Citations

Abstract Objectives Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays. Methods To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS. Results Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL. Conclusions Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, usability, footprint, and intended use, should be considered.

Abstract Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

Abstract Background Medulloblastoma in adults is rare and treatment decisions are largely driven from pediatric literature. We sought to characterize recurrent medulloblastoma in adults. Methods From a single-institution dataset of 200 adult patients diagnosed with medulloblastoma during 1978–2017, those with recurrence were analyzed for clinical features, treatment, and outcome. Results Of the 200 patients, 82 (41%) with median age of 29 years (18–59) had recurrence after a median follow-up time of 8.4 years (95% CI = 7.1, 10.3). Of these, 30 (37%) were standard-risk, 31 (38%) were high-risk, and 21 (26%) had unknown-risk diseases at the time of initial diagnosis. Forty-eight (58%) presented with recurrence outside the posterior fossa, of whom 35 (43%) had distant recurrence only. Median Progression-free survival (PFS) and OS from initial surgery were 33.5 and 62.4 months, respectively. Neither PFS nor OS from initial diagnosis differed between the standard-risk and high-risk groups in those who experience recurrence (P = .505 and .463, respectively). Median OS from first recurrence was 20.3 months, also with no difference between the standard-risk and high-risk groups (P = .518). Recurrences were treated with combinations of re-resection (20 patients; 25%), systemic chemotherapy (61 patients; 76%), radiation (29 patients; 36%), stem cell transplant (6 patients; 8%), and intrathecal chemotherapy (4 patients; 5%). Patients who received radiation at recurrence had better OS (32.9 months) than those who did not (19.2 months) (P = .034). Conclusions Recurrent medulloblastoma in adults has a poor prognosis irrespective of initial risk stratification. Recurrence commonly arises outside the posterior fossa years after initial diagnosis.

Abstract Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set–based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set–based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set–based genetic association approach as an alternative method for TWAS analysis.

Abstract Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Abstract ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.

Abstract INTRODUCTION Prospective studies for adult medulloblastoma (MB) are scarce and management guidelines are largely derived from pediatric experience and retrospective data. However, adult MB is a distinct disease for which limited data exist regarding clinical characteristic, prognostic factors, outcome based on upfront treatment, or patterns of recurrence. METHODS 200 patients (≥18 years at diagnosis) were identified from 1978 to 2017. Survival analysis was performed using the Kaplan-Meier method. RESULTS Median age at diagnosis 29 (18–63); 111 (55.5%) standard-risk (SR), 59 (29.5%) high-risk (HR), 30 (15%) unknown. 188 (94%) and 97 (48.5%) underwent radiotherapy and upfront chemotherapy, respectively. Median PFS: 6.28 years (4.9–11.2); median OS: 8.8 (7.8–12.4) years. Median time to first recurrence: 8.2 (5.1-not reached); 5-year recurrence-free rate: 71% in SR and 45% in HR patients. Survival after first recurrence: 2 years (1.64–2.4). Documented recurrence and risk group were associated with survival (HR 30.4, p< 0.0001 and 2.33, p< 0.001), but metastatic status and local vs. distant recurrence were not. The effect of upfront chemotherapy on survival did not reach statistical significance in SR patients. The use of chemotherapy regimens with or without vincristine or containing cisplatin vs. carboplatin, did not alter the survival outcome. In a subgroup of 57 SR patients who were seen at initial diagnosis and for whom complete staging and treatment information were available 3 and 5-year PFS were 94% (88%, 100%) and 76% (66%, 86%); OS at 5 years, 94% (87%, 100%). CONCLUSION No statistically significant difference was noted in outcome of patients treated without vincristine or with carboplatin instead of cisplatin, suggesting attenuated upfront regimens could be considered to reduce toxicity. Adult MB patients recur late and have a poor post-recurrence survival, therefore long-term follow-up, development of molecular risk-adjusted upfront treatment, and optimization of rescue treatments are needed.

Objective Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. Design We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. Results We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10−5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. Conclusions This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.