Impact of Social Disparities on 5-Year Survival Rates in Pediatric Hematologic Malignancies.

BACKGROUND: Socioeconomic disparities exist in pediatric patients with hematologic malignancies, leading to suboptimal survival rates. Social determinants of health impact health outcomes, and in children, they may not only lead to worse survival outcomes but carry over into late effects in adult life. The social deprivation index (SDI) is a composite score using geographic county data to measure social determinants of health. Using the SDI, the purpose of the present study is to stratify survival outcomes in pediatric patients with hematologic malignancies based on area deprivation. METHODS: A retrospective cohort study was performed using the national Surveillance, Epidemiology, and End Results oncology registry in the USA from 1975 to 2016 based on county-level data. Pediatric patients (≤18 y old) with a diagnosis of leukemia or lymphoma based on the International Classification for Oncology, third edition (ICD-O-3) were used for inclusion criteria. Patients were grouped by cancer subtype for leukemia into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia while for lymphoma into non-Hodgkin's lymphoma and Hodgkin's lymphoma. SDI scores were calculated for each patient and divided into quartiles, with Q1 being the lowest area of deprivation and Q4 being the highest, respectively. RESULTS: A total of 38,318 leukemia and lymphoma patients were included. Quartile data demonstrated stratification in survival based on area deprivation for ALL, with no survival differences in the other cancer subtypes. Patients with ALL from the most deprived area had a roughly 3% difference in both overall and cancer-specific morality at 5 years compared with the least deprived area. CONCLUSION: Disparities in pediatric patients with ALL represent a significant area for quality improvement. Social programs may have value in improving survival outcomes and could rely on metrics such as SDI.

Symptom management care pathway adaptation process and specific adaptation decisions.

BACKGROUND: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions. METHODS: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, resulting in institution-specific symptom management care pathway drafts. Institutional adaption teams distributed the 14 care pathway drafts to their respective teams; their feedback led to care pathway modifications. RESULTS: Initial care pathway adaptation decision making was completed over a median of 4.2 (interquartile range 2.0-5.3) weeks per institution. Across all institutions and among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision. Most commonly, the reason for rejection was not agreeing with the statement (70/86, 81.4%). Institutional-level factors were not significantly associated with statement rejection. CONCLUSIONS: Acceptability of the 14 care pathways was evident by most statements being adopted or adapted. The adaptation process was accomplished over a relatively short timeframe. Future work should focus on evaluation of care pathway compliance and determination of the impact of care pathway-consistent care on patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT04614662. Registered 04/11/2020, https://clinicaltrials.gov/ct2/show/NCT04614662?term=NCT04614662&draw=2&rank=1 .

A phase I study of irinotecan and temozolomide with bevacizumab in children with recurrent/refractory central nervous system tumors.

PURPOSE: Children with relapsed/refractory central nervous system (CNS) tumors require novel combinations of therapies. Irinotecan and temozolomide (IT) is a frequently used therapy with an established toxicity profile. Bevacizumab is an anti-VEGF monoclonal antibody with demonstrated activity in CNS tumors. Therefore, the combination of these agents has therapeutic potential in CNS tumors. The objective of this study was to determine the maximum tolerated dose (MTD) of escalating dose IT combined with a fixed dose of bevacizumab (BIT) in children with relapsed/refractory CNS tumors. METHODS: A phase I trial was performed in a 3 + 3 design. Therapy toxicities and radiologic responses to treatment were described. RESULTS: One hundred eighty cycles of therapy were administered to 26 patients. The MTD of BIT was dose level 1, (bevacizumab 10 mg/kg on days 1 and 15, irinotecan 125 mg/m2 on days 1 and 15, and temozolomide 125 mg/m2 on days 1-5 of 28-day cycles). The regimen was well tolerated with primarily hematologic toxicity, which was not dose limiting. Among 22 response-evaluable patients, there was 1 complete response (CR), 6 partial responses (PR), and 10 stable diseases (SD) with an overall response rate (ORR: CR + PR) of 31.8%. CONCLUSION: At the MTD, BIT therapy was well tolerated, and prolonged treatment courses of up to 24 cycles were feasible, with radiographic responses observed. Further evaluation is needed for efficacy in a phase II trial (NCT00876993, registered April 7, 2009, www. CLINICALTRIALS: gov ).

Pleuropulmonary blastoma-like peritoneal sarcoma: a newly described malignancy associated with biallelic DICER1 pathogenic variation.

Since the original description of pathogenic germline DICER1 variation underlying pleuropulmonary blastoma (PPB), the spectrum of extrapulmonary neoplasms known to be associated with DICER1 has continued to expand and now includes tumors of the ovary, thyroid, kidney, eye, and brain among other sites. This report documents our experience with another manifestation: a primitive sarcoma that resembles PPB and DICER1-associated sarcoma of the kidney. These tumors are distinguished by their unusual location in the peritoneal cavity, associated with visceral and/or parietal mesothelium. A total of seven cases were identified through pathology review in children presenting at a median age of 13 years (range 3-14 years). Primary sites of origin included the fallopian tube (four cases), serosal surface of the colon (one case), and pelvic sidewall (two cases). One case had pathologic features of type I PPB, another type Ir (regressed) PPB, and the remaining five had features of type II or III PPB with a mixed primitive sarcomatous pattern with or without cystic elements. All had a pathogenic DICER1 variation identified in germline and/or tumor DNA. PPB-like peritoneal tumors represent a newly described manifestation of DICER1 pathogenic variation whose pathologic features are also recapitulated in DICER1-related renal sarcoma, cervical embryonal rhabdomyosarcoma, and some Sertoli-Leydig cell tumors with heterologous elements. Tumors arising from the fallopian tube or elsewhere in the abdomen/pelvis, especially those with heterogeneous rhabdomyosarcomatous and/or cartilaginous differentiation, should prompt consideration of germline and tumor DICER1 testing.

Outcomes following proton therapy for Ewing sarcoma of the cranium and skull base.

PURPOSE: Despite the dosimetric advantages of proton therapy, little data exist on patients who receive proton therapy for Ewing sarcoma of the cranium and skull base. This study reports local disease control and toxicity in such patients. MATERIALS/METHODS: We reviewed 25 patients (≤21 years old) with nonmetastatic Ewing sarcoma of the cranium and skull base treated between 2008 and 2018. Treatment toxicity was graded per the Common Terminology Criteria for Adverse Events v4.0. The Kaplan-Meier product limit method provided estimates of disease control and survival. RESULTS: Median patient age was 5.9 years (range, 1-21.7). Tumor subsites included the skull base (48%), non-skull-base calvarial bones (28%), paranasal sinuses (20%), and nasal cavity (4%). All patients underwent multiagent alkylator- and anthracycline-based chemotherapy; 16% underwent gross total resection (GTR) before radiation. Clinical target volume (CTV) 1 received 45 GyRBE and CTV2 received 50.4 GyRBE following GTR or 54-55.8 GyRBE following biopsy or subtotal resection. Median follow-up was 3.7 years (range, 0.26-8.3); no patients were lost. The 4-year local control, disease-free survival, and overall survival rates were 96%, 86%, and 92%, respectively. Two patients experienced in-field recurrences. One patient experienced bilateral conductive hearing loss requiring aids, two patients developed intracranial vasculopathy, and 6 patients required hormone replacement therapy for neuroendocrine deficits. None developed a secondary malignancy. CONCLUSION: Proton therapy is associated with a favorable therapeutic ratio in children with large Ewing tumors of the cranium and skull base. Despite its high conformality, we observed excellent local control and no marginal recurrences. Treatment dosimetry predicts limited long-term neurocognitive and neuroendocrine side effects.

45 GyRBE for group III orbital embryonal rhabdomyosarcoma.

Purpose: Despite widespread concerns of radiotherapy toxicity in children with head and neck tumors, recent Children's Oncology Group (COG) findings suggest that the use of 45 Gy results in an unacceptably high rate of local recurrences in patients with low-risk orbital rhabdomyosarcoma. We therefore evaluated outcomes in our pediatric patients who received 45 GyRBE using proton therapy. Material and methods: To assess disease control and toxicity, we reviewed the medical records of 30 children (≤21 years old) with COG stage 1, group III embryonal orbital rhabdomyosarcoma enrolled on a prospective outcome study and treated with proton therapy between 2007 and 2018. Results: Median age at the time of radiation was 4.8 years old. Twenty-one and nine patients received ifosfamide- and cyclophosphamide-based chemotherapy according to their respective cooperative group regimens. Median duration between the start of induction chemotherapy and radiation was 12 weeks. Two patients had a complete response to induction chemotherapy and two had stable disease. Twenty-six patients had a partial response to induction chemotherapy, with a median volume reduction of 66%. With a median follow-up of 4.0 years (range, 0.5-9.5 years), we observed 1 local failure 6 months following treatment in a patient who had a partial response to cyclosphophomide-based induction chemotherapy. The 5-year local control, progression-free survival, and overall survival rates were 97%, 97%, and 100%, respectively. Serious late toxicities included 18 patients with cataracts, 4 with exposure keratoconjunctivitis resulting in permanently reduced visual acuity, and 1 with chronic sinusitis. Conclusion: 45 GyRBE offers effective local control for most patients with group III orbital rhabdomyosarcoma. The delivery of proton therapy to the postinduction tumor volume plus a small margin can mitigate early- and intermediate-term toxicity, but side effects still occur and long-term data are needed to demonstrate the dosimetric advantage of proton therapy.

Esophagitis associated with multimodality management of pediatric Ewing sarcoma of thorax.

BACKGROUND: Ewing sarcoma of the thoracic spine and chest wall is frequently treated with concurrent chemotherapy and radiation therapy (RT). Treatment-related acute esophagitis can lead to hospitalization and treatment delays. The aim of this study was to analyze the incidence, risk factors, and management of esophagitis in pediatric patients with Ewing sarcoma of the thoracic region. METHODS: We conducted a single-institution retrospective review of patients treated over a 10-year period. Medical records were reviewed for patient and treatment characteristics associated with Common Terminology Criteria for Adverse Events grade 2 or higher esophagitis. RT plans were also reviewed and various esophageal dose metrics were analyzed. RESULTS: Twelve of 37 patients (32%) developed acute esophagitis. Neutropenia was associated with an increased risk of esophagitis (60% vs. 14%; P < 0.01). RT significantly contributed to its incidence when maximum esophageal dose was >47 Gy (69% vs. 5%; P < 0.0001) and esophageal D5cm3 was >15 Gy (67% vs. 9%; P < 0.001). All 12 patients with esophagitis were managed with oral opioid analgesics. Nine patients with persistent symptoms received subsequent fluconazole for empiric fungal treatment and each had a decreased need for opioid analgesics within 2-5 days. CONCLUSION: Approximately one-third of patients with Ewing sarcoma of the thoracic region will develop acute esophagitis. An esophageal D5cm3 dose < 15 Gy and maximal esophageal dose < 47 Gy may keep the rate of acute esophagitis under 5%. However, the association with neutropenia and consistent response to antifungal therapy suggest chemotherapy-associated toxicity and an infectious component as part of the process.

False Lung Metastasis: Concurrent Ewing Sarcoma and Minimally Invasive Adenocarcinoma.

Pediatric lung cancer is a very rare occurrence, particularly as a primary lesion. A concurrent diagnosis is even more unusual and only reported a handful of times in Ewing sarcoma. Our patient is a 13-year-old boy who had concurrent diagnoses of Ewing sarcoma and minimally invasive adenocarcinoma of the lung, formerly bronchoalveolar carcinoma. To our knowledge this has also been found in at least 1 other case. There are some classic genetic mutations associated with Ewing sarcoma. None have been found to be linked with the concurrent diagnosis. A biological linkage is worth considering.

Glutamic acid not beneficial for the prevention of vincristine neurotoxicity in children with cancer.

BACKGROUND: Vincristine causes known side effects of peripheral sensory, motor, autonomic and cranial neuropathies. No preventive interventions are known. PROCEDURE: We performed a randomized, placebo-controlled, double-blind trial of oral glutamic acid as a preventive agent in pediatric patients with cancer who would be receiving vincristine therapy for at least 9 consecutive weeks (Stratum 1 = Wilms tumor and rhabdomyosarcoma) or 4 consecutive weeks in conjunction with steroids (Stratum 2 = Acute lymphoblastic leukemia and non-Hodgkin lymphoma). At designated time points, a scored neurologic exam using the Modified Balis Pediatric Scale of Peripheral Neuropathies was performed to document neurologic toxicity. RESULTS: Between 2007 and 2012, 250 patients were enrolled (Stratum 1 = 50, Stratum 2 = 200). The glutamic acid treated group did not have a significantly lower percentage of neurotoxicity compared to placebo treated group either overall or within stratum or age subgroups. The only subgroup which was suggestive of treatment effect was for age. Patients 13 years or older showed a larger benefit in favor of glutamic acid (P = 0.055) compared to patients less than 13 years (P = 1.00). Constipation was the most frequently reported (14%) Grade II or higher neurotoxicity. CONCLUSION: Vincristine-associated neurotoxicity in pediatric oncology remains a frequent complication of chemotherapy for multiple diagnoses with an approximate 30% of patients affected. Glutamic acid is not effective for prevention in pre-adolescents. There is a suggestion of benefit in patients 13 years or older, but the study was not designed to provide adequate power to test the treatment effect within this age group alone.

Impact of social disparities on 10 year survival rates in paediatric cancers: a cohort study.

Background: Studies reporting on the impact of social determinants of health on childhood cancer are limited. The current study aimed to examine the relationship between health disparities, as measured by the social deprivation index, and mortality in paediatric oncology patients using a population-based national database. Methods: In this cohort study of children across all paediatric cancers, survival rates were determined using the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2016. The social deprivation index was used to measure and assess healthcare disparities and specifically the impact on both overall and cancer-specific survival. Hazard ratios were used to assess the association of area deprivation. Findings: The study cohort was composed of 99,542 patients with paediatric cancer. Patients had a median age of 10 years old (IQR: 3-16) with 46,109 (46.3%) of female sex. Based on race, 79,984 (80.4%) of patients were identified as white while 10,801 (10.9%) were identified as Black. Patients from socially deprived areas had significantly higher hazard of death overall for both non-metastatic [1.27 (95% CI: 1.19-1.36)] and metastatic presentations [1.09 (95% CI: 1.05-1.15)] compared to in more socially affluent areas. Interpretation: Patients from the most socially deprived areas had lower rates of overall and cancer-specific survival compared to patients from socially affluent areas. With an increase in childhood cancer survivors, implementation of social determinant indices, such as the social deprivation index, might aid improvement in healthcare outcomes for the most vulnerable patients. Funding: There was no study sponsor or extramural funding.

Trends in Pediatric Cancer Care in Florida From 1981-2020: Changing Patterns in a Growing and Increasingly Diverse Population.

Background The Florida Association of Pediatric Tumor Programs (FAPTP) has used the Statewide Patient Information Reporting System (SPIRS) since 1981 to track all new cases of pediatric cancer. We reviewed the last 40 years of data to see how pediatric cancer care has evolved. Methods We retrospectively analyzed SPIRS data from 1981 through 2020 in five-year increments, looking at numbers of new diagnoses, care delivery sites, and trial enrollment in Children's Oncology Group (COG) studies. Results From 1981-2020 Florida's population increased almost 88% while the pediatric population only grew 61%. New pediatric cancer diagnoses increased 326% to over 1,000 new cases/year. The percentage of patients treated at FAPTP centers grew from 30% to 57% with an annual percentage change (APC) of 10.3% (95% Confidence Interval [CI] of 0.6 to 20.9%). The rate of COG clinical trial enrollment decreased from 32% in 1981-1985 to 20% in 2016-2020, for an APC of 8.91% (95% CI of -13.3 to -4.3%). Conclusions The striking increase in pediatric cancer cases in Florida over the last 40 years was out of proportion to the population growth. More patients received care at FAPTP centers, but a lower percentage were enrolled on COG trials.

Modern Therapy for Chest Wall Ewing Sarcoma: An Update of the University of Florida Experience.

PURPOSE: Owing to adjacent critical organs, the aggressive multimodality local therapy necessary for Ewing sarcoma of the chest wall is a challenge. Our previous review of historical outcomes at our institution revealed suboptimal disease control and a high incidence of grade ≥3 toxic effects in patients treated before 2006. The purpose of this study was to evaluate changes during the past decade since the introduction of proton therapy. METHODS AND MATERIALS: Thirty-nine consecutive pediatric patients with a chest wall Ewing sarcoma treated between 2006 and 2020 at the University of Florida were identified. The median maximum tumor diameter was 10 cm (range, 4-28 cm). At diagnosis, 19 patients had local disease and the others had a pleural effusion (11), pleural nodules (5), or pulmonary metastases (4). Patients were treated with chemotherapy regimens according to contemporary North American and European protocols: 7 were treated with preoperative, 18 with postoperative, and 14 with definitive radiation. Preceding primary site treatment, 15 patients required hemithorax radiation and 4 patients underwent whole-lung irradiation using photon techniques. The total median radiation dose to the primary tumor was 52.8 GyRBE [relative biological effectiveness] (range, 44.4-55.8 GyRBE). RESULTS: With a median follow-up of 4 years (range, 0.7-14.7 years), the 5-year local control, progression-free survival, and overall survival rates were 97.2%, 74.4%, and 81.6%, respectively, for the whole cohort. For the 19 patients with nonmetastatic disease, the 5-year local control, progression-free survival, and overall survival rates were 100%, 78.9%, and 78.9%, respectively. No patients developed grade ≥4 toxic effects. Two patients (5%) experienced grade 3 toxic effects related to multimodality treatment; both were patients who required surgery to correct scoliosis. Two patients (5%) developed grade 2 pneumonitis. CONCLUSIONS: Compared with our prior published institutional experience, our data suggest improvements in disease control and multimodality toxic effects since the introduction of proton therapy. This should be confirmed with a larger sample size and longer follow-up.

Modern Therapy for Spinal and Paraspinal Ewing Sarcoma: An Update of the University of Florida Experience.

PURPOSE: In 2010, we published a comprehensive review of our institutional outcomes about treating children with spinal and paraspinal Ewing sarcoma using photon therapy. Multimodality therapy was associated with fair disease control but also with serious toxicity, including a 37% rate of grade 3 or greater toxicity. We therefore sought to assess our more recent experience about treating children with more modern technology and treatment regimens. METHODS AND MATERIALS: Between 2010 and 2021, 32 pediatric patients with nonmetastatic spinal and paraspinal Ewing sarcoma were treated at University of Florida and enrolled in a retrospective outcome study. Median age at diagnosis was 9.8 years (range, 2.1-21.8 years). Within the cervical, thoracic, and lumbar spine regions, 3, 22, and 7 tumors arose, respectively. Median maximum tumor diameter was 5 cm (range, 3-19 cm). At diagnosis, 28 of 32 patients had motor, bowel, or bladder deficits. Chemotherapy was delivered according to contemporary North American and European interval-compressed regimens. Before radiation therapy, 14 patients underwent gross total resection, whereas 18 underwent a biopsy or subtotal resection with cord decompression. All patients were treated with proton therapy; 6 with hardware stabilization also received a component of intensity modulated photon therapy. Median prescription dose was 50.4 gray relative biological effectiveness (GyRBE; range, 45-55.8 GyRBE). Median maximum dose to the spinal cord was 50.2 GyRBE (range, 0-54.9 GyRBE). RESULTS: With a median follow-up of 4.1 years (range, 0.7-9.4 years), the 5-year local control, progression-free survival, and overall survival rates were 92%, 79%, and 85%, respectively. Ten of 30 living patients have residual motor, bowel, or bladder deficits. Overall, 22% of patients experienced Common Terminology Criteria for Adverse Events grade 3 late toxicity related to multimodality treatment: kyphosis (n = 4), esophagitis (n = 2), and chronic kidney disease (n = 1). No patients developed grade 4 or greater toxicity, new neurologic deficits, or second malignancy. CONCLUSIONS: Modern treatment advances may offer an improved therapeutic ratio for pediatric patients with spinal and paraspinal Ewing sarcoma. With appropriate management, most patients can be cured with recovery of long-term neurologic function and modest side effects.

Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults.

Voriconazole pharmacokinetics are not well characterized in children despite prior studies. To assess the appropriate pediatric dosing, a study was conducted in 40 immunocompromised children aged 2 to <12 years to evaluate the pharmacokinetics and safety of voriconazole following intravenous (IV)-to-oral (PO) switch regimens based on a previous population pharmacokinetic modeling: 7 mg/kg IV every 12 h (q12h) and 200 mg PO q12h. Area under the curve over the 12-h dosing interval (AUC(0-12)) was calculated using the noncompartmental method and compared to that for adults receiving approved dosing regimens (6 → 4 mg/kg IV q12h, 200 mg PO q12h). On average, the AUC(0-12) in children receiving 7 mg/kg IV q12h on day 1 and at IV steady state were 7.85 and 21.4 µg · h/ml, respectively, and approximately 44% and 40% lower, respectively, than those for adults at 6 → 4 mg/kg IV q12h. Large intersubject variability was observed. At steady state during oral treatment (200 mg q12h), children had higher average exposure than adults, with much larger intersubject variability. The exposure achieved with oral dosing in children tended to decrease as weight and age increased. The most common treatment-related adverse events were transient elevated liver function tests. No clear threshold of voriconazole exposure was identified that would predict the occurrence of treatment-related hepatic events. Overall, voriconazole IV doses higher than 7 mg/kg are needed in children to closely match adult exposures, and a weight-based oral dose may be more appropriate for children than a fixed dose. Safety of voriconazole in children was consistent with the known safety profile of voriconazole.

Proton radiotherapy for infant rhabdomyosarcoma: Rethinking young age as an adverse prognostic factor.

BACKGROUND & PURPOSE: In infants with rhabdomyosarcoma, young age is considered an adverse prognostic factor and treatment is often attenuated to reduce side effects. Proton therapy may improve the therapeutic ratio in these patients. We report outcomes in infants with rhabdomyosarcoma treated with proton therapy. MATERIALS & METHODS: Between 2009 and 2019, 37 infants <24 months old with non-metastatic rhabdomyosarcoma received proton therapy. Local control (LC), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier product limit. The log-rank test assessed significance between selected prognostic factors. Toxicity was graded per CTCAEv5.0. RESULTS: Median follow-up was 5.1 years. Overall, 76% of patients had an unfavorable primary site. Median dose was 50.4GyRBE. At 5 years, LC, PFS, and OS rates were 83%, 78%, and 83%. On univariate analysis, 5-year LC and OS were inferior for favorable versus unfavorable disease sites (67% vs 89%, 67% vs 89%, respectively; p < .05) and 5-year OS was superior in stage 3 versus stage 1-2 disease (91% vs 69%; p = .05), owing to inclusion of nasal ala patients among stage 1. Of 9 recurrences, 7 were in-field, 4 occurring in infants with nasal ala primaries. Recategorizing nasal ala as an unfavorable site resulted in 100% 5-year LC and OS for favorable sites. Six infants experienced late grade 3 toxicity. None developed grade 4 or 5 late toxicity. CONCLUSIONS: Young age alone may not be an adverse prognostic factor provided infants receive local therapy similar to older children. Consideration should be given to classifying nasal ala primaries as an unfavorable site.

Treatment Outcomes After Proton Therapy for Ewing Sarcoma of the Pelvis.

PURPOSE: Ewing sarcoma of the pelvis is associated with inferior local control compared with those arising from other primary sites. Despite its increased use, outcome data for treatment with proton therapy remain limited. We report 3-year disease control and toxicity in pediatric patients treated with proton therapy. METHODS AND MATERIALS: Thirty-five patients aged ≤21 years (median, 14 years) with nonmetastatic pelvic Ewing sarcoma received proton therapy and chemotherapy between 2010 and 2018. Overall survival and tumor control rates were calculated using the Kaplan-Meier method. A log-rank test assessed significance between strata of prognostic factors. Significant toxicity was reported per the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Most patients received definitive radiation (n = 26; median dose 55.8 Gy relative biological effectiveness [RBE]; range, 54.0-64.8), 7 received preoperative radiation (50.4 Gy RBE), and 2 received postoperative radiation (45 Gy RBE and 54 Gy RBE). The median primary tumor size was 10.5 cm. With a median follow-up of 3 years (range, 0.3-9.0 years), the 3-year overall survival, progression-free survival, and local control rates were 83% (95% confidence interval [CI], 65%-93%), 64% (95% CI, 45%-79%), and 92% (95% CI, 74%-98%), respectively. There was no association between local control, progression-free survival, or overall survival and tumor size, patient age, radiation dose, or definitive versus pre-/postoperative radiation therapy. Median time to progression was 1 year (range, 0.1-1.9 years). All patients with large tumors (≥8 cm) who underwent definitive proton therapy with a higher dose (≥59.4 Gy RBE) remained free from tumor recurrence (n = 5). Five patients experienced grade ≥2 subacute/late toxicity, all of whom were treated with combined surgery and radiation. CONCLUSIONS: Definitive proton therapy offers local control comparable to photon therapy in pediatric patients with pelvic Ewing sarcoma. These data lend preliminary support to radiation dose escalation without significant toxicity, which may contribute to the favorable outcomes. Combined surgery and radiation therapy, particularly preoperative radiation, is associated with postoperative complications, but not survival, compared with radiation alone.

Outcomes Following Proton Therapy for Group III Pelvic Rhabdomyosarcoma.

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.

Intravenous and Oral Posaconazole Pharmacokinetics in a Five-Year-Old With Mucor: A Case Report and Review of the Literature.

Posaconazole is a lipophilic triazole antifungal that exhibits variable absorption when administered orally. It possesses a broad spectrum of activity against various fungi, such as Aspergillus and traditionally resistant molds such as Rhizopus and Mucor, which carry a poor prognosis. Unfortunately, the tablet and suspension formulations of posaconazole are Food and Drug Administration approved for treatment of fungal diseases only in patients older than 13 years of age. Furthermore, the approval of the IV formulation is exclusively for adult patients. Nevertheless, the extended spectrum of activity and available dosage forms make it an attractive option for pediatric use. The data that exist to guide dosing of posaconazole in young pediatric patients are limited primarily to case series and case reports. Thus, we recommend therapeutic drug monitoring to ensure both safety and efficacy in pediatric patients. Herein we describe our experience with both oral and IV posaconazole in the salvage therapy of a 5-year-old female with extensive cutaneous Mucor. In contrast to previous reports, which show larger doses may be necessary to obtain therapeutic concentrations in pediatric patients as compared with adults, our patient reached targeted concentrations with weight-based dosing.

Zinc, copper, or cerium accumulation from metal oxide nanoparticles or ions in sweet potato: Yield effects and projected dietary intake from consumption.

The potential release of metal oxide engineered nanoparticles (ENP) into agricultural systems has created the need to evaluate the impact of these materials on crop yield and food safety. The study here grew sweet potato (Ipomoea batatas) to maturity in field microcosms using substrate amended with three concentrations (100, 500 or 1000 mg kg DW-1) of either nZnO, nCuO, or nCeO2 or equivalent amounts of Zn2+, Cu2+, or Ce4+. Adverse effects on tuber biomass were observed only for the highest concentration of Zn or Cu applied. Exposure to both forms of Ce had no adverse effect on yield and a slight positive benefit at higher concentrations on tuber diameter. The three metals accumulated in both the peel and flesh of the sweet potato tubers, with concentrations higher in the peel than the flesh for each element. For Zn, >70% of the metal was in the flesh and for Cu >50%. The peels retained 75-95% of Ce in the tubers. The projected dietary intake of each metal by seven age-mass classes from child to adult only exceeded the oral reference dose for chronic toxicity in a scenario where children consumed tubers grown at the highest metal concentration. The results throughout were generally not different between the ENP- and ionic-treatments, suggesting that the added ENPs underwent dissolution to release their component ions prior to accumulation. The results offer insight into the fate and impact of these ENPs in soils.