The latest medical research on Neurosurgery

Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the noncoding RNA genome, in particular long noncoding RNAs (lncRNAs), contributes to MB subgrouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in Group 3 MBs.

Publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify lncRNAs that differentiate between MB subgroups. After characterizing a subset of differentially expressed lncRNAs in vitro and in vivo, lnc-HLX-2-7 was deleted by CRISPR/Cas9 in the MB cell line. Intracranial injected tumors were further characterized by bulk and single-cell RNA-seq.

Lnc-HLX-2-7 is highly upregulated in Group 3 MB cell lines, patient-derived xenografts, and primary MBs compared with other MB subgroups as assessed by quantitative real-time, RNA-seq, and RNA fluorescence in situ hybridization. Depletion of lnc-HLX-2-7 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. Lnc-HLX-2-7-deleted cells injected into mouse cerebellums produced smaller tumors than those derived from parental cells. Pathway analysis revealed that lnc-HLX-2-7 modulated oxidative phosphorylation, mitochondrial dysfunction, and sirtuin signaling pathways. The MYC oncogene regulated lnc-HLX-2-7, and the small-molecule bromodomain and extraterminal domain family‒bromodomain 4 inhibitor Jun Qi 1 (JQ1) reduced lnc-HLX-2-7 expression.

Lnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in Group 3 MBs.

Primary brain tumours are a complex heterogenous group of benign and malignant tumours. Reports on their occurrence in the English population by sex, age, and morphological subtype and on their incidence are currently not available. Using data from the National Cancer Registration and Analysis Service (NCRAS), the incidence of adult primary brain tumour by major subtypes in England will be described.

Data on all adult English patients diagnosed with primary brain tumour between 1995 and 2017, excluding spinal, endocrinal and other CNS tumours, were extracted from NCRAS. Incidence rates were standardised to the 2013 European Standard Population. Results are presented by sex, age, and morphological subtype.

Between 1995 and 2017, a total of 133,669 cases of adult primary brain tumour were registered in England. Glioblastoma was the most frequent tumour subtype (31.8%), followed by meningioma (27.3%). The age-standardised incidence for glioblastoma increased from 3.27 per 100,000 population per year in 1995 to 7.34 in men in 2013 and from 2.00 to 4.45 in women. Meningioma incidence also increased from 1.89 to 3.41 per 100,000 in men and from 3.40 to 7.46 in women. The incidence of other astrocytic and unclassified brain tumours declined between 1995 and 2007 and remained stable thereafter.

Part of the increase in the incidence of major subtypes of brain tumours in England could be explained by advances in clinical practice including the adoption of new diagnostic tools, classifications and molecular testing, and improved cancer registration practices.

Vismodegib specifically inhibits Sonic Hedgehog (SHH). We report results of a Phase I/II evaluating vismodegib + temozolomide in immunohistochemically defined SHH recurrent/refractory adult medulloblastoma.

Temozolomide naïve patients were randomized 2:1 to receive vismodegib + temozolomide (Arm A) or temozolomide (Arm B). Patients previously treated with temozolomide were enrolled in an exploratory cohort of vismodegib (Arm C). If the safety run showed no excessive toxicity, a Simon's two-stage Phase II design was planned to explore the 6-month progression free survival (PFS-6). Stage II was to proceed if arm A PFS-6 was ≥3/9 at the end of Stage I.

A total of 24 patients were included: Arm A (10), Arm B (5), and Arm C (9). Safety analysis showed no excessive toxicity. At the end of Stage I, the PFS-6 of arm A was 20% (2/10 patients, 95% Unilateral Lower Confidence Limit: 3.7%) and the study was prematurely terminated. The overall response rates (ORR) were 40% [95% CI: 12.2; 73.8] and 20% [95% CI: 0.5; 71.6] in arm A and B, respectively. In arm C, PFS-6 was 37.5% (95% CI: 8.8; 75.5) and ORR was 22.2% [95% CI: 2.8; 60.0]. Among 11 patients with an expected sensitivity according to NGS, 3 had partial response (PR), 4 remained stable (SD) while out of 7 potentially resistant patients, 1 had PR and 1 SD.

Addition of vismodegib to temozolomide did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma. Prediction of sensitivity to vismodegib needs further refinements.