Approaches to supratentorial brain tumours in children.

The differential diagnosis of supratentorial brain tumours in children can be challenging, especially considering the recent changes to the WHO classification of CNS tumours published in 2021. Many new tumour types have been proposed which frequently present in children and young adults and their imaging features are currently being described by the neuroradiology community. The purpose of this article is to provide guidance to residents and fellows new to the field of paediatric neuroradiology on how to evaluate an MRI of a patient with a newly diagnosed supratentorial tumour. Six different approaches are discussed including: 1. Tumour types, briefly discussing the main changes to the recent WHO classification of CNS tumours, 2. Patient age and its influence on incidence rates of specific tumour types, 3. Growth patterns, 4. Tumour location and how defining the correct location helps in narrowing down the differential diagnoses and 5. Imaging features of the tumour on DWI, SWI, FLAIR and post contrast sequences.

Imaging in malignant germ cell tumors involving the hypothalamo-neurohypophyseal axis: the evaluation of the posterior pituitary bright spot is essential.

PURPOSE: Malignant intracranial germ cell tumors (GCTs) are rare diseases in Western countries. They arise in midline structures and diagnosis is often delayed. We evaluated imaging characteristics and early tumor signs of suprasellar and bifocal GCT on MRI. METHODS: Patients with the diagnosis of a germinoma or non-germinomatous GCT (NGGCT) who received non-contrast sagittal T1WI on MRI pre-therapy were included. Loss of the posterior pituitary bright spot (PPBS), the expansion and size of the tumor, and the expansion and infiltration of surrounding structures were evaluated. Group comparison for histologies and localizations was performed. RESULTS: A total of 102 GCT patients (median age at diagnosis 12.3 years, range 4.4-33.8; 57 males; 67 in suprasellar localization) were enrolled in the study. In the suprasellar cohort, NGGCTs (n = 20) were noticeably larger than germinomas (n = 47; p < .001). Each tumor showed involvement of the posterior lobe or pituitary stalk. A PPBS loss (total n = 98) was observed for each localization and entity in more than 90% and was related to diabetes insipidus. Osseous infiltration was observed exclusively in suprasellar GCT (significantly more frequent in NGGCT; p = .004). Time between the first MRI and therapy start was significantly longer in the suprasellar cohort (p = .005), with an even greater delay in germinoma compared to NGGCT (p = .002). The longest interval to treatment had circumscribed suprasellar germinomas (median 312 days). CONCLUSION: A loss of the PPBS is a hint of tumor origin revealing small tumors in the neurohypophysis. Using this sign in children with diabetes insipidus avoids a delay in diagnosis.

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.

Impact of parental body mass index at diagnosis on obesity in survivors of pediatric craniopharyngioma.

OBJECTIVE: It is well known that both genetic background and lifestyle influence the development of "general" obesity. However, the role of parental body mass index (BMI) on the development of obesity in long-term survivors of childhood-onset craniopharyngioma (CP) is not well understood. This study analyzed the correlation of patients' BMI at diagnosis and last visit and parental BMI at CP diagnosis and further explored potential risk factors for obesity in CP patients. DESIGN: Registry-based retrospective cohort study. METHODS: 291 CP patients and their parents recruited in the German KRANIOPHARYNGEOM studies were included. Correlations between patient's BMI SDS at CP diagnosis and last visit and parental BMI at CP diagnosis were analyzed. The associations between hypothalamic damage, maternal/paternal BMI and CP patients' obesity at last visit were analyzed by multivariable logistic regression. RESULTS: At follow-up, 52% of CP patients developed obesity (BMI>3SDS). Patient's BMI SDS at last visit was moderately correlated with BMI-SDS at CP diagnosis (r=0.48, 95%-CI 0.38-0.58, p<0.001), and also with maternal BMI at diagnosis (r=0.28, 95%-CI 0.17-0.38, p<0.001) and paternal BMI at diagnosis (r=0.3, 95% CI-0.19-0.41, p<0.001). However, the contributing role of parental BMI to the pathogenesis of obesity was small compared to the impact of hypothalamic damage. CONCLUSIONS: We conclude that besides hypothalamic damage, parental disposition for obesity is associated with the development of obesity in patients after CP. Our results indicate that also the family situation could have an influence on the development of obesity after CP and might be a therapeutic target.

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.

Adaption of neurosurgical resection patterns for pediatric low-grade glioma spanning two decades-Report from the German LGG-studies 1996-2018.

INTRODUCTION: Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long-term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. PATIENTS AND METHODS: Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1-5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1-status, sex, and age. RESULTS: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. CONCLUSIONS: The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.

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.

Human-Level Differentiation of Medulloblastoma from Pilocytic Astrocytoma: A Real-World Multicenter Pilot Study.

Medulloblastoma and pilocytic astrocytoma are the two most common pediatric brain tumors with overlapping imaging features. In this proof-of-concept study, we investigated using a deep learning classifier trained on a multicenter data set to differentiate these tumor types. We developed a patch-based 3D-DenseNet classifier, utilizing automated tumor segmentation. Given the heterogeneity of imaging data (and available sequences), we used all individually available preoperative imaging sequences to make the model robust to varying input. We compared the classifier to diagnostic assessments by five readers with varying experience in pediatric brain tumors. Overall, we included 195 preoperative MRIs from children with medulloblastoma (n = 69) or pilocytic astrocytoma (n = 126) across six university hospitals. In the 64-patient test set, the DenseNet classifier achieved a high AUC of 0.986, correctly predicting 62/64 (97%) diagnoses. It misclassified one case of each tumor type. Human reader accuracy ranged from 100% (expert neuroradiologist) to 80% (resident). The classifier performed significantly better than relatively inexperienced readers (p < 0.05) and was on par with pediatric neuro-oncology experts. Our proof-of-concept study demonstrates a deep learning model based on automated tumor segmentation that can reliably preoperatively differentiate between medulloblastoma and pilocytic astrocytoma, even in heterogeneous data.

Outcome After Modern Proton Beam Therapy in Childhood Craniopharyngioma: Results of the Prospective Registry Study KiProReg.

PURPOSE: Craniopharyngiomas (CPs) are rare tumors of the sellar region often leading to significant comorbidities due to their close proximity to critical structures. The aim of this study was to analyze survival outcome and late toxicities after surgery and proton beam therapy (PBT) in childhood CPs. METHODS AND MATERIALS: Within the prospective registry study "KiProReg" (DRKS0000536), data of 74 childhood patients with CP, receiving PBT between August 2013 to June 2022 were eligible. Late toxicities were analyzed according to the grading system of the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Median follow-up since first diagnosis was 4.3 years (range, 0.8-14.7). In addition, 75.7% of patients received PBT at time of disease progression or recurrence, whereas 24.3% as part of their primary therapy (definitive or adjuvant). Predominantly (85.1%), pencil beam scanning technique was used. The median total dose and initial tumor volume were 5400 cGy relative biologic effectiveness (RBE) and 17.64 cm³ (range, 3.07-300.59), respectively. The estimated (±SE) 3-year overall survival, progression-free, and cystic failure-free survival rate after PBT were 98.2% (±1.7), 94.7% (±3.0), and 76.8% (±5.4), respectively. All local failures (n = 3) were in-field relapses necessitating intervention and occurred exclusively in patients receiving PBT at progression or recurrence. Early cystic enlargements after PBT were typically asymptomatic and self-limiting. Fatigue, headaches, vision disorders, obesity, and endocrinopathies were the predominant late toxicities. No high-grade (≥3) new-onset visual impairment or cognitive deterioration occurred compared with baseline. The presence of cognitive impairments at the end of follow-up correlated with size of the planning target volume (P = .034), Dmean dose to the temporal lobes (P = .032, P = .045) and the number of surgical interventions before PBT (P = .029). CONCLUSIONS: Our findings demonstrate favorable local control rates using modern PBT with acceptable late toxicities. Cyst growth within 12 months after radiation therapy is typically not associated with tumor progression. Longer follow-up must be awaited to confirm results.

A Retrospective Analysis of Temporal Lobe Gliosis after Middle Fossa Resection of Small Vestibular Schwannomas.

INTRODUCTION: The middle cranial fossa (MCF) approach is a well-established procedure in surgery of the internal auditory canal, as well as with the retrosigmoid and translabyrinthine approaches. It is commonly used in the hearing-preserving microsurgery of small vestibular schwannomas (VS). The debate about the "best" approach for the microsurgery of small VS without contact to the brainstem is controversial. It has been stated that the MCF approach leads to irreversible damage to the temporal lobe, which may be evident in follow-up magnet resonance imaging (MRI) as gliosis in up to 70% of patients. MATERIALS AND METHODS: This study represents a retrospective chart analysis conducted at a tertiary university hospital. Here, 76 postoperative MRIs were re-evaluated by an experienced neuroradiologist and compared with the preoperative images. Temporal lobe gliosis was classified on an ordinal scale as absent, slight, moderate or severe. Occurrence of gliosis was matched to the clinical predictors (tumor stage, tumor volume, sex, age, and side). RESULTS: No case of severe or moderate gliosis was found in the patient group. Slight gliosis of the temporal lobe was rare and was only detected in four patients (5%). There was no relation between clinical predictors and the incidence of gliosis. CONCLUSIONS: In our cohort, postoperative MR imaging did not reveal relevant damage to the temporal lobe parenchyma. This confirms the safe concept of microsurgery of small tumors via the middle fossa approach. The severe glioses described in other studies may be caused by a forced insertion of the retractor or by more extended approaches. However, further prospective neurocognitive studies seem to be necessary in order to assess functional changes in the temporal lobe.

Brain stem tumors in children less than 3 months: Clinical and radiologic findings of a rare disease.

PURPOSE: Brain stem tumors in children < 3 months at diagnosis are extremely rare. Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management. METHODS: This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers, including patients with a brainstem tumor diagnosed between 2009 and 2020 and aged < 3 months at diagnosis. Clinical data were collected, and imaging characteristics were analyzed blindly and independently by two neuroradiologists. RESULTS: Five cases were identified. No patient received any therapy. The epicenter of two tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in three. For patients with tumor in equal parts in the medulla oblongata and the pons (n = 3), the extension at diagnosis involved the spinal cord; for the two patients with the tumor epicenter in the medulla oblongata alone (n = 2), the extension at diagnosis included the pons (n = 2) and the spinal cord (n = 1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died. In one patient, autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n = 2) or stable disease (n = 1). Survivors were followed up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma. CONCLUSIONS: No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy may provide useful information regarding the patient management.

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.

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.

Outcome after proton beam therapy versus photon-based radiation therapy in childhood-onset craniopharyngioma patients-results of KRANIOPHARYNGEOM 2007.

Background: Proton beam therapy (PBT) is being increas16ingly used to treat residual craniopharyngioma (CP) after hypothalamus-sparing surgery. Compared to photon-based radiation therapy (XRT) with PBT, less irradiation in the penumbra reduces the scattered dose to critical organs neighboring but outside the area of treatment, minimizing the risk of sequelae. Patients and methods: Between 2007 and 2019, 99 of 290 (34%) childhood-onset CP patients recruited in KRANIOPHARYNGEOM 2007 received external radiation therapy (RT) (65% PBT, 35% XRT). Outcome was analyzed in terms of survival, endocrinological and anthropometric parameters (BMI and height SDS), quality of life (QoL using PEDQOL), and functional capacity (FMH) with special regard to irradiation technique. Results: PBT became predominant (used in 43% and 72% of all irradiated patients registered within the first and second halves of the recruitment period, between 2008 and 2013 and 2013 and 2018, respectively). Five-year event-free survival rates after PBT or XRT were comparable (92% ± 4% vs. 91% ± 4%, p = 0.42) and higher than for the whole cohort since diagnosis, including non-RT patients (37% ± 4%). Radiation doses to the hypothalamus and pituitary did not differ between PBT and XRT. Endocrine deficits due to disturbances of the hypothalamic-pituitary axis (HPA) were already common before irradiation. During the first 5 years after CP diagnosis/RT, no differences between PBT, XRT, and non-RT CP patients concerning functional capacity and anthropometric parameters have been obtained. Only for the PEDQOL domain "physical function", parental-assessed QoL was lower 12 months after PBT versus XRT or non-RT patients. Conclusion: QoL, functional capacity, degree of obesity, and endocrinopathy varied over time from diagnosis, but by 5 years, there was no significant difference between PBT and XRT upfront or delayed, nor was there any compromise in historic survival rates, which remained high >90%. RT of any type is extremely effective at stabilizing disease after hypothalamic-sparing surgery. The purported specific benefits of PBT-reducing sequelae are not proven in this study where the organ of critical interest is itself diseased, increasing an urgent need to better address and treat the tumor-induced endocrine harm from diagnosis in dedicated pituitary services. Other hypothesized benefits of PBT versus XRT on vascular events and secondary cancers await longer comparison. Clinical trial registration number: https://clinicaltrials.gov/study/, identifier NCT01272622.

Perinatally diagnosed congenital craniopharyngiomas in the KRANIOPHARYNGEOM trials.

Background: Craniopharyngiomas (CPs) are rare embryonic tumors. Clinical presentation and outcome of patients perinatally diagnosed with congenital CP (cCP) are not clear and refer mainly to a few case reports in the literature. The aim of this study was to analyze clinical presentation and outcome in patients with cCP. Study design: Three hundred and sixty-one patients diagnosed with adamantinomatous CP were recruited 2007-2022 in KRANIOPHARYNGEOM 2007/Registry 2019 and prospectively observed. In two cases, cCP was diagnosed prenatally and in one case on the second day of life. Pre- and perinatal diagnostic findings, postnatal evaluation, and therapeutic interventions and outcome in these three cases of cCP were analyzed. Results: All patients survived. One patient developed psychomotor retardation and a mild hemiparesis. Prenatal routine ultrasound examination led to the diagnosis of cCP. Tumor resection was performed during the early postnatal period (range: 11-51 days of age). Functional capacity, measured by Fertigkeitenskala-Münster-Heidelberg (FMH) was reduced in three and behavioral parameters, measured by the Strength and Difficulties Questionnaire (SDQ) were abnormal in two cases. Conclusion: cCP is a rare diagnosis with a prevalence of 0.83% in our study group. Compared to cases reported in the literature, the presented cases were treated immediately and had a better prognosis. Based on improvements of diagnostic and therapeutic techniques, prenatal diagnosis of cCP should lead to transfer prior to delivery of cCP patients to a specialized center for delivery and postnatal treatment of newborns with sellar masses by a multidisciplinary team to secure the improved prognosis of these patients. Significance statement: We previously reported that lower event-free survival rates after craniopharyngioma are associated with younger age at diagnosis. Perinatally diagnosed congenital craniopharyngiomas are very rare. This article presents three unique cases with congenital craniopharyngioma, comparing their diagnostics, therapy, and development. All three cases had surgery during the early postnatal period with sparing of the posterior hypothalamus. In each case, endocrinopathy was present at follow-up. Low functional capacity was reported in all cases and an abnormal total difficulties score in two cases. Compared to the literature, the presented cases had better prognosis in morbidity and mortality. This report and the review of the literature confirm the importance of a multidisciplinary approach in the diagnostic and treatment of the very rare condition of congenital craniopharyngioma.

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.

A multi-institutional retrospective pooled outcome analysis of molecularly annotated pediatric supratentorial ZFTA-fused ependymoma.

Background: ZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma (ZFTAfus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTAfus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTAfus ST-EPN patients treated in multiple institutions. Methods: We conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTAfus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches. Results: A total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort. Conclusion: This is the largest study to date of contemporaneously treated molecularly confirmed ZFTAfus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma.

Neurosurgical morbidity in pediatric supratentorial midline low-grade glioma: Results from the German LGG studies.

Surgical resection is a mainstay of treatment for pediatric low-grade glioma (LGG) within all current therapy algorithms, yet associated morbidity is scarcely reported. As supratentorial midline (SML) interventions are particularly challenging, we investigated the frequency of neurosurgical complications/new impairments aiming to identify their risk factors. Records were retrospectively analyzed from 318 patients with SML-LGG from successive German multicenter LGG studies, undergoing surgery between May 1998 and June 2020. Exactly 537 operations (230 resections, 167 biopsies, 140 nontumor procedures) were performed in 318 patients (54% male, median age: 7.6 years at diagnosis, 9.5 years at operation, 11% NF1, 42.5% optic pathway glioma). Surgical mortality rate was 0.93%. Applying the Drake classification, postoperative surgical morbidity was observed following 254/537 (47.3%) and medical morbidity following 97/537 (18.1%) patients with a 40.1% 30-day persistence rate for newly developed neurological deficits (65/162). Neuroendocrine impairment affected 53/318 patients (16.7%), visual deterioration 34/318 (10.7%). Postsurgical morbidity was associated with patient age <3 years at operation, tumor volume ≥80 cm3 , presence of hydrocephalus, complete resection, surgery in centers with less than median reported tumor-related procedures and during the earlier study period between 1998 and 2006, while the neurosurgical approach, tumor location, NF1 status or previous nonsurgical treatment were not. Neurosurgery-associated morbidity was frequent in pediatric patients with SML-LGG undergoing surgery in the German LGG-studies. We identified patient- and institution-associated factors that may increase the risk for complications. We advocate that local multidisciplinary teams consider the planned extent of resection and surgical skills.

[Pediatric Intracranial Ependymoma - Recommendations for First-Line Treatment from the German HIT-MED study group]. / Kinder und Jugendliche mit intrakraniellem Ependymom ­ Empfehlungen der HIT-MED-Studiengruppe der GPOH zur Erstlinientherapie.

Biological subtypes of ependymoma (EPN) have been introduced by the recent WHO classification and appear to have great impact on the clinical course, but have not yet found their way into clinical risk stratification. Further, the overall unfavorable prognosis underlines the fact that current therapeutic strategies need further evaluation for improvement. To date, there is no international consensus regarding first-line treatment for children with intracranial EPN. Extent of resection is known to be the most important clinical risk factor, leading to the consensus that consequent evaluation for re-surgery of postoperative residual tumor needs to have highest priority. Furthermore, efficacy of local irradiation is unquestioned and recommended for patients aged>1 year. In contrast, efficacy of chemotherapy is still under discussion. The European trial SIOP Ependymoma II aims at evaluating efficacy of different chemotherapy elements, leading to the recommendation to include German patients. The BIOMECA study, as biological accompanying study, aims at identifying new prognostic parameters. These results might help to develop targeted therapies for unfavorable biological subtypes. For patient who are not qualified for inclusion into the interventional strata, the HIT-MED Guidance 5.2 provides specific recommendations. This article is meant as an overview of national guidelines regarding diagnostics and treatment as well as of treatment according to the SIOP Ependymoma II trial protocol.