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The purpose of this study was to define the prevalence of and risk factors for elevated serum alanine aminotransferase (ALT) level among adult childhood cancer survivors (CCS). The study cohort comprised 2,751 CCS from the St. Jude Lifetime Cohort Study (>10 years postdiagnosis, age ≥18 years). Serum ALT level was graded using the Common Terminology Criteria for Adverse Events v. 4.03. Modified Poisson regression models were used to estimate relative risks and 95% confidence intervals for the association between demographic and clinical factors and grades 1-4 ALT on the selected models. A total of 1,339 (48.7%) CCS were female; 2,271 (82.6%) were non-Hispanic white. Median age at evaluation was 31.4 years (interquartile range [IQR] = 25.8-37.8); median elapsed time from diagnosis to evaluation was 23.2 years (IQR = 17.6-29.7). A total of 1,137 (41.3%) CSS had ALT > upper limit of normal (Common Terminology Criteria for Adverse Events v. 4.03 grade 1-1,058 (38.5%); grade 2-56 (2.0%); grade 3-23 (0.8%); grade 4-none). Multivariable models demonstrated non-Hispanic white race/ethnicity, age at evaluation in years, being overweight or obese, presence of the metabolic syndrome, current treatment with atorvastatin or rosuvastatin or simvastatin, hepatitis C virus infection, prior treatment with busulfan or thioguanine, history of hepatic surgery, and the percentage of liver treated with ≥10 Gray, ≥15 Gray, or ≥20 Gray were associated with elevated ALT. Conclusion: Grade 3 or 4 hepatic injury is infrequent in CCS. Mild hepatic injury in this group may be amenable to lifestyle modifications., (© 2018 by the American Association for the Study of Liver Diseases.)

Background: Intensification of systemic therapy for high-risk neuroblastoma (HRNB) has resulted in improved local control and overall survival (OS) leaving potential for de-escalation of primary site radiotherapy. The utility of primary site de-escalation should be evaluated in the context of potential for successful local-regional salvage. We evaluated salvage strategies and outcomes in patients with HRNB with local-regional recurrence as a component of first failure., Methods: Twenty of 89 patients with HRNB experienced local-regional recurrence as a component of first relapse after chemotherapy, radiotherapy, surgery, and stem cell transplant from 1997 to 2013. We reviewed salvage therapy strategies and disease control, and report on the impact of local therapy as salvage for local-regional relapse., Results: Six of 20 patients with local-regional failure (LRF) were alive after a median follow-up of 13 years (range, 0.9-25.2 years). Median OS was 4.6 years (95% CI, 0.6 to not reached) versus 0.6 years (95% CI, 0.05-2.6) after LRF with and without distant failure, respectively (P = 0.03). OS in patients receiving salvage radiotherapy was comparable to those receiving initial adjuvant but no salvage radiotherapy. Time to first failure and death was significantly impacted by the intensity of frontline systemic therapy (P = 0.03). Salvage radiotherapy reduced the hazard for subsequent LRF (hazard ratio 0.3, 95% CI 0.1-0.9, P = 0.04) but not OS (P = 0.07)., Conclusions: Our study highlights the potential of local control strategies at first failure in patients with LRF when primary site radiotherapy was initially omitted, and delineates potential selection factors which may further improve the therapeutic ratio., (© 2018 Wiley Periodicals, Inc.)

Background and Purpose: Limited data exist detailing the role of salvage reirradiation following local-regional recurrence (LR) in previously irradiated pediatric patients with rhabdomyosarcoma (RMS)., Materials and Methods: We evaluated outcomes and prognostic factors in a multi-institutional cohort of 23 patients with LR-only (N = 19) or LR with distant failure (N = 4) RMS managed with (N = 12) or without (N = 11) re-irradiation who were treated from 1996 to 2012., Results: At a median follow-up of 4.6 years from LR, 7 (30%) patients were alive and 5 (22%) had no evidence of disease. Median OS and PFS from LR were 19.3 and 16.9 months, respectively. LFFS and DFFS at 3 years from relapse were 54% and 56%, respectively. Salvage re-irradiation occurred in 12 (52%) patients, with 9 (75%) receiving resection before re-irradiation. Patients classified as low-risk at diagnosis with favorable primary tumor location had improved 3-year PFS 80% (95% CI 51.6-100%) vs. 47.1% (95% CI 27.3-81.2%), p = 0.066], and OS 80% [(95% CI 22.4-100%) vs. 47.1% (95% CI 27.3-81.3%), p = 0.051] following LR. Median LFFS and OS in unirradiated vs. re-irradiated patients was 12.4 vs. 19.6 (p = 0.1) and 18.8 vs. 26.1 months (p = 0.46). No patients experienced ≥grade 4 acute toxicity from re-irradiation. LR failure was a component of cancer-related death in 60% vs. 40% of the unirradiated and re-irradiated group (p = 0.02)., Conclusion: Salvage re-irradiation appears tolerable with acceptable morbidity and may reduce the risk of subsequent LR as a component of death in patients with LR RMS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: We reviewed the effect of ovarian transposition (OT) on ovarian function among long-term survivors of childhood Hodgkin lymphoma (HL) treated with pelvic radiotherapy., Procedure: Female participants (age 18+ years) with HL in the St. Jude Lifetime Cohort Study (SJLIFE) were clinically evaluated for premature ovarian insufficiency (POI) 10 or more years after pelvic radiotherapy. Reproductive history including age at menopause and pregnancy/live births was available on all patients., Results: Of 127 eligible females with HL, 90 (80%) participated in SJLIFE, including 49 who underwent OT before pelvic radiotherapy. Median age at STLIFE evaluation was 38 years (range 25-60). In a multiple regression adjusted for age at diagnosis, pelvic radiotherapy doses > 1,500 cGy (hazard ratio [HR] = 25.2, 95% confidence interval [CI] = 3.1-207.3; P = 0.0027) and cumulative cyclophosphamide equivalent doses of alkylating agents > 12,000 mg/m 2 (HR = 11.2, 95% CI = 3.4-36.8; P < 0.0001) were significantly associated with POI. There was no significant association between OT and occurrence of POI (HR = 0.6, 95% CI = 0.2-1.9; P = 0.41)., Conclusions: OT did not appear to modify risk of POI in this historic cohort of long-term survivors of HL treated with gonadotoxic therapy. Modern fertility preservation modalities, such as mature oocyte cryopreservation, should be offered to at-risk patients whenever feasible., (© 2018 Wiley Periodicals, Inc.)

Background: Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown., Methods: Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS)., Results: PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways., Conclusions: The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.

Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.

Pediatric patients with parameningeal rhabdomyosarcoma and high-risk features are recommended to receive radiotherapy at initiation of protocol therapy due to concerns about the increased risk of local and leptomeningeal failure from treatment delay. We report our early experience on a multi-institutional prospective trial incorporating delayed primary site radiation and reduced dose cyclophosphamide in all patients with parameningeal tumors. We observed an excessive number of locoregional treatment failures following this approach and have subsequently amended our trial to move radiation therapy upfront for those patients with high-risk features. We suggest that investigators should be vigilant for treatment failure given our early prospective experience with delayed radiotherapy and reduced dose cyclophosphamide.

Aim: To describe the clinical implementation and optimization of magnetic resonance imaging (MRI) systems installed in a radiation oncology department for dedicated use in radiotherapy (RT) simulation and treatment planning for pediatric patients., Methods: Two wide-bore MRI systems were installed and commissioned in 2016. Patient setups, coil placements, and scan protocols were developed to image various anatomic sites in children. Patients with brain tumors were routinely imaged using a pair of flexible loop coils and a posterior receiver coil integrated into the patient couch. The integrated posterior coil and the flexible anterior torso coil supported by the coil bridge were used together when imaging the abdomen, pelvis, or spine. A three-dimensional acquisition was most often performed, given the benefit of high-resolution multiplanar reformation as well as elimination of B0-related distortions in the slice selection direction., Results: We performed 542 MRI studies (265 for planning and 277 for monitoring on-treatment tumor changes) on pediatric patients in the first year after system installation. Multisequence images of pediatric RT patients with ependymoma, medulloblastoma, craniopharyngioma, rhabdomyosarcoma, or Ewing sarcoma were shown to illustrate the image quality obtainable with optimized planning sequences., Conclusions: Magnetic resonance imaging (MRI) of pediatric patients in their treatment positions with setup devices in place can be performed with coil arrangements that include flexible coils. The resulting image quality is suitable for treatment planning and on-treatment monitoring. We provide optimized site-specific sequence parameters to support the continued improvement of MRI for pediatric RT planning., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: To evaluate the feasibility of using on-treatment magnetic resonance imaging (MRI) to detect proton range changes during treatment courses., Methods: MRI-based virtual computed tomography (vCT) was generated to calculate water-equivalent path length (WEPL) at the distal surface of a clinical target volume. T2-weighted MR images with and without fat suppression were processed by thresholding and fuzzy c-mean clustering to assign a bulk HU (Hounsfield Unit) to each segment of fat, water, and air. Bony tissues in vCT were transferred from planning CT via a region-based registration. We validated this method using images from three patients (aged 9, 12, and 17 yr old) with pelvic sarcomas who underwent proton therapy. MRI-based WEPL was evaluated against those of repeat CT (rCT) and cone beam CT (CBCT)., Results: The vCT agreed well with the rCT, wherein the use of bulk HU and imperfect bone registration contributed to discrepancies. The 99th percentile error of the MRI-based WEPL was up to 3.3 mm for posterior fields when we compensated the effect of mobile air. The gamma index (2-mm WEPL/2-mm pixel distance) was greater than 99% for those fields. We observed larger errors for anterior fields, which were due to bowel gas movement, mismatched respiratory motion, and differences in patient posture between the vCT and rCT. Applied to multiple on-treatment MRI of a patient, the estimated WEPL demonstrated an underrange trend, which was consistent with the CBCT results and the increased patient body circumference., Conclusions: The MRI-based vCT produced highly accurate WEPL estimates, demonstrating the potential of using on-treatment MRI for detecting changes in proton ranges., (© 2018 American Association of Physicists in Medicine.)

Purpose: Proton dose coverage is sensitive to proton beam range. The current practice of CT number-based registration for patient positioning focuses on matching the target and is not sufficient for proton therapy because the proton range depends on the medium traversed by the beam. Patient body deformations and anatomical changes result in range deviation in the target. We propose proton range-based registration to minimize the range deviation., Methods: The range was calculated from cone beam-computed tomography (CBCT) of the patient on couch, and the range deviation was the difference of the calculated range from that on the initial (day 1) CBCT. In the investigated prostate cases in which the main cause of range deviation was the rotation of femur bones, and in the investigated abdomen cases in which the main cause of range deviation was body growth and anatomic change, our range-based registration was used to obtain the optimal beam angle by minimizing the range deviation. The new angle was limited to be ±5° from that planned to prevent potentially increased dose to the organs at risk. To demonstrate the benefit of range-based registration, we investigated the range at the voxels on the surface of the target volume. The calculation error of range deviation due to CBCT scatter was investigated by using solid water phantoms with different thicknesses. Range-based registration using both CBCTs and CTs was performed in cases of two patients with pelvic rhabdomyosarcoma and one patient with upper abdominal tumor. The range was represented by the water-equivalent thickness to shorten the computation for online application purposes., Results: In the phantom study, the calculation error of range deviation due to CBCT scatter was within 2 mm for a 1-cm thickness change (the mean range deviation was 0.8 mm). In the CT study of the prostate cases, the range deviation (mean ± root-mean-square deviation) on the contour in each slice was efficiently reduced from 3.6 ± 2.8 mm to 2.1 ± 1.4 mm, with most slices being within 3 mm; in the CT study of the abdomen cases, the range deviation of the whole set was reduced from 4.4 ± 1.9 mm to 3.5 ± 2.1 mm. Both the mean and root-mean-square deviation of the range deviation on each treatment day were decreased. The dose coverage on the target was improved and the dose on the OARs was only slightly changed., Conclusion: Range-based registration can efficiently mitigate range deviation due to patient positioning and anatomical changes. It can shorten patient positioning time and reduce the patient's dose from CBCT., (© 2018 American Association of Physicists in Medicine.)

Background: Indications for and delivery of adjuvant therapies for pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) have been derived largely from adult studies; therefore, significant concern remains regarding radiation exposure to normal tissue. The authors report long-term treatment outcomes and toxicities for pediatric and young adult patients with high-grade NRSTS who were treated on a prospective trial using limited-margin radiotherapy., Methods: Sixty-two patients (ages 3-22 years) with predominantly high-grade NRSTS requiring radiation were treated on a phase 2 institutional study of conformal external-beam radiotherapy and/or brachytherapy using a 1.5-cm to 2-cm anatomically constrained margin. The estimated cumulative incidence of local failure, Gray's method estimated cumulative incidence of local failure, Kaplan-Meier method estimated survival, competing-risk regression model determined predictors of disease outcome, and toxicity was reported according to CTCAE v2.0., Results: At a median follow-up of 5.1 years (range, 0.2-10.9 years), 9 patients had experienced local failure. The 5-year overall cumulative incidence of local failure was 14.8% (95% confidence interval [CI], 7.2%-25%), and all but 1 local failure occurred outside the highest-dose irradiation volume. The 5-year Kaplan-Meier estimates for event-free and overall survival were 49.3% (95% CI, 36.3%-61.1%) and 67.9% (95% CI, 54.2%-78.3%), respectively. Multivariable analysis indicated that younger age was the only independent predictor of local recurrence (P = .004). The 5-year cumulative incidence of grade 3 or 4 late toxicity was 15% (95% CI, 7.2%-25.3%)., Conclusions: The delivery of limited-margin radiotherapy using conformal external-beam radiotherapy or brachytherapy provides a high rate of local tumor control without an increase in marginal failures and with acceptable treatment-related morbidity. Cancer 2017;123:4419-29. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Purpose: To investigate the contribution of radiation therapy to acute and late toxicity in pediatric chest wall sarcoma patients and evaluate dosimetric correlates of higher incidence toxicities such as scoliosis and pneumonitis., Methods and Materials: The data from 23 consecutively treated pediatric patients with chest wall sarcomas of various histologies (desmoid, Ewing, rhabdomyosarcoma, nonrhabdomyosarcoma-soft tissue sarcomas) were reviewed to evaluate the relationship between end-organ radiation dose, clinical factors, and the risk of subsequent late effects (scoliosis, pneumonitis). Cobb angles were used to quantify the extent of scoliosis. Doses to the spine and lung were calculated from the radiation treatment plan., Results: The range of scoliosis identified on follow-up imaging ranged from -47.6 to 64° (median, 2.95°). No relationship was identified between either radiation dose to the ipsilateral or contralateral vertebral body or tumor size and the degree or direction of scoliosis. The extent of surgical resection and number and location of resected ribs affected the extent of scoliosis. The dominant predictor of extent of scoliosis at long-term follow-up was the extent of scoliosis following surgical resection. Radiation pneumonitis was uncommon and was not correlated with mean dose or volume of lung receiving 24 Gy; however, 1 of 3 surviving patients who received whole pleural surface radiation therapy developed significant restrictive lung disease., Conclusions: Acute and late radiation therapy-associated toxicities in pediatric chest wall sarcoma patients are modest. The degree of scoliosis following resection is a function of the extent of resection and of the number and location of ribs resected, and the degree of scoliosis at the last follow-up visit is a function of the extent of scoliosis following surgery. Differential radiation therapy dose across the vertebral body does not increase the degree of scoliosis. Severe restrictive pulmonary disease is a late complication of survivors after whole pleural surface radiation therapy., (Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Longer survival for children with sarcoma has led to the recognition of chronic health conditions related to prior therapy. We sought to study the association of sarcoma therapy with the development of scoliosis., Methods: We reviewed patient demographics, treatment exposures, and functional outcomes for patients surviving >10 years after treatment for sarcoma between 1964 and 2002 at our institution. The diagnosis of scoliosis was determined by imaging. Functional performance and standardized questionnaires were completed in a long-term follow-up clinic., Results: We identified 367 patients, with median age at follow-up of 33.1 years. Scoliosis was identified in 100 (27.2%) patients. Chest radiation (relative risk (RR), 1.88 (95% confidence interval (CI), 1.21-2.92), p < 0.005) and rib resection (RR, 2.64 (CI, 1.79-3.89), p < 0.0001) were associated with an increased incidence of scoliosis; thoracotomy without rib resection was not. Of 21 patients who underwent rib resection, 16 (80.8%) had the apex of scoliosis towards the surgical side. Scoliosis was associated with worse pulmonary function (RR, 1.74 (CI, 1.14-2.66), p < 0.01) and self-reported health outcomes, including functional impairment (RR, 1.60 (CI, 1.07-2.38), p < 0.05) and cancer-related pain (RR, 1.55 (CI, 1.11-2.16), p < 0.01). Interestingly, pulmonary function was not associated with performance on the 6-min walk test in this young population., Conclusions: Children with sarcoma are at risk of developing scoliosis when treatment regimens include chest radiation or rib resection. Identification of these risk factors may allow for early intervention designed to prevent adverse long-term outcomes., Implications for Cancer Survivors: Cancer survivors at risk of developing scoliosis may benefit from monitoring of pulmonary status and early physical therapy.

Purpose: To characterize respiration-induced abdominal organ motion in children receiving radiation treatment with a 4-dimensional (4D) magnetic resonance imaging (MRI) method., Methods and Materials: We analyzed free-breathing coronal 4D MRI datasets acquired from 35 patients (aged 1-20 years) with abdominal tumors. A deformable image registration of the 4D MRI datasets was performed to derive motion trajectories of selected anatomic landmarks, from which organ motions were quantified. The association between organ motion and patient characteristics was investigated and compared with previous studies. The relation between patient height and organ motion was further investigated to predict organ motion in prospective patients., Results: Organ motion and its individual variation were reduced in younger patients (eg, kidney peak-to-peak motion <5 mm for all but 1 patient aged ≤8 years), although special motion management may be warranted in some adolescents. The liver and spleen exhibited greater motion than did the kidneys, while intraorgan variation was present. The motions in the liver and kidneys agreed with those reported by the previous 4D computed tomography studies. Individual variations of organ motion in younger patients were due, in part, to changes in respiration rate, which ostensibly reflected the effect of anesthesia. The prediction of organ motion was limited by large individual variations, particularly for older patients., Conclusions: The 4D MRI acquisition method and motion analysis described in this study provide a nonionizing approach to understand age-associated organ motion, which aids in the planning of abdominal radiation therapy for pediatric patients. Use of 4D MRI facilitates monitoring of changes in target motion patterns during treatment courses and in various studies of the effect of organ motion on radiation treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Context: Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited., Objective: To describe the prevalence of POI, its risk factors, and associated long-term adverse health outcomes., Design: Cross-sectional., Setting: The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center., Patients: Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis., Main Outcome Measure: POI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED)., Results: The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m2. Patients with a body mass index ≥30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI., Conclusion: High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes., (Copyright © 2017 Endocrine Society)

Background: Electrocardiography (ECG), predictive of adverse outcomes in the general population, has not been studied in cancer survivors. We evaluated the prevalence of ECG abnormalities and associations with mortality among childhood cancer survivors., Methods: Major and minor abnormalities were coded per the Minnesota Classification system for participants in the St Jude Lifetime Cohort Study (n = 2,715) and community controls (n = 268). Odds ratios (ORs) and 95% CIs were calculated using multivariable logistic regression; and hazard ratios, using Cox proportional hazards regression., Results: Survivors were a median age of 31.3 (range 18.4-63.8) years at evaluation and 7.4 (range 0-24.8) years at diagnosis. Prior therapies included cardiac-directed radiation (29.5%), anthracycline (57.9%), and alkylating (60%) chemotherapies. The prevalence of minor ECG abnormalities was similar among survivors and controls (65.2% vs 67.5%, P = .6). Major ECG abnormalities were identified in 10.7% of survivors and 4.9% of controls (P < .001). Among survivors, the most common major abnormalities were isolated ST/T wave abnormalities (7.2%), evidence of myocardial infarction (3.7%), and left ventricular hypertrophy with strain pattern (2.8%). Anthracyclines ≥300 mg/m 2 (OR 1.7 95% CI 1.1-2.5) and cardiac radiation (OR 2.1 95% CI 1.5-2.9 [1-1,999 cGy], 2.6 95% CI 1.6-3.9 [2,000-2,999 cGy], 10.5 95% CI 6.5-16.9 [≥3,000 cGy]) were associated with major abnormalities. Thirteen participants had a cardiac-related death. Major abnormalities were predictive of all-cause mortality (hazard ratio 4.0 95% CI 2.1-7.8)., Conclusions: Major ECG abnormalities are common among childhood cancer survivors, associated with increasing doses of anthracyclines and cardiac radiation, and predictive of both cardiac and all-cause mortality., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the epidemiologic, demographic, and clinical characteristics, as well as prognostic factors and long-term outcomes of mediastinal germ cell tumors (MGCT) in children., Patients and Methods: A retrospective study of pediatric patients diagnosed with a primary MGCT between January 1963 and August of 2014 was performed., Results: Twenty-five patients were identified. Six children with teratomas were treated with resection alone (median age 7.8 years, range newborn to 15 years) and were cured without recurrence or progression. Nineteen children were treated for a malignant MGCT (median age 11.7 years, range 7 months-18 years); 5 year overall survival (OS) was 0.39 ± 0.12. For malignant non-seminomatous mediastinal germ cell tumors, platinum-based chemotherapy regimen (OS 0.56 vs 0.14, p = 0.03), complete surgical resection with negative margins (OS 0.73 vs 0.11, p = 0.03); and localized disease (OS 0.76 vs 0.0, p = 0.004) demonstrated a survival advantage., Conclusions: Initial surgical resection is appropriate for teratomas. Localized disease, complete resection, and platinum-based chemotherapy are associated with improved survival in malignant non-seminomatous mediastinal germ cell tumors. Neoadjuvant, platinum-based three drug regimens followed by delayed surgical resection is the appropriate treatment modality for malignant mediastinal germ cell tumors.

Objectives: The purpose of this study was to perform a comprehensive assessment of long-term renal function in patients treated at our institution for synchronous bilateral Wilms tumor (BWT) and to determine the optimal method for estimating glomerular filtration rate (eGFR)., Methods: Surgical approach, adjuvant therapy, and pathology reports were reviewed for patients with at least six months follow-up from definitive surgery. eGFRs, as assessed by the Schwartz and Chronic Kidney Disease in Children (CKiD) formulas, were compared to measured GFR (mGFR) determined by 99m Tc-DTPA scanning. Urine studies, including microalbumin, β-microglobulin, and FE Na were also reviewed., Results: Forty-two patients were identified. Of 36 living patients, 28 (77.8%) had greater than 6months follow-up, with a median overall follow-up of 5.2years (range: 1.4-13.4). The median mGFR was 97mL/min/1.73m 2 , while the median eGFR Schwartz and eGFR CKiD were 103.3mL/min/1.73m 2 and 79.7mL/min/1.73m 2 , respectively, (p=0.13 and p=0.75, compared to mGFR). Eleven (39.3%) patients had at least one abnormal urine study (microalbumin >30μg/g creatinine, n=3; β-2 microglobulin >133μg/g creatinine, n=9; FE Na >1%, n=4)., Conclusions: In our series, few patients had an abnormally low GFR. Neither method for estimating GFR gave a significantly different result from measured GFR, suggesting that the Schwartz equation is adequate, although specific urine tests may be more sensitive for detecting subtle renal dysfunction., Level of Evidence: Level IV - retrospective case series with no comparison group., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To determine the rate of local failure using focal conformal, limited margin radiation therapy (RT) and dose escalation for tumors ≥8 cm (greatest dimension at diagnosis) in children and young adults with Ewing sarcoma (EWS)., Methods and Materials: Eligible patients with EWS were treated on a phase 2 institutional trial of focal conformal, limited margin RT using conformal or intensity modulated techniques. The treatment volume incorporated a 1-cm constrained margin around the gross tumor. Unresected tumors, <8 cm at diagnosis, received a standard dose of 55.8 Gy and tumors ≥8 cm, an escalated dose to 64.8 Gy. Patients with microscopic residual disease after resection received adjuvant RT to 50.4 Gy. Adjuvant brachytherapy was permitted in selected patients., Results: Forty-five patients were enrolled: 26 with localized and 19 with metastatic disease. Median (range) age, tumor size, and follow-up were 13.0 years (2.9-24.7 years), 9.0 cm (2.4-17.0 cm), and 54.5 months (1.9-122.2 months), respectively. All patients received systemic chemotherapy. The median (range) RT dose for all patients was 56.1 Gy (45-65.5 Gy). Seventeen patients received adjuvant, 16 standard-dose, and 12 escalated-dose RT. Failures included 1 local, 10 distant, and 1 local/distant. The estimated 10-year cumulative incidence of local failure was 4.4% ± 3.1%, with no statistical difference seen between RT treatment groups and no local failures in the escalated-dose RT treatment group., Conclusions: Treatment with focal conformal, limited margin RT, including dose escalation for larger tumors, provides favorable local tumor control in EWS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The magnitude of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is not known. Using medically ascertained data, we applied the cumulative burden metric to compare chronic cardiovascular health conditions in survivors of Hodgkin's lymphoma and general population controls., Methods: For this study, participant data were obtained from two ongoing cohort studies at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE) and the St Jude Long-term Follow-up Study (SJLTFU). SJLIFE is a cohort study initiated on April 27, 2007, to enable longitudinal clinical evaluation of health outcomes of survivors of childhood cancer treated or followed at St Jude Children's Research Hospital, and SJLTFU is an administrative system-based study initiated in 2000 to collect outcome and late toxicity data for all patients treated at the hospital for childhood cancer. The patient cohort for our study was defined as patients treated at St Jude Children's Research Hospital who reached 18 years of age and were at least 10 years post-diagnosis of pathologically confirmed primary Hodgkin's lymphoma. Outcomes in the Hodgkin's lymphoma survivors were compared with a sample of SJLIFE community control participants, aged 18 years or older at the time of assessment, frequency-matched based on strata defined by 5-year age blocks within each sex, who were selected irrespective of previous medical history. All SJLIFE participants underwent assessment for 22 chronic cardiovascular health conditions. Direct assessments, combined with retrospective clinical reviews, were used to assign severity to conditions using a modified Common Terminology Criteria of Adverse Events (CTCAE) version 4.03 grading schema. Occurrences and CTCAE grades of the conditions for eligible non-SJLIFE participants were accounted for by multiple imputation. The mean cumulative count (treating death as a competing risk) was used to estimate cumulative burden., Findings: Of 670 survivors treated at St Jude Children's Research Hospital, who survived 10 years or longer and reached age 18 years, 348 were clinically assessed in the St Jude Lifetime Cohort Study (SJLIFE); 322 eligible participants did not participate in SJLIFE. Age and sex frequency-matched SJLIFE community controls (n=272) were used for comparison. At age 50 years, the cumulative incidence of survivors experiencing at least one grade 3-5 cardiovascular condition was 45·5% (95% CI 36·6-54·3), compared with 15·7% (7·0-24·4) in community controls. The survivor cohort at age 50 experienced a cumulative burden of 430·6 (95% CI 380·7-480·6) grade 1-5 and 100·8 (77·3-124·3) grade 3-5 cardiovascular conditions per 100 survivors; these numbers were appreciably higher than those in the control cohort (227·4 [192·7-267·5] grade 1-5 conditions and 17·0 [8·4-27·5] grade 3-5 conditions per 100 individuals). Myocardial infarction and structural heart defects were the major contributors to the excess grade 3-5 cumulative burden in survivors. High cardiac radiation dose (≥35 Gy) was associated with an increased proportion of grade 3-5 cardiovascular burden, whereas increased anthracyline dose was not., Interpretation: The true effect of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is reflected in the cumulative burden. Survivors aged 50 years will experience more than two times the number of chronic cardiovascular health conditions and nearly five times the number of more severe (grade 3-5) cardiovascular conditions compared with community controls and, on average, have one severe, life-threatening, or fatal cardiovascular condition. The cumulative burden metric provides a more comprehensive approach for assessing overall morbidity compared with currently used cumulative incidence based analytic methodologies, and will assist clinical researchers when designing future trials and refining general practice screening guidelines., Funding: US National Cancer Institute, St Baldrick's Foundation, and American Lebanese Syrian Associated Charities., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Rationale: The relationship between treatment-related impairment of pulmonary function in adult survivors of childhood cancer and subsequent physical function has not been studied., Objectives: In this prospective evaluation of 606 adult survivors of childhood cancer, we sought to determine the risk factors for, as well as the functional impact of, clinically ascertained pulmonary function impairment., Methods: We measured FEV1, FVC, total lung capacity (TLC), and single-breath diffusing capacity of the lung for carbon monoxide corrected for hemoglobin (DlCOcorr), expressing the results as percent predicted and lower limit of normal (LLN) values, and we also assessed functional exercise capacity (6-minute-walk distance). Lung radiation exposure was expressed as the estimated percentage of lung tissue that received at least 10 Gy (V10). Associations of clinical and treatment factors with pulmonary function measures were assessed using log-binomial regression to calculate relative risks and 95% confidence intervals., Measurements and Main Results: The participants' median age at evaluation was 34.2 years, and the median elapsed time from diagnosis was 21.9 years. Among the sample population, 50.7% had an FEV1 percent predicted less than 80%, 47.2% had an FVC percent predicted less than 80%, 31.2% had a TLC percent predicted less than 75%, and 44.6% had DlCOcorr percent predicted less than 75%. Also, 49.0% had FEV1 less than the LLN on the basis of the Global Lung Function Initiative (GLI) criteria, and 45.4% had FVC less than LLN. Obstructive lung defects (FEV1/FVC, <0.7) were found in 0.8%, but none had obstructive lung defects on the basis of the GLI criterion of FEV1/FVC less than the LLN. Restrictive lung defects (TLC, <75%) were found in 31.2% of participants. V10 and elapsed time since diagnosis were associated with abnormal FEV1 and FVC based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 criteria, and with abnormal FEV1 using the GLI criterion. Age at diagnosis was an additional risk factor for abnormal FVC based on the GLI criteria. Age at diagnosis and V10 were associated with abnormal TLC. Increased body mass index, V10, and elapsed time since diagnosis were risk factors for abnormal DlCOcorr. Abnormal pulmonary function tests were associated with decreased 6-minute walk distance., Conclusions: Impaired pulmonary function in adult survivors of childhood cancer is associated with decreased physical function. These patients may benefit from interventions designed to preserve and/or improve pulmonary function.

Background: Cancer survivors exposed to therapeutic radiation are at increased risk for basal cell carcinoma (BCC). Despite the notable influence of race on rates of BCC in the general population, the same is not clearly defined in previously irradiated cancer survivors. We investigated the influence of race on the development of BCC in adult survivors of childhood cancer., Methods: Using a retrospective cohort study, outcomes were collected through June 30, 2015, for 1,746 irradiated childhood cancer survivors participating in the St. Jude Lifetime Cohort Study (SJLIFE), comprising a total of 33,147 person-years of follow-up. Subsequent neoplasms identified in survivors through self-report and prospective clinical assessment were validated by pathology reports. Expected numbers of each type of radiation-associated neoplasm, including BCC, were calculated for irradiated black survivors based on rates in irradiated white survivors, accounting for primary cancer diagnosis, diagnosis year, attained age, and sex., Results: On the basis of the rate of BCC in previously irradiated white survivors, 56.1 BCCs were expected among 237 black survivors, yet none observed. In contrast, the observed-to-expected ratio of non-BCC radiation-associated neoplasms (melanoma, brain, breast, thyroid cancer) was 0.88 (30 observed/34.2 expected, 95% confidence interval, 0.59-1.25)., Conclusions: We identified an unexpected absence of BCC in irradiated black survivors in SJLIFE. We observe a similar absence of BCC in black individuals among two additional cohorts treated with irradiation for childhood cancer., Impact: Black survivors are at a substantially reduced or absent risk for BCC from therapeutic radiation for reasons not yet fully understood. Cancer Epidemiol Biomarkers Prev; 25(9); 1356-60. ©2016 AACR., Competing Interests: The authors declare no competing interests., (©2016 American Association for Cancer Research.)

Background: Children with malignant bone tumors have average 5-year survival rates of 60% to 70% with current multimodality therapy. Local control modalities aimed at preserving function greatly influence the quality of life of long-term survivors. In developing countries, the limited availability of multidisciplinary care and limited expertise in specialized surgery and pediatric radiation therapy, as well as financial cost, all form barriers to achieving optimal outcomes in this population., Methods: We describe the establishment of a collaborative pediatric bone tumor program among a group of pediatric oncologists in Lebanon and Syria. This program provides access to specialized local control at a tertiary children's cancer center to pediatric patients with newly diagnosed bone tumors at participating sites. Central review of pathology, staging, and treatment planning is performed in a multidisciplinary tumor board setting. Patients receive chemotherapy at their respective centers on a unified treatment plan. Surgery and/or radiation therapy are performed centrally by specialized staff at the children's cancer center. Cost barriers were resolved through a program development initiative led by St Jude Children's Research Hospital. Once program feasibility was achieved, the Children's Cancer Center of Lebanon Foundation, via fundraising efforts, provided continuation of program-directed funding., Results: Findings over a 3-year period showed the feasibility of this project, with timely local control and protocol adherence at eight collaborating centers. We report success in providing standard-of-care multidisciplinary therapy to this patient population with complex needs and financially challenging surgical procedures., Conclusion: This initiative can serve as a model, noting that facilitating access to specialized multidisciplinary care, resolution of financial barriers, and close administrative coordination all greatly contributed to the success of the program., Competing Interests: Authors’ disclosures of potential conflicts of interest and contributions are found at the end of this article.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. A Collaborative Pediatric Bone Tumor Program to Improve Access to Specialized Care: An Initiative by the Lebanese Children’s Oncology GroupRaya SaabNo relationship to discloseZeina MerabiNo relationship to discloseMiguel R. AbboudHonoraria: Novartis Research Funding: Eli Lilly, Mast TherapeuticsSamar MuwakkitNo relationship to disclosePeter NounTravel, Accommodations, Expenses: Novo Nordisk, Baxter, LFB BiotechnologiesGladys GemayelNo relationship to discloseElie BecharaNo relationship to discloseHassan KhalifehNo relationship to discloseRoula FarahNo relationship to discloseNabil KabbaraNo relationship to discloseTarek El-KhouryNo relationship to discloseRasha Al-YousefNo relationship to discloseRachid HaidarNo relationship to discloseSaid SaghiehNo relationship to discloseToufic EidNo relationship to discloseSamir AkelNo relationship to discloseNabil KhouryNo relationship to discloseLayal BayramNo relationship to discloseMatthew J. KrasinNo relationship to discloseSima JehaNo relationship to discloseHassan El-SolhNo relationship to disclose

Purpose: To assess the prevalence and severity of neurocognitive impairment in adult survivors of pediatric CNS tumors and to examine associated treatment exposures., Patients and Methods: Participants included 224 survivors of CNS tumors who were treated at St Jude Children's Research Hospital (current median age [range], 26 years [19 to 53 years]; time from diagnosis, 18 years [11 to 42 years]) and completed neurocognitive testing. Information on cranial radiation therapy (CRT) doses and parameters of delivery were abstracted from medical records. The prevalence of severe impairment (ie, at least two standard deviations below normative mean) was compared across radiation treatment groups (no CRT, focal irradiation, craniospinal irradiation) using the χ(2) test. Log-binomial models were used to estimate risk ratios (RRs) and corresponding 95% CIs for severe impairment., Results: In multivariable models, craniospinal irradiation was associated with a 1.5- to threefold increased risk of severe impairment compared with no CRT (eg, intelligence: RR = 2.70; 95% CI, 1.37 to 5.34; memory: RR = 2.93; 95% CI, 1.69 to 5.08; executive function: RR = 1.74; 95% CI, 1.24 to 2.45). Seizures were associated with impaired academic performance (RR = 1.48; 95% CI, 1.02 to 2.14), attention (RR = 1.54; 95% CI, 1.12 to 2.13), and memory (RR = 1.44; 95% CI, 1.04 to 1.99). Hydrocephalus with shunt placement was associated with impaired intelligence (RR = 1.78; 95% CI, 1.12 to 2.82) and memory (RR = 1.42; 95% CI, 1.03 to 1.95). Differential follow-up time contributed to variability in prevalence estimates between survivors treated with older nonconformal and those treated with more contemporary conformal radiation therapy methods. Neurocognitive impairment was significantly associated with lower educational attainment, unemployment, and nonindependent living., Conclusion: Survivors of pediatric CNS tumors are at risk of severe neurocognitive impairment in adulthood. The prevalence of severe impairment is greater than expected in the general population, even in the absence of CRT, and is associated with disrupted attainment of adult social milestones., (© 2016 by American Society of Clinical Oncology.)

Background: Studies of cardiac disease among adult survivors of childhood cancer have generally relied on self-reported or registry-based data., Objective: To systematically assess cardiac outcomes among survivors of childhood cancer., Design: Cross-sectional study., Setting: St. Jude Children's Research Hospital., Patients: 1853 adult survivors of childhood cancer, aged 18 years or older, who received cancer-related cardiotoxic therapy at least 10 years earlier., Measurements: Baseline history and physical examination, fasting metabolic and lipid panels, echocardiography, electrocardiography, and 6-minute walk test., Results: One half of the survivors (52.3%) were men with a median age of 8 years (range, 0 to 24 years) at cancer diagnosis and 31 years (range, 18 to 60 years) at evaluation. Cardiomyopathy was present in 7.4% survivors (newly identified at the time of evaluation in 4.7%), coronary artery disease in 3.8% (newly identified in 2.2%), valvular regurgitation or stenosis in 28.0% (newly identified in 24.8%), and conduction or rhythm abnormalities in 4.4% (newly identified in 1.4%). Nearly all survivors were asymptomatic. The prevalence of cardiac conditions increased with age at evaluation, ranging from 3% to 24% among survivors aged 30 to 39 years to 10% to 37% among those aged 40 years or older. In multivariable analysis, survivors exposed to anthracycline doses of 250 mg/m2 or more had greater odds of cardiomyopathy (odds ratio, 2.7 [95% CI, 1.1 to 6.9]) than those who were not exposed. Survivors exposed to heart radiation also had increased odds of cardiomyopathy (odds ratio, 1.9 [CI, 1.1 to 3.7]) compared with those who were not exposed. Radiation exposure greater than 1500 cGy with any anthracycline exposure conferred the greatest odds for valve findings., Limitations: Sixty-one percent of survivors exposed to anthracycline chemotherapy or cardiac-directed radiation participated. A comparison group and longitudinal assessments were not available., Conclusion: Cardiovascular screening identified considerable subclinical disease among adult survivors of childhood cancer., Primary Funding Source: National Cancer Institute, American Lebanese Syrian Associated Charities.

Objectives: Wilms tumor is the most common renal cancer in children. Approximately 5% of children with Wilms tumor present with disease in both kidneys. The treatment challenge is to achieve a high cure rate while maintaining long-term renal function. We retrospectively reviewed our institutional experience with nephron sparing surgery (NSS) in patients with synchronous bilateral Wilms tumor (BWT) operated on between 2001 and 2014., Methods: Imaging studies, surgical approach, adjuvant therapy, and pathology reports were reviewed. Outcomes evaluated included surgical complications, tumor recurrence, patient survival, and renal function, as assessed by estimated glomerular filtration rate., Results: A total of 42 patients with BWT were identified: 39 (92.9%) patients underwent bilateral NSS; only 3 patients (7.1%) underwent unilateral nephrectomy with contralateral NSS. Postoperative complications included prolonged urine leak (10), infection (6), intussusception (2), and transient renal insufficiency (1). Three patients required early (within 4 months) repeat of NSS for residual tumor. In the long-term, 7 (16.7%) patients had local tumor recurrence (managed with repeat NSS in 6 and completion nephrectomy in 1) and 3 had an episode of intestinal obstruction requiring surgical intervention. Overall survival was 85.7% (mean follow-up, 4.1 years). Of the 6 patients who died, 5 had diffuse anaplastic histology. All of the patients had an estimated glomerular filtration rate more than 60 mL/min/1.73 m at the last follow-up; no patient developed end-stage renal disease., Conclusions: In patients with synchronous, BWT, bilateral NSS is safe and almost always feasible, thereby preserving maximal renal parenchyma. With this approach, survival was excellent, as was maintenance of the renal function.

Purpose: To estimate the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulatin hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after cranial radiotherapy (CRT) in childhood cancer survivors (CCS) and assess the impact of untreated deficiencies., Patients and Methods: Retrospective study in an established cohort of CCS with 748 participants treated with CRT (394 men; mean age, 34.2 years [range, 19.4 to 59.6 years] observed for a mean of 27.3 years [range, 10.8 to 47.7 years]). Multivariable logistic regression was used to study associations between demographic and treatment-related risk factors and pituitary deficiencies, as well as associations between untreated deficiencies and cardiovascular health, bone mineral density (BMD), and physical fitness., Results: The estimated point prevalence was 46.5% for GHD, 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD, and the cumulative incidence increased with follow-up. GHD and LH/FSHD were not treated in 99.7% and 78.5% of affected individuals, respectively. Male sex and obesity were significantly associated with LH/FSHD; white race was significant associated with LH/FSHD and TSHD. Compared with CRT doses less than 22 Gy, doses of 22 to 29.9 Gy were significantly associated with GHD; doses ≥ 22 Gy were associated with LH/FSHD; and doses ≥ 30 Gy were associated with TSHD and ACTHD. Untreated GHD was significantly associated with decreased muscle mass and exercise tolerance; untreated LH/FSHD was associated with hypertension, dyslipidemia, low BMD, and slow walking; and both deficits, independently, were associated with with abdominal obesity, low energy expenditure, and muscle weakness., Conclusion: Anterior pituitary deficits are common after CRT. Continued development over time is noted for GHD and LH/FSHD with possible associations between nontreatment of these conditions and poor health outcomes., (© 2015 by American Society of Clinical Oncology.)

Background: Female survivors of central nervous system (CNS) tumors are at an increased risk for gonadal damage and variations in the timing of puberty following radiotherapy and alkylating agent-based chemotherapy., Procedure: Clinical and laboratory data were obtained from 30 evaluable female patients with newly diagnosed embryonal CNS tumors treated on a prospective protocol (SJMB 96) at St. Jude Children's Research Hospital (SJCRH). Pubertal development was evaluated by Tanner staging. Primary ovarian insufficiency (POI) was determined by Tanner staging and FSH level. Females with Tanner stage I-II and FSH > 15 mIU/ml, or Tanner stage III-V, FSH > 25 mIU/ml and FSH greater than LH were defined to have ovarian insufficiency. Recovery of ovarian function was defined as normalization of FSH without therapeutic intervention., Results: Median length of follow-up post completion of therapy was 7.2 years (4.0-10.8 years). The cumulative incidence of pubertal onset was 75.6% by the age of 13. Precocious puberty was observed in 11.1% and delayed puberty in 11.8%. The cumulative incidence of POI was 82.8%, though recovery was observed in 38.5%., Conclusions: Treatment for primary CNS embryonal tumors may cause variations in the timing of pubertal development, impacting physical and psychosocial development. Female survivors are at risk for POI, a subset of whom will recover function over time. Further refinement of therapies is needed in order to reduce late ovarian insufficiency. Pediatr Blood Cancer 2015;62:329-334. © 2014 Wiley Periodicals, Inc., Competing Interests: All Authors agree to no disclosure., (© 2014 Wiley Periodicals, Inc.)

Background: Survivors of Hodgkin lymphoma (HL) have significant cardiovascular risk and require long-term surveillance. The current study assessed the prevalence of coronary artery disease (CAD) by coronary computed tomography angiography (CCTA) in adult survivors of childhood HL., Methods: Thirty-one survivors of HL, 13 of whom (42%) were treated with radiotherapy (RT) only and 18 of whom (58%) were treated with multimodal therapy, underwent CCTA, echocardiography, electrocardiography (ECG), and treadmill stress testing. Obstructive CAD was defined as ≥50% occlusion of the left main or ≥70% occlusion of the left anterior descending, left circumflex, or right coronary arteries on CCTA. Echocardiograms with resting wall motion abnormalities or an ejection fraction <50%; ECGs with Q waves, ST abnormalities without Q waves, or T-wave abnormalities without Q waves; and a J-point depression of ≥1 mm with a horizontal or downsloping ST segment on stress testing were considered abnormal., Results: The prevalence of disease in participants (median age, 40 years [range, 26 years-55 years]; median time from cancer diagnosis, 24 years [range, 17 years-39 years]) was 39%, with 39 plaques detected among 12 survivors. Three participants (10%) treated with RT only had 4 obstructive lesions; 9 patients (29%; 5 of whom were treated with RT only and 4 of whom were treated with multimodal therapy) had nonobstructive lesions. Approximately 15% of lesions involved the left main, 21% involved the proximal left anterior descending, 18% involved the proximal right coronary, and 13% involved the proximal left circumflex arteries. Of the 12 participants found to have CAD by CCTA, 7 had a positive ECG, 1 had a positive echocardiogram, and 1 had a positive stress test., Conclusions: CCTA identified CAD in a substantial percentage of survivors of HL and may be an effective screening modality for this population., (© 2014 American Cancer Society.)

Purpose: Survivors of childhood cancer are at an increased risk of developing subsequent neoplasms. In long-term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms., Methods: To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. Of the survivors, 164 had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT) and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms., Results: Nineteen of the 219 survivors (8.7 %) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4 % (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review., Conclusion: Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated., Implications for Cancer Survivors: The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed.

Background: Renal insufficiency is a significant complication of Wilms tumor treatment in the 5% with bilateral disease. Nephron-sparing surgery (NSS) is recommended after neoadjuvant chemotherapy initially. However, the role of NSS in recurrent disease is unknown. We reviewed our experience to assess the feasibility and oncologic and functional outcomes of repeat NSS for children with recurrent disease., Methods: A retrospective review was performed of all children treated at our institution for bilateral, favorable histology (FH) Wilms tumor. Patients undergoing repeat NSS for locally recurrent disease were identified. The outcomes evaluated included tumor recurrence, renal function, and patient survival., Results: Since 2001, 36 children with bilateral FH Wilms tumor have been treated at our institution. Eight patients (22%) underwent repeat NSS for locally recurrent disease. Two patients had a second local recurrence and underwent a third NSS. Six patients are alive without disease (75%) with an average follow-up of 4.5years. Two patients have died, each with blastemal-predominant histology at repeat NSS. The surviving patients have normal renal function, although two patients require medical management of hypertension., Conclusions: Our experience suggests that repeat NSS for local recurrence of FH bilateral Wilms tumor is feasible and affords acceptable oncologic outcome with preservation of renal function. However, more aggressive therapy may be required for patients whose recurrence has blastemal-predominant histology, given the poor outcome for these patients in our series., (© 2014.)

Purpose: To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL)., Patients and Methods: Survivors of childhood ALL treated at St Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion., Results: Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk [RR], 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment., Conclusion: This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.

Background: The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well defined., Procedures: We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse., Results: Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival., Conclusions: In pediatric HL, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted., (Copyright © 2013 Wiley Periodicals, Inc.)

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy (CRT) are at risk for cognitive impairment, although whether impairment progresses with age into adulthood is unknown. We report change in intelligence for 102 adult survivors of childhood ALL (age range, 26.6-54.7 years) during a median interval of 28.5 years. Survivors demonstrated lower Performance intelligence (mean, 95.3; standard deviation, 16.5; P = .005) but not Verbal IQ (mean, 97.4; standard deviation, 15.44; P = .09) at initial testing. Verbal intelligence declined an average of 10.3 points (P < .0001) during the follow-up interval with no decline in Performance intelligence. Decline was associated with current attention problems (P = .002) but not gender, CRT dose, age at CRT exposure, or years between testing. Results suggest long-term survivors of childhood ALL treated with CRT are at risk for progressive decline in verbal intellect, which may be driven by attention deficits. This trial was registered at clinicaltrials.gov as no. NCT00760656.

Purpose: Nephron-sparing surgery (NSS) has been advocated for patients with bilateral Wilms tumor (BWT). We sought to determine whether margin status impacted local tumor recurrence., Methods: A retrospective review of patients undergoing NSS for BWT from November 1999 to March 2009 at our institution in which local recurrence rates based on margin status were compared., Results: Of 21 patients, five (23.8%) had positive margins. These and 2 (9.5%) with focal anaplasia received flank XRT. Seven (33%) patients developed recurrent disease, a mean of 18.0 (range 1.3-39.9) months after NSS. Recurrence rates were similar in patients with positive and negative margins (1/5 [20%] vs 6/16 [37.5%]; p = 0.47). Hypertension occurred more frequently in patients who received XRT (57.1% vs 28.6%). At a median follow-up of 28.6 months (range 5.2-142.3), 19 patients are alive, without evidence of disease; one patient (with a positive margin at initial NSS) died of metastatic anaplastic WT and another died of a brain tumor. One patient, with multiple risk factors, developed renal failure., Conclusions: In our experience, local recurrence rates after NSS were not affected by surgical margin status although all patients with positive margins received XRT. These results support the aggressive use of NSS for patients with BWT., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Over the past decade, PET-CT has been used to assess rhabdomyosarcoma (RMS) in children. However, the role of PET-CT in staging RMS is unknown., Procedure: Thirty subjects with RMS, median age 7.3 years, underwent PET-CT before therapy. PET-CTs and conventional imaging (CI) were independently reviewed by two radiologists and two nuclear medicine physicians to determine the presence of metastases. Accuracy, sensitivity, and specificity of PET-CT for detecting metastases were compared to CI using biopsy and clinical follow-up as reference standards. Maximum standardized uptake values (SUV(max)) of primary tumors, lymph nodes, and pulmonary nodules were measured., Results: Primary tumors had an average SUV(max) of 7.2 (range, 2.5-19.2). Accuracy rates for 17 subjects with nodal disease were 95% for PET-CT and 49% for CI. PET-CT had 94% sensitivity and 100% specificity for nodal disease. Of seven pulmonary nodules detected by CI, three were not identified by PET-CT, two were indeterminate, and one was malignant with a SUV(max) (3.4) > twice that of benign nodules. Two subjects had bone disease; both were identified by PET-CT but only one by CI. Four subjects had bone marrow disease, two had positive PET-CTs but none had positive CI. Two subjects had soft tissue metastases detected by PET-CT but not CI., Conclusions: PET-CT performed better than CI in identifying nodal, bone, bone marrow, and soft tissue disease in children with RMS. CI remains essential for detection of pulmonary nodules. We recommend PET-CT for staging of children with RMS. CI with Tc(99m) bone scan can be eliminated., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Infantile fibrosarcoma (IFS) is an uncommon soft-tissue sarcoma. Here we review our experience treating this tumor., Patients and Methods: We retrospectively reviewed records of patients with IFS treated at St. Jude Children's Research Hospital between 1980 and 2009., Results: We identified 15 patients, 8 girls and 7 boys; 13 white and 2 black. Median age at diagnosis was 3 months. Primary sites included the leg (n = 3), chest wall (n = 2), foot (n = 2), and one each in the tongue, occipital region, axilla, parascapular region, arm, forearm, retroperitoneum, and thigh. All patients underwent resection; 11 upfront surgery, and 4 delayed. Complications included loss of the posterior tibial nerve and artery, axillary vein, biceps, pectoralis major, gallbladder, and transverse/sigmoid sinus. Eight received chemotherapy and three radiotherapy. Seven experienced local recurrence and three lung metastasis. Median follow-up was 65 months. At the time of the review, 12 patients were alive and 3 had died. All deaths were in patients older than 1 year at diagnosis with an axial primary site., Conclusions: Non-mutilating surgery should be the primary treatment for IFS. Neoadjuvant chemotherapy is indicated when upfront resection is unfeasible. Patients with positive surgical margins should receive adjuvant chemotherapy. Radiotherapy is indicated for axial primary sites where complete resection is impossible.

Background: Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood cancer and may increase risk for mild cognitive impairment and dementia in adulthood., Methods: We performed a cross-sectional evaluation of survivors of childhood acute lymphoblastic leukemia (ALL) treated with 18 Gy (n = 127) or 24 Gy (n = 138) CRT. Impairment (age-adjusted score >1 standard deviation below expected mean, two-sided exact binomial test) on the Wechsler Memory Scale IV (WMS-IV) was measured. A subset of survivors (n = 85) completed structural and functional neuroimaging., Results: Survivors who received 24 Gy, but not 18 Gy, CRT had impairment in immediate (impairment rate = 33.8%, 95% confidence interval [CI] = 25.9% to 42.4%; P < .001) and delayed memory (impairment rate = 30.2%, 95% CI = 22.6% to 38.6%; P < .001). The mean score for long-term narrative memory among survivors who received 24 Gy CRT was equivalent to that for individuals older than 69 years. Impaired immediate memory was associated with smaller right (P = .02) and left (P = .008) temporal lobe volumes, and impaired delayed memory was associated with thinner parietal and frontal cortices. Lower hippocampal volumes and increased functional magnetic resonance imaging activation were observed with memory impairment. Reduced cognitive status (Brief Cognitive Status Exam from the WMS-IV) was identified after 24 Gy (18.5%, 95% CI = 12.4% to 26.1%; P < .001), but not 18 Gy (8.7%, 95% CI = 4.4% to 15.0%; P = .11), CRT, suggesting a dose-response effect. Employment rates were equivalent (63.8% for 24 Gy CRT and 63.0% for 18 Gy CRT)., Conclusions: Adult survivors who received 24 Gy CRT had reduced cognitive status and memory, with reduced integrity in neuroanatomical regions essential in memory formation, consistent with early onset mild cognitive impairment.

Purpose: Our objective was to evaluate the association between low bone mineral density (BMD) and incidental renal stones among long-term survivors of childhood acute lymphoblastic leukemia (ALL)., Methods: Adult participants who were 10+ years from their childhood ALL diagnosis and members of the St. Jude Lifetime Cohort study were recruited between December 2007 and March 2011. During their risk-based medical evaluations, they underwent quantitative computed tomography (QCT) to evaluate BMD. Incidental renal stones were identified by radiologists' review of axial QCT source images. Demographic and dietary information were abstracted from health surveys and the Block Food Frequency questionnaire, respectively. The multivariable logistic regression model was used for analysis., Results: At a median of 26.1 years from diagnosis, BMD Z scores were ≤-2 in 34 of 662 (5.2 %) and renal stones detected in 73 of 662 (11 %) participants. Adjusted for age, renal radiation, dietary vitamin D, gender, and body mass index, when compared to those with BMD Z scores ≥0, the risk of renal stones was increased among those with BMD Z scores ≤-2 (odds ratio [OR], 2.92; 95 % confidence interval [CI] 1.14-7.48). Risk of renal stones significantly increased for older age (45-54 vs.18-24 years; OR, 3.70; 95 % CI 1.11-12.35) whereas the risk was higher but nonsignificant for >141.5 IU (sample median) daily intake of vitamin D (OR, 1.64; 95 % CI 0.98-2.75)., Conclusions and Implications for Cancer Survivors: Older ALL survivors with BMD Z scores ≤-2 are at risk for renal stones and should be counseled so that appropriate follow-up care can be provided for those among whom renal stones are detected.

Background: Ewing sarcoma (ES) is the most common chest wall malignancy in adolescents. Current therapy incorporates chemotherapy to treat systemic disease and radiotherapy to assist with local control. We sought to evaluate the timing of surgery and role of adjuvant radiotherapy., Methods: We reviewed the St. Jude Children's Research Hospital chest wall ES experience from 1979 to 2009. Patient demographics, tumor characteristics, treatment variables, and outcomes were analyzed with respect to timing of surgery and use of adjuvant radiotherapy., Results: Our cohort consisted of 36 patients with chest wall ES; median follow-up was 14.2 years, and 15-year estimate of overall survival was 66 %. In patients with localized disease, the timing of surgery (up-front vs. delayed) did not impact margin negativity or the use of adjuvant radiotherapy, but it did decrease the extent of chest wall resection. When considering radiotherapy in patients with localized disease, we found that patients who did not receive radiotherapy had smaller tumor size (median 6 vs. 10 cm) (p = 0.04) and were more likely to have had negative margins (p = 0.01) than patients who received adjuvant radiotherapy. One patient in each group developed a locoregional recurrence. The 15-year estimated of overall survival for patients who received adjuvant radiotherapy was 80 versus 100 % for those who did not., Conclusions: Delayed surgery decreased the extent of chest wall resection and helped define a patient population with favorable tumor biology. Patients with complete pathologic responses to chemotherapy, and those with tumors <8 cm and negative surgical margins may be spared adjuvant radiotherapy without any decrement in overall survival.

Background: Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. Clinical data of extraosseous ESFT are scarce., Methods: A retrospective analysis of all patients with extraosseous ESFT treated at St. Jude Children's Research Hospital (SJCRH) from June 1982 to August 2009., Results: Forty-six patients with extraosseous ESFT were identified. The mean age at diagnosis was 13.8 years. The majority of patients were male and white. The most common site of primary tumor was the trunk. Twelve patients had subcutaneous tumors. The median tumor size was 8 cm. Six patients (13 %) had metastatic disease at diagnosis. A total of 59 % of patients were alive at the time of analysis, with a median follow-up from diagnosis of 15.3 years. Fifteen-year estimates of survival and event-free survival (EFS) for all patients were 53.3 ± 9.4 and 50 ± 9.1 %, respectively. Fifteen-year estimates of survival and EFS with localized disease were 61.4 ± 9.8 and 57.6 ± 9.7 %, respectively. Stage and subcutaneous ESFT were significant predictors of outcome. There was no significant difference in patient's demographics and tumor characteristics between patients with skeletal ESFT and extraosseous Ewing sarcoma. The outcome for patients with localized extraosseous Ewing sarcoma was similar to that reported for all localized ESFT patients treated at SJCRH., Conclusions: The outcome for localized patients treated with extraosseous ESFT was similar to that reported for all ESFT patients treated on protocols at SJCRH. Patients with subcutaneous ESFT had a favorable prognosis when compared to their counterparts.

Purpose: Long-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL., Patients and Methods: In all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (≥ 30 Gy) thoracic radiation (n = 38) or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline (n = 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations., Results: Compared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/E'; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [E']; P = .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DL(co)(corr); P = .04), and leukoencephalopathy (P = .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P = .001). Working memory impairment was associated with E/E', although impaired sustained attention and naming speed were associated with DL(co)(corr). Neurocognitive performance was associated with academic and vocational functioning., Conclusion: These results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.

Background/purpose: Bones of the hands and feet are uncommon sites for Ewing sarcoma. In this study, we reviewed our experience in the management of these tumors., Methods: We retrospectively reviewed clinical presentation, management, and outcome of patients with Ewing sarcoma of the bones of hands and feet treated at our institution (1981-2006)., Results: The cohort included 6 males and 3 females (8 white, 1 African American; median age at diagnosis, 15 years). Primary tumor site was the hand in 6 and the foot in 3 patients. Three patients had distant metastatic disease at diagnosis (lung [n = 2]; ipsilateral axillary lymph node[(n = 1]). All patients had painful swelling at the primary site, and 2 (22%) had pathological fracture. All patients received chemotherapy and local control measures (surgery [n = 6], radiation [n = 2], surgery and radiation [(n = 1]). Three patients received radiotherapy for distant metastases. Three patients had systemic recurrence (lungs [n = 2], lung and brain [n = 1]); none had local tumor recurrence. Median follow-up was 5 years. Five patients (55.6%) are alive at last follow-up., Conclusions: Chemotherapy and surgical excision of primary tumor are the mainstays of treatment. Radiotherapy is recommended for local control of lesions in the hand for patients declining excisional therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: While FDG PET/CT for the evaluation of nasopharyngeal carcinoma (NPC) in adult patients has documented advantages and disadvantages compared with conventional imaging, to our knowledge, no studies of FDG PET/CT for the evaluation of NPC in pediatric patients have been performed. In this investigation, we studied the utility of FDG PET/CT in children with NPC., Methods: The study group comprised 18 children with biopsy-proven NPC who underwent FDG PET/CT and MRI (total 38 pairs of images). All baseline and follow-up FDG PET/CT and MRI studies were independently reviewed for restaging of disease., Results: The concordance between FDG PET/CT and MRI in T, N, and overall staging was 29%, 64%, and 43%, respectively. Compared with MRI, FDG PET/CT yielded lower T and overall staging and showed less cervical and retropharyngeal lymphadenopathy. The concordance between follow-up FDG PET/CT and MRI was 79% overall and 100% 9 months after therapy. In patients who achieved complete remission, FDG PET/CT showed disease clearance 3-6 months earlier than MRI. There were no false-positive or false-negative FDG PET/CT scans during follow-up., Conclusion: FDG PET/CT may underestimate tumor extent and regional lymphadenopathy compared with MRI at the time of diagnosis, but it helps to detect metastases and clarify ambiguous findings. FDG PET/CT is sensitive and specific for follow-up and enables earlier determination of disease remission. FDG PET/CT is a valuable imaging modality for the evaluation and monitoring of NPC in pediatric patients.

Context: More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects., Objective: To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy., Design, Setting, and Patients: Multi-institutional, unblinded, nonrandomized single group phase 2 clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (<3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000, and December 9, 2008. Follow-up data are current to March 12, 2012., Interventions: The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy., Main Outcome Measures: Two-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low., Results: Two-year event-free survival was 90.8% (95% CI, 84.7%-96.9%). For patients who did not require radiotherapy, it was 89.4% (95% CI, 80.8%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed., Conclusions: Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free survival., Trial Registration: clinicaltrials.gov Identifier: NCT00145600.

Objectives: Abdominal intensity-modulated radiation therapy and proton therapy require quantification of target and organ motion to optimize localization and treatment. Although addressed in adults, there is no available literature on this issue in pediatric patients. We assessed physiologic renal motion in pediatric patients., Methods and Materials: Twenty free-breathing pediatric patients at a median age of 8 years (range, 2-18 years) with intra-abdominal tumors underwent computed tomography simulation and four-dimensional computed tomography acquisition (slice thickness, 3 mm). Kidneys and diaphragms were contoured during eight phases of respiration to estimate center-of-mass motion. We quantified center of kidney mass mobility vectors in three dimensions: anteroposterior (AP), mediolateral (ML), and superoinferior (SI)., Results: Kidney motion decreases linearly with decreasing age and height. The 95% confidence interval for the averaged minima and maxima of renal motion in children younger than 9 years was 5-9 mm in the ML direction, 4-11 mm in the AP direction, and 12-25 mm in the SI dimension for both kidneys. In children older than 9 years, the same confidence interval reveals a widening range of motion that was 5-16 mm in the ML direction, 6-17 mm in the AP direction, and 21-52 mm in the SI direction. Although not statistically significant, renal motion correlated with diaphragm motion in older patients. The correlation between diaphragm motion and body mass index was borderline (r = 0.52, p = 0.0816) in younger patients., Conclusions: Renal motion is age and height dependent. Measuring diaphragmatic motion alone does not reliably quantify pediatric renal motion. Renal motion in young children ranges from 5 to 25 mm in orientation-specific directions. The vectors of motion range from 5 to 52 mm in older children. These preliminary data represent novel analyses of pediatric intra-abdominal organ motion., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Although whole lung irradiation is used to treat pulmonary metastases of pediatric solid malignancies, few studies have addressed its long-term pulmonary consequences., Methods: The authors conducted a retrospective study of longitudinal changes in 171 pulmonary function tests (PFTs) and their relation with clinical features in 48 survivors of pediatric malignant solid tumors treated with whole lung irradiation., Results: Although active respiratory symptoms were seen in only 9 patients (18.8%), abnormalities in forced vital capacity (FVC; 58.3%), forced expiratory volume in 1 second (FEV(1) ; 64.6%), total lung capacity (TLC; 72.9%), and diffusion capacity of the lung for carbon monoxide corrected for hemoglobin (DLCO(corr) ; 70.8%) were common. At a median follow-up of 9.7 years after whole lung irradiation, FVC, FEV(1) , and TLC significantly declined longitudinally (P = .04, .03, and .02, respectively). Focal pulmonary boost irradiation was significantly associated with abnormal FEV(1) /FVC (P = .03), forced expiratory flow between 25% and 75% forced vital capacity (P = .005), residual volume (RV; P = .005), and RV/TLC (P = .002). Ten patients had baseline PFTs, and FVC, FEV(1) , TLC, and DLCO(corr) worsened immediately after radiation, followed by transient improvement but subsequent decline. Thirteen of 32 (40.6%) patients aged >18 years were smokers., Conclusions: Pulmonary dysfunction was prevalent after whole lung irradiation and worsened over time, although most patients were asymptomatic. Boost irradiation impaired pulmonary function, and a significant proportion of patients were smokers. Further studies are planned to assess the predictors and clinical consequences of progressive PFT abnormalities and to evaluate educational interventions., (Copyright © 2011 American Cancer Society.)

Purpose: To investigate the relationship between jaw function, patient and treatment variables, and radiation dosimetry of the mandibular muscles and joints in children and young adults receiving radiation for soft-tissue and bone sarcomas., Methods and Materials: Twenty-four pediatric and young adult patients with head-and-neck sarcomas were treated on an institutional review board-approved prospective study of focal radiation therapy for local tumor control. Serial jaw depression measurements were related to radiation dosimetry delivered to the medial and lateral pterygoid muscles, masseter muscles, and temporomandibular joints to generate mathematical models of jaw function., Results: Baseline jaw depression was only influenced by the degree of surgical resection. In the first 12 weeks from initiation of radiation, surgical procedures greater than a biopsy, administration of cyclophosphamide containing chemotherapy regimes, and large gross tumor volumes adversely affected jaw depression. Increasing dose to the pterygoid and masseter muscles above 40 Gy predicted loss of jaw function over the full course of follow-up., Conclusions: Clinical and treatment factors are related to initial and subsequent jaw dysfunction. Understanding these complex interactions and the affect of specific radiation doses may help reduce the risk for jaw dysfunction in future children and young adults undergoing radiation therapy for the management of soft-tissue and bone sarcomas., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background/purpose: The aim of this study was to retrospectively analyze the clinical presentation, histology, treatment, and outcomes of children with vaginal tumors who were treated at a single institution., Methods: A retrospective review of medical records and pathologic materials of all children with vaginal tumors treated at St Jude Children's Research Hospital between 1970 and 2009 was conducted., Results: Eighteen patients (median age, 3.7 years; range, 0.1-15 years) were identified. Three different histologies were found: rhabdomyosarcoma (RMS; n = 13), germ cell tumor (n = 3), and clear cell adenocarcinoma (n = 2). Bleeding or blood-tinged discharge was the most common clinical presentation (66%), followed by a protruding mass (39%). Vaginal and uterine salvage was 44.4% (8 of 18 patients). Thirteen patients (72.2%) remain disease-free, with a median follow-up of 23.2 years (range, 2-39 years). Four patients (22.2%) died of disease progression (1 RMS, 2 germ cell tumor, and 1 clear cell adenocarcinoma), and 1 patient with RMS died of colon cancer 12 years after the primary diagnosis had been made., Conclusions: Vaginal tumors are extremely rare in the pediatric population. Early recognition of symptoms like bleeding and a protruding vaginal mass may prevent morbidity and mortality. Our findings confirm the good prognosis of vaginal RMS., (Copyright © 2011 Elsevier Inc. All rights reserved.)