449 results on '"Merchant TE"'
Search Results
2. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma
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Kumar, R, Smith, KS, Deng, M, Terhune, C, Robinson, GW, Orr, BA, Liu, APY, Lin, T, Billups, CA, Chintagumpala, M, Bowers, DC, Hassall, TE, Hansford, JR, Khuong-Quang, DA, Crawford, JR, Bendel, AE, Gururangan, S, Schroeder, K, Bouffet, E, Bartels, U, Fisher, MJ, Cohn, R, Partap, S, Kellie, SJ, McCowage, G, Paulino, AC, Rutkowski, S, Fleischhack, G, Dhall, G, Klesse, LJ, Leary, S, Nazarian, J, Kool, M, Wesseling, P, Ryzhova, M, Zheludkova, O, Golanov, A, McLendon, RE, Packer, RJ, Dunham, C, Hukin, J, Fouladi, M, Faria, CC, Pimentel, J, Walter, AW, Jabado, N, Cho, Y-J, Perreault, S, Croul, SE, Zapotocky, M, Hawkins, C, Tabori, U, Taylor, MD, Pfister, SM, Klimo, P, Boop, FA, Ellison, DW, Merchant, TE, Onar-Thomas, A, Korshunov, A, Jones, DTW, Gajjar, A, Ramaswamy, V, Northcott, PA, Kumar, R, Smith, KS, Deng, M, Terhune, C, Robinson, GW, Orr, BA, Liu, APY, Lin, T, Billups, CA, Chintagumpala, M, Bowers, DC, Hassall, TE, Hansford, JR, Khuong-Quang, DA, Crawford, JR, Bendel, AE, Gururangan, S, Schroeder, K, Bouffet, E, Bartels, U, Fisher, MJ, Cohn, R, Partap, S, Kellie, SJ, McCowage, G, Paulino, AC, Rutkowski, S, Fleischhack, G, Dhall, G, Klesse, LJ, Leary, S, Nazarian, J, Kool, M, Wesseling, P, Ryzhova, M, Zheludkova, O, Golanov, A, McLendon, RE, Packer, RJ, Dunham, C, Hukin, J, Fouladi, M, Faria, CC, Pimentel, J, Walter, AW, Jabado, N, Cho, Y-J, Perreault, S, Croul, SE, Zapotocky, M, Hawkins, C, Tabori, U, Taylor, MD, Pfister, SM, Klimo, P, Boop, FA, Ellison, DW, Merchant, TE, Onar-Thomas, A, Korshunov, A, Jones, DTW, Gajjar, A, Ramaswamy, V, and Northcott, PA
- Abstract
PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular ta
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- 2021
3. Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03)
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Gajjar, A, Robinson, GW, Smith, KS, Lin, T, Merchant, TE, Chintagumpala, M, Mahajan, A, Su, J, Bouffet, E, Bartels, U, Schechter, T, Hassall, T, Robertson, T, Nicholls, W, Gururangan, S, Schroeder, K, Sullivan, M, Wheeler, G, Hansford, JR, Kellie, SJ, McCowage, G, Cohn, R, Fisher, MJ, Krasin, MJ, Stewart, CF, Broniscer, A, Buchhalter, I, Tatevossian, RG, Orr, BA, Neale, G, Klimo, P, Boop, F, Srinivasan, A, Pfister, SM, Gilbertson, RJ, Onar-Thomas, A, Ellison, DW, Northcott, PA, Gajjar, A, Robinson, GW, Smith, KS, Lin, T, Merchant, TE, Chintagumpala, M, Mahajan, A, Su, J, Bouffet, E, Bartels, U, Schechter, T, Hassall, T, Robertson, T, Nicholls, W, Gururangan, S, Schroeder, K, Sullivan, M, Wheeler, G, Hansford, JR, Kellie, SJ, McCowage, G, Cohn, R, Fisher, MJ, Krasin, MJ, Stewart, CF, Broniscer, A, Buchhalter, I, Tatevossian, RG, Orr, BA, Neale, G, Klimo, P, Boop, F, Srinivasan, A, Pfister, SM, Gilbertson, RJ, Onar-Thomas, A, Ellison, DW, and Northcott, PA
- Abstract
Purpose: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. Patients and Methods: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. Results: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort (P = .74) or when patients were stratified by clinical risk (P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medu
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- 2021
4. Cerebral microbleeds in adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation
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Phillips, NS, Hillenbrand, CM, Mitrea, BG, Yan, J, Li, C, Scoggins, MA, Merchant, TE, Armstrong, GT, Srivastava, D, Pui, CH, Robison, LL, Hudson, MM, Krull, KR, Sabin, ND, Phillips, NS, Hillenbrand, CM, Mitrea, BG, Yan, J, Li, C, Scoggins, MA, Merchant, TE, Armstrong, GT, Srivastava, D, Pui, CH, Robison, LL, Hudson, MM, Krull, KR, and Sabin, ND
- Abstract
Cranial radiation therapy is associated with white matter-specific brain injury, cortical volume loss, mineralization, microangiopathy and neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia. In this retrospective cross-sectional analysis, neurocognitive testing and 3 T brain MRI’s were obtained in 101 survivors treated with cranial radiation. Small focal intracerebral hemorrhages only visible on exquisitely sensitive MRI sequences were identified and localized using susceptibility weighted imaging. Modified Poisson regression was used to assess the effect of cranial radiation on cumulative number and location of microbleeds in each brain region, and multiple linear regression was used to evaluate microbleeds on neurocognitive outcomes, adjusting for age at diagnosis and sex. At least one microbleed was present in 85% of survivors, occurring more frequently in frontal lobes. Radiation dose of 24 Gy conveyed a 5-fold greater risk (95% CI 2.57–10.32) of having multiple microbleeds compared to a dose of 18 Gy. No significant difference was found in neurocognitive scores with either the absence or presence of microbleeds or their location. Greater prevalence of microbleeds in our study compared to prior reports is likely related to longer time since treatment, better sensitivity of SWI for detection of microbleeds and the use of a 3 T MRI platform. © The Author(s) 2020.
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- 2020
5. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants
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Pajtler, KW, Mack, SC, Ramaswamy, V, Smith, CA, Witt, H, Smith, A, Hansford, JR, von Hoff, K, Wright, KD, Hwang, E, Frappaz, D, Kanemura, Y, Massimino, M, Faure-Conter, C, Modena, P, Tabori, U, Warren, KE, Holland, EC, Ichimura, K, Giangaspero, F, Castel, D, von Deimling, A, Kool, M, Dirks, PB, Grundy, RG, Foreman, NK, Gajjar, A, Korshunov, A, Finlay, J, Gilbertson, RJ, Ellison, DW, Aldape, KD, Merchant, TE, Bouffet, E, Pfister, SM, Taylor, MD, Pajtler, KW, Mack, SC, Ramaswamy, V, Smith, CA, Witt, H, Smith, A, Hansford, JR, von Hoff, K, Wright, KD, Hwang, E, Frappaz, D, Kanemura, Y, Massimino, M, Faure-Conter, C, Modena, P, Tabori, U, Warren, KE, Holland, EC, Ichimura, K, Giangaspero, F, Castel, D, von Deimling, A, Kool, M, Dirks, PB, Grundy, RG, Foreman, NK, Gajjar, A, Korshunov, A, Finlay, J, Gilbertson, RJ, Ellison, DW, Aldape, KD, Merchant, TE, Bouffet, E, Pfister, SM, and Taylor, MD
- Abstract
Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.
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- 2017
6. SU-D-207A-06: Pediatric Abdominal Organ Motion Quantified Via a Novel 4D MRI Method
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Uh, J, primary, Krasin, MJ, additional, Lucas, JT, additional, Tinkle, C, additional, Merchant, TE, additional, and Hua, C, additional
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- 2016
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7. Clinical Magnetic Resonance Spectroscopy of Human Breast Disease
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Glonek T, De Graaf Pw, Den Otter W, Thelissen Gr, and Merchant Te
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Adult ,Pathology ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Phosphocreatine ,Breast Neoplasms ,Phosphates ,Breast Diseases ,chemistry.chemical_compound ,Adenosine Triphosphate ,In vivo ,Parenchyma ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,skin and connective tissue diseases ,Aged ,medicine.diagnostic_test ,Magnetic resonance imaging ,General Medicine ,Nuclear magnetic resonance spectroscopy ,Middle Aged ,chemistry ,Female ,Adenosine triphosphate ,Ex vivo ,Phosphomonoesters - Abstract
Using image-guided volume-selection techniques, in vivo phosphorus-31 magnetic resonance (MR) spectroscopic profiles were obtained from 12 patients with malignant breast tumors, six patients with benign breast tumors, and nine volunteers with no underlying pathologic condition. Phosphatic metabolites identified in the spectral profiles included the phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphorylated glycans (PG), phosphocreatine (PCr) and adenosine triphosphate (ATP). Based on the results of previous high-resolution ex vivo 31P MR spectroscopic analyses of breast tissues, the resonance of PG was identified in malignant and benign breast tumors. Malignant tumors were found to have a significantly (P less than .05) lower concentration of (PME + Pi) than normal breast parenchyma, and were distinguishable from both benign tumors and normal breast parenchymal tissue by significantly (P less than .01) elevated levels of (PDE + PG). 31P MR spectroscopy is the first technique potentially capable of differentiating among malignant breast tumors, benign breast tumors, and normal breast parenchymal tissues based on their in vivo phosphatic metabolic profiles.
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- 1991
8. Phase II trial of conformal radiation therapy for pediatric low-grade glioma.
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Merchant TE, Kun LE, Wu S, Xiong X, Sanford RA, Boop FA, Merchant, Thomas E, Kun, Larry E, Wu, Shengjie, Xiong, Xiaoping, Sanford, Robert A, and Boop, Frederick A
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- 2009
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9. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits.
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Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X, Merchant, Thomas E, Conklin, Heather M, Wu, Shengjie, Lustig, Robert H, and Xiong, Xiaoping
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- 2009
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10. Proton beam therapy in pediatric oncology.
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Merchant TE
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Pediatric caregivers and parents are eager to know the role of proton beam therapy (PBT) in the treatment of children with brain and solid tumors and other diseases for which radiation therapy is indicated. Although the number of children treated with PBT for the most common pediatric tumors is relatively small and outcome data are clearly lacking, modeling radiation dose, volume, and outcomes based on photon benchmark data and clinical experience suggest an advantage for PBT and an opportunity to reduce or eliminate many of the early and late effects of radiation therapy. As the number of centers available to treat children increases, it is incumbent on those with access to this modality to optimize other critical aspects of radiotherapy and cancer care and follow-up that are requisite to achieving disease control and high-quality survivorship. Even though the focus of pediatric radiation oncology is weighted toward side effect reduction, there is an opportunity for dose escalation or biologically optimized radiotherapy in a number of diseases or settings in which high-dose irradiation is considered unapproachable. Justification for PBT in pediatric patients should be realized once the costs of treating acute symptoms, growth hormone deficiency, orthopedic deformities, and secondary malignancies are studied and reduced. [ABSTRACT FROM AUTHOR]
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- 2009
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11. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study.
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Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA, Merchant, Thomas E, Li, Chenghong, Xiong, Xiaoping, Kun, Larry E, Boop, Frederic A, and Sanford, Robert A
- Abstract
Background: Therapy for ependymoma includes aggressive surgical intervention and radiotherapy administered by use of methods that keep the risk of side-effects to a minimum. We extended this treatment approach to include children under the age of 3 years with the aim of improving tumour control.Methods: Between July 11, 1997, and Nov 18, 2007, 153 paediatric patients (median age 2.9 years [range 0.9-22.9 months]) with localised ependymoma were treated. 85 patients had anaplastic ependymoma; the tumours of 122 were located in the infratentorial region, and 35 had received previous chemotherapy. Patients received conformal radiotherapy after definitive surgery (125 patients had undergone gross total, 17 near total, and 11 subtotal resection). Doses of 59.4 Gy (n=131) or 54.0 Gy (n=22) were prescribed to a 10 mm margin around the target volume. Disease control, patterns of failure, and complications were recorded for patients followed over 10 years. Overall survival, event-free survival (EFS), cumulative incidence of local recurrences, and cumulative incidence of distant recurrences were assessed. Variables considered included tumour grade, tumour location, ethnic origin, sex, age when undergoing conformal radiotherapy, total radiotherapy dose, number of surgical procedures, surgery extent, and preradiotherapy chemotherapy.Findings: After a median follow-up of 5.3 years (range 0.4-10.4), 23 patients had died and tumour progression noted in 36, including local (n=14), distant (n=15), and combined failure (n=7). 7-year local control, EFS, and overall survival were 87.3% (95% CI 77.5-97.1), 69.1% (56.9-81.3), and 81.0% (71.0-91.0), respectively. The cumulative incidences of local and distant failure were 16.3% (9.6-23.0) and 11.5% (5.9-17.1), respectively. In the 107 patients treated with immediate postoperative conformal radiotherapy (without delay or chemotherapy), 7-year local control, EFS, and overall survival were 88.7% (77.9-99.5), 76.9% (63.4-90.4), and 85.0% (74.2-95.8), respectively; the cumulative incidence of local and distant failure were 12.6% (5.1-20.1), and 8.6% (2.8-14.3), respectively. The incidence of secondary malignant brain tumour at 7 years was 2.3% (0-5.6) and brainstem necrosis 1.6% (0-4.0). Overall survival was affected by tumour grade (anaplastic vs differentiated: HR 3.98 [95% CI 1.51-10.48]; p=0.0052), extent of resection (gross total vs near total or subtotal: 0.16 [0.07-0.37]; p<0.0001), and ethnic origin (non-white vs white: 3.0 [1.21-7.44]; p=0.018). EFS was affected by tumour grade (anaplastic vs differentiated: 2.52 [1.2705.01]; p=0.008), extent of resection (gross total vs near total or subtotal: 0.20 [0.11-0.39]; p<0.0001]), and sex (male vs female: 2.19 [1.03-4.66]; p=0.042). Local failure was affected by extent of resection (gross total vs near total or subtotal: 0.16 [0.067-0.38]; p<0.0001), sex (male vs female: 3.85 [1.10-13.52]; p=0.035), and age (<3 years vs >/=3 years: 3.25 [1.30-8.16]; p=0.012). Distant recurrence was only affected by tumour grade (anaplastic vs differentiated: 4.1 [1.2-14.0]; p=0.017).Interpretation: Treatment of ependymoma should include surgery with the aim of gross-total resection and conformal, high-dose, postoperative irradiation. Future trials might consider treatment stratification based on sex and age. [ABSTRACT FROM AUTHOR]- Published
- 2009
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12. 31P Magnetic resonance phospholipid profiles of neoplastic human breast tissues
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Merchant, TE, primary, Meneses, P, additional, Gierke, LW, additional, Den Otter, W, additional, and Glonek, T, additional
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- 1991
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13. Predicting change in academic abilities after conformal radiation therapy for localized ependymoma.
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Conklin HM, Li C, Xiong X, Ogg RJ, Merchant TE, Conklin, Heather M, Li, Chenghong, Xiong, Xiaoping, Ogg, Robert J, and Merchant, Thomas E
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- 2008
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14. Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma.
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Fouladi M, Chintagumpala M, Ashley D, Kellie S, Gururangan S, Hassall T, Gronewold L, Stewart CF, Wallace D, Broniscer A, Hale GA, Kasow KA, Merchant TE, Morris B, Krasin M, Kun LE, Boyett JM, Gajjar A, Fouladi, Maryam, and Chintagumpala, Murali
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- 2008
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15. Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial.
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Laughton SJ, Merchant TE, Sklar CA, Kun LE, Fouladi M, Broniscer A, Morris EB, Sanders RP, Krasin MJ, Shelso J, Xiong Z, Wallace D, and Gajjar A
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- 2008
16. Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors.
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Hudson MM, Rai SN, Nunez C, Merchant TE, Marina NM, Zalamea N, Cox C, Phipps S, Pompeu R, Rosenthal D, Hudson, Melissa M, Rai, Shesh N, Nunez, Cesar, Merchant, Thomas E, Marina, Neyssa M, Zalamea, Nia, Cox, Cheryl, Phipps, Sean, Pompeu, Ronald, and Rosenthal, David
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- 2007
17. Survival and late mortality in long-term survivors of pediatric CNS tumors.
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Morris EB, Gajjar A, Okuma JO, Yasui Y, Wallace D, Kun LE, Merchant TE, Fouladi M, Broniscer A, Robison LL, and Hudson MM
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- 2007
18. 31P NMR of phospholipid glycerol phosphodiester residues.
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Merchant, TE, primary and Glonek, T, additional
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- 1990
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19. Late neurocognitive sequelae in survivors of brain tumours in childhood.
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Mulhern RK, Merchant TE, Gajjar A, Reddick WE, and Kun LE
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As survival among children treated for cancer continues to improve, more attention is being focussed on the late effects of cancer treatment. In children treated for brain tumours, chronic neurocognitive effects are especially challenging. Deficits in cognitive development have been described most thoroughly among children treated for posterior-fossa tumours, specifically medulloblastomas and ependymomas, which account for about 30% of all newly diagnosed cases of brain tumours in children. Most children who have survived brain tumours have required surgical resection and focal or craniospinal radiotherapy (irradiation of the entire subarachnoid volume of the brain and spine), with or without systemic chemotherapy. Historically, intelligence quotient (IQ) scores have provided a benchmark against which to measure changes in cognitive development after treatment. Observed declines in IQ are most likely a result of failure to learn at a rate that is appropriate for the age of the child, rather than from a loss of previously acquired knowledge. The rate of IQ decline is associated with a several risk factors, including younger age at time of treatment, longer time since treatment, female sex, as well as clinical variables such as hydrocephalus, use of radiotherapy and radiotherapy dose, and the volume of the brain that received treatment. Loss of cerebral white matter and failure to develop white matter at a rate appropriate to the developmental stage of the child could partly account for changes in IQ score. Technical advances in radiotherapy hold promise for lowering the frequency of neurocognitive sequelae. Further efforts to limit neurocognitive sequelae have included design of clinical trials to test the effectiveness of cognitive, behavioural, and pharmacological interventions. [ABSTRACT FROM AUTHOR]
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- 2004
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20. Children's distress in anticipation of radiation therapy procedures.
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Tyc VL, Klosky JL, Kronenberg M, de Armendi AJ, and Merchant TE
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We investigated levels of anticipatory distress in 80 pediatric patients, 2 to 7 years old, awaiting their initial radiation therapy (RT) procedure, and we examined demographic, medical, and psychosocial variables associated with their distress. Both observed behavior and heart rate outcomes were employed as measures of distress. Sixty-five percent of patients exhibited at least some degree of anticipatory behavioral distress prior to their RT simulation procedure. Thirty-four percent of patients displayed high levels of anticipatory behavioral distress; 16.3% exhibited high behavioral distress as well as high heart rates. Younger age and higher parent expectations of child distress were characteristic of children who displayed both high anticipatory behavioral distress and high heart rates. Child demographic factors, particularly younger age, were found to contribute significantly to the prediction of parent expectations of child distress. Implications for at-risk children in need of preparatory interventions for RT procedures are discussed. [ABSTRACT FROM AUTHOR]
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- 2002
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21. Predicting pediatric distress during radiation therapy procedures: the role of medical, psychosocial, and demographic factors.
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Klosky JL, Tyc VL, Tong X, Srivastava DK, Kronenberg M, de Armendi AJ, and Merchant TE
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- 2007
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22. Patterns of cognitive functioning among survivors of pediatric medulloblastoma: a longitudinal analysis.
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Palmer, SL, Glass, JO, Reddick, WE, Goloubeva, O, Gajjar, A, Merchant, TE, and Mulhern, RK
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- 2000
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23. Redesigning radiotherapy quality assurance: opportunities to develop an efficient, evidence-based system to support clinical trials--report of the National Cancer Institute Work Group on Radiotherapy Quality Assurance.
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Bekelman JE, Deye JA, Vikram B, Bentzen SM, Bruner D, Curran WJ Jr, Dignam J, Efstathiou JA, Fitzgerald TJ, Hurkmans C, Ibbott GS, Lee JJ, Merchant TE, Michalski J, Palta JR, Simon R, Ten Haken RK, Timmerman R, Tunis S, and Coleman CN
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Purpose: In the context of national calls for reorganizing cancer clinical trials, the National Cancer Institute sponsored a 2-day workshop to examine challenges and opportunities for optimizing radiotherapy quality assurance (QA) in clinical trial design.Methods and Materials: Participants reviewed the current processes of clinical trial QA and noted the QA challenges presented by advanced technologies. The lessons learned from the radiotherapy QA programs of recent trials were discussed in detail. Four potential opportunities for optimizing radiotherapy QA were explored, including the use of normal tissue toxicity and tumor control metrics, biomarkers of radiation toxicity, new radiotherapy modalities such as proton beam therapy, and the international harmonization of clinical trial QA.Results: Four recommendations were made: (1) to develop a tiered (and more efficient) system for radiotherapy QA and tailor the intensity of QA to the clinical trial objectives (tiers include general credentialing, trial-specific credentialing, and individual case review); (2) to establish a case QA repository; (3) to develop an evidence base for clinical trial QA and introduce innovative prospective trial designs to evaluate radiotherapy QA in clinical trials; and (4) to explore the feasibility of consolidating clinical trial QA in the United States.Conclusion: Radiotherapy QA can affect clinical trial accrual, cost, outcomes, and generalizability. To achieve maximum benefit, QA programs must become more efficient and evidence-based. [ABSTRACT FROM AUTHOR]- Published
- 2012
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24. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial [corrected] [published erratum appears in LANCET ONCOL 2006 Oct;7(10):797].
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Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, and Boyett JM
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BACKGROUND: Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. METHODS: After resection, patients were classified as having average-risk medulloblastoma (=1.5 cm(2) residual tumour and no metastatic disease) or high-risk medulloblastoma (>1.5 cm(2) residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with , number . FINDINGS: Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. INTERPRETATION: Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma. [ABSTRACT FROM AUTHOR]
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- 2006
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25. Multidisciplinary rounds. Rehabilitation of an adolescent with medulloblastoma.
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Cremer L, McGarvey CL, Copeland DR, Davis AB, and Merchant TE
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- 1998
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26. Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: A retrospective multicohort analysis
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Uri Tabori, Marta M. Alonso, Frank S. Lieberman, James T. Rutka, Xing Fan, Kevin Petrecca, Michael A. Grotzer, Lyndsey Emery, Jennifer A. Chan, Luca Massimi, Elizabeth Vera-Bolanos, Antonio Omuro, Richard Everson, Stewart Goldman, Sarah Leary, Alvaro Lassaletta, Sofia Nunes, Ralph P. Ermoian, Betty Luu, Cynthia Hawkins, Amulya A. Nageswara Rao, Jeffrey R. Leonard, Maura Massimino, Teresa Tuñón, Massimo Zollo, James M. Olson, Almos Klekner, Andrey Korshunov, Ute Bartels, Tong Lin, Roger J. Packer, Matthias A. Karajannis, David W. Ellison, Christopher Dunham, David D. Eisenstat, Jaume Mora, Martin Mynarek, Erwin G. Van Meir, Roger E. McLendon, Karel Zitterbart, Corrine Gardner, Giuseppe Cinalli, Amar Gajjar, Kenneth Aldape, Karin M. Muraszko, Vijay Ramaswamy, Thomas Hielscher, Ronald L. Hamilton, Lola B. Chambless, Michael D. Prados, David T.W. Jones, Harshad Ladha, Horacio Soto, Wiesława Grajkowska, Jason E. Cain, Felice Giangaspero, Marcel Kool, Eric S. Lipp, William H. Yong, Andrew J. Grossbach, Tibor Hortobágyi, Tarek Shalaby, Helen Wheeler, Peter Hauser, Marie Lise C. van Veelen, Kristian W. Pajtler, Dorcas Fulton, Mariarita Santi, László Bognár, Jaroslav Sterba, Jing Wu, Ji Yeoun Lee, Carlos Gilberto Carlotti, Katja von Hoff, Stefan Rutkowski, Michael D. Taylor, Daniela Pretti da Cunha Tirapelli, Phillipe Metellus, Stephen C. Mack, Thomas E. Merchant, Samer K. Elbabaa, Marc Remke, Girish Dhall, Riccardo Soffietti, Eric Bouffet, Miguel A. Guzman, Khalida Wani, Charles G. Eberhart, Terri S. Armstrong, Tom Mikkelsen, Francesca R. Buttarelli, Nada Jabado, Paul G. Fisher, Juliette Hukin, Maryam Fouladi, Sama Ahsan, Sueli Mieko Oba-Shinjo, Linda M. Liau, Satoru Osuka, Sridharan Gururangan, Peter B. Dirks, Eugene Hwang, Howard Colman, H. Ian Robins, Caterina Giannini, Suely Kazue Nagahashi Marie, Frank van Landeghem, Mark R. Gilbert, Ulrich Schüller, Florence M.G. Cavalli, David Zagzag, Ian F. Pollack, Claudia C. Faria, Stefan M. Pfister, Shin Jung, Ramaswamy, V, Hielscher, T, Mack, Sc, Lassaletta, A, Lin, T, Pajtler, Kw, Jones, Dt, Luu, B, Cavalli, Fm, Aldape, K, Remke, M, Mynarek, M, Rutkowski, S, Gururangan, S, Mclendon, Re, Lipp, E, Dunham, C, Hukin, J, Eisenstat, Dd, Fulton, D, van Landeghem, Fk, Santi, M, van Veelen, Ml, Van Meir, Eg, Osuka, S, Fan, X, Muraszko, Km, Tirapelli, Dp, Oba Shinjo, Sm, Marie, Sk, Carlotti, Cg, Lee, Jy, Rao, Aa, Giannini, C, Faria, Cc, Nunes, S, Mora, J, Hamilton, Rl, Hauser, P, Jabado, N, Petrecca, K, Jung, S, Massimi, L, Zollo, Massimo, Cinalli, G, Bognár, L, Klekner, A, Hortobágyi, T, Leary, S, Ermoian, Rp, Olson, Jm, Leonard, Jr, Gardner, C, Grajkowska, Wa, Chambless, Lb, Cain, J, Eberhart, Cg, Ahsan, S, Massimino, M, Giangaspero, F, Buttarelli, Fr, Packer, Rj, Emery, L, Yong, Wh, Soto, H, Liau, Lm, Everson, R, Grossbach, A, Shalaby, T, Grotzer, M, Karajannis, Ma, Zagzag, D, Wheeler, H, von Hoff, K, Alonso, Mm, Tuñon, T, Schüller, U, Zitterbart, K, Sterba, J, Chan, Ja, Guzman, M, Elbabaa, Sk, Colman, H, Dhall, G, Fisher, Pg, Fouladi, M, Gajjar, A, Goldman, S, Hwang, E, Kool, M, Ladha, H, Vera Bolanos, E, Wani, K, Lieberman, F, Mikkelsen, T, Omuro, Am, Pollack, If, Prados, M, Robins, Hi, Soffietti, R, Wu, J, Metellus, P, Tabori, U, Bartels, U, Bouffet, E, Hawkins, Ce, Rutka, Jt, Dirks, P, Pfister, Sm, Merchant, Te, Gilbert, Mr, Armstrong, T, Korshunov, A, Ellison, Dw, Taylor, M. d., Ramaswamy V., Hielscher T., Mack S.C., Lassaletta A., Lin T., Pajtler K.W., Jones D.T.W., Luu B., Cavalli F.M.G., Aldape K., Remke M., Mynarek M., Rutkowski S., Gururangan S., McLendon R.E., Lipp E.S., Dunham C., Hukin J., Eisenstat D.D., Fulton D., Van Landeghem F.K.H., Santi M., Van Veelen M.-L.C., Van Meir E.G., Osuka S., Fan X., Muraszko K.M., Tirapelli D.P.C., Oba-Shinjo S.M., Marie S.K.N., Carlotti C.G., Lee J.Y., Rao A.A.N., Giannini C., Faria C.C., Nunes S., Mora J., Hamilton R.L., Hauser P., Jabado N., Petrecca K., Jung S., Massimi L., Zollo M., Cinalli G., Bognar L., Klekner A., Hortobagyi T., Leary S., Ermoian R.P., Olson J.M., Leonard J.R., Gardner C., Grajkowska W.A., Chambless L.B., Cain J., Eberhart C.G., Ahsan S., Massimino M., Giangaspero F., Buttarelli F.R., Packer R.J., Emery L., Yong W.H., Soto H., Liau L.M., Everson R., Grossbach A., Shalaby T., Grotzer M., Karajannis M.A., Zagzag D., Wheeler H., Von Hoff K., Alonso M.M., Tunon T., Schuller U., Zitterbart K., Sterba J., Chan J.A., Guzman M., Elbabaa S.K., Colman H., Dhall G., Fisher P.G., Fouladi M., Gajjar A., Goldman S., Hwang E., Kool M., Ladha H., Vera-Bolanos E., Wani K., Lieberman F., Mikkelsen T., Omuro A.M., Pollack I.F., Prados M., Robins H.I., Soffietti R., Wu J., Metellus P., Tabori U., Bartels U., Bouffet E., Hawkins C.E., Rutka J.T., Dirks P., Pfister S.M., Merchant T.E., Gilbert M.R., Armstrong T.S., Korshunov A., Ellison D.W., Taylor M.D., and Neurosurgery
- Subjects
Male ,Ependymoma ,Cancer Research ,medicine.medical_treatment ,cancer research ,oncology ,posterior fossa ependymoma ,cytoreductive surgery ,radiation therapy ,Infratentorial Neoplasms ,Cohort Studies ,0302 clinical medicine ,Retrospective Studie ,Medicine ,Pediatric ependymoma ,Child ,10. No inequality ,Infratentorial Neoplasm ,biology ,Cytoreduction Surgical Procedures ,Combined Modality Therapy ,3. Good health ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,Radiology ,Human ,Adult ,medicine.medical_specialty ,Adolescent ,Fossa ,Ependymoma, biomarkers ,03 medical and health sciences ,Original Reports ,Humans ,Retrospective Studies ,Chemotherapy ,business.industry ,Proportional hazards model ,Infant ,Retrospective cohort study ,biology.organism_classification ,medicine.disease ,Surgery ,Radiation therapy ,Cohort Studie ,business ,030217 neurology & neurosurgery - Abstract
Purpose Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_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_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_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_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_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_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.
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- 2016
27. Radiation dose-volume effects in the brain.
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Lawrence YR, Li XA, el Naqa I, Hahn CA, Marks LB, Merchant TE, Dicker AP, Lawrence, Yaacov Richard, Li, X Allen, el Naqa, Issam, Hahn, Carol A, Marks, Lawrence B, Merchant, Thomas E, and Dicker, Adam P
- Abstract
We have reviewed the published data regarding radiotherapy (RT)-induced brain injury. Radiation necrosis appears a median of 1-2 years after RT; however, cognitive decline develops over many years. The incidence and severity is dose and volume dependent and can also be increased by chemotherapy, age, diabetes, and spatial factors. For fractionated RT with a fraction size of <2.5 Gy, an incidence of radiation necrosis of 5% and 10% is predicted to occur at a biologically effective dose of 120 Gy (range, 100-140) and 150 Gy (range, 140-170), respectively. For twice-daily fractionation, a steep increase in toxicity appears to occur when the biologically effective dose is >80 Gy. For large fraction sizes (>or=2.5 Gy), the incidence and severity of toxicity is unpredictable. For single fraction radiosurgery, a clear correlation has been demonstrated between the target size and the risk of adverse events. Substantial variation among different centers' reported outcomes have prevented us from making toxicity-risk predictions. Cognitive dysfunction in children is largely seen for whole brain doses of >or=18 Gy. No substantial evidence has shown that RT induces irreversible cognitive decline in adults within 4 years of RT. [ABSTRACT FROM AUTHOR]
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- 2010
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28. Central nervous system tumors in adolescents and young adults: A Society for Neuro-Oncology consensus review on diagnosis, management, and future directions.
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Lim-Fat MJ, Bennett J, Ostrom Q, Touat M, Franceschi E, Schulte J, Bindra RS, Fangusaro J, Dhall G, Nicholson J, Jackson S, Davidson TB, Calaminus G, Robinson G, Whittle JR, Hau P, Ramaswamy V, Pajtler KW, Rudà R, Foreman NK, Hervey-Jumper SL, Das S, Dirks P, Bi WL, Huang A, Merchant TE, Fouladi M, Aldape K, Van den Bent MJ, Packer RJ, Miller JJ, Reardon DA, Chang SM, Haas-Kogan D, Tabori U, Hawkins C, Monje M, Wen PY, Bouffet E, and Yeo KK
- Abstract
Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population. In this position paper from the Society for Neuro-Oncology (SNO), the diagnosis and management of CNS tumors in AYA is reviewed, focusing on the most common tumor types in this population, namely glioma, medulloblastoma, ependymoma, and CNS germ cell tumor. Current challenges and future directions specific to AYA are also highlighted. Finally, possible solutions to address barriers in the care of AYA patients are discussed, emphasizing the need for multidisciplinary and collaborative approaches that span the pediatric and adult paradigms of care, and incorporating advanced molecular testing, targeted therapy, and AYA-centered care., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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29. Radiotherapy for pediatric low-grade glioma.
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Bansal I and Merchant TE
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- Humans, Child, Glioma radiotherapy, Brain Neoplasms radiotherapy
- Abstract
Introduction: Radiotherapy is a highly effective treatment for pediatric low-grade glioma, serving as the standard for evaluating progression-free and overall survival, as well as vision preservation. Despite its proven efficacy, concerns about treatment complications have led to increased use of chemotherapy and targeted therapy, which are associated with poorer progression-free survival outcomes., Methods: This review by Indu Bansal and Thomas E. Merchant examines the indications, timing, and results of radiotherapy for pediatric low-grade glioma. The authors provide a comprehensive analysis of clinical management strategies, addressing the controversies surrounding the use and timing of radiotherapy compared to other therapies., Results: The review highlights that while radiotherapy is essential for certain patients, particularly those who are not candidates for complete resection due to the tumor's infiltrative nature or location, it is often deferred in favor of systemic therapies. This deferral can lead to significant morbidity, including poor visual outcomes. Reports indicate that systemic therapy negatively impacts progression-free survival in patients who eventually undergo radiotherapy. Newer radiotherapy techniques have been developed to minimize complications, offering potential benefits over traditional methods., Discussion: The evolving clinical management of pediatric low-grade glioma involves balancing the benefits of radiotherapy with concerns about its side effects. Although systemic therapies are increasingly favored, their associated inferior progression-free survival and potential for significant morbidity underscore the need for careful consideration of radiotherapy, particularly in older children, adolescents, or those with progressive disease post-systemic therapy. The emerging role of targeted therapy presents additional challenges, including uncertainties about long-term side effects and its interaction with radiotherapy. Further research is needed to optimize treatment strategies and improve outcomes for pediatric patients with low-grade glioma., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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30. Outcomes for children with recurrent/refractory atypical teratoid rhabdoid tumor: A single-institution study with molecular correlation.
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Carey SS, Huang J, Myers JR, Mostafavi R, Orr BA, Dhanda SK, Michalik LH, Tatevossian RG, Klimo P Jr, Boop F, Lu C, Sioson E, Zhou X, Nichols KE, Merchant TE, Ellison DW, Robinson GW, Onar-Thomas A, Gajjar A, and Upadhyaya SA
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- Humans, Male, Female, Child, Child, Preschool, Retrospective Studies, Infant, Adolescent, Survival Rate, Follow-Up Studies, Prognosis, Infant, Newborn, Biomarkers, Tumor genetics, Rhabdoid Tumor mortality, Rhabdoid Tumor therapy, Rhabdoid Tumor pathology, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local mortality, Teratoma mortality, Teratoma pathology, Teratoma therapy
- Abstract
Background: Survival data for recurrent pediatric atypical teratoid rhabdoid tumor (ATRT) and its association to molecular groups are extremely limited., Methods: Single-institution retrospective study of 64 children less than 21 years old with recurrent or treatment-refractory (progressive disease [PD]) ATRT treated at St. Jude Hospital from January 2000 to December 2020. Demographic, clinicopathologic, treatment, molecular grouping (SHH, TYR, and MYC) and germline data were collected. Progression-free survival (PFS2: time from PD to subsequent first progression) and overall survival (OSpostPD: time from PD to death/last follow-up) were estimated by Kaplan-Meier analysis., Results: Median age at and time from initial diagnosis to PD were 2.1 years (range: 0.5-17.9 years) and 5.4 months (range: 0.5-125.6 months), respectively. Only five of 64 children (7.8%) are alive at median follow-up of 10.9 (range: 4.2-18.1) years from PD. The 2/5-year PFS2 and OSpostPD were 3.1% (±1.8%)/1.6% (±1.1%) and 20.3% (±4.8%)/7.3% (±3.5%), respectively. Children with TYR group (n = 10) had a better OSpostPD compared to those with MYC (n = 11) (2-year survival estimates: 60.0% ± 14.3% vs. 18.2% ± 9.5%; p = .019), or those with SHH (n = 21; 4.8% ± 3.3%; p = .014). In univariate analyses, OSpostPD was better with older age at diagnosis (p = .037), female gender (p = .008), and metastatic site of PD compared to local or combined sites of PD (p < .001). Two-year OSpostPD for patients receiving any salvage therapy (n = 39) post PD was 33.3% ± 7.3%., Conclusions: Children with recurrent/refractory ATRT have dismal outcomes. Older age at diagnosis, female gender, TYR group, and metastatic site of PD were associated with relatively longer survival in our study., (© 2024 Wiley Periodicals LLC.)
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- 2024
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31. CT- and MR-based image-based data mining are consistent in the brain.
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Wilson LJ, Davey A, Vasquez Osorio E, Faught AM, Green A, Bulbeck H, Thomson A, Goddard J, McCabe MG, Merchant TE, van Herk M, and Aznar MC
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- Humans, Child, Child, Preschool, Adolescent, Young Adult, Male, Image Processing, Computer-Assisted methods, Female, Radiotherapy Planning, Computer-Assisted methods, Magnetic Resonance Imaging, Tomography, X-Ray Computed, Brain diagnostic imaging, Data Mining, Brain Neoplasms diagnostic imaging, Brain Neoplasms radiotherapy
- Abstract
Purpose: Image-based data mining (IBDM) is a voxel-based analysis technique to investigate dose-response. Most often, IBDM uses radiotherapy planning CTs because of their broad accessibility, however, it was unknown whether CT provided sufficient soft tissue contrast for brain IBDM. This study evaluates whether MR-based IBDM improves upon CT-based IBDM for studies of children with brain tumours., Methods: We compared IBDM pipelines using either CT- or MRI-based spatial normalisation in 128 children (ages 3.3-19.7 years) who received photon radiotherapy for primary brain tumours at a single institution. We quantified spatial-normalisation accuracy using contour comparison measures (centre-of-mass separation, average contour distance-to-agreement (DT
avg ), and Hausdorff distance) at multiple anatomic loci. We performed an end-to-end test of CT- and MRI-IBDM using modified clinical dose distributions and simulated effect labels to detect associations in pre-defined anatomic loci. Accuracy was assessed via sensitivity and specificity., Results: Spatial normalisation accuracy was comparable for both modalities, with a significant but small improvement for MRI compared to CT in all structures except the brainstem. The median (range) difference between the DTavg for the two pipelines was 0.37 (0.00-2.91) mm. The end-to-end test revealed no significant difference in sensitivity of the IBDM-identified regions for the two pipelines. Specificity slightly improved for MR-IBDM at the 99% significance level., Conclusion: CT-based IBDM was comparable to MR-based IBDM, despite a small advantage in spatial normalisation accuracy with MRI. The use of CT-IBDM over MR-IBDM is useful for multi-institutional retrospective IBDM studies, where the availability of standardised MRI data can be limited., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)- Published
- 2024
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32. Academic Readiness among Young Children Treated for Brain Tumors: A Multisite, Prospective, Longitudinal Trial.
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Somekh MR, Ashford JM, Swain MA, Harder LL, Carlson-Green BL, Wallace J, Kaner RJ, Billups CA, Onar-Thomas A, Ali JS, Harman JL, Merchant TE, Gajjar A, and Conklin HM
- Abstract
Background: Young children treated for central nervous system (CNS) malignancies are at high risk for difficulties with academic functioning due to increased vulnerability of the developing brain and missed early developmental opportunities. Extant literature examining academics in this population is limited. We investigated academic readiness, its clinical and demographic predictors, and its relationship with distal academic outcomes among patients treated for CNS tumors during early childhood., Methods: Seventy patients with newly diagnosed CNS tumors were treated on a prospective, longitudinal, multisite study with chemotherapy, with or without photon or proton irradiation. Patients underwent assessments of academic skills at baseline, six months, one year, and then annually for five years. Assessments measured academic readiness and academic achievement in reading and math., Results: Mixed linear models revealed slowed development of academic readiness skills over time. Socioeconomic status (SES) was predictive of academic readiness at all time points. Other demographic (eg, age at treatment) and clinical (eg, shunt status, treatment exposure) variables were not predictive of academic readiness. Distal reading difficulties were proportionally greater than normative expectations while math difficulties did not differ. Academic readiness was predictive of distal academic outcomes in reading and math., Conclusions: Treatment for CNS malignancies in early childhood appears to slow development of academic readiness skills, with SES predictive of risk. Academic readiness skills were predictive of subsequent academic achievement. A disproportionate number of long-term survivors performed below age-based expectations in reading. These findings suggest the need for monitoring and interventions targeting early academic skills in this population., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2024
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33. Histone serotonylation regulates ependymoma tumorigenesis.
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Chen HC, He P, McDonald M, Williamson MR, Varadharajan S, Lozzi B, Woo J, Choi DJ, Sardar D, Huang-Hobbs E, Sun H, Ippagunta SM, Jain A, Rao G, Merchant TE, Ellison DW, Noebels JL, Bertrand KC, Mack SC, and Deneen B
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- Animals, Female, Humans, Male, Mice, Brain Neoplasms pathology, Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Line, Tumor, Chromatin metabolism, Chromatin genetics, Disease Progression, DNA-Binding Proteins metabolism, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Transcription Factors metabolism, Tumor Microenvironment, Serotonergic Neurons metabolism, Serotonin metabolism, Carcinogenesis genetics, Carcinogenesis pathology, Carcinogenesis metabolism, Ependymoma genetics, Ependymoma metabolism, Ependymoma pathology, Histones chemistry, Histones metabolism
- Abstract
Bidirectional communication between tumours and neurons has emerged as a key facet of the tumour microenvironment that drives malignancy
1,2 . Another hallmark feature of cancer is epigenomic dysregulation, in which alterations in gene expression influence cell states and interactions with the tumour microenvironment3 . Ependymoma (EPN) is a paediatric brain tumour that relies on epigenomic remodelling to engender malignancy4,5 ; however, how these epigenetic mechanisms intersect with extrinsic neuronal signalling during EPN tumour progression is unknown. Here we show that the activity of serotonergic neurons regulates EPN tumorigenesis, and that serotonin itself also serves as an activating modification on histones. We found that inhibiting histone serotonylation blocks EPN tumorigenesis and regulates the expression of a core set of developmental transcription factors. High-throughput, in vivo screening of these transcription factors revealed that ETV5 promotes EPN tumorigenesis and functions by enhancing repressive chromatin states. Neuropeptide Y (NPY) is one of the genes repressed by ETV5, and its overexpression suppresses EPN tumour progression and tumour-associated network hyperactivity through synaptic remodelling. Collectively, this study identifies histone serotonylation as a key driver of EPN tumorigenesis, and also reveals how neuronal signalling, neuro-epigenomics and developmental programs are intertwined to drive malignancy in brain cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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34. Motor and sensory impairment in survivors of childhood central nervous system (CNS) tumors in the St. Jude Lifetime Cohort (SJLIFE).
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Rodwin RL, Wang F, Lu L, Li Z, Srivastava DK, Phillips NS, Khan RB, Brinkman TM, Krull KR, Boop FA, Armstrong GT, Merchant TE, Gajjar A, Robison LL, Hudson MM, Kadan-Lottick NS, and Ness KK
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- Humans, Female, Male, Adolescent, Adult, Young Adult, Middle Aged, Child, Prevalence, Cohort Studies, Sensation Disorders etiology, Sensation Disorders epidemiology, Aged, Central Nervous System Neoplasms epidemiology, Cancer Survivors statistics & numerical data, Quality of Life
- Abstract
Background: Survivors of childhood central nervous system (CNS) tumors can develop motor and sensory impairment from their cancer and treatment history. We estimated the prevalence of motor and sensory impairment in survivors compared with controls through clinical assessment and identified associated treatment exposures and functional, quality of life (QOL), and social outcomes., Methods: Survivors of childhood CNS tumors from the St. Jude Lifetime Cohort (n = 378, median [range] age 24.0 [18.0-53.0] years, 43.4% female) ≥5 years from diagnosis and controls (n = 445, median [range] age 34.0 [18.0-70.0] years, 55.7% female) completed in-person evaluation for motor and sensory impairment using the modified Total Neuropathy Score. Impairment was graded by modified Common Terminology Criteria for Adverse Events. Multivariable models estimated associations between grade ≥2 motor/sensory impairment, individual/treatment characteristics, and secondary outcomes (function by Physical Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form-36 physical/mental summary scores, social attainment)., Results: Grade ≥2 motor or sensory impairment was more prevalent in survivors (24.1%, 95% Confidence Interval [CI] 19.8%-29.4%) than controls (2.9%, CI 1.4-4.5%). Among survivors, in multivariable models, motor impairment was associated with vinca exposure <15 mg/m
2 versus none (OR 4.38, CI 1.06-18.08) and etoposide exposure >2036 mg/m2 versus none (OR 12.61, CI 2.19-72.72). Sensory impairment was associated with older age at diagnosis (OR 1.09, CI 1.01-1.16) and craniospinal irradiation versus none (OR 4.39, CI 1.68-11.50). There were lower odds of motor/sensory impairment in survivors treated in the year 2000 or later versus before 1990 (Motor: OR 0.29, CI 0.10-0.84, Sensory: OR 0.35, CI 0.13-0.96). Motor impairment was associated with impaired physical QOL (OR 2.64, CI 1.22-5.72)., Conclusions: In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation. Treating motor impairment may improve survivors' QOL., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)- Published
- 2024
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35. Memory T-cell enriched haploidentical transplantation with NK cell addback results in promising long-term outcomes: a phase II trial.
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Naik S, Li Y, Talleur AC, Selukar S, Ashcraft E, Cheng C, Madden RM, Mamcarz E, Qudeimat A, Sharma A, Srinivasan A, Suliman AY, Epperly R, Obeng EA, Velasquez MP, Langfitt D, Schell S, Métais JY, Arnold PY, Hijano DR, Maron G, Merchant TE, Akel S, Leung W, Gottschalk S, and Triplett BM
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- Humans, Female, Male, Child, Adolescent, Child, Preschool, Graft vs Host Disease prevention & control, Graft vs Host Disease etiology, Infant, Young Adult, Adult, Treatment Outcome, Graft vs Leukemia Effect, Killer Cells, Natural transplantation, Killer Cells, Natural immunology, Transplantation, Haploidentical methods, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cell Transplantation adverse effects, Transplantation Conditioning methods, Memory T Cells, Hematologic Neoplasms therapy
- Abstract
Background: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen., Methods: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy., Results: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72-98) and 88% (95% CI: 67-96); ≥ CR2 were 81% (95% CI: 61-92) and 68% (95% CI: 47-82) and refractory disease were 32% (95% CI: 11-54) and 20% (95% CI: 6-40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64-87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035)., Conclusion: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611)., (© 2024. The Author(s).)
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- 2024
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36. Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review.
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Ajithkumar T, Avanzo M, Yorke E, Tsang DS, Milano MT, Olch AJ, Merchant TE, Dieckmann K, Mahajan A, Fuji H, Paulino AC, Timmermann B, Marks LB, Bentzen SM, Jackson A, and Constine LS
- Subjects
- Humans, Child, Adolescent, Ependymoma radiotherapy, Young Adult, Child, Preschool, Medulloblastoma radiotherapy, Radiation Injuries pathology, Re-Irradiation adverse effects, Necrosis etiology, Neoplasm Recurrence, Local radiotherapy, Central Nervous System Neoplasms radiotherapy, Central Nervous System Neoplasms pathology, Brain radiation effects, Brain pathology, Brain Stem radiation effects, Brain Stem pathology
- Abstract
Purpose: Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation., Methods and Materials: A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies., Results: Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD2
2 ; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46)., Conclusions: Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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37. Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.
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Sienna J, Kahalley LS, Mabbott D, Grosshans D, Santiago AT, Paulino ADC, Merchant TE, Manzar GS, Dama H, Hodgson DC, Chintagumpala M, Okcu MF, Whitehead WE, Laperriere N, Ramaswamy V, Bartels U, Tabori U, Bennett JM, Das A, Craig T, and Tsang DS
- Subjects
- Child, Humans, Protons, Retrospective Studies, Drug Tapering, Brain radiation effects, Cognition radiation effects, Radiotherapy Dosage, Medulloblastoma radiotherapy, Proton Therapy adverse effects, Cerebellar Neoplasms radiotherapy
- Abstract
Purpose: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy., Methods and Materials: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores., Results: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores., Conclusions: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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38. [11C]-methionine positron emission tomography in the evaluation of pediatric low-grade gliomas.
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Kim EY, Vavere AL, Snyder SE, Chiang J, Li Y, Patni T, Qaddoumi I, Merchant TE, Robinson GW, Holtrop JL, Shulkin BL, and Bag AK
- Abstract
Background: [
11 C]-Methionine positron emission tomography (PET; [11 C]-MET-PET) is principally used for the evaluation of brain tumors in adults. Although amino acid PET tracers are more commonly used in the evaluation of pediatric brain tumors, data on [11 C]-MET-PET imaging of pediatric low-grade gliomas (pLGG) is scarce. This study aimed to investigate the roles of [11 C]-MET-PET in the evaluation of pLGGs., Methods: Eighteen patients with newly diagnosed pLGG and 26 previously treated pLGG patients underwent [11 C]-MET-PET met the inclusion and exclusion criteria. Tumor-to-brain uptake ratio (TBR) and metabolic tumor volumes were assessed for diagnostic performances (newly diagnosed, 15; previously treated 26), change with therapy (newly diagnosed, 9; previously treated 7), and variability among different histology ( n = 12) and molecular markers ( n = 7) of pLGGs., Results: The sensitivity of [11 C]-MET-PET for diagnosing pLGG, newly diagnosed, and previously treated combined was 93% for both TBRmax and TBRpeak , 76% for TBRmean , and 95% for qualitative evaluation. TBRmax showed a statistically significant reduction after treatment, while other PET parameters showed a tendency to decrease. Median TBRmax , TBRpeak , and TBRmean values were slightly higher in the BRAFV600E mutated tumors compared to the BRAF fused tumors. Median TBRmax , and TBRpeak in diffuse astrocytomas were higher compared to pilocytic astrocytomas, but median TBRmean , was slightly higher in pilocytic astrocytomas. However, formal statistical analysis was not done due to the small sample size., Conclusions: Our study shows that [11 C]-MET-PET reliably characterizes new and previously treated pLGGs. Our study also shows that quantitative parameters tend to decrease with treatment, and differences may exist between various pLGG types., Competing Interests: Financial disclosure: No potential conflicts of interest relevant to this article exist. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)- Published
- 2024
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39. Prediabetes and Associated Risk of Cardiovascular Events and Chronic Kidney Disease Among Adult Survivors of Childhood Cancer in the St Jude Lifetime Cohort.
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Dixon SB, Wang F, Lu L, Wilson CL, Green DM, Merchant TE, Srivastava DK, Delaney A, Howell RM, Jefferies JL, Robison LL, Ness KK, Hudson MM, Chemaitilly W, and Armstrong GT
- Subjects
- Adult, Humans, Child, Middle Aged, Risk Factors, Survivors, Prediabetic State epidemiology, Prediabetic State diagnosis, Cancer Survivors, Neoplasms drug therapy, Diabetes Mellitus epidemiology, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic complications, Stroke
- Abstract
Purpose: Little is known about the prevalence of prediabetes and associated risk of cardiovascular events and chronic kidney disease (CKD) with this reversable condition in survivors., Methods: Prevalence of prediabetes (fasting plasma glucose 100-125 mg/dL or hemoglobin A1c 5.7%-6.4%) and diabetes was clinically assessed in 3,529 adults ≥5 years from childhood cancer diagnosis and 448 controls stratified by age. Cox proportional hazards regression estimated progression from prediabetes to diabetes, and risk of future cardiac events, stroke, CKD, and death., Results: Among survivors, median age 30 years (IQR, 18-65), and the prevalence of prediabetes was 29.2% (95% CI, 27.7 to 30.7) versus 18.1% (14.5 to 21.6) in controls and of diabetes was 6.5% (5.7 to 7.3) versus 4.7% (2.7 to 6.6). By age 40-49 years, more than half of the survivors had prediabetes (45.5%) or diabetes (14.0%). Among 695 survivors with prediabetes and longitudinal follow-up, 68 (10%; median follow-up, 5.1 years) progressed to diabetes. After adjustment for demographic factors and body composition, risk of progression was associated with radiation exposure to the pancreatic tail ≥10 Gy (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.8]) and total-body irradiation (4.4 [1.5 to 13.1]). Compared with survivors with normal glucose control, adjusting for relevant treatment exposures, those with prediabetes were at increased risk of future myocardial infarction (HR, 2.4 [95% CI, 1.2 to 4.8]) and CKD (2.9 [1.04 to 8.15]), while those with diabetes were also at increased risk of future cardiomyopathy (3.8 [1.4 to 10.5]) or stroke (3.4 [1.3 to 8.9])., Conclusion: Prediabetes is highly prevalent in adult survivors of childhood cancer and independently associated with an increased risk of future cardiovascular and kidney complications. Prediabetes, a modifiable risk factor among childhood cancer survivors, represents a new target for intervention that may prevent subsequent morbidity and mortality.
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- 2024
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40. Performance analysis and knowledge-based quality assurance of critical organ auto-segmentation for pediatric craniospinal irradiation.
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Hanna EM, Sargent E, Hua CH, Merchant TE, and Ates O
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- Humans, Child, Neural Networks, Computer, Organs at Risk, Radiotherapy Planning, Computer-Assisted methods, Image Processing, Computer-Assisted methods, Tomography, X-Ray Computed, Craniospinal Irradiation
- Abstract
Craniospinal irradiation (CSI) is a vital therapeutic approach utilized for young patients suffering from central nervous system disorders such as medulloblastoma. The task of accurately outlining the treatment area is particularly time-consuming due to the presence of several sensitive organs at risk (OAR) that can be affected by radiation. This study aimed to assess two different methods for automating the segmentation process: an atlas technique and a deep learning neural network approach. Additionally, a novel method was devised to prospectively evaluate the accuracy of automated segmentation as a knowledge-based quality assurance (QA) tool. Involving a patient cohort of 100, ranging in ages from 2 to 25 years with a median age of 8, this study employed quantitative metrics centered around overlap and distance calculations to determine the most effective approach for practical clinical application. The contours generated by two distinct methods of atlas and neural network were compared to ground truth contours approved by a radiation oncologist, utilizing 13 distinct metrics. Furthermore, an innovative QA tool was conceptualized, designed for forthcoming cases based on the baseline dataset of 100 patient cases. The calculated metrics indicated that, in the majority of cases (60.58%), the neural network method demonstrated a notably higher alignment with the ground truth. Instances where no difference was observed accounted for 31.25%, while utilization of the atlas method represented 8.17%. The QA tool results showed that the two approaches achieved 100% agreement in 39.4% of instances for the atlas method and in 50.6% of instances for the neural network auto-segmentation. The results indicate that the neural network approach showcases superior performance, and its significantly closer physical alignment to ground truth contours in the majority of cases. The metrics derived from overlap and distance measurements have enabled clinicians to discern the optimal choice for practical clinical application., (© 2024. The Author(s).)
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- 2024
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41. Evaluating the Impact of Bowel Gas Variations for Wilms' Tumor in Pediatric Proton Therapy.
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Ates O, Pirlepesov F, Uh J, Hua CH, Merchant TE, Boria A, Davidoff AM, Graetz DE, and Krasin MJ
- Abstract
(1) Background: Proton therapy, a precise form of radiation treatment, can be significantly affected by variations in bowel content. The purpose was to identify the most beneficial gantry angles that minimize deviations from the treatment plan quality, thus enhancing the safety and efficacy of proton therapy for Wilms' tumor patients. (2) Methods: Thirteen patients with Wilms' tumor, enrolled in the SJWT21 clinical trial, underwent proton therapy. The variations in bowel gas were systematically monitored using daily Cone Beam Computed Tomography (CBCT) imaging. Air cavities identified in daily CBCT images were analyzed to construct daily verification plans and measure water equivalent path length (WEPL) changes. A worst-case scenario simulation was conducted to identify the safest beam angles. (3) Results: The study revealed a maximum decrease in target dose (ΔD100%) of 8.0%, which corresponded to a WEPL variation (ΔWEPL) of 11.3 mm. The average reduction in target dose, denoted as mean ΔD100%, was found to be 2.8%, with a standard deviation (SD) of 3.2%. The mean ΔWEPL was observed as 3.3 mm, with an SD of 2.7 mm. The worst-case scenario analysis suggested that gantry beam angles oriented toward the patient's right and posterior aspects from 110° to 310° were associated with minimized WEPL discrepancies. (4) Conclusions: This study comprehensively evaluated the influence of bowel gas variability on treatment plan accuracy and proton range uncertainties in pediatric proton therapy for Wilms' tumor.
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- 2024
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42. Performance and symptom validity indicators among children undergoing cognitive surveillance following treatment for craniopharyngioma.
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Potter BS, Crabtree VM, Ashford JM, Li Y, Liang J, Guo Y, Wise MS, Skoda ES, Merchant TE, and Conklin HM
- Abstract
Background: Performance validity tests (PVTs) and symptom validity tests (SVTs) are essential to neuropsychological evaluations, helping ensure findings reflect true abilities or concerns. It is unclear how PVTs and SVTs perform in children who received radiotherapy for brain tumors. Accordingly, we investigated the rate of noncredible performance on validity indicators as well as associations with fatigue and lower intellectual functioning., Methods: Embedded PVTs and SVTs were investigated in 98 patients with pediatric craniopharyngioma undergoing proton radiotherapy (PRT). The contribution of fatigue, sleepiness, and lower intellectual functioning to embedded PVT performance was examined. Further, we investigated PVTs and SVTs in relation to cognitive performance at pre-PRT baseline and change over time., Results: SVTs on parent measures were not an area of concern. PVTs identified 0-31% of the cohort as demonstrating possible noncredible performance at baseline, with stable findings 1 year following PRT. Reliable digit span (RDS) noted the highest PVT failure rate; RDS has been criticized for false positives in pediatric populations, especially children with neurological impairment. Objective sleepiness was strongly associated with PVT failure, stressing need to consider arousal level when interpreting cognitive performance in children with craniopharyngioma. Lower intellectual functioning also needs to be considered when interpreting task engagement indices as it was strongly associated with PVT failure., Conclusions: Embedded PVTs should be used with caution in pediatric craniopharyngioma patients who have received PRT. Future research should investigate different cut-off scores and validity indicator combinations to best differentiate noncredible performance due to task engagement versus variable arousal and/or lower intellectual functioning., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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43. The feasibility and acceptability of mobile ecological momentary assessment to evaluate sleep, family functioning, and affect in patients with pediatric craniopharyngioma.
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Al Ghriwati N, Winter M, Semko J, Merchant TE, and Crabtree VM
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- Child, Adolescent, Humans, Ecological Momentary Assessment, Feasibility Studies, Sleep, Craniopharyngioma therapy, Pituitary Neoplasms therapy, Sleep Wake Disorders
- Abstract
Purpose/objectives: We aimed to assess the feasibility and acceptability of mobile ecological momentary assessment (mEMA) for youth with craniopharyngioma and evaluate daily associations among family functioning, affect, and sleep difficulties., Design/research Approach: Youth completed two mEMA diaries per day for one week., Sample/participants: Thirty-nine youth who underwent surgery and proton radiotherapy (when indicated) for craniopharyngioma., Methods/methodological Approach: Descriptive statistics and multi-level modeling were used to examine feasibility and acceptability of mEMA and daily associations among family functioning, affect, and sleep., Findings: Youth reported satisfaction and minimal burden from completing daily mEMA diaries. Poorer family functioning was not related to lower sleep efficiency., Conclusions/interpretation: mEMA is an acceptable and feasible method for evaluating sleep and related variables in children and adolescents with craniopharyngioma., Implications for Psychosocial Providers or Policy: Results highlight the utility of gathering mEMA data in youth at elevated risk for sleep difficulties as a function of their illness/treatment.
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- 2024
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44. Sleep-related challenges and family functioning in children and adolescents previously treated for craniopharyngioma.
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Semko J, Al Ghriwati N, Winter M, Merchant TE, and Crabtree VM
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- Child, Humans, Adolescent, Sleep, Self Report, Craniopharyngioma therapy, Disorders of Excessive Somnolence, Pituitary Neoplasms therapy
- Abstract
Purpose: We investigated sleep-related challenges and their association with family functioning in children and adolescents previously treated for craniopharyngioma., Design: Quantitative approach using psychometrically validated measures., Sample: Thirty-nine children and adolescents who had been treated for craniopharyngioma and their primary caregivers., Methods: Caregivers and youth completed measures of family functioning, family routines, daytime sleepiness, and children's sleep patterns., Findings: Children and adolescents with craniopharyngioma had significantly higher ratings of self-reported excessive daytime sleepiness, bedtime fears/worries, and restless legs symptoms compared to their relatively healthy peers. Lack of family routines and poor family functioning were related to poor sleep-related outcomes and increased excessive daytime sleepiness., Implications for Psychosocial Providers: Providers should consider assessing sleep difficulties in pediatric brain tumor survivors from a family systems perspective. Intervening on family-related factors may help improve sleep and other health-related outcomes, whereas intervening on sleep may help improve family functioning.
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- 2024
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45. Shifting Strategies in the Treatment of Pediatric Craniopharyngioma.
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Gabay S, Merchant TE, Boop FA, Roth J, and Constantini S
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- Child, Humans, Quality of Life, Retrospective Studies, Combined Modality Therapy, Treatment Outcome, Craniopharyngioma surgery, Craniopharyngioma pathology, Pituitary Neoplasms surgery
- Abstract
Purpose of Review: Craniopharyngiomas represent one of the most challenging diseases to treat. Despite their benign histology, and after many decades of surgical experience and technological advancements, there is still no clear consensus regarding the most effective management for this tumor. Due to their location and aggressive local characteristics, purely surgical approaches all too often result in unacceptable morbidity., Recent Findings: Partial resection combined with radiation therapy results in similar control rates when compared to aggressive surgery, while also minimalizing the neuro-endocrinological morbidity. In this manuscript, we describe the historical progression of the shifting strategies in the management of pediatric craniopharyngioma. Time has also altered our expectations for outcomes, evolving from purely morbidity and mortality to simple Glasgow Outcomes Scales, now to formal neuro-psychometric and quality of life data., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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46. Setup Uncertainty of Pediatric Brain Tumor Patients Receiving Proton Therapy: A Prospective Study.
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Becksfort J, Uh J, Saunders A, Byrd JA, Worrall HM, Marker M, Melendez-Suchi C, Li Y, Chang J, Raghavan K, Merchant TE, and Hua CH
- Abstract
This study quantifies setup uncertainty in brain tumor patients who received image-guided proton therapy. Patients analyzed include 165 children, adolescents, and young adults (median age at radiotherapy: 9 years (range: 10 months to 24 years); 80 anesthetized and 85 awake) enrolled in a single-institution prospective study from 2020 to 2023. Cone-beam computed tomography (CBCT) was performed daily to calculate and correct manual setup errors, once per course after setup correction to measure residual errors, and weekly after treatments to assess intrafractional motion. Orthogonal radiographs were acquired consecutively with CBCT for paired comparisons of 40 patients. Translational and rotational errors were converted from 6 degrees of freedom to a scalar by a statistical approach that considers the distance from the target to the isocenter. The 95th percentile of setup uncertainty was reduced by daily CBCT from 10 mm (manual positioning) to 1-1.5 mm (after correction) and increased to 2 mm by the end of fractional treatment. A larger variation existed between the roll corrections reported by radiographs vs. CBCT than for pitch and yaw, while there was no statistically significant difference in translational variation. A quantile mixed regression model showed that the 95th percentile of intrafractional motion was 0.40 mm lower for anesthetized patients (p=0.0016). Considering additional uncertainty in radiation-imaging isocentricity, the commonly used total plan robustness of 3 mm against positional uncertainty would be appropriate for our study cohort.
- Published
- 2023
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47. Novel Monthly Quality Assurance Regimen and 5-Year Analysis Using a Proton Metrology System.
- Author
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Ates O, Faught J, Pirlepesov F, Sobczak D, Hua CH, and Merchant TE
- Abstract
Purpose: To develop a novel, monthly quality assurance (QA) regimen for a proton therapy system that uses 2 custom phantoms, each housing a commercial scintillator detector and a charge-coupled device camera. The novel metrology system assessed QA trends at a pediatric proton therapy center from 2018 to 2022., Materials and Methods: The measurement system was designed to accommodate horizontal and vertical positioning of the commercial device and to enable gantry and couch isocentricity measurements (using a star shot procedure), proton spot profile verification, and imaging and radiation congruence tests to be performed simultaneously in the dual-phantom setup. Gantry angles and proton beam energies were varied and alternated each month, using gantry angles of 0°, 30°, 60°, 90°, 120°, 150°, and 180° and discrete beam energies of 69.4, 84.5, 100, 139.1, 180.4, 200.4, and 221.3 MeV after radiographic verification. A total of 1176 individual monthly QA measurements of gantry and couch isocentricity, spot size, and congruence were analyzed., Results: Gantry and couch star shot measurements showed beam isocentricities of 0.3 ± 0.2 mm and 0.2 ± 0.2 mm, respectively, which were within the threshold of 1.0 mm. Spot sizes for each discrete energy were within the threshold of ± 10% of the baseline values for all 3 proton rooms. The imaging and radiation coincidence test results for the 1176 individual monthly QA measurements were 0.5 mm for the 50
th percentile and 1.2 mm (the clinical threshold) for the 97.6th percentile., Conclusions: Integrating a commercial device with custom phantoms improved the quality of proton system checks compared with previous methods using radiochromic films, loose ball bearings, and foam. The scheme of alternating beam angles with discrete energies in the monthly QA-enabled, clinically meaningful verification of beam energy and gantry angle combinations while the machine performance and accuracy were being checked., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose., (©Copyright 2023 The Author(s).)- Published
- 2023
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48. Interplay Effect of Splenic Motion for Total Lymphoid Irradiation in Pediatric Proton Therapy.
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Ates O, Uh J, Pirlepesov F, Hua CH, Triplett B, Qudeimat A, Sharma A, Merchant TE, and Lucas JT Jr
- Abstract
(1) Background: The most significant cause of an unacceptable deviation from the planned dose during respiratory motion is the interplay effect. We examined the correlation between the magnitude of splenic motion and its impact on plan quality for total lymphoid irradiation (TLI); (2) Methods: Static and 4D CT images from ten patients were used for interplay effect simulations. Patients' original plans were optimized based on the average CT extracted from the 4D CT and planned with two posterior beams using scenario-based optimization (±3 mm of setup and ±3% of range uncertainty) and gradient matching at the level of mid-spleen. Dynamically accumulated 4D doses (interplay effect dose) were calculated based on the time-dependent delivery sequence of radiation fluence across all phases of the 4D CT. Dose volume parameters for each simulated treatment delivery were evaluated for plan quality; (3) Results: Peak-to-peak splenic motion (≤12 mm) was measured from the 4D CT of ten patients. Interplay effect simulations revealed that the ITV coverage of the spleen remained within the protocol tolerance for splenic motion, ≤8 mm. The D100% coverage for ITV spleen decreased from 95.0% (nominal plan) to 89.3% with 10 mm and 87.2% with 12 mm of splenic motion; (4) Conclusions: 4D plan evaluation and robust optimization may overcome problems associated with respiratory motion in proton TLI treatments. Patient-specific respiratory motion evaluations are essential to confirming adequate dosimetric coverage when proton therapy is utilized.
- Published
- 2023
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49. Social determinants of cognitive outcomes in survivors of pediatric brain tumors treated with conformal radiation therapy.
- Author
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Mule' TN, Hodges J, Wu S, Li Y, Ashford JM, Merchant TE, and Conklin HM
- Subjects
- Child, Humans, Female, Male, Prospective Studies, Social Determinants of Health, Intelligence, Cognition, Survivors, Brain Neoplasms pathology, Pituitary Neoplasms
- Abstract
Background: Social determinants of health including parental occupation, household income, and neighborhood environment are predictors of cognitive outcomes among healthy and ill children; however, few pediatric oncology studies have investigated this relationship. This study utilized the Economic Hardship Index (EHI) to measure neighborhood-level social and economic conditions to predict cognitive outcomes among children treated for brain tumors (BT) with conformal radiation therapy (RT)., Methods: Two hundred and forty-one children treated on a prospective, longitudinal, phase II trial of conformal photon RT (54-59.4 Gy) for ependymoma, low-grade glioma, or craniopharyngioma (52% female, 79% white, age at RT = 7.76 ± 4.98 years) completed serial cognitive assessments (intelligence quotient [IQ], reading, math, and adaptive functioning) for ten years. Six US census tract-level EHI scores were calculated for an overall EHI score: unemployment, dependency, education, income, crowded housing, and poverty. Established socioeconomic status (SES) measures from the extant literature were also derived., Results: Correlations and non-parametric tests revealed EHI variables share modest variance with other SES measures. Income, unemployment, and poverty overlapped most with individual SES measures. Linear mixed models, accounting for sex, age at RT, and tumor location, revealed EHI variables predicted all cognitive variables at baseline and change in IQ and math over time, with EHI overall and poverty most consistent predictors. Higher economic hardship was associated with lower cognitive scores., Conclusions: Neighborhood-level measures of socioeconomic conditions can help inform understanding of long-term cognitive and academic outcomes in survivors of pediatric BT. Future investigation of poverty's driving forces and the impact of economic hardship on children with other catastrophic diseases is needed., (© The Author(s) 2023. 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.)
- Published
- 2023
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50. Social cognition and adjustment in adult survivors of pediatric central nervous system tumors.
- Author
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Papini C, Willard VW, Gajjar A, Merchant TE, Srivastava D, Armstrong GT, Hudson MM, Krull KR, and Brinkman TM
- Subjects
- Child, Adult, Humans, Female, Male, Social Cognition, Survivors, Social Adjustment, Cognition physiology, Central Nervous System Neoplasms radiotherapy, Central Nervous System Neoplasms epidemiology, Cognition Disorders epidemiology
- Abstract
Background: Survivors of pediatric central nervous system (CNS) tumors are at risk for neurocognitive and social difficulties throughout childhood. This study characterized social cognition (perception and reasoning from social cues) and adjustment in adulthood., Methods: A total of 81 adult survivors of pediatric CNS tumors (51% female; mean [SD] age, 28.0 [5.8] years), were recruited across four groups: (1) no radiation therapy (RT) [n = 21], (2) infratentorial (IT) tumors + focal RT [n = 20], (3) IT tumors + craniospinal irradiation [n = 20], and (4) supratentorial tumors + focal RT [n = 20]. Prevalence of social cognitive and adjustment impairments was compared to test norms. Multivariable models examined clinical and neurocognitive predictors of social cognition and its impact on functional outcomes., Results: Survivors demonstrated elevated risk of severe social cognitive impairments (social perception Morbidity Ratio [95% CI] 5.70 [3.46-9.20]), but self-reported few social adjustment problems. Survivors of IT tumors treated with craniospinal irradiation performed nearly 1 SD worse than survivors treated without RT on multiple measures of social cognition (e.g., social perception: β = -0.89, p = .004). Impaired executive functioning and nonverbal reasoning were associated with worse social cognitive performance (e.g., social perception: β = -0.75, p < .001; β = -0.84, p < .001, respectively). Better social perception was associated with higher odds of attaining full-time employment (odds ratio, 1.52 [1.17-1.97]) and at least some college education (odds ratio, 1.39 [1.11-1.74])., Conclusions: Adult survivors of CNS tumors are at elevated risk of severely impaired social cognition, but do not perceive social adjustment difficulties. Better understanding of potential mechanisms underlying social cognitive deficits may inform intervention targets to promote better functional outcomes for at-risk survivors., (© 2023 American Cancer Society.)
- Published
- 2023
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- View/download PDF
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