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Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management.Significance:Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related video: https://vimeo.com/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

BackgroundEndocrine deficiencies, including hypothalamic-pituitary-gonadal axis (HPGA) impairment, are common in survivors of childhood and adolescent medulloblastoma. Still, data regarding pubertal development and fecundity are limited, and few studies assessed HPGA function in males. We aimed to describe HPGA function in a large cohort of patients with medulloblastoma.MethodsA retrospective study comprising all 62 medulloblastoma patients treated in our center between 1987 and 2021, who were at least 2 years from completion of therapy. HPGA function was assessed based on clinical data, biochemical markers, and questionnaires.ResultsOverall, 76% of female patients had clinical or biochemical evidence of HPGA dysfunction. Biochemical evidence of diminished ovarian reserve was seen in all prepubertal girls (n = 4). Among the males, 34% had clinical or biochemical evidence of gonadal dysfunction, 34% had normal function, and 29% were age-appropriately clinically and biochemically prepubertal. The difference between males and females was significant (P = .003). Cyclophosphamide-equivalent dose was significantly associated with HPGA function in females, but not in males. There was no association between HPGA dysfunction and other endocrine deficiencies, length of follow-up, weight status, and radiation treatment protocol. Two female and 2 male patients achieved successful pregnancies, resulting in 6 live births.ConclusionsHPGA dysfunction is common after treatment for childhood medulloblastoma. This is seen more in females, likely due to damage to the ovaries from spinal radiotherapy. Our findings may assist in counseling patients and their families regarding risk to future fertility and need for fertility preservation.

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. Significance: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related video: https://vimeo.com/438254885 See related commentary by Szulzewsky and Cimino, p. 904. This article is highlighted in the In This Issue feature, p. 890

Chemotherapy; Childhood cancer; Radiotherapy Quimioterapia; Cáncer infantil; Radioterapia Quimioteràpia; Càncer infantil; Radioteràpia Introduction Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Method Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. Results Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Conclusion Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers. Open access funding enabled and organized by Projekt DEAL.

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Background The MAPK pathway, is a signal transduction pathway involved in the oncogenesis of a variety of pediatric tumors. The clinical use of BRAF inhibitors and MEK inhibitors is increasingly used in oncology practice. The toxicity profile of these drugs in the pediatric population, particularly in relation to development, growth and sexual maturation remains insufficiently studied. Procedure This study includes 22 pediatric patients with molecularly confirmed MAPK pathway driven tumors treated with MEK or BRAF between August 2014 and March 2020. Throughout treatment they underwent regular laboratory, endocrine, cardiac, ophthalmic and dermatologic evaluation. Toxicity was recorded and evaluated according to CTCA v4. Results Overall an adverse event frequency of 86% was encountered. Dermatological disorders accounted for 68% of the adverse events. Overall 8 patients suffered from severe adverse events including Erythema Nodosum, PLEVA-like rash, osteoporosis, Sarcoid-like massive lymphadenopathy, retinal toxicity and elevated liver enzymes & CPK. Four patients discontinued treatment as a result of adverse events. In this cohort we did not encounter any treatment-related abnormalities of sexual maturation or gonadal function nor statistically significant growth retardation, however a slower than expected growth rate was observed in one patient. In addition dose-dependent, non-symptomatic and within normal range for age decreased cardiac SF% was noted in two patients treated with MEK inhibitor. Conclusion Treatment with BRAF and MEK inhibitors was shown to be generally safe, we report drug tolerability of 82%. However, further prospective studies should be preformed to are characterize the full scope of side effects in the pediatric population.

Targeted medications and immunotherapies are being developed to specifically target the pathways involved in tumours. There is limited experience with these new medications and their cutaneous side-effects in the paediatric population. A retrospective study of all paediatric oncological patients treated with targeted therapies and immunotherapies between 1 January 2013 and 1 August 2020 was carried out in 2 haemato-oncological referral centres. A total of 103 children were included in the study. The median (interquartile range) age was 13 years (8.4–16.9), male:female ratio 1.5:1, median (interquartile range) follow-up was 7 months (2–18). Fifty (48%) of the children developed cutaneous adverse events. Treatment was discontinued in only 3 (6%) cases and was altered in only (2%) 1 case due to a cutaneous adverse event. When targeted therapies and immunotherapies for tumours in children are used, there is an increased incidence of cutaneous adverse events. Nevertheless, treatment modification or discontinuation due to cutaneous side-effects is rarely needed.

1517 Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutation in the TP53 tumor suppressor gene. As a result of increased awareness and surveillance imaging, more asymptomatic low-grade brain lesions are being identified, raising important questions regarding the management of those patients. Sporadic low-grade gliomas (LGG) in the pediatric age rarely transform to malignant lesions, whereas the prognosis of high-grade gliomas (HGG) is grim in all age groups. Although HGG is a hallmark of LFS, little is known of the natural history of these lesions in this syndrome. Methods: For this multi-institutional retrospective study, anonymized clinicopathologic data from TP53 mutation carriers with gliomas were collected and analysed. Results: Our cohort included 61 patients, of whom 71% (n = 45) were children or young adults (age < 25 years). 39% of patients with known family history of cancer had a close relative with a brain tumor. Of 31 patients with low grade lesions at presentation, 83% (n = 26) were identified through surveillance. Five-year progression free survival (PFS) for these patients was 48%, though two patients progressed later. Furthermore, at 5 years 25% of these patients had biopsy proven malignant transformation to HGG. This “transformation free survival” rate did not plateau, as at 7 years 56% of patients transformed. When considering death from a brain tumor, the 5- and 10- year overall survival (OS) for the LGG group was 100% and 83%, respectively. Additional 3 patients succumbed to other LFS related malignancies. For the HGG group, consisting of 30 patients, the 5 year OS was 35% (median follow-up 19.5 months), comparing favorably with the sporadic HGG population as reported in the literature. Almost all of these patients presented with clinical symptoms. Notably, 12 (40%) of them had a prior malignancy. Conclusions: Our analysis suggests that the risk of transformation of LGG in the setting of LFS is high and warrants ongoing surveillance. Interestingly, there are a considerable number of long- term survivors in our HGG group, although the median follow up is still short. Further study to examine potential genotype- phenotype correlations in germline TP53 mutation carriers will inform strategies to identify those patients at highest risk of glioma progression.