Citations

Abstract Introduction Safe, effective access to the fourth ventricle for oncologic resection remains challenging given the depth of location, restricted posterior fossa boundaries, and surrounding eloquent neuroanatomy. Despite description in the literature, a practical step-by step dissection guide of the suboccipital approaches to the fourth ventricle targeted to all training levels is lacking. Methods Two formalin-fixed, latex-injected specimens were dissected under microscopic magnification and endoscopic visualization. Dissections of the telovelar, transvermian, and supracerebellar infratentorial-superior transvelar approaches were performed by one neurosurgery resident (D.D.D.), under guidance of senior authors. The dissections were supplemented with representative clinical cases to highlight pertinent surgical principles. Results The telovelar and transvermian corridors afford excellent access to the caudal two-thirds of the fourth ventricle with the former approach offering expanded access to the lateral recess, foramen of Luschka, adjacent skull base, and cerebellopontine angle. The supracerebellar infratentorial-superior transvelar approach reaches the rostral third of the fourth ventricle, the cerebral aqueduct, and dorsal mesencephalon. Key steps described include positioning and skin incision, myofascial dissection, burr hole and craniotomy, durotomy, the aforementioned transventricular routes, and identification of relevant skull base landmarks. Conclusion The midline suboccipital craniotomy represents a foundational cranial approach, particularly for lesions involving the fourth ventricle. Operatively oriented resources that combine stepwise neuroanatomic dissections with representative cases provide a crucial foundation for neurosurgical training. We present a comprehensive guide for trainees in the surgical anatomy laboratory to optimize familiarity with fourth ventricle approaches, mastery of relevant microsurgical anatomy, and simultaneous preparation for learning in the operating room.

OBJECTIVE Paroxysmal sympathetic hyperactivity (PSH) is a complication of severe traumatic or hypoxic brain injury characterized by transient episodes of tachycardia, tachypnea, hypertension, hyperthermia, diaphoresis, and/or dystonic posturing. Posttraumatic "sympathetic storms" are associated with poor outcomes. PSH rarely occurs after brain tumor resection in pediatric patients; only 4 cases have been published since 1929. Thus, the authors sought to report their experience with postcraniotomy PSH in pediatric brain tumor patients. METHODS A retrospective study of patients younger than 18 years of age who underwent craniotomy for brain tumor resection at a single center by a single surgeon over a 7-year period was performed. A clinical diagnosis of postoperative PSH was recorded. Recorded outcomes included the interval between surgery and initiation of cytotoxic therapy, need for long-term CSF diversion, length of hospital stay, and survival. RESULTS Of the 150 patients who were included for analysis, 4 patients were diagnosed with postoperative PSH for an overall occurrence of 2.7%. PSH patients were younger than non-PSH patients (1.8 ± 0.4 years vs 9.2 ± 5.3 years, p = 0.010) and tended to have intraventricular tumors close to the thalamus, basal ganglia, and/or brainstem. PSH patients experienced longer hospital admissions (44.3 ± 23.4 days vs 6.8 ± 9.4 days, p = 0.001), a shorter interval between surgery and initiation of cytotoxic cancer-directed therapy (14.3 ± 8.0 days vs 90.7 days ± 232.9 days, p = 0.011), and increased need for long-term CSF diversion compared with non-PSH patients (75% vs 25%, p = 0.005). At the last follow-up, 50% of PSH patients had died compared with 13% of non-PSH patients (p = 0.094). CONCLUSIONS PSH is a rare postoperative complication that may affect young children with periventricular tumors and is associated with poorer clinical outcomes. Increasing awareness of this condition is vital to improving patient outcomes.

Abstract Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brainstem tumor that is the leading cause of death among pediatric brain malignancies. Despite over 200 clinical trials, no significant progress has been made, leading our lab to consider suicide gene therapy. The brainstem has particularly sensitive anatomy, creating the potential for toxic inflammation. Furthermore, the clinical standard of care for DIPG includes conventional radiation therapy (RT) followed by dexamethasone (DEX), each of which can alter the efficacy of gene therapy. In this study we found that a variety of gliomas, including human DIPG and murine glioma cell lines, are infectable in vitro with a replication-competent Moloney murine leukemia virus (MoMLV) (currently in Phase 2/3 clinical trials) and susceptible to ganciclovir (GCV)-mediated killing via the HSV thymidine kinase (tk) suicide gene. A B16 melanoma cell line expressing HSV tk implanted into the brainstem of mice, extended median survival with GCV therapy from 13 days to 38.5 days (p=.0006) with no signs of toxic inflammation. Pre-treatment with RT and DEX did not affect therapeutic efficacy. We have shown that GCV/TK therapy is mediated by NK and CD8 cells in subcutaneous tumors, and we are investigating whether a similar immunologic mechanism is involved in this brainstem model. These preclinical data will pave the way for novel clinical trials for the treatment of DIPG.

OBJECTIVE Tethered cord syndrome (TCS) can lead to significant downstream neurological deficits including gait deterioration, incontinence, and often unexplained chronic low-back pain. Surgical intervention may relieve symptoms, but there are no defined radiological parameters associated with surgical outcomes and functional status. The authors aimed to define pre- and postoperative radiological parameters for assessing surgical outcomes in TCS. METHODS The authors performed a single-center retrospective review of all pediatric patients treated for TCS between 2016 and 2021. Patient baseline characteristics and operative metrics included age, sex, level of conus, level of procedure, tethering pathology, symptoms at presentation, complications, improvement of symptoms, and reoperation rate. MRI measurements included pre- and postoperative anterior canal distance (ACD) and bending angle (BA). RESULTS Thirty-three pediatric patients were identified who underwent untethering of the spinal cord and had pre- and postoperative MRI between 2016 and 2021. The mean patient age was 5.64 ± 5.33 years. Twenty patients (60.60%) were female. Regarding the site of untethering, 31 procedures (93.93%) were performed at the lumbosacral region and 2 (6.06%) were performed at the thoracolumbar region. The conus medullaris was found above L3 in 21.21% of patients. Postoperatively, 18.18% of patients experienced complications, 48.48% showed improvement in their symptoms, and 48.48% were equivocal or had persistent symptoms. The mean preoperative ACD0 (measured from the posterior vertebral body margin [middle] to the anterior margin of the conus medullaris) was 6.15 ± 3.18 mm, the postoperative ACD0 was 2.25 ± 2.72 mm, and the average change in ACD0 was −0.90 ± 1.31 mm. The mean preoperative BA was 26.00° ± 11.56°, the mean postoperative BA was 15.92° ± 9.81°, and the average change in BA was −10.08° ± 8.80°. An optimal cutoff value for preoperative BA to predict reoperation in pediatric patients with complex TCS undergoing surgery was ≥ 31.70° (area under the curve = 0.83). CONCLUSIONS In surgically treated patients with TCS, certain preoperative radiological parameters may be important in predicting postoperative surgical outcomes; these parameters can be evaluated and reported to indicate patients at high risk for complications. Further prospective multicenter research is warranted to offer robust evidence of association of patient outcomes with preoperative radiological parameters in TCS.

Abstract Diffuse midline gliomas (DMG) are high-grade pediatric gliomas that frequently harbor heterozygous histone H3.3 K27M, G34R, or G34V mutations. These mutations alter histone methylations, although the precise mechanism(s) of gliomagenesis remains uncertain. H3.3 contains a unique Serine at position 31 that is phosphorylated in prophase and dephosphorylated in anaphase during normal cell division. In an aberrant division, chromosome missegregation triggers S31 phosphorylation along chromosome arms in anaphase leading to p53-induced cell cycle arrest. Here we show in vitro and in vivo, that H3.3 K27M, G34R, and G34V significantly suppress S31 phosphorylation by Chk1 (the mitotic S31 kinase). In diploid cells, overexpression of H3.3 K27M, G34R, G34V, or non-phosphorylatable S31A significantly increases the frequency of chromosome missegregation, while H3.3 K36M did not. This missegregation phenotype could be rescued by overexpression of K27M/S31E or G34R/S31E double mutants. Next, we used genome editing to revert K27M or G34V patient-derived DMG cells to WT or replace the mutant allele with S31A. Reversion to WT increased metaphase S31 phosphorylation and reduced chromosome missegregations, but inserting an S31A mutation caused more mitotic defects. Following a mitotic error, newly formed aneuploid cells overexpressing K27M, G34R, or G34V suppress p53 levels and continue to divide, while WT overexpressing cells always arrest. To test the effects of diminished S31 phosphorylation on gliomagenesis, we utilized a novel mouse model of DMG. Expression of PDGFβ linked to H3.3K27M, H3.3G34R, and H3.3S31A in neural stem cells in vivo promoted the development of high-grade gliomas in under 100 days, whereas PDGFβ-H3.3WT did not. Notably, the S31A tumors had histologically normal levels of K27me3 and K36me3. This work shows that a single DMG-associated point mutation in H3.3 can generate chromosomal instability and suggests that chromosomal instability is a major contributing factor to DMG K27-altered and DMG G34-altered tumor formation.

Abstract INTRODUCTION Medulloblastomas (MB) are embryonal tumors arising in the cerebellum, predominantly affecting pediatric patients. Recognition of molecularly defined subgroups has advanced management. Factors influencing the prognosis and management of adult MB patients remain poorly understood. METHODS We retrospectively reviewed our experience with adult (> 18 years at initial diagnosis) MB patients, diagnosed between 1992-2020. Molecular subtyping corresponding to the 2021 WHO Classification was performed. Kaplan-Meier estimates (Log-rank test assessing for group differences) were performed for univariate survival analysis with cox regression used for multivariate (subgroup, age, gender, disseminated disease, extent of resection) analyses. RESULTS Our cohort included 76 adult MB patients (62% male), with a median age of 31.7 years (range: 18-66) at diagnosis, and median follow-up of 7.7 years (range: 0.6-26.9). 58 patients had sufficient tissue for molecular characterization by immunohistochemistry and corresponded to the SHH-activated (n=37; 64%), non-WNT/non-SHH (n=12; 21%), WNT-activated (n=9; 15%) subgroups. At initial diagnosis, all patients underwent radiotherapy, with 97% (n=66) receiving craniospinal irradiation with a boost either to the posterior fossa (75%) or tumor bed (22%); and underwent gross total resection (n=51; 67%) and chemotherapy (n=56; 75%). Median overall survival (OS) for the whole cohort was 14.8 years (93% 2-year OS; 86% 5-year OS; 64% 10-year OS) and was longer for younger patients (< 30: > 15.4 years, > 30: 9.9 years; Log-rank p< 0.001). No significant OS difference was identified by MB molecular subgroup (SHH, TP53-wt: 14 years, WNT: 11.4 years, non-WNT/non-SHH: > 14.8 years; Log-rank p=0.1167) or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses. DISCUSSION We report one of the largest retrospective cohorts in adult MB patients with molecular subtyping. Survival and molecular subgroup frequencies were similar to previous reports. Survival was longer for younger patients and was not significantly different by MB molecular subgroup or extent of resection.

Abstract Background Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized. Methods The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively. Results Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. Conclusions Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.

Abstract INTRODUCTION Malignancies of the central nervous system (CNS) have had largely unchanged survival outcomes despite decades of research. Recently, viral-based therapeutics have shown some benefit for patients with CNS malignancies in early clinical trials. Adenovirus has been demonstrated as safe and is currently being examined in several phase I and II clinical trials. We recently demonstrated that adenovirus expressing CD40L is effective in enhancing survival in murine models of diffuse midline glioma. Therefore, to enhance the tumor specificity of this virotherapy, we hypothesized that by using a novel conditionally replicative adenovirus expressing CD40L, CRAd657-CD40L, we would maintain this survival benefit in multiple murine models for high grade glioma while decreasing off-target toxicity. METHODS We examined the utility of conditionally replicative adenovirus expressing CD40L in both in vitro and in vivo studies. Human cell lines from diffuse intrinsic pontine glioma (DIPG) and glioblastoma were used to confirm infectivity and CD40L expression, and syngeneic murine models of glioma were evaluated for toxicity and survival following intratumoral injection of a conditionally replicative adenoviral vector. RESULTS CRAd657-CD40L generated strong expression of CD40L in human in vitro DIPG XIII and U251 cell lines and induced MHCII expression on CD11c+ DC’s in U251/DC co-culture. Further, in syngeneic murine models of glioma, conditionally replicative adenoviral treatment significantly reduced toxicity while retaining survival efficacy. CONCLUSIONS Given these promising results as well as the critical need for novel therapeutics in CNS malignancies, we are now progressing to human trials targeting pediatric HGG, an unmet need in pediatric neuro-oncology. This would be the first-in-human study using CRAd-657-CD40L in pediatric HGG. In this Phase 1 clinical trial, we hypothesize that intratumoral injection of CRAd657-CD40L will cause selective expression of CD40L, increased infiltration of immune cells into the tumor, and safely enhance tumor clearance.