Functional network disorganization and cognitive decline following fractionated whole-brain radiation in mice.

Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain's functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of temporally evolving neural dynamics as they relate to cerebral hemodynamics for bridging with human studies. In order to adequately study the underlying mechanisms of RT-induced cognitive dysfunction, the development of clinically mimetic RT protocols in animal models is needed. To address these challenges, we developed a fractionated whole-brain RT protocol (3Gy/day for 10 days) and applied longitudinal wide field optical imaging (WFOI) of neural and hemodynamic brain activity at 1, 2, and 3 months post RT. At each time point, mice were subject to repeated behavioral testing across a variety of sensorimotor and cognitive domains. Disruptions in cortical neuronal and hemodynamic activity observed 1 month post RT were significantly worsened by 3 months. While broad changes were observed in functional brain organization post RT, brain regions most impacted by RT occurred within those overlapping with the mouse default mode network and other association areas similar to prior reports in human subjects. Further, significant cognitive deficits were observed following tests of novel object investigation and responses to auditory and contextual cues after fear conditioning. Our results fill a much-needed gap in understanding the effects of whole-brain RT on systems level brain organization and how RT affects neuronal versus hemodynamic signaling in the cortex. Having established a clinically-relevant injury model, future studies can examine therapeutic interventions designed to reduce neuroinflammation-based injury following RT. Given the overlap of sequelae that occur following RT with and without chemotherapy, these tools can also be easily incorporated to examine chemotherapy-related cognitive impairment.

Cognition and Brain System Segregation in Pediatric Brain Tumor Patients Treated with Proton Therapy.

Purpose: Pediatric brain tumor patients often experience significant cognitive sequelae. Resting-state functional MRI (rsfMRI) provides a measure of brain network organization, and we hypothesize that pediatric brain tumor patients treated with proton therapy will demonstrate abnormal brain network architecture related to cognitive outcome and radiation dosimetry. Participants and Methods: Pediatric brain tumor patients treated with proton therapy were enrolled on a prospective study of cognitive assessment using the NIH Toolbox Cognitive Domain. rsfMRI was obtained in participants able to complete unsedated MRI. Brain system segregation (BSS), a measure of brain network architecture, was calculated for the whole brain, the high-level cognition association systems, and the sensory-motor systems. Results: Twenty-six participants were enrolled in the study for cognitive assessment, and 18 completed rsfMRI. There were baseline cognitive deficits in attention and inhibition and processing speed prior to radiation with worsening performance over time in multiple domains. Average BSS across the whole brain was significantly decreased in participants compared with healthy controls (1.089 and 1.101, respectively; P = 0.001). Average segregation of association systems was significantly lower in participants than in controls (P < 0.001) while there was no difference in the sensory motor networks (P = 0.70). Right hippocampus dose was associated with worse attention and inhibition (P < 0.05) and decreased segregation in the dorsal attention network (P < 0.05). Conclusion: Higher mean dose to the right hippocampus correlated with worse dorsal attention network segregation and worse attention and inhibition cognitive performance. Patients demonstrated alterations in brain network organization of association systems measured with rsfMRI; however, somatosensory system segregation was no different from healthy children. Further work with preradiation rsfMRI is needed to assess the effects of surgery and presence of a tumor on brain network architecture.

Cognitive deficits and altered functional brain network organization in pediatric brain tumor patients.

Survivors of pediatric brain tumors experience significant cognitive deficits from their diagnosis and treatment. The exact mechanisms of cognitive injury are poorly understood, and validated predictors of long-term cognitive outcome are lacking. Resting state functional magnetic resonance imaging allows for the study of the spontaneous fluctuations in bulk neural activity, providing insight into brain organization and function. Here, we evaluated cognitive performance and functional network architecture in pediatric brain tumor patients. Forty-nine patients (7-18 years old) with a primary brain tumor diagnosis underwent resting state imaging during regularly scheduled clinical visits. All patients were tested with a battery of cognitive assessments. Extant data from 139 typically developing children were used as controls. We found that obtaining high-quality imaging data during routine clinical scanning was feasible. Functional network organization was significantly altered in patients, with the largest disruptions observed in patients who received propofol sedation. Awake patients demonstrated significant decreases in association network segregation compared to controls. Interestingly, there was no difference in the segregation of sensorimotor networks. With a median follow-up of 3.1 years, patients demonstrated cognitive deficits in multiple domains of executive function. Finally, there was a weak correlation between decreased default mode network segregation and poor picture vocabulary score. Future work with longer follow-up, longitudinal analyses, and a larger cohort will provide further insight into this potential predictor.

Pediatric Experience and Outcomes from the First Single-Vault Compact Proton Therapy Center.

The first single-vault compact proton therapy center opened in 2013, utilizing a gantry-mounted synchrocylotron. The center was placed within a large academic radiation oncology department with a high priority for pediatric cancer care. Here we performed a retrospective study of pediatric (≤21 years) patients treated with proton therapy at our institution between 2013-2022. Patient, tumor, and treatment characteristics were obtained including race, socioeconomic status, insurance type, distance travelled, need for anesthesia, and outside referrals for proton therapy. In total, 250 pediatric patients were treated with proton therapy comprising 18% of our proton patient volume. Median follow-up was 3.1 years, 38.4% were female and 83% were white. The majority of cases were CNS (69.6%) and a large number of patients (80/250, 32%) required craniospinal irradiation. Anesthesia was required for 39.6% of patients. Average distance travelled for treatment was 111 miles and 23% of patients were referred from outside institutions for proton therapy. Insurance type was private/commercial for 61.2% followed by Medicaid for 32%. We found that 23% of patients lived in census tracts with >25% of people living below the national poverty line. Overall survival at 3 years was excellent at 83.7% with better outcomes for CNS patients compared to non-CNS patients. There were no cases of secondary malignancy at this early time point. As the world's first compact proton therapy center, we found that proton therapy increased our pediatric volume and provided proton therapy to a diverse group of children in our region. These data highlight some of the expected patient and tumor characteristics and necessary resources for providing pediatric proton beam therapy.

Feasibility of the Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) System for Anesthesia Avoidance in Pediatric Patients: A Multicenter Trial.

PURPOSE: The Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system was the first published radiation therapy (RT)-compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluated the feasibility of AVATAR implementation and effects on anesthesia use, quality of life, and anxiety in a multicenter pediatric trial. METHODS AND MATERIALS: Pediatric patients 3 to 10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least 1 fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were nonsuccessful (NS). The PedsQL3.0 Cancer Module (PedsQL) survey assessed quality of life and was administered to the patient and guardian at RT simulation, midway through RT, and at final treatment. The modified Yale Preoperative Anxiety Scale (mYPAS) assessed anxiety and was performed at the same 3 time points. Success was evaluated using the χ2 test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject. RESULTS: Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (P = .04) and private versus public insurance (P < .001). Both patient (P = .008) and parent (P = .006) PedsQL scores significantly improved over the course of RT for patients aged 5 to 7. Anxiety in the treatment room decreased for both S and NS patients over RT course (P < .001), by age (P < .001), and by S versus NS patients (P < .001). CONCLUSIONS: In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children aged 3 to 10 years, higher than among age-matched historical controls (49%; P < .001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction.

An Analysis of Major Target Deviations in Craniospinal Irradiation Treatment Plans for Patients With Intermediate-Risk Medulloblastoma Within a Phase 3 Clinical Trial (Children's Oncology Group Study ACNS0331).

Purpose: Craniospinal irradiation remains an essential and yet difficult part of the treatment of patients with medulloblastoma. Whereas technological advances offer promise of increased conformity, realiance on advanced technology is not without risk, and it remains critical to carefully delineate targets. We describe examples of target deviations (TDs) in craniospinal irradiation treatment plans for postoperative patients with medulloblastoma in a phase 3 clinical trial (ACNS 0331). Methods and Materials: The principal investigator independently performed a review of the treatment plans and portal films of enrolled patients and evaluated the plans for TDs. TDs of dose, dose uniformity, and volume were defined as major or minor deviations. Major TDs scored as protocol violations. The effect of major TDs on event-free survival (EFS) and overall survival (OS) was evaluated using the stratified Cox proportional hazards model. Results: Of the 549 patients enrolled, 461 were available for this analysis. Thirty-two (7%) plans did not have data sufficient for TD evaluation. Major TDs were found in 32 of the 461 plans (7%). Of those, 21 were deviations of target volume alone, 7 were deviations of target dose alone, and 4 were deviations of both target volume and dose. The 25 patients with TDs of volume involved 29 sites. The most common major TDs of volume involved the brain (9 of 29) and the posterior fossa (9 of 29). On Cox proportional hazards modeling, the presence of a major TD did not statistically significantly affect EFS (hazard ratio, 0.98; 95% confidence interval, 0.45-2.11; P = .9541) or OS (hazard ratio, 1.10; 95% confidence interval, 0.51-2.38; P = .8113). Conclusions: Although intensity modulated radiation therapy and proton therapy are promising in improving conformity and sparing organs at risk, technology does not substitute for careful anatomic definition of target volumes. The study was not powered to evaluate the effect of TDs on EFS and OS; therefore, the statistical analysis presented in this study must be interpreted with caution.

Failure modes and effects analysis of pediatric I-131 MIBG therapy: Program design and potential pitfalls.

BACKGROUND: There is growing interest among pediatric institutions for implementing iodine-131 (I-131) meta-iodobenzylguanidine (MIBG) therapy for treating children with high-risk neuroblastoma. Due to regulations on the medical use of radioactive material (RAM), and the complexity and safety risks associated with the procedure, a multidisciplinary team involving radiation therapy/safety experts is required. Here, we describe methods for implementing pediatric I-131 MIBG therapy and evaluate our program's robustness via failure modes and effects analysis (FMEA). METHODS: We formed a multidisciplinary team, involving pediatric oncology, radiation oncology, and radiation safety staff. To evaluate the robustness of the therapy workflow and quantitatively assess potential safety risks, an FMEA was performed. Failure modes were scored (1-10) for their risk of occurrence (O), severity (S), and being undetected (D). Risk priority number (RPN) was calculated from a product of these scores and used to identify high-risk failure modes. RESULTS: A total of 176 failure modes were identified and scored. The majority (94%) of failure modes scored low (RPN <100). The highest risk failure modes were related to training and to drug-infusion procedures, with the highest S scores being (a) caregivers did not understand radiation safety training (O = 5.5, S = 7, D = 5.5, RPN = 212); (b) infusion training of staff was inadequate (O = 5, S = 8, D = 5, RPN = 200); and (c) air in intravenous lines/not monitoring for air in lines (O = 4.5, S = 8, D = 5, RPN = 180). CONCLUSION: Through use of FMEA methodology, we successfully identified multiple potential points of failure that have allowed us to proactively mitigate risks when implementing a pediatric MIBG program.

Risk of suicide among individuals with a history of childhood cancer.

BACKGROUND: Previous studies have described suicidal ideation among survivors of childhood cancer, but small numbers of events limit the understanding of suicide risk. The objectives of this study were to assess whether childhood cancer survivors are at increased risk of suicide in comparison with the general population and to determine risk factors associated with risk in a population-based cohort. METHODS: First primary malignancies among individuals aged 0 to 19 years from 1975 to 2016 were identified from Surveillance, Epidemiology, and End Results (SEER) databases. Standardized mortality ratios (SMRs) of suicide were obtained via SEER*Stat software from SEER 9. Fine and Gray proportional hazards models were used to identify suicide-associated factors among childhood cancer patients included in SEER 18. RESULTS: In all, 96,948 childhood cancer cases and 89 suicides were identified. Across all attained ages, the suicide risk for individuals with a childhood cancer history (11.64 per 100,000 person-years) was similar to the risk for those without a cancer history (SMR, 1.14; 95% confidence interval [CI], 0.91-1.43). However, for survivors alive beyond the age of 28 years (the median age of death by suicide), the suicide risk was significantly elevated (suicides per 100,000 person-years, 22.43; SMR, 1.40; 95% CI, 1.02-1.87). Females (hazard ratio, 0.29; 95% CI, 0.18-0.59; P < .01) had lower risks than males. CONCLUSIONS: These results suggest that long-term childhood cancer survivors may be at increased suicide risk. Male sex is an independent risk factor for suicide. However, the absolute risk of suicide in older survivors is still low at ~1 per 5000 person-years. Future efforts should identify survivorship strategies to mitigate suicide risk.

Factors Associated With Acute Toxicity in Pediatric Patients Treated With Proton Radiation Therapy: A Report From the Pediatric Proton Consortium Registry.

PURPOSE: Limited prospective information regarding acute toxicity in pediatric patients receiving proton therapy (PT) exists. In this study, Pediatric Proton Consortium Registry (PPCR) data was analyzed for factors associated with development of acute toxicity in children receiving passively scattered or pencil beam scanning PT. METHODS AND MATERIALS: Pediatric patients treated with PT and enrolled on the PPCR from 2016 to 2017 at 7 institutions were included. Data were entered on presence versus absence of acute general, cardiac, endocrine, eye, gastrointestinal, genitourinary, hematologic, mouth, musculoskeletal, neurologic, psychological, respiratory, and skin toxicities before (baseline) and at the end of PT (acute). Associations between patient and treatment variables with development of acute toxicity were assessed with multivariable modeling. RESULTS: Of 422 patients included, PT technique was passively scattered in 241 (57%), pencil beam scanning in 180 (43%), and missing in 1 (<1%) patient. Median age was 9.9 years. Daily anesthesia for treatment was used in 169 (40%). Treatments were categorized as craniospinal irradiation (CSI; n = 100, 24%), focal central nervous system PT (n = 157, 38%), or body PT (n = 158, 38%). Passively scattered PT was associated with increased risk of hematologic toxicity compared with pencil beam scanning PT (odds ratio [OR]: 3.03; 95% confidence interval [CI], 1.38-6.70; P = .006). There were no other differences toxicities between PT techniques. Uninsured patients had increased risk of GI (OR: 2.71; 95% CI, 1.12-6.58; P = .027) and hematologic toxicity (OR: 10.67; 95% CI, 2.68-42.46; P <.001). Patients receiving concurrent chemotherapy were more likely to experience skin (OR: 2.45; 95% CI, 1.23-4.88; P = .011), hematologic (OR: 2.87; 95% CI, 1.31-6.25; P = .008), GI (OR: 2.37; 95% CI, 1.33-4.21; P = .003), and mouth toxicities (OR: 2.03; 95% CI, 1.10-3.73; P = .024). Patients receiving 49 to 55 Gy were more likely to experience skin (OR: 2.18; 95% CI, 1.06-4.44; P = .033) toxicity than those receiving <49 Gy. CONCLUSIONS: The PPCR registry highlights broad differences in acute toxicity rates in children receiving PT, and identifies opportunities for improvements in prevention, monitoring, and treatment of toxicities.

Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.

PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.

Radiation therapy for infants with cancer.

The clinical outcomes for infants with malignant tumors are often worse than older children due to a combination of more biologically aggressive disease in some cases, and increased toxicity-or deintensification of therapies due to concern for toxicity-in others. Especially in infants and very young children, finding the appropriate balance between maximizing treatment efficacy while minimizing toxicity-in particular late side effects-is crucial. We review here the management of malignant tumors in infants and very young children, focusing on central nervous system (CNS) malignancies and rhabdomyosarcoma.

Multifocal primary central nervous system Ewing sarcoma presenting with intracranial hemorrhage and leptomeningeal dissemination: illustrative case.

BACKGROUND: Ewing sarcoma is a neoplasm within the family of small round blue cell tumors and most frequently arises from skeletal bone. Primary involvement of the central nervous system in these lesions is extremely rare, with an incidence of 1%. OBSERVATIONS: A case is presented of a 34-year-old man who presented with left facial numbness, multiple intracranial lesions, a lumbar intradural lesion, and diffuse spinal leptomeningeal involvement. A lumbar laminectomy and biopsy were performed, which revealed the diagnosis of extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. The patient had a rapidly progressive clinical decline despite total neuroaxis radiation and multiple lines of chemotherapeutic treatments, eventually dying from his disease and its sequelae 6 months after diagnosis. LESSONS: The authors' review of 40 cases in the literature revealed only 2 patients with isolated intraaxial cranial lesions, 4 patients with cranial and spine involvement, and an additional 34 patients with spine lesions. The unique characteristics of this patient's case, including his presentation with diffuse disease and pathology that included a rare V600E BRAF mutation, are discussed in the context of the available literature.

Internal dose escalation associated with increased local control for melanoma brain metastases treated with stereotactic radiosurgery.

OBJECTIVE: The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non-small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM. METHODS: The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC. RESULTS: Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31-86 years). The median follow-up was 7.6 months (range 0.5-81.6 months), and the median survival was 9.3 months (range 1.3-81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30. CONCLUSIONS: For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.

Associations of Early Medicaid Expansion With Insurance Status and Stage at Diagnosis Among Cancer Patients Receiving Radiation Therapy.

PURPOSE: Medicaid expansion in 2014 is associated with improved insurance coverage and stage at diagnosis in cancer patients. However, little is known about the effect of early Medicaid expansions in 2010 to 2011 on outcomes in radiation therapy recipients. The objective of this study was to estimate the effect of early Medicaid expansion on insurance status and stage at diagnosis among radiation therapy recipients. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was queried for cases aged 18 to 64 diagnosed in 2007 to 2013 with a first primary malignancy treated with radiation therapy. Difference-in-differences analyses were used to compare changes in insurance coverage and stage at diagnosis from 2007 to 2009 and 2011 to 2013 in expansion relative to nonexpansion states. RESULTS: There was a -0.48 (95% confidence interval [CI], -0.84 to -0.13; P = .007) percentage point (PP) reduction in uninsured in expansion relative to nonexpansion states, primarily among counties with lower educational attainment (-1.73 PP; 95% CI, -2.72 to -0.75). Increases in early stage diagnoses in expansion relative to nonexpansion states were found overall and in breast (1.56 PP; 95% CI, 0.45-2.68; P = .006), colorectal (3.72 PP; 95% CI, 0.33-7.12; P = .032), and lung (1.49 PP; 95% CI, 0.25-2.72; P = .018) cancers. Decreases in late stage diagnoses were found in cervical (-5.91 PP; 95% CI, -9.58 to -2.25; P = .002), colorectal (-2.72 PP; 95% CI, -5.43 to -0.01; P = .05), and lung (-3.28 PP; 95% CI, -5.47 to -1.1; P = .003) cancers. CONCLUSIONS: For radiation therapy recipients, early Medicaid expansion was associated with decreased percent uninsured, particularly among low education counties, and earlier stage diagnoses for screenable cancers. Thus, early Medicaid expansion may improve access to care and decrease disparities for radiation therapy recipients.

Characterization and validation of an intra-fraction motion management system for masked-based radiosurgery.

PURPOSE: Characterize the intra-fraction motion management (IFMM) system found on the Gamma Knife Icon (GKI), including spatial accuracy, latency, temporal performance, and overall effect on delivered dose. METHODS: A phantom was constructed, consisting of a three-axis translation mount, a remote motorized flipper, and a thermoplastic sphere surrounding a radiation detector. An infrared marker was placed on the translation mount secured to the flipper. The spatial accuracy of the IFMM was measured via the translation mount in all Cartesian planes. The detector was centered at the radiation focal point. A remote signal was used to move the marker out of the IFMM tolerance and pause the beam. A two-channel electrometer was used to record the signals from the detector and the flipper when motion was signaled. These signals determined the latency and temporal performance of the GKI. RESULTS: The spatial accuracy of the IFMM was found to be <0.1 mm. The measured latency was <200 ms. The dose difference with five interruptions was <0.5%. CONCLUSION: This work provides a quantitative characterization of the GKI IFMM system as required by the Nuclear Regulatory Commission. This provides a methodology for GKI users to satisfy these requirements using common laboratory equipment in lieu of a commercial solution.

An Update From the Pediatric Proton Consortium Registry.

BACKGROUND/OBJECTIVES: The Pediatric Proton Consortium Registry (PPCR) was established to expedite proton outcomes research in the pediatric population requiring radiotherapy. Here, we introduce the PPCR as a resource to the oncology community and provide an overview of the data available for further study and collaboration. DESIGN/METHODS: A multi-institutional registry of integrated clinical, dosimetric, radiographic, and patient-reported data for patients undergoing proton radiation therapy was conceived in May 2010. Massachusetts General Hospital began enrollment in July of 2012. Subsequently, 12 other institutions joined the PPCR and activated patient accrual, with the latest joining in 2017. An optional patient-reported quality of life (QoL) survey is currently implemented at six institutions. Baseline health status, symptoms, medications, neurocognitive status, audiogram findings, and neuroendocrine testing are collected. Treatment details of surgery, chemotherapy, and radiation therapy are documented and radiation plans are archived. Follow-up is collected annually. Data were analyzed 25 September, 2017. RESULTS: A total of 1,854 patients have consented and enrolled in the PPCR from October 2012 until September 2017. The cohort is 55% male, 70% Caucasian, and comprised of 79% United States residents. Central nervous system (CNS) tumors comprise 61% of the cohort. The most common CNS histologies are as follows: medulloblastoma (n = 276), ependymoma (n = 214), glioma/astrocytoma (n = 195), craniopharyngioma (n = 153), and germ cell tumors (n = 108). The most common non-CNS tumors diagnoses are as follows: rhabdomyosarcoma (n = 191), Ewing sarcoma (n = 105), Hodgkin lymphoma (n = 66), and neuroblastoma (n = 55). The median follow-up is 1.5 years with a range of 0.14 to 4.6 years. CONCLUSION: A large prospective population of children irradiated with proton therapy has reached a critical milestone to facilitate long-awaited clinical outcomes research in the modern era. This is an important resource for investigators both in the consortium and for those who wish to access the data for academic research pursuits.

Patterns of care and treatment outcomes of patients with astroblastoma: a National Cancer Database analysis.

AIM: To evaluate the use of chemotherapy and radiation, and their outcomes for patients with astroblastoma. PATIENTS & METHODS: This is a retrospective review of patients extracted from the National Cancer Database. We investigated overall survival (OS) using Kaplan-Meier curves. Cox proportional hazards models were used to correlate OS with risk variables and treatments. RESULTS: OS at 5 years was 79.5%. Patients with high-grade tumors were more likely to receive chemotherapy and radiation. Patients with high-grade astroblastoma who did not receive adjuvant radiation had poor survival. CONCLUSION: Patients with astroblastoma should be treated with curative intent. Radiation is likely beneficial in high-grade astroblastoma. The exact role of radiation and chemotherapy following surgical resection warrant further investigation.

Disparity in Outcomes for Adolescent and Young Adult Patients Diagnosed With Pediatric Solid Tumors Across 4 Decades.

OBJECTIVE: Cancer mortality is a leading cause of disease-related death in the adolescent and young adult (AYA) population. Compared with older and younger patients, AYA patients often experience worse cancer-specific outcomes. Here, we compare AYA and pediatric overall survival (OS) in the most common pediatric extracranial solid tumors. MATERIALS AND METHODS: Using the US Surveillance, Epidemiology, and End Results database, we studied patients (age, 0 to 39 y) diagnosed with Ewing sarcoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, and Wilms tumor. RESULTS: A total of 12,375 patients (age, 0 to 39 y) were diagnosed between 1973 and 2010 (8247 pediatric and 4128 AYA patients). AYA patients with rhabdomyosarcoma and Ewing sarcoma were more likely to present with metastatic disease. OS was significantly worse in the AYA cohort for all tumor types (P<0.001) with the exception of osteosarcoma (P=0.29). Across 2 treatment time periods (1973 to 1989 and 1990 to 2010), there was significant improvement in 5-year OS in all tumor types with the exception of rhabdomyosarcoma; however, AYA patients continued to experience worse OS in the modern treatment cohort with the exception of osteosarcoma patients. There was no improvement in OS among AYA patients with Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, or Wilms tumor over the 2 treatment eras. CONCLUSIONS: For the most common pediatric extracranial solid tumors, AYA patients experience significantly worse OS compared with pediatric patients. Although improvements in therapy have led to gain in survival for pediatric patients, with the exception of osteosarcoma, AYA experienced no increase in survival over the study period. This investigation demonstrates the importance for further research in the AYA population.

Distant intracranial failure in melanoma brain metastases treated with stereotactic radiosurgery in the era of immunotherapy and targeted agents.

PURPOSE: Stereotactic radiosurgery (SRS) in combination with immunotherapy (IMT) or targeted therapy is increasingly being used in the setting of melanoma brain metastases (MBMs). The synergistic properties of combination therapy are not well understood. We compared the distant intracranial failure rates of intact MBMs treated with SRS, SRS + IMT, and SRS + targeted therapy. METHODS AND MATERIALS: Combination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors). The primary endpoint was distant intracranial failure after SRS, which was defined as any new MBM identified on brain magnetic resonance imaging. Outcomes were evaluated using the Kaplan Meier method and Cox proportional hazards. RESULTS: A total of 72 patients with melanoma with 233 MBMs were treated between April 2006 and April 2016. The number of MBMs within each treatment group was as follows: SRS: 121; SRS + IMT: 48; and SRS + targeted therapy: 64. The median follow-up was 8.9 months. One-year distant intracranial control rates for SRS, SRS + IMT, and SRS + targeted therapy were 11.5%, 60%, and 10%, respectively (P < .001). On multivariate analysis, after adjusting for steroid use and number of MBMs, SRS + IMT remained associated with a significant reduction in distant intracranial failure compared with SRS (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29-0.80; P = .003) and compared with SRS + targeted therapy (HR, 0.41; 95% CI, 0.25-0.68; P = .001).One-year local control for SRS, SRS + IMT, and SRS + targeted therapy was 66%, 85%, and 72%, respectively (P = .044). On multivariate analysis, after adjusting for dose, SRS + IMT remained associated with a significant reduction in local failure compared with SRS alone (HR, 0.37; 95% CI, 0.14-0.95; P = .04). CONCLUSIONS: SRS with immunotherapy is associated with decreased distant and local intracranial failure compared with SRS alone. Prospective studies are warranted to validate this result.