Single-agent Bevacizumab in the Treatment of Symptomatic Newly Diagnosed and Recurrent/Refractory Pediatric Cervicomedullary Brainstem Low-grade Gliomas: A Single Institutional Experience.

Bevacizumab-based therapies have been utilized as single or combination therapy of refractory/recurrent pediatric low-grade gliomas. Its efficacy for symptomatic cervicomedullary low-grade gliomas (cmLGGs) in the upfront and the recurrent setting is less known. We report our retrospective single institutional experience from 2015 to 2021 with single-agent bevacizumab for symptomatic cmLGG. Six consecutive patients (4 female, ages 2 to 12 y) with newly diagnosed (n=3) and recurrent/refractory (n=3) symptomatic nondisseminated cmLGG (5/6 biopsy-proven, 2 BRAFV600E, 2 BRAF-KIAA1549) were treated with single-agent bevacizumab. All demonstrated radiographic response most pronounced on post-gadolinium T1-weighted magnetic resonance imaging (2 complete, 4 partial) at a median of 8 weeks (range: 2 to 12 wk). Clinical response was seen in all patients with improvement in cranial nerve abnormalities (3 recurrent/refractory, 1 newly diagnosed), strength (2 recurrent/refractory, 2 newly diagnosed), pain (2 recurrent/refractory), and anorexia (1 newly diagnosed). Four patients (2 recurrent/refractory, 2 newly diagnosed) experienced disease progression on subsequent adjunct therapies, 2 of which (the 2 newly diagnosed patients) are currently being rechallenged. At a mean follow-up of 7 months, all patients are clinically stable without disease progression. Single-agent bevacizumab may be effective in the management of symptomatic newly diagnosed and recurrent/refractory cmLGG and warrants further evaluation in a clinical trial setting.

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma.

Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative 'enhancer rewiring' events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.

Intestinal malrotation and catastrophic volvulus in infancy.

BACKGROUND: Intestinal malrotation in the newborn is usually diagnosed after signs of intestinal obstruction, such as bilious emesis, and corrected with the Ladd procedure. OBJECTIVES: The objective of this report is to describe the presentation of severe cases of midgut volvulus presenting in infancy, and to discuss the characteristics of these cases. CASE REPORT: We performed a 7-year review at our institution and present two cases of catastrophic midgut volvulus presenting in the post-neonatal period, ending in death soon after the onset of symptoms. These two patients also had significant laboratory abnormalities compared to patients with more typical presentations resulting in favorable outcomes. CONCLUSIONS: Although most cases of intestinal malrotation in infancy can be treated successfully, in some circumstances, patients' symptoms may not be detected early enough for effective treatment, and therefore may result in catastrophic midgut volvulus and death.