Abstract High-grade gliomas are deadly tumors in children and young adults (CAYA). Mismatch Repair Deficiency (MMRD) is present in 5-10% of CAYA gliomas and is typically associated with favorable response to immune checkpoint inhibitors (ICI). Interestingly, a subset of MMRD-CAYA gliomas harboring IDH1 mutations fails to respond to ICI. At the molecular level, the interaction of MMRD with mutant IDH (mIDH) and the causes of ICI resistance are not well understood. To tackle this challenge and develop effective therapeutic strategies for these cancers, we performed trans-species clinical, multi-omic, and immune analysis of human and murine tumors. Molecularly, MMRD-mIDH gliomas displayed a profile resembling mismatch repair proficient (MMRP) astrocytomas, characterized by frequent TP53 (83%) and ATRX (76%) mutations and absence of oligodendroglioma-associated alterations (1p/19q codeletion). Nevertheless, in contrast to MMRP-mIDH gliomas, which more commonly present as low-grade tumors, >91% of MMRD-mIDH gliomas were high-grade, exhibiting significantly worse outcomes (p<0.001). Compared with MMRD-IDH wildtype gliomas, MMRD-mIDH gliomas exhibited reduced tumor mutation burden (TMB, 113 vs 28 mutations/Mb, p<0.05) and immune infiltration, quantified by Tumor Inflammation Signature and CD8+ T cell density, partially explaining their inferior survival under ICI treatment. In order to study tumor development, metabolic and immune profiles, as well as response to combination therapy, we developed a novel MMRD-mIDH glioma mouse model (Olig2-Cre+/Msh2LoxP/LoxP/Trp53LoxP/LoxP/LSL-Idh1R132H/+). Mouse MMRD-mIDH gliomas displayed characteristic features of human gliomas, including TMB (20 mutations/Mb), altered glioma driver genes (ATRX, NF1), diffuse cerebral involvement, and low immune infiltrates (p<0.05) as compared with MMRD-IDH wildtype models. Preliminary data reveals that mIDH inhibition does not impact proliferative and stemness capacity of MMRD-mIDH mouse glioma cells in vitro, while detailed analysis of the effect of mIDH inhibition on genomic, transcriptomic, and immune profiles are ongoing. Strikingly, informed by our trans-species analysis, an initial trial using the addition of IDH inhibitor to ICI (n=13 patients) led to objective radiological responses and prolonged survival at 12-months compared to ICI monotherapy (p=0.01). MMRD-mIDH gliomas are a genetically and biologically distinct group of tumors with limited therapeutic options. Molecular and immune profiling of MMRD-mIDH gliomas, from both patients and a novel mouse model, enables investigation of the biology underlying glioma development and testing of improved therapeutic approaches. Citation Format: Vienna Mazzoli, Nicholas R. Fernandez, Zoya Aamir, Olha Kos, Emma Gattoni, Owen Crump, Lucie Stengs, Nuno M. Nunes, Katharine O'Flaherty, Hope Friedman, Olfat Ahmad, Abigail Suwala, Kevin Bielamowicz, Gadi Abebe-Campino, Shani Caspi, Per Nyman, Richard Graham, John Y. Kim, Mari Wilhelmsson, Mette Jorgensen, Orli Michaeli, Maria Baro, Alyssa Reddy, Nicolas Jose Llosa, Amanda Li, Adrian Levine, Logine Negm, Melissa Edwards, Vanessa Bianchi, Birgit Ertl-Wagner, Julie Bennett, Stefan M. Pfister, Peter B. Dirks, Eric Bouffet, Cynthia E. Hawkins, Anirban Das, Uri Y. Tabori. Trans-species analysis of mismatch repair deficient IDH1 mutant gliomas reveals a unique genomic and immune landscape resulting in favorable response to combination immune and targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1173.

Infants, less than 1 year, with chiasmatic gliomas (ICG) present a major therapeutic challenge due to large tumor size, decreased vision, rapid progression, and poor response to vincristine/carboplatin chemotherapy. The majority have a BRAF fusion, which may respond to downstream MEK inhibitors but response time is slow. There are no safety or efficacy data for MEK inhibitors in infants or in combination with chemotherapy. We report two infants with BRAF-fused ICG presenting at age 5 months with nystagmus and diencephalic syndrome. Significant tumor progression occurred after only 6 weeks on chemotherapy and showed dramatic response to the addition of trametinib.

Purpose This study aimed to expand the clinical and biological understanding of POT1 tumor predisposition syndrome and raise awareness of its broad tumor spectrum and association with ultralong telomeres. Methods We conducted a retrospective analysis of 44 individuals carrying pathogenic or likely pathogenic POT1 variants identified between 2018 and 2025. Clinical, pathologic, and demographic data were extracted from medical records. Telomere length was assessed using in-gel hybridization of telomeric restriction fragments. Results Of 44 heterozygotes, 31 had the c.233T>C; p.(Ile78Thr) variant, 8 had c.1672dup; p.(Tyr558Leufs∗6), and 5 had other frameshifting, likely loss-of-function variants. Cancer was diagnosed in 27 heterozygotes (61%), totaling 84 primary malignancies (range: 0-8 per person), with most cases (79%) occurring after the age of 50 years. Melanoma (34%) and breast cancer in females (45%) were the most common. Additional tumors included papillary thyroid carcinoma, desmoid tumors, and diverse malignant and benign neoplasms. Colonic polyps were frequent. POT1 heterozygotes with the p.(Ile78Thr) variant exhibited significantly longer telomeres than control participants, with a 62-year-old woman showing comparable or even longer telomeres than her children. Conclusion POT1 pathogenic variants confer susceptibility to a wide tumor spectrum, notably melanoma and, unexpectedly, breast cancer. At least some of these variants are linked to ultralong telomeres, consistent with findings from this study and others. These findings support incorporating POT1 into multigene panels and suggest telomere length as a potential biomarker for diagnosis.

Cancer Predisposition Syndromes (CPS) are heritable genetic conditions associated with an increased risk of developing various cancers throughout life. While early identification and tumour surveillance can improve outcomes, CPS are often underdiagnosed in clinical practice. To evaluate clinicians’ perspectives and identify barriers to CPS identification and care across Europe, we conducted the SCOPE study: a three-part cross-sectional survey of paediatric haematology/oncology professionals, followed by a modified Delphi consensus process with members of the SIOP Europe Host Genome Working Group. A total of 185 paediatric oncologists from 22 countries participated in the survey. More than 40% of participants reported low or uncertain confidence across different CPS-related tasks, particularly in counselling families (64.3%) and interpreting germline genetic findings (57.3%). Access to clinical geneticists and dedicated CPS clinics were predictors of higher confidence for some domains, while individual experience and institutional patient volume had limited influence. Regular use of universal CPS screening tools was low (42.3%), with most clinicians relying on personal judgement rather than structured criteria. The most cited barriers were lack of screening guidelines (57%) and difficulties in interpreting results (35.1%). Regular training and workshops, availability of genetic counsellors or educators for patient support, and patient-friendly education material were most cited as areas of improvement. The Delphi process led to three recommendations: (1) improve clinician training and communication strategies, (2) integrate CPS screening into standard treatment plans, and (3) develop accessible, patient-centred educational materials. These recommendations highlight opportunities to enhance CPS care through structured support, interdisciplinary collaboration, and systematic screening approaches.

Abstract Background IDH mutant (mIDH) gliomas are the most common primary brain tumors in age <50 years. Checkpoint-inhibitors have historically failed to demonstrate responses after their inevitable malignant transformation. We identified that primary DNA replication-repair deficiency (RRD) drives >60% of malignant mIDH malignant gliomas in age <40 years and have an exceptionally poor outcome. We aimed to decipher their biology and identify novel vulnerabilities. Methods Multi-omic analyses were performed on mIDH RRD-glioma registered to the International RRD Consortium and a novel immunocompetent mouse model was generated. Results mIDH RRD-glioma was frequent in older children and young adults with CMMRD and Lynch syndrome, majority were high-grade, with diffuse frontal lobe or multifocal distribution. Mutation burden was lower than IDH-wildtype RRD-glioma (TMB, 113 vs 28 mutations/Mb; p < 0.05). Loss of TP53, ATRX and CDKN2A/2B, and global hypomethylation were observed. CD8-T-cell infiltration (immunohistochemistry) and tumor inflammation score (transcriptome) were lower than IDH-wildtype RRD-glioma (p < 0.05), contributing to extremely poor survival, even after anti-PD1 monotherapy (p < 0.05). A novel mouse model (Olig2Cre+/Msh2LoxP/LSL-Idh1R132H) demonstrated similar lower TMB, diffuse involvement and low immune infiltrate, mimicking human disease. Cell lines demonstrated high levels of 2-hydroxyglutarate, an immuno-suppressive oncometabolite, that was reduced following IDH-inhibition. Adding a 1st-generation IDH-inhibitor (ivosidenib) after progression on anti-PD1 demonstrated objective responses and prolonged survival in refractory human patients (n = 13; p = 0.01). Conclusion Tumors in patients with hypermutant mIDH RRD-glioma that do not respond to anti-PD1 monotherapy harbor an immune-suppressed microenvironment that can be overcome by IDH-inhibition. Additional data demonstrating superior efficacy and CNS-penetration of vorasidenib (2nd-generation IDH1/IDH2 inhibitor), and higher sensitivity of RRD-gliomas to combined PD1+LAG3 inhibition, have now provided the rationale for developing a prospective international clinical trial in adolescents and young adults with mIDH RRD-glioma spanning five countries.

Schwannomatosis (SWN) is a distinct cancer predisposition syndrome caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is a significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal, and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome, with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas, and less commonly, ependymoma. SMARCB1-related SWN is a familial SWN syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence of radiation. These individuals do not develop bilateral vestibular schwannomas. Finally, patients with LZTR1-related SWN typically present with peripheral schwannomas, and unilateral vestibular schwannomas have been reported. The following perspective is intended to highlight the clinical presentation and international tumor surveillance recommendations across these SWN syndromes.

Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.

Oxford Nanopore Technology (ONT)-based methylation sequencing is emerging as a powerful approach for the rapid and accurate classification of brain tumors, an essential component of precision oncology. However, its broader clinical adoption has been limited by reliance on fresh-frozen (FF) tissue, whereas the vast majority of clinical specimens are formalin-fixed paraffin-embedded (FFPE). In this study, we address this limitation by evaluating the effects of FFPE processing on DNA methylation profiles and introducing a validated protocol for ONT-based classification using DNA extracted directly from pathology-marked regions on stained FFPE slides. This approach enables the targeted selection of tumor-rich areas following histological assessment, thereby improving DNA input quality and tumor content. We demonstrate that even small, low-input samples (≥25 ng) can be successfully classified using this method, with high concordance to final integrated neuropathological diagnoses. Our results show that, despite modest methylation loss associated with formalin fixation, classification performance remains robust. Notably, we identify a correlation between methylation degradation and fixation time, supporting a recommendation to limit formalin exposure to ≤3-4 days when possible. By enabling accurate methylation-based tumor classification from routinely processed, stained FFPE tissue, our protocol integrates seamlessly into existing clinical workflows. This expands the accessibility of ONT-based diagnostics and supports informed, timely treatment decisions-even in cases with minimal tissue availability or urgent clinical need.

BACKGROUND:Low-grade gliomas (LGG), both sporadic and neurofibromatosis type 1 (NF1)-associated, are the most common pediatric brain tumors. When unresectable, progressive, or symptomatic, they require treatment. Bevacizumab (BVZ), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has shown efficacy for progressive LGG, especially optic pathway gliomas. Reported toxicities include hypertension (HTN) and proteinuria. Children with NF1 are predisposed to HTN and vasculopathy, but data on BVZ safety in this group are lacking. We compared the incidence of BVZ-associated toxicity in children with LGG with and without NF1. METHODS:Retrospective study of all BVZ-treated LGG patients (2010-2023) at a single center. RESULTS:Seventeen children with LGG were treated with BVZ: 8 NF1, 82% optic glioma, 18% other. All received BVZ as second- or third-line therapy combined with chemotherapy. In the non-NF1 group, 77% patients developed grade 1-2 HTN; none received antihypertensives. Six developed grade 1 proteinuria. In the NF1 group, 62.5% developed grade 1-2 HTN, including one with aortic coarctation who had worsening of previous HTN, 2 required antihypertensive therapy (p nonsignificant HTN non-NF1 vs. NF1). Only 1 NF1 patient developed proteinuria. No patients in either group stopped BVZ prematurely for toxicity. HTN was reversible after BVZ cessation in all except the coarctation of the aorta patient. CONCLUSIONS:HTN is more common than previously reported in both NF1 and non-NF1 patients treated with BVZ for LGG, but reversible. Blood pressure should be monitored and treated appropriately. BVZ appears to be a safe and efficacious therapeutic option for young patients with NF1-related optic glioma.

The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for health care professionals. The 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection and intervention and reduce morbidity associated with such neoplasms. In this article, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline whole-body MRI and routine monitoring of potential malignant transformation of bony lesions. Hereditary multiple osteochondromas carry a lower risk of chondrosarcoma (<6%) but still require lifelong surveillance and baseline imaging. Related syndromes of benign bone lesions are also described. Hereditary leiomyomatosis and renal cell carcinoma syndrome, associated with fumarate hydratase pathogenic variants, is discussed in detail. Surveillance for renal cell carcinoma in pediatric age is recommended, as well as prompt intervention when a lesion is detected. Schinzel-Giedion syndrome and Rubinstein-Taybi syndrome are described for their associated malignancies and other complications, as well as expert consensus on the need for childhood cancer surveillance. Clinical recommendations, including imaging modalities and frequency of screenings, are proposed and are tailored to each syndrome's age-specific tumor risk profile. In all syndromes, patients and their families should be educated about the potential malignancy risk and advised to seek medical care for rapid growth of a mass, persistent pain, or other unexplained symptoms.

Abstract Background. Based primarily on in vitro and animal studies, germline TP53 variants are considered to confer sensitivity to ionizing radiation-induced DNA damage, but data in humans are sparse. We sought to quantify risk of developing radiotherapy and chemotherapy-related subsequent neoplasms by pooling individual-level data from nine cohorts of individuals with confirmed pathogenic/likely pathogenic germline TP53 variants. Methods. 891 individuals were followed from six months after first cancer until diagnosis of a subsequent neoplasm, death or date of last follow-up. Radiotherapy and chemotherapy for each cancer were considered as time-dependent covariates in Cox regression models with age as the time-scale, adjusted for sex and occurrence of prior malignant or benign tumors. Subsequent cancers were classified as in- or out-of-field based on the body region of previous cancers. Results. Among 891 individuals, 643 (72.2%) were female and 297 (33.3%) were diagnosed with a first cancer before age 20 years. Breast cancer was the most commonly diagnosed first cancer (N=371), followed by soft tissue sarcoma (N=131) and central nervous system cancers (N=84). First cancer treatment included radiotherapy for 237 (26.6%) and/or chemotherapy for 421 (47.3%) individuals. Analyses are underway to define the characteristics of subsequent neoplasms (including age at diagnosis, latency, and distribution of diagnosis type) and to calculate relative and absolute risk estimates for radiotherapy and chemotherapy overall and by subsequent neoplasm type. Conclusions. This study will quantify the contribution of radiotherapy and chemotherapy to the risk of subsequent cancers among individuals with Li-Fraumeni syndrome. Understanding the magnitude of this risk will support health care providers and patients in making informed decisions about cancer management. *These authors contributed equally Citation Format: Anita Villani, Payal Khincha, Jessica Hatton, Sara Schonfeld, Catherine Goudie, Leatrisse Oba, Kishan Pithadia, Birte Sänger, Christian Kratz, Anh N. Le, Caitlin Orr, Kara N. Maxwell, Anne Naumer, Jennie Vagher, Wendy Kohlmann, Joshua Schiffman, Elizabeth Santana dos Santos, Orli Michaeli, Jacob J. Carson, Derek S. Tsang, Raymond Kim, Jamie L. Maciaszek, Kim E. Nichols, Victoria E. Goodman, Suzanne P. MacFarland, Lara Reichman, Maria Isabel Achatz, Sharon Savage, David Malkin, Lindsay M. Morton. Risk of therapy-related subsequent cancers in individuals with germline TP53 variants [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA004.

Background: Children with hemato-oncological diseases or following stem cell transplantation (SCT) are at high risk for life-threatening infections; sepsis in this population constitutes a substantial proportion of pediatric intensive care unit (PICU) admissions. The current pediatric prognostic scoring tools to evaluate illness severity and mortality risk are designed for the general pediatric population and may not be adequate for this vulnerable subpopulation. Methods: Retrospective analysis was performed on all PICU admissions for sepsis in children with hemato-oncological diseases or post-SCT, in a single tertiary pediatric hospital between 2008 and 2021 (n = 233). We collected and analyzed demographic, clinical, and laboratory data and outcomes for all patients, and evaluated the accuracy of two major prognostic scoring tools, the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) and the Pediatric Risk of Mortality III (PRISM III). Furthermore, we created a new risk-assessment model that contains additional parameters uniquely relevant to this population. Results: The survival rate for the cohort was 83%. The predictive accuracies of PELOD-2 and PRISM III, as determined by the area under the curve (AUC), were 83% and 78%, respectively. Nine new parameters were identified as clinically significant: age, SCT, viral infection, fungal infection, central venous line removal, vasoactive inotropic score, bilirubin level, C-reactive protein level, and prolonged neutropenia. Unique scoring systems were established by the integration of these new parameters into the algorithm; the new systems significantly improved their predictive accuracy to 91% (p = 0.01) and 89% (p < 0.001), respectively. Conclusions: The predictive accuracies (AUC) of the PELOD-2 and PRISM III scores are limited in children with hemato-oncological diseases admitted to PICU with sepsis. These results highlight the need to develop a risk-assessment tool adjusted to this special population. Such new scoring should represent their unique characteristics including their degree of immunosuppression and be validated in a large multi-center prospective study.

BACKGROUND Infant chiasmatic gliomas present a major therapeutic challenge due to large size, threat to vision and progressive nature. Infants <1 year respond poorly to Vincristine/Carboplatinum chemotherapy (SIOP-LGG2). BRAF fusion is common, so MEK inhibitors have been used second line in older children, but time to response is slow (median ~20 months). Data on the use of these drugs in infants is limited as is data on the safety and efficacy of combining chemotherapy with MEK inhibitors. METHODS We report two infants treated successfully for BRAF fused chiasmatic glioma - both presented age 5 months with nystagmus and diencephalic syndrome. Both had significant tumor progression within 6 weeks of starting Vincristine/ Carboplatin which responded rapidly to the addition of Trametinib. RESULTS Case 1 required tumor debulking at week 6 of chemotherapy due to progressive hyponatremia, hydrocephalus and brainstem compression. Surgery caused diabetes insipidus, hemianopia and hemiparesis. Tumor growth continued despite reinstating chemotherapy. Addition of trametinib caused tumor shrinkage by 75% within 12 weeks and 90% by 1 year. Minirin doses were reduced by 80% on Trametinib. After 1.3 years, chemotherapy was stopped & Trametinib continued alone. Case 2 - tumor growth and severe hyponatremia by week 6 of chemotherapy prompted addition of Trametinib without surgery. There was tumor reduction of 50% over 6 months and improvement of severe failure to thrive. Hyponatremia, requiring sodium and urea supplementation, stabilized. Bilateral vision and age-appropriate development are maintained. Hypertension developed early, but resolved completely after stopping and then gradually reintroducing Trametinib. Recurrent diarrhea required dose reduction. CONCLUSIONS We show the safety and efficacy of combined treatment with chemotherapy and MEK inhibition in infants and postulate that both the combination and the young age at initiation of therapy may have contributed to the excellent outcome. We urge for clinical trials of combination therapy in this age group.

Abstract BACKGROUND AND AIMS IDH-mutant gliomas comprise <10% of HGG in children. RRD-HGG comprise 5-10% of childhood HGG, demonstrate high mutation burden (TMB) and respond to immune-checkpoint inhibition (ICI). The impact of RRD within childhood IDH-mutant gliomas, and effective therapeutic options for these patients are not well-established. METHODS Clinical and multi-omic analyses were performed on IDH mut -RRD-HGG registered to the IRRDC and the Toronto glioma taskforce. Tumor development and genomic data were studied from a novel IDH mut -RRD-HGG immunocompetent mouse model. Outcome following ICI and targeted therapy were evaluated. RESULTS RRD was detected in >60% of childhood IDH mut -HGG. IDH1-mutations were detected in 20% of RRD-HGG. All patients with IDH mut -RRD-HGG (n=49) harboured germline variants in MMR genes (CMMRD: 65%, Lynch: 35%). Contrary to sporadic IDH mut -gliomas, >91% were WHO-grades 3/4. Diffuse/multifocal disease involving the frontal lobe was frequent. TMB (median: 28 mutations/Mb) was lower than IDH-wildtype RRD-HGG (p<0.05). POLE/POLD1 mutations were absent. TP53 and ATRX were frequent somatic hits. Copy number changes, particularly CDKN2A/2B loss, were common. IDH-mutation contributed to an immune-suppressed microenvironment, with lower CD8-T-cell infiltration (immunohistochemistry) and tumor-inflammation scores (transcriptome; p<0.05). A novel mouse model (Olig2-Cre+/Msh2LoxP/LoxP/LSL-Idh1R132H/+) demonstrated similar TMB, diffuse cerebral involvement, slower growth, and lesser immune infiltrates as compared with IDH-wildtype RRD-HGG models, and provided opportunity for therapeutic testing. RRD contributed to poor survival in IDHmut-gliomas (p<0.001). Despite hypermutation, ICI monotherapy resulted in inferior survival in IDH mut -RRD-HGG vs IDH-wildtype RRD-HGG (p<0.05). Five patients developed metachronous IDH mut -RRD-HGG while on anti-PD1 treatment for IDH-wildtype RRD-HGG, suggesting intrinsic ICI-resistance. Ivosidenib (IDH-inhibitor) demonstrated objective response in 4/8 IDH mut -RRD-HGG. Furthermore, for IDH mut -RRD-HGG on ICI treatment, the addition of ivosidenib prolonged survival at 12-months in comparison to those without IDH-inhibition (p=0.01) CONCLUSIONS Hypermutant RRD-HGG with IDH1;p.R132H harbour unique immuno-biology and do not respond to anti-PD1 monotherapy. The addition of IDH-inhibition demonstrated favourable responses, supporting need for evaluation of the combination in clinical trials.

Neurofibromatosis type 1 (NF1), Noonan syndrome, and related syndromes, grouped as RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together, RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared with the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the past decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multidisciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other health care professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.

Abstract BACKGROUND Infant chiasmatic gliomas present a major therapeutic challenge due to large size, threat to vision and progressive nature. Infants <1 year respond poorly to Vincristine/Carboplatinum chemotherapy (SIOP-LGG2). BRAF fusion is common, so MEK inhibitors have been used second line in older children, but time to response is slow (median ~20 months). Data on the use of these drugs in infants is limited as is data on the safety and efficacy of combining chemotherapy with MEK inhibitors. METHODS We report two infants treated successfully for BRAF fused chiasmatic glioma - both presented age 5 months with nystagmus and diencephalic syndrome. Both had significant tumor progression within 6 weeks of starting Vincristine/ Carboplatin which responded rapidly to the addition of Trametinib. RESULTS Case 1 required tumor debulking at week 6 of chemotherapy due to progressive hyponatremia, hydrocephalus and brainstem compression. Surgery caused diabetes insipidus, hemianopia and hemiparesis. Tumor growth continued despite reinstating chemotherapy. Addition of trametinib caused tumor shrinkage by 75% within 12 weeks and 90% by 1 year. Minirin doses were reduced by 80% on Trametinib. After 1.3 years, chemotherapy was stopped & Trametinib continued alone. Case 2 - tumor growth and severe hyponatremia by week 6 of chemotherapy prompted addition of Trametinib without surgery. There was tumor reduction of 50% over 6 months and improvement of severe failure to thrive. Hyponatremia, requiring sodium and urea supplementation, stabilized. Bilateral vision and age-appropriate development are maintained. Hypertension developed early, but resolved completely after stopping and then gradually reintroducing Trametinib. Recurrent diarrhea required dose reduction. CONCLUSIONS We show the safety and efficacy of combined treatment with chemotherapy and MEK inhibition in infants and postulate that both the combination and the young age at initiation of therapy may have contributed to the excellent outcome. We urge for clinical trials of combination therapy in this age group.