A second allogeneic (allo-)hematopoietic stem cell transplantation (HSCT2) is a potential curative option for pediatric patients with acute lymphoblastic leukemia (ALL) following relapse after first allogeneic transplantation (HSCT1), but its efficacy is limited by high relapse rates and transplant-related toxicity in highly pretreated patients. This retrospective multicenter study analyzed 75 pediatric patients enrolled in the PRSZT registry who underwent HSCT2 between 2011 and 2020. Indications for HSCT2 were relapse in 55 patients (73%) and graft failure in 16 patients (21%). In 4 patients (6%), the indication could not be clearly determined due to incomplete documentation. At 2 and 5 years, overall survival (OS) was 48% and 40%, while relapse-free survival (RFS) was 35.2% and 29.9%. Relapse was the leading cause of mortality, occurring in 36% of patients post-HSCT2, with a median time to relapse of 8.2 months. Univariate analysis identified a longer duration of remission after HSCT1 (>6 months) as a predictor of improved OS (p = 0.013) and chronic graft-versus-host disease (cGVHD) after HSCT2 as beneficial for OS (p = 0.034) and RFS (p = 0.024). In multivariate analysis, older age (>10 years) (HR: 2.778, p < 0.01) and precursor T-cell ALL (HR: 6.62, p = 0.001) were associated with inferior OS, as well as with inferior RFS (HR: 2.2, p = 0.03; HR: 3.89, p < 0.005), while male sex (HR: 0.354, p = 0.02) and ATG administration (HR: 0.35, p = 0.019) predicted improved OS. Despite high relapse rates, HSCT2 remains a potentially curative treatment in a subgroup of patients. These findings highlight the need for better patient selection and the integration of novel immunotherapeutic strategies to further improve outcomes.

Abstract Children, adolescent and young adults (CAYA) with relapsed high-grade gliomas (rHGG) share a dismal prognosis. Singular immunotherapeutic interventions like therapeutic vaccines have shown safety and immunogenicity, yet limited clinical efficacy. In the HIT-HGG Rez Immunovac phase I/II study (Eudra-CT 2013-000419-26) we optimzed induction and persistance of immune responses by combining upfront Treg-depletion using metronomic cyclophosphamide followed by therapeutic dendritic cell-based vaccines and subsequent checkpoint inibitor blockade (4x Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg q3wk followed by Nivo mono 6 mg/kg q4wk for up to one year). Primary efficacy endpoint was to reach a 6-month post-relapse overall survival (prOS) of at least 82%. Twenty-five CAYAs with a mean age of 13.8 years [4.3-19.5] were enrolled between 2018-2024. Five patients were excluded due to progression before vaccine start or insufficient tumor material, 20 patients received therapy as per protocol. Fifteen SAEs were noted with no unexpected toxicities. The primary end point was confirmed with a 6-month prOS of 84% and one patient being alive after 31.2 months follow-up. PrOS was significantly improved over a historical control group (HCG, n = 87) from the HIT-HGG database (median OS 9.0 months, range 3.3-31.2 vs. 4.98 months, range 0.26-47.77 in Immunovac vs. HCG patients respectively, p=0.0003). Patients with stable disease at the end of vaccination had a better prOS than those relapsing during the vaccine schedule. Immunomonitoring demonstrated a decline in Tregs and a shift from naïve to memory T-cell subsets under treatment. Vaccine-specific CD4+ and CD8+ T-cell responses were observed in almost all patients, including responses against tumor-specific HLA-class I/II epitopes from the respective immunopeptidomes. Furthermore, spatial omics using cyclic immunofluorescence imaging technology at baseline revealed an immune-cold tumor microenvironment (TME) dominated by myeloid cells (∼50%), predominantly M2-polarized macrophages. T- and NK-cells contributed ∼10% and 15%, respectively. Immune effector cells were spatially dispersed, displayed an exhausted phenotype and were typically embedded within immunosuppressive glial niches or stromal compartments. The tumor compartment exhibited aggressive features, including high Ki67, strong GFAP expression, and frequent p53 alterations, but showed robust HLA-class II expression, revealing potential vulnerability to CD4+ T-cell-mediated responses. In conclusion, our data demonstrate safety and clinical efficacy of an optimized immunotherpeutic regime in CAYA with rHGG. Our immunomonitoring data show substantial T-cell responses and changes in the peripheral immune compartments. Together with insights from the TME these results will shape the design of future immunotherapy trials in HGG.

Abstract Graft failure (GF) after allogeneic hematopoietic stem cell transplant (HSCT) is a life-threatening complication. The Inborn Errors Working Party conducted a retrospective study to examine the outcome of a second HSCT for children with nonsevere combined immunodeficiency (SCID) inborn errors of immunity (IEI); 159 children from 37 centers who received a second transplant between 2009 and 2020 were included in this analysis. The median interval between first and second HSCT was 6.9 months (0.7-155.2 months). The 5-year overall survival (OS) and event-free survival (EFS) rates were 78% and 69%, respectively. The second HSCT for primary GF had a significantly lower OS (69%, 55%-83% vs secondary GF, 81%, 73%-89%; P = .044) and EFS (52%, 37%-68% vs secondary GF, 75%, 67%-84%; P< .001). Improved EFS was observed in patients who received myeloablative conditioning/reduced-toxicity conditioning (74%, 66%-81%) compared with nonmyeloablative conditioning (50%, 29%-71%; P = .003), but this association was not observed in OS. Upon multivariable analysis, cord blood was the only independent negative predictor for EFS (hazard ratio, 4.9, 1.3-18.7; P = .020). The 1-year cumulative incidence (CIN) of all GF after the second HSCT was 13% (95% confidence interval, 8%-19%). The day-100 CINs of grade 2 and grade 3 to 4 acute graft-versus-host disease were 19% (13%-25%) and 8% (4%-13%), respectively. Whole-blood chimerism >90% was reported in 84.3% at last follow-up. We report, to our knowledge, the first international experience with the largest cohort of second conditioned HSCT in non-SCID IEI to date. This study provides valuable insights into the clinical outcomes following second transplant, identifying key predictors of survival.

BACKGROUND:The HIT network was established in 2000 to create a population-based structure aiming to improve survival rates and reduce late effects for children with central nervous system (CNS) tumors by conducting comprehensive clinical trials. METHODS:The HIT network currently consists of 10 coordinating trial centers mandated by the German Society for Pediatric Oncology and Hematology (GPOH) to conduct clinical trials and research projects, and to provide counseling to local centers for individual patients. The network is complemented by 11 reference centers (neuropathology, tumor biology, neuroradiology, pediatric neurosurgery, cerebrospinal fluid [CSF], assessments, radiotherapy, genetics), biostatistical support, and currently 72 local treatment sites. RESULTS:Numbers of children and adolescents with newly diagnosed CNS tumors registered to trials and registries increased from approximately 500 to more than 600 per year, corresponding to >95% of affected HIT-eligible children and adolescents in Germany. Clinical counseling and upfront reference assessments ensure homogeneous clinical standards and avoid inadequate treatment of individual patients. Since 2007, the established reference services have been partially re-funded by German health insurances. DISCUSSION:The HIT network provides a unique structure for population-based state-of-the-art diagnostic assessments, treatment recommendations and counseling. It increases the "a priori" accuracy of stratification parameters, and the timely inclusion into clinical trials and tumor-specific registries. Favorable outcomes are achieved within the trials and registry landscape, for example, through consistent reference assessments, reducing the gap to real world data. Resulting data facilitate representative, unbiased high-quality research projects across all CNS tumor entities. Interdisciplinary cooperation and competitive scientific output are enhanced.

As clinical outcomes for children and adolescents with relapsed or refractory (R/R) malignancies remain poor, targeted molecular therapies are increasingly used in salvage settings. However, real-world evidence on their use and toxicity outside clinical trials is scarce.We conducted a retrospective multicentre analysis of 366 children and adolescents with R/R malignancies treated across six paediatric oncology centres in Bavaria, Germany between 2017 and 2021. Data on patient demographics, diagnosis, treatment, response, and toxicity were extracted from routine clinical records to describe treatment patterns, the use and toxicity profile of targeted therapeutic agents. Of 366 eligible patients (40.4% female; median age at primary diagnosis 6 years), 56.8% were alive at last follow-up. CNS tumours (37.4%), solid tumours (28.4%), and leukaemia (23.8%) constituted the main diagnostic groups. Chemotherapy remained the backbone of salvage treatment (68.6%), while targeted molecular therapies were administered to 50 patients (13.7%). Tyrosine kinase inhibitors, MAP/BRAF kinase inhibitors, and mTOR inhibitors were the most frequently used drug classes; dasatinib, trametinib, and sirolimus were the most commonly administered agents. Adverse events were documented in 40.3% of targeted therapy courses (n=67), predominantly CTCAE grade 2–3. Gastrointestinal (n=12) and haematological toxicities (n=10) were the most frequent adverse events. Three patients achieved durable complete remission following multimodal salvage therapy incorporating a targeted agent.Our results highlight both the promise and current limitations of precision oncology in routine paediatric practice, and underscore the urgent need for prospective real-world data collection to inform clinical decision-making for this vulnerable population.

NFAT is a family of transcription factors whose activation is inhibited by calcineurin inhibitors (CNIs). In allogeneic hematopoietic stem cell transplantation (allo-HCT), CNIs are employed to prevent and treat graft- versus-host disease (GvHD). Unfortunately, control of cytomegalovirus (CMV), which exacerbates clinical outcomes, is simultaneously lost. Since single NFAT deficiency in T cells ameliorates GvHD in our major mismatch model, we investigated whether protection is maintained during CMV infection. Reassuringly, NFAT-deficient T cells still improved GvHD upon acute CMV infection and after allo-HCT in latently CMV-infected mice, showing reduced proinflammatory and cytotoxic potential. In sharp contrast, CMV-specific NFAT-deficient CD8+ inflated memory T cells expanded more and with higher levels of interferon gamma (IFN-g) and GzmB expression, effectively controlling CMV. Notably, NFAT-deficient inflated memory T cells could migrate to non-lymphoid tissues and fight CMV. Therefore, CMV infection does not interfere with the protective effect of NFAT inhibition to attenuate GvHD while allowing an anti-CMV response.

Background:Young children with medulloblastoma (MB) are especially susceptible for tumor and treatment-related brain damage. Craniospinal irradiation (CSI) has been identified as a main risk factor for cognitive and motor dysfunction 2-5 years after diagnosis. Longitudinal follow-up data on these children beyond 10 years after diagnosis are scarce. Methods:To characterize their long-term neurocognitive outcome, we analyzed a cohort of 24 MB patients below the age of 3 years at diagnosis treated within the HIT-SKK'87 (systemic chemotherapy and deferred CSI) and HIT-SKK'92 (systemic chemotherapy and intraventricular methotrexate (MTXi.vt.), no radiotherapy) trials after 5 and 15 years. A comprehensive test battery was used to measure cognitive operations, executive functions with selective attention, and psychomotor abilities. Results:Overall, MB survivors showed subnormal test results independent of treatment, especially in the domain of motor function. CSI had an additional detrimental effect on general and fluid intelligence and simultaneous processing, whereas MTXi.vt.-recipients never scored worse than irradiated patients. Upon longitudinal follow-up, tests assessing sequential processing and general IQ showed stable or even improved results. In contrast, fluid intelligence, visual-motor integration, and most pronounced tapping speed further declined at 15 years in both the treatment groups and reached the disability zone. Conclusion:Impairment of motor and cognitive skills represents a major handicap for MB survivors. Long-term development of fluid intelligence and visuomotor integration is hindered in all children. CSI further aggravated these dysfunctions. Visual or auditory domains and memory performance are less affected. Long-term neurocognitive support is warranted in young pediatric survivors of MB.

Background: The HIT-HGG-2007 trial investigated temozolomide (TMZ) radio-chemotherapy for pediatric patients with high-grade gliomas (pHGG) to demonstrate therapeutic non-inferiority compared to previous intensive radio-chemotherapy regimens (HIT-GBM-C/-D). Methods: Between June 2009 and December 2016, 456 patients were enrolled into this international, prospective, single-arm, multicenter phase II trial in Germany, Austria, and Switzerland of whom 438 patients were evaluable for confirmatory analysis. Patients from the HIT-GBM-C/-D trials served as historic control (n = 439). Tumors of both cohorts with available tissue were re-classified according to the 2021 WHO classification of CNS tumors (n = 140). Results: Regarding event-free-survival (EFS) rate at 6 months, non-inferiority of the HIT-HGG-2007 regimen was confirmed (p = 0.0125). In terms of exploratory analyses, median EFS and overall survival (OS) was 9.5 months (95 % confidence interval [CI95], 8.9-10.4) and 14.7 months (CI95, 13.5-16.3), superior to intensive chemotherapy regimens (p < 0.0001 and p = 0.0328). EFS and OS remained superior after re-classification of tumors according to WHO2021 criteria. TMZ radio-chemotherapy had lower rates of severe hematological, gastrointestinal, and hepatic toxicity compared to HIT-GBM-C/-D. Younger age, WHO grade IV histology, tumor location in the brainstem or basal ganglia, and lower extent of resection were independent adverse risk factors for OS and EFS. MGMT gene promoter methylation status had no impact on EFS and OS. Conclusions: The HIT-HGG-2007 trial demonstrated non-inferiority compared with intensive chemotherapy regimens. MGMT promotor methylation status had no impact on survival. Exploratory analysis supports treatment of newly diagnosed non-pontine pHGG according to the HIT-HGG-2007 regimen due to improved EFS and OS rates together with a favorable toxicity profile.

BACKGROUND:Invasive fungal diseases (IFD) pose significant challenges in paediatric oncology. Their management is complicated by limited paediatric-specific evidence, lack of standardised protocols and variability in resources across centres. This study assessed current practices and addressed the challenges in the prevention, diagnosis and treatment of IFDs in paediatric oncology centres across Germany, Austria and Switzerland. METHODS:A questionnaire was distributed to senior paediatric oncologists in 70 paediatric oncology centres across Germany, Austria and Switzerland, gathering data on centre infrastructure, infectious disease (ID) expertise, annual cumulative IFD incidence in 2023, diagnostic tools, antifungal prophylaxis, treatment and follow-up practices for IFD. Responses were analysed descriptively. RESULTS:Sixty-two centres responded, with a median of 56 (IQR 40-75) new oncological diagnoses per centre; 54.8% of centres managed allogeneic HCT patients. IFDs were reported in 88.7% of centres, with a median cumulative IFD incidence of 4.6% (IQR 3.0%-5.9%). No significant association was found between cumulative IFD incidence and the number of transplants, antifungal prophylaxis protocols and availability of ID consultation services. ID consultation was available in 58.1% of centres, with 24/7 support provided in 41.7% of these centres. Larger centres more frequently had paediatric ID specialists, ID consultation services and access to therapeutic drug monitoring. CONCLUSIONS:The observed heterogeneity in mycology expertise and IFD management strategies across centres reflects the inherent complexity of IFDs and the diagnostic and therapeutic uncertainties amid limited evidence. Strengthening oncology-ID networks and implementing digital consultation platforms may promote high-quality, equitable care, particularly for those with fewer in-house resources.

Medulloblastoma is the most frequent malignant primary brain tumor in children. Despite recent advances in integrated genomics, the prognosis in children with high-risk medulloblastoma remains devastating, and new tumor-specific therapeutic approaches are needed. Here, we present an atlas of naturally presented T cell antigens in medulloblastoma. We map the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and perform comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma is shown to be a rich source of tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins are subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) is rare. Functional testing of top-ranking novel candidate antigens demonstrates the induction of peptide-specific T cell responses, supporting their potential for T cell immunotherapy. This study is an in-depth mapping of naturally presented T cell antigens in medulloblastoma. Integration of immunopeptidomics, transcriptomics, and epigenetic data leads to the identification of a large set of actionable targets that can be further used for the translation into the clinical setting by facilitating the informed design of immunotherapeutic approaches to children with medulloblastoma.

ABSTRACT:HFE-related hemochromatosis induces systemic iron overload. Although extensive studies indicate a pivotal role for iron homeostasis in αβ T-cell immunity, its effect on γδ T cells is unknown. Here, we found a reversal of the Vδ2+/Vδ2- ratio in the γδ T-cell compartment as a feature of hemochromatosis, which is associated with a Vδ2+ population that cannot be enriched by zoledronic acid (ZOL) stimulation, despite evidence of T-cell receptor (TCR)-ligand formation and strong proliferative behavior. In vivo, reactive oxygen species (ROS) production and exhaustion marker expression are significantly increased on Vδ2+ T cells in hemochromatosis compared with healthy individuals. Ex vivo, hemochromatosis donor-derived Vδ2+ cells are hyporesponsive to TCR stimulation in terms of ROS production but significantly increase their paramount expression of exhaustion markers. Fas-Fas ligand coexpression indicates their high susceptibility to activation-induced cell death. Consistent therewith, FeSO4 alone induces Vδ2+ subset-specific proliferation in healthy peripheral blood mononuclear cells comparable to stimulation by ZOL, and blocking experiments identify FeSO4-induced proliferation as BTN3A1/TCR mediated. Pyrophosphate is key for Vδ2+-TCR ligand formation. Iron, by suppressing pyrophosphatase alkaline phosphatase, promotes their stability. Therefore, our data suggest that the transcriptional repression of pyrophosphatases, as under the conditions of iron overload in hemochromatosis in vivo, leads to the constitutive availability of stress-signaling Vδ2+-TCR ligand and permanent TCR triggering in Vδ2+ T cells even under homeostatic conditions, which ultimately results in their subset-specific, activation-induced cell death. A similar phenotype was observed in patients with iron overload due to inborn hemoglobinopathies, suggesting an inverted Vδ2+/Vδ2- ratio in the γδ T-cell compartment as a hallmark of iron overload.

Background:We assessed clinical features, treatment, and survival of pediatric patients with neurofibromatosis type 1 (NF1) with high-grade glioma (HGG). Methods:Patients from this retrospective cohort study were identified through an international collaborative effort by the SIOPE HGG/DIPG working group. NF1 was diagnosed based on clinical presentation and confirmed by either a pathogenic germline NF1 gene alteration or the exclusion of mismatch repair deficiency. A control cohort without genetic cancer predisposition was matched in a 2:1-ratio from the HIT-HGG database. Results:We identified 29 pediatric patients with NF1-associated HGG. Median age at diagnosis of HGG was 11 years. All but 1 tumor arose outside the optic pathway and included circumscribed and diffuse HGG. Molecular analysis in a subset of tumors identified an enrichment of alterations in CDKN2A, TP53, and ATRX. Event-free and overall survival were as poor as in matched sporadic HGG patients. The prognosis was not superior with upfront radiotherapy compared with delayed radiotherapy. Conclusions:NF1-associated HGGs behave as aggressively as their sporadic counterparts. The relevance of delaying radiotherapy until the time of progression and adjuvant MEK inhibitor treatment needs further investigation.

Background: The incorporation of anti-GD2 antibodies such as ch14.18/SP2/0 into the multimodal treatment of high-risk neuroblastoma (HR-NB) patients has improved their outcomes. As studies assessing the long-term outcomes, long-term sequelae, and health-related quality of life (HRQoL) of this treatment are limited, this retrospective analysis aimed to explore these. Patients and Methods: Between 1991 and 2002, 65 children received a multimodal treatment, including ch14.18/SP2/0, for primary HR-NB. All received chemotherapy according to the NB90/NB97 trial, 51 received high-dose chemotherapy, and all received ch14.18/SP2/0 treatment. We analyzed the long-term sequelae and HRQoL (EORTC QLQ-C30), and evaluated overall and event-free survival (OS/EFS). Results: Twenty-five survivors were evaluated for HRQoL and long-term effects. All reported long-term sequelae, including ototoxicity in 16/25 (64%), cardiac toxicity in 6/25 (24%), and endocrine toxicity in 19/25 (76%) patients. Chronic diarrhea was reported in 20% of female patients. Seven patients developed autoimmune diseases. HRQoL scores were better across multiple scales than those of the matched German general population. Twenty-five-year OS and EFS were 50.8% (95% confidence interval: 31–55) and 43% (30.1–55.3), with 33 (50.8%) long-term survivors. Thirty-two patients died: 28 (43.1%) because of progression/relapse and 4 (6.2%) because of secondary neoplasms. Conclusions: Multimodal treatment, including ch14.18/SP2/0, can achieve long-term survival in HR-NB patients, with a substantial proportion of survivors reporting better HRQoL compared to the general population. All patients reported long-term side effects mostly attributable to chemotherapy and radiotherapy. The relatively high prevalence of autoimmune diseases and persistent diarrhea warrants additional longitudinal research on individuals treated with anti-GD2 antibodies.

Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients' families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including MSH2 hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.

Malignant glioma is a highly aggressive, therapeutically non-responsive, and deadly disease with a unique tumor microenvironment (TME). Of the 14 currently recognized and described cancer hallmarks, five are especially implicated in malignant glioma and targetable with repurposed drugs: cancer stem-like cells, in general, and glioma stem-like cells in particular (GSCs), vascularization and hypoxia, metabolic reprogramming, tumor-promoting inflammation and sustained proliferative signaling. Each hallmark drives malignant glioma development, both individually and through interactions with other hallmarks, in which the TME plays a critical role. To combat the aggressive malignant glioma spatio-temporal heterogeneity driven by TME interactions, and to overcome its therapeutic challenges, a combined treatment strategy including anticancer therapies, repurposed drugs and multimodal immunotherapy should be the aim for future treatment approaches.

Background and aims: High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) improves the prognosis in pediatric patients with several solid tumors and lymphomas. Little is known about the reconstitution of the immune system after ASCT and the influence of CD34+ cell selection on the reconstitution in pediatric patients. Methods: Between 1990 and 2001, 94 pediatric patients with solid tumors and lymphomas received autologous CD34+ selected or unmanipulated peripheral stem cells after HDC. CD34+ selection was carried out with magnetic microbeads. The absolute numbers of T cells, B cells and natural killer (NK) cells were measured and compared in both groups at various time points post-transplant. Results: Recovery of T cells was significantly faster in the unmanipulated group at day 30, with no significant difference later on. Reconstitution of B and NK cells was similar in both groups without significant differences at any time. The CD34+-selected group was divided into patients receiving less or more than 5.385 x 10(6)/kg CD34+ cells. Patients in the CD34+ high-dose group displayed significantly faster reconstitutions of neutrophiles and lymphocyte subsets than the CD34+ low-dose group. Conclusions: Engraftment and reconstitution of leukocytes, B cells and NK cells after transplantation of CD34+ selected stem cells were comparable to that in patients receiving unmanipulated grafts. T-cell recovery was faster in the unmanipulated group only within the first month. However, this delay could be compensated by transplantation of >5.385 x 10(6) CD34+ cells/kg. Especially for patients receiving immunotherapy after HDC large numbers of immune effector cells such as NK and T cells are necessary to mediate antibody-dependent cellular cytotoxicity. Therefore, in patients receiving autologous CD34+-selected grafts, our data emphasize the need to administer high stem cell counts.

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.