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3rd August 2021
Medulloblastoma is the second most common, malignant brain tumour in children. It develops in between 250 and 400 children each year and more than 70% of cases occur in those younger than 10 years of age. It is a highly invasive cancer that arises in the cerebellum and disseminates throughout the central nervous system. Survival depends to a large extent on whether or not the disease has spread. For example, among children without disseminated disease, the event-free survival at 5 years has been shown to be around 80%. However, the cancer can return and the 3-year survival rate for relapsed cancer is low at around 18%. Medulloblastomas are categorised into different groups, with group 3 being more aggressive and therefore high-risk, with a 5-year survival of approximately 20%–30%. The use of carboplatin as a radiosensitiser has been found to be a promising strategy in patients with high-risk medulloblastoma and isotretinoin has been shown to induce apoptosis of medulloblastoma cells. There is also data showing that the addition of isotretinoin to carboplatin, enhances tumour sensitivity in squamous cell carcinoma xenografts.
With some evidence suggesting that the combination of isotretinoin and carboplatin may be of greater value in the treatment of medulloblastoma, a team from the Cancer and Blood Disorders Centre, Seattle, US, decided to undertake a randomised trial to examine the impact on survival of combination therapy in children with high-risk (group 3) medulloblastoma. Included patients were randomised to chemotherapy with 36-GY craniospinal radiation therapy and weekly vincristine with or without daily carboplatin, followed by 6 cycles of maintenance chemotherapy with or without 12 cycles of isotretinoin. The primary outcome of the trial was event-free survival.
There were 261 children with a mean age of 8.6 years (70% male), 72% of whom at metastatic disease included in the analysis and the median follow-up time was 6.7 years. For all participants, the 5-year overall survival was 73.4% (95% CI 66.7–80.1%). The overall 5-year event-free survival with carboplatin was 66.4% (95% CI 56.4%–76.4%) vs 59.2% (95% CI 48.8%–69.6%) without carboplatin. However, in the subgroup of patients with group 3 medulloblastoma, the 5-year event-free survival for patients given carboplatin was even higher, 73.2% vs 53.7% without carboplatin. In addition, the overall survival with carboplatin was 82.8% vs 63.7% without the drug. The isotretinoin arm was closed early due to an interim analysis finding that addition of the drug was unlikely to have a positive effect on event-free survival, i.e., 68.6% with isotretinoin vs 67.8% without.
The authors concluded that the use of carboplatin and radiotherapy should be recommended for paediatric patients with high risk medulloblastoma although use of isotretinoin added little value.
Leary SES et al. Efficacy of Carboplatin and Isotretinoin in Children with High-risk Medulloblastoma. A Randomised Clinical Trial from the Children’s Oncology Group. JAMA Oncol 2021
22nd June 2021
Few people undergo routine brain scans to help identify potential early signs of a tumour. While imaging modalities such as MRI and CT are a very sensitive and effective means of testing, these are expensive and thus unsuitable for mass screening. Nevertheless, the detection of shed tumour components such as DNA or cellular fragments into the general circulation could be used for the early detection of a tumour. The use of microRNAs, i.e., small and non-coding fragments of RNA, in blood samples has already been utilised of early detection of breast, ovarian and bladder cancers. However, urine-based detection of microRNAs offers some advantages over blood samples in so far as these can be self-performed and repeated with minimal effort. The use of urine-based methods has yet to be explored in detail and this was the subject of a study by a team from the Department of Neurosurgery, Graduate School of Medicine, Nagoya, Japan. The researchers developed a device that contained 100 million zinc oxide nanowires, that could be sterilised and equally importantly, mass produced. The device required only 1 ml of urine but was able to extract a much larger number of microRNAs compared to ultracentrifugation, which is the most commonly used extraction device. The researchers examined urine samples from patients with and without brain tumours and used microarray analysis to determine whether there was a specific and diagnostic microRNA profile that could be used as a biomarker.
The researcher used urine samples from 109 patients with a brain tumour and compared the microRNA profile with 100 non-cancer patients. Initially, the team used organoids (i.e., a collection of cells) from glioblastoma, an aggressive form of brain tumour, to determine the profile of urinary microRNAs likely to be produced by patients with the tumour. The analysis revealed how the glioblastoma organoid-derived sample differentially expressed microRNAs, included 73.4% of the microRNAs found in the urine samples of patients with glioblastoma. In comparison, this microRNA profile was produced in only 3.9% of the non-cancer patient samples.
Having established that this profile, which contained 23 separate microRNAs, was characteristically produced in patients with glioblastoma, the researchers sought to determine if the profile could serve as a biomarker. Using the area under the receiver operator curves, the profile produced a sensitivity of 100% and a specificity of 97%.
Based on these findings, the authors concluded that this specific microRNA profile, could potentially be used for mass screening purposes for the early detection of potentially aggressive brain tumours.
Kitano Y et al. Urinary MicroRNA-Based Diagnostic Model for Central Nervous System Tumours Using Nanowire Scaffolds. ACS Appl Mater interfaces 2021;13:17316 – 17329