Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class "spinal ependymoma" (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

Pineal anlage tumor: clinical and diagnostic features, and rationales for treatment.

PURPOSE: To provide a treatment-focused review and develop basic treatment guidelines for patients diagnosed with pineal anlage tumor (PAT). METHODS: Prospectively collected data of three patients with pineal anlage tumor from Germany was combined with clinical details and treatment information from 17 published cases. RESULTS: Overall, 20 cases of PAT were identified (3 not previously reported German cases, 17 cases from published reports). Age at diagnosis ranged from 0.3 to 35.0 (median: 3.2 ± 7.8) years. All but three cases were diagnosed before the age of three years. For three cases, metastatic disease at initial staging was described. All patients underwent tumor surgery (gross-total resection: 9, subtotal resection/biopsy: 9, extent of resection unknown: 2). 15/20 patients were alive at last follow-up. Median follow-up for 10/15 surviving patients with available follow-up and treatment data was 2.4 years (0.3-6.5). Relapse was reported for 3 patients within 0.8 years after diagnosis. Five patients died, 3 after relapse and 2 from early postoperative complications. Two-year-progression-free- and -overall survival were 65.2 ± 12.7% and 49.2 ± 18.2%, respectively. All 4 patients who received intensive chemotherapy including high-dose chemotherapy combined with radiotherapy (2 focal, 2 craniospinal [CSI]) had no recurrence. Focal radiotherapy- and CSI-free survival rates in 13 evaluable patients were 46.2% (6/13) and 61.5% (8/13), respectively. CONCLUSION: PAT is an aggressive disease mostly affecting young children. Therefore, adjuvant therapy using intensive chemotherapy and considering radiotherapy appears to comprise an appropriate treatment strategy. Reporting further cases is crucial to evaluate distinct treatment strategies.

Survivors of infant atypical teratoid/rhabdoid tumors present with severely impaired cognitive functions especially for fluid intelligence and visual processing: data from the German brain tumor studies.

BACKGROUND: The contribution of tumor type, multimodal treatment, and other patient-related factors upon long-term cognitive sequelae in infant brain tumor survivors remains undefined. We add our retrospective analysis of neuropsychological and quality of survival (QoS) outcome data of survivors of atypical teratoid/rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors of the soft tissues (eMRT) and kidneys (RTK) treated within the same framework. Neuropsychological data from children with ATRT were compared to data from children with non-irradiated low-grade glioma (LGG). PATIENTS AND METHODS: Following surgery, patients (0-36 months at diagnosis) had received radio-chemotherapy (up to 54 Gy; ATRT: n = 13; eMRT/RTK: n = 7), chemotherapy only (LGG: n = 4; eMRT/RTK: n = 1) or had been observed (LGG: n = 11). Neuropsychological evaluation employing comparable tests was performed at median 6.8 years (ATRT), 6.6 years (eMRT/RTK), and 5.2 years (LGG) post diagnosis. RESULTS: We detected sequelae in various domains for all tumor types. Group comparison showed impairments, specifically in fluid intelligence (p = .041; d = 1.11) and visual processing (p = .001; d = 2.09) in ATRT patients when compared to LGG patients. Results for psychomotor speed and attention abilities were significantly below the norm for both groups (p < .001-.019; d = 0.79-1.90). Diagnosis predicted impairments of cognitive outcome, while sex- and age-related variables did not. QoS outcome for all rhabdoid patients displayed impairments mainly in social (p = .008; d = 0.74) and school functioning (p = .048; d = 0.67), as well as lower overall scores in psychosocial functioning (p = .023; d = 0.78) and quality of life (p = .006; d = 0.79) compared to healthy controls. CONCLUSION: Survivors of infant ATRT experience various late effects in cognition and QoS following multimodal treatment, while infant LGG patients without radiotherapy demonstrated comparable impairments in psychomotor and attention abilities. Early onset and multimodal treatment of rhabdoid tumors require close monitoring of neuropsychological and QoS sequelae.

Medulloblastoma in children with Fanconi anemia: Association with FA-D1/FA-N, SHH type and poor survival independent of treatment strategies.

BACKGROUND: Outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not been described systematically. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study aims at giving a comprehensive overview about clinical and molecular characteristics of pediatric FA MB patients. METHODS: Clinical data including detailed information on treatment and toxicities of six previously unreported FA MB patients were supplemented with data of 16 published cases. RESULTS: We identified 22 cases of children with FA and MB with clinical data available. All MBs with subgroup reporting were SHH-activated (n=9), confirmed by methylation profiling in five patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n=16) or FA-N (n=3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT)±chemotherapy (27%). 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. Median overall survival (OS) was 1 year (95%CI 0.3-1.8). 1-year-progression-free-survival (PFS) was 26.3±10.1% and 1-year-OS was 42.1±11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3±12.9%/33.3±12.2% with adjuvant therapy, p=0.006/p=0.086). CONCLUSIONS: MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may prolong survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Curative therapy for FA MB-SHH remains an unmet medical need.

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.

Radiotherapy for Recurrent Medulloblastoma in Children and Adolescents: Survival after Re-Irradiation and First-Time Irradiation.

BACKGROUND: Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are limited and associated with severe side-effects. METHODS: For pre-irradiated patients, patients with re-irradiation (RT2) were matched by sex, histology, time to recurrence, disease status and treatment at recurrence to patients without RT2. RESULTS: A total of 42 pre-irradiated patients with RT2 were matched to 42 pre-irradiated controls without RT2. RT2 improved the median PFS [21.0 (CI: 15.7-28.7) vs. 12.0 (CI: 8.1-21.0) months] and OS [31.5 (CI: 27.6-64.8) vs. 20.0 (CI: 14.0-36.7) months]. Concerning long-term survival after ten years, RT2 only lead to small improvements in OS [8% (CI: 1.4-45.3) vs. 0%]. RT2 improved survival most without (re)-resection [PFS: 17.5 (CI: 9.7-41.5) vs. 8.0 (CI: 6.6-12.2)/OS: 31.5 (CI: 27.6-NA) vs. 13.3 (CI: 8.1-20.1) months]. In the RT-naïve patients, CSI at recurrence improved their median PFS [25.0 (CI: 16.8-60.6) vs. 6.6 (CI: 1.5-NA) months] and OS [40.2 (CI: 18.7-NA) vs. 12.4 (CI: 4.4-NA) months]. CONCLUSIONS: RT2 could improve the median survival in a matched cohort but offered little benefit regarding long-term survival. In RT-naïve patients, CSI greatly improved their median and long-term survival.

Risk factors for domain-specific neurocognitive outcome in pediatric survivors of a brain tumor in the posterior fossa - Results of the HIT 2000 trial.

BACKGROUND: Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization and biology in pediatric survivors of a posterior fossa tumor. METHODS: Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic (NBD) tool based on Cattell-Horn-Carroll's model for intelligence were analyzed. RESULTS: Cognitive performance 5.14 years (mean; range=1.52-13.02) after diagnosis was significantly below normal for all subtests. Processing speed and psychomotor abilities were most affected. Influencing factors were domain-specific: CSI-dose had strong impact on most subtests. pCMS was associated with psychomotor abilities (ß=-0.25 to -0.16) and processing speed (ß=-0.32). Postoperative hydrocephalus correlated with crystallized intelligence (ß=-0.20) and short-term memory (ß=-0.15), age with crystallized intelligence (ß=0.15) and psychomotor abilities (ß=-0.16 and ß=-0.17). Scores for fluid intelligence (ß=-0.23), short-term memory (ß=-0.17) and visual processing (ß=-0.25) declined, and scores for selective attention improved (ß=0.29) with time after diagnosis. CONCLUSION: Dose of CSI was strongly associated with neurocognitive outcome. Low psychomotor abilities and processing speed both in patients treated with and without CSI suggest a strong contribution of the tumor and its surgery on these functions. Future research therefore should analyze strategies to both reduce CSI-dose and toxicity caused by other treatment modalities.

SNO-EANO-EURACAN consensus on management of pineal parenchymal tumors.

Pineal parenchymal tumors are rare neoplasms for which evidence-based treatment recommendations are lacking. These tumors vary in biology, clinical characteristics, and prognosis, requiring treatment that ranges from surgical resection alone to intensive multimodal antineoplastic therapy. Recently, international collaborative studies have shed light on the genomic landscape of these tumors, leading to refinement in molecular-based disease classification in the 5th edition of the World Health Organization (WHO) classification of tumors of the central nervous system. In this review, we summarize the literature on diagnostic and therapeutic approaches, and suggest pragmatic recommendations for the clinical management of patients presenting with intrinsic pineal region masses including parenchymal tumors (pineocytoma, pineal parenchymal tumor of intermediate differentiation, and pineoblastoma), pineal cyst, and papillary tumors of the pineal region.

Multiomic profiling of medulloblastoma reveals subtype-specific targetable alterations at the proteome and N-glycan level.

Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically heterogenous. The application of omics technologies-mainly studying nucleic acids-has significantly improved MB classification and stratification, but treatment options are still unsatisfactory. The proteome and their N-glycans hold the potential to discover clinically relevant phenotypes and targetable pathways. We compile a harmonized proteome dataset of 167 MBs and integrate findings with DNA methylome, transcriptome and N-glycome data. We show six proteome MB subtypes, that can be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pG3myc), and synapses/immunological processes (pSHHs, pG3 and pG4). Multiomic analysis reveals different conservation levels of proteome features across MB subtypes at the DNA methylome level. Aggressive pGroup3myc MBs and favorable pWNT MBs are most similar in cluster hierarchies concerning overall proteome patterns but show different protein abundances of the vincristine resistance-associated multiprotein complex TriC/CCT and of N-glycan turnover-associated factors. The N-glycome reflects proteome subtypes and complex-bisecting N-glycans characterize pGroup3myc tumors. Our results shed light on targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.