A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition.

Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.

Clinical and molecular study of radiation-induced gliomas.

In this study, we provide a comprehensive clinical and molecular biological characterization of radiation-induced gliomas (RIG), including a risk assessment for developing gliomas. A cohort of 12 patients who developed RIG 9.5 years (3-31 years) after previous cranial radiotherapy for brain tumors or T-cell acute lymphoblastic leukemia was established. The derived risk of RIG development based on our consecutive cohort of 371 irradiated patients was 1.6% at 10 years and 3.02% at 15 years. Patients with RIG glioma had a dismal prognosis with a median survival of 7.3 months. We described radiology features that might indicate the suspicion of RIG rather than the primary tumor recurrence. Typical molecular features identified by molecular biology examination included the absence of Histon3 mutation, methylation profile of pedHGG-RTK1 and the presence of recurrent PDGFRA amplification and CDKN2A/B deletion. Of the two long-term surviving patients, one had gliomatosis cerebri, and the other had pleomorphic xanthoastrocytoma with BRAF V600E mutation. In summary, our experience highlights the need for tissue diagnostics to allow detailed molecular biological characterization of the tumor, differentiation of the secondary tumor from the recurrence of the primary disease and potentially finding a therapeutic target.

Current management in the treatment of intramedullary ependymomas in children.

PURPOSE: Current management of pediatric intramedullary ependymoma is extrapolated from adult series since large studies in children are unavailable. This has led us to share our experience with this rare tumor and compare it to the literature and to review and highlight important aspects of current management and point out inconsistencies. METHODS: This is a retrospective analysis of patients with intramedullary ependymoma managed at our institution between 2004 and 2021. RESULTS: During the study period, 5 patients were treated for intramedullary ependymoma. Cases of myxopapillary ependymoma were excluded. The mean age of our cohort was 11.2 years. We identified 4 cases of grade II ependymoma and 1 case of grade III ependymoma. Gross tumor removal (GTR) was achieved in two patients (40%) of patients. One patient was treated with radiotherapy for recurrence and two patients received chemotherapy. There were no cases of recurrence among patients treated with GTR, but in all patients treated with STR. Eighty percent of patients either improved or stayed stable neurologically. During follow-up (mean 73 months), 2 patients died of disease. CONCLUSION: GTR and tumor grade remain the key prognostic factor of long-term tumor-free survival. Many questions prevail regarding outcomes, correct use of adjuvant therapy, and prognostic factors.

Integrated genomic analysis reveals actionable targets in pediatric spinal cord low-grade gliomas.

Gliomas are the most common central nervous tumors in children and adolescents. However, spinal cord low-grade gliomas (sLGGs) are rare, with scarce information on tumor genomics and epigenomics. To define the molecular landscape of sLGGs, we integrated clinical data, histology, and multi-level genetic and epigenetic analyses on a consecutive cohort of 26 pediatric patients. Driver molecular alteration was found in 92% of patients (24/26). A novel variant of KIAA1549:BRAF fusion (ex10:ex9) was identified using RNA-seq in four cases. Importantly, only one-third of oncogenic drivers could be revealed using standard diagnostic methods, and two-thirds of pediatric patients with sLGGs required extensive molecular examination. The majority (23/24) of detected alterations were potentially druggable targets. Four patients in our cohort received targeted therapy with MEK or NTRK inhibitors. Three of those exhibited clinical improvement (two with trametinib, one with larotrectinib), and two patients achieved partial response. Methylation profiling was implemented to further refine the diagnosis and revealed intertumoral heterogeneity in sLGGs. Although 55% of tumors clustered with pilocytic astrocytoma, other rare entities were identified in this patient population. In particular, diffuse leptomeningeal glioneuronal tumors (n = 3) and high-grade astrocytoma with piloid features (n = 1) and pleomorphic xanthoastrocytoma (n = 1) were present. A proportion of tumors (14%) had no match with the current version of the classifier. Complex molecular genetic sLGGs characterization was invaluable to refine diagnosis, which has proven to be essential in such a rare tumor entity. Moreover, identifying a high proportion of drugable targets in sLGGs opened an opportunity for new treatment modalities.

Survival and functional outcomes in paediatric thalamic and thalamopeduncular low grade gliomas.

BACKGROUND: Childhood thalamopeduncular gliomas arise at the interface of the thalamus and cerebral peduncle. The optimal treatment is total resection but not at the cost of neurological function. We present long-term clinical and oncological outcomes of maximal safe resection. METHODS: Retrospective review of prospectively collected data: demography, symptomatology, imaging, extent of resection, surgical complications, histology, functional and oncological outcome. RESULTS: During 16-year period (2005-2020), 21 patients were treated at our institution. These were 13 girls and 8 boys (mean age 7.6 years). Presentation included progressive hemiparesis in 9 patients, raised intracranial pressure in 9 patients and cerebellar symptomatology in 3 patients. The tumour was confined to the thalamus in 6 cases. Extent of resection was judged on postoperative imaging as total (6), near-total (6) and less extensive (9). Surgical complications included progression of baseline neurological status in 6 patients, and 5 of these gradually improved to preoperative status. All tumours were classified as low-grade gliomas. Disease progression was observed in 9 patients (median progression-free survival 7.3 years). At last follow-up (median 6.1 years), all patients were alive, median Lansky score of 90. Seven patients were without evidence of disease, 6 had stable disease, 7 stable following progression and 1 had progressive disease managed expectantly. CONCLUSION: Paediatric patients with low-grade thalamopeduncular gliomas have excellent long-term functional and oncological outcomes when gross total resection is not achievable. Surgery should aim at total resection; however, neurological function should not be endangered due to excellent chance for long-term survival.

Methylation pattern in the diagnosis and prognosis of brain cancer.

Examination of changes in the methylation profile of DNA in cancer is currently used to determine the diagnosis or prognostic and predictive biomarkers. It complements histological or molecular biological examinations. At the same time, it helps to identify new diagnostic groups and subgroups. Currently, this diagnosis is most common in brain tumors, where it has become a routine examination. The established methylation profile may help even where the diagnosis or subgroup classification of the disease cannot be determined in any other way, as is the case with medulloblastoma.

An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma.

Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6-NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4-ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4-ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities.

Older age is a protective factor for academic achievements irrespective of treatment modalities for posterior fossa brain tumours in children.

The treatment of children with posterior fossa brain tumours (PFBT) impacts their long term functional and imaging outcomes. This study aimed to evaluate academic achievement correlated with long-term sequelae after different PFBT treatment modalities. The study cohort consisted of 110 survivors (median age at diagnosis 10.1 years and median time of follow up 13.2 years) who completed hearing questionnaires, neurological assessment and MRI of the brain ≥5 years after the end of treatment. There were three treatment groups. A cisplatin group which underwent cisplatin chemotherapy, radiotherapy and surgery (medulloblastoma N = 40), a radiotherapy group which underwent radiotherapy and surgery (astrocytoma/ependymoma N = 30), and a surgery group (astrocytoma N = 40). Academic achievement was correlated to the age at diagnosis, ototoxicity, Karnofsky score (KS), and MRI findings (Fazekas Score (FS)- treatment related parenchymal changes). For a modelled age at diagnosis of five years, the cisplatin group had lower academic achievements compared to the radiotherapy (p = 0.028) and surgery (p = 0.014) groups. Academic achievements evaluated at a modelled age of 10 years at diagnosis did not significantly differ among the treatment groups. The cisplatin group exhibited a higher occurrence of ototoxicity than the radiotherapy (p<0.019) and surgery groups (p<0.001); however, there was no correlation between ototoxicity and academic achievements (p = 0.722) in older age at diagnosis. The radiotherapy group exhibited lower KS than the surgery group (p<0.001). KS significantly influenced academic achievements in all groups (p<0.000). The cisplatin group exhibited higher FS than the surgery group (p<0.001) while FS did not correlate with academic achievement (p = 0.399). Older age is a protective factor for academic achievements irrespective of a treatment modality.

Incidence of Hippocampal Metastases: Laterality and Implications for Unilateral Hippocampal Avoiding Whole Brain Radiotherapy.

INTRODUCTION: Hippocampi sparing whole brain radiotherapy (WBRT) is an evolving approach in the treatment of patients with multiple brain metastases, pursuing mitigation of verbal memory decline as a consequence of hippocampal radiation injury. Accumulating data are showing different postradiotherapy changes in the left and right hippocampus with a theoretical proposal of only unilateral (dominant, left) hippocampal sparing during WBRT. METHOD: The aim of this retrospective study is to describe spatial distribution of brain metastases on MRI in a cohort of 260 patients (2595 metastases) and to evaluate distribution separately in the left and right hippocampus and in respective hippocampal avoiding zones (HAZ, region with subtherapeutic radiation dose), including evaluation of location of metastatic mass centre. RESULTS: The median number of brain metastases was three, with lung cancer being the most common type of primary tumour; 36% had single metastasis. Almost 8% of patients had metastasis within hippocampus (1.1% of all metastases) and 18.1% of patients within HAZ (3.3% of all metastases). No statistically significant difference was observed in the laterality of hippocampal involvement, also when the location of centre of metastases was analyzed. There were more patients presenting the centre of metastasis within left (15) versus right (6) HAZ approaching the borderline of statistical significance. CONCLUSION: No significant difference in the laterality of BM seeding within hippocampal structures was observed. The hypothesized unilateral sparing WBRT would have theoretical advantage in about 50% reduction in the risk of subsequent recurrence within spared regions.