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.

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.

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.

[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.

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology.

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation-Sparing Approaches: An International Cohort Study.

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

Proton Beam Therapy for Pediatric Tumors of the Central Nervous System-Experiences of Clinical Outcome and Feasibility from the KiProReg Study.

As radiotherapy is an important part of the treatment in a variety of pediatric tumors of the central nervous system (CNS), proton beam therapy (PBT) plays an evolving role due to its potential benefits attributable to the unique dose distribution, with the possibility to deliver high doses to the target volume while sparing surrounding tissue. Children receiving PBT for an intracranial tumor between August 2013 and October 2017 were enrolled in the prospective registry study KiProReg. Patient's clinical data including treatment, outcome, and follow-up were analyzed using descriptive statistics, Kaplan-Meier, and Cox regression analysis. Adverse events were scored according to the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 before, during, and after PBT. Written reports of follow-up imaging were screened for newly emerged evidence of imaging changes, according to a list of predefined keywords for the first 14 months after PBT. Two hundred and ninety-four patients were enrolled in this study. The 3-year overall survival of the whole cohort was 82.7%, 3-year progression-free survival was 67.3%, and 3-year local control was 79.5%. Seventeen patients developed grade 3 adverse events of the CNS during long-term follow-up (new adverse event n = 7; deterioration n = 10). Two patients developed vision loss (CTCAE 4°). This analysis demonstrates good general outcomes after PBT.

Long-term outcome after management of pilocytic astrocytoma in the posterior fossa in a pediatric population.

Background and purpose: To assess the impact of posterior fossa pilocytic astrocytoma (PA) removal in pediatric patients, with special focus on postoperative neurological outcome after repeated surgery for tumor remnants. Methods: Our institutional database was screened for patients with PA treated between 2000 and 2019. Patients ≤ 18 years of age with complete clinical records, preoperative contrast enhanced magnetic resonance imaging (MRI) and postoperative follow-up time of ≥ 6 months were suitable for study inclusion. Functional outcome was quantified with the modified Ranking Scale (mRS) score and assessed at admission, at discharge and at every follow-up investigation. Predictors of hydrocephalus, cranial nerve deficits and tumor recurrence were evaluated. Results: A total of 57 pediatric patients with a mean age of 7.7 ± 4.8 years were included in the analysis. 27 (47.3%) children suffered from hydrocephalus at diagnosis, out of which 19 (33.3%) required a subsequent VP-Shunt. 22 (39.3%) patients had a partial resection, of which 9 (40.9%) went through second-look surgery. 2 patients with initially radiological confirmation of complete resection, had a tumor recurrence at FU and needed second-look surgery. Among the children requiring second-look surgery, 7 (63.6%) had a complete resection. Favorable outcome (mRS≤2) after initial and second-look surgery was observed in 52 patients (91.2%). Univariate analysis identified tumor location in the floor of the 4th ventricle (p = 0.030), and repeated surgery for tumor remnant removal (p = 0.043) as predictors for post-operative cranial nerve deficits. Multivariate analysis confirmed this independent association. The incidence of tumor recurrence occurred more often in patients with previous partial resection (p = 0.009) as well as in lesions located in the cerebellar peduncles (p = 0.043). Partial resection remained an independent predictor after multivariate logistic regression analysis (p = 0.045). Conclusions: Incomplete resection of posterior fossa PA is a risk factor for tumor recurrence and repeated surgery to remove tumor remnants increases the risk of new postoperative deficits. Thus, the risk of iatrogenic deterioration due to second look surgery should be implemented in the primary pre- and intraoperative decision-making.

Prevalence of osteopathologies in a single center cohort of survivors of childhood primary brain tumor.

Background: Childhood primary brain tumors (CPBT) are the second largest group of childhood malignancies and associated with a high risk for endocrine late effects. Objective: To assess endocrine late effects and their relevance for the development of osteopathologies in survivors. Methods: This single center cross sectional study investigated data from 102 CPBT survivors with a mean age of 13.0 years and a mean age at diagnosis of 8.7 years. Clinical, biochemical, radiographic, and anamnestic data regarding endocrine and bone health were obtained at study visits. In addition, data regarding tumor stage and therapy was obtained by chart review. An expert opinion was applied to define presence of osteopathologies. Results: Impaired bone health, defined by at least one pathological screening parameter, was present in 65% of patients. 27.5% were found to have overt osteopathologies per expert opinion. 37.8% displayed a severe vitamin D deficiency (25-OH vitamin D < 10 ng/ml) and 11% a secondary hyperparathyroidism. Patients with osteopathologies had lower 25-OH vitamin D levels compared to patients without osteopathologies. Multiple endocrine late effects were present: diabetes insipidus in 10.8%, aberrant pubertal development in 13.7%, central hypocortisolism in 14.9%, thyroid dysfunction in 23.8% and growth hormone deficiency in 21.8%. A total of 31.3% of survivors displayed any endocrinopathy. Tumors located near hypothalamic structures and patients who received irradiation had a higher likelihood of endocrine morbidity. Conclusion: This study indicates that endocrine deficiencies are common in pediatric survivors of CPBTs. Osteopathologies are present in this cohort. A prominent effect of hormonal deficiencies on bone health was not detected, possibly because patients were sufficiently treate for their endocrine conditions or indicating resilience of the childhood bone remodeling process. Vitamin D deficiency is frequent and should be treated as recommended.

Local and Systemic Therapy of Recurrent Medulloblastomas in Children and Adolescents: Results of the P-HIT-REZ 2005 Study.

Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9-16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7-10.0) and 18.5 months (CI: 13.6-23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients' survival.

The Current Landscape of Targeted Clinical Trials in Non-WNT/Non-SHH Medulloblastoma.

Medulloblastoma is an embryonal pediatric brain tumor and can be divided into at least four molecularly defined groups. The category non-WNT/non-SHH medulloblastoma summarizes medulloblastoma groups 3 and 4 and is characterized by considerable genetic and clinical heterogeneity. New therapeutic strategies are needed to increase survival rates and to reduce treatment-related toxicity. We performed a noncomprehensive targeted review of the current clinical trial landscape and literature to summarize innovative treatment options for non-WNT/non-SHH medulloblastoma. A multitude of new drugs is currently evaluated in trials for which non-WNT/non-SHH patients are eligible, for instance immunotherapy, kinase inhibitors, and drugs targeting the epigenome. However, the majority of these trials is not restricted to medulloblastoma and lacks molecular classification. Whereas many new molecular targets have been identified in the last decade, which are currently tested in clinical trials, several challenges remain on the way to reach a new therapeutic strategy for non-WNT/non-SHH medulloblastoma. These include the severe lack of faithful preclinical models and predictive biomarkers, the question on how to stratify patients for clinical trials, and the relative lack of studies that recruit large, homogeneous patient collectives. Innovative trial designs and international collaboration will be a key to eventually overcome these obstacles.

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.

Evaluation of dose, volume, and outcome in children with localized, intracranial ependymoma treated with proton therapy within the prospective KiProReg Study.

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.

Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies.

PURPOSE: Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN. METHODS: Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated. RESULTS: Median age at first recurrence was 7.6 years (IQR: 4.0-13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3-20.0) and 36.9 months (CI 29.7-53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74-1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found. CONCLUSION: No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation.

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659.

Eye Tumors in Childhood as First Sign of Tumor Predisposition Syndromes: Insights from an Observational Study Conducted in Germany and Austria.

Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013-2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in DICER1 was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality.

Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas.

Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors. SIGNIFICANCE: ZFTA-RELA fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by ZFTA fusion-positive tumors, such as GLI2.This article is highlighted in the In This Issue feature, p. 2113.

Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia.

Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMT genotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG (P < 0.0001). Eight of the 13 patients were heterozygous for low-activity TPMT variants, resulting in a 22.4-fold (95% confidence interval 7.1-70.7; P ≤ 0.0001) increased risk of hepatic SOS for heterozygotes in comparison to TPMT wild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMT genotypes.