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Abstract Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.

In the multidisciplinary management of gastrointestinal stromal tumours (GISTs), there is a need to coordinate the efforts of pathology, radiology, surgery and oncology. Surgery is the mainstay for resectable nonmetastatic GISTs, but virtually all GISTs are associated with a risk of metastasis. Imatinib 400 mg/day with or without surgery is the recommended first-line treatment for recurrent or metastatic GIST; a higher dose may be considered in patients who progress, develop secondary resistance or present with specific genotypic characteristics. Adjuvant or neoadjuvant imatinib is not advised for resectable non-metastatic GISTs. Neoadjuvant imatinib may be considered when surgery would result in significant morbidity or loss of organ function. Follow-up computed tomography imaging is recommended every three to six months for at least five years. Patients with metastatic disease should be continued on imatinib due to the high risk of recurrence on discontinuation of therapy. Treatment should be continued until there is progression or intolerable adverse effects. If dose escalation with imatinib fails, a clinical trial with novel agents alone or in combination may be considered. The present recommendations were developed at a surgical subcommittee meeting and a subsequent full Advisory Committee meeting held in Toronto, Ontario, in April 2005, under the sponsorship of Novartis Pharmaceuticals Canada Inc.