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OBJECTIVEGiven the paucity of data on the natural history of brainstem cavernous malformations (CMs), the authors aimed to evaluate the annual hemorrhage rate and hemorrhagic risk of brainstem CMs.METHODSNine hundred seventy-nine patients diagnosed with brainstem CMs were referred to Beijing Tiantan Hospital from 2006 to 2015; 224 patients were excluded according to exclusion criteria, and 47 patients were lost to follow-up. Thus, this prospective observational cohort included 708 cases (324 females). All patients were registered, clinical data were recorded, and follow-up was completed.RESULTSSix hundred ninety (97.5%) of the 708 patients had a prior hemorrhage, 514 (72.6%) had hemorrhagic presentation, and developmental venous anomaly (DVA) was observed in 241 cases (34.0%). Two hundred thirty-seven prospective hemorrhages occurred in 175 patients (24.7%) during 3400.2 total patient-years, yielding a prospective annual hemorrhage rate of 7.0% (95% CI 6.2%–7.9%), which decreased to 4.7% after the 1st year. Multivariate Cox regression analysis after adjusting for sex and age identified hemorrhagic presentation (HR 1.574, p = 0.022), DVA (HR 1.678, p = 0.001), mRS score ≥ 2 on admission (HR 1.379, p = 0.044), lesion size > 1.5 cm (HR 1.458, p = 0.026), crossing the axial midpoint (HR 1.446, p = 0.029), and superficially seated location (HR 1.307, p = 0.025) as independent adverse factors for prospective hemorrhage, but history of prior hemorrhage was not significant. The annual hemorrhage rates were 8.3% and 4.3% in patients with and without hemorrhagic presentation, respectively; the rate was 9.9%, 6.0%, and 1.0% in patients with ≥ 2, only 1, and 0 prior hemorrhages, respectively; and the rate was 9.2% in patients with both hemorrhagic presentation and focal neurological deficit on admission.CONCLUSIONSThe study reported an annual hemorrhage rate of 7.0% exclusively for brainstem CMs, which significantly increased if patients presented with both hemorrhagic presentation and focal neurological deficit (9.2%), or any other risk factor. Patients with a risk factor for hemorrhage needed close follow-up regardless of the number of prior hemorrhages. It should be noted that the referral bias in this study could have overestimated the annual hemorrhage rate. This study improved the understanding of the natural history of brainstem CMs, and the results are important for helping patients and physicians choose a suitable treatment option based on the risk factors and stratified annual rates.Clinical trial registration no.: ChiCTR-POC-17011575 (http://www.chictr.org.cn/).

BackgroundSkull-base chordomas are rare malignant bone cancers originating from the remnant of the notochord. Survival is variable, and clinical or molecular factors cannot reliably predict their outcomes. This study therefore identified epigenetic subtypes that defined new chordoma epigenetic profiles and their corresponding characteristics.MethodsMethylation profiles of 46 chordoma-resected neoplasms between 2008 and 2014, along with clinical information, were collected. K-means consensus clustering and principal component analysis were used to identify and validate the clusters. Single-sample gene set enrichment analysis, methylCIBERSORT algorithm, and copy number analysis were used to identify the characteristics of the clusters.ResultsUnsupervised clustering analysis confirmed two clusters with a progression-free survival difference. Gene set enrichment analysis indicated that the early and late estrogen response pathways and the hypoxia pathway were activated whereas the inflammatory and interferon gamma responses were suppressed. Forty-six potential therapeutic targets corresponding to differentially methylated sites were identified from chordoma patients. Subgroups with a worse outcome were characterized by low immune cell infiltration, higher tumor purity, and higher stemness indices. Moreover, copy number amplifications mostly occurred in cluster 1 tumors and the high-risk group. Additionally, the presence of a CCNE1 deletion was exclusively found in the group of chordoma patients with better outcome, whereas RB1 and CDKN2A/2B deletions were mainly found in the group of chordoma patients with worse outcome.ConclusionsChordoma prognostic epigenetic subtypes were identified, and their corresponding characteristics were found to be variable.