutation, conflicting reports, and the absence of multicenter studies on this topic. METHODS The authors studied a cohort of 30 adult patients with diffuse HGSG who underwent histological confirmation of diagnosis, surgical intervention, and treatment between January 2000 and July 2020 at six tertiary academic centers. The primary outcome was the effect of H3 K27M mutation status on progression-free survival (PFS) and overall survival (OS). RESULTS Thirty patients (18 males and 12 females) with a median (range) age of 50.5 (19–76) years were included in the analysis. Eighteen patients had H3 K27M mutation–positive tumors, and 12 had H3 K27M mutation–negative tumors. The median (interquartile range) PFS was 3 (10) months, and the median (interquartile range) OS was 9 (23) months. The factors associated with increased survival were treatment with concurrent chemotherapy/radiation (p = 0.006 for PFS, and p ≤ 0.001 for OS) and American Spinal Injury Association grade C or better at presentation (p = 0.043 for PFS, and p < 0.001 for OS). There were no significant differences in outcomes based on tumor location, extent of resection, sex, or H3 K27M mutation status. Analysis restricted to HGSG containing necrosis and/or microvascular proliferation (WHO grade IV histological features) revealed increased OS for patients with H3 K27M mutation–positive tumors (p = 0.017). CONCLUSIONS Although H3 K27M mutant–positive HGSG was associated with poor outcomes in adult patients, the outcomes of patients with H3 K27M mutant–positive HGSG were somewhat more favorable compared with those of their H3 K27M mutant–negative HGSG counterparts. Further preclinical animal studies and larger clinical studies are needed to further understand the age-dependent effects of H3 K27M mutation.

Study Design Retrospective case series. Objective To determine the effect of obesity on the resource utilization and cost in 3270 consecutive patients undergoing elective noninstrumented decompressive surgeries for degenerative spine disease at Mayo Clinic Rochester between 2005 and 2012. Methods Groups were assessed for baseline differences (age, gender, and American Society of Anesthesiologists [ASA] classification, procedure type, and number of operative levels). Outcome variables included the transfusion requirements during surgery, the total anesthesia and surgical times, intensive care unit (ICU) admissions, standardized costs, as well as the ICU and hospital length of stay (LOS). Regression analysis was used to evaluate for strength of association between obesity and outcome variables. Results Baseline differences between the groups (nonobese: n = 1,853; obese: n = 1,417) were found with respect to age, ASA class, gender, procedure type, and number of operative levels. After correcting for differences, we found significant associations between obesity and surgical ( p < 0.0001) and anesthesia times ( p < 0.0001) and hospital LOS ( p < 0.0001). Additionally, ICU admission rates ( p = 0.02) and requirement for postoperative ventilation ( p = 0.048) were significantly higher in obese patients. Finally, mean difference in total cost ($1,632, p < 0.0001) was significantly higher for the obese cohort. Conclusion Obesity is associated with increased resource utilization and cost in patients undergoing a noninstrumented decompressive surgery for degenerative spine disease.

Object Rathke cleft cysts (RCCs) are benign masses arising from the embryological Rathke pouch, and are commonly treated by transsphenoidal surgery. The authors retrospectively compared RCC extent of resection—either gross-total resection (GTR) or decompression—to the primary outcome measure, which was recurrences resulting in repeat surgery, and the secondary outcome measure, which was complications. Methods Seventy-four patients presenting to the neurosurgical department with RCC were analyzed retrospectively. Sixty-eight patients had a total of 78 surgical procedures, with the diagnosis of RCC confirmed by histological investigation; of these, 61 patients had adequate operative notes for the authors to evaluate extent of resection. Groups were separated into GTR (32 patients) or decompression (subtotal resection or fenestration into the sphenoid sinus; 29 patients) based on operative notes and postoperative imaging. The mean follow-up duration was 60.5 ± 72.1 months (the mean is expressed ± SD throughout). Results The average age at the time of the initial surgery was 42.8 ± 17.4 years, and 70% of patients were female. The mean cyst diameter preoperatively was 16.9 ± 17.8 mm. Eight patients had repeat surgery, our primary outcome measure; 3 repeat operations occurred in the GTR group, and 5 in the decompression group. There was no significant difference in recurrence when comparing groups (GTR 9%, decompression 17%; p = 0.36). There were no major complications; however, analysis of postoperative minor complications revealed that 11 (34%) GTRs resulted in surgical complications, whereas the decompression cohort accounted for only 3 complications (10%) (p = 0.03), with diabetes insipidus (6) and CSF leaks (5) being the most common. Gross-total resection also resulted in an increase in postoperative hyperprolactinemia compared with decompression (p = 0.03). Conclusions It appears that RCCs require repeat surgery in 13% of cases, and attempted GTR does not appear to reduce the overall rate of recurrence. However, more aggressive resections are associated with more complications in this series.

Object Obesity as a consequence of management of pediatric craniopharyngioma is a well-described phenomenon related to the degree of hypothalamic involvement. However, weight change and obesity have not been analyzed in adult patients. Therefore, the purpose of this study was 1) to evaluate the pattern of postoperative weight gain related to preoperative body mass index (BMI), 2) determine if postoperative weight gain is an issue in adult patients, and 3) develop an objective MR imaging grading system to predict risk of postoperative weight gain and obesity in adults treated for craniopharyngioma. Methods The authors retrospectively screened 296 patients with known craniopharyngioma for the following inclusion criteria: pathologically confirmed craniopharyngioma, index surgery at the authors' institution, and operative weight and height recorded with at least 3 months of follow-up including body weight measurement. Patients aged 18 years or younger were excluded, yielding 28 cases for analysis. Cases of craniopharyngiomas were compared with age- and sex-matched controls (pituitary adenoma patients) to evaluate the pattern and significance of perioperative weight changes. Results Mean age was 46 ± 17 years at surgery, and 64% of the patients were male. Complete resection was achieved in 71% of cases. There was no correlation of preoperative BMI and postoperative weight gain testing in a linear model. Sixty-one percent and 46% of patients had postoperative weight gains greater than 4 and 9%, respectively. Comparing craniopharyngioma patients (cases) to age- and sex-matched controls, the preoperative BMIs were similar (p = 0.93) between cases (mean 28.9 [95% CI 30.9–26.9]) and controls (mean 29.3 [95% CI 31.9–26.7]). However, there was a trend to a greater mean postoperative weight change (percentage) in cases (10.1%) than in controls (5.6%) (p = 0.24). Hypothalamic T2 signal change and irregular contrast enhancement correlated and predicted higher-grade hypothalamic involvement. Furthermore, they can be used to objectively grade hypothalamic involvement as the authors propose. Progressive hypothalamic involvement correlated with larger postoperative weight gains (p = 0.022); however, hypothalamic involvement did not correlate with preoperative BMI (p = 0.5). Conclusions Postoperative weight gain in adult patients undergoing surgery for craniopharyngioma is a significant problem and correlates with hypothalamic involvement, as it does in pediatric patients. Finally, objective MR imaging criteria can be used to predict risk of postoperative weight gain and aid in grading of hypothalamic involvement.