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ObjectiveCraniopharyngiomas (CP) are rare malformational tumors. Clinical presentation and outcome of pediatric patients with CP with specific regard to age at diagnosis is not clear. The aim of this cohort study was to determine clinical presentation and outcome in these patients diagnosed at different ages at diagnosis.DesignSeven hundred and nine patients diagnosed with CP were recruited from 1999 to 2021 in HIT-Endo and KRANIOPHARYNGEOM 2000/2007/Registry 2019 and prospectively observed.MethodsAge at diagnosis was categorized as infants and toddlers (ResultsSevere obesity (body mass index [BMI] >3 standard deviation score [SDS]) was prevalent in 45.4% at last visit. A lower EFS but better QoL was observed in children with age at diagnosis ConclusionsDiagnosis of CP at age Clinical trial registration numbersNCT00258453; NCT01272622; NCT04158284.

Background Radiotherapy (RT) of ependymoma in children is an important part of the interdisciplinary treatment concept. However, feasibility and dose concepts are still under investigation, particularly in very young children. The aim of this study was to evaluate the standard dose and volume of proton therapy (PT) in children with ependymoma. Methods In this analysis, 105 patients with localized, intracranial ependymoma under the age of 18 years treated with PT between 2013 and 2018 were included. Patient characteristics, treatment, outcome, and follow-up data were analyzed using descriptive statistics, Kaplan-Meier, and Cox regression analysis. Results The median age of patients at PT was 2.8 years (0.9-17.0 years). The molecular subgroup analysis was performed in a subset of 50 patients (37 EP-PFA, 2 EP-PFB, 7 EP-RELA, 2 EP-YAP, 2 NEC [not elsewhere classified]). The median total dose was 59.4 Gy (54.0-62.0 Gy). The median follow-up time was 1.9 years. The estimated 3-year overall survival (OS), local control (LC), and progression-free survival (PFS) rates were 93.7%, 74.1%, and 55.6%, respectively. Within univariable analysis, female gender and lower dose had a positive impact on OS, whereas age ≥4 years had a negative impact on OS and PT given after progression had a negative impact on PFS. In the multivariable analysis, multiple tumor surgeries were associated with lower PFS. New ≥3° late toxicities occurred in 11 patients. Conclusion For children with localized ependymoma, PT was effective and well tolerable. Multiple surgeries showed a negative impact on PFS.

BACKGROUND: Therapy of infants with brain tumors predisposes these patients to increased risks for cognitive sequelae, especially following radiotherapy. Neuropsychological outcome gains importance for those 40-60% of patients with an atypical teratoid/rhabdoid tumor (ATRT) who survive beyond 2 years. Still, reports on cognitive late-effects in children with ATRT are scarce compared to other pediatric brain tumor groups. We analyzed neuropsychological outcome for long-term ATRT-survivors registered in EU-RHAB and infant low-grade glioma (LGG) survivors from the SIOP-LGG 2004-study and LGG-registry. PATIENTS+METHODS: Age at diagnosis of both cohorts was 0-36 months. ATRT-patients (n=13) treated with up to 54Gy radiotherapy (median age 22 months (±7.1)) were evaluated with the “ATRT-Neuropsychology” tool based on SIOPE-BTG QoS-Group recommendations at median 6.8 years (±2.8) after diagnosis. LGG-patients (n=15) treated without radiotherapy (4/15 with chemotherapy) were analyzed with the German “Neuropsychological-Basic-Diagnostic” tool 5.2 years (±0.6) post-diagnosis. RESULTS: The ATRT- vs. LGG-cohorts were comparable for median age at diagnosis, sex-ratio and tumor-localization, though they differed slightly in median age at assessment (9.5/7.2 years (±2.5/1.1)). Results of age-appropriate tests showed increased impairments for ATRT-patients in fluid intelligence (FI) (p=.006, d=1.214) and in visual-spatial processing (VSP) (p

BACKGROUND: Cognitive impairments following pediatric brain tumors are generally attributed to tumor site, surgical intervention, complications as well as to nonsurgical treatment. We investigated impairments for patients with medulloblastoma (MB), ependymoma (EP) and low-grade glioma (LGG) of the cerebellum treated within the German pediatric brain tumor network to compare and rank major determents. PATIENTS+METHODS: Following protocol treatment, 245 patients with MB (n=106), EP (n=32), and cerebellar LGG (n=107, surgery only) were examined 2 + 5 years after diagnosis using the German “Neuropsychological-Basic-Diagnostic” (NBD) tool based on the Cattell-Horn-Carroll model for intelligence. Within this retrospective study, multiple linear regression models were applied. RESULTS: The MB+EP vs. LGG-cohort differed slightly in median age at diagnosis (8.7/6.1 years) and location (cerebellar hemispheres: 8%MB+EP/49.5%LGG), while sex-ratio, grade of resection, extent of pre-operative hydrocephalus were comparable. With smaller median tumor-volume in the MB+EP vs. LGG-cohort (34.1/44.1cm3), ranges broadly overlapped. Median scores of age-appropriate tests were in the lower normal range for all patients for fluid and crystallized intelligence, selective attention, visual-spatial processing (VSP) and verbal short-term memory (median=93-103), but distinctly below for processing speed (PS), and psychomotor speed abilities (PMS) (median=65-84). Higher doses of craniospinal irradiation (>23.4Gy/23.4Gy) resulted in lower scores for most domains for MB-patients compared to LGG-patients (e.g., PS-estimate: >23.4Gy:-27.71, p=0.026/23.4Gy:-9.93, p=0.286). EP-patients (surgery+54Gy local radiation) scored better than LGG-patients except for PS (estimate:-15.65, p=0.111). Impairments were accentuated with higher degrees of hydrocephalus (estimate:-7.64, p=0.103) in patients with incomplete resection (estimate:12.23, p=0.006) for PMS both hands. CONCLUSION: Following age-adapted comprehensive treatment, survivors of a cerebellar tumor show significant impairments of PMS abilities in our trials. Our data suggest that slow growing LGG impair neurocognitive development more than local radiotherapy for ependymoma, while craniospinal irradiation compromises VSP and PS in MB. Initial symptomatic intracranial pressure remains a strong predictor for general neuropsychological impairment.

PURPOSE To evaluate prognostic factors and impact of participation in a randomized trial in non-metastatic medulloblastoma. METHODS AND PATIENTS 382 patients with non-metastatic medulloblastoma aged 4–21 years with primary neurosurgical resections between 2001 and 2011 were enrolled into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176 of these patients participated in the randomized trial HIT-SIOP PNET 4. Three different radiotherapy protocols were applied. Molecular subgroup was available for 157 patients. RESULTS Median follow-up was 6.35 [0.09–13.86] years. The 5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1 % and 86.5 % ± 1.8 %, respectively. On univariate analysis, there was no difference in PFS and OS according to radiotherapy protocols or in patients who participated in the HIT-SIOP PNET 4 trial or not, while histology, molecular subgroup and postoperative residual tumor influenced PFS significantly. Time interval between surgery and irradiation (≤48 days vs. ≥49 days) failed the significance level (p=0.052). On multivariate analyses, molecular subgroup (WNT activated vs. Group3 HR 5.49; p=0.014) and time interval between surgery and irradiation (HR 2.2; p=0.018) were confirmed as independent risk factors. CONCLUSION Using a centralized review system, multiprofessional and multiinstitutional collaboration as established for pediatric brain tumor patients in Germany, and risk-stratified therapy, outcome for non-metastatic medulloblastoma treated within HIT-SIOP PNET4 could be maintained outside the randomized trial. Prolonged time to radiotherapy negatively influenced survival.

INTRODUCTION The efficacy of chemotherapy in recurrent ependymoma is unclear. We present results from the German HIT-REZ-studies. METHODS 137 patients were analyzed regarding the treatment with chemotherapy at first recurrence, the time from first relapse to progression (PFS) and to either time-point of death or last follow-up (OS). Tumor response evaluation was based on MRI and clinically; molecular data was available in 80. RESULTS In our cohort, 96 patients (20 supratentorial, 73 infratentorial, 3 spinal) received chemotherapy during first recurrence: 49 (51.0%) temozolomide (TMZ) monotherapy, 12 (12.5%) HIT-SKK regime, 9 (9.4%) carboplatin/etoposide (CE) and 26 (27.1%) other combinations. In 19.8% (26.5% in TMZ), chemotherapy was administered prior to surgery (neoadjuvant), which resulted in tumor progression in 78% (85% in TMZ). Gross-total resection was achieved in 86% without neoadjuvant chemotherapy and in 74% (69% in TMZ) with neoadjuvant treatment. Switching to trofosfamide/etoposide (TE) after surgery and unresponsiveness to TMZ showed further progression in all cases of tumor-residuum after surgery. Regarding 1-year-PFS, treatment with HIT-SKK (50.0%±14.4%) or CE (55.6%±16.6%) was advantageous over TMZ (30.2%±6.7%). However, 5-y-OS was lower in CE (19.0% ±16.8%) than in TMZ (39.8%±7.7%) and HIT-SKK (42.9%±8.7%). Long-term control was seen in individual cases of TMZ, HIT-SKK and CE, with TMZ providing longest response of 72 months. CONCLUSION Neoadjuvant TMZ has no significant advantage regarding PFS. However, in few cases chemotherapy prevented progression after incomplete resection. Difficulties in response evaluation and variability in therapies hinder conclusions. Supported by the German Children’s Cancer Foundation

BACKGROUND For infant ependymoma (EP), decision for radiotherapy during first-line therapy is a dilemma. We analyzed therapy outcomes of EP patients younger than 12 months at diagnosis according to molecular subgroup. PATIENTS AND METHODS Between 2001 and 2017, 30 patients with histological diagnosis of intracranial EP RESULTS In 3/30, DNA methylation-based CNS tumor classification suggested a diagnosis other than EP or could not be assigned to a reference class. Of the remaining 27 tumors, 16 were classified as PF-A, 8 as RELA-fusion positive and 3 as YAP-fusion positive. Median age at diagnosis was 0.73 (0.30–0.99) years. After a median follow-up time of 5.36 (0.20–12.90) years, 59.3% experienced progressive disease (PD). 5y-PFS and -OS for the whole cohort were 38.2% and 73.1%. RELA- and YAP-fusion positive EP had significantly better OS than PF-A (5y-OS for PF-A: 55.9%; RELA 100%; YAP 100%; p=0.023). PFS was not significantly different. All but one patient with relapsed PF-A died despite multimodal salvage strategies. In contrast, patients with relapsing RELA- and YAP-fusion positive EP (n=5), survived with a combination of re-surgery and first or second local radiotherapy. CONCLUSION In this cohort of infants

Choroid plexus tumors (CPT) comprise choroid plexus papilloma (CPP, WHO grade I), atypical choroid plexus papilloma (aCPP, WHO grade II), and choroid plexus carcinoma (CPC, WHO grade III). CPT from 20 nations were prospectively recruited into the CPT-SIOP-2000 study (01/2000–03/2010, n=129, median follow-up 7.4 years) and the CPT-SIOP registry (04/2010-01/2018, n=119). Non-surgical risk-stratified treatment consisted of i) chemotherapy for all CPC, all metastatic CPT and incompletely resected aCPP regardless of metastases ii) focal radiotherapy in non-metastatic CPC >3y, iii) craniospinal radiotherapy in non-metastatic CPC >3y during the registry phase. Non-metastatic CPP and aCPP R0 were followed by surveillance. CPT-SIOP-2000 randomized six cycles of carboplatin/VP16/VCR vs. cyclophosphamide/VP16/VCR. Alternating combination of these cycles were given to registry patients with CPC (n=16). WHO grading was the most significant prognostic variable for OS and EFS in CPT patients, five-year OS/EFS accounting for 100/96% in CPP (n=84), 97/79% in aCPP (n=88) and 58/35% in CPC (n=76). Of note, 5y OS/EFS was 100/92% for aCPP patients 2y (n=22). CPCs opting for postop surveillance only progressed with dissemination. Carboplatin based chemotherapy trended superiorly. Clinical staging had minor impact on survival in the primary treatment groups. Radiotherapy for CPC without Li-Fraumeni syndrome had a survival advantage in the first five years of follow-up, craniospinal field did not improve survival for non-metastatic CPC. Delayed radiotherapy for young patients with CPC that progressed on chemotherapy achieved meaningful responses (n=8). In conclusion: adjuvant therapy improves outcome for high risk CPT.

A retrospective European survey was conducted to collect data sets on treatment and outcome of children with intramedullary spinal cord AT/RT. Twelve patients (male, n=4; median age 32 [range, 0.7–97] months) were identified. Lumbar (n=9) and thoracic segments (n=9) were most commonly involved, followed by sacral (n=3) and cervical segments (n=2). In 8 patients more than one spinal cord region was affected. Half of the patients presented with metastatic disease. Primary tumor resection was partial in 6 and gross total in 2 patients. In 4 patients tumors were biopsied only. Central pathology review was performed in 10 patients. Systemic postoperative chemotherapy was administered to all patients. Three patients only received intrathecal therapy and five were irradiated (craniospinal, n=3; local, n=2). Median observation time of the entire cohort was 6 (range, 1–71) months. Three patients, treated according to the EU-RHAB guidelines are alive in complete remission 58, 60, and 71 months after diagnosis. One patient died of intracerebral haemorrhage prior to response evaluation. Five patients progressed early and died within 1–3 months following diagnosis. Three patients died after 7–22 months due to disease progression after having achieved a partial remission (n=1) or disease stabilization (n=2). Event-free and overall survival rates at 1 and (2 years) were 38.9 ± 14.7% (29.2 ± 13.9%) and 41.7 ± 14.2% (25 ± 12.5%), respectively. Spinal cord AT/RT carry a rather grave prognosis. Long-term survival in selected patients is achievable using aggressive multimodality treatment.

OBJECTIVE: Recommendations for primary treatment of pediatric CHG are well established, but comprehensive therapeutic strategies for subsequent progressive disease are needed. We evaluated salvage therapies applied within the German/Swiss SIOP-LGG-2004/LGG-register cohort. PATIENTS: 446 patients with CHG among 2589 patients with low-grade glioma were registered between 2004 and 2015. Neurofibromatosis type 1: 209; histology: 159 pilocytic astrocytomas, 18 pilomyxoid astrocytomas, 27 other histologies and 242 radiological diagnosis. RESULTS: Resection (complete/subtotal/partial) was achieved in 115, biopsy in 89 patients. Only 131/446 patients remained observed without treatment for up to12.8 years. First non-surgical treatment was chemotherapy (ChT) for 268 (263 vincristine/carboplatin ±etoposide) and radiotherapy (RT) for 47. After primary treatment 136/315 patients progressed (median time 2.2 years), of whom 107 received second- (85ChT, 22RT), 54 third- (39ChT, 15RT), 15 fourth- (11ChT, 4RT) and 5 fifth-line therapy (2ChT, 3RT). Five-year overall survival (OS) of the complete cohort is 96.8%. Although 23/53 infants (age