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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. This retrospective study examined the feasibility of ICG in guiding nephron-sparing surgery for pediatric renal tumors. 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. 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. [ABSTRACT FROM AUTHOR]

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). 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. 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. Minimally invasive RPLND appears to offer a faster recovery without compromising lymph node yield for patients with PT-RMS. III. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m2 (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. [ABSTRACT FROM AUTHOR]

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 6 months follow-up, with a median overall follow-up of 5.2 years (range: 1.4–13.4). The median mGFR was 97 mL/min/1.73 m 2 , while the median eGFR Schwartz and eGFR CKiD were 103.3 mL/min/1.73 m 2 and 79.7 mL/min/1.73 m 2 , respectively, (p = 0.13 and p = 0.75, compared to mGFR). Eleven (39.3%) patients had at least one abnormal urine study (microalbumin > 30 μg/g creatinine, n = 3; β-2 microglobulin > 133 μg/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. [ABSTRACT FROM AUTHOR]

Background The long-term physiologic and oncologic outcomes of treatment for inferior vena cava (IVC) thrombosis in children with malignant abdominal tumors are unclear. Methods We conducted a retrospective review of children with malignant IVC tumor thrombosis treated at our institution between January 1996 and December 2011. Extent of tumor thrombus was classified using the Hinman system. Disease stage, management, and oncologic and physiologic outcomes and complications were evaluated. Results We identified 15 patients (median age, 4.7 years): 12 with Wilms tumor, 2 with hepatoblastoma, and 1 with adrenocortical carcinoma. Neoadjuvant chemotherapy changed Hinman levels in 2 (13%) patients. IVC thrombus resection was complete in 6 (40%) patients, partial in 7 (47%) patients, and not performed in 1 (6.7%) patient. On follow-up imaging, 8 (53%) patients' IVCs were patent, 6 (40%) had residual thrombus, and 1 (6.7%) was surgically interrupted. Three (20%) patients had perioperative complications, and 2 (13%) experienced transient effects related to IVC occlusion. Conclusions Surgical management of tumor thrombus in the vena cava of children with solid abdominal tumors is challenging. Evidence on which to base strong treatment recommendations is lacking. Few long-term physiologic complications were observed. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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 28.6months (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 &y& Elsevier]

Abstract: 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 &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]

Purpose: To estimate radiation therapy planning margins based on inter- and intrafractional uncertainty for pediatric brain and head and neck tumor patients at different imaging frequencies. Methods: Pediatric patients with brain (n = 83) and head and neck (n = 17) tumors (median age = 7.2 years) were enrolled on an internal review board–approved localization protocol and stratified according to treatment position and use of anesthesia. Megavoltage cone-beam CT (CBCT) was performed before each treatment and after every other treatment. The pretreatment offsets were used to calculate the interfractional setup uncertainty (SU), and posttreatment offsets were used to calculate the intrafractional residual uncertainty (RU). The SU and RU are the patient-related components of the setup margin (SM), which is part of the planning target volume (PTV). SU data was used to simulate four intervention strategies using different imaging frequencies and thresholds. Results: The SM based on all patients treated on this study was 2.1 mm (SU = 0.9 mm, RU = 1.9 mm) and varied according to treatment position (supine = 1.8 mm, prone = 2.6 mm) and use of anesthesia (with = 1.7 mm, without = 2.5 mm) because of differences in the RU. The average SU for a 2-mm threshold based on no imaging, once per week imaging, initial five images, and daily imaging was 3.6, 2.1, 2.2, and 0.9 mm, respectively. Conclusion: On the basis of this study, the SM component of the PTV may be reduced to 2 mm for daily CBCT compared with 3.5 mm for weekly CBCT. Considering patients who undergo daily pretreatment CBCT, the SM is larger for those treated in the prone position or smaller for those treated under anesthesia because of differences in the RU. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of the study was to compare outcomes of pediatric patients with high-risk metastatic neuroblastoma who received radiotherapy (RT) with those of patients who did not. Patients and methods: We reviewed the records of 63 patients with newly diagnosed metastatic neuroblastoma treated at our institution (1989-2001) to investigate their characteristics at presentation, dose and field of RT, treatment response, and failure patterns. Results: Seventeen patients received RT, and 46 did not. In the RT group, a greater percentage of patients had residual disease before consolidation than did those in the no-RT group (88.2% vs 69.6%, P = .008). Gross total resection was achieved less often in the RT group (65% vs 89%, P = .055), but the 5-year cumulative incidences of local failure were similar (35.3% ± 12.4% vs 32.6% ± 7.1%). Although there was no difference in 5-year event-free survival, overall survival was better in the no-RT group (47.8% ± 7.2% vs 23.5% ± 9.2%, P = .026). Conclusion: The addition of RT to the therapy of a group of patients with more residual locoregional disease appeared to improve the local failure rate to approximately that of patients with less residual disease. Radiotherapy may provide even greater benefit to those with less residual disease before consolidation. [Copyright &y& Elsevier]

Purpose: To demonstrate the safety and efficacy of limited margin radiotherapy in the local control of pediatric and young adult patients with high-grade nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Methods and Materials: Pediatric patients with high-grade NRSTS requiring radiation were treated on an institutional review board approved prospective institutional study of conformal/intensity-modulated/interstitial brachytherapy using a 2-cm anatomically constrained margin. Results: A total of 32 patients (median age, 15.3 years; range, 2–22 years) received adjuvant (27 patients) or definitive (5 patients) irradiation. With a median follow-up of 32 months, the 3-year cumulative incidence of local failure was 3.7% for patients undergoing irradiation after surgical resection. Four patients experienced local failure; the mean dose to the volume of recurrence was ≥97% of the prescribed dose. Conclusions: Delivery of limited margin radiotherapy using external beam or brachytherapy provides a high rate of local tumor control without marginal failure. Further follow-up is required to determine whether normal tissue effects are minimized using this approach. [Copyright &y& Elsevier]

Radiation related effects in children and adults limit the delivery of effective radiation doses and result in long-term morbidity affecting function and quality of life. Improvements in our understanding of the etiology and biology of these effects, including the influence of clinical variables, dosimetric factors, and the underlying biological processes have made treatment safer and more efficacious. However, the approach to studying and understanding these effects differs between children and adults. Using the pulmonary and skeletal organ systems as examples, comparisons are made across the age spectrum for radiation related effects, including pneumonitis, pulmonary fibrosis, osteonecrosis, and fracture. Methods for dosimetric analysis, incorporation of imaging and biology as well a length of follow-up are compared, contrasted, and discussed for both organ systems in children and adults. Better understanding of each age specific approach and how it differs may improve our ability to study late effects of radiation across the ages. [Copyright &y& Elsevier]

Abstract: Background: Predictors of outcome have not been established for pediatric visceral and body wall nonrhabdomyosarcoma soft tissue sarcomas (NRSTS). Methods: The study used a retrospective review of clinical features and outcome of 61 patients with visceral and body wall NRSTS evaluated at our institution between March 1962 and December 1999. Results: Median age at diagnosis was 9.9 years (range, birth to 17.4 years). Tumors were greater than 5 cm in 43 (70%), high grade in 33 (54%), invasive in 25 (41%), and metastatic at presentation in 14 (23%) patients. Visceral tumors (n = 27) were more likely than body wall tumors (n = 34) to be greater than 5 cm (93% vs 53%; P < .001) and invasive (70% vs 18%; P < .001) and were less likely to be resected at diagnosis (44% vs 85%; P = .001). Estimated 10-year event-free survival (EFS) and overall survival (OS) for the entire cohort were 45.5% ± 6.9% and 56.8% ± 6.7%, respectively. The 10-year EFS and OS were better for patients with body wall sites than for those with visceral sites (61.8% ± 8.5% and 67.5% ± 8.2% vs 24.2% ± 9.4% and 43.0% ± 10.3%; P = .004 and P = .004). The 10-year estimated cumulative incidence (CI) of local recurrence was higher for patients with visceral sites than for those with body wall sites (64.3% ± 9.8% vs 26.5% ± 7.7%; P = .004), whereas CI of distant recurrence was similar for the 2 sites (15.2% ± 7.2% vs 23.5% ± 7.4%; P = .39). Conclusions: Pediatric patients with visceral NRSTS are more likely to have invasive, large, and unresectable tumors compared to those with body wall tumors. More than two thirds of visceral NRSTS recur locally, and fewer than half of patients with visceral tumors survive. [Copyright &y& Elsevier]

Abstract: Purpose: The incidence of pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) of the groin and axilla is unknown, and the optimal surgical approach to these patients is unclear. Methods: We conducted a retrospective study of patients treated at St Jude Children''s Research Hospital from January 1962 to March 2007 for NRSTSs of the groin and axilla. Demographic variables, tumor pathology, clinical management, and outcome were reviewed. Results: Of the 300 patients treated for NRSTSs, only 10 had tumors of the axilla or groin (6 of whom had synovial sarcoma). Surgical interventions included wide resection of the tumor (n = 7), marginal resection (n = 1), subtotal resection (n = 1), and biopsy only (n = 1). Six patients underwent lymph node sampling; all were negative for tumor. Short- and long-term surgical complications were rare. Four patients received adjuvant chemotherapy (n = 3) and/or radiotherapy (n = 2). At a median follow-up of 8.5 years, 7 of the 10 were surviving free of disease. Two of these patients died of tumor progression (1 with metastases at diagnosis and 1 with an unresectable tumor at diagnosis), and one patient who was free of NRSTS died of secondary breast carcinoma. Conclusions: Pediatric NRSTSs of the axilla and groin are rare, but outcomes are similar to those of other patients with NRSTS. Wide local excision of the tumor with preservation of good limb function should be the surgical goal and may be sufficient therapy in some cases. [Copyright &y& Elsevier]

Abstract: Purpose/Objective: This study aimed to develop objective models of radiation effects on musculature in children with soft tissue sarcoma using treatment dosimetry and clinical and quantitative magnetic resonance imaging (MRI) parameters that may be used to guide treatment planning or predict side effects. Methods: In the initial 13 patients undergoing external beam radiation therapy (RT) on a Phase II study of conformal or intensity-modulated RT for the treatment of soft tissue sarcoma approved by an Institutional Review Board, we evaluated quantitative MRI changes in the musculature to assess radiation-related treatment effects. Patients with soft tissue sarcoma, including Ewing''s sarcoma, had quantitative T 1, T 2 and dynamic enhanced MRI (DEMRI) performed before, during (Week 4) and after RT (Week 12). Regions of interest were selected in consistent locations within and outside the high-dose regions (on ipsilateral and contralateral sides when available). Mean RT dose, T 1, T 2 and DEMRI parameters were calculated and modeled using a mixed random coefficient dose model. Results: The mean doses to the high- and low-dose regions were 56.4 Gy (41.8–75.3 Gy) and 13.0 Gy (0.1–37.5 Gy), respectively. Compared with tissues distant from the tumor bed, maximal enhancement was significantly increased in tissues adjacent to the tumor/tumor bed prior to RT (60.6 vs. 44.2, P=.045) and remained elevated after 12 weeks. T 1 was significantly elevated in tissues adjacent to the tumor bed prior to RT (942.4 vs. 759.0, P=.0078). The slope of longitudinal change in T 1 was greater for tissues that received low-dose irradiation than those that received high-dose irradiation (P=.0488). The effect of dose on the slope of T 2 was different (P=.0333) when younger and older patients are compared. Conclusions: Acute affects of irradiation in muscle are quantifiable via MRI. These models provide evidence that quantifiable MRI parameters may be correlated with patient parameters of radiation dose and clinical factors including patient age. Long-term follow-up will be required to determine if acute changes correlate with clinically significant late effects. [Copyright &y& Elsevier]

Purpose: To model the effects of external beam irradiation on the developing flat bones of pediatric patients undergoing radiation therapy (RT) for tumors involving the musculoskeletal system. Methods and Materials: Patients with image-guided RT plans including areas adjacent to facial or pelvic flat bones underwent retrospective contouring of nontumor involved flat bones ipsilateral and contralateral to the treatment side. Radiation dose-volume information and bone volume data (initial and the most recent follow-up) were analyzed in 15 paired flat bones from 10 patients (ages 1.0–17.0 years). The models to predict bone growth after completion of RT (v post ) were based on initial bone volume (v pre ), the patient’s age, time to follow-up (t), and the dose-volume parameter (vInt35+ ). Results: We developed a dose effects model as follows: Log (vpost / vpre ) = βtimet + βage groupt + βdoset vInt35 . The dose-volume parameter vInt35 predicted significantly for alterations in growth in younger patients, but not for older patients. The predictability of the fitted model for relative change in bone growth improved in the younger age group with the addition of the dose-volume term vInt35 (correlation coefficient of r = 0.5510 to r = 0.6760 with the addition vInt35 ). Conclusions: Our model accurately predicted flat bone growth and is notable for the inclusion of radiation dose-volume information, which is now available in the image-guided RT era. Further refinement of this model in a prospective patient population is underway. [Copyright &y& Elsevier]

Purpose: To assess the effect of radiation dose on local tumor control of the Ewing sarcoma family of tumors in 79 patients with localized disease treated at a single institution.Methods and materials: Thirty-seven patients received vincristine, actinomycin D, cyclophosphamide, and doxorubicin, and 42 received vincristine, actinomycin D, and cyclophosphamide, with alternating cycles of ifosfamide and etoposide; all underwent definitive radiotherapy (median dose, 37.5 Gy) with either low-dose (<40 Gy) or standard dose (≥40 Gy) radiation delivered according to the protocol. We calculated the cumulative incidence of local treatment failure, disease recurrence, and overall survival and analyzed the effect of known prognostic factors and radiation dose.Results: The cumulative incidence of local treatment failure at 10 years was 30.4% and that of disease recurrence was 40%. The overall survival rate was 64.5%. Patient age ≥14 years and tumor size ≥8 cm were adverse prognostic factors for local treatment failure; patient age ≥14 years was also associated with worse survival. Although the radiation dose alone did not predict for local treatment failure, the cumulative incidence of local failure at 10 years was 19% when tumors <8 cm were treated with <40 Gy, and no patient treated with standard doses (≥40 Gy) developed local recurrence (p = 0.084).Conclusion: Tumor size and patient age predict for local tumor control in patients with Ewing sarcoma family of tumors treated with systemic therapy and definitive radiotherapy. Patients treated with reduced-dose radiotherapy experienced unacceptably high rates of local recurrence. [Copyright &y& Elsevier]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

1. Increase awareness of the pediatric oncology population receiving pXRT at the EOL and highlight how interdisciplinary team care can improve quality of life during this time. 2. Promote standards of care surrounding the use of pXRT to help increase its availability and use during the EOL. Palliative radiation has the potential to relieve suffering related to refractory symptoms like pain and spinal cord compression for pediatric oncology patients in the end-of-life period. However, this tool remains underutilized in this population for reasons likely related to lack of standardized practice guidelines and subpar identification of eligible patients. Refractory symptom management at the EOL can impact suffering and bereavement for patients and families of children with cancer. Palliative radiation (pXRT) is an underutilized tool that can potentially mitigate suffering and improve quality of life. To describe the patient population receiving pXRT at the EOL at a single tertiary pediatric oncology center. Retrospective chart review of pediatric oncology patients over a 10-year period. Descriptive analysis and non-parametric tests to compare groups were used. 2202 total deaths occurred; 168 patients met study criteria, reflecting a 7.6% incidence of pXRT at the EOL. Most patients were white (68%) and male (59%), with a median age of 11 years. The most common diagnosis was a solid tumor (52%), followed by CNS tumors (37%), and leukemia (10%). pXRT was primarily used to treat pain (36%) or for palliation (32%) and focused on the brain/spine (35%), head/neck (25%), and pelvis (12%). Median radiation dose delivered was 23.6Gy (range of doses received 1.8-55.8Gy) in a median of 7 fractions (range 1-31). Half of patients required anesthesia for pXRT and a majority did not experience acute side effects (64%). Patients receiving cancer-directed therapy in the last month of life were more likely to receive longer courses of pXRT and were found to have a longer lifespan following pXRT. One in five patients receiving pXRT had a decrease in reported pain scores. Additionally, 88% received a palliative care (PC) consultation which was found to increase the likelihood for hospice referral, documented DNR preferences and decrease episodes of CPR on the day of death. There is significant variability in the use of pXRT during pediatric oncology care at the EOL. Guidelines to help standardize palliative XRT may guide clinician decision making for refractory EOL symptom management and increase the utilization of this important tool in addressing suffering. Palliative care in oncology/Pain and symptom control [ABSTRACT FROM AUTHOR]

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 cm3 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. [ABSTRACT FROM AUTHOR]

The Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system was the first published radiation therapy (RT)–compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluated the feasibility of AVATAR implementation and effects on anesthesia use, quality of life, and anxiety in a multicenter pediatric trial. Pediatric patients 3 to 10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least 1 fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were nonsuccessful (NS). The PedsQL3.0 Cancer Module (PedsQL) survey assessed quality of life and was administered to the patient and guardian at RT simulation, midway through RT, and at final treatment. The modified Yale Preoperative Anxiety Scale (mYPAS) assessed anxiety and was performed at the same 3 time points. Success was evaluated using the χ2 test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject. Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (P =.04) and private versus public insurance (P <.001). Both patient (P =.008) and parent (P =.006) PedsQL scores significantly improved over the course of RT for patients aged 5 to 7. Anxiety in the treatment room decreased for both S and NS patients over RT course (P <.001), by age (P <.001), and by S versus NS patients (P <.001). In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children aged 3 to 10 years, higher than among age-matched historical controls (49%; P <.001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction. [ABSTRACT FROM AUTHOR]

Purpose: There is renewed attention to primary site irradiation and local control for patients with high-risk neuroblastoma (NB). We conducted a retrospective review to identify factors that might predict for locoregional tumor control and its impact on overall survival. Methods and Materials: Between July 2000 through August 2006, a total of 44 pediatric patients with NB received radiation therapy (RT) with curative intent using computed tomography (CT)–based treatment planning. The median age was 3.4 years and the median cumulative dose was 23.4 Gy. Overall survival and locoregional tumor control were measured from the start of RT to the date of death or event as determined by CT/magnetic resonance imaging/meta-iodobenzylguanidine. The influence of age at irradiation, gender, race, cumulative radiation dose, International Neuroblastoma Staging System stage, treatment protocol and resection status was determined with respect to locoregional tumor control. Results: With a median follow-up of 34 months ± 21 months, locoregional tumor progression was observed in 11 (25%) and was evenly divided between primary site and adjacent nodal/visceral site failure. The influence of locoregional control reached borderline statistical significance (p = 0.06). Age (p = 0.5), dose (p = 0.6), resection status (p = 0.7), and International Neuroblastoma Staging System stage (p = 0.08) did not influence overall survival. Conclusions: Overall survival in high-risk neuroblastoma is influenced by locoregional tumor control. Despite CT-based planning, progression in adjacent nodal/visceral sites appears to be common; this requires further investigation regarding target volume definitions, dose, and the effects of systemic therapy. [Copyright &y& Elsevier]

Purpose: Limiting the neurocognitive sequelae of radiotherapy (RT) has been an objective in the treatment of medulloblastoma. Conformal RT to less than the entire posterior fossa (PF) after craniospinal irradiation might reduce neurocognitive sequelae and requires evaluation. Methods and Materials: Between October 1996 and August 2003, 86 patients, 3–21 years of age, with newly diagnosed, average-risk medulloblastoma were treated in a prospective, institutional review board–approved, multi-institution trial of risk-adapted RT and dose-intensive chemotherapy. RT began within 28 days of definitive surgery and consisted of craniospinal irradiation (23.4 Gy), conformal PF RT (36.0 Gy), and primary site RT (55.8 Gy). The planning target volume for the primary site included the postoperative tumor bed surrounded by an anatomically confined margin of 2 cm that was then expanded with a geometric margin of 0.3–0.5 cm. Chemotherapy was initiated 6 weeks after RT and included four cycles of high-dose cyclophosphamide, cisplatin, and vincristine. Results: At a median follow-up of 61.2 months (range, 5.2–115.0 months), the estimated 5-year event-free survival and cumulative incidence of PF failure rate was 83.0% ± 5.3% and 4.9% ± 2.4% (± standard error), respectively. The targeting guidelines used in this study resulted in a mean reduction of 13% in the volume of the PF receiving doses >55 Gy compared with conventionally planned RT. The reductions in the dose to the temporal lobes, cochleae, and hypothalamus were statistically significant. Conclusion: This prospective trial has demonstrated that irradiation of less than the entire PF after 23.4 Gy craniospinal irradiation for average-risk medulloblastoma results in disease control comparable to that after treatment of the entire PF. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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 (MRItx) 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 MRItx 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 MRItx scans) available for analysis. The median MRItx 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 MRItx 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. [ABSTRACT FROM AUTHOR]

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 [18F]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. [ABSTRACT FROM AUTHOR]

Purpose: The predictive value of Image-Defined Risk Factors (IDRFs) developed by the International Neuroblastoma Risk Group Task Force as it relates to primary-site management is undefined and may aid patient selection for de-escalation of adjuvant radiation therapy to the primary site in high-risk neuroblastoma.Methods and Materials: Patients (N = 76) with high-risk neuroblastoma treated on prospective trials at our institution from 1997 to 2014 were eligible for inclusion. IDRFs were defined based on pretherapy imaging. Overall survival, progression-free survival, and locoregional failure-free survival (LRFFS) were described using the Kaplan-Meier estimator and tested across strata by using the log-rank test.Results: Twenty of 76 patients (26%) experienced local (n = 6), regional (n = 6), or combined locoregional failure (n = 8) with or without distant failure. Ten (50%) of the locoregional failures had concurrent distant relapse. Of patients who completed all therapy, both those with no IDRFs and those with >90% resection had a 3-year LRFFS of 100%, with or without radiation therapy. Patients with either ≥1 IDRF or Conclusions: Patients with >90% tumor resection and no primary site IDRFs at diagnosis may be candidates for de-escalation of adjuvant primary-site radiation therapy, although validation of these findings in future studies is required. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Pediatric RMSs contain transcriptional states of developing muscle • Treatment of embryonal RMS selects for cells in a progenitor mesoderm-like state • Mesoderm-like cells are sensitive to EGFR inhibition • Targeting myogenic states using both EGFR blockade and chemotherapy improves outcomes Rhabdomyosarcoma is a pediatric cancer with features of skeletal muscle. Patel et al. show that intratumoral heterogeneity within rhabdomyosarcoma mimics the developmental states of embryonal myogenesis. Furthermore, treatment selects for cells in a mesoderm-like state that are vulnerable to EGFR inhibition. Combining EGFR inhibitors with chemotherapy therefore improves treatment outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients are at risk of second malignancies (SM) after treatment for Ewing sarcoma family of tumours (ESFT). Methods: We performed a retrospective review of 237 patients with ESFT treated at our institution from September 1979 through to February 2004. Cumulative incidence (CI) of SM by the type of malignancy and treatment was estimated. Results: Twelve patients with SM were identified. Secondary leukaemia (SL) developed in 8 patients (2 ALL, 6 MDS/AML), a median 2.6 years (range 1.4–19.6 years) after diagnosis of ESFT. Four patients had secondary solid tumours, a median 8.0 years (range 7.4–9.4 years) after the ESFT diagnosis. Five- and 10-year estimates of the CI of SM were 3.0±1.1% and 4.7±1.5%, respectively. Patients treated on recent protocols with higher cumulative doses or an increased dose intensity of alkylators and epipodophyllotoxins and the use of G-CSF had a higher estimated CI of SL than those in earlier studies (5-year CI 6.4±2.4% versus 0.0±0.0%, respectively, P =0.004). Conclusions: Patients with ESFT are at risk for SM after treatment. The cumulative incidence of SM is higher with the current treatment protocols and may be related to the intensification of chemotherapeutic agents. [Copyright &y& Elsevier]

Purpose: To describe and review the radiotherapy (RT) treatment planning and delivery techniques used for pediatric sarcoma patients at St. Jude Children''s Research Hospital. The treatment characteristics serve as a baseline for future comparison with developing treatment modalities. Patients and Methods: Since January 2003, we have prospectively treated pediatric and young-adult patients with soft-tissue and bone sarcomas on an institutional Phase II protocol evaluating local control and RT-related treatment effects from external-beam RT (conformal or intensity-modulated RT; 83.4%), low-dose-rate brachytherapy (8.3%), or both (8.3%). Here we describe the treatment dosimetry and delivery parameters of the initial 72 patients (median, 11.6 years; range, 1.4–21.6 years). Results: Cumulative doses from all RT modalities ranged from 41.4 to 70.2 Gy (median, 50.4 Gy). Median D95 and V95 of the planning target volume of external-beam RT plans were, respectively, 93.4% of the prescribed dose and 94.6% of the target volume for the primary phase and 97.8% and 99.2% for the cone-down/boost phase. The dose–volume histogram statistics for 27 critical organs varied greatly. The spinal cord in 13 of 36 patients received dose >45 Gy (up to 52 Gy in 1 cc) because of tumor proximity. Conclusions: Planning and delivery of complex multifield external beam RT is feasible in pediatric patients with sarcomas. Improvements on conformity and dose gradients are still desired in many cases with sensitive adjacent critical structures. Long-term follow-up will determine the risk of local failure and the benefit of normal tissue avoidance for this population. [Copyright &y& Elsevier]

Purpose: To estimate the effects of radiotherapy and clinical factors on vertebral growth in patients with medulloblastoma and supratentorial primitive neuroectodermal tumors treated with craniospinal irradiation (CSI) and chemotherapy. Methods and Materials: The height of eight individual or grouped vertebral bodies (C3, C3-C4, T4, T4-T5, C6–T3, T4–T7, L3, L1–L5) was measured before and after CSI (23.4 or 36–39.6 Gy) in 61 patients. Of the 61 patients, 40 were boys and 21 were girls (median age, 7 years; range, 3–13 years), treated between October 1996 and October 2003. Sagittal T1-weighted magnetic resonance images were used for the craniocaudal measurements. The measurements numbered 275 (median, 5/patient; range, 3–7). The median follow-up after CSI was 44.1 months (range, 13.8–74.9 months). Results: Significant growth was observed in all measured vertebrae. Excluding C3-C4, the growth rate of the grouped vertebrae was affected by age, gender, and CSI dose (risk classification). The risk classification alone affected the growth rates of C3 (p = 0.002) and L3 (p = 0.02). Before CSI, the length of all vertebral bodies was an increasing function of age (p <0.0001). The C3 length before CSI was affected by gender and risk classification: C3 was longer for female (p = 0.07) and high-risk (p = 0.07) patients. Conclusion: All vertebrae grew significantly after CSI, with the vertebrae of the boys and younger patients growing at a rate greater than that of their counterparts. The effect of age was similar across all vertebrae, and gender had the greatest effect on the growth of the lower cervical and upper thoracic vertebrae. The effect of the risk classification was greatest in the lumbar spine by a factor of ≤10. [Copyright &y& Elsevier]

Purpose: To estimate potential differences in volumetric bone growth in children with sarcoma treated with intensity-modulated (IMRT) and conformal (CRT) radiation therapy using an empiric dose–effect model. Methods and Materials: A random coefficient model was used to estimate potential volumetric bone growth of 36 pelvic bones (ischiopubis and ilium) from 11 patients 4 years after radiotherapy. The model incorporated patient age, pretreatment bone volume, integral dose >35 Gy, and time since completion of radiation therapy. Three dosimetry plans were entered into the model: the actual CRT/IMRT plan, a nontreated comparable IMRT/CRT plan, and an idealized plan in which dose was delivered only to the planning target volume. The results were compared with modeled normal bone growth. Results: The model predicted that by using the idealized, IMRT, and CRT approaches, patients would maintain 93%, 87%, and 84%, respectively (p = 0.06), of their expected normal growth. Patients older than 10 years would maintain 98% of normal growth, regardless of treatment method. Those younger than 10 years would maintain 87% (idealized), 76% (IMRT), or 70% (CRT) of their expected growth (p = 0.015). Post hoc testing (Tukey) revealed that the CRT and IMRT approaches differed significantly from the idealized one but not from each other. Conclusions: Dose–effect models facilitate the comparison of treatment methods and potential interventions. Although treatment methods do not alter the growth of flat bones in older pediatric patients, they may significantly impact bone growth in children younger than age 10 years, especially as we move toward techniques with high conformity and sharper dose gradient. [Copyright &y& Elsevier]

Summary: 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 cm2 residual tumour and no metastatic disease) or high-risk medulloblastoma (>1·5 cm2 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 ClinicalTrials.gov, number NCT00003211. 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. [Copyright &y& Elsevier]

: PurposeCentral nervous system (CNS) irradiation can cause sensorineural hearing loss. The relationship between the dose to the cochlea and the development of hearing loss is unknown. Conformal radiation therapy (CRT) techniques facilitate accurate cochlear dosimetry. We modeled hearing threshold levels (HTL) after CRT in children with localized primary brain tumors (ependymoma, low- or high-grade astrocytoma, craniopharyngioma, or CNS germinoma) by using cochlear dose and clinical variables.: Patients and methodsWe evaluated 72 children (median age, 9.5 years) with audiograms before and every 6 months after CRT (median follow-up, 16.6 months; range, 4.3–42.6 months). We used a mixed-effects model to predict change in hearing for each ear as a function of time, cochlear dose, and clinical variables.: ResultsHearing was affected the greatest in patients with CSF shunts and pre-CRT ototoxic chemotherapy, enhanced by cochlear dose, and was more prominent on the right side. Hearing impairment after CRT alone occurred at low and intermediate frequencies in patients with shunts and supratentorial tumors when the cochlear dose exceeded 32 Gy. Patients with shunts and central supratentorial tumors developed intermediate-frequency hearing loss after CRT alone regardless of dose.: ConclusionsHearing loss during the first 4 years after CRT alone is uncommon, although patients with shunts and supratentorial tumors appear to be at increased risk for low- and intermediate-frequency effects. CSF shunting and increased cochlear dose enhance the effect of ototoxic chemotherapy. If possible, the average cochlear dose should be <32 Gy over a 6-week course of treatment until more specific dose data become available. [Copyright &y& Elsevier]