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.

Rhabdoid tumors in patients conceived following ART: is there an association?

STUDY QUESTION: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY: Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT_ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE: The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION: RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS: This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts.

Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I-VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I-VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification.

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.

Decreased eukaryotic initiation factors expression upon temozolomide treatment-potential novel implications for eIFs in glioma therapy.

PURPOSE: Since glioma therapy is currently still limited until today, new treatment options for this heterogeneous group of tumours are of great interest. Eukaryotic initiation factors (eIFs) are altered in various cancer entities, including gliomas. The purpose of our study was to evaluate the potential of eIFs as novel targets in glioma treatment. METHODS: We evaluated eIF protein expression and regulation in 22 glioblastoma patient-derived xenografts (GBM PDX) after treatment with established cytostatics and with regards to mutation profile analyses of GBM PDX. RESULTS: We observed decreased expression of several eIFs upon temozolomide (TMZ) treatment independent from the phosphatidylinositol 3-kinase (PI3K)/ AKT/ mammalian target of the rapamycin (mTOR) signalling pathway. These effects of TMZ treatment were not present in TMZ-resistant PDX. Combination therapy of regorafenib and TMZ re- established the eIF/AKT/mTOR axis. CONCLUSION: Our study provides novel insights into chemotherapeutic effects on eIF regulation in gliomas and suggests that eIFs are interesting candidates for future research to improve glioma therapy.

Incidence and Risk Factors of Venous Thromboembolism in Childhood Acute Lymphoblastic Leukaemia - a Population-Based Analysis of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group.

Venous thromboembolism (VTE) is a well-known complication of the treatment of pediatric acute lymphoblastic leukemia (ALL). We analyzed 1026 ALL patients 1-18-years-old, who were enrolled into the AIEOP-BFM ALL 2000 or 2009 studies in Austria, with regard to the incidence and risk factors of VTE. The 2.5-year cumulative incidence (CI) of VTE ≥ grade 2 was 4%±1% (n = 36/1026). Twenty VTE (56%) were found in the central nervous system (19 cerebral venous sinus and 1 cortical vein thrombosis), and 16 (44%) at other sites (7 deep vein thromboses (DVT) of the lower extremity, 4 DVT of the upper extremity, 4 central venous line-thromboses, 1 pulmonary embolism). Most VTE occurred during induction and early consolidation therapy (81%) and were associated with L-asparaginase within 4 and corticosteroids withing 1 week(s) preceding the event (89 and 86%, respectively). In multivariable analysis, two independent risk factors were found. Patients 10-18-years-old had an increased (hazard-ratio: 2.156, p = 0.0389), whereas treatments in trial AIEOP-BFM ALL 2009 had a lower risk for VTE (hazard-ratio: 0.349, p = 0.0270). In conclusion, the 2.5-year CI of VTE among our pediatric patient cohort was <5% and adolescent age was the main patient-related risk factor. This older age group might benefit from primary prophylactic measures.

The Immune Deficiency and Dysregulation Activity (IDDA2.1 'Kaleidoscope') Score and Other Clinical Measures in Inborn Errors of Immunity.

Quantifying the phenotypic features of rare diseases such as inborn errors of immunity (IEI) helps clinicians make diagnoses, classify disorders, and objectify the disease severity at its first presentation as well as during therapy and follow-up. Furthermore, it may allow cross-sectional and cohort comparisons and support treatment decisions such as an evaluation for transplantation. On the basis of a literature review, we provide a descriptive comparison of ten selected scores and measures frequently used in IEI and divide these into three categories: (1) diagnostic tools (for Hyper-IgE syndrome, hemophagocytic lymphohistiocytosis, and Wiskott-Aldrich syndrome), (2) morbidity and disease activity measures (for common variable immune deficiency [CVID], profound combined immune deficiency, CTLA-4 haploinsufficiency, immune deficiency and dysregulation activity [IDDA], IPEX organ impairment, and the autoinflammatory disease activity index), and (3) treatment stratification scores (shown for hypogammaglobulinemia). The depth of preclinical and statistical validations varies among the presented tools, and disease-inherent and user-dependent factors complicate their broader application. To support a comparable, standardized evaluation for prospective monitoring of diseases with immune dysregulation, we propose the IDDA2.1 score (comprising 22 parameters on a 2-5-step scale) as a simple yet comprehensive and powerful tool. Originally developed for use in a retrospective study in LRBA deficiency, this new version may be applied to all IEI with immune dysregulation. Reviewing published aggregate cohort data from hundreds of patients, the IDDA kaleidoscope function is presented for 18 exemplary IEI as an instructive phenotype-pattern visualization tool, and an unsupervised, hierarchically clustered heatmap mathematically confirms similarities and differences in their phenotype expression profiles.

Types of deviation and review criteria in pretreatment central quality control of tumor bed boost in medulloblastoma-an analysis of the German Radiotherapy Quality Control Panel in the SIOP PNET5 MB trial.

PURPOSE: In Germany, Austria, and Switzerland, pretreatment radiotherapy quality control (RT-QC) for tumor bed boost (TB) in non-metastatic medulloblastoma (MB) was not mandatory but was recommended for patients enrolled in the SIOP PNET5 MB trial between 2014 and 2018. This individual case review (ICR) analysis aimed to evaluate types of deviations in the initial plan proposals and develop uniform review criteria for TB boost. PATIENTS AND METHODS: A total of 78 patients were registered in this trial, of whom a subgroup of 65 patients were available for evaluation of the TB treatment plans. Dose uniformity was evaluated according to the definitions of the protocol. Additional RT-QC criteria for standardized review of target contours were elaborated and data evaluated accordingly. RESULTS: Of 65 initial TB plan proposals, 27 (41.5%) revealed deviations of target volume delineation. Deviations according to the dose uniformity criteria were present in 14 (21.5%) TB plans. In 25 (38.5%) cases a modification of the RT plan was recommended. Rejection of the TB plans was rather related to unacceptable target volume delineation than to insufficient dose uniformity. CONCLUSION: In this analysis of pretreatment RT-QC, protocol deviations were present in a high proportion of initial TB plan proposals. These findings emphasize the importance of pretreatment RT-QC in clinical trials for MB. Based on these data, a proposal for RT-QC criteria for tumor bed boost in non-metastatic MB was developed.

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.

Clinical and molecular characterization of isolated M1 disease in pediatric medulloblastoma: experience from the German HIT-MED studies.

PURPOSE: To evaluate the clinical impact of isolated spread of medulloblastoma cells into cerebrospinal fluid without additional macroscopic metastases (M1-only). METHODS: The HIT-MED database was searched for pediatric patients with M1-only medulloblastoma diagnosed from 2000 to 2019. Corresponding clinical and molecular data was evaluated. Treatment was stratified by age and changed over time for older patients. RESULTS: 70 patients with centrally reviewed M1-only disease were identified. Clinical data was available for all and molecular data for 45/70 cases. 91% were non-WNT/non-SHH medulloblastoma (Grp3/4). 5-year PFS for 52 patients ≥ 4 years was 59.4 (± 7.1) %, receiving either upfront craniospinal irradiation (CSI) or SKK-sandwich chemotherapy (CT). Outcomes did not differ between these strategies (5-year PFS: CSI 61.7 ± 9.9%, SKK-CT 56.7 ± 6.1%). For patients < 4 years (n = 18), 5-year PFS was 50.0 (± 13.2) %. M1-persistence occurred exclusively using postoperative CT and was a strong negative predictive factor (pPFS/OS < 0.01). Patients with additional clinical or molecular high-risk (HR) characteristics had worse outcomes (5-year PFS 42.7 ± 10.6% vs. 64.0 ± 7.0%, p = 0.03). In n = 22 patients ≥ 4 years with full molecular information and without additional HR characteristics, risk classification by molecular subtyping had an effect on 5-year PFS (HR 16.7 ± 15.2%, SR 77.8 ± 13.9%; p = 0.01). CONCLUSIONS: Our results confirm that M1-only is a high-risk condition, and further underline the importance of CSF staging. Specific risk stratification of affected patients needs attention in future discussions for trials and treatment recommendations. Future patients without contraindications may benefit from upfront CSI by sparing risks related to higher cumulative CT applied in sandwich regimen.

Immunological recovery following HLA-matched CD3+ TCR αß+/CD19+ depleted hematopoietic stem cell transplantation in children.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for children with both malignant and nonmalignant diseases. T-cell depletion techniques may result in reduced transplant-related mortality compared with unmanipulated grafts due to a lower incidence of GvHD. METHODS: Immune recovery and outcome were analyzed in a cohort of 23 patients with malignant and nonmalignant diseases who received CD3+TCRαß+ T- and B-cell-depleted allografts from matched donors after reduced-intensity or myeloablative conditioning. The median number of CD34+, CD3+TCRαß+, and CD19+B-cells infused was 12.7 × 106 /kg, 16.8 × 103 /kg, and 96 × 103 /kg bodyweight. RESULTS: With a median follow-up of 36 (range 1-73) months, overall survival and disease-free survival at 3 years were 65.2% and 60.8%. Eight patients died, six due to the underlying disease and two of extended visceral cGvHD. Immune reconstitution, disease-free, and overall survivals were similar compared with a historical cohort of 23 patients transplanted with matched unmanipulated bone marrow. A significant lower rate of higher grade (III-IV) aGvHD was observed in the manipulated HSCT group (8.7% vs. 26%; p = 0.001), whereas the incidence of cGvHD was equal. CONCLUSIONS: Our data suggest that this graft manipulation strategy could be a safe and effective alternative to conventional HSCT techniques in matched donors.

Pretreatment central quality control for craniospinal irradiation in non-metastatic medulloblastoma : First experiences of the German radiotherapy quality control panel in the SIOP PNET5 MB trial.

PURPOSE: Several studies have demonstrated the negative impact of radiotherapy protocol deviations on tumor control in medulloblastoma. In the SIOP PNET5 MB trial, a pretreatment radiotherapy quality control (RT-QC) program was introduced. A first analysis for patients enrolled in Germany, Switzerland and Austria with focus on types of deviations in the initial plan proposals and review criteria for modern radiation technologies was performed. METHODS AND PATIENTS: Sixty-nine craniospinal irradiation (CSI) plans were available for detailed analyses. RT-QC was performed according to protocol definitions on dose uniformity. Because of the lack of definitions for high-precision 3D conformal radiotherapy within the protocol, additional criteria for RT-QC on delineation and coverage of clinical target volume (CTV) and planning target volume (PTV) were defined and evaluated. RESULTS: Target volume (CTV/PTV) deviations occurred in 49.3% of initial CSI plan proposals (33.3% minor, 15.9% major). Dose uniformity deviations were less frequent (43.5%). Modification of the RT plan was recommended in 43.5% of CSI plans. Unacceptable RT plans were predominantly related to incorrect target delineation rather than dose uniformity. Unacceptable plans were negatively correlated to the number of enrolled patients per institution with a cutoff of 5 patients (p = 0.001). CONCLUSION: This prospective pretreatment individual case review study revealed a high rate of deviations and emphasizes the strong need of pretreatment RT-QC in clinical trials for medulloblastoma. Furthermore, the experiences point out the necessity of new RT-QC criteria for high-precision CSI techniques.

Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor.

Background. The phenotypes of patients with the recently discovered, dominant, ETV6-linked leukaemia predisposition and familial thrombocytopenia syndrome are variable, and the exact mechanism of leukaemogenesis remains unclear. Patients and Methods. Here, we present novel clinical and laboratory phenotypes of seven individuals from three families with ETV6 germline mutations and a refined genetic analysis of one child with additional high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL), aiming to elucidate second oncogenic hits. Results. Four individuals from two pedigrees harboured one novel or one previously described variant in the central domain of ETV6 (c.592C>T, p.Gln198* or c.641C>T, p.Pro241Leu, respectively). Neutropenia was an accompanying feature in one of these families that also harboured a variant in RUNX1 (c.1098_1103dup, p.Ile366_Gly367dup), while in the other, an autism-spectrum disorder was observed. In the third family, the index patient suffered from HD-ALL and life-threatening pulmonary mucor mycosis, and had a positive family history of 'immune' thrombocytopenia. Genetic analyses revealed a novel heterozygous mutation in the ETS domain of ETV6 (c.1136T>C, p.Leu379Pro) along with absence of heterozygosity of chromosome (10)(q21.2q21.3), yielding a biallelic leukaemia risk allele in ARID5B (rs7090445-C). The neutrophil function was normal in all individuals tested, and the platelet immune histochemistry of all three pedigrees showed delta-storage-pool defect-like features and cytoskeletal defects. Conclusions. Our clinical observations and results of high-resolution genetic analyses extend the spectrum of possible phenotypes cosegregating with ETV6 germline mutations. Further, we propose ARID5B as potential leukaemogenic cofactor in patients with ETV6-linked leukaemia predisposition and familial thrombocytopenia syndrome.

Management of children and adolescents with gray zone lymphoma: A case series.

BACKGROUND: Data on management of gray zone lymphoma (GZL) in children and adolescents are scarce. PROCEDURE: This retrospective study assessed clinical characteristics and outcome in six Austrian patients with GZL less than 18 years of age (male-to-female ratio: 1:1; median age: 15.8 years). RESULTS: Two patients each had a classical Hodgkin lymphoma (cHL)-like and composite GZL subtype, and one patient each had a large B-cell non-Hodgkin lymphoma (LBCL)-like and sequential GZL subtype. All had advanced disease with mediastinal and extranodal involvement. Five patients received an LBCL- and one patient a cHL-directed polychemotherapy ± radiotherapy. Out of the former patients, three survived, including two who relapsed and underwent high-dose chemotherapy with autologous stem cell rescue. The latter patient survived. CONCLUSIONS: GZL remains a diagnostic and therapeutic challenge, necessitating the development of novel treatment concepts performed in a prospective setting.

Spinal cord atypical teratoid/rhabdoid tumors in children: Clinical, genetic, and outcome characteristics in a representative European cohort.

BACKGROUND: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT. METHODS: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3). RESULTS: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation. CONCLUSIONS: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.

Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series.

BACKGROUND: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce. PATIENTS AND METHODS: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed. RESULTS: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA-fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n = 1; PF-EPN-A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively. CONCLUSION: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified. IMPLICATIONS FOR PRACTICE: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA-fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.

Enterovirus infections in pediatric hematologic/oncologic patients.

BACKGROUND: Enteroviruses (EV) are a large group of Picornaviruses associated with respiratory, gastrointestinal, and neurologic symptoms in the immunocompetent host. Little is known about the epidemiologic and clinical impact in pediatric hematologic/oncologic patients. PROCEDURE: From 2001 through 2017, different clinical specimens were collected from pediatric hematologic/oncologic patients and were tested for enteroviral RNA. RESULTS: Of 13 004 specimens collected from 761 patients, 38 (0.3%) obtained from 14 patients (1.8%) tested positive for EV RNA. Viral shedding was observed without viremia and vice versa. None of 80 cerebrospinal fluid specimens obtained from 60 patients with neurologic symptoms were positive for EV RNA. None of 14 patients positive for EV RNA showed EV-specific symptoms. In 11/14 patients, EV RNA was found to be negative in the follow-up specimen. The remaining patient with a severe primary immune deficiency showed repeated positive EV RNA results for >5 years. CONCLUSIONS: In this pediatric hematologic/oncologic cohort, EV infection occurred rarely and without related symptoms. Specimens concurrently obtained from one patient are commonly not in accordance with each other. In the vast majority of patients, EV RNA appears to turn negative in the follow-up specimen. EV infections seem to have a low impact in this patient cohort.

Correction to: A suggestion to introduce the diagnosis of "diffuse midline glioma of the pons, H3 K27 wildtype (WHO grade IV)".

The citation of the original publication in PubMed contains an error. The seventh author name is wrongly cited.

Malignancy and chemotherapy induced haemophagocytic lymphohistiocytosis in children and adolescents-a single centre experience of 20 years.

Haemophagocytic lymphohistiocytosis (HLH) is a possibly life-threatening syndrome of immune dysregulation and can be divided into primary (hereditary) and secondary forms (including malignancy-associated HLH (M-HLH)). We retrospectively analysed epidemiological, clinical, virological and laboratory data from patients with M-HLH treated at our department between 1995 and 2014. Out of 1.706 haemato-/oncologic patients treated at our department between 1995 and 2014, we identified 22 (1.29%) patients with secondary HLH (1.3-18.0, median 10.1 years; malignancy induced n = 2; chemotherapy induced n = 20). Patients with acute myeloblastic leukaemia (AML) developed HLH significantly more often than patients with acute lymphoblastic leukaemia (ALL) (10/55, 18.2% vs. 6/148, 4.1%, p = 0.0021). As possible viral triggers, we detected BKV (53.8% of the tested patients), HHV-6 (33.3%), EBV (27.8%), CMV (23.5%), ADV (16.7%) and PVB19 (16.7%) significantly more frequently than in haemato-/oncologic patients without HLH. Despite lacking evidence of concurrent bacterial infection, C-reactive protein (CRP) and procalcitotnin (PCT) were elevated in 94.7 and 77.7% of the patients, respectively. Ferritin and sIL2R were markedly elevated in all patients. HLH-associated mortality significantly (p = 0.0276) decreased from 66.6% (1995-2004) to 6.25% (2005-2014), suggesting improved diagnostic and therapeutic management. Awareness of HLH is important, and fever refractory to antibiotics should prompt to consider this diagnosis. Elevated ferritin and sIL2R seem to be good markers, while inflammatory markers like CRP and PCT are not useful to discriminate viral triggered HLH from severe bacterial infection. Re-/activation of several viruses may play a role as possible trigger.

The Iceberg Map of germline mutations in childhood cancer: focus on primary immunodeficiencies.

PURPOSE OF REVIEW: The risk of cancer is higher, and its outcome is worse in patients with primary immunodeficiency (PID) than in members of the general population. Thus, the inter-relationship of malignant diseases with PIDs requires more study. RECENT FINDINGS: Large genetic screens identified a vast number of germline mutations in childhood cancer patient samples. Although TP53 was the most frequent single gene identified as mutated, many PID disorders like DNA repair defects are among the inborn causes of childhood cancer. We provide a comprehensive analysis of compiled data from seven recent studies that focused on germline genetic landscapes and preexisting conditions in pediatric oncology. As potentially causal germline variants were identified in ≈8% of malignancies in children and adolescents, we visualized this proportion as the 'tips of the icebergs'. The results of additional network analyses showed the shared patterns of germline mutations in various malignancies and yielded a spatial distribution of the 'icebergs'. SUMMARY: The 'iceberg map of germline mutations in childhood cancers' was created to increase the awareness of the inborn genetic underpinnings of childhood malignancies and their relationships with immunodeficiencies. Needs and perspectives of clinical immunologists and pediatric oncologists to both improve patient care and guide research at this critical interface are discussed. VIDEO ABSTRACT.