Search

Background: The purpose of this article is to summarize the literature that documents the long-term impact of cancer treatment modalities on pulmonary function among survivors of cancer and to identify potential areas for further research.Methods: Systematic reviews of clinical trials, observational studies, case series, and review articles were conducted. Articles were limited to the studies that discussed pulmonary toxicity or late effects among pediatric cancer survivors and to follow-up investigations that were conducted a minimum of 2 years after completion of cancer-related treatment or 1 year after hematopoietic stem cell transplant.Results: Sixty publications (51 clinical studies/reports and nine reviews) published from January 1970 to June 2010 in PubMed met the inclusion criteria. Data showed an association between radiotherapy, alkylating agents, bleomycin, hematopoietic stem cell transplant, and thoracic surgery and pulmonary toxicity, as well as possible interactions among these modalities.Conclusions: Pulmonary toxicity is a common long-term complication of exposure to certain anticancer therapies in childhood and can vary from subclinical to life threatening. Pulmonary function and associated loss of optimal exercise capacity may have adverse effects on long-term quality of life in survivors. Lung function diminishes as a function of normal aging, and the effects of early lung injury from cancer therapy may compound these changes. The information presented in this review is designed to provide a stimulus to promote both observational and interventional research that expands our knowledge and aids in the design of interventions to prevent or ameliorate pulmonary late effects among survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. METHODS: After resection, patients were classified as having average-risk medulloblastoma (1.5 cm(2) residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with , number . FINDINGS: Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. INTERPRETATION: Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma. [ABSTRACT FROM AUTHOR]

Background: Suffering at the end-of-life (EOL) can impact the perception of a "good death" and ultimately affect bereavement for families of children with cancer. Palliative radiation (pXRT) is a tool that can address pain, mitigate suffering and improve quality of life., Methods: A retrospective medical record review of pediatric oncology patients who died over an 11-year period was completed. Descriptive analysis and nonparametric tests to compare groups were used., Results: 2202 total deaths occurred during the study period; 167 patients met study criteria, reflecting a 7.6% incidence of pXRT use at the EOL. Most patients were white (68%) and male (59%), with a median age of 9 years. Solid tumors were most common (52%), followed by CNS tumors (38%), and leukemia (10%). pXRT was primarily used to treat pain (37%) and focused on sites including brain/spine (37%), head/neck (24%), and pelvis (12%). Mean radiation dose delivered was 23.8Gy (range: 1.8-55.8 Gy) in a median of 7 fractions (range: 1-31). Side effects were rare and 58% of patients had a decrease in reported pain scores. Additionally, 87% received a pediatric palliative care (PPC) consultation which increased the likelihood for hospice referral, documented DNR preferences and decrease episodes of CPR on the day of death., Conclusions: There is underutilization and significant variability in the use of pXRT during EOL in pediatric oncology. Barriers to this tool may include physician perceptions, family/patient preferences, and logistical hardships. Guidelines to standardize pXRT, alongside earlier PPC integration, may guide clinician decision making and increase pXRT utilization., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Patients with bilateral Wilms tumor initially receive neoadjuvant chemotherapy to shrink the tumors and increase the likelihood of successful nephron-sparing surgery. Biopsy of poorly responding tumors is often done to better understand therapy resistance. The purpose of this retrospective, single-institution study was to determine whether initial chemotherapy response is associated with tumor histology, potentially obviating the need for biopsy or change in chemotherapy., Methods: Patients with synchronous bilateral Wilms tumors who underwent surgery at St Jude Children's Research Hospital from January 2000 to March 2022 were considered for this study. A mixed-effects logistic regression model was used to evaluate the likelihood of the tumor being stromal predominant, as predicted by tumor response to neoadjuvant chemotherapy., Results: A total of 68 patients were eligible for this study. Tumors that increased in size had an odds ratio of 19.5 (95% confidence interval [CI] = 2.46 to 155.03) for being stromal predominant vs any other histologic subtype. Age at diagnosis was youngest in patients with stromal-predominant tumors, with a mean age of 18.8 (14.1) months compared with all other histologic subtypes (χ2 = 7.05, P = .07). The predictive value of a tumor growing combined with patient aged younger than 18 months for confirming stromal-predominant histology was 85.7% (95% CI = 57.18% to 93.5%)., Conclusions: Tumors that increased in size during neoadjuvant chemotherapy were most frequently stromal-predominant bilateral Wilms tumor, especially in younger patients. Therefore, nephron-sparing surgery, rather than biopsy, or extension or intensification of neoadjuvant chemotherapy, should be considered for bilateral Wilms tumors that increase in volume during neoadjuvant chemotherapy, particularly in patients aged younger than 18 months., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Wilms tumor (WT) is the most common kidney tumor in pediatric patients. Intravascular extension of WT above the level of the renal veins is a rare manifestation that complicates surgical management. Patients with intravascular extension are frequently asymptomatic at diagnosis, and tumor thrombus extension is usually diagnosed by imaging. Neoadjuvant chemotherapy is indicated for thrombus extension above the level of the hepatic veins and often leads to thrombus regression, obviating the need for cardiopulmonary bypass in cases of cardiac thrombus at diagnosis. In cases of tumor extension to the retrohepatic cava, neoadjuvant therapy is not strictly indicated, but it may facilitate the regression of tumor thrombi, making resection safer. Hepatic vascular isolation and cardiopulmonary bypass increase the risk of bleeding and other complications when utilized for tumor thrombectomy. Fortunately, WT patients with vena caval with or with intracardiac extension have similar overall and event-free survival when compared to patients with WT without intravascular extension when thrombectomy is successfully performed. Still, patients with metastatic disease at presentation or unfavorable histology suffer relatively poor outcomes. Dedicated pediatric surgical oncology and pediatric cardiothoracic surgery teams, in conjunction with multimodal therapy directed by a multidisciplinary team, are preferred for optimized outcomes in this patient population.

Background: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described., Procedure: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions., Results: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT., Conclusion: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies., (© 2024 Wiley Periodicals LLC.)

Background and Purpose: The purpose of this study was to address the lack of published data on the use of brachytherapy in pediatric rhabdomyosarcoma by describing current practice as starting point to develop consensus guidelines., Materials and Methods: An international expert panel on the treatment of pediatric rhabdomyosarcoma comprising 24 (pediatric) radiation oncologists, brachytherapists and pediatric surgeons met for a Brachytherapy Workshop hosted by the European paediatric Soft tissue Sarcoma Study Group (EpSSG). The panel's clinical experience, the results of a previously distributed questionnaire, and a review of the literature were presented., Results: The survey indicated the most common use of brachytherapy to be in combination with tumor resection, followed by brachytherapy as sole local therapy modality. HDR was increasingly deployed in pediatric practice, especially for genitourinary sites. Brachytherapy planning was mostly by 3D imaging based on CT. Recommendations for patient selection, treatment requirements, implant technique, delineation, dose prescription, dose reporting and clinical management were defined., Conclusions: Consensus guidelines for the use of brachytherapy in pediatric rhabdomyosarcoma have been developed through multicenter collaboration establishing the basis for future work. These have been adopted for the open EpSSG overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma (FaR-RMS)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflicts of interest Dr. Mark N. Gaze is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and by the Radiation Research Unit at the Cancer Research UK City of London Centre Award [C7893/A28990]. Prof. Dr. Peter Hoskin is supported by the NIHR Manchester Biomedical Centre. Dr. Henry C. Mandeville is supported by the National Institute for Health Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Local control for patients with Ewing sarcoma (EWS) who present with large tumors are suboptimal when treated with standard radiation therapy (RT) doses of 54-55.8 Gy. The purpose of this study is to determine local control and toxicity of dose-escalated RT for tumors ≥8 cm (greatest diameter at diagnosis) in pediatric and young adult patients with EWS., Methods: Eligible patients ≤30 years old with newly diagnosed EWS ≥8 cm treated with definitive conformal or intensity modulated photon, or proton radiation therapy techniques were included. All patients in the study received dose-escalated RT doses. Outcomes included overall survival (OS), event-free survival (EFS), local failure rates, and toxicity., Results: Thirty-two patients were included, 20 patients presented with metastatic disease and 12 patients with localized disease. The median RT dose was 64.8 Gy (range, 59.4-69.4 Gy) with variability of doses to protect normal surrounding tissues. All patients received systemic chemotherapy. The 5-year OS and EFS for the cohort was 64.2% and 42%, respectively. The 5-year cumulative incidence of local failure was 6.6%. There were two combined local and distant failures with no isolated local failures. Twenty-nine patients experienced short term toxicity, 90% of those being radiation dermatitis. Twenty-seven patients experienced long-term toxicity, with only one experiencing grade 4 toxicity, a secondary malignancy after therapy., Conclusion: This study demonstrates that definitive RT for pediatric and young adult patients with EWS ≥8 cm provides high rates of local control, while maintaining a tolerable toxicity profile., (© 2024 American Cancer Society.)

(1) Background: Proton therapy, a precise form of radiation treatment, can be significantly affected by variations in bowel content. The purpose was to identify the most beneficial gantry angles that minimize deviations from the treatment plan quality, thus enhancing the safety and efficacy of proton therapy for Wilms' tumor patients. (2) Methods: Thirteen patients with Wilms' tumor, enrolled in the SJWT21 clinical trial, underwent proton therapy. The variations in bowel gas were systematically monitored using daily Cone Beam Computed Tomography (CBCT) imaging. Air cavities identified in daily CBCT images were analyzed to construct daily verification plans and measure water equivalent path length (WEPL) changes. A worst-case scenario simulation was conducted to identify the safest beam angles. (3) Results: The study revealed a maximum decrease in target dose (ΔD100%) of 8.0%, which corresponded to a WEPL variation (ΔWEPL) of 11.3 mm. The average reduction in target dose, denoted as mean ΔD100%, was found to be 2.8%, with a standard deviation (SD) of 3.2%. The mean ΔWEPL was observed as 3.3 mm, with an SD of 2.7 mm. The worst-case scenario analysis suggested that gantry beam angles oriented toward the patient's right and posterior aspects from 110° to 310° were associated with minimized WEPL discrepancies. (4) Conclusions: This study comprehensively evaluated the influence of bowel gas variability on treatment plan accuracy and proton range uncertainties in pediatric proton therapy for Wilms' tumor.

(1) Background: Synthetic CT images of the pelvis were generated from daily CBCT images to monitor changes in water equivalent path length (WEPL) and determine the dosimetric impact of anatomy changes along the proton beam's path; (2) Methods: Ten pediatric patients with pelvic tumors treated using proton therapy with daily CBCT were included. The original planning CT was deformed to the same-day CBCT to generate synthetic CT images for WEPL comparison and dosimetric evaluation; (3) Results: WEPL changes of 20 proton fields at the distal edge of the CTV ranged from 0.1 to 12 mm with a median of 2.5 mm, and 75th percentile of 5.1 mm for (the original CT-rescanned CT) and ranged from 0.3 to 10.1 mm with a median of 2.45 mm and 75th percentile of 4.8 mm for (the original CT-synthetic CT). The dosimetric impact was due to proton range pullback or overshoot, which led to reduced coverage in CTV Dmin averaging 12.1% and 11.3% in the rescanned and synthetic CT verification plans, respectively; (4) Conclusions: The study demonstrated that synthetic CT generated by deforming the original planning CT to daily CBCT can be used to quantify proton range changes and predict adverse dosimetric scenarios without the need for excessive rescanned CT scans during large interfractional variations in adaptive proton therapy of pediatric pelvic tumors.

Objective . This study aimed to develop a novel method for generating synthetic CT (sCT) from cone-beam CT (CBCT) of the abdomen/pelvis with bowel gas pockets to facilitate estimation of proton ranges. Approach . CBCT, the same-day repeat CT, and the planning CT (pCT) of 81 pediatric patients were used for training ( n = 60), validation ( n = 6), and testing ( n = 15) of the method. The proposed method hybridizes unsupervised deep learning (CycleGAN) and deformable image registration (DIR) of the pCT to CBCT. The CycleGAN and DIR are respectively applied to generate the geometry-weighted (high spatial-frequency) and intensity-weighted (low spatial-frequency) components of the sCT, thereby each process deals with only the component weighted toward its strength. The resultant sCT is further improved in bowel gas regions and other tissues by iteratively feeding back the sCT to adjust incorrect DIR and by increasing the contribution of the deformed pCT in regions of accurate DIR. Main results . The hybrid sCT was more accurate than deformed pCT and CycleGAN-only sCT as indicated by the smaller mean absolute error in CT numbers (28.7 ± 7.1 HU versus 38.8 ± 19.9 HU/53.2 ± 5.5 HU; P ≤ 0.012) and higher Dice similarity of the internal gas regions (0.722 ± 0.088 versus 0.180 ± 0.098/0.659 ± 0.129; P ≤ 0.002). Accordingly, the hybrid method resulted in more accurate proton range for the beams intersecting gas pockets (11 fields in 6 patients) than the individual methods (the 90th percentile error in 80% distal fall-off, 1.8 ± 0.6 mm versus 6.5 ± 7.8 mm/3.7 ± 1.5 mm; P ≤ 0.013). The gamma passing rates also showed a significant dosimetric advantage by the hybrid method (99.7 ± 0.8% versus 98.4 ± 3.1%/98.3 ± 1.8%; P ≤ 0.007). Significance . The hybrid method significantly improved the accuracy of sCT and showed promises in CBCT-based proton range verification and adaptive replanning of abdominal/pelvic proton therapy even when gas pockets are present in the beam path., (© 2023 Institute of Physics and Engineering in Medicine.)

Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly by NTRK fusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. The NTRK fusion acts as a driver for tumor formation, which can be targeted by first- and second-generation TRK inhibitors. Although NTRK gatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy and TRK inhibition that developed metastatic, progressive disease with multiple acquired mutations, including TP53 , SUFU , and an NTRK F617L gatekeeper mutation. Alterations in pathways of SUFU and TP53 have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response to TRK inhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma with ETV6::NTRK3 and acquired SUFU , TP53 , and NTRK F617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes., (© 2023 Furtado et al.; Published by Cold Spring Harbor Laboratory Press.)

Purpose: To characterize on-treatment changes in GTV morphology in children with parameningeal rhabdomyosarcoma receiving upfront proton therapy with concurrent chemotherapy and thereby provide guidance on the timing of on-treatment imaging and adaptive replanning., Methods and Materials: GTV was delineated on 86 simulation and weekly MR images of 15 prospectively enrolled patients (aged 1-21 years). Temporal changes from baseline in volume and surface (95% Hausdorff distance) were analyzed in relation to the need for plan verification and the resultant doses with hypothetical no treatment adaptation., Results: The median time was 6 days from the initiation of chemotherapy to CT+MR simulation and 15 days from the simulation to the start of radiotherapy. All but 1 patient showed a continuous decrease in GTV (0.16-1.52%/day) after simulation. At 3 weeks from simulation, 10 of 15 patients exhibited a significant reduction in volume (median, 20%; range, 6-29%). Without replanning, these changes could lead to a reduction in CTV V95 by 7-14% (n = 2) and/or an increase in D0.01 cc/Dmean of adjacent organs at risk by 6-21% of the prescribed target dose (n = 7). Significant dosimetric consequences occurred in cases with (1) a considerable weight gain, (2) shrinkage of the skin surface, or (3) tumor regression in the oral or nasal cavity and sinus that altered air-tissue components in the beam path. The subsequent GTV and dosimetry after 3 weeks from simulation (4 weeks from chemotherapy initiation) demonstrated a relatively stable trend., Conclusions: On-treatment imaging at 3 weeks after simulation is recommended, if the simulation is performed at 1 week after the initiation of chemotherapy, to detect significant anatomic changes that could result in >5% deviation from planned target coverage and/or organ doses in pediatric patients with parameningeal rhabdomyosarcoma receiving early proton therapy., (Copyright © 2023 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objectives: We aimed to clinically characterize the health, neurocognitive, and physical function outcomes of curative treatment of Wilms tumor., Methods: Survivors of Wilms tumor (n = 280) participating in the St. Jude Lifetime Cohort, a retrospective study with prospective follow-up of individuals treated for childhood cancer at St. Jude Children's Research Hospital, were clinically evaluated and compared to age and sex-matched controls (n = 625). Health conditions were graded per a modified version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Standardized neurocognitive testing was graded by using age-adjusted z-scores. Impaired physical function was defined by age- and sex-matched z-scores >1.5 SD below controls. Modified Poisson regression was used to compare the prevalence of conditions and multivariable logistic regression to examine treatment associations., Results: Median age at evaluation was similar between survivors and controls (30.5 years [9.0-58.0] and 31.0 [12.0-70.0]). Therapies included nephrectomy (100%), vincristine (99.3%), dactinomycin (97.9%), doxorubicin (66.8%), and abdominal (59.3%) and/or chest radiation (25.0%). By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7-13.8) grade 1-4 and 7.5 (CI: 6.7-8.2) grade 2 to 4 health conditions, compared to 4.2 (CI: 3.9-4.6) and 2.3 (CI: 2.1-2.5), respectively, among controls. Grade 2 to 4 endocrine (53.9%), cardiovascular (26.4%), pulmonary (18.2%), neurologic (8.6%), neoplastic (7.9%), and kidney (7.2%) conditions were most prevalent. Survivors exhibited neurocognitive and physical performance impairments., Conclusions: Wilms tumor survivors experience a threefold higher burden of chronic health conditions compared to controls and late neurocognitive and physical function deficits. Individualized clinical management, counseling, and surveillance may improve long-term health maintenance., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Indocyanine green (ICG), a water-soluble tricarbocyanine fluorophore, is being increasingly used for tumor localization based on its passive intra-tumoral accumulation due to enhanced permeability and retention in tumor tissue. Therefore, we hypothesized that ICG can provide contrast to facilitate accurate, real-time recognition of renal tumors at the time of nephron-sparing surgery in children., Methods: This retrospective study examined the feasibility of ICG in guiding nephron-sparing surgery for pediatric renal tumors., Results: We reviewed the medical records of 8 pediatric patients with renal tumors in 12 kidneys. Intraoperative localization of tumor with near infrared guidance was successful in all 12 kidneys. However, we consistently found an inverse pattern of near infrared signal in which the normal kidney demonstrated increased fluorescent signal relative to the kidney tumor., Conclusions: Fluorescence-guided renal tumor delineation is unique because it has an inverse pattern of near infrared signal in which the normal kidney demonstrates increased signal relative to the adjacent tumor. Nevertheless fluorescence-guided distinguishing of renal tumor from surrounding normal kidney is feasible., Competing Interests: Declaration of Competing Interest The authors have no conflicts to declare., (Copyright © 2021. Published by Elsevier Inc.)

Therapy-related pulmonary complications are among the leading causes of morbidity among long-term survivors of childhood cancer. Restrictive ventilatory defects (RVD) are prevalent, with risks increasing after exposures to chest radiotherapy and radiomimetic chemotherapies. Using whole-genome sequencing data from 1,728 childhood cancer survivors in the St. Jude Lifetime Cohort Study, we developed and validated a composite RVD risk prediction model that integrates clinical profiles and polygenic risk scores (PRS), including both published lung phenotype PRSs and a novel survivor-specific pharmaco/radiogenomic PRS (surPRS) for RVD risk reflecting gene-by-treatment (GxT) interaction effects. Overall, this new therapy-specific polygenic risk prediction model showed multiple indicators for superior discriminatory accuracy in an independent data set. The surPRS was significantly associated with RVD risk in both training (OR = 1.60, P = 3.7 × 10-10) and validation (OR = 1.44, P = 8.5 × 10-4) data sets. The composite model featuring the surPRS showed the best discriminatory accuracy (AUC = 0.81; 95% CI, 0.76-0.87), a significant improvement (P = 9.0 × 10-3) over clinical risk scores only (AUC = 0.78; 95% CI: 0.72-0.83). The odds of RVD in survivors in the highest quintile of composite model-predicted risk was ∼20-fold higher than those with median predicted risk or less (OR = 20.01, P = 2.2 × 10-16), exceeding the comparable estimate considering nongenetic risk factors only (OR = 9.20, P = 7.4 × 10-11). Inclusion of genetic predictors also selectively improved risk stratification for pulmonary complications across at-risk primary cancer diagnoses (AUCclinical = 0.72; AUCcomposite = 0.80, P = 0.012). Overall, this PRS approach that leverages GxT interaction effects supports late effects risk prediction among childhood cancer survivors., Significance: This study develops a therapy-specific polygenic risk prediction model to more precisely identify childhood cancer survivors at high risk for pulmonary complications, which could help improve risk stratification for other late effects., (©2022 American Association for Cancer Research.)

Background: We characterize the patterns of progression across medulloblastoma (MB) clinical risk and molecular subgroups from SJMB03, a Phase III clinical trial., Methods: One hundred and fifty-five pediatric patients with newly diagnosed MB were treated on a prospective, multi-center phase III trial of adjuvant radiotherapy (RT) and dose-intense chemotherapy with autologous stem cell transplant. Craniospinal radiotherapy to 23.4 Gy (average risk, AR) or 36-39.6 Gy (high risk, HR) was followed by conformal RT with a 1 cm clinical target volume to a cumulative dose of 55.8 Gy. Subgroup was determined using 450K DNA methylation. Progression was classified anatomically (primary site failure (PSF) +/- distant failure (DF), or isolated DF), and dosimetrically., Results: Thirty-two patients have progressed (median follow-up 11.0 years (range, 0.3-16.5 y) for patients without progression). Anatomic failure pattern differed by clinical risk (P = .0054) and methylation subgroup (P = .0034). The 5-year cumulative incidence (CI) of PSF was 5.1% and 5.6% in AR and HR patients, respectively (P = .92), and did not differ across subgroups (P = .15). 5-year CI of DF was 7.1% vs. 28.1% for AR vs. HR (P = .0003); and 0% for WNT, 15.3% for SHH, 32.9% for G3, and 9.7% for G4 (P = .0024). Of 9 patients with PSF, 8 were within the primary site RT field and 4 represented SHH tumors., Conclusions: The low incidence of PSF following conformal primary site RT is comparable to prior studies using larger primary site or posterior fossa boost volumes. Distinct anatomic failure patterns across MB subgroups suggest subgroup-specific treatment strategies should be considered., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rhabdomyosarcoma (RMS) is a pediatric cancer with features of skeletal muscle; patients with unresectable or metastatic RMS fare poorly due to high rates of disease recurrence. Here, we use single-cell and single-nucleus RNA sequencing to show that RMS tumors recapitulate the spectrum of embryonal myogenesis. Using matched patient samples from a clinical trial and orthotopic patient-derived xenografts (O-PDXs), we show that chemotherapy eliminates the most proliferative component with features of myoblasts within embryonal RMS; after treatment, the immature population with features of paraxial mesoderm expands to reconstitute the developmental hierarchy of the original tumor. We discovered that this paraxial mesoderm population is dependent on EGFR signaling and is sensitive to EGFR inhibitors. Taken together, these data serve as a proof of concept that targeting each developmental state in embryonal RMS is an effective strategy for improving outcomes by preventing disease recurrence., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients., Methods and Materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later., Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors., Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes., Methods: This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored., Results: The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age < 5 years (OR, 1.05; 95% CI, 1.01-1.09). Primary hypothyroidism was associated with frailty (OR, 1.54; 95% CI, 1.05-2.26), dyslipidemia (OR, 1.52; 95% CI, 1.14-2.04), impaired physical QOL (OR, 1.66; 95% CI, 1.12-2.48), and having health care insurance (OR, 1.51; 95% CI, 1.07-2.12)., Conclusions: Primary hypothyroidism is common in survivors and is associated with unfavorable physical health and QOL outcomes. The impact of thyroid hormone replacement practices on these outcomes should be investigated further., (© 2021 American Cancer Society.)

Purpose: Image-defined risk factors (IDRFs) are associated with surgical risks in neuroblastoma. We sought to evaluate the impact of neoadjuvant therapy on IDRFs and associated ability to achieve gross total resection (GTR) of locoregional disease in patients with high-risk neuroblastoma., Methods: We retrospectively reviewed charts of patients treated on four consecutive high-risk neuroblastoma protocols over a 20-year period at a single institution. The number of IDRFs at diagnosis and just prior to surgery, and the percent decrease of tumor volume from just prior to surgery to the end of induction were determined., Results: Eighty-eight patients were included. There were 438 IDRFs (average 5.0 ± 3.1 per patient) at diagnosis and 198 (average 2.3 ± 1.9 per patient) after neoadjuvant chemotherapy (p < 0.01). A reduction in IDRFs was seen in 81.8% of patients with average decrease of 2.9 ± 2.5 per patient. The average percent reduction in tumor volume was 89.8 ± 18.9% and correlated with the number of IDRFs present after chemotherapy (p < 0.01). Three or fewer IDRFs prior to surgery was associated with the highest odds ratio for > 90% GTR at 9.33 [95% confidence interval 3.14-31.5]., Conclusion: Neoadjuvant chemotherapy reduced the number of IDRFs in the majority of patients with high-risk neuroblastoma. The number of IDRFs present after neoadjuvant therapy correlated with the extent of resection., (© 2021. Society of Surgical Oncology.)

Purpose: Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL., Methods: Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov (identifier: NCT01920932)., Results: Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy., Conclusion: The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes., Competing Interests: Monika L. MetzgerResearch Funding: Seattle Genetics Michael P. LinkConsulting or Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology Jamie FlerlageResearch Funding: Seattle Genetics Matthew J. EhrhardtHonoraria: Optum Torunn I. YockConsulting or Advisory Role: Huron Consulting Services, LLCResearch Funding: MIM Software Sue C. KasteStock and Other Ownership Interests: GE Healthcare Barry ShulkinConsulting or Advisory Role: Navidea Melissa M. HudsonConsulting or Advisory Role: Oncology Research Information Exchange Network, Princess Máxima Center Matthew J. KrasinConsulting or Advisory Role: Debiopharm GroupNo other potential conflicts of interest were reported.

Purpose: To train a deep neural network for correcting abdominal and pelvic cone-beam computed tomography (CBCT) of children and young adults in the presence of diverse patient size, anatomic extent, and scan parameters., Materials and Methods: Pretreatment CBCT and planning/repeat CT image pairs from 64 children and young adults treated with proton therapy (aged 1-23 years) were analyzed. To evaluate the impact of anatomic extent in CBCT and data size in the training data, we compared the performance of three cycle-consistent generative adversarial network models that were separately trained by three datasets comprising abdominal (n = 21), pelvic (n = 29), and combined abdominal-pelvic image pairs (n = 50), respectively. The maximum body width of each patient was normalized to a fixed width before training and model application to reduce the impact of variations in body size. The corrected CBCT images by the three models were comparatively evaluated against the repeat CT closest in time to the CBCT (median gap, 0 days; range, 0-6 days) in HU accuracy, estimated dose distribution, and proton range., Results: The network model trained by the combined dataset significantly outperformed the abdomen and pelvis models in mean absolute HU error of the corrected CBCT from 14 testing patients (47 ± 7 HU versus 51 ± 8 HU; paired Wilcoxon signed-rank test, P < 0.01). The larger error (60 ± 7 HU) without the body-size normalization confirmed the efficacy of the preprocessing. The model trained with the combined dataset resulted in gamma passing rates of 98.5 ± 1.9% (2%/2 mm criterion) and the range (80% distal fall-off) differences from the reference within ±3 mm for 91.2 ± 11.5% beamlets., Conclusion: Combining data from adjacent anatomic sites and normalizing age-dependent body sizes in children and young adults were beneficial in training a neural network to accurately estimate proton dose from CBCT despite limited training data size and anatomic diversities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The role of surgery, chemotherapy, and radiation therapy for retinoblastoma has evolved considerably over the years with the efficacy of intraarterial chemotherapy and the high incidence of secondary malignant neoplasms following radiation therapy. The use of spot scanning intensity-modulated proton therapy may reduce the risk of secondary malignancies. For pediatric nasopharyngeal carcinoma, the current standard of care is induction chemotherapy followed by chemoradiation therapy. For adrenocortical carcinoma, the mainstay of treatment is surgery and chemotherapy. The role of radiation therapy remains to be defined., (© 2021 Wiley Periodicals LLC.)

Purpose: The use of stereotactic body radiation therapy (SBRT) in pediatric patients has been underreported. We reviewed practice patterns, outcomes, and toxicity of SBRT in this population., Methods and Materials: In this multi-institutional study, 55 patients with 107 non-central nervous system lesions treated with SBRT between 2010 and 2016 were reviewed. Treatment response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST v1.1 criteria for soft-tissue and bone lesions, respectively. Patterns of local failure (LF) were assessed dosimetrically. The cumulative incidence of LF and toxicity were estimated accounting for the competing risk event of death. Predictors of LF were identified through joint frailty models for clustered competing risks., Results: The median (range) dose/fraction was 7 (4.5-25) Gy, the total (range) dose/site was 35 (12-45), and the median (range) number of fractions was 5 (1-9). The radiographic response rates of bone and soft-tissue lesions were 90.6% and 76.7%, respectively. Symptom improvement was observed for 62% of symptomatic sites. A total of 27 LFs were documented, with 14 in-field, 9 marginal, and 4 out-of-field LFs. The 1-year estimated cumulative LF rate, progression-free survival, and overall survival were 25.2% (95% confidence interval [CI], 17.2%-36.1%), 17.5% (95% CI, 9.0%-34.1%), and 61% (95% CI, 48.9%-76.1%), respectively. Lesion type (soft tissue vs bone) was the only significant predictor of LF on multivariable analysis (P = .04), with increased hazard for soft-tissue lesions. No acute or late toxicity of grade 4 or higher was observed; the estimated 1-year cumulative incidence of late toxicity of any grade was 7.5% (95% CI, 3.6%-12.1%)., Conclusions: The SBRT was well tolerated and resulted in radiographic response and symptom palliation in most pediatric patients with advanced disease. The 1-year cumulative LF rate of 25% will serve as a benchmark for further modifications to radiation therapy indications, parameters, and combination therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Metastasectomy is standard of care for pediatric patients with metastatic sarcoma with limited disease. For patients with unresectable disease, stereotactic body radiotherapy (SBRT) may serve as an alternative. Herein, the authors report the results of a prospective, multi-institutional phase 2 trial of SBRT in children and young adults with metastatic sarcoma., Methods: Patients aged >3 years and ≤40 years with unresected, osseous metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone were eligible. Patients received SBRT to a dose of 40 Gray (Gy) in 5 fractions. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method., Results: Fourteen patients with a median age of 17 years (range, 4-25 years) were treated to 37 distinct metastatic lesions. With a median follow-up of 6.8 months (30.5 months in surviving patients), the Kaplan-Meier patient-specific and lesion-specific LC rates at 6 months were 89% and 95%, respectively. The median PFS was 6 months and the median OS was 24 months. In a post hoc analysis, PFS (median, 9.3 months vs 3.7 months; log-rank P = .03) and OS (median not reached vs 12.7 months; log-rank P = .02) were improved when all known sites of metastatic disease were consolidated with SBRT compared with partial consolidation. SBRT was well tolerated, with 2 patients experiencing grade 3 toxicities., Conclusions: SBRT achieved high rates of LC in pediatric patients with inoperable metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone. These results suggest that the ability to achieve total consolidation of metastatic disease with SBRT is associated with improved PFS and OS., (© 2020 American Cancer Society.)

Purpose: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma., Patients and Methods: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories., Results: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%)., Conclusion: These results establish a new risk stratification for future medulloblastoma trials.

Purpose: Pencil-beam scanning proton therapy is particularly sensitive to anatomic changes, which may affect the delivered dose distribution. This study examined whether offline adaptation using on-treatment magnetic resonance imaging (MRI) scan during proton therapy could improve plan quality for pediatric patients., Methods and Materials: Pediatric patients with at least 1 MRI scan in the treatment position (MRI tx ) during proton therapy between January 2017 and July 2019 were retrospectively reviewed. Patients underwent MRI and computed tomography simulation. Cases were planned with scenario-based optimization with 3 mm/3% positional/range uncertainty. Patients demonstrating anatomic change on MRI tx were recontoured. The original plans were applied to the anatomy-of-the-day for dose recalculation (delivered plans). Plans were subsequently reoptimized offline, using original beam angles and dose-volume constraints (adapted plans). Delivered plans were compared with adapted plans to detect significant changes in plan quality, defined as a ≥5% decrease in the clinical target volume (CTV) receiving 95% of the prescription dose (V95) or a ≥5% increase in the dose-volume parameter used as an organ-at-risk constraint., Results: Seventy-three pediatric patients were eligible, with 303 MRI scans (73 simulation and 230 MRI tx scans) available for analysis. The median MRI tx scans per patient was 3 (range, 1-7). Twenty patients (27%) showed anatomic change, with 11 (55%) demonstrating a significant change in delivered plan quality. Significant changes were noted on MRI tx from week 2 (n = 3) or week 3 (n = 8). Seven of these 11 patients (64%) had a significantly reduced CTV V95 (median decrease, 7.6%; range, 5%-16%). Four (36%) had a significantly increased dose to the brain stem, hippocampus, and/or optic apparatus. Eight had a suprasellar low-grade glioma or head and neck rhabdomyosarcoma., Conclusion: On-treatment MRI was useful in detecting anatomic changes during proton therapy. MRI-based offline adaptation improved plan quality for most patients with anatomic changes. Further studies should determine the clinical value of MRI-based adaptive therapy for pediatric patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to evaluate outcomes based on surgical approach for retroperitoneal lymph node dissection (RPLND) in patients with paratesticular rhabdomyosarcoma (PT-RMS)., Methods: Patients undergoing RPLND for PT-RMS over 10 years at a single institution were retrospectively reviewed. Length of stay (LOS), complications, oral morphine equivalents per kilogram (OME/Kg), lymph node yield, and time to chemotherapy were assessed. The surgical approaches compared were: open transabdominal, open extraperitoneal, laparoscopic, and retroperitoneoscopic. For cases with lymphatic mapping, indocyanine green (ICG) was injected into the spermatic cord., Results: Twenty patients were included: five open transabdominal, six open extraperitoneal, three laparoscopic, and six retroperitoneoscopic operations. LOS was shorter in the retroperitoneoscopic group than laparoscopic (p = 0.029) and both open groups (p < 0.001). Mean OME/kg used was lowest in the retroperitoneoscopic (0.13 ± 0.15) group compared to laparoscopic (0.68 ± 0.53, p = 0.043), open transabdominal (14.90 ± 8.87, p = 0.003), and extraperitoneal (10.11 ± 2.44, p < 0.001). Time to chemotherapy was shorter for retroperitoneoscopic patients (0.13 days ± 0.15) compared to open transabdominal (15.6 days±6.5, p = 0.005). There was no difference in lymph node yield between groups. Spermatic cord ICG demonstrated iliac lymph node avidity on near-infrared spectroscopy., Conclusions: Minimally invasive RPLND appears to offer a faster recovery without compromising lymph node yield for patients with PT-RMS., Level of Evidence: III., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image-guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in-room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients., (© 2020 Wiley Periodicals LLC.)

Introduction: There is a growing population of childhood cancer survivors at risk for adverse outcomes, including sexual dysfunction., Aim: To estimate the prevalence of and risk factors for sexual dysfunction among adult female survivors of childhood cancer and evaluate associations between dysfunction and psychological symptoms/quality of life (QOL)., Methods: Female survivors (N = 936, mean 7.8 ± 5.6 years at diagnosis; 31 ± 7.8 years at evaluation) and noncancer controls (N = 122) participating in the St. Jude Lifetime Cohort Study completed clinical evaluations, Sexual Functioning Questionnaires (SFQ), and Medical Outcomes Survey Short Forms 36 (SF-36). Linear models compared SFQ scores between sexually active survivors (N = 712) and controls; survivors with scores <10th percentile of controls were classified with sexual dysfunction. Logistic regression evaluated associations between survivor characteristics and sexual dysfunction, and between sexual dysfunction and QOL., Outcomes: Sexual dysfunction was defined by scores <10th percentile of noncancer controls on the SFQ overall, as well as the domains of arousal, interest, orgasm, and physical problems, while QOL was measured by scores on the SF-36 with both physical and mental summary scales., Results: Sexual dysfunction was prevalent among 19.9% (95% CI 17.1, 23.1) of survivors. Those diagnosed with germ cell tumors (OR = 8.82, 95% CI 3.17, 24.50), renal tumors (OR = 4.49, 95% CI 1.89, 10.67), or leukemia (OR = 3.09, 95% CI 1.50, 6.38) were at greater risk compared to controls. Age at follow-up (45-54 vs 18-24 years; OR = 5.72, 95% CI 1.87, 17.49), pelvic surgery (OR = 2.03, 95% CI 1.18, 3.50), and depression (OR = 1.96, 95% CI 1.10, 3.51) were associated with sexual dysfunction. Hypogonadism receiving hormone replacement (vs nonmenopausal/nonhypogonadal; OR = 3.31, 95% CI 1.53, 7.15) represented an additional risk factor in the physical problems (eg, vaginal pain and dryness) subscale. Survivors with sexual dysfunction, compared to those without sexual dysfunction, were more likely to score <40 on the physical (21.1% vs 12.7%, P = .01) and mental health (36.5% vs 18.2%, P < .01) summary scales of the SF-36. Only 2.9% of survivors with sexual dysfunction reported receiving intervention., Clinical Implications: Health care providers should be aware of the increased risk of sexual dysfunction in this growing population, inquire about symptomology, and refer for appropriate intervention., Strengths & Limitations: Strengths of this study include the use of a validated tool for evaluating sexual function in a large population of clinically assessed female childhood cancer survivors. Limitations include potential for selection bias, and lack of clinically confirmed dysfunction., Conclusion: Sexual dysfunction is prevalent among female childhood cancer survivors and few survivors receive intervention; further research is needed to determine if those with sexual dysfunction would benefit from targeted interventions. Bjornard KL, Howell CR, Klosky JL, et al. Psychosexual Functioning of Female Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort Study. J Sex Med 2020;17:1981-1994., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The impact of specific treatment modalities on long-term renal function and blood pressure among adult survivors of Wilms tumor (WT) has not been well documented., Methods: Among 40 WT survivors and 35 noncancer controls, we estimated the glomerular filtration rate (eGFR) using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equations with and without cystatin C, obtained 24-hour ambulatory blood pressure readings, and, among survivors only, measured 99m Tc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. Survivors were treated with unilateral nephrectomy and nonnephrotoxic chemotherapy. Twenty received whole abdomen radiation therapy (WART) [median -16.5 Gray (Gy)], and 20 received no radiation therapy. Pairwise comparisons between survivors treated with and without WART, and each group to controls were performed using two-sample t tests., Results: Twenty-six (65%) WT survivors were female, and 33 (83%) were non-Hispanic white. GFR estimated with creatinine or creatinine + cystatin C was decreased among irradiated survivors compared with controls. No irradiated or unirradiated participant had an eGFR (creatinine + cystatin C) < 60 mL/min/1.73 m 2 . The prevalence of hypertension was significantly increased among unirradiated (25%) and irradiated survivors (35%) compared with controls (0%). Of the 24-hour ambulatory blood pressure monitoring parameters evaluated, only mean sleep period diastolic blood pressure load of those who received WART was significantly different from that of controls., Conclusions: Chronic kidney disease was infrequent in long-term survivors of unilateral nonsyndromic WT, whether treated with WART or no radiation. The prevalence of hypertension was increased in both groups compared with controls, emphasizing the need for ongoing monitoring of renal and cardiovascular health., (© 2020 Wiley Periodicals, Inc.)

Exposure to high doses of alkylating agents is associated with increased risk of impaired spermatogenesis among nonirradiated male survivors of childhood cancer, but there is substantial variation in this risk. Here we conducted a genetic study for impaired spermatogenesis utilizing whole-genome sequencing data from 167 nonirradiated male childhood cancer survivors of European ancestry from the St. Jude Lifetime Cohort treated with cyclophosphamide equivalent dose (CED) ≥4,000 mg/m 2 . Sperm concentration from semen analysis was assessed as the primary outcome. Common variants (MAF > 0.05) were adjusted for age at cancer diagnosis, CED, and top principal components. Rare/low-frequency variants (MAF ≤ 0.05) were evaluated jointly by various functional annotations and 4-kb sliding windows. A novel locus at 7q21.3 containing TAC1 / ASNS was associated with decreased sperm concentration (rs7784118: P = 3.5 × 10 -8 ). This association was replicated in two independent samples of SJLIFE survivors of European ancestry, including 34 nonirradiated male survivors treated with 0 < CED < 4,000 mg/m 2 ( P = 3.1 × 10 -4 ) and 24 male survivors treated with CED ≥4,000 mg/m 2 and radiotherapy <40 Gray ( P = 0.012). No association was observed among survivors not exposed to alkylating agents included in the CED ( P > 0.29). rs7784118 conferred 3.48- and 9.73-fold increases in risk for clinically defined oligospermia and azoospermia and improved prediction of normospermic, oligospermic, and azoospermic states by 13.7%, 5.3%, and 21.7%. rs7784118 was associated with decreased testosterone level, increased levels of follicle stimulating and luteinizing hormones, and 8.52-fold increased risk of Leydig cell failure. Additional research is warranted to determine how this SNP influences spermatogenesis and to assess its clinical utility in characterizing high-risk survivors and guiding intervention strategies. SIGNIFICANCE: The identified genetic markers harbor potential clinical utility in characterizing high-risk survivors and guiding intervention strategies including pretreatment patient counseling and use of fertility preservation services., (©2020 American Association for Cancer Research.)

Purpose: Our purpose was to assess disease outcomes and late toxicities in pediatric patients with rhabdomyosarcoma treated with conformal photon radiation therapy (RT)., Methods and Materials: Sixty-eight patients (median age, 6.9 years) were treated with conformal photon RT to the primary site on a prospective clinical trial. Target volumes included a 1-cm expansion encompassing microscopic disease. Prescribed doses were 36 Gy to this target volume and 50.4 Gy to gross residual disease. Chemotherapy consisted of vincristine/dactinomycin (n = 6), vincristine/dactinomycin/cyclophosphamide (n = 37), or vincristine/dactinomycin/cyclophosphamide-based combinations (n = 25). Patients were evaluated with primary-site magnetic resonance imaging, whole-body [ 18 F]fluorodeoxyglucose positron emission tomography, and chest computed tomography for 5 years after treatment., Results: Five-year disease-free survival was 88% for low-risk (n = 8), 76% for intermediate-risk (n = 37), and 36% for high-risk (n = 23) patients (P ≤ .01 for low risk/intermediate risk vs high risk). The cumulative incidence of local failure (LF) at 5 years for the entire cohort was 10.4%. Tumor size at diagnosis was a significant predictor of LF (P < .01). Patients with head and neck primary tumors (n = 31) had a 35% cumulative incidence of cataracts; the risk correlated with lens dose (P = .0025). Jaw dysfunction was more severe when the pterygoid and masseter muscles received a mean dose of >20 Gy (P = .013). Orbital hypoplasia developed more frequently after a mean bony orbit dose of >30 Gy (P = .041). Late toxicity in patients with genitourinary tumors included microscopic hematuria (9 of 14), bladder-wall thickening (10 of 14), and vaginal stenosis (2 of 5)., Conclusions: Long-term LF rates were low, and higher rates correlated with larger tumors. Treatment-related toxicities resulting in measurable functional deficits were not infrequent, despite the conformal RT approach., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to report on the institutional outcomes after proton therapy for pelvic rhabdomyosarcoma (RMS)., Methods and Materials: Thirty-one children (≤21 years old) with group III pelvic RMS were enrolled on a prospective outcome study and treated between 2007 and 2018. Patients with vaginal/cervical RMS were excluded. The median age was 2.6 years. Twenty-four patients had embryonal RMS. At diagnosis, the median tumor volume was 185 cm 3 and the median maximum diameter was 9.4 cm. Seven patients had N1 disease. Nineteen and 12 patients received European Pediatric Soft Tissue Sarcoma Study Group- and Children's Oncology Group-based chemotherapy, respectively. Fourteen patients underwent resection of the primary tumor after induction chemotherapy, including 6 patients who had a total cystectomy. The median radiation dose was 50.4 Gy relative biological effectiveness., Results: With a median follow-up of 4.2 years, the 5-year local control, progression-free survival, and overall survival rates were 83%, 80%, and 84%, respectively. Patients <3 years old had better local control (100% vs 68%; P = .02), and patients with embryonal histology had better survival (96% vs 54%; P = .02). No other factors were significantly associated with disease control or survival. Specifically, no statistically significant difference was observed in local control, progression-free survival, or overall survival when comparing patients who underwent biopsy versus gross total resection (75% vs 93%, 68% vs 93%, 75% vs 93%, respectively). Excluding patients who underwent cystectomy, urinary toxicity was limited to 2 patients with nocturnal enuresis. Exploratory surgery to address a persistent mass or thickened bladder wall after radiation was the most common source of serious toxicity., Conclusions: This cohort of young children with large pelvic tumors treated with proton therapy demonstrates similar local control with less toxicity than historic reports. Functional bladder preservation is possible in most patients. Exploratory biopsy in the 18 months after radiation should be approached with caution., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response., Materials and Methods: We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes., Results: Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% ± 6.4% and 49.6% ± 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P < 0.001) but not improved OS (P = 0.065). Post-induction pulmonary CR was associated with a lower incidence of lung failure (P = 0.031)., Conclusions: Post-induction pulmonary CR is associated with improved EFS in patients with Ewing sarcoma who present with pulmonary metastases., (© 2020 Wiley Periodicals, Inc.)

Background: The objective of this study was to characterize chronic disease, health-related quality of life (HRQOL), emotional distress, and social attainment among long-term survivors of neuroblastoma., Methods: Chronic health conditions among 136 ≥10-year neuroblastoma survivors (median age, 31.9 years; range, 20.2-54.6 years) and 272 community controls (median age, 34.7 years; range, 18.3-59.6 years) were graded with a modified version of the Common Terminology Criteria for Adverse Events (version 4.03). HRQOL and emotional distress were assessed with the Medical Outcomes Study 36-Item Short Form Health Survey and the Brief Symptom Inventory-18. Log-binomial regression and logistic regression were used to compare the prevalence of chronic conditions and the frequency of reduced HRQOL, distress, and social attainment between survivors and controls. The cumulative burden approach was used to estimate multimorbidity., Results: By the age of 35 years, survivors had experienced, on average, 8.5 grade 1 to 5 conditions (95% confidence interval [CI], 7.6-9.3), which was higher than the average for controls (3.3; 95% CI, 2.9-3.7). Compared with controls, survivors had a higher prevalence of any pulmonary (P = .003), auditory (P < .001), gastrointestinal (P < .001), neurological (P = .003), or renal condition (P < .001); were more likely to report poor physical HRQOL (P = .01) and symptoms of anxiety (P = .01) and somatization (P = .01); and were less likely to live independently (P = .01) or marry (P = .01). In analyses limited to survivors, those with 1 or more grade 3 to 5 conditions were more likely to report reduced general health (odds ratio [OR], 6.6; 95% CI, 1.6-26.9), greater bodily pain (OR, 4.2; 95% CI, 1.0-17.0), and unemployment (OR, 3.2; 95% CI, 1.2-8.5)., Conclusions: Because of the high burden of chronic diseases and the associations of these morbidities with reduced HRQOL and social attainment, screening and interventions that provide opportunities to optimize health are important among neuroblastoma survivors., (© 2020 American Cancer Society.)

Purpose: The treatment of childhood nasopharyngeal carcinoma has been adapted from adult regimens; pediatric-specific studies are limited. The ARAR0331 study sought to evaluate the impact of induction chemotherapy (IC) and concurrent chemoradiotherapy (CCR)., Patients and Methods: Patients with American Joint Committee on Cancer stages IIb to IV were scheduled to receive three cycles of IC with cisplatin and fluorouracil, followed by CCR with three cycles of cisplatin. Patients with complete or partial response to IC received 61.2 Gy to the nasopharynx and neck, and patients with stable disease received 71.2 Gy., Results: Between February 2006 and January 2012, 111 patients (75 male) were enrolled. Median age was 15 years, and 46.8% of the patients were African American. After a feasibility analysis, the study was amended to reduce cisplatin to two cycles during CCR. The 5-year event-free survival (EFS) and overall survival estimates were 84.3% and 89.2%, respectively. The 5-year EFS for stages IIb, III, and IV were 100%, 82.8%, and 82.7%, respectively. The 5-year cumulative incidence estimates of local, distant, and combined relapse were 3.7%, 8.7%, and 1.8%, respectively. Patients treated with three versus two CCR cycles of cisplatin had improved 5-year postinduction EFS (90.7% v 81.2%, P = .14)., Conclusion: Patients in ARAR0331 were characterized by advanced disease and by a high proportion of black children and adolescents. Treatment with IC and CRT resulted in excellent outcomes. A radiation dose reduction is possible for patients responding to IC. Although the outcomes are comparable, we observed a trend toward decreased EFS for patients assigned to receive fewer doses of cisplatin during CCR.

Purpose: Direct assessment of Leydig cell function in childhood cancer survivors has been limited. The objectives of this study were to describe the prevalence of and risk factors for Leydig cell failure (LCF), Leydig cell dysfunction (LCD), and associated adverse health outcomes., Patients and Methods: In this retrospective study with cross-sectional health outcomes analysis, we evaluated 1,516 participants (median age, 30.8 years) at a median of 22.0 years after cancer diagnosis. LCF was defined as serum total testosterone less than 250 ng/dL (or 8.67 nmol/L) and luteinizing hormone greater than 9.85 IU/L, and LCD by testosterone as 250 ng/dL or greater and luteinizing hormone greater than 9.85 IU/L. Polytomous logistic regression evaluated associations with demographic and treatment-related risk factors. Log-binomial regression evaluated associations with adverse physical and psychosocial outcomes. Piecewise exponential models assessed the association with all-cause mortality., Results: The prevalence of LCF and LCD was 6.9% and 14.7%, respectively. Independent risk factors for LCF included an age of 26 years or older at assessment, testicular radiotherapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m 2 or greater. The risk increased with older age, higher doses of testicular radiotherapy, and cyclophosphamide equivalent doses. LCF was significantly associated with abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF; no significant associations were found with adverse physical or psychosocial outcomes., Conclusion: Older age, testicular radiotherapy, and exposure to alkylating agents were associated with LCF, which was associated with adverse physical and psychosexual outcomes. LCD, although having similar risk factors, was not associated with adverse health outcomes. Additional studies are needed to investigate the role of sex hormone replacement in mitigating the burden from adverse outcomes in survivors.

Purpose: We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma., Patients and Methods: We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative 123 I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction., Results: Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6-88.0]. This was accompanied by primary tumor volume reductions (median, -76%; range, -100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9-93.3)., Conclusions: Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma., (©2019 American Association for Cancer Research.)

Background: Hippocampal avoidance has been suggested as a strategy to reduce short-term memory decline in adults receiving whole-brain radiation therapy (RT). The purpose of this study was to determine whether the hippocampal dose in children and adolescents undergoing RT for low-grade glioma was associated with memory, as measured by verbal recall., Methods: Eighty patients aged at least 6 years but less than 21 years with low-grade glioma were treated with RT to 54 Gy on a phase II protocol. Patients underwent age-appropriate cognitive testing at baseline, 6 months posttreatment, yearly through 5 years posttreatment, year 7 or 8, and year 10 posttreatment. Random coefficient models were used to estimate the longitudinal trends in cognitive assessment scores., Results: Median neurocognitive follow-up was 9.8 years. There was a significant decline in short-delay recall (slope = -0.01 standard deviation [SD]/year, P < 0.001), total recall (slope = -0.09 SD/y, P = 0.005), and long-delay recall (slope = -0.01 SD/y, P  = 0.002). On multivariate regression, after accounting for hydrocephalus, decline in short-delay recall was associated with the volume of right (slope = -0.001 SD/y, P = 0.019) or left hippocampus (slope = -0.001 SD/y, P = 0.025) receiving 40 Gy (V40 Gy). On univariate regression, decline in total recall was only associated with right hippocampal dosimetry (V40 Gy slope = -0.002, P = 0.025). In children <12 years, on univariate regression, decline in long-delay recall was only associated with right (V40 Gy slope = -0.002, P = 0.013) and left (V40 Gy slope = -0.002, P = 0.014) hippocampal dosimetry., Conclusion: In this 10-year longitudinal study, greater hippocampal dose was associated with a greater decline in delayed recall. Such findings might be informative for radiation therapy planning, warranting prospective evaluation., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Radiation therapy (RT) confers local tumor control and survival advantages in some patients with osteosarcoma, yet pediatric and adolescent and young adult (AYA) population studies are limited., Methods: Twenty-eight patients treated with curative-intent RT (median dose, 59.4 Gy; range, 40-76 Gy) at our institution from 1990 to 2017 were retrospectively identified. Cumulative incidence (CIN) of local failure (LF) was estimated by Gray's method and overall survival (OS) by the Kaplan-Meier method. Competing-risk regression and Cox proportional hazards models determined predictors of outcome. Toxicity was reported according to CTCAE v4.0., Results: With a median follow-up of 99.1 months in living patients, nine patients (32.1%) developed LF. Estimated CINs of LF with competing risk of death at 5 years for the entire cohort, patients at initial diagnosis (n = 16), and recurrent/refractory patients (n = 12) were 32.7% (95% CI, 16.0-50.5%), 25.0% (95% CI, 7.3-48.0%), and 43.8% (95% CI, 13.6-71.0%), respectively (P  =  0.31). Estimated 5-year OS was 42.6% (95% CI, 23.2-62.0%), 54.6% (95% CI, 29.5-79.6%), and 24.3% (95% CI, 0-52.2%), respectively (P  =  0.15). No clinicopathologic features were significantly associated with LF, yet lack of chemotherapy or metastasis at the time of RT was independent significant prognostic factors of decreased OS. Eleven patients experienced RT-related morbidity, with two grade 3 toxicities and no grade 4/5 events., Conclusions: Curative-intent RT in pediatric and AYA patients was well tolerated and achieved a local tumor control rate of 75% in patients with primary disease. Local control rates were similar to those in primarily adult studies, with similar or lower doses., (© 2019 Wiley Periodicals, Inc.)

Background and Purpose: The use of radiotherapy (RT) for pediatric patients with Hodgkin lymphoma (HL) experiencing disease progression or recurrence (15%) is controversial. We report treatment patterns and outcomes for pediatric patients with refractory/recurrent HL (rrHL) treated with curative-intent RT., Materials and Methods: Forty-six patients with rrHL treated with salvage RT at our institution were identified. All received risk-adapted, response-based frontline therapy and were retrieved with cytoreductive regimens followed by RT to failure sites, with or without autologous hematopoietic cell transplantation (AHCT). Cumulative incidence (CIN) of local failure (LF) and survival were estimated after salvage RT and regression models determined predictors of LF after salvage RT., Results: RT was administered as part of frontline therapy in 70% of patients, omitted for early response assessment in 13%, or deferred for primary progression in 17%. AHCT was omitted in 20% of patients. Median initial and salvage dose/site were 25.5 Gy and 30.6 Gy, respectively. Eight patients experienced progression. Two died without progression (median follow-up from salvage RT = 3.8 years). The 5-year CIN of LF after salvage RT was 17.7% (95% confidence interval [CI], 8.2-30.2%). The 5-year freedom from subsequent treatment failure and overall survival (OS) was 80.1% (95% CI, 69.2-92.6%) and 88.5% (95% CI, 79.5-98.6%), respectively. Inadequate response to salvage systemic therapy (p = 0.048) and male sex (p = 0.049) were significantly associated with LF after salvage RT., Conclusion: rrHL is responsive to salvage RT, with low LF rates after moderate doses. OS is excellent, despite refractory disease. Initial salvage therapy response predicts subsequent LF., (Published by Elsevier B.V.)