Case report: durable response of gliomatosis cerebri with concurrent tumor-treating fields (TTFields) and chemoradiotherapy treatment.

BACKGROUND: Gliomatosis cerebri (GC) is a rare and aggressive form of widely disseminated glioma infiltrating at least 3 lobes of the brain. It is a diffuse pattern of growth seen in glioma rather than a distinct pathological diagnosis based on new Word Health Organization (WHO) classification. Despite this, it is associated with worse prognosis than equally graded gliomas. Tumor treating fields (TTFields) treatment is a more recent advancement in glioma treatment delivered through low energy, intermediate frequency (200 kHz) electromagnetic fields, with multi-modal mechanisms of action. It is Food and Drug Administration (FDA) approved for newly diagnosed and recurrent glioblastoma (GBM). The aim of this case report is to present a durable response of GBM associated GC to concurrent TTFields with chemoradiation. CASE DESCRIPTION: We report a 64-year-old male with left parietal GBM, IDH wild type, WHO grade 4 with extensive GC change. After resection of the enhancing lesion, the patient received concurrent tumor-treating fields (TTFields) with radiation and temozolomide, enrolled in SPARE trial (NCT03477110). The patient had a rapid response in the areas of gliomatosis change demonstrated on the magnetic resonance imaging 1 month post-radiation treatment. The response of GC was durable. His glioma recurred 11 months after surgery with new enhancing lesions, treated with radiosurgery. He had further extensive progression of enhancing lesions 13 months after surgery, and received bevacizumab treatment. The patient ultimately passed away 17 months after surgery. Despite progression of enhancing lesions, the GC changes remained controlled. He also had favorable progression-free survival of 11 months and overall survival of 17 months. CONCLUSIONS: This case serves as an example of how combination TTFields with chemoradiation may elicit a durable response of GC in patients with GBM.

H19X-encoded miR-322(424)/miR-503 regulates muscle mass by targeting translation initiation factors.

BACKGROUND: Skeletal muscle atrophy is a debilitating complication of many chronic diseases, disuse conditions, and ageing. Genome-wide gene expression analyses have identified that elevated levels of microRNAs encoded by the H19X locus are among the most significant changes in skeletal muscles in a wide scope of human cachectic conditions. We have previously reported that the H19X locus is important for the establishment of striated muscle fate during embryogenesis. However, the role of H19X-encoded microRNAs in regulating skeletal mass in adults is unknown. METHODS: We have created a transgenic mouse strain in which ectopic expression of miR-322/miR-503 is driven by the skeletal muscle-specific muscle creatine kinase promoter. We also used an H19X mutant mouse strain in which transcription from the locus is interrupted by a gene trap. Animal phenotypes were analysed by standard histological methods. Underlying mechanisms were explored by using transcriptome profiling and validated in the two animal models and cultured myotubes. RESULTS: Our results demonstrate that the levels of H19X microRNAs are inversely related to postnatal skeletal muscle growth. Targeted overexpression of miR-322/miR-503 impeded skeletal muscle growth. The weight of gastrocnemius muscles of transgenic mice was only 54.5% of the counterparts of wild-type littermates. By contrast, interruption of transcription from the H19X locus stimulates postnatal muscle growth by 14.4-14.9% and attenuates the loss of skeletal muscle mass in response to starvation by 12.8-21.0%. Impeded muscle growth was not caused by impaired IGF1/AKT/mTOR signalling or a hyperactive ubiquitin-proteasome system, instead accompanied by markedly dropped abundance of translation initiation factors in transgenic mice. miR-322/miR-503 directly targets eIF4E, eIF4G1, eIF4B, eIF2B5, and eIF3M. CONCLUSIONS: Our study illustrates a novel pathway wherein H19X microRNAs regulate skeletal muscle growth and atrophy through regulating the abundance of translation initiation factors, thereby protein synthesis. The study highlights how translation initiation factors lie at the crux of multiple signalling pathways that control skeletal muscle mass.