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.

Current Molecular and Clinical Landscape of ATRT - The Link to Future Therapies.

ATRT is a highly aggressive and rare pediatric CNS tumor of very young children. Its genetic hallmark is bi-allelic inactivation of SMARCB1 encoding INI1. Rarely SMARCA4 encoding BRG1 is affected. Up to 30% are associated with constitutional heterozygous pathogenic variants in one of the two genes, giving rise to the Rhabdoid-Tumor-Predisposition-Syndromes (RTPS) 1 and 2. Characteristic DNA methylation profiles distinguish ATRT from other SMARCB1-deficient entities. Three distinct subtypes ATRT-MYC, -TYR, and -SHH are on record. ATRT-SHH may be further divided into the subgroups ATRT-SHH1A, -SHH1B, and -SHH2. The cure of ATRT remains challenging, notwithstanding an increasing understanding of molecular pathomechanisms and genetic background. The implementation of multimodal institutional treatment protocols has improved prognosis. Regardless of treatment approaches, clinical risk factors such as age, metastases, and DNA methylation subtype affect survival probability. We provide a critical appraisal of current conventional multimodal regimens and emerging targeted treatment approaches investigated in clinical trials and entity-specific registries. Intense treatment approaches featuring radiotherapy (RT) and high-dose chemotherapy (HDCT) face the difficulty of balancing tumor control and treatment-related toxicity. Current approaches focus on minimizing radiation fields by proton beam therapy or to withhold RT in HDCT-only approaches. Still, a 40-75% relapse rate upon first-line treatment reveals the need for novel treatment strategies in primary and even more in recurrent/refractory (r/r) disease. Among targeted treatments, immune checkpoint inhibitors and epigenetically active agents appear most promising. Success remains limited in single agent approaches. We hypothesize that mechanism-informed combination therapy will enhance response, as the low mutational burden of ATRT may contribute to acquiring resistance to single targeted agents. As DNA methylation group-specific gene expression profiles appear to influence response to distinct agents, the future treatment of ATRT should respect clinical and biological heterogeneity in risk group adjusted treatment protocols.