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Pediatric patients with craniopharyngioma risk cognitive deficits when treated with radiation therapy. We investigated cognitive outcomes after conformal photon radiation therapy (CRT) and the effect of visual deficits and hormone deficiencies.One hundred one pediatric patients were enrolled on a single institutional protocol beginning in 1998 (n = 76) or followed a similar nonprotocol treatment plan (n = 25). CRT (54 Gy) was administered using a 1.0- or 0.5-cm clinical target volume margin. Median age at CRT was 9.50 years (range, 3.20-17.63 years). Patients were followed for 10 years with assessment of hearing, vision, hormone deficiencies, and cognitive performance.Intellectual functioning (intelligence quotient) was significantly lower in children treated at a younger age and those who received higher doses to temporal lobes and hippocampi. Black race (-17.77 points, P = .002) and cerebrospinal fluid shunting (-11.52 points, P = .0068) were associated with lower baseline intelligence quotient. Reading scores were lower over time in models incorporating age, shunt, and dose to specific brain structures. Patients treated for growth hormone deficiency within 12 months of CRT had better intelligence and attention outcomes. Among patients with normal baseline vision, the 10-year cumulative incidence of change in visual acuity was 4.00% ± 2.82% and in visual field 10.42% ± 4.48%. Reading scores decreased after treatment (0.7873 points/y, P = .0451) in those with impaired baseline vision.Cognitive outcomes are selectively affected by dose to brain subvolumes, comorbidities of visual deficits, and treatment of endocrinopathy in pediatric craniopharyngioma. Improved treatment selection, normal tissue sparing methods of irradiation, and posttreatment management of endocrinopathy should be considered.

Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.

Refereed/Peer-reviewed Background and Purpose: Proton therapy (PT) can reduce side effects for paediatric cranial malignancies. Despite the high number of paediatric patients treated with PT, radiation induced risk factors for second primary cancer (SPC) in out-of-field organs are unknown. This study estimated lifetime attributable risk (LAR) of SPC as a function of age and sex for out-of-field organs following passive scattering and scanning beam PT in paediatric brain tumours. Materials and Methods: Measured neutron dose equivalent spectra for scattered and scanning PT were sourced from literature. The physical distance of 12 measured organs from paediatric CT dataset-based phantoms (5, 9 and 13 years-of-age) were applied to Schneider et al.’s analytical model using MATLAB (R2020B) to calculate the organ-specific LAR of SPC. Results: Scanning beam PT demonstrated smaller LAR (per 10,000 person years) of SPC compared to scattering. This was prominent for more radiosensitive organs, including the lung (320 vs 50), breast (1000 vs 150) and thyroid (350 vs 75), but not for all (i.e., rectum and reproductive organs were

Background Social determinants of health including parental occupation, household income, and neighborhood environment are predictors of cognitive outcomes among healthy and ill children; however, few pediatric oncology studies have investigated this relationship. This study utilized the Economic Hardship Index (EHI) to measure neighborhood-level social and economic conditions to predict cognitive outcomes among children treated for brain tumors (BT) with conformal radiation therapy (RT). Methods Two hundred and forty-one children treated on a prospective, longitudinal, phase II trial of conformal photon RT (54–59.4 Gy) for ependymoma, low-grade glioma, or craniopharyngioma (52% female, 79% white, age at RT = 7.76 ± 4.98 years) completed serial cognitive assessments (intelligence quotient [IQ], reading, math, and adaptive functioning) for ten years. Six US census tract-level EHI scores were calculated for an overall EHI score: unemployment, dependency, education, income, crowded housing, and poverty. Established socioeconomic status (SES) measures from the extant literature were also derived. Results Correlations and non-parametric tests revealed EHI variables share modest variance with other SES measures. Income, unemployment, and poverty overlapped most with individual SES measures. Linear mixed models, accounting for sex, age at RT, and tumor location, revealed EHI variables predicted all cognitive variables at baseline and change in IQ and math over time, with EHI overall and poverty most consistent predictors. Higher economic hardship was associated with lower cognitive scores. Conclusions Neighborhood-level measures of socioeconomic conditions can help inform understanding of long-term cognitive and academic outcomes in survivors of pediatric BT. Future investigation of poverty’s driving forces and the impact of economic hardship on children with other catastrophic diseases is needed.

IntroductionCraniopharyngioma is a brain tumor arising in the region of the hypothalamic-pituitary axis. Children and adolescents with craniopharyngioma have high survival rates, but often experience significant morbidity, including high rates of sleep disorders. Vulnerabilities to circadian disruption are present in this population, but little is known about circadian health.MethodsWe present exploratory circadian findings from a prospective trial at a single center. Data presented here are from the baseline timepoint. Fifty-three patients between the ages of 7 and 20 years provided salivary melatonin samples, following surgical resection and prior to completion of proton therapy, when indicated. We estimated dim light melatonin onset (DLMO) and collected additional sleep data from actigraphy, overnight polysomnography, and the multiple sleep latency test.ResultsAlmost half of participants did not have a valid DLMO estimate during the sampling window, with most being above the threshold at the first sample timepoint. Those with greater disease severity variables (greater hypothalamic involvement and the presence of diabetes insipidus) were significantly more likely to have missed DLMO. For those with valid estimates, DLMO timing correlated with BMI and other sleep variables, including mean sleep latency values on the MSLT.DiscussionThese findings suggest that a subset of those with pediatric craniopharyngioma may experience a phase advance and that this may relate to poorer prognostic indicators. Furthermore, circadian timing correlates with other sleep and health factors. Further research with earlier sampling is needed to better understand circadian rhythms in pediatric craniopharyngioma and associations with other health and disease variables.

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Supplementary Methods

Purpose:Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.Materials and Methods:Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3–21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.Results:Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and 2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS.Conclusions:Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Tumor proliferation measured as Ki67 index in (A) mSEP-CR(-)RTBDNb and (B) mCPC treated with the indicated dose and route of administration of gemcitabine.

Germline methodology

information on drugs used in preclinical studies

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with “standard-of-care” surgery and radiotherapy.Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP.Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654–66. ©2018 AACR.

Purpose: Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.Experimental Design: Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m2 once daily) and dasatinib (65 and 85 mg/m2 twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated.Results: Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs.Conclusions: The MTD of vandetanib and dasatinib in combination was 65 mg/m2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer. Clin Cancer Res; 19(11); 3050–8. ©2013 AACR.

PDF file - 93K, Supplemental data provides details about the methods to obtain pharmacokinetic and pharmacodynamic studies.

Accuracy of stopping power ratio calculation and experimental validation of proton range with dual-layer computed tomography

Refereed/Peer-reviewed Purpose: Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT). Methods: Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio. Results: IMPT plans resulted in lower NTCP compared to IMRT across all models (p < 0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (> 20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p < 0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p < 0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p < 0.0001). Conclusion: Due to the scarcity of pediatric NTCP data available, sensitivity analyses were performed using plausible ranges based on published adult data. In the clinical scenario where, if female pediatric patients were 20% more radiosensitive (lower TD50 value), they could be up to twice as likely to experience side-effects of brainstem necrosis and cochlea tinnitus compared to males, highlighting the need for considering the sex in NTCP models. Based on our sensitivity analyses, age and sex of a pediatric patient could significantly affect the resultant NTCP from cranial radiotherapy, especially at higher α/β values.

Background We characterize the patterns of progression across medulloblastoma (MB) clinical risk and molecular subgroups from SJMB03, a Phase III clinical trial. Methods One hundred and fifty-five pediatric patients with newly diagnosed MB were treated on a prospective, multi-center phase III trial of adjuvant radiotherapy (RT) and dose-intense chemotherapy with autologous stem cell transplant. Craniospinal radiotherapy to 23.4 Gy (average risk, AR) or 36-39.6 Gy (high risk, HR) was followed by conformal RT with a 1 cm clinical target volume to a cumulative dose of 55.8 Gy. Subgroup was determined using 450K DNA methylation. Progression was classified anatomically (primary site failure (PSF) +/– distant failure (DF), or isolated DF), and dosimetrically. Results Thirty-two patients have progressed (median follow-up 11.0 years (range, 0.3–16.5 y) for patients without progression). Anatomic failure pattern differed by clinical risk (P = .0054) and methylation subgroup (P = .0034). The 5-year cumulative incidence (CI) of PSF was 5.1% and 5.6% in AR and HR patients, respectively (P = .92), and did not differ across subgroups (P = .15). 5-year CI of DF was 7.1% vs. 28.1% for AR vs. HR (P = .0003); and 0% for WNT, 15.3% for SHH, 32.9% for G3, and 9.7% for G4 (P = .0024). Of 9 patients with PSF, 8 were within the primary site RT field and 4 represented SHH tumors. Conclusions The low incidence of PSF following conformal primary site RT is comparable to prior studies using larger primary site or posterior fossa boost volumes. Distinct anatomic failure patterns across MB subgroups suggest subgroup-specific treatment strategies should be considered.

OBJECTIVE Youth with craniopharyngioma experience weight gain, fragmented sleep, excessive daytime sleepiness (EDS), fatigue, and psychosocial problems that negatively impact their overall health-related quality of life (HRQoL). Greater hypothalamic tumor involvement (HI) may be associated with higher rates or severity of these impairments; however, the direct and indirect impact of HI on the physical and psychosocial consequences associated with pediatric craniopharyngioma remain unclear. The purpose of the current study was to examine relations between HI, body mass index (BMI), fragmented sleep, EDS, fatigue, psychosocial problems, and HRQoL among youth with craniopharyngioma. METHODS Eighty-four youth with craniopharyngioma (Mage = 10.27 ± 4.3 years, 53.6% female, 64.3% White) were assessed with actigraphy, nocturnal polysomnography, and multiple sleep latency tests prior to proton therapy, when indicated. Caregivers completed measures of fatigue, psychosocial functioning, and HRQoL. RESULTS Hypothalamic tumor involvement was associated with greater BMI (Est. = 2.97, p = 0.003) and daytime sleepiness (Est. = 2.53, p = 0.01). Greater fatigue predicted more psychosocial problems (Est. = 0.29, p

Estimate the cumulative incidence of endocrinopathy in pediatric patients treated for medulloblastoma with surgery, risk-adapted photon craniospinal irradiation, and dose-intensive chemotherapy.Children and adolescents (n=156) treated between 2003 and 2013 were evaluated for evidence of endocrinopathy. Clinical information and mean radiation dose to hypothalamus and thyroid were calculated and used to estimate cumulative incidence of growth hormone deficiency, hypothyroidism, adrenal insufficiency, hypogonadism, and precocious puberty.The 5-year cumulative incidences were estimated for growth hormone deficiency, 68.9% (60.9%, 75.6%); hypothyroidism, 48.4% (95% CI: 40.2%, 56.1%); adrenal insufficiency, 13.0% (95% CI: 8.3%, 18.9%); hypogonadism, 33.9% (95% CI: 25.2%, 42.7%); and precocious puberty, 2.0% (95% CI: 0.6%, 5.4%). Growth hormone deficiency was associated with increased hypothalamus dose HR 1.035 (95% CI: 1.010, 1.061) (P=.0055) in average risk patients and CSF shunt HR 2.532 (95% CI: 1.325, 4.838) (P=.0049) in high-risk patients. In average-risk patients, hypothyroidism was associated with younger age HR 0.902 (95% CI: 0.842, 0.973) (P=.0070), hypothalamus dose HR 1.039 (95% CI: 1.004, 1.075) (P=.0273) and thyroid dose HR 1.070 (95% CI: 1.008, 1.136) (P=.0263). In high-risk patients, hypothyroidism was associated with increased hypothalamus dose HR 1.068 (95% CI: 0.995, 1.147) (P=.0671) and thyroid dose HR 1.050 (95% CI: 1.000, 1.104) (P=.0515). Adrenal insufficiency was associated with increased hypothalamus dose HR 1.112 (95% CI: 1.058, 1.170) (P.0001). Growth hormone deficiency incidence was higher when comparing patients treated with CSF shunt vs. those not having a shunt/extraventricular drain placed during initial surgery, HR 1.712 (95% CI: 1.109, 2.643).Incidence and time to onset of clinically significant endocrinopathy after photon craniospinal irradiation for pediatric medulloblastoma is influenced by radiation dose to target organs and patient age at time of treatment. Advanced radiation therapy methods and dose reduction strategies are needed to reduce the incidence of endocrinopathy.

BACKGROUND AND PURPOSE: Posterior fossa type A (PFA) ependymomas have 2 molecular subgroups (PFA-1 and PFA-2) and 9 subtypes. Gene expression profiling suggests that PFA-1 and PFA-2 tumors have distinct developmental origins at different rostrocaudal levels of the brainstem. We, therefore, tested the hypothesis that PFA-1 and PFA-2 ependymomas have different anatomic MR imaging characteristics at presentation. MATERIALS AND METHODS: Two neuroradiologists reviewed the preoperative MR imaging examinations of 122 patients with PFA ependymomas and identified several anatomic characteristics, including extension through the fourth ventricular foramina and encasement of major arteries and tumor type (midfloor, roof, or lateral). Deoxyribonucleic acid methylation profiling assigned ependymomas to PFA-1 or PFA-2. Information on PFA subtype from an earlier study was also available for a subset of tumors. Associations between imaging variables and subgroup or subtype were evaluated. RESULTS: No anatomic imaging variable was significantly associated with the PFA subgroup, but 5 PFA-2c subtype ependymomas in the cohort had a more circumscribed appearance and showed less tendency to extend through the fourth ventricular foramina or encase blood vessels, compared with other PFA subtypes. CONCLUSIONS: PFA-1 and PFA-2 ependymomas did not have different anatomic MR imaging characteristics, and these results do not support the hypothesis that they have distinct anatomic origins. PFA-2c ependymomas appear to have a more anatomically circumscribed MR imaging appearance than the other PFA subtypes; however, this needs to be confirmed in a larger study.

ImportanceEarly reports suggest adverse events following proton therapy (PT) for childhood cancer are more prevalent given the increased number of PT centers and use in clinical trials.ObjectiveTo assess treatment-failure and toxicity events following Pencil Beam Scanning (PBS)-PT in children.Design, Setting, and ParticipantsThe single-institution Phase IV surveillance trial screened 856 children, of which 528 were eligible for PBS-PT, and 500 enrolled in SJPROTON1 from 2017–2020. The median follow-up was 2.1 years (range 1.1-4.4). PBS-RT attributable toxicities were systematically identified, and graded at baseline to four years following PBS-PT.InterventionsAll patients underwent PBS-PT or combined photon/PBS-PT.Main Outcomes and MeasuresThe primary objective was the CI of ≥grade 3 non-hematologic, PBS-PT attributable Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Additional outcomes included PBS-PT attributable hospitalization, toxicity related procedures, and treatment-related mortality. Pre-specified toxicities including necrosis, vasculopathy, neurologic deficits, and fracture/osteoradionecrosis were further characterized (any grade) as a secondary objective. Medical record review augmented in-person visits for failure and adverse event reporting. Competing risk regression was used to evaluate predictors of ≥grade 3 PBS-PT attributable toxicity.ResultsAt two years, the event-free survival was 73.2% (95% CI, 68.9%-77.8%). Distant and local failure predominated with a 2-year cumulative incidence (CI) of 16.5% (95% CI 13.1-20.4) and 6.8% (95% CI 4.6-9.5) respectively. The CI of ≥ grade 3 toxicity events at four years was 24.5%; including necrosis (3.7%), permanent neurologic deficit (2.9%), and fracture/osteoradionecrosis (0.79%). The rates of hospitalization and procedures due to PBS-PT– attributable toxicity was 3.9% and 7.6%, respectively. Predictors of an increased event-specific hazard for any ≥ grade 3 toxicity included baseline total toxicity burden (TTB) (HR 1.043, 95% CI 1.012-1.07, p=0.007), use of mixed photon/PBS-PT (HR 2.62, 95% CI 1.51-4.54, p=0.006) in the CNS population, and treatment of the pelvic body site (HR 4.25, 95% CI 1.08-16.72, p=0.038), and TTB (HR 1.1, 95% CI 1.04-1.16, p=0.002) in the non-CNS population, respectively.Conclusions and RelevanceChildren treated with PBS-PT experience a low incidence of toxicity, but subsets may be at increased risk, and experience toxicity that requires additional procedures or hospitalization.Key PointsQuestionWhat is the efficacy and safety profile of Pencil Beam Scanning Proton therapy (PBS-PT) in children?FindingsIn this single institution phase IV trial, the rate of local failure and clinically significant ≥grade 3 PBS-RT attributable toxicity were low, but a subset of patients may be at increased risk for hospitalization and procedures related to managing PBS-RT attributable adverse events.MeaningPBS-RT has an acceptable therapeutic ratio in children but the risk of adverse events requiring hospitalization or subsequent procedures may be increased in select populations.

PURPOSE: Challenges in proton therapy include identifying patients most likely to benefit; ensuring consistent, high-quality plans as its adoption becomes more widespread; and recognizing biological uncertainties that may be related to increased relative biologic effectiveness driven by linear energy transfer (LET). Knowledge-based planning is a domain that may help to address all three. METHODS: Artificial neural networks were trained using 117 unique treatment plans and associated dose and dose-weighted LET (LET(D)) distributions. The data set was split into training (n=82), validation (n=17), and test (n=18) sets. Model performance was evaluated on the test set using dose- and LET(D)-volume metrics in the clinical target volume (CTV) and nearby organs at risk and Dice similarity coefficients comparing predicted and planned isodose lines at 50%, 75%, and 95% of the prescription dose. RESULTS: Dose-volume metrics significantly differed (α = 0.05) between predicted and planned dose distributions in only one dose-volume metric, D(2%) to the CTV. The maximum observed root mean square (RMS) difference between corresponding metrics was 4.3 Gy(RBE) (8% of prescription) for D(1cc) to optic chiasm. Dice similarity coefficients were 0.90, 0.93, and 0.88 for the 50%, 75%, and 95% isodose lines, respectively. LET(D)-volume metrics significantly differed in all but one metric, L(0.1cc) of the brainstem. The maximum observed difference in RMS differences for LET(D) metrics was 1.0 keV/μm for L(0.1cc) to brainstem. CONCLUSIONS: We have devised the first three-dimensional dose and LET(D) prediction model for cranial proton radiation therapy. Dose accuracy compared favorably with that of previously published models in other treatment sites. The agreement in LET(D) supports future investigations with biological doses in mind to enable the full potential of knowledge-based planning in proton therapy.

PURPOSE Infants treated for CNS malignancies experience a significantly poorer response to treatment and are particularly at risk for neuropsychological deficits. The literature is limited and inconsistent regarding cognitive outcomes among this group. We investigated predictors of cognitive outcomes in children treated for brain tumors during infancy as part of a large, prospective, multisite, longitudinal trial. PATIENTS AND METHODS One hundred thirty-nine infants with a newly diagnosed CNS tumor were treated with chemotherapy, with or without focal proton or photon radiation therapy (RT). Cognitive assessments were conducted at baseline, 6 months, 1 year, and then annually for 5 years. The median length of follow-up was 816 days (26.8 months). Neurocognitive testing included assessment of intellectual functioning (intellectual quotient [IQ]), parent ratings of executive functioning and emotional and behavioral functioning, and socioeconomic status. RESULTS At baseline, IQ, parent-reported working memory, and parent-reported adaptive functioning were worse than normative expectations. Baseline cognitive difficulties were associated with younger age at diagnosis and lower socioeconomic status. Linear mixed models did not demonstrate a decline in IQ over time. There were increased parent-reported attention and executive problems over time. Increased concerns were related to supratentorial tumor location and CSF diversion. There were no differences in cognitive outcomes based on treatment exposure (chemotherapy-only v chemotherapy with RT and proton v photon focal RT). CONCLUSION Even before adjuvant therapy, young children with brain tumors experience cognitive difficulties that can affect quality of life. Changes in cognitive functioning over time were dependent on tumor location and surgical factors rather than adjuvant therapy. These findings may serve to guide treatment planning and indicate targets for cognitive monitoring and intervention.

Purpose To determine whether self-attention cycle-generative adversarial networks (cycle-GANs), a novel deep-learning method, can generate accurate synthetic computed tomography (sCT) to facilitate adaptive proton therapy in children with brain tumors. Materials and Methods Both CT and T1-weighted magnetic resonance imaging (MRI) of 125 children (ages 1-20 years) with brain tumors were included in the training dataset. A model introducing a self-attention mechanism into the conventional cycle-GAN was created to enhance tissue interfaces and reduce noise. The test dataset consisted of 7 patients (ages 2-14 years) who underwent adaptive planning because of changes in anatomy discovered on MRI during proton therapy. The MRI during proton therapy-based sCT was compared with replanning CT (ground truth). Results The Hounsfield unit-mean absolute error was significantly reduced with self-attention cycle-GAN, as compared with conventional cycle-GAN (65.3 ± 13.9 versus 88.9 ± 19.3, P Conclusion The novel cycle-GAN model with self-attention outperforms conventional cycle-GAN for children with brain tumors. Encouraging dosimetric results suggest that sCT generation can be used to identify patients who would benefit from adaptive replanning.

Purpose: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. Materials and Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3–21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Craniopharyngioma is a histologically benign brain tumor that arises in the suprasellar region affecting critical neurovascular structures including the hypothalamic-pituitary-adrenal axis and optic pathways. Children with craniopharyngioma often experience excessive daytime sleepiness which may be compounded by anxiety and depression. The current study investigated disparate sleep profiles to better understand psychological adjustment among children diagnosed with craniopharyngioma. Method: Actigraphs recorded nightly sleep data, including measures of sleep onset latency and wake after sleep onset, in a cohort of 80 youth between the ages of 2 and 20 years (median age = 9). Parent reports of behavioral and emotional functioning were included in the analysis. A latent profile analysis examined disparate sleep profiles, and a multinomial logistic regression examined differences of anxiety and depression among the sleep profiles. Results: The latent profile analysis revealed three sleep profiles: "variable sleepers" (48.3%), "consistently poor sleepers" (45.4%), and "night wakers" (6.4%). Consistently poor sleepers had lower rates of anxiety (g = .76; p = .009) and depression (g = .81; p = .003) than variable sleepers and had significantly lower rates of anxiety than night wakers (g = .52; p = .05); all other differences were nonsignificant (ps > .05). Discussion: Youth with craniopharyngioma who have nightly variations in sleep may have worse psychological functioning than those with more consistent, albeit poor, sleep patterns. Patients with craniopharyngioma who report variable sleep should be assessed for anxiety and depression to prevent and intervene on emotional difficulties that may be reciprocally related to sleep.

Objectives The preschool years (ages 4–6) are essential for the development of social–emotional skills, such as problem solving, emotion regulation, and conflict resolution. For children with cancer treated during this period, especially those with brain tumors, there are questions regarding the consequences of missed normative social experiences. The objective of this pilot study was to explore the social–emotional functioning of young children with brain tumors, as compared to those with non-CNS solid tumors, who have recently completed treatment. Methods Children with brain (n = 23) or solid tumors (n = 20) 4–6 years of age (5.42 ± 0.73 years; 60.5% male, 65.1% white) who were 8.21 (SD = 2.42) months post-treatment completed objective measures (Challenging Situations Task, NEPSY-II) of social functioning while a caregiver completed questionnaires (e.g., BASC-3, NIH Toolbox Emotion Measures). Results A large portion of the sample (brain tumor: 65.2%, solid tumor: 44.4%) fell in the clinical range on parent-report measures of peer interaction. There were no statistically significant differences between patient groups across measures, but effect sizes suggest youth with brain tumors potentially experienced more difficulties on some indices. All children were more likely to choose prosocial responses when presented with a challenging social situation where they were physically provoked (e.g., hit) versus socially provoked (e.g., left out). Conclusions Preschool-aged children with cancer may experience weaknesses in social functioning shortly after treatment, with youth with brain tumors potentially demonstrating greater concerns. Emphasizing social interaction is critical to ensure young children have the opportunity to develop critical social–emotional skills.

BackgroundRecent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked power to integrate molecular and clinical findings. The different proposed subgroup structures also highlighted a need to reach consensus on a robust and relevant classification system.MethodsWe performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical and genomic features of patients and samples from these pineal tumor subgroups were annotated.FindingsFour clinically and biologically relevant consensus PB subgroups were defined: PB-miRNA1 (n=96), PB-miRNA2 (n=23), PB-MYC/FOXR2 (n=34) and PB-RB1 (n=25); with PPTID (n=43) remaining as a molecularly distinct entity. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual subgroups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection and metastatic status varied significantly among tumor subgroups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 and PB-RB1.InterpretationWe systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease subgroups, laying the groundwork for future studies as well as routine use in tumor classification.

BACKGROUND The St Jude Global Academy Neuro-Oncology Training Seminar (NOTS) is a hybrid course in pediatric neuro-oncology specifically designed for physicians from low-income and middle-income countries. METHODS The curriculum for the course was created by conducting a targeted needs assessment that evaluated 11 domains of care for children with central nervous system (CNS) tumors. The targeted needs assessment was completed by 24 institutions across the world, and the data were used to define 5 core elements included in the 2 components of the NOTS: a 9-week online course and a 7-day in-person workshop. Participant acquisition of knowledge and changes in clinical behavior were evaluated as measures of success. RESULTS Teams from 8 institutions located in 8 countries enrolled in the online course, and it was successfully completed by 36 participants representing 6 specialties. On the basis of their performance in the online course, 20 participants from 7 institutions took part in the on-site workshop. The participants exhibited improved knowledge in core elements of treating children with CNS tumors, including barriers of care, possible solutions, and steps for project implementation (P < .0001). All participants expressed a belief that they acquired new concepts and knowledge, leading to changes in their clinical practice. Those present at the workshop created an international multidisciplinary group focused on treating CNS tumors in low-income and middle-income countries. CONCLUSIONS By using a hybrid online and in-person approach, the authors successfully created a multidisciplinary course focused on pediatric CNS tumors for resource-limited settings. Their experience supports this strategy as a feasible mechanism for driving further global collaborations.

Background To estimate the incidence of endocrinopathy in children and adolescents with craniopharyngioma after treatment with photon-based conformal and intensity-modulated radiation therapy (CRT). Methods One hundred one pediatric patients were enrolled on a phase II single-institution protocol beginning in 1998 (n = 76) or followed a similar non-protocol treatment plan (n = 25). Surgery was individualized. CRT (54 Gy) was administered using a 1.0-cm or ≤0.5-cm clinical target volume margin. Patients underwent baseline and serial evaluation of the hypothalamic-pituitary axis. Results The 10-year cumulative incidence (CI) of growth hormone deficiency (GHD) was 68.42% (±11.27) for black patients and 94.23% (±3.57) for white patients (P = .0286). The CI of thyroid-stimulating hormone deficiency (TSHD) was 70.94% (±8.44) at 10 years for non-shunted patients and 91.67% (±10.40) at 6 years for shunted patients (P = .0260). The CI of TSHD was 100% (±14.29) at 4 years for those with diabetes insipidus (DI) and 71.36% (±8.86) at 10 years for those without DI (P = .0008). The 10-year CI of adrenocortical hormone deficiency was 70.00% (±16.15) for those with DI and 48.39% (±9.19) for those without DI (P = .0080). The 10-year CI of LH/FSH deficiency was 43.33% (±9.32) age Conclusions Hormone deficiencies are common in pediatric patients with craniopharyngioma and are associated with host, tumor, and treatment factors. Understanding the incidence and time to onset may facilitate intervention and patient selection for treatment.