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.

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.

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.

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.

Assessment of the treatment approach and survival outcomes in a modern cohort of patients with atypical teratoid rhabdoid tumors using the National Cancer Database.

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRTs) are rare brain tumors that occur primarily in children under the age of 3 years. This report evaluates the treatment approach and survival outcomes in a large cohort of patients treated in the United States. METHODS: Using the National Cancer Database, the analysis included all ATRT patients aged 0 to 18 years who were diagnosed between 2004 and 2012 and had complete treatment data. RESULTS: Three hundred sixty-one ATRT patients were evaluated. The 5-year overall survival (OS) rate was 29.9%, and it was significantly lower for children who were less than 3 years old (5-year OS, 27.7%) versus those who were 3 years old or older (5-year OS, 37.5%; P < .001). The best outcome was seen for patients with localized disease who received trimodality therapy (surgery, chemotherapy, and radiation therapy [RT]) with a 5-year OS rate of 46.8%. The utilization of trimodality therapy significantly increased during the study period (27.7% in 2004-2008 vs 45.1% in 2009-2012; P < .01), largely because of the increased use of RT. In a multivariate analysis, treatment that did not utilize trimodality therapy was associated with significantly worse OS (hazard ratio, 2.52; 95% confidence interval (1.82-3.51). Children aged 0 to 2 years were significantly less likely to receive trimodality therapy because of decreased utilization of RT in this age group. CONCLUSIONS: The use of trimodality therapy significantly increased during the study period and was associated with improved outcomes. For patients with localized disease who received trimodality therapy, the OS rate at 5 years approached 50%. However, further research into the optimal management of children less than 3 years old is needed because of their significantly worse OS in comparison with older children. Cancer 2017;123:682-687. © 2016 American Cancer Society.

Patterns of care and treatment outcomes of patients with Craniopharyngioma in the national cancer database.

To investigate the patterns of care and outcomes in patients with craniopharyngioma in the National Cancer Data Base (NCDB). This study included 697 patients (166 pediatric and 531 adult cases) treated for craniopharyngioma between 2004 and 2012 in the NCDB. Adjuvant radiotherapy (RT) was defined if within 6 months of surgery. Limited surgery (LS) was defined as biopsy or subtotal resection. Proportional-hazards models were used to evaluate associations between covariates and overall survival (OS). A time-dependent analysis of RT was performed to account for early deaths after surgery. Median follow-up was 46 months. Overall, 21% of patients received adjuvant RT. Of patients with known surgical extent (n = 195), 71% had LS. Utilization of adjuvant RT increased from 18% in 2004-2007 to 24% in 2008-2012. Patterns of care regarding adjuvant RT or LS were not significantly different between adult and pediatric patients. Tumor size, low comorbidity, and LS were associated with increased utilization of adjuvant RT. The 5-year OS among patients treated with LS, LS+RT, and gross total resection were 75, 85, and 82% (p = 0.02). On multivariate analysis of the 195 patients with known surgical extent, LS+RT was associated with improved OS compared to LS (HR 0.22, 95% CI 0.05-0.99, p = 0.04), but was not significant when early deaths (<2 months from surgery) were removed to adjust for immortal-time bias. Medical practice regarding surgical approach and adjuvant RT are similar for pediatric and adult craniopharyngiomas. Immortal-time bias may confound assessment of OS for adjuvant RT. Prospective studies comparing adjuvant RT versus observation after LS are warranted.

Impact of concurrent chemotherapy with radiation therapy for elderly patients with newly diagnosed glioblastoma: a review of the National Cancer Data Base.

To investigate the utilization and overall survival (OS) impact of concurrent chemotherapy in combination with radiation therapy (RT) for elderly glioblastoma (GBM) patients. Elderly patients (age >70) with supratentorial and nonmetastatic GBM who received RT of 20-75 Gy with concurrent single-agent chemotherapy (ChemoRT) or without (RT alone) during 2004-2012 were identified from the National Cancer Data Base (NCDB). The Cochran-Armitage test was used for trend analysis. Hazard ratios (HR) and 95% confidence intervals (CIs) were determined using Cox proportional hazards. Propensity score analysis was performed to reduce selection bias in treatment allocation. A total of 5252 patients were identified (RT alone: n = 1389; ChemoRT: n = 3863). There was increasing utilization of chemotherapy during this period (45-80%, P < .001). A similar trend was also observed for the subset of age >80 (25-68%, P < .001). ChemoRT was associated with significantly better OS than RT alone (HR 0.79, 95% CI 0.70-0.89, P < .001) on multivariate analysis, and similar OS benefit was demonstrated with 1202 pairs of propensity-matched patients (HR 0.79, 95% CI 0.73-0.86, P < .001). For the matched pair, the median OS was 5.8 months with ChemoRT and 5.0 months with RT alone; the 2-year OS rate was 9% with ChemoRT and 4% with RT alone (P < .001). Concurrent chemotherapy has been administered with RT for the majority of elderly GBM patients. Addition of chemotherapy to RT for elderly GBM patients is associated with significantly improve OS in routine clinical practice.

Effects of Race/Ethnicity and Socioeconomic Status on Outcome in Childhood Acute Lymphoblastic Leukemia.

With modern therapy, overall survival (OS) for children with acute lymphoblastic leukemia approaches 90%. However, inferior outcomes for minority children have been reported. Data on the effects of ethnicity/race as it relates to socioeconomic status are limited. Using state cancer registry data from Texas and Florida, we evaluated the impact of neighborhood-level poverty rate and race/ethnicity on OS for 4719 children with acute lymphoblastic leukemia. On multivariable analysis, patients residing in neighborhoods with the highest poverty rate had a 1.8-fold increase in mortality compared with patients residing in neighborhoods with the lowest poverty rate (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.41-2.30). Hispanic and non-Hispanic black patients also had increased risk of mortality compared with non-Hispanic white patients (Hispanic: HR, 1.18; 95% CI, 1.01-1.39; non-Hispanic black: HR, 1.31; 95% CI, 1.03-1.66). On subgroup analysis, there was a 21.7% difference in 5-year OS when comparing non-Hispanic white children living in the lowest poverty neighborhoods (5-year OS, 91.2%; 95% CI, 88.6-93.2) to non-Hispanic black children living in the highest poverty neighborhoods (5-year OS, 69.5%; 95% CI, 61.5-76.1). To address such disparities in survival, further work is needed to identify barriers to cancer care in this pediatric population.

Evidence of high mortality in long term survivors of childhood medulloblastoma.

The diagnosis of pediatric medulloblastoma now carries a much improved overall survival; however as outcomes advance, late mortality, from causes such as disease recurrence and subsequent malignancies, are of increasing concern for these patients. Using the Surveillance, Epidemiology, and End Results database, the causes of late mortality in long term survivors of medulloblastoma were evaluated. Patients diagnosed with a medulloblastoma between the ages of 0-19 years who survived at least 5 years after diagnosis were included. Using U.S. population data, standardized mortality ratios (SMRs) were calculated. Cumulative incidence estimates and standardized incidence ratios (SIRs) of subsequent malignancies were calculated. A total of 455 patients were included in the analysis. All patients received radiation as part of therapy. Median age at diagnosis was 7 years, and mean follow-up was 16 years. By the time of last follow-up, 20.4 % of patients had died, representing an SMR of 24.0 (95 % CI 19.3-29.4). Overall survival at 30 years was 65.5 %. Primary recurrence accounted for 59 % of late deaths, while subsequent malignancy accounted for 11.8 %. SIR for subsequent malignancy in these patients was 10.4 (95 % CI 6.9-15.1). The most common secondary tumor was another brain tumor (32 %), followed by thyroid cancer (21 %). These data demonstrate that late mortality remains a significant problem in these patients. The causes of death are largely attributable to disease recurrence and secondary malignancies. Efforts to improve risk stratification and tailor therapy will help in reducing late mortality in this population.

Subsequent malignancies and their effect on survival in patients with retinoblastoma.

BACKGROUND: As cure rates for retinoblastoma have improved, it is clear that patients with hereditary retinoblastoma experience increased risk of subsequent malignant neoplasms (SMNs). METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database, we evaluated risk of SMNs in survivors or retinoblastoma. Standardized mortality ratios (SMRs) were calculated to compare number of deaths observed to the expected number for the cohort. Cumulative incidence of SMNs and standardized incidence ratios (SIRs) of observed to expected SMNs were calculated RESULTS: A total of 595 patients were included in the analysis. Cumulative incidence of secondary malignancy at 30 years for patients with unilateral and bilateral disease was 1.7% and 28.5%, respectively (P < 0.001). SIRs of subsequent malignancies for patients with unilateral and bilateral disease were 2.1 (95% CI = 0.6-5.4) and 38.3 (95% CI = 24.3-57.5), respectively. Patients with bilateral disease treated with and without radiotherapy both experienced an increased risk of SMNs (SIRs = 45.9, 95% CI = 26.8-73.6 and 27.3, 95% CI = 10.0-59.4, respectively). The most common cause of death for the patients with bilateral disease was subsequent malignancy (52% of deaths). Beginning in the 1990s, there was a significant decrease in the use of radiotherapy as 30.5% of patients received radiotherapy in the 1980s compared to 2.6% after 1999 (P < 0.001). CONCLUSIONS: Survivors of bilateral retinoblastoma experience an increased risk of SMNs which adversely affects survival. The use of radiotherapy in the management of retinoblastoma has declined; however, patients with bilateral disease remain at an increased risk of subsequent cancers.

BRAF V600E mutational status in pediatric thyroid cancer.

BACKGROUND: Clinical outcome of papillary thyroid carcinoma (PTC) in children differs significantly from that of adults. There is no clear explanation of this difference although previous studies have demonstrated a lower prevalence of the BRAF(V600E) mutation in PTC of children. However, data are limited due to the rarity of this diagnosis. BRAF(V600E) mutation prevalence and its relationship with outcome in pediatric PTC remain unclear. PROCEDURE: BRAF(V600E) mutational status was determined in 27 PTC patients less than 22 years of age using restriction fragment length polymorphism (RFLP) analysis. The relationship between BRAF(V600E) mutation status, patient and tumor characteristics as well as progression-free survival (PFS) were analyzed. RESULTS: BRAF(V600E) was present in 63% of patients and occurred more often in male patients versus females (P = 0.033). Presence of the mutation did not correlate with any difference in extent of disease at diagnosis, tumor size, capsular invasion, vascular invasion, soft tissue invasion, or margin status. At 10 years, PFS for BRAF(V600E) positive versus negative patients was 55.5% versus 70.0%, respectively (P = 0.48). Overall survival was 100% and median follow-up was 13.9 years. CONCLUSIONS: This study of pediatric PTC demonstrates that BRAF(V600E) mutations occur in children at a rate comparable to adults. We found a correlation of BRAF(V600E) with the male gender, but no evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that differences in disease course of PTC in children versus adults are not strongly dependent upon the presence of the BRAF(V600E) mutation.

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.

Novel roles for A-type lamins in telomere biology and the DNA damage response pathway.

A-type lamins are intermediate filament proteins that provide a scaffold for protein complexes regulating nuclear structure and function. Mutations in the LMNA gene are linked to a variety of degenerative disorders termed laminopathies, whereas changes in the expression of lamins are associated with tumourigenesis. The molecular pathways affected by alterations of A-type lamins and how they contribute to disease are poorly understood. Here, we show that A-type lamins have a key role in the maintenance of telomere structure, length and function, and in the stabilization of 53BP1, a component of the DNA damage response (DDR) pathway. Loss of A-type lamins alters the nuclear distribution of telomeres and results in telomere shortening, defects in telomeric heterochromatin, and increased genomic instability. In addition, A-type lamins are necessary for the processing of dysfunctional telomeres by non-homologous end joining, putatively through stabilization of 53BP1. This study shows new functions for A-type lamins in the maintenance of genomic integrity, and suggests that alterations of telomere biology and defects in DDR contribute to the pathogenesis of lamin-related diseases.

Late causes of death in children treated for CNS malignancies.

As the outcome for pediatric central nervous system (CNS) malignancies improves, data regarding long term effects and risk of early mortality are needed. Using the Surveillance, Epidemiology, and End Results database, we evaluated the causes of mortality in 5-year survivors of a CNS tumor diagnosed prior to the age of 20 years. Using United States population data, standardized mortality ratios (SMRs) were calculated to compare number of deaths observed to the expected number for the cohort. Cumulative incidence of subsequent malignant neoplasms (SMNs) and standardized incidence ratios of observed to expected SMNs were calculated. 3,627 patients were included in the study. 20-year overall survival (OS) was 85.7 % compared to an expected rate of 98.5 % (p < 0.001). Death from the primary brain tumor accounted for 51 % of deaths, while death from a SMN accounted for 10 % of deaths. Patients were at an increased risk of death due to cardiovascular and cerebrovascular disease (SMRs = 2.5, 95 % confidence interval (CI) 1.2-4.8 and 7.9, 2.6-19.0, respectively). Cumulative incidence of SMN at 30 years was 6.4 % (95 % CI 4.8-7.7). Patients treated after 1986 enjoyed a small improvement in mortality (20-year OS 86.5 vs 83.8 %, p = 0.005). Five-year survivors of a childhood CNS tumor experienced a nearly 13-fold increased risk of death compared to their peers. Patients were at an increased risk of death due to recurrent disease, SMNs, cerebrovascular and cardiovascular events.

Treatment approach and outcomes of vaginal melanoma.

OBJECTIVE: To describe the characteristics of primary vaginal melanoma patients in the Surveillance, Epidemiology, and End Result database and to determine the outcome from the treatment approaches. MATERIALS/METHODS: From the Surveillance, Epidemiology, and End Result registry, 201 patients with vaginal melanoma were identified. Patients' characteristics and prognostic factors including age, race, extent of surgery, and use of radiation therapy were obtained. RESULTS: The median age was 68 years (range, 28-100 years). The population was 73% white, 11% black, and 16% Asian/American Indian. International Federation of Gynecology and Obstetrics staging results were stage I (46%), stage II (18%), stage III (3%), stage IVA (3%), stage IVB (12%), and unknown (18%). Treatment approach included surgical resection of the primary site in 70%, whereas 35% of the patients underwent lymph node resection. Approximately 40% of the patients received radiotherapy, which was primarily used in the adjuvant setting. Overall survival at 2 and 5 years was 24% and 15%, respectively. Presence of lymph nodes at diagnosis was associated with worse overall survival (hazard ratio, 1.98; P = 0.02). Adjuvant radiation did not offer a statistically significant overall survival advantage compared to surgery alone. CONCLUSIONS: Vaginal melanoma is a rare diagnosis primarily affecting the elderly. Overall survival is low even for patients presenting with disease limited to the vagina. Lymph node involvement at diagnosis is strongly predictive of worse overall survival. Most patients are treated with surgical resection with varying use of adjuvant radiotherapy. Further research is needed to identify the etiology and improve the outcome of this aggressive disease.

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.

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.

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.

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.

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.