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Opinion Statement: As the peak incidence of isocitrate dehydrogenase (IDH)-mutant gliomas is amongst young adults, there is a need to balance tumor control with long term side effects of therapy. Following initial clinical presentation and acquisition of contrasted diagnostic imaging, tissue diagnosis is essential in suspected diffuse glioma. Depending on the location and extent of disease, maximal surgical resection is preferred both for histologic diagnosis and initial therapy. Partial resection or biopsy alone is considered when the tumor cannot be completely resected or if there are clinical reservations regarding a more significant operation. The classification of diffuse glioma has evolved over time, with histopathology and molecular marker status guiding discussions of prognosis and postoperative management. In patients with IDH-mutant grade 2 glioma and low-risk features, observation with active surveillance is generally recommended following a gross total resection. For those with high-risk features, which historically included age > 40 years or subtotal resection, adjuvant chemotherapy and radiation therapy are generally recommended, however decisions for adjuvant therapy pose challenges as many of the landmark historical trials guiding adjuvant therapy were performed prior to the molecularly defined era. This is an area where multiple clinical trials are ongoing and hold promise to inform treatment paradigms, including recent data on the use of IDH-mutant inhibitors in grade 2 tumors with recurrent or residual disease. For IDH-mutant grade 3 and 4 glioma, adjuvant chemotherapy and radiation are recommended for all patients after initial resection., Competing Interests: Declarations. Competing Interests: Sasha Swensen has nothing to disclose and declares no conflicts of interest. Karl Cristie Figuracion received a grant or contract from the National Institute of Health (Biobehavioral Cancer Prevention and Control Post-Doctoral Research Training). Vyshak Venur has nothing to disclose and declares no conflicts of interest. Samuel Emerson has nothing to disclose and declares no conflicts of interest. Yolanda Tseng has nothing to disclose and declares no conflicts of interest. Simon Lo receives research funding from the Kuni Foundation and from Hutchinson Center as Lead Academic Participating Site (UG1 CA 233328), has received support for meeting and travel attendance for JASTRO, and serves in leadership for the Radiosurgical Society (Member of Board Directors and Medical Director of Distinction in Practice in Stereotactic Radiotherapy Program) and for the American College of Radiology (Assistant Councilor and Chair of CARROS Nominating Committee). Ralph Ermoian has nothing to disclose and declares no conflicts of interest. Lia Halasz reports grants from Biomimetix outside the submitted work. Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Pediatric acute myeloid leukemia (AML) often involves extramedullary sites, which can be resistant to standard induction chemotherapy. Consolidative radiation therapy can be used in select cases to improve local control rates and help bridge patients to curative stem cell transplants. However, there is no previously published data to support the use of proton radiotherapy (PT) in this setting. We present radiographic findings and pathologic outcomes of the first reported patient with extramedullary ocular AML to be treated with PT., Patients and Methods: Details regarding diagnostic evaluation and treatment were obtained from the electronic medical records at the University of Florida Proton Therapy Institute, Nemours Children's Health, and St. Joseph's Children's Hospital., Results: This 7-month-old patient presented with biopsy-proven relapsed AML in the bilateral anterior chambers of the eyes, which did not resolve with induction chemotherapy. The patient then received PT to a dose of 24 cobalt gray equivalent to both eyes and was found to have no evidence of disease following treatment., Conclusion: This case provides further evidence that consolidative radiotherapy may be considered for select patients with extramedullary AML who have limited response to induction chemotherapy. Given the increased prevalence of extramedullary AML in pediatric patients, it is worth considering the utilization of PT to mitigate damage to nearby organs and the risk of secondary malignancies., Competing Interests: All authors report no conflict of interest., (© 2024 The Authors.)

Background and Objective: The use of radiotherapy (RT) in the palliative and emergent settings for pediatric cancers is an under-utilized resource. Our objective was to provide an evidence-based review of the data to increase awareness of the benefit for this population along with providing guidance on pediatric specific treatment considerations for palliative care physicians, pediatric oncologists, and radiation oncologists., Methods: A narrative review was performed querying PubMed, MEDLINE, ClinicalTrials.gov databases, and supplemented with review articles, survey studies, current and recent clinical trials. When limited data existed, well-designed retrospective and prospective studies in the adult setting were evaluated and expert opinion was provided from pediatric oncologists., Key Content and Findings: Pediatric specific treatment considerations include the use of anesthesia, impact of treatment on the developing child, and logistical challenges of RT. Treatment modality and dose selection are driven by histology and symptomatic site of pain, where we discuss detailed recommendations for hematologic, central nervous system, and solid tumors. For palliative RT, an underlying principle of searching for the lowest effective dose to balance response rate with minimal acute and late treatment related morbidity and logistical hardships is of paramount importance when caring for a pediatric patient. Lastly, we outline how to effectively communicate this option to patients and their caregivers., Conclusions: Palliative RT can be of valuable benefit in most settings for patients with pediatric cancer. There is an unmet need for prospective data to inform on dose-fractionation along with patient and caregiver reported outcomes.

Somatic versus Germline-A Case Series of Three Children with ATM- mutated Medulloblastoma.

Pineal anlage tumor is a rare pediatric tumor with clinical and histological features overlapping with pineoblastoma. Two patients with pineal anlage tumor, a 13-month-old female and an 11-month-old male, underwent subtotal resection, high-dose chemotherapy with autologous stem cell rescue, and radiation. Neither had tumor progression 50 months after diagnosis. The tumors underwent next-generation sequencing on a panel of 340 genes. Chromosomal copy gains and losses were present and differed between the tumors. No mutations or amplifications, including none specific to pineoblastoma, were identified., (© 2022 Wiley Periodicals LLC.)

Purpose: Craniospinal irradiation (CSI) is commonly used for pediatric brain tumors with a propensity for spread in craniospinal fluid, principally medulloblastoma. Evolving technology has led to the use of highly conformal radiation therapy (RT) techniques for CSI, including proton therapy. Target delineation and plan coverage are critical for CSI, but there is ongoing controversy and variability in these realms, with little available data on practice patterns. We sought to characterize proton CSI practice patterns in the United States by examining CSI plans in the Pediatric Proton/Photon Consortium Registry (PPCR)., Materials and Methods: PPCR was queried for data on proton CSI patients from 2015 to early 2020. Each plan was manually reviewed, determining patient position; prescription dose; and coverage of optic nerves, vertebral bodies, spinal nerve roots, sacral nerves, and cranial foramina, among other variables. Two radiation oncologists blinded to clinical data and treating institution assessed coverage at the 95% prescription isodose line and per published European Society for Paediatric Oncology guidelines. Variability in coverage was assessed with nonparametric tests and univariate and multivariate logistic regression., Results: PPCR supplied data for 450 patients, 384 of whom had an evaluable portion of a CSI plan. Most patients (90.3%) were supine. Optic nerves were fully covered in 48.2%; sacral nerves in 87.7%; cranial foramina in 69.3%; and spinal nerves in 95.6%. Vertebral body (VB) sparing was used in 18.6% of skeletally immature cases, increasing over time (P < .001). Coverage in all categories was significantly different among treating institutions, on univariate and multivariate analyses. Cribriform plate deficits were rare, with marginal misses of the foramen ovale (17.4%) and frontal lobe (12%) most common., Conclusion: We found consistent variation based on treating institution in proton CSI practices including optic nerve, VB, sacral nerve, cranial, and spinal nerve coverage. These data may serve as a baseline quantification of current proton CSI practices in the United States as they continue to evolve., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Proton radiation therapy (PR) is well established in the treatment of pediatric malignancies in the central nervous system (CNS) with dosimetric advantages that reduce late radiation therapy (RT) effects. In this analysis, we sought to evaluate the utilization of PR in children with primary CNS malignancies and characterize the clinical and sociodemographic factors predictive of receipt of PR., Methods and Materials: The National Cancer Database was queried to identify all pediatric patients with primary CNS malignancies treated with curative intent RT from 2004 to 2017. Clinical characteristics and demographics were analyzed using standard t and χ 2 testing. Predictors of PR receipt were identified with univariable and multivariable logistic regression., Results: We identified 9126 patients ≤18 years of age treated with RT between 2004 and 2017, of which 1045 (11.5%) received PR. PR usage continued to increase significantly, from <1% in 2004 to 28% in 2017. The proportion of white and Asian patients receiving PR for nonhigh-grade glioma and nonmeningioma CNS malignancies during the study period rose from <1% for both to 35% and 44%, respectively, and in black patients the proportion rose from <1% to 26%. Multivariable predictors of receipt of PR include year of diagnosis, age <6 years, income level, distance from PR facility, and histology; multivariable predictors of receipt of photon RT include black race, rural residence, and Medicaid insurance. These factors remained significant when isolating the most recent 5 years of data., Conclusions: Proton radiation therapy usage for CNS malignancies increased significantly during the study period. Despite the potential clinical advantages of PR for pediatric primary CNS malignancies, there are notable socioeconomic, geographic, and racial disparities in the receipt of PR that persisted despite the increased availability and accessibility. Further study is warranted to identify how to address the disparities and better support these patients., (© 2022 The Authors.)

Non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) comprise 4% of childhood cancers and consist of numerous histologic subtypes. Prognostic factors associated with poor outcome include high histologic grade, large tumor size, presence of metastases, and unresectability. Complete surgical resection is critical for the best oncologic outcomes and is prioritized in treatment algorithms. The use of radiation therapy (RT) and chemotherapy is based upon factors such as resectability, histologic grade, tumor size, and stage. North American and European trials are defining a risk-based approach to NRSTS to limit treatment-related toxicity and to maximize therapeutic efficacy. In this paper, we summarize the current roles of surgery, RT, and chemotherapy in NRSTS and describe ongoing research that is advancing the care of NRSTS patients., (© 2021 Wiley Periodicals LLC.)

Introduction: Beyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation., Methods: We retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated., Results: Median age at diagnosis was 10.9 years (18 months-18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG., Conclusion: Our single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.

Aim/objectives/background: The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for image-guided radiation therapy (IGRT). IGRT is radiation therapy that employs imaging to maximize accuracy and precision throughout the entire process of treatment delivery with the goal of optimizing accuracy and reliability of radiation therapy to the target, while minimizing dose to normal tissues., Methods: The ACR-ASTRO Practice Parameter for IGRT was revised according to the process described on the ACR website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parametersand-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the ASTRO. Both societies then reviewed and approved the document., Results: This practice parameter is developed to serve as a tool in the appropriate application of IGRT in the care of patients with conditions where radiation therapy is indicated. It addresses clinical implementation of IGRT including personnel qualifications, quality assurance standards, indications, and suggested documentation., Conclusions: This practice parameter is a tool to guide clinical use of IGRT and does not make recommendations on site-specific IGRT directives. It focuses on the best practices and principles to consider when using IGRT effectively, especially with the significant increase in imaging data that is now available with IGRT. The clinical benefit and medical necessity of the imaging modality and frequency of IGRT should be assessed for each patient.

Rationale and Objectives: We hypothesized that providing visual-spatial information to radiologists on where radiation has been delivered in an easily accessible way may improve the accuracy of image interpretation and thereby improve quality of patient care. We present a national representation of radiologists' opinions regarding the usefulness and optimal approach for implementing a system to promote access to radiotherapy (RT) plans., Methods: An anonymous survey was sent to the members of the Association of University Radiologists. Descriptive statistics were performed., Results: Questionnaires were returned by 95 of 1383 members. Demographics comprised of 76% attendings with 94% practicing within an academic setting. Only 40% of radiologists reported that they knew most of the time whether a patient has received RT in the field scanned. A large majority of respondents (88%) felt that a history of prior radiation in a cancer patient was at least an occasional barrier that affected the ability to interpret imaging findings in a clinically useful way. The following types of information was considered helpful when interpreting a scan: screenshots of the radiation plan (85%), scrollable DICOM data on planning CT showing delivered RT dose lines (54%), and written text RT treatment summary (47%). Nearly all (89%) desired DICOM data within the clinical radiology Picture Archiving and Communication System system. Radiologists expected the ease of accessibility to RT plans to result in increased efficiency (76%) and accuracy (88%)., Conclusion: Diagnostic radiologists desire improved access and integration of radiotherapy plans into the diagnostic radiology clinical workup in the form of visual-spatial data., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The Pediatric Proton/Photon Consortium Registry (PPCR) is a comprehensive data registry composed of pediatric patients treated with radiation. It was established to expedite outcomes-based research. The attributes which allow the PPCR to be a successful collaboration are reviewed., Methods and Materials: Current eligibility criteria are radiotherapy patients < 22 years treated at one of the 15 US participating institutions. Detailed health and treatment data are collected about the disease presentation and treatment exposures, and annually thereafter, in REDCap (Research Electronic Data Capture). DICOM (Digital Imaging and Communications in Medicine) imaging and radiation plans are collected through MIM/MIMcloud. An optional patient-reported quality-of-life (PedsQL) study is administered at 10 sites., Results: Accrual started October 2012 with 2,775 participants enrolled as of 25 July 2019. Most patients, 62.0%, were treated for central nervous system (CNS) tumors, the most common of which are medulloblastoma ( n = 349), ependymoma ( n = 309), and glial/astrocytoma tumors ( n = 279). The most common non-CNS diagnoses are rhabdomyosarcoma ( n = 284), Ewing's sarcoma ( n = 153), and neuroblastoma ( n = 130). While the majority of participants are US residents, 18.7% come from 36 other countries. Over 685 patients participate in the PedsQL study., Conclusions: The PPCR is a valuable research platform capable of answering countless research questions that will ultimately improve patient care. Centers outside of the USA are invited to participate directly or may engage with the PPCR to align data collection strategies to facilitate large-scale international research., Advances in Knowledge: For investigators looking to carry out research in a large pediatric oncology cohort or interested in registry work, this paper provides an updated overview of the PPCR.

Background: Lower-dose cone-beam computed tomography protocols for image-guided radiotherapy may permit target localization while minimizing radiation exposure. We prospectively evaluated a lower-dose cone-beam protocol for central nervous system image-guided radiotherapy across a multinational pediatrics consortium., Methods: Seven institutions prospectively employed a lower-dose cone-beam computed tomography central nervous system protocol (weighted average dose 0.7 mGy) for patients ≤21 years. Treatment table shifts between setup with surface lasers versus cone-beam computed tomography were used to approximate setup accuracy, and vector magnitudes for these shifts were calculated. Setup group mean, interpatient, interinstitution, and random error were estimated, and clinical factors were compared by mixed linear modeling., Results: Among 96 patients, with 2179 pretreatment cone-beam computed tomography acquisitions, median age was 9 years (1-20). Setup parameters were 3.13, 3.02, 1.64, and 1.48 mm for vector magnitude group mean, interpatient, interinstitution, and random error, respectively. On multivariable analysis, there were no significant differences in mean vector magnitude by age, gender, performance status, target location, extent of resection, chemotherapy, or steroid or anesthesia use. Providers rated >99% of images as adequate or better for target localization., Conclusions: A lower-dose cone-beam computed tomography protocol demonstrated table shift vector magnitude that approximate clinical target volume/planning target volume expansions used in central nervous system radiotherapy. There were no significant clinical predictors of setup accuracy identified, supporting use of this lower-dose cone-beam computed tomography protocol across a diverse pediatric population with brain tumors.

Background: Female and male trajectories of cerebellar and lobar brain structures are sexually dimorphic, making sex a potential candidate moderator of neurocognitive late effects from radiation treatment. We sought to evaluate longitudinal neurocognitive functioning in male versus female children treated for posterior fossa brain tumors., Methods: Fifty-one female and 63 male survivors of posterior fossa tumors completed neuropsychological testing at 2 timepoints. We included patients treated with surgical resection, chemotherapy, and radiation therapy. Multilevel mixed modeling was used to predict IQ score as a function of patient sex following treatment (~2 or ~4 years post treatment). Effect sizes were used as a measure of clinical significance., Results: Multilevel models resulted in a significant sex by time interaction (F = 6.69, P = 0.011). Females' cognitive scores were considerably higher compared with males at 4 years posttreatment. Females demonstrated an average improvement of 7.61 standard score IQ points compared with a decline of 2.97 points for males at 4 years follow-up. Effect sizes for female IQ compared with male IQ at 4 years posttreatment were between 0.8 and 0.9., Conclusion: Trajectories of neurocognitive functioning following posterior fossa tumor treatment differed between female and male children. Sexual dimorphism in radiation late effects may alter treatment decisions in children. Research into sex-specific neuroprotective mechanisms underlying neurocognitive development following pediatric brain tumor treatments is warranted., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We examined the impact of total body irradiation (TBI) dose and fractionation on risk of subsequent malignant neoplasms (SMNs) in the era of reduced-intensity and nonmyeloablative conditioning regimens for hematopoietic cell transplantation (HCT). Among 4905 1-year survivors of allogeneic HCT for hematologic malignancies (N = 4500) or nonmalignant disorders (N = 405) who received transplants between 1969 and 2014, we identified 581 SMNs (excluding squamous and basal cell of skin) in 499 individuals. With a median length of follow-up of 12.5 years, the cumulative incidence of SMNs by 30 years after HCT was 22.0%. Compared with age-, sex-, and calendar year-matched Surveillance, Epidemiology, and End Results (SEER) population rates, the standardized incidence ratio (SIR) of SMNs was increased 2.8-fold. The highest SIRs were for SMNs of bones (SIR, 28.8), oral cavity (SIR, 13.8), skin (SIR, 7.3), central nervous system (SIR, 6.0), and endocrine organs (SIR, 4.9). The highest excess absolute risks (EARs) were seen with breast cancer (EAR, 2.2) and cancers of the oral cavity (EAR, 1.5) and skin (EAR, 1.5) per 1000 person-years. The highest incidence of SMNs was in survivors exposed to unfractionated (600-1000 cGy) or high-dose fractionated (1440-1750 cGy) TBI. For patients receiving low-dose TBI, the incidence was comparable to myeloablative chemotherapy alone, although still twofold higher than in the general population. These data demonstrate a strong effect of TBI dose, dose fractionation, and risk of SMNs after HCT. The cumulative incidence of SMNs increases with follow-up time; thus, HCT survivors require lifetime monitoring for early detection and effective therapy of SMNs., (© 2019 by The American Society of Hematology.)

Purpose/objectives: There is little consensus regarding the application of stereotactic radiotherapy (SRT) in pediatrics. We evaluated patterns of pediatric SRT practice through an international research consortium., Materials and Methods: Eight international institutions with pediatric expertise completed a 124-item survey evaluating patterns of SRT use for patients 21 years old and younger. Frequencies of SRT use and median margins applied with and without SRT were evaluated., Results: Across institutions, 75% reported utilizing SRT in pediatrics. SRT was used in 22% of brain, 18% of spine, 16% of other bone, 16% of head and neck, and <1% of abdomen/pelvis, lung, and liver cases across sites. Of the hypofractionated SRT cases, 42% were delivered with definitive intent. Median gross tumor volume to planning target volume margins for SRT versus non-SRT plans were 0.2 versus 1.4 cm for brain, 0.3 versus 1.5 cm for spine/other bone, 0.3 versus 2.0 cm for abdomen/pelvis, 0.7 versus 1.5 cm for head and neck, 0.5 versus 1.7 cm for lung, and 0.5 versus 2.0 cm for liver sites., Conclusions: SRT is commonly utilized in pediatrics across a range of treatment sites. Margins used for SRT were substantially smaller than for non-SRT planning, highlighting the utility of this approach in reducing treatment volumes.

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.

In this prospective, randomized, phase II "pick the winner" trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine ± 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m 2 /day on days -6 to -4 and i.v. fludarabine, 30 mg/m 2 /day on days -6 to -2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background/objectives: The practice of palliative radiation therapy (RT) is based on extrapolation from adult literature. We evaluated patterns of pediatric palliative RT to describe regimens used to identify opportunity for future pediatric-specific clinical trials., Design/methods: Six international institutions with pediatric expertise completed a 122-item survey evaluating patterns of palliative RT for patients ≤21 years old from 2010 to 2015. Two institutions use proton RT. Palliative RT was defined as treatment with the goal of symptom control or prevention of immediate life-threatening progression., Results: Of 3,225 pediatric patients, 365 (11%) were treated with palliative intent to a total of 427 disease sites. Anesthesia was required in 10% of patients. Treatment was delivered to metastatic disease in 54% of patients. Histologies included neuroblastoma (30%), osteosarcoma (18%), leukemia/lymphoma (12%), rhabdomyosarcoma (12%), medulloblastoma/ependymoma (12%), Ewing sarcoma (8%), and other (8%). Indications included pain (43%), intracranial symptoms (23%), respiratory compromise (14%), cord compression (8%), and abdominal distention (6%). Sites included nonspine bone (35%), brain (16% primary tumors, 6% metastases), abdomen/pelvis (15%), spine (12%), head/neck (9%), and lung/mediastinum (5%). Re-irradiation comprised 16% of cases. Techniques employed three-dimensional conformal RT (41%), intensity-modulated RT (23%), conventional RT (26%), stereotactic body RT (6%), protons (1%), electrons (1%), and other (2%). The most common physician-reported barrier to consideration of palliative RT was the concern about treatment toxicity (83%)., Conclusion: There is significant diversity of practice in pediatric palliative RT. Combined with ongoing research characterizing treatment response and toxicity, these data will inform the design of forthcoming clinical trials to establish effective regimens and minimize treatment toxicity for this patient population., (© 2017 Wiley Periodicals, Inc.)

Background: Recent Children's Oncology Group (COG) trials tested the efficacy of reduced therapy in an effort to lessen late effects compared to the Intergroup Rhabdomyosarcoma Study (IRS) IV regimen with associated hematologic and hepatic toxicity, and infertility. Here, we analyze the efficacy of 45 Gray (Gy) local radiotherapy (RT) in patients with Group III orbital embryonal rhabdomyosarcoma (ERMS) enrolled on the COG low-risk study ARST0331., Procedure: Sixty-two patients with Group III orbital ERMS were treated on ARST0331 with four cycles of vincristine (VCR), dactinomycin (DACT), and cyclophosphamide (CPM; VAC, total cumulative CPM dose 4.8 g/m 2 ) followed by four cycles of VCR and DACT over 22 weeks. Forty-five Gray of radiation was administered in 25 fractions beginning at week 13 of therapy., Results: Fifty-three patients were evaluable for this response analysis; seven had missing week 12 response evaluation data and two had progressive disease prior to starting RT. Median follow-up was 7.8 years. None of the 15 patients with radiographic complete response (CR) compared to 6 of the 38 patients with

Purpose: Proton beam therapy (PBT) potentially allows for improved sparing of normal tissues, hopefully leading to decreased late side effects in children. Using a national registry, we sought to perform a patterns-of-care analysis for children receiving PBT for primary malignancies of the central nervous system (CNS)., Methods and Materials: Using the National Cancer Data Base, we identified pediatric patients with primary CNS malignancies that were diagnosed between 2004 and 2012. We used a standard t test for comparison of means and χ 2 testing to identify differences in demographic and clinical characteristics. Univariate and multivariate logistical regression was applied to identify predictors of PBT use., Results: We identified 4637 pediatric patients receiving radiation therapy from 2004 to 2012, including a subset of 267 patients treated with PBT. We found that PBT use increased with time from <1% in 2004 to 15% in 2012. In multivariate logistical regression, we found the following to be predictors of receipt of PBT: private insurance, the highest income bracket, younger age, living in a metropolitan area, and residing >200 miles from a radiation treatment facility (P<.05)., Conclusions: We noted the proportion of children receiving PBT to be significantly increasing over time from <1% to 15% from 2004 to 2012. We also observed important disparities in receipt of PBT based on socioeconomic status. Children from higher-income households and with private insurance were more likely to use this expensive technology. As we continue to demonstrate the potential benefits of PBT in children, efforts are needed to expand the accessibility of PBT for children of all socioeconomic backgrounds and regions of the country., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN&#95;PFA and EPN&#95;PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known., Methods: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses., Results: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN&#95;PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN&#95;PFA, a substantial proportion of patients with EPN&#95;PFB can be cured with surgery alone, and patients with relapsed EPN&#95;PFB can often be treated successfully with delayed external-beam irradiation., Conclusion: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN&#95;PFA and EPN&#95;PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN&#95;PFA, even with adjuvant radiation therapy. Patients with EPN&#95;PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence., (© 2016 by American Society of Clinical Oncology.)

Purpose: Radiation treatment planning involves a complex workflow that has multiple potential points of vulnerability. This study utilizes an incident reporting system to identify the origination and detection points of near-miss errors, in order to guide their departmental safety improvement efforts. Previous studies have examined where errors arise, but not where they are detected or applied a near-miss risk index (NMRI) to gauge severity., Methods: From 3/2012 to 3/2014, 1897 incidents were analyzed from a departmental incident learning system. All incidents were prospectively reviewed weekly by a multidisciplinary team and assigned a NMRI score ranging from 0 to 4 reflecting potential harm to the patient (no potential harm to potential critical harm). Incidents were classified by point of incident origination and detection based on a 103-step workflow. The individual steps were divided among nine broad workflow categories (patient assessment, imaging for radiation therapy (RT) planning, treatment planning, pretreatment plan review, treatment delivery, on-treatment quality management, post-treatment completion, equipment/software quality management, and other). The average NMRI scores of incidents originating or detected within each broad workflow area were calculated. Additionally, out of 103 individual process steps, 35 were classified as safety barriers, the process steps whose primary function is to catch errors. The safety barriers which most frequently detected incidents were identified and analyzed. Finally, the distance between event origination and detection was explored by grouping events by the number of broad workflow area events passed through before detection, and average NMRI scores were compared., Results: Near-miss incidents most commonly originated within treatment planning (33%). However, the incidents with the highest average NMRI scores originated during imaging for RT planning (NMRI = 2.0, average NMRI of all events = 1.5), specifically during the documentation of patient positioning and localization of the patient. Incidents were most frequently detected during treatment delivery (30%), and incidents identified at this point also had higher severity scores than other workflow areas (NMRI = 1.6). Incidents identified during on-treatment quality management were also more severe (NMRI = 1.7), and the specific process steps of reviewing portal and CBCT images tended to catch highest-severity incidents. On average, safety barriers caught 46% of all incidents, most frequently at physics chart review, therapist's chart check, and the review of portal images; however, most of the incidents that pass through a particular safety barrier are not designed to be capable of being captured at that barrier., Conclusions: Incident learning systems can be used to assess the most common points of error origination and detection in radiation oncology. This can help tailor safety improvement efforts and target the highest impact portions of the workflow. The most severe near-miss events tend to originate during simulation, with the most severe near-miss events detected at the time of patient treatment. Safety barriers can be improved to allow earlier detection of near-miss events.

In many cancers, intratumoral heterogeneity has been found in histology, genetic variation and vascular structure. We developed an algorithm to interrogate different scales of heterogeneity using clinical imaging. We hypothesize that heterogeneity of perfusion at coarse scale may correlate with treatment resistance and propensity for disease recurrence. The algorithm recursively segments the tumor image into increasingly smaller regions. Each dividing line is chosen so as to maximize signal intensity difference between the two regions. This process continues until the tumor has been divided into single voxels, resulting in segments at multiple scales. For each scale, heterogeneity is measured by comparing each segmented region to the adjacent region and calculating the difference in signal intensity histograms. Using digital phantom images, we showed that the algorithm is robust to image artifacts and various tumor shapes. We then measured the primary tumor scales of contrast enhancement heterogeneity in MRI of 18 rhabdomyosarcoma patients. Using Cox proportional hazards regression, we explored the influence of heterogeneity parameters on relapse-free survival. Coarser scale of maximum signal intensity heterogeneity was prognostic of shorter survival (p = 0.05). By contrast, two fractal parameters and three Haralick texture features were not prognostic. In summary, our algorithm produces a biologically motivated segmentation of tumor regions and reports the amount of heterogeneity at various distance scales. If validated on a larger dataset, this prognostic imaging biomarker could be useful to identify patients at higher risk for recurrence and candidates for alternative treatment.

Purpose: Image guided radiation therapy (IGRT) has become common practice for both photon and proton radiation therapy, but there is little consensus regarding its application in the pediatric population. We evaluated clinical patterns of pediatric IGRT practice through an international pediatrics consortium comprised of institutions using either photon or proton radiation therapy., Methods and Materials: Seven international institutions with dedicated pediatric expertise completed a 53-item survey evaluating patterns of IGRT use in definitive radiation therapy for patients ≤21 years old. Two institutions use proton therapy for children and all others use IG photon therapy. Descriptive statistics including frequencies of IGRT use and means and standard deviations for planning target volume (PTV) margins by institution and treatment site were calculated., Results: Approximately 750 pediatric patients were treated annually across the 7 institutions. IGRT was used in tumors of the central nervous system (98%), abdomen or pelvis (73%), head and neck (100%), lung (83%), and liver (69%). Photon institutions used kV cone beam computed tomography and kV- and MV-based planar imaging for IGRT, and all proton institutions used kV-based planar imaging; 57% of photon institutions used a specialized pediatric protocol for IGRT that delivers lower dose than standard adult protocols. Immobilization techniques varied by treatment site and institution. IGRT was utilized daily in 45% and weekly in 35% of cases. The PTV margin with use of IGRT ranged from 2 cm to 1 cm across treatment sites and institution., Conclusions: Use of IGRT in children was prevalent at all consortium institutions. There was treatment site-specific variability in IGRT use and technique across institutions, although practices varied less at proton facilities. Despite use of IGRT, there was no consensus of optimum PTV margin by treatment site. Given the desire to restrict any additional radiation exposure in children to instances where the exposure is associated with measureable benefit, prospective studies are warranted to optimize IGRT protocols by modality and treatment site., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to report a rare case of ocular metastasis from prostate cancer treated successfully with external beam radiation therapy., Methods: Case report and literature review., Patient: A 60-year-old man with a history of metastatic castration-resistant prostate cancer presented with decreased visual acuity in the right eye. Ophthalmoscopic examination showed a choroidal mass with characteristic surface retinal pigment epithelium spots (leopard spots), consistent with a metastatic tumor. The patient was treated with external beam radiation therapy. He had a dramatic improvement in visual acuity within 4 weeks of completing radiation treatment. Two and half years from radiation treatment to the right eye, he has maintained excellent vision (20/20 with best correction) in spite of systemic disease progression., Conclusion: Uveal metastasis is a rare cause of unexplained blurred vision in the setting of metastatic adenocarcinoma of prostate. Palliative external beam radiotherapy provides effective and durable relief of symptoms during treatment and is generally a well-tolerated regimen with low risk of long-term morbidity.

Purpose: To interrogate grade II, III, and IV gliomas and characterize the critical effectors within the PI3-kinase pathway upstream and downstream of mTOR. Experimental design Tissues from 87 patients who were treated at UCSF between 1990 and 2004 were analyzed. Twenty-eight grade II, 17 grade III glioma, 26 grade IV gliomas, and 16 non-tumor brain specimens were analyzed. Protein levels were assessed by immunoblots; RNA levels were determined by polymerase chain reaction amplification. To address the multiple comparisons, first an overall analysis was done comparing the four groups using Spearman's Correlation Coefficient. Only if this analysis was statistically significant were individual pairwise comparisons done., Results: Multiple comparison analyses revealed a significant correlation with grade for all variables examined, except phosphorylated-S6. Expression of phosphorylated-4E-BP1, phosphorylated-PKB/Akt, PTEN, TSC1, and TSC2 correlated with grade (P < 0.01 for all). We extended our analyses to ask whether decreases in TSC proteins levels were due to changes in mRNA levels, or due to changes in post-transcriptional alterations. We found significantly lower levels of TSC1 and TSC2 mRNA in GBMs than in grade II gliomas or non-tumor brain (P < 0.01)., Conclusions: Expression levels of critical signaling molecules upstream and downstream of mTOR differ between non-tumor brain and gliomas of any grade. The single variable whose expression did not differ between non-tumor brain and gliomas was phosphorylated-S6, suggesting that other protein kinases, in addition to mTOR, contribute significantly to S6 phosphorylation. mTOR provides a rational therapeutic target in gliomas of all grades, and clinical benefit may emerge as mTOR inhibitors are combined with additional agents.

We investigated the mechanisms of MDR1 gene activation by CCAAT/enhancer binding protein beta (C/EBPbeta, or nuclear factor for interleukin 6) in human cancer cells. Transfection of the breast cancer cell line MCF-7 and its doxorubicin-selected variant MCF-7/ADR by either C/EBPbeta or C/EBPbeta-LIP (a dominant-negative form of C/EBPbeta) confirmed their roles in the activation or repression of the endogenous, chromosomally embedded MDR1 gene. Cotransfection experiments with promoter constructs revealed a C/EBPbeta interaction on the MDR1 promoter via the region within -128 to -75. Deletions within the putative AP-1 box (-123 to -111) increased MDR1 promoter activity when stimulated by C/EBPbeta, suggesting that the AP-1 site negatively regulates MDR1 activation by C/EBPbeta. Mutations within the inverted CCAAT box (Y box) (-82 to -73) abolished the C/EBPbeta-stimulated MDR1 promoter activity, indicating that the Y box is required for MDR1 activation by C/EBPbeta. Chromatin immunoprecipitation (ChIP) revealed that C/EBPbeta precipitates a transcription complex containing C/EBPbeta, the MDR1 promoter sequences (-250 to +54), and the hBrm protein. In conclusion, alteration of expression or function of C/EBPbeta plays an important role in MDR1 gene regulation. C/EBPbeta activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBPbeta interaction region within the proximal MDR1 promoter (-128 to -75). The mechanisms of MDR1 activation by C/EBPbeta include C/EBPbeta binding of the chromatin of the MDR1 gene and interactions of C/EBPbeta with the Y box and Y box-associated proteins.

Purpose: This study assessed whether putative effectors of phosphatidylinositol3-kinase, including PTEN, protein kinase B (PKB), and p27(kip1), correlate with each other, with glioma histology, and with patient outcome., Experimental Design: Components of the phosphatidylinositol 3-kinase signaling cascade were characterized in 25 glioblastoma multiforme (GBM) tumors, 8 grade II oligoastrocytomas, and 13 normal human brain specimens. The protein levels of PTEN and p27(kip1) were assessed by immunoblot analyses. PKB kinase activity was evaluated through the expression level of the phosphorylated (activated) PKB protein and the ability of PKB to phosphorylate a specific peptide substrate in vitro. Cox regression analyses between expression/activity variables and survival were performed across and within histology types. Actual value for expression/activity was used as a continuous variable. Survival time was displayed by Kaplan Meier., Results: A strong inverse correlation was evident between PTEN levels and both phosphorylated PKB expression (P < 0.01) and PKB activity (P = 0.01). p27(kip1) levels did not correlate with PTEN expression or PKB activity. A significant association was evident between PTEN expression level and histology (P < 0.01). PTEN levels were highest in normal brain, lowest in GBM tumors, and intermediate in grade II oligoastrocytomas. PKB activity and phosphorylated PKB levels differed significantly among histologies, whereas p27(kip1) levels exhibited no association with histology. PTEN expression correlated significantly with survival time within the entire cohort (P < 0.01) and was associated with survival within the subgroup of GBM tumors (P = 0.11)., Conclusions: Reduced PTEN expression is ubiquitous among GBM tumors and may play a role in the development of low-grade gliomas. PTEN inactivation in gliomas portends a particularly aggressive clinical behavior.