The Prognostic Significance of Early Tumor Volume Change in Rhabdomyosarcoma.

Purpose: To describe early tumor volume change in patients with rhabdomyosarcoma (RMS) and investigate its association with overall survival (OS) and local failure. Methods and Materials: This retrospective study included patients who received diagnoses of group III/IV RMS with available computed tomography and/or magnetic resonance imaging scans at 2 time points: (1) pretherapy and (2) early therapy (acquired during weeks 8-12 of chemotherapy). Relative volumetric change (RVC) was calculated as the percentage of (early therapy - pretherapy volume) / (pretherapy volume). Cox regression was used to identify variables associated with OS. The Fine-Gray model was used to estimate local failure. Results: Eligible patients (n = 55) had the following characteristics: median age at diagnosis, 9.6 years and median follow-up, 30.4 months. Most tumors were alveolar (61.8%), followed by embryonal (34.6%) and spindle cell/sclerosing (4%). The median RVC was -86.4% with larger decreases observed in alveolar versus nonalveolar RMS (-89.4% vs -69.8%, P = .043). For embryonal and spindle cell/sclerosing RMS, all of which were FOXO1 fusion negative, RVC was independently associated with OS (hazard ratio for every 50% reduction in RVC [HRRVC], 0.5; 95% CI, 0.26-0.96; P = .037) and local failure (HRRVC, 0.57; 95% CI, 0.33-0.99; P = .049). The predominant pattern of failure in embryonal and spindle cell/sclerosing RMS was local, and most were group III. Conclusions: There was a greater reduction in tumor volume in alveolar versus nonalveolar RMS. Early tumor volume reduction was associated with OS and local failure in embryonal or spindle cell/sclerosing RMS, all of which were confirmed FOXO1 fusion negative and had higher incidence of local compared with distant failures.

Neighborhood resources are associated with neuropsychological outcomes among pediatric brain tumor survivors.

Background: Cancer-related cognitive impairment in survivors of pediatric brain tumors is a public health concern, yet studies seldom explore the role of social determinants of health beyond treatment effects. We investigated the influence of neighborhood resources using the Child Opportunity Index (COI) on neuropsychological functioning in survivors. Methods: Intelligence (IQ) and untimed reading and math proficiency were assessed retrospectively in 190 survivors. Multiple regression analyses explored associations among the COI composite and indices (Education, Health-Environment, Social-Economic) and neuropsychological outcomes, controlling for cumulative neurological risk and treatment exposures (Neurological Predictor Scale; NPS) and parental education. Results: Performance was on average within normal limits: IQ (M = 94.08, SD = 15.85, d=.37) with 13.4% of scores below impairment thresholds; reading (M = 95.08, SD = 17.36, d=.28) and math calculation (M = 91.84, SD = 18.82, d=.43) with 16.92% and 20.63% of scores below impairment thresholds, respectively. Each COI domain predicted reading and IQ after controlling for NPS, parental education, and age at diagnosis; however, the Education domain was the only significant predictor of math outcomes. Conclusion: The COI domains significantly predicted IQ and untimed academic skills in survivors, revealing the critical role of neighborhood resources on cognition above and beyond parental education and treatment factors. This is among the first studies to illuminate the influence of neighborhood resources on cognition in survivors. Future research should examine neighborhood context, an understudied construct, with importance in the move toward precision medicine.

Neuroblastoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.

Deep learning segmentation of organs-at-risk with integration into clinical workflow for pediatric brain radiotherapy.

PURPOSE: Radiation therapy (RT) of pediatric brain cancer is known to be associated with long-term neurocognitive deficits. Although target and organs-at-risk (OARs) are contoured as part of treatment planning, other structures linked to cognitive functions are often not included. This paper introduces a novel automatic segmentation tool specifically designed for the unique challenges posed by pediatric patients undergoing brain RT, as well as its seamless integration into the existing clinical workflow. METHODS AND MATERIALS: Images of 47 pediatric brain cancer patients aged 1 to 20 years old and 33 two-year-old healthy infants were used to train a vision transformer, UNesT, for the segmentation of five brain OARs. The trained model was then incorporated to clinical workflow via DICOM connections between a treatment planning system (TPS) and a server hosting the trained model such that scans are sent from TPS to the server, automatically segmented, and sent back to TPS for treatment planning. RESULTS: The proposed automatic segmentation framework achieved a median dice similarity coefficient of 0.928 (frontal white matter), 0.908 (corpus callosum), 0.933 (hippocampi), 0.819 (temporal lobes), and 0.960 (brainstem) with a mean ± SD run time of 1.8 ± 0.67 s over 20 test cases. CONCLUSIONS: The pediatric brain segmentation tool showed promising performance on five OARs linked to neurocognitive functions and can easily be extended for additional structures. The proposed integration to the clinic enables easy access to the tool from clinical platforms and minimizes disruption to existing workflow while maximizing its benefits.

Impact of Consolidative Radiation on Overall and Progression-Free Survival in Pediatric, Adolescent, and Young Adult Metastatic Bone and Soft Tissue Sarcoma.

PURPOSE: To determine the association between consolidative radiation (RT) and survival in children, adolescents, and young adults with metastatic sarcoma. METHODS AND MATERIALS: Eligibility criteria included patients aged ≤39 years with newly diagnosed metastatic bone or soft tissue sarcoma who completed local control of the primary tumor without disease progression. Consolidative RT was defined as RT to all known sites of metastatic disease. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). The least absolute shrinkage and selection operator Cox provided adjusted estimates. To account for immortal time bias, consolidative RT was used as a time-varying covariate in a time dependent Cox model. Distant failure was estimated using the Fine-Gray model. RESULTS: Patients (n = 85) had a median age at diagnosis of 14.8 years. Most common histology was Ewing Sarcoma (45.9%) followed by rhabdomyosarcoma (40.0%). Receipt of consolidative RT was associated with Ewing Sarcoma (P < .001) and local control modality as those who underwent local control with surgery and RT compared with surgery alone were more likely to be treated with consolidative RT (P = .034). Consolidative RT was independently associated with improved OS (hazard ratio [HR], 0.41; 95% CI, 0.17-0.98; P = .045) and improved PFS (HR, 0.37; 95% CI, 0.16-0.88; P = .024) after adjusting for confounding variables and immortal time bias. Patients treated with consolidative RT also experienced a lower risk of distant failure (HR, 0.33; 95% CI, 0.17-0.64; P = .001). In an independent data set of patients with metachronous progression (n = 36), consolidative RT remained independently associated with improved OS. CONCLUSIONS: Consolidative RT was independently associated with improved OS and PFS and decreased risk of distant failure in child, adolescent, and young adult patients with metastatic sarcoma. Future work should evaluate biomarkers to optimize patient selection, timing, and dose for consolidative RT.

Impact of socioeconomic status and chemotherapy on neurocognitive performance in children with brain tumors.

Background: Although the relationship between radiation and neurocognition has been extensively studied in the pediatric brain tumor population, it is increasingly recognized that neurocognitive impairment is multifactorial. Therefore, we quantified the effect of socioeconomic status (SES) and chemotherapy on neurocognitive impairment and decline post-treatment. Methods: Eligible patients included those diagnosed with a brain tumor at < 22 years of age with ≥1 neurocognitive assessment. Neurocognitive impairment was defined as performance 1.5 standard deviations below the normative mean using age-standardized measures of intellectual function. Neurocognitive decline was defined as a negative slope. Neurocognitive outcomes included Wechsler indices of Full-Scale Intelligence Quotient (IQ). Logistic regression identified variables associated with neurocognitive impairment. Longitudinal data was analyzed using linear mixed models. Results: Eligible patients (n = 152, median age at diagnosis = 9.6 years) had a mean neurocognitive follow-up of 50.2 months. After accounting for age and receipt of craniospinal irradiation, patients with public insurance had 8-fold increased odds of impaired IQ compared to private insurance (odds ratio [OR]: 7.59, P < .001). After accounting for age, change in IQ was associated with chemotherapy use (slope: -0.45 points/year with chemotherapy vs. 0.71 points/year without chemotherapy, P = .012). Conclusions: Public insurance, an indicator of low SES, was associated with post-treatment impairment in IQ, highlighting the need to incorporate SES measures into prospective studies. Chemotherapy was associated with change in IQ. Further work is needed to determine whether impairment associated with low SES is secondary to baseline differences in IQ prior to brain tumor diagnosis, brain tumor/therapy itself, or some combination thereof.

Clinical Characterization of a Table Mounted Range Shifter Board for Synchrotron-Based Intensity Modulated Proton Therapy for Pediatric Craniospinal Irradiation.

Purpose: To report our design, manufacturing, commissioning and initial clinical experience with a table-mounted range shifter board (RSB) intended to replace the machine-mounted range shifter (MRS) in a synchrotron-based pencil beam scanning (PBS) system to reduce penumbra and normal tissue dose for image-guided pediatric craniospinal irradiation (CSI). Methods: A custom RSB was designed and manufactured from a 3.5 cm thick slab of polymethyl methacrylate (PMMA) to be placed directly under patients, on top of our existing couch top. The relative linear stopping power (RLSP) of the RSB was measured using a multi-layer ionization chamber, and output constancy was measured using an ion chamber. End-to-end tests were performed using the MRS and RSB approaches using an anthropomorphic phantom and radiochromic film measurements. Cone beam CT (CBCT) and 2D planar kV X-ray image quality were compared with and without the RSB present using image quality phantoms. CSI plans were produced using MRS and RSB approaches for two retrospective pediatric patients, and the resultant normal tissue doses were compared. Results: The RLSP of the RSB was found to be 1.163 and provided computed penumbra of 6.9 mm in the phantom compared to 11.8 mm using the MRS. Phantom measurements using the RSB demonstrated errors in output constancy, range, and penumbra of 0.3%, -0.8%, and 0.6 mm, respectively. The RSB reduced mean kidney and lung dose compared to the MRS by 57.7% and 46.3%, respectively. The RSB decreased mean CBCT image intensities by 86.8 HU but did not significantly impact CBCT or kV spatial resolution providing acceptable image quality for patient setup. Conclusions: A custom RSB for pediatric proton CSI was designed, manufactured, modeled in our TPS, and found to significantly reduce lateral proton beam penumbra compared to a standard MRS while maintaining CBCT and kV image-quality and is in routine use at our center.

The clinical and molecular characteristics of progressive hypothalamic/optic pathway pilocytic astrocytoma.

BACKGROUND: Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) often progresses despite multiple therapies. Identifying clinical and molecular characteristics of progressive tumors may aid in prognostication and treatment. METHODS: We collected 72 unresectable, non-neurofibromatosis type 1-associated hypothalamic/optic pathway PA to identify clinical and biologic factors associated with tumor progression. Tumors that progressed after therapy, metastasized, or resulted in death were categorized into Cohort B; those that did not meet these criteria were categorized into Cohort A. DNA methylation and transcriptome analyses were performed on treatment-naïve tumors, and the findings were validated by immunohistochemistry (IHC). RESULTS: The median follow-up of the entire cohort was 12.3 years. Cohort B was associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs 6.7 years, P = .005), and high incidence of KIAA1549-BRAF fusion (81.5% vs 38.5%, P = .0032). Cohort B demonstrated decreased CpG methylation and increased RNA expression in mitochondrial genes and genes downstream of E2F and NKX2.3. Transcriptome analysis identified transcription factor TBX3 and protein kinase PIM1 as common downstream targets of E2F and NKX2.3. IHC confirmed increased expression of TBX3 and PIM1 in Cohort B tumors. Gene enrichment analysis identified enrichment of MYC targets and MAPK, PI3K/AKT/mTOR, and p53 pathways, as well as pathways related to mitochondrial function. CONCLUSIONS: We identified risk factors associated with progressive PA. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognostication.

Dosimetric evaluation of cone-beam CT-based synthetic CTs in pediatric patients undergoing intensity-modulated proton therapy.

PURPOSE: To evaluate dosimetric changes detected using synthetic computed tomography (sCT) derived from online cone-beam CTs (CBCT) in pediatric patients treated using intensity-modulated proton therapy (IMPT). METHODS: Ten pediatric patients undergoing IMPT and aligned daily using proton gantry-mounted CBCT were identified for retrospective analysis with treated anatomical sites fully encompassed in the CBCT field of view. Dates were identified when the patient received both a CBCT and a quality assurance CT (qCT) for routine dosimetric evaluation. sCTs were generated based on a deformable registration between the initial plan CT (pCT) and CBCT. The clinical IMPT plans were re-computed on the same day qCT and sCT, and dosimetric changes due to tissue change or response from the initial plan were computed using each image. Linear regression analysis was performed to determine the correlation between dosimetric changes detected using the qCT and the sCT. Gamma analysis was also used to compare the dose distributions computed on the qCT and sCT. RESULTS: The correlation coefficients (p-values) between qCTs and sCTs for changes detected in target coverage, overall maximum dose, and organ at risk dose were 0.97 (< .001), 0.84 (.002) and 0.91 (< .001), respectively. Mean ± SD gamma pass rates of the sCT-based dose compared to the qCT-based dose at 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria were 96.5%±4.5%, 93.2%±6.3%, and 91.3%±7.8%, respectively. Pass rates tended to be lower for targets near lung. CONCLUSION: While insufficient for re-planning, sCTs provide approximate dosimetry without administering additional imaging dose in pediatric patients undergoing IMPT. Dosimetric changes detected using sCTs are correlated with changes detected using clinically-standard qCTs; however, residual differences in dosimetry remain a limitation. Further improvements in sCT image quality may both improve online dosimetric evaluation and reduce imaging dose for pediatric patients by reducing the need for routine qCTs.

Facilitating MR-Guided Adaptive Proton Therapy in Children Using Deep Learning-Based Synthetic CT.

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 < .01). The average 3-dimensional gamma passing rates (2%/2 mm criteria) for the original plan on the anatomy of the day and for the adapted plan were high (97.6% ± 1.2% and 98.9 ± 0.9%, respectively) when using sCT generated by self-attention cycle-GAN. The mean absolute differences in clinical target volume (CTV) receiving 95% of the prescription dose and 80% distal falloff along the beam axis were 1.1% ± 0.8% and 1.1 ± 0.9 mm, respectively. Areas of greatest dose difference were distal to the CTV and corresponded to shifts in distal falloff. Plan adaptation was appropriately triggered in all test patients when using sCT. 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.