Citations

Abstract INTRODUCTION High grade gliomas (HGG) are devastating diseases with largely unchanged survival outcomes despite decades of research. Recent studies suggest the interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is selectively upregulated in up to 80% of HGG, including glioblastoma (GBM) and diffuse midline gliomas (DMG) harboring H3K27 alterations. Immunotoxins targeting IL-13Rα2 have been demonstrated as safe and have shown some benefit for patients with HGG in previous phase I/II and III clinical trials. We hypothesized that by using GB-13 (IL13.E13K-PE4E), a novel peptide-toxin that binds IL-13Rα2 with high specificity and possesses a Pseudomonas exotoxin moiety, we would enhance the anti-tumor effects of this immunotherapy for HGG in vitro and in vivo while decreasing off-target toxicity. METHODS We examined the pharmacological effects of GB-13 in multiple patient-derived cell lines and rodent models of HGG. GBM and DMG lines were used to confirm IL-13Rα2 expression and sensitivity towards GB-13. Tumor naïve rats were evaluated for toxicity, and orthotopic PDX mice were used to monitor tumor size and survival following loco-regional infusion of GB-13. RESULTS GB-13 induced a potent cytotoxic response strongly predicated on IL-13Rα2 expression in vitro. No treatment-related adverse effects were noted after 7-day continuous intracranial infusion of GB-13 in tumor naïve rats. Further, in IL-13Rα2-upregulated orthotopic PDX mice, direct intratumoral administration of GB-13 via convection-enhanced delivery abrogated tumor growth and prolonged survival. CONCLUSIONS Given these promising results as well as the critical need for novel therapies in CNS malignancies, we are progressing to human trials using GB-13 targeting recurrent HGG. Ongoing safety studies in tumor-bearing animals will be able to define dose levels for the initial adult study-arm and the following pediatric study-arm. In this Phase 1 clinical trial, we hypothesize that loco-regional infusion of GB-13 will safely enhance tumor clearance by causing selective killing of IL-13Rα2-upregulated HGG cells.

Neurosurgical education is a continually developing field with an aim of training competent and compassionate surgeons who can care for the needs of their patients. The Mayo Clinic utilizes a unique mentorship model for neurosurgical training. In this paper, the authors detail the historical roots as well as the logistical and experiential characteristics of this teaching model. This model was first established in the late 1890s by the Mayo brothers and then adopted by the Mayo Clinic Department of Neurological Surgery at its inception in 1919. It has since been implemented enterprise-wide at the Minnesota, Florida, and Arizona residency programs. The mentorship model is focused on honing resident skills through individualized attention and guidance from an attending physician. Each resident is closely mentored by a consultant during a 2- or 3-month rotation, which allows for exposure to more complex cases early in their training. In this model, residents take ownership of their patients’ care, following them longitudinally during their hospital course with guided oversight from their mentors. During the chief year, residents have their own clinic, operating room (OR) schedule, and OR team and service nurse. In this model, chief residents conduct themselves more in the manner of an attending physician than a trainee but continue to have oversight from staff to provide a “safety net.” The longitudinal care of patients provided by the residents under the mentorship model is not only beneficial for the trainee and the hospital, but also has a positive impact on patient satisfaction and safety. The Mayo Clinic Mentorship Model is one of many educational models that has demonstrated itself to be an excellent approach for resident education.

OBJECTIVE Arteriovenous malformations (AVMs) are a major cause of intracerebral hemorrhage in children, resulting in significant morbidity and mortality. Moreover, the rate of AVM recurrence in children is significantly higher than in adults. The aim of this study was to define the risk of delayed pediatric AVM (pAVM) recurrence following confirmed radiological obliteration. Further understanding of this risk could inform the role of long-term radiological surveillance. METHODS The authors conducted a retrospective review of ruptured and unruptured pAVM cases treated at a single tertiary care referral center between 1994 and 2019. Demographics, clinical characteristics, treatment modalities, and AVM recurrence were analyzed. RESULTS A total of 102 pediatric patients with intracranial AVMs, including 52 (51%) ruptured cases, were identified. The mean patient age at presentation was 11.2 ± 4.4 years, and 51 (50%) patients were female. The mean nidus size was 2.66 ± 1.44 cm. The most common Spetzler-Martin grades were III (32%) and II (31%). Stereotactic radiosurgery was performed in 69.6% of patients. AVM obliteration was radiologically confirmed in 68 (72.3%) of 94 patients with follow-up imaging, on angiography in 50 (73.5%) patients and on magnetic resonance imaging in 18 (26.5%). AVM recurrence was identified in 1 (2.3%) of 43 patients with long-term surveillance imaging over a mean follow-up of 54.7 ± 38.9 months (range 2–153 months). This recurrence was identified in a boy who had presented with a ruptured AVM and had been surgically treated at 5 years of age. The AVM recurred 54 months after confirmed obliteration on surveillance digital subtraction angiography. Two other cases of presumed AVM recurrence following resection in young children were excluded from recurrence analysis because of incomplete sets of imaging available for review. CONCLUSIONS AVM recurrence following confirmed obliteration on imaging is a rare phenomenon, though it occurs more frequently in the pediatric population. Regular long-term follow-up with dedicated surveillance angiography is recommended even after obliteration following resection.

Abstract The heterozygous H3.3 K27M mutation is found in the majority of pediatric High-Grade Glioma’s (pHGG). H3.3 K27M is thought to promote tumor formation through altered epigenetic gene regulation. However, it is unclear if epigenetic reprogramming alone is sufficient for glioma formation. H3.3 contains a unique Serine at position 31 which is phosphorylated in early mitosis (where it functions in chromosome segregation) and again in late M/early G1 when a mitotic error has occurred (triggering p53 expression). We found that pHGG cell lines harboring H3.3 K27M have significantly reduced S31 phosphorylation as compared to both pHGG and non-transformed H3.3 WT cells. When compared to WT H3.3 in an in vitro kinase assay, H3.3 K27M exhibits an ~60% reduction in S31 phosphorylation by Chk1, the mitotic S31 kinase. In normal diploid cells, expression of K27M or non-phosphorylatable S31A mutant significantly increased chromosome missegregation. Yet expressing a phosphomimetic double mutant (K27M/S31E) did not significantly alter the rate of chromosome mis-segregation compared to WT. Furthermore, patient-derived pHGG lines harboring K27M have significantly higher rates of chromosome mis-segregation compared to an H3.3 WT pHGG line or H3.3 WT non-transformed human cells. We used CRISPR gene editing to remove the H3.3 K27M allele or replace it with WT H3.3. In both cases, loss of K27M elevated pS31 levels and reduced chromosome mis-segregations. Yet, when K27M was replaced with S31A, the mis-segregation rate remained similar to the parental K27M cells. In normal cells, chromosome missegregation stimulates p53-dependent cell cycle arrest in G1 to prevent the proliferation of aneuploid daughters. However, cells expressing H3.3 K27M or S31A failed to arrest following missegregation - despite having WT p53. To determine if the induction of chromosomal instability would alter tumor formation, we expressed H3.3 WT, K27M or S31A in combination with PDGFβ in a glioma mouse model. Expression of WT H3.3 failed to generate high-grade tumors. But 66% of mice expressing K27M and 93% of those expressing H3.3 S31A developed diffuse high-grade brain tumors by 100 days. Our results suggest that loss of phospho-S31 alone is oncogenic because H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that H3.3 K27M inhibits Ser31 phosphorylation both in vitro and in vivo, leading to both chromosome missegregation and loss of subsequent G1 arrest - thus creating diffuse midline gliomas with both dynamic, complex karyotypes and epigenetic reprogramming. Citation Format: Charles Day, Florina Grigore, Alyssa Langfald, David J. Daniels, James Robinson, Edward Hinchcliffe. Inhibition of H3.3 S31 phosphorylation by the pediatric glioma driver mutation, H3.3 K27M, results in chromosomal instability, loss of p53 regulation, and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 705.

Abstract INTRODUCTION: Craniopharyngioma (CP) is a histologically benign tumor of the pituitary stalk that accounts for 4% of pediatric central nervous system (CNS) tumors. Given its location, CP often causes neuro-endocrine, hypothalamic, and vision dysfunction. Standard therapy consists of maximally safe resection +/- radiation therapy (RT). Medical management, including intra-cystic therapy, may have utility in certain contexts. Survival after CP is excellent, but quality of life is often poor secondary to functional deficits from the tumor and/or treatment. Few prospective CP trials have been performed, and response assessment has not been standardized. METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, formed of international experts in relevant subspecialties, devised consensus guidelines from published literature and/or expert opinion to assess CP response in prospective clinical trials. RESULTS: Magnetic resonance imaging (MRI) is the recommended radiological modality for baseline and follow-up CP assessment. Computed tomography can be useful for identification of calcification in the initial diagnostic work-up. The committee defined specific standard MRI-based sequences focused on comprehensive evaluation of the suprasellar space. Radiologic CP response is defined by two-dimensional measurements of both solid and cystic tumor components. Three-dimensional measurements are also encouraged in prospective trials. In certain clinical contexts, response of solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment (including transient cyst growth during or after RT). Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into CP response definitions. In most circumstances, cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. CONCLUSION: CP is a common pediatric CNS tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for baseline and longitudinal assessments of CP to uniformly define response in future prospective trials.

Abstract Diffuse midline glioma (DMG) of the pons remains the leading cause of death among pediatric patients with brain tumors, despite numerous attempts to intensify treatment. While standard treatment includes 54Gy in 30 fractions of radiation over six weeks of time, nearly all patients progress within the treatment field, and many experience symptomatic radionecrosis with steroid dependence. Symptom improvement typically begins after 20Gy to the tumor. Both hypofractionation and reirradiation after recurrence have been found to be safe for patients with DMG. Our study aims to enroll patients with newly diagnosed pontine DMG aged >1 year (no maximum age), and collect molecular information about DMG via stereotactic biopsy, followed by a short 2 week course of 25Gy in 10 fractions of radiation, with volumes guided by MRI with tractography reconstruction and FDOPA PET radiotracer uptake. Patients are followed closely and can complete the 25Gy in 10 fraction radiation course up to 3 times total for meeting radiographic and clinical progression criteria. Our primary endpoint is to estimate the time to progression from diagnosis to after receiving the second 25Gy course, and to compare this to the historical 7 month standard from diagnosis to progression after one 54Gy course. We aim to improve the time interval where patients are asymptomatic at home while minimizing time receiving daily treatments. Other endpoints will include the patient quality of life, caregiver quality of life, PFS intervals after each course, overall survival, and toxicity.

Abstract H3K27-altered diffuse midline glioma (DMG) is a uniformly lethal CNS cancer that predominately occurs in children. In the last decade, while studies revealing the molecular underpinnings of the disease have paved the way for novel therapeutic strategies, this tumor remains a death sentence. Our lab and others have identified numerous drugs of high interest for treating this devasting disease, however, every trial has failed to show benefit. Is our failure to translate these laboratory findings due to the fact we have not found the right drugs or treatment regimens yet? Or is this a failure to get the drugs to the tumor? Or is this simply a very bad disease to treat? The answer is likely multifactorial. Our lab, in collaboration with others, have strong data to show that simply getting drugs to the tumor will not result in a positive benefit. Most drugs are rapidly cleared from their target space. Utilizing techniques that increase the drug-tumor resonance time is necessary to translate our basic science findings to our patients. Picking the right drug and the delivery mechanism is not enough for a positive effect. Here, we assessed the efficacy of a previously identified inhibitor, alisertib, delivered by short-term convection-enhanced delivery or a continuous osmotic pump and found that continuous, direct delivery results in a significant increase in survival (p = 0.0002). Furthermore, long-term survivors showed a decreased tumor burden and on-target drug effects. These data support that translation into patients must consider three factors: 1) selection of a potent therapy, 2) selection of the proper delivery method for that therapy, 3) modulation to ensure that the therapy remains in the targeted tissue long enough for desired effect. Keeping these basic tenets at the forefront of development may finally lead to a more effective treatment strategy for this devastating disease

Abstract High-grade gliomas (HGG) encompass a large proportion of malignant tumors within the central nervous system. Despite advances in our understanding of underlying disease mechanisms, the prognosis remains dismal and efficacious therapies are lacking. As such, there is a dire, unmet, gap in clinical practice for treating this devastating disease. Here, we performed convection-enhanced delivery (CED) of GB-13 (also known as IL13.E13K-PE4E), a tumor-specific immunotoxin, into the mouse brain in an effort to assess safety and efficacy. Fifty-five nude mice were inoculated with cells from 3 distinct patient-derived HGG cell lines (low, medium and high IL-13Rα2 expression). After tumor size reached a pre-determined threshold, mice underwent stereotactic cannula placement into the tumor followed by a single 40-min ramped infusion (rate 0.2-0.8 ul/min) of GB-13 (volume of infusion 20 ul) at concentrations ranging from 5 to 50 ug/ml. Tumor progression was monitored semiweekly and animals were euthanized at the indication of progressive neurologic deficit. All animals tolerated the infusions without exhibiting any neurological changes. GB-13 decreased tumor burden and prolonged survival in a manner strongly associated with IL-13Rα2 expression. While no survival benefit was observed in animals harboring IL-13Rα2-low expressing HGG, IL-13Rα2-medium and -high animals lived significantly longer after GB-13 infusion than vehicle-treated animals (median survival prolongation >25 days). Postmortem examination of the brains revealed no morphological changes beyond the site of the cannula tract. While GB-13 decreased cell proliferation and increased the number of apoptotic cells, neuronal cell density in ipsilateral brain regions was retained and no monocyte infiltrate was evidenced following GB-13 exposure. These findings indicate that a single therapeutic infusion of GB-13 administered by CED is well tolerated and underscore the potential of IL-13Rα2-targeted therapies in a subset of HGG with increased IL-13Rα2 expression.

OBJECTIVE The coronavirus disease 2019 (COVID-19) pandemic has significantly changed clinical practice across US healthcare. Increased adoption of telemedicine has emerged as an alternative to in-person contact for patient-physician interactions. The aim of this study was to analyze the impact of telemedicine on workflow and care delivery from January 2019 to December 2021 in a neurosurgical department at a quaternary care center. METHODS Prospectively captured data on clinic appointment utilization, duration, and outcomes were queried. Visits were divided into in-person visits and telemedicine appointments, categorized as follow-up visits of previously surgically treated patients, internal consultations, new patient visits, and early postoperative returns after surgery. Appointment volume was compared pre- and postpandemic using March 2020 as the pandemic onset. Clinical efficiency was measured by time to appointment, rate of on-time appointments, proportion of appointments resulting in surgical intervention (surgical yield), and patient-reported satisfaction, the latter measured as the proportion of patients indicating “high likelihood to recommend practice.” RESULTS A total of 54,562 visits occurred, most commonly for follow-up for previously operated patients (51.8%), internal new patient referrals (24.5%), and external new patient referrals (19.8%). Total visit volume was stable pre- to postpandemic (1521.3 vs 1512, p = 0.917). However, in-person visits significantly decreased (1517/month vs 1220/month, p < 0.001), with a nadir in April 2020, while telemedicine appointment utilization increased significantly (0.3% vs 19.1% of all visits). Telemedicine utilization remained stable throughout the 1st calendar year following the pandemic. Telemedicine appointments were associated with shorter time to appointment than in-person visits both before and after the pandemic onset (0–5 days from appointment request: 60% vs 33% vs 29.8%, p < 0.001). Patients had on-time appointments in 87% of telemedicine encounters. Notably, telemedicine appointments resulted in surgery in 31.8% of internal consultations or new patient visits, a significantly lower rate than that for in-person visits (51.8%). After the widespread integration of telemedicine, patient satisfaction for all visits was higher than before the pandemic onset (85.9% vs 88.5%, p = 0.027). CONCLUSIONS Telemedicine use significantly increased following the pandemic onset, compensating for observed decreases in face-to-face visits. Utilization rates have remained stable, suggesting effective integration, and delays between referrals and appointments were lower than for in-person visits. Importantly, telemedicine integration was not associated with a decrease in overall patient satisfaction, although telemedicine appointments had a lower surgical yield. These data suggest that telemedicine smoothened the impact of the pandemic on clinical workflow and helped to maintain continuity and quality of outpatient care.