Mustafa Khasraw

BACKGROUND: Histone mutant gliomas (HMG) with histone H3 K27 and G34 mutations are recognized as biologically discrete entities with distinct anatomical locations, younger age at presentation (in comparison to the most common high-grade gliomas, IDH wildtype glioblastoma), and poor prognosis. There is a paucity of data regarding the management of adult HMG patients and no consensus on management. This study aims to identify current patterns of Australian and US neuro-oncology clinical practice for this entity. METHODS: Following institutional approvals, patterns of care questionnaire designed to capture relevant clinical variables was circulated through the Cooperative Trials Group for Neuro-Oncology (COGNO) in Australia and the Caris Precision Oncology Alliance in the United States (US). RESULTS: Between 4/2021 and 10/2021, 43 responses were collected. 33% (n = 14) of responders tested all patients for HMGs routinely; 40.92% (n = 18) tested in select patients 26% (n = 11) did not test for HMGs. The common indications for testing selected patients were midline anatomic location (n = 18) and age (n = 11) (<50 years). 23 used molecular sequencing, 22 used IHC at their centers. Nine participants stated knowledge of histone H3 mutations did not affect their management of these gliomas, 11 said it affected their management at the time of recurrence, 23 stated it affected the management of midline K27M patients, 11 participants stated it affected the management of K27M mutant gliomas in other locations, and 3 felt it affected the management of G34R/V mutant gliomas. CONCLUSION: Here we present a description of how the discovery of a new molecular subtype of primary glial tumors, histone mutated gliomas in adults, is being introduced into clinical practice.

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA and synaptophysin and the proliferation marker Ki-67 are used. These parameters, however, are qualitative and lack the capacity to fully define the tumour phenotype. Molecules of epithelial-mesenchymal transition (EMT) are potential candidates for improved tumour characterisation. Using qRT-PCR, we measured mRNA levels of 27 tumour markers, including 25 EMT-associated markers, in tumour tissue and matched non-tumour tissues for 13 patients with pancreatic NENs. Tissue from patients with three different grades of tumour had distinctly different mRNA profiles. Of the 25 EMT-associated markers analysed, 17 were higher in G3 tissue relative to matched non-tumour tissue, including CD14, CD24, CD31, CD44, CD45, CD56, CK6, CK7, CK13, CK20, NSE, CDX2, CgA, DAXX, PCNA, laminin and Ki-67. The differences in levels of seven EMT-associated markers, Ki-67, DAXX, CD24, CD44, vimentin, laminin and PDX1 plus CgA and NSE (neuroendocrine markers) enabled a distinct molecular signature for each tumour grade to be generated. EMT molecules differentially expressed in three tumour grades have potential for use in tumour stratification and prognostication and as therapeutic targets for treatment of neuroendocrine cancers, following validation with additional samples.