Assessment of Social Vulnerability in Pediatric Head and Neck Cancer Care and Prognosis in the United States.

Importance: Prior investigations in social determinants of health (SDoH) in pediatric head and neck cancer (HNC) have only considered a narrow scope of HNCs, SDoH, and geography while lacking inquiry into the interrelational association of SDoH with disparities in clinical pediatric HNC. Objectives: To evaluate the association of SDoH with disparities in HNC among children and adolescents and to assess which specific aspects of SDoH are most associated with disparities in dynamic and regional sociodemographic contexts. Design, Setting, and Participants: This retrospective cohort study included data about patients (aged ≤19 years) with pediatric HNC who were diagnosed from 1975 to 2017 from the Surveillance, Epidemiology, and End Results Program (SEER) database. Data were analyzed from October 2021 to October 2022. Exposures: Overall social vulnerability and its subcomponent contributions from 15 SDoH variables, grouped into socioeconomic status (SES; poverty, unemployment, income level, and high school diploma status), minority and language status (ML; minoritized racial and ethnic group and proficiency with English), household composition (HH; household members aged ≥65 and ≤17 years, disability status, single-parent status), and housing and transportation (HT; multiunit structure, mobile homes, crowding, no vehicle, group quarters). These were ranked and scored across all US counties. Main Outcomes and Measures: Regression trends were performed in continuous measures of surveillance and survival period and in discrete measures of advanced staging and surgery receipt. Results: A total of 37 043 patients (20 729 [55.9%] aged 10-19 years; 18 603 [50.2%] male patients; 22 430 [60.6%] White patients) with 30 different HNCs in SEER had significant relative decreases in the surveillance period, ranging from 23.9% for malignant melanomas (mean [SD] duration, lowest vs highest vulnerability: 170 [128] months to 129 [88] months) to 41.9% for non-Hodgkin lymphomas (mean [SD] duration, lowest vs highest vulnerability: 216 [142] months vs 127 [94] months). SES followed by ML and HT vulnerabilities were associated with these overall trends per relative-difference magnitudes (eg, SES for ependymomas and choroid plexus tumors: mean [SD] duration, lowest vs highest vulnerability: 114 [113] months vs 86 [84] months; P < .001). Differences in mean survival time were observed with increasing social vulnerability, ranging from 11.3% for ependymomas and choroid plexus tumors (mean [SD] survival, lowest vs highest vulnerability: 46 [46] months to 41 [48] months; P = .43) to 61.4% for gliomas not otherwise specified (NOS) (mean [SD] survival, lowest vs highest vulnerability: 44 [84] months to 17 [28] months; P < .001), with ML vulnerability followed by SES, HH, and HT being significantly associated with decreased survival (eg, ML for gliomas NOS: mean [SD] survival, lowest vs highest vulnerability: 42 [84] months vs 19 [35] months; P < .001). Increased odds of advanced staging with non-Hodgkin lymphoma (OR, 1.21; 95% CI, 1.02-1.45) and retinoblastomas (OR, 1.31; 95% CI, 1.14-1.50) and decreased odds of surgery receipt for melanomas (OR, 0.79; 95% CI, 0.69-0.91) and rhabdomyosarcomas (OR, 0.90; 95% CI, 0.83-0.98) were associated with increasing overall social vulnerability. Conclusions and Relevance: In this cohort study of patients with pediatric HNC, significant decreases in receipt of care and survival time were observed with increasing SDoH vulnerability.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Ependimomas intracraneales pediátricos: Si el objetivo es la curación, ¿cuál es el verdadero costo? / Pediatric Intracranial Ependymomas: If the Goal Is Cure, What Is the True Cost?

Introducción: Para caracterizar mejor la morbilidad neurológica después de una cirugía de resección máxima seguida de radioterapia en niños con ependimoma infratentorial, decidimos estudiar el estado neurológico prequirúrgico y compararlo con las evaluaciones postoperatorias a corto y largo plazo. Al mismo tiempo realizamos un estudio de sobrevida libre de progresión (SLP) tumoral para conocer qué factores tienen mayor impacto en el pronóstico de este tipo de lesiones. Métodos: Se realizó un estudio de cohorte retrospectivo donde se incluyeron todos los pacientes pediátricos con diagnóstico de ependimoma infratentorial. Se identificaron los distintos factores de riesgo y se observó cómo evolucionaron en el tiempo. Los pacientes se siguieron por un mínimo de 24 meses para el análisis de supervivencia. Resultados: Se analizaron 26 pacientes pediátricos con ependimomas de fosa posterior entre 2008-2019. Encontramos una diferencia estadísticamente significativa entre el FSS (Escala funcional neurológica) prequirúrgico y el FSS postoperatorio inmediato (p=0.03), sin embargo esta diferencia se pierde cuando comparamos el prequirúrgico con el FSS posterior al año (p=0.07).La exéresis total de la lesión tiene un efecto protector en la SLP tumoral (p=0.02), mientras que haber requerido más de 3 cirugías afecta negativamente la SLP tumoral (p=0.04), al igual que la localización lateralizada del tumor (p=0.04). Conclusión: La exéresis completa de los ependimomas de fosa posterior continúa siendo el factor pronóstico más importante para la sobrevida libre de progresión tumoral. El deterioro neurológico inmediato producido a causa del procedimiento quirúrgico parecería mejorar en la evaluación a largo plazo.

Introduction: To better characterize the neurological morbidity after maximal resection surgery followed by radiotherapy in children with infratentorial ependymoma, we decided to study the preoperative neurological status and compare it with short and long-term postoperative evaluations. At the same time, we conducted a tumor progression-free survival (PFS) study to find out which factors have the greatest impact on the prognosis of this type of injury. Methods: A retrospective cohort study was carried out in which all pediatric patients with a diagnosis of infratentorial ependymoma were included. The different risk factors were identified and it was observed how they evolved over time. Patients were followed for a minimum of 24 months for survival analysis. Results: 26 pediatric patients with posterior fossa ependymomas were analyzed between 2008-2019. We found a statistically significant difference between the presurgical FSS (Functional Status Scale) and the immediate postoperative FSS (p = 0.03), however this difference is lost when we compare the presurgical with the FSS after one year (p = 0.07).Total excision of the lesion has a protective effect on tumor PFS (p = 0.02), while having required more than 3 surgeries negatively affects tumor PFS (p = 0.04), as does the lateralized location of the tumor (p = 0.04). Conclusion: Complete excision of posterior fossa ependymomas continues to be the most important prognostic factor for tumor progression-free survival. The immediate neurological deterioration produced by the surgical procedure would appear to improve on the long-term evaluation

A coordinated approach for the assessment of molecular subgroups in pediatric ependymomas using low-cost methods.

Although ependymoma (EPN) molecular subgroups have been well established by integrated high-throughput platforms, low- and middle-income countries still need low-cost techniques to promptly classify these molecular subtypes. Here, we applied low-cost methods to classify EPNs from a Brazilian cohort with 60 pediatric EPN patients. Fusion transcripts (C11orf95-RELA, YAP1-MAMLD1, and YAP1-FAM118B) were investigated in supratentorial EPN (ST-EPNs) samples through RT-PCR/Sanger sequencing and immunohistochemistry (IHC) for p65/L1CAM. qRT-PCR and IHC were used to evaluate expression profiling of CXorf67, LAMA2, NELL2, and H3K27me3 in posterior fossa EPN (PF-EPNs) samples. In silico analysis was performed using public microarray data to validate the molecular assignment PF-EPNs with LAMA2/NELL2 markers. RELA cases and YAP1-MAMLD1 fusions were identified in nine and four ST-EPNs, respectively. An additional RELA case was identified by IHC. Of note, LAMA2 and NELL2 gene expression and immunoprofiling were less accurate for classifying PF-EPNs, which were confirmed by in silico analysis. Yet, H3K27me3 staining was sufficient to classify PF-EPN subgroups. Our results emphasize the feasibility of a simplified strategy to molecularly classify EPNs in the vast majority of cases (49/60; 81.7%). A coordinated combination of simple methods can be effective to screen pediatric EPN with the available laboratory resources at most low-/mid-income countries, giving support for clinical practice in pediatric EPN. KEY MESSAGES: Low- and middle-income countries need effective low-cost approaches to promptly distinguish between EPN molecular subgroups. RT-PCR plus Sanger sequencing is able to recognize the most common types of RELA and YAP1 fusion transcripts in ST-EPNs. Genetic and protein expressions of LAMA2 and NELL2 are of limited value to accurately stratify PF-EPNs. Immunohistochemical staining for H3K27me3 may be used as a robust method to accurately diagnose PF-EPNs subgroups. A coordinated flow diagram based on these validated low-cost methods is proposed to help clinical-decision making and to reduce costs with NGS assessment outside research protocols.

Proton beam therapy utilization in adults with primary brain tumors in the United States.

The utilization of proton beam therapy (PBT) as the primary treatment of adults with primary brain tumors (APBT) was evaluated through query of the National Cancer Database (NCDB) between the years 2004 and 2015. International Classification of Diseases for Oncology code for each patient was stratified into six histology categories; high-grade gliomas, medulloblastomas, ependymomas, other gliomas, other malignant tumors, or other benign intracranial tumors. Demographics of the treatment population were also analyzed. A total of 1,296 patients received PBT during the 11-year interval for treatment of their primary brain tumor. High-grade glioma, medulloblastoma, ependymoma, other glioma, other malignant, and other benign intracranial histologies made up 39%, 20%, 13%, 12%, 13%, and 2% of the cohort, respectively. The number of patients treated per year increased from 34 to 300 in years 2004 to 2015. Histologies treated with PBT varied over the 11-year interval with high-grade gliomas comprising 75% and 45% at years 2004 and 2015, respectively. The majority of the patient population was 18-29 years of age (59%), Caucasian race (73%), had median reported income of over $63,000 (46%), were privately insured (68%), and were treated at an academic institution (70%). This study characterizes trends of malignant and benign APBT histologies treated with PBT. Our data from 2004 through 2015 illustrates a marked increase in the utilization of PBT in the treatment of APBT and shows variability in the tumor histology treated over this time.

Quantitative assessment and clinical relevance of VEGFRs-positive tumor cells in refractory brain tumors.

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-ß and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.

Monte Carlo study of out-of-field exposure in carbon-ion radiotherapy: Organ doses in pediatric brain tumor treatment.

PURPOSE: To estimate out-of-field doses during carbon-ion radiotherapy (CIRT) for pediatric cerebellar ependymoma. METHODS: Given that the out-of-field dose of CIRT depends on beam parameters, we set them for treatment of typical pediatric cerebellar ependymoma based on a previous study. The out-of-field dose during CIRT for pediatric cerebellar ependymoma was then estimated using the Particle and Heavy-Ion Transport code System with Monte Carlo simulations and a computational phantom developed at the University of Florida. From the simulation results, out-of-field doses at dose equivalents of passive beam and active scanning beam CIRT were calculated and compared to the secondary neutron-equivalent dose of passive beam CIRT and proton therapy. RESULTS: The out-of-field dose equivalent decreases from 1.45 mSv/Gy (relative biological effectiveness - RBE) at the thyroid to 0.06 mSv/Gy (RBE) at the bladder, verifying decay as the distance from the treatment target increases. The out-of-field neutron-equivalent dose in organs per prescribed dose for passive beam CIRT is lower than that for passive beam proton therapy. Moreover, the out-of-field organ dose equivalent per prescribed dose for the active scanning beam CIRT is lower than that for the passive beam CIRT. CONCLUSIONS: Active scanning beam CIRT is promising for pediatric cerebellar ependymoma regarding out-of-field exposure, outperforming the comparison radiotherapy modalities.

Review of ependymomas: assessment of consensus in pathological diagnosis and correlations with genetic profiles and outcome.

We focused on histological and immunohistochemical characteristics of ependymoma (EPN) with molecular profiles to develop more reproducible criteria of the diagnosis. Three expert neuropathologists reviewed the pathology of 130 samples from the Japan Pediatric Molecular Neuro-Oncology Group study. Confirmed cases were assessed for histology, surrogate markers, molecular subgrouping, and survival data. We reached a consensus regarding the diagnosis of EPNs in 100% of spinal cord tumors and 93% of posterior fossa (PF) tumors that had been diagnosed as EPNs by local pathologists, whereas we reached a consensus regarding only 77% of the local diagnosis of supratentorial (ST) EPNs. Among the PF-EPNs, most of anaplastic ependymomas (AEPNs) were defined as EPN-A by methylation profiling, which was significantly correlated with the subgroup assignment. Regarding prognosis, the overall survival of patients with PF-EPN was significantly better than that of patients with PF AEPN (p = 0.01). Histologically, all ependymoma, RELA fusion-positive (EPN-RELA) qualified as Grade III. Both L1 cell adhesion molecule and nuclear factor kappaB p65 antibodies showed good sensitivity for detecting EPN-RELA. This study indicated that the expert consensus pathological diagnosis could correlate well with the molecular classifications in EPNs. ST EPNs should be diagnosed more carefully by histological and molecular analyses.

Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost.

BACKGROUND: Posterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors' knowledge, the long-term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years. METHODS: Demographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome-wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3). RESULTS: A total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10-year progression-free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%-53.1%). Analysis of consecutive 10-year epochs revealed significant improvements in progression-free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full-scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (-1.33 ± 0.42 points/year; P = .0042). CONCLUSIONS: Data from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors' knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time.

Can differences in linear energy transfer and thus relative biological effectiveness compromise the dosimetric advantage of intensity-modulated proton therapy as compared to passively scattered proton therapy?

PURPOSE: To investigate the effect of differences in linear energy transfer (LET) and thus the relative biological effectiveness (RBE) between passively scattered proton therapy (PS) and pencil-beam scanning intensity-modulated proton therapy (IMPT). METHODS: IMPT treatment plans were generated for six ependymoma patients, originally treated with PS, using the original plan's computed tomography image sets and beam directions, and its dose-volume values as optimization constraints. Two beam spot sizes and both single-field optimization (SFO) and multi-field optimization (MFO) techniques were used for each patient. Three-dimensional variable-RBE-weighted dose distributions were computed, using Monte Carlo calculated dose and LET distributions, and a linear dose and LET-based RBE model, and were compared between the two delivery methods. RESULTS: Increased target dose coverage and decreased mean and maximum dose to the OARs was achieved with IMPT compared to PS, for constant RBE value of 1.1. Nevertheless, the maximum variable-RBE-weighted dose to the brainstem, was increased up to 6% for the IMPT plans compared to the corresponding PS plans. CONCLUSIONS: IMPT can be dosimetrically superior to PS for ependymoma patients. However, caution should be exercised so that the increased dose conformity is not counteracted by an increase in radiobiological effect in adjacent critical structures.

Socioeconomic factors affect the selection of proton radiation therapy for children.

BACKGROUND: Proton radiotherapy remains a limited resource despite its clear potential for reducing radiation doses to normal tissues and late effects in children in comparison with photon therapy. This study examined the impact of race and socioeconomic factors on the use of proton therapy in children with solid malignancies. METHODS: This study evaluated 12,101 children (age ≤ 21 years) in the National Cancer Data Base who had been diagnosed with a solid malignancy between 2004 and 2013 and had received photon- or proton-based radiotherapy. Logistic regression analysis was used to evaluate patient, tumor, and socioeconomic variables affecting treatment with proton radiotherapy versus photon radiotherapy. RESULTS: Eight percent of the patients in the entire cohort received proton radiotherapy, and this proportion increased between 2004 (1.7%) and 2013 (17.5%). Proton therapy was more frequently used in younger patients (age ≤ 10 years; odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.2) and in patients with bone/joint primaries and ependymoma, medulloblastoma, and rhabdomyosarcoma histologies (P < .05). Patients with metastatic disease were less likely to receive proton therapy (OR, 0.4; 95% CI, 0.3-0.6). Patients with private/managed care were more likely than patients with Medicaid or no insurance to receive proton therapy (P < .0001). A higher median household income and educational attainment were also associated with increased proton use (P < .001). Patients treated with proton therapy versus photon therapy were more likely to travel more than 200 miles (13% vs 5%; P < .0001). CONCLUSIONS: Socioeconomic factors affect the use of proton radiotherapy in children. Whether this disparity is related to differences in the referral patterns, the knowledge of treatment modalities, or the ability to travel for therapy needs to be further clarified. Improving access to proton therapy in underserved pediatric populations is essential. Cancer 2017;123:4048-56. © 2017 American Cancer Society.

Proton Treatment Techniques for Posterior Fossa Tumors: Consequences for Linear Energy Transfer and Dose-Volume Parameters for the Brainstem and Organs at Risk.

PURPOSE: In proton therapy of posterior fossa tumors, at least partial inclusion of the brainstem in the target is necessary because of its proximity to the tumor and required margins. Additionally, the preferred beam geometry results in directing the field distal edge toward this critical structure, raising concerns for brainstem toxicity. Some treatment techniques place the beam's distal edge within the brainstem (dose-sparing techniques), and others avoid elevated linear energy transfer (LET) of the proton field by placing the distal edge beyond it (LET-sparing techniques). Hybrid approaches are also being used. We examine the dosimetric efficacy of these techniques, accounting for LET-dependent and dose-dependent variable relative biologic effectiveness (RBE) distributions. METHODS: Six techniques were applied in ependymoma cases: (a) 3-field dose-sparing; (b) 3-field LET-sparing; (c) 2-field dose-sparing, wide angles; (d) 2-field LET-sparing, wide angles; (e) 2-field LET-sparing, steep angles; and (f) 2-field LET-sparing with feathered distal end. Monte Carlo calculated dose, LET, and RBE-weighted dose distributions were compared. RESULTS: Decreased LET values in the brainstem by LET-sparing techniques were accompanied by higher, not statistically significant, median dose: 53.6 Gy(RBE), 53.4 Gy(RBE), and 54.3 Gy(RBE) for techniques (b), (d), and (e) versus 52.1 Gy(RBE) for technique (a). Accounting for variable RBE distributions, the brainstem volume receiving at least 55 Gy(RBE) increased from 72.5% for technique (a) to 80.3% for (b) (P<.01) and from 70.7% for technique (c) to 77.6% for (d) (P<.01). Less than 2%, but statistically significant, decrease in maximum variable RBE-weighted brainstem dose was observed for the LET-sparing techniques compared with the corresponding dose-sparing (P=.03 and .004). CONCLUSIONS: Extending the proton range beyond the brainstem to reduce LET results in clinically comparable maximum radiobiologic effective dose to this sensitive structure. However this method significantly increasing the brainstem volume receiving RBE-weighted dose higher than 55 Gy(RBE) with possible consequences based on known dose-volume parameters for increased toxicity.

Reoptimization of Intensity Modulated Proton Therapy Plans Based on Linear Energy Transfer.

PURPOSE: We describe a treatment plan optimization method for intensity modulated proton therapy (IMPT) that avoids high values of linear energy transfer (LET) in critical structures located within or near the target volume while limiting degradation of the best possible physical dose distribution. METHODS AND MATERIALS: To allow fast optimization based on dose and LET, a GPU-based Monte Carlo code was extended to provide dose-averaged LET in addition to dose for all pencil beams. After optimizing an initial IMPT plan based on physical dose, a prioritized optimization scheme is used to modify the LET distribution while constraining the physical dose objectives to values close to the initial plan. The LET optimization step is performed based on objective functions evaluated for the product of LET and physical dose (LET×D). To first approximation, LET×D represents a measure of the additional biological dose that is caused by high LET. RESULTS: The method is effective for treatments where serial critical structures with maximum dose constraints are located within or near the target. We report on 5 patients with intracranial tumors (high-grade meningiomas, base-of-skull chordomas, ependymomas) in whom the target volume overlaps with the brainstem and optic structures. In all cases, high LET×D in critical structures could be avoided while minimally compromising physical dose planning objectives. CONCLUSION: LET-based reoptimization of IMPT plans represents a pragmatic approach to bridge the gap between purely physical dose-based and relative biological effectiveness (RBE)-based planning. The method makes IMPT treatments safer by mitigating a potentially increased risk of side effects resulting from elevated RBE of proton beams near the end of range.

Clinical evidence of variable proton biological effectiveness in pediatric patients treated for ependymoma.

BACKGROUND AND PURPOSE: A constant relative biological effectiveness (RBE) is used for clinical proton therapy; however, experimental evidence indicates that RBE can vary. We analyzed pediatric ependymoma patients who received proton therapy to determine if areas of normal tissue damage indicated by post-treatment image changes were associated with increased biological dose effectiveness. MATERIAL AND METHODS: Fourteen of 34 children showed T2-FLAIR hyperintensity on post-treatment magnetic resonance (MR) images. We delineated regions of treatment-related change and calculated dose and linear energy transfer (LET) distributions with Monte Carlo. Voxel-level image change data were fit to a generalized linear model incorporating dose and LET. Cross-validation was used to determine model parameters and for receiver operating characteristic curve analysis. Tolerance dose (TD50; dose at which 50% of patients would experience toxicity) was interpolated from the model. RESULTS: Image changes showed dependence on increasing LET and dose. TD50 decreased with increasing LET, indicating an increase in biological dose effectiveness. The cross-validated area under the curve for the model was 0.91 (95% confidence interval 0.88-0.94). CONCLUSIONS: Our correlation of changes on MR images after proton therapy with increased LET constitutes the first clinical evidence of variable proton biological effectiveness.

Symptoms and socio-economic impact of ependymoma on adult patients: results of the Adult Ependymoma Outcomes Project 2.

Ependymoma is a rare central nervous system tumor of adults. Reports of patient symptoms, interference patterns and costs encountered by patients and families are limited. Adult ependymoma patients completed the online Ependymoma Outcomes Questionnaire II. The survey assesses disease and functional status as well as socio-economic factors. Descriptive statistics were used to report disease characteristics as well as economic and social impact. Independent samples t test was used to test if differences exist between high- and low-income groups in terms of symptom severity. Correlations were calculated between symptoms and cost estimates. 86 international patients participated (male = 50 %). The economic analysis focused on 78 respondents from the US. 48 % were employed and 55 % earned ≥$60,000. Tumors were located in the brain (44 %), spine (44 %) or both (12 %). Spine patients compared to brain patients reported significantly worse pain (4.4 versus 2.2, p < .003), numbness (5.3 versus 2.2, p < .001), fatigue (5.1 versus 3.6, p < .03), changes in bowel patterns (3.8 versus 1.4, p < .003) and weakness (4.2 versus 2.1, p < .006). Brain patients compared with spine patients had increased lack of appetite (.4 versus 2, p < .014). Patients with lower income (≤$59,999) had more problems concentrating (p < .024) and worse cognitive module severity scores (p < .024). Estimated average monthly out-of-pocket spending was $168 for medical co-pays and $59 for prescription medication. Patients with ependymoma are highly affected by their symptoms. Spinal patients report higher severity of symptoms. Patients in the lower income group report significantly higher severity of cognitive symptoms independent of disease site.

The use of proton therapy in the treatment of benign or low-grade pediatric brain tumors.

Radiation therapy (RT) plays a critical role in the local tumor control of benign and low-grade central nervous system tumors in children but is not without the risk of long-term treatment-related sequelae. Proton therapy (PRT) is an advanced RT modality with a unique dose-deposition pattern that allows for treatment of a target volume with reduced scatter dose delivered to normal tissues compared with conventional photon RT and is now increasingly utilized in children with the hope of mitigating radiation-induced late effects. This article reviews the current literature evaluating the use of PRT in benign and low-grade pediatric central nervous system tumors such as low-grade glioma, craniopharyngioma, and ependymoma. Multiple dosimetric studies support the use of PRT by demonstrating the ability of PRT to better spare critical structures important for cognitive development, endocrine function, and hearing preservation and to reduce the total body dose associated with second malignancy risk. Early clinical data demonstrate that PRT is well tolerated with rates of local tumor control comparable to conventional photon RT series, and long-term clinical data are awaited.

Proton therapy dose distribution comparison between Monte Carlo and a treatment planning system for pediatric patients with ependymoma.

PURPOSE: Compare dose distributions for pediatric patients with ependymoma calculated using a Monte Carlo (MC) system and a clinical treatment planning system (TPS). METHODS: Plans from ten pediatric patients with ependymoma treated using double scatter proton therapy were exported from the TPS and calculated in our MC system. A field by field comparison of the distal edge (80% and 20%), distal fall off (80% to 20%), field width (50% to 50%), and penumbra (80% to 20%) were examined. In addition, the target dose for the full plan was compared. RESULTS: For the 32 fields from the 10 patients, the average differences of distal edge at 80% and 20% on central axis between MC and TPS are -1.9 ± 1.7 mm (p < 0.001) and -0.6 ± 2.3 mm (p = 0.13), respectively. Excluding the fields that ranged out in bone or an air cavity, the 80% difference was -0.9 ± 1.7 mm (p = 0.09). The negative value indicates that MC was on average shallower than TPS. The average difference of the 63 field widths of the 10 patients is -0.7 ± 1.0 mm (p < 0.001), negative indicating on average the MC had a smaller field width. On average, the difference in the penumbra was 2.3 ± 2.1 mm (p < 0.001). The average of the mean clinical target volume dose differences is -1.8% (p = 0.001), negative indicating a lower dose for MC. CONCLUSIONS: Overall, the MC system and TPS gave similar results for field width, the 20% distal edge, and the target coverage. For the 80% distal edge and lateral penumbra, there was slight disagreement; however, the difference was less than 2 mm and occurred primarily in highly heterogeneous areas. These differences highlight that the TPS dose calculation cannot be automatically regarded as correct.

Kilovoltage imaging doses in the radiotherapy of pediatric cancer patients.

PURPOSE: To investigate doses induced by kilovoltage cone-beam computed tomography (kVCBCT) to pediatric cancer patients undergoing radiotherapy, as well as strategies for dose reduction. METHODS AND MATERIALS: An EGS4 Monte Carlo code was used to calculate three-dimensional dose deposition due to kVCBCT on 4 pediatric cancer patients. Absorbed doses to various organs were analyzed for both half-fan and full-fan modes. Clinical conditions, such as distance from organ at risk (OAR) to CBCT field border, kV peak energy, and testicular shielding, were studied. RESULTS: The mean doses induced by one CBCT scan operated at 125 kV in half-fan mode to testes, liver, kidneys, femoral heads, spinal cord, brain, eyes, lens, and optical nerves were 2.9, 4.7, 7.7, 10.5, 8.8, 7.6, 7.7, 7.8, and 7.2 cGy, respectively. Increasing the distances from OARs to CBCT field border greatly reduced the doses to OARs, ranging from 33% reduction for spinal cord to 2300% reduction for testes. As photon beam energy increased from 60 to 125 kV, the dose increase due to kVCBCT ranged from 170% for lens to 460% for brain and spinal cord. A testicular shielding made of 1-cm cerrobend could reduce CBCT doses down to 31%, 51%, 68%, and 82%, respectively, for 60, 80, 100, and 125 kV when the testes lay within the CBCT field. CONCLUSIONS: Generally speaking, kVCBCT deposits much larger doses to critical structures in children than in adults, usually by a factor of 2 to 3. Increasing the distances from OARs to CBCT field border greatly reduces doses to OARs. Depending on OARs, kVCBCT-induced doses increase linearly or exponentially with photon beam energy. Testicular shielding works more efficiently at lower kV energies. On the basis of our study, it is essential to choose an appropriate scanning protocol when kVCBCT is applied to pediatric cancer patients routinely.

Ependymomas of the central nervous system and adult extra-axial ependymomas are morphologically and immunohistochemically distinct--a comparative study with assessment of ovarian carcinomas for expression of glial fibrillary acidic protein.

Extra-axial ependymomas are very rare but have been reported in the ovary, broad ligament, sacrococcygeal region, lung, and mediastinum. The histogenesis is obscure, and a thorough immunohistochemical analysis is lacking. We reviewed the morphologic and immunohistochemical features of 5 extra-axial ependymomas occurring in adults, 1 arising in an infantile sacrococcygeal teratoma, and a control group of 10 central nervous system (CNS) ependymomas in adults. All cases were evaluated for expression of epithelial membrane antigen, estrogen receptor (ER), progesterone receptor (PR), WT1, CD99, CK18, AE1:3, CAM 5.2, 34betaE12, CK7, CK20, synaptophysin, chromogranin, and glial fibrillary acidic protein (GFAP) using formalin-fixed, paraffin-embedded tissue. One hundred twelve ovarian carcinomas in 3 tissue microarrays were also studied with GFAP. The adult extra-axial cases demonstrated more architectural variability than the CNS cases. We observed that both the CNS and adult extra-axial ependymomas expressed GFAP diffusely, whereas only 9 stage III, high-grade ovarian serous papillary carcinomas stained with GFAP (2 strongly and diffusely and 7 exhibiting focally weak expression). There were significant immunophenotypic differences between adult extra-axial and CNS ependymomas, with extra-axial cases preferentially expressing 34betaE12 (60% vs. 0%), CK18 (100% vs. 20%), CAM 5.2 (60% vs. 10%), CK7 (80% vs. 10%), ER (100% vs. 10%), and PR (80% vs. 20%). Two spinal cord ependymomas expressed CK18, 1 expressed CK7, and 1 expressed CAM 5.2. CNS ependymomas more frequently expressed CD99 (100% vs. 20%). The following stains were not differentially expressed: epithelial membrane antigen (expressed in 2 of 15 cases, including both extra-axial and CNS ependymomas), synaptophysin (1/15), chromogranin (0/15), WT1 (8/15), AE1:3 (10/15), and CK20 (0/15). The ependymal elements of the sacrococcygeal tumor failed to express 34betaE12, CK18, CAM 5.2, and CK7, like most CNS ependymomas. The morphologic and immunophenotypic differences between extra-axial and CNS ependymomas suggest that they derive from distinct precursors and/or differentiate along distinct pathways. The differential diagnosis of extra-axial ependymomas is extensive, and GFAP expression in primary ovarian serous carcinomas, although rare, could theoretically contribute to diagnostic difficulties. ER and PR expression in extra-axial ependymomas may provide targets for hormonal therapy.