Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.

BACKGROUND: The term Gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features have not been established yet. METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-years survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n=49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wildtype (n=31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n=19), pedHGG_A/B (n=6), and pedHGG_MYCN (n=5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wildtype subgroup, recurrent alterations in EGFR (n=10) and BCOR (n=9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wildtype subgroup TP53 alterations had a significant negative effect on OS. CONCLUSION: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

Treatment response as surrogate to predict risk for disease progression in pediatric medulloblastoma with persistent MRI lesions after first-line treatment.

BACKGROUND: This study aims at clarifying the impact of persistent residual lesions following first-line treatment for pediatric medulloblastoma. METHODS: Data on 84 pediatric patients with medulloblastoma and persistent residual lesions on centrally reviewed MRI at the end of first-line therapy were analyzed. RESULTS: Twenty patients (23.8%) had residual lesions in the tumor bed (R+/M0), 51 (60.7%) had distant lesions (R0/M+) and 13 (15.5%) had both (R+/M+). Overall response to first-line therapy was minor or partial (≥25% reduction, MR/PR) for 64 (76.2%) and stable disease (SD) for 20 patients (23.8%). Five-year post-primary-treatment progression-free (pptPFS) and overall survival (pptOS) were superior after MR/PR (pptPFS: 62.5±7.0%[MR/PR] vs. 35.9±12.8%[SD], p=0.03; pptOS: 79.7±5.9[MR/PR] vs. 55.5±13.9[SD], p=0.04). Further, R+/M+ was associated with a higher risk for progression (5-year pptPFS: 22.9±17.9%[R+,M+] vs. 72.4±12.0%[R+,M0]; p=0.03). Watch-and-wait was pursued in 58 patients, while n=26 received additional treatments (chemotherapy only, n=19; surgery only, n=2; combined, n=3; valproic acid, n=2), and their outcomes were not superior to watch-and-wait (5-year pptPFS: 58.5±7.7% vs. 51.6±10.7% p=0.71; 5-year pptOS: 76.3±6.9% vs. 69.8±9.7%, p=0.74). For the whole cohort, five-year pptPFS by molecular subgroup (58 cases) were WNT: 100%, SHH: 50.0±35.4%, Group-4, 52.5±10.5, Group-3 54.2±13.8%; (p=0.08). CONCLUSION: Overall response and extent of lesions can function as surrogate parameters to predict outcomes in pediatric MB patients with persistent lesions after first-line therapy. Especially in case of solitary persistent medulloblastoma MRI lesion, additional therapy was not beneficial. Therefore, treatment response, extent/kind of residual lesions and further diagnostic information needs consideration for indication of additional treatments for persisting lesions.

Boswellic acid formulations are not suitable for treatment of pediatric high-grade glioma due to tumor promoting potential.

Background and aim: Pediatric high-grade gliomas (pedHGG) comprise a very poor prognosis. Thus, parents of affected children are increasingly resorting to complementary and alternative medicine (CAM), among those Boswellia extracts. However, nothing is known about the therapeutic effectiveness of their active substances, Boswellic acids (BA) in pedHGG. Thus, we aimed to investigate if the three main Boswellic acids (BA) present in Boswellia plants, alpha-boswellic acid (α-BA), beta-boswellic acid (ß-BA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA) hold any promising potential for treatment of affected pedHGG patients. Experimental procedure: Histone 3 (H3)-wildtype and H3.3K27M-mutant pedHGG cell lines were treated with BA, either alone or in combination with radio-chemotherapy with temozolomide. Cell viability, stemness properties, apoptosis, in ovo tumor growth and the transcriptome was investigated upon BA treatment. Results and conclusion: Interestingly, α-BA and ß-BA treatment promoted certain tumor properties in both pedHGG cells. AKBA treatment reduced cell viability and colony growth accompanied by induction of slight anti-inflammatory effects especially in H3.3K27M-mutant pedHGG cells. However, no effects on apoptosis and in ovo tumor growth were found. In conclusion, besides positive anti-tumor effects of AKBA, tumor promoting effects were observed upon treatment with α-BA and ß-BA. Thus, only pure AKBA formulations may be used to exploit any potential positive effects in pedHGG patients. In conclusion, the use of commercially available supplements with a mixture of different BA cannot be recommended due to detrimental effects of certain BA whereas pure AKBA formulations might hold some potential as therapeutic supplement for treatment of pedHGG patients.

How I treat recurrent pediatric high-grade glioma (pHGG): a Europe-wide survey study.

PURPOSE: As there is no standard of care treatment for recurrent/progressing pediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies. METHODS: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG). RESULTS: 139 clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8-92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55-77% recommended (re-)irradiation, preferably local radiotherapy > 20 Gy. Most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% proposed immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumor-treating fields (1-26%), and intraventricular chemotherapy (4-24%). CONCLUSION: In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressing HGG.

Pediatric high-grade gliomas and the WHO CNS Tumor Classification-Perspectives of pediatric neuro-oncologists and neuropathologists in light of recent updates.

Background: The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring. Molecularly defined diagnostic criteria were introduced in 2016 (revised 4th edition) and expanded in 2021 (5th edition) to incorporate further essential diagnostic molecular parameters. We investigated potential differences between specialists in perception of these molecularly defined subtypes for pediatric high-grade gliomas (pedHGG). Methods: We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to examine the spectrum of viewpoints and possible differences between neuro-oncologists and neuropathologists. Results: 465 participants from 53 countries were included; 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%), and 118 additional experts (26%). Neuro-oncologists reported issues with the introduction of molecularly defined tumor types, as well as the abolishment or renaming of established tumor entities, while neuropathologists did not to the same extent. Both groups indicated less relevant or insufficient diagnostic definitions were available in 2016. Reported issues were classified and assessed in the 2021 WHO classification and a substantial improvement was perceived. However, issues of high clinical relevance remain to be addressed, including the definition of clinical phenotypes for diffuse intrinsic pontine glioma and gliomatosis cerebri. Conclusions: Within the WHO classification of pediatric brain tumors, such as pedHGG, rapid changes in molecular characterization have been introduced. This study highlights the ongoing need for cross talk between pathologist and oncologist to advance the classification of pedHGG subtypes and ensure biological relevance and clinical impact.

Hepatoblastoma in molecularly defined, congenital diseases.

Beckwith-Wiedemann spectrum, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18 are the most common congenital conditions associated with an increased incidence of hepatoblastoma (HB). In patients with these genetic disorders, screening protocols for HB are proposed that include periodic abdominal ultrasound and measurement of alpha-fetoprotein levels. Surveillance in these children may contribute to the early detection of HB and possibly improve their chances of overall survival. Therefore, physicians must be aware of the high HB incidence in children with certain predisposing genetic diseases.

Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells.

Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal (BET) protein BRD4, and leads to the reprogramming of the enhancer landscape contributing to the activation of DIPG super enhancer-driven oncogenes. The activity of the acetyltransferase CREB-binding protein (CBP) is enhanced by BRD4 and associated with acetylation of nucleosomes at super enhancers (SE). In addition, CBP contributes to transcriptional activation through its function as a scaffold and protein bridge. Monotherapy with either a CBP (ICG-001) or BET inhibitor (JQ1) led to the reduction of tumor-related characteristics. Interestingly, combined treatment induced strong cytotoxic effects in H3.3K27M-mutated DIPG cell lines. RNA sequencing and chromatin immunoprecipitation revealed that these effects were caused by the inactivation of DIPG SE-controlled tumor-related genes. However, single treatment with ICG-001 or JQ1, respectively, led to activation of a subgroup of detrimental super enhancers. Combinatorial treatment reversed the inadvertent activation of these super enhancers and rescued the effect of ICG-001 and JQ1 single treatment on enhancer-driven oncogenes in H3K27M-mutated DIPG, but not in H3 wild-type pedHGG cells. In conclusion, combinatorial treatment with CBP and BET inhibitors is highly efficient in H3K27M-mutant DIPG due to reversal of inadvertent activation of detrimental SE programs in comparison with monotherapy.