Marina Kastelan

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations—heterozygous deletions (HeD), point mutations, and promoter methylation—is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker.

Background: Glioblastomas are the most common and fatal primary brain malignancy in adults. There is a growing interest in identifying the molecular mechanisms of these tumors to develop novel treatments. Glioblastoma neo-angiogenesis is driven by VEGF, and another potential molecule linked to angiogenesis is PSMA. Our study suggests the potential for an association between PSMA and VEGF expression in glioblastoma neo-vasculature. Methods: Archived IDH1/2 wild-type glioblastomas were accessed; demographic and clinical outcomes were recorded. PSMA and VEGF expression by IHC were examined. Patients were dichotomized into PSMA expression high (3+) and low (0–2+) groups. The association between PSMA and VEGF expression was evaluated using Chi² analysis. OS in PSMA high and low expression groups were compared using multi-linear regression. Results: In total, 247 patients with IDH1/2 wild-type glioblastoma with archival tumor samples (between 2009–2014) were examined. PSMA expression correlated positively with VEGF expression (p = 0.01). We detected a significant difference in median OS between PSMA vascular endothelial expression high and low groups—16.1 and 10.8 months, respectively (p = 0.02). Conclusion: We found a potential positive correlation between PSMA and VEGF expression. Secondly, we showed a potential positive correlation between PSMA expression and overall survival.

Both IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both IDH1 and IDH2 mutations were detected within the same tumour. The patient remains disease-free, nine and a half years after her initial diagnosis. Interrogation of cancer genomic databases and a systematic review was undertaken, demonstrating the rarity of the co-occurrence of IDH1 and IDH2 mutations in a variety of cancer types, and in glioma specifically. Due to the favourable outcome observed in this patient, the potential effect of concurrent IDH1 and IDH2 mutations on survival was also investigated.

Medulloblastomas are rare embryonal primary brain tumours originating in the cerebellum. Most medulloblastomas arising in adults are associated with mutations in the Sonic Hedge Hog (SHH) pathway. Patient 1 was prescribed Sonidegib for recurrent metastatic SHH mutated medulloblastoma multiple lines of treatment. His leptomeningeal disease responded after 3 months of therapy. The drug was continued for a further 3 months until progressive central nervous system (CNS) and leptomeningeal disease arose. Progression free survival (PFS) from initiation of Sonidegib of 3 months was observed (overall survival 8.8 years). Patient 2 presented with un-resectable SHH mutated meduloblastoma with high risk of relapse who received 14 months of adjuvant Sonidegib. Following biopsy she was treated with chemotherapy and cranio-spinal radiotherapy, followed by 14 months of adjuvant Sonigedib. She remains free of disease over 51 months later. Both clinical scenarios are poorly described in the literature or evaluated in clinical trials with Sonidegib.

Characterise patterns of failure of Temporal Lobe (TL) Glioblastoma (GBM) following treatment with relation to normal temporal lobe anatomy and neural pathways. 335 GBM patients received radiotherapy between 03/2007 and 07/2014, 100 were located in TL. Site of initial tumour and subsequent relapse were subdivided into 5 local TL sites (anterior, lateral, medial, posterior and superior); 5 adjacent regional sites (occipital lobe, inferior frontal lobe, caudate/thalamus/internal/external capsules, fornix/ventricular trigone), and 5 distant failure sites (ventricles, contralateral hemisphere, brainstem, leptomeninges and spine). Extension along major neuroanatomical pathways at initial presentation and at first documented Magnetic Resonance Imaging (MRI) failure were categorised into anterior, superior, medial and posterior pathways. Of the 100 patients, 86 had radiological progress with a median survival of 17.3 months. At initial diagnosis, 74% of tumours were linked to one TL site and 94% were confined to the TL. 19% had neural pathway disease at initial pre-treatment MRI. At first recurrence locoregional site failure was 74%. 26% failed within distant sites and 53% patients were noted to have neural pathway involvement. Initial tumour location predicted for local site recurrence (p < 0.0001), regional site recurrence (p = 0.004) and neural pathway recurrence pattern (p = 0.005), but not for distant sites (p = 0.081). Most GBMs fail at local or adjacent regional sites. Many of the recurrences occurred in a predictable pattern within a local or regional site, unique to initial TL site with more than half involving neural pathways. Knowledge of tumour infiltration and failure may improve target definition and radiotherapy.