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Background Glucocorticoids used to treat childhood leukemia and lymphoma can result in osteonecrosis, leading to physical dysfunction and pain. Improving survival rates warrants research into long-term outcomes among this population. Objective The objective of this study was to compare the physical function and quality of life (QOL) of survivors of childhood cancer who had an osteonecrosis history with that of survivors who had no osteonecrosis history and with that of people who were healthy (controls). Design This was a cross-sectional study. Methods This study included St Jude Lifetime Cohort Study participants who were ≥ 10 years from the diagnosis of childhood leukemia or lymphoma and ≥ 18 years old; 135 had osteonecrosis (52.5% men; mean age = 27.7 [SD = 6.08] years) and 1560 had no osteonecrosis history (52.4% men; mean age = 33.3 [SD = 8.54] years). This study also included 272 people who were from the community and who were healthy (community controls) (47.7% men; mean age = 35.1 [SD = 10.46] years). The participants completed functional assessments and questionnaires about QOL. Results Survivors with osteonecrosis scored lower than other survivors and controls for dorsiflexion strength (mean score = 16.50 [SD = 7.91] vs 24.17 [SD = 8.61] N·m/kg) and scored lower than controls for flexibility with the sit-and-reach test (20.61 [SD = 9.70] vs 23.96 [SD = 10.73] cm), function on the Physical Performance Test (mean score = 22.73 [SD = 2.05] vs 23.58 [SD = 0.88]), and mobility on the Timed “Up & Go” Test (5.66 [SD = 2.25] vs 5.12 [SD = 1.28] seconds). Survivors with hip osteonecrosis requiring surgery scored lower than survivors without osteonecrosis for dorsiflexion strength (13.75 [SD = 8.82] vs 18.48 [SD = 9.04] N·m/kg), flexibility (15.79 [SD = 8.93] vs 20.37 [SD = 10.14] cm), and endurance on the 6-minute walk test (523.50 [SD = 103.00] vs 572.10 [SD = 102.40] m). Limitations Because some eligible survivors declined to participate, possible selection bias was a limitation of this study. Conclusions Survivors of childhood leukemia and lymphoma with and without osteonecrosis demonstrated impaired physical performance and reported reduced QOL compared with controls, with those requiring surgery for osteonecrosis most at risk for impairments. It may be beneficial to provide strengthening, flexibility, and endurance interventions for patients who have pediatric cancer and osteonecrosis for long-term function.

Background Osteonecrosis of the femoral head (ONFH) is a potentially severe toxicity associated with glucocorticoid treatment for pediatric hematologic malignancy. We examined clinical outcomes of THA in adolescents and young adults treated for hematologic malignancies who developed advanced ONFH. Methods In a single-institution cohort, we retrospectively reviewed medical records and imaging for perioperative complications, reoperations, functional assessment at last follow-up, and radiological outcomes. Twenty-seven patients (41 hips) underwent THA (bilateral in 14 patients). There were 11 males. Median (interquartile range [IQR]) age at primary diagnosis was 14.9 years [1.8-18.9]. The median (IQR) age at THA was 19.8 years [14.6-30.3]. Mean (range) post-THA follow-up was 111.5 months (65.4-165.8). Results Perioperative complications included one intraoperative calcar fracture that was secured with a cerclage wire and one posterior hip dislocation that occurred 6 days postoperatively, requiring closed reduction. One hip required a revision 21.1 months post-THA due to a fractured ceramic liner. The radiographic review was available for 38 of 41 hips and demonstrated none with loosening, subsidence, or osteolysis; nine developed periacetabular stress shielding. Incidence of stress shielding was associated with increased postoperative pain (P = .0130). There was a significant functional improvement in range of motion (ROM), pain, use of supports, participation in school, work, and sports, and use of pain medication from preoperative to postoperative clinical visits (P Discussion Total hip arthroplasty in adolescents and young adults offers symptomatic and functional improvement in patients with ONFH. We found it to be safe with low perioperative complication rates even in patients undergoing active treatment for malignancy. Level of Evidence Level IV, case series study. See Instructions for authors for a complete description of levels of evidence.

Background Osteonecrosis of the hips and knees is an often debilitating adverse event in children treated with glucocorticoids for leukemia and lymphoma but the impact of shoulder involvement has been understudied. Thus, we investigated the severity and functional impairment of shoulder osteonecrosis in a well-characterized population of pediatric patients treated for acute lymphoblastic leukemia or lymphoma. Methods We retrospectively reviewed orthopaedic clinic and physical therapy evaluations to determine range of motion (ROM), pain, and impact of magnetic resonance-defined osteonecrosis (ON) on activities of daily living. Adverse events were classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.03. Results We identified 35 patients (22 female), median age at cancer diagnosis 14.2 (range, 4.3 to 19) years; median age at ON diagnosis 16.7 (range, 5.5 to 28) years. Median time to last follow-up from diagnosis of primary malignancy was 6.4 (range, 0 to 12.7) years and from diagnosis of ON was 4.0 (range, 0 to 8.9) years. Twenty-two patients had magnetic resonance evidence of ON; 43 shoulders involved at least 30% of the articular surface of the capital humeral epiphyses.Common Terminology Criteria for Adverse Events mean scores for initial assessments of 55 shoulders (29 patients) showed moderate negative impact of ON on activity of daily living (1.94), decreased ROM limiting athletic activity (0.98), and mild to moderate levels of pain (1.38). Analysis of this group's most recent assessment showed improvement in pain and ON over time, with an average pain grade of 0.58 indicating no pain to mild pain, and 1.37 for ON grade, indicating asymptomatic to mildly symptomatic impact on activities of daily living. We also found minimal worsening average ROM grades (1.11). Conclusions Shoulder ON is an underappreciated adverse late effect of therapy in children treated for leukemia/lymphoma which can limit quality of life and functionality. In most cases, pain and disability can be improved with treatment. Level of evidence Level IV-case series.

Background Osteonecrosis is a debilitating complication in children and adolescents with acute lymphoblastic leukemia or acute lymphoblastic lymphoma (LLy). An objective screening test to identify patients at risk for symptomatic, extensive joint involvement will help manage osteonecrosis. Methods We performed a prospective, longitudinal pilot study with whole-joint magnetic resonance imaging (MRI) of shoulders, elbows, hips, knees, ankles, and hindfeet to evaluate the incidence and timing of osteonecrosis involving multiple joints in 15 patients with LLy aged 9-21 years at diagnosis. Results Osteonecrosis affecting ≥30% of the epiphysis occurred in eight of 15 patients, with a high prevalence in hips (12 of 26 examined [46%]) and knees (10 of 26 [38%]) post reinduction I and in shoulders (seven of 20 [35%]) post reinduction II. Most osteonecrotic hips and knees with ≥30% epiphyseal involvement became symptomatic and/or underwent surgery (100% and 82%, respectively). All eight patients with ≥30% epiphyseal involvement had multijoint involvement. Seven of these patients had hip or knee osteonecrosis by the end of remission induction, and only these patients developed osteonecrosis that became symptomatic and/or underwent surgery in their hips, knees, shoulders, ankles, and/or feet; all of these joints were associated with epiphyseal abnormalities on post reinduction I imaging. Conclusions MRI screening in adolescent patients with LLy revealed osteonecrosis in multiple joints. Initial screening with hip and knee MRI at the end of induction may identify susceptible patients who could benefit from referrals to subspecialties, more extensive follow-up imaging of other joints, and early medical and surgical interventions.

Background: Few studies have analyzed the benefit of limb amputations in children with metastatic osteosarcoma and limited life span. Objective: We studied outcomes of limb amputations in children with metastatic osteosarcoma. Design: We performed a retrospective review of patients who underwent limb amputations (January 1995-June 2015) and died within 1 year of surgery. Setting/Participants: We studied 12 patients with osteosarcoma at a single institution. Measurements: Data on mobility, pain, and emotional and psychological well-being were retrieved from medical records from 1 month before surgery to 6 months after surgery. Results: Of the 12 patients (7 females and 5 males; median age at surgery 13 years [range, 7-20 years]) meeting study criteria, 3 patients and 9 patients had primary osteosarcoma in upper and lower limbs, respectively. Mobility improved postamputation in 8 bedridden/wheelchair-bound patients. Postamputation, emotional, and psychological well-being improved for 9 patients, 3 patients had persistent psychological and/or emotional symptoms, and no patient experienced signs of regret. Daily mean pain scores were significantly lower at 1 week (median 3 [range, 0-6]; P = .03) and 3 months (median 0 [range, 0-8]; P = .02) postsurgery than at 1 week presurgery (median 5.5 [range, 0-10]). Morphine consumption (mg/kg/d) showed a trend toward higher values at 1 week (median 0.2 [range, 0-7.6]; P = .6) and 3 months (median 0.2 [range, 0-0.5]; P = .3) postsurgery than at 1 week presurgery (median 0.1 [range, 0-0.5]). Conclusions: Patients undergoing limb amputations had reduced pain and improved mobility and emotional and psychological well-being. Amputations are likely to benefit children with limited life expectancy.

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

With current treatments for acute lymphoblastic leukemia (ALL), the overall prognosis for survival is favorable. Increasing emphasis is placed on recognizing and managing the long-term consequences of ALL and its treatment, particularly involving osteonecrosis. Early osteonecrosis diagnosis and management may improve outcomes and is best accomplished through coordinated teams that may include hematologic oncologists, radiologists, orthopedic surgeons, physical therapists, and the patient and their family. Magnetic resonance imaging is the "gold standard" for diagnosis of early-stage and/or multifocal osteonecrosis. Treatments for osteonecrosis in ALL patients are risk stratified and may include observation, corticosteroid or chemotherapy adjustment, and pharmaceutical or surgical approaches.

e22012 Background: Primary Extremity Bone Sarcomas (PEBS) were historically managed by upfront amputation. Early success rates utilizing neoadjuvant chemotherapy followed by LSS showed promise in halting disease progression and achieving local control. This prompted surgical oncologists to consider LSS in more patients. In anatomic locations for which no functional reconstruction exists, amputation is still considered the best option. Oncologic control, patient satisfaction and improved function are the primary goals of LSS. Three Dimensional CT and MRI have made for more accurate surgical planning, ensuring adequate margins and improved local control. Methods: Between January 1983 and December 2019 the senior author (BNR) has performed, or mentored over 590 LSS worldwide.Improvement in imaging modalities has been the most important advancement contributing to decreasing tumor margins. Initially bone scans determined the margins at 7cm. In the 1970s CT became the modality used to determine local tumor extent. The resection margins were reduced to 5 cm. The early 90’s saw MRI as the main imaging modality. Margins are now set at 1-2cm.LSS was initiated in the mid 80’s using the strict criteria of age > 13, no metastasis, intramedullary extension less than 50%, and small extraosseus extent. Results: Of the 134 cases enrolled through 1990, the local control rate was 90%. Between July 1991 through December 2019, 388 patients enrolled in bone sarcoma protocols, 354 patients underwent LSS ( > 95%). The primary site was the femur (171 cases, 43%) Histological Diagnosis was OS in 93%. Ages ranged from 3-25 years (median 10.8 years) The average length of tumor resection was 7cms(range 1-38cms). 5 patients presented with pathological fracture. All successfully underwent LSS without an increase in local recurrence. Intraoperative complications included, excessive hemorrhage defined as > 10%of blood volume in 88 patients, 25%, Vascular injuries requiring repair in 9 patients, post operative neuropraxia in 28 patients. Mid and late term complications included, Superficial wound infection in 45 patients (19 requiring some surgical intervention), Deep wound problems were identified in 11 patients ( 3 required subsequent amputation), 9 patients had their prosthesis revised due to refractory infection, Local relapse in 5 patients , < 1%. Long term implant related complications, loosening of the prosthesis in 16 , Stem fracture in 13, nonunion of the allograft in 3 patients. Conclusions: Disadvantages are the need for repeat surgeries consequent to either growth discrepancy, loosening, or implant fracture.LSS is feasible in over 95% of patients, complications are generally manageable. Successful oncologic results, satisfaction and function are readily obtained. Early rehabilitation is key to functional success.

Background Survivors of lower extremity (LE) malignancies experience functional deficits. Purpose The purpose of this prospective clinical trial was to determine feasibility and functional outcomes of adding pre-habilitation during the 10-12 week period prior to a planned surgery to remove the tumor in children and adolescents with a LE sarcoma. Design Pilot study. Setting St. Jude Children's Research Hospital (SJCRH). Patients Participants included 14 individuals between the ages of 8 and 20 years who were diagnosed with a LE sarcoma. Participant outcomes were compared to a control group of 35 individuals treated for osteosarcoma that obtained the same functional assessments but no pre-habilitation. Intervention The intervention group received strengthening exercises and mobility training 3 times per week for 30-60 minutes for 10-12 weeks preoperatively. Measurements Participants completed the Functional Mobility Assessment (FMA) and measures of strength and range of motion (ROM) of bilateral lower extremities (BLEs) at baseline, after 10-12 weeks of preoperative PT, and at 20-22 weeks. Results Twelve participants completed at least 50% of their schedule pre-habilitative sessions. The intervention group scored significantly better on the FMA than the control group at weeks 20-22 (35.6 vs. 25.7, p .0267). No significant difference was found in ROM or strength. Limitations Due to this study being a pilot study, the sample size was small. Therefore, we cannot infer generalizability. Conclusions Findings suggest that those diagnosed with a LE malignancy awaiting a limb sparing procedure or amputation participate in at least 50% of scheduled PT sessions and benefit from them.

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).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.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.Treatment with focal conformal, limited margin RT, including dose escalation for larger tumors, provides favorable local tumor control in EWS.

Osteosarcoma (OS) and the Ewing sarcoma family of tumors (ESFT) are the most common primary pediatric bone malignancies. We sought to assess the diagnostic accuracy of initial tumor biopsies in patients with OS or ESFT at a pediatric cancer center.All biopsies performed at initial presentation of patients with OS or ESFT at our institution from 2003 to 2012 were retrospectively reviewed. Diagnostic accuracy and incidence of complications were correlated with study variables using logistic regression analysis.One hundred forty-two biopsies were performed in 105 patients (median age 13.4years, range: 1.8-23.0), 104 (73.2%) OS and 38 (27.8%) ESFT. Thirty-one (21.8%) were performed on metastatic sites. Eighty-five (76.6%) of 111 primary site biopsies were open procedures, and 26 were percutaneous (23.4%). Primary site biopsies were successful in 94.1% of open and 73.1% of percutaneous procedures. Odds of obtaining a successful diagnostic specimen were 7.8 times higher with open approach (CI: 1.6-36.8). Metastatic site biopsies were successful in 66.7% of percutaneous and 100% of open and thoracoscopic procedures.Biopsy of metastatic sites was equal to primary site in obtaining diagnostic material with the added benefit of accurate staging, with few adverse events and high diagnostic yield.

Bone void fillers (BVFs) containing calcium sulfate, tricalcium phosphate (TCP), and hydroxyapatite can be loaded with antibiotics for infection treatment or prevention under surgeon-directed use. The aim of this study was to characterize the handling and elution properties of a triphasic BVF loaded with common antibiotics. BVF was mixed with vancomycin and/or tobramycin to form pellets, and the set time was recorded. A partial refreshment elution study was conducted with time points at 4, 8, and 24 h, as well as 2, 7, 14, 28, and 42 days. Effects on dissolution were evaluated in a 14-day dissolution study. Set time increased to over 1 h for groups containing tobramycin, although vancomycin had a minimal effect. Pellets continued to elute antibiotics throughout the 42-day elution study, suggesting efficacy for the treatment or prevention of orthopedic infections. BVF containing vancomycin or tobramycin showed similar dissolution at 14 days compared to BVF without antibiotics, however, BVF containing both antibiotics showed significantly more dissolution.

Modular and non-invasive expandable prostheses have been developed to provide a functional knee joint that allows future expansion as growth occurs in the contralateral extremity in children with bone sarcomas that require removal of the growth plate. This study aimed to evaluate the functional outcomes of paediatric patients who received either a non-invasive expandable or modular prosthesis for bone sarcomas arising around the knee.We evaluated clinician-reported, patient-reported and measured function in 42 paediatric patients at least one year (median age at assessment 19.1 years) after limb salvage surgery, and compared patients who received modular system prostheses (N = 29, median age 15.5), who did not require lengthening procedures to those who received non-invasive expandable prostheses (N = 13, median age 11.1) requiring lengthening procedures (median 5).The number of revisions and time to first revision did not differ between the two groups. There were no differences between the two groups in total scores on the Enneking Musculoskeletal Tumor Society Scale, the Toronto Extremity Salvage Scale, and the Functional Mobility Assessment. Children with non-invasive expandable prostheses climbed stairs (11.93 ± 4.83 versus 16.73 ± 7.24 s, p = 0.02) in less time than those with modular prostheses.Our results suggest that the non-invasive expandable prosthesis produces similar functional results to the more traditional modular prosthesis.

Purpose: To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design: Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results: Bevacizumab concentration–time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P < 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P < 0.05). Conclusion: A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. Clin Cancer Res; 20(10); 2783–92. ©2014 AACR.

Induction of fetal hemoglobin (HbF, α2γ2) via genome editing-mediated disruption of DNA regulatory elements that repress expression of γ-globin genes (HBG1 and HBG2) is a promising therapeutic strategy for b-hemoglobinopathies including sickle cell disease (SCD) and β-thalassemia. Optimal technical approaches and safety profiles are yet to be fully defined. We used CRISPR/Cas9 to target a DNA repressor element near the distal CCAAT box of the HBG1/HBG2 promoters. This region contains a "TGACC" motif recognized by BCL11A, a transcriptional repressor protein that regulates γ-to-β globin switch after birth. Rare germline variants at or near this motif are associated with hereditary persistence of fetal hemoglobin, a benign genetic condition that alleviates the clinical manifestations of co-inherited b-hemoglobinopathies. Previously, we showed that transduction of human CD34+ cells with lentiviral vector encoding Cas9 and guideRNA (gRNA) targeting the HBG1/HBG2 promoter caused induction of HbF in red blood cell (RBC) progeny generated in vitro (Traxler et. al, Nature Medicine v22,2016). Here we present a clinically tractable approach for disrupting the HBG1/HBG2 BCL11A binding site in human hematopoietic stem cells (HSCs). Electroporation of Cas9:gRNA ribonucleoprotein (RNP) complex into healthy or SCD donor CD34+ cells resulted in up to 80% on-target insertion-deletion (indel) mutations and 35% HbF in erythroid progeny generated in vitro. Sixteen to 17 weeks after transplantation of gene edited CD34+ cells into immunodeficient NBSGW mice, up to 75% of donor CD34+ cells in recipient bone marrow contained on-target indels, demonstrating efficient modification of repopulating human HSCs. No differences in CD34+ cell regeneration or differentiation into erythroid, T, B, or myeloid cell lineages were observed between edited and control cells. Moreover, up to 78% of gene edited erythroid cells stained with anti-HbF antibody ("F-cells") compared to 15% in control erythroid cells, suggesting a "pan-cellular" pattern of HbF expression after editing. Strikingly, human donor-derived erythroid cells in recipient bone marrow expressed up to 40% HbF compared to 3% HbF in controls. Although the editing frequencies of HBG1 and HBG2 promoters varied between different donor CD34+ cells, an engineered variant of Cas9 containing 3 nuclear localization sequences (Wu et. al,Nature Medicine v25, 2019) edited repopulating HSCs more efficiently and consistently than conventional Cas9 with two nuclear localization signals. Simultaneous on-target RNP-induced DSBs at both HBG1 and HBG2 can result in the deletion of the intervening 4.9-kb region, leaving a single hybrid gene with HBG2 promoter sequences fused to the downstream HBG1 gene. We detected this deletion in approximately 30% of edited cells, with no associated decline in HbF expression determined by clonal analysis of erythroid colonies. No off-target mutations were detected by targeted sequencing of the 26 top candidate sites identified by CIRCLE-seq, an in vitro genome-scale method for detecting Cas9 activity. Analysis of gene edited human donor cells purified from mouse bone marrow showed no chromosomal rearrangements by G-banding (n=20) or fluorescence in situ hybridization with a probe located distal to the HBG1/HBG2 loci (n=225). Taken together, our studies provide novel and essential preclinical evidence supporting the safety, feasibility, and efficacy of a CRISPR-Cas9 genome editing approach to induce HbF for treating hemoglobinopathies. Figure. Gene editing of the HBG1/HBG2 promoters in HSCs and HbF induction of erythroid progeny in vivo. Plerixafor-mobilized CD34+ cells from an individual with SCD were edited with RNP and transplanted into NBSGW mice, which were analyzed 16-17 weeks later. A. On-target indel frequency before (Pre) and after bone marrow transplantation (BM). The black bars represent a 13-nucleotide deletion associated with human hereditary persistence of fetal hemoglobin. B. Human erythroblasts and reticulocytes derived from RNP-edited and non-edited Control CD34+ donor cells. Scale bar = 10 mm. C. HbF immunostaining control and RNP edited erythroid cells in recipient bone marrow assessed by flow cytometry. D. %HbF protein in hemolysates of control (C) and RNP edited erythroid cells assessed by ion-exchange HPLC. n= 3 biological replicates. **** P < 0.0001. Figure Disclosures Metais: MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Sharma:Doris Duke Foundation: Research Funding; Vertex Pharmaceuticals: Other: Study PI. Weiss:Beam Therapeutics: Consultancy; Rubius INC: Consultancy; GlaxoSmithKline: Consultancy; Cellarity INC: Consultancy; Esperian: Consultancy.

BACKGROUND Chemotherapy has improved the outcome of patients with newly diagnosed osteosarcoma, but its role in relapsed disease is unclear. METHODS We reviewed the records of all patients who were treated for relapsed high-grade osteosarcoma at our institution between 1970 and 2004. Postrelapse event-free survival (PREFS) and postrelapse survival (PRS) were estimated, and outcome comparisons were made using an exact log-rank test. RESULTS The 10-year PREFS and PRS of the 110 patients were 11.8% ± 3.5% and 17.0% ± 4.3%, respectively. Metastasis at initial diagnosis (14%), and relapse in lung only (75%) were not significantly associated with PREFS or PRS. Time from initial diagnosis to first relapse (RL1) ≥18 months (43%), surgery at RL1 (76%), and ability to achieve second complete remission (CR2, 56%) were favorably associated with PREFS and PRS (P ≤ 0.0002). In patients without CR2, chemotherapy at RL1 was favorably associated with PREFS (P = 0.01) but not with PRS. In patients with lung relapse only, unilateral relapse and number of nodules ( ≤ 3) were associated with better PREFS and PRS (P ≤ 0.0005); no patients with bilateral relapse survived 10 years. The median PREFS after treatment with cisplatin, doxorubicin, methotrexate, and ifosfamide was 3.5 months (95% confidence interval, 2.1-5.2), and the median PRS was 8.2 months (95% confidence interval, 5.2-15.1). CONCLUSIONS Late relapse, surgical resection, and unilateral involvement (in lung relapse only) favorably impact outcome after relapse. Surgery is essential for survival; chemotherapy may slow disease progression in patients without CR2. These data are useful for designing clinical trials that evaluate novel agents. Cancer 2013;119:2645-2653. © 2013 American Cancer Society.

Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2-4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (

Neuropathic pain (NP) after definitive surgery for extremity osteosarcoma (OS) has not been previously characterized. This study prospectively investigates the incidence, duration, and treatment of NP in limb sparing surgery and amputation groups.In patients treated for OS on a chemotherapy and definitive surgery (limb sparing vs. amputation) protocol (OS08), we prospectively collected the following data: (i) demographical data (age, sex, race); (ii) NP time of onset and duration; and (iii) dose (starting, maximum) and duration of gabapentin, amitriptyline, and methadone treatment.Thirty-seven patients underwent 38 definitive surgeries: limb sparing (26, 68.4%) or amputations (12, 31.6%). Localization included lower extremity (30, 81%), upper extremity (6, 16%), or pelvis (1, 3%). Thirty patients (81%) developed NP and 26 of them required NP-specific medications (87.7%). The mean [standard deviation (SD)] duration of NP was 6.5 weeks (7.2) (median 4.4, range 0.3-29.9). All 26 patients (27 surgeries) treated with NP medications received gabapentin, either as single therapy (65.4%) (17 patients, 18 surgeries), dual therapy with gabapentin and amitriptyline (five patients), or triple therapy with gabapentin, amitriptyline, and methadone (four patients). The mean starting (maximum) doses of gabapentin, amitriptyline, and methadone (mg/kg/day) were 20.2 (43.8), 0.5 (0.7), and 0.3 (0.3), respectively. The incidence and duration of NP, duration of treatment, and NP-specific dose regimens were similar in the limb sparing and the amputation groups.NP after definitive surgery for OS is frequently encountered, can persist for a significant time, and NP outcomes are similar in limb sparing and amputation groups.

Osteonecrosis after hematopoietic stem cell transplantation (HCT) has seldom been addressed in pediatric populations. At our institution, since January 2002, children undergoing allogeneic HCT (alloHCT) receive yearly follow-up magnetic resonance imaging (MR) of hips and knees. To estimate the prevalence, longitudinal changes and associated risk factors for osteonecrosis after alloHCT, we reviewed MRs for children who underwent single alloHCT during the study period. We analyzed 149 of 344 patients who had post HCT MRI imaging performed [84 males; median age11 years (range, 0.5–21years)], median follow-up time was 32.6 months (range, 2.8–97.2 months). Forty-four (29.5%) developed osteonecrosis of hips and/or knees; of those, 20 (45%) had at least 30% epiphyseal involvement. In 23 (52%) osteonecrosis lesions were identified in the first, and 43 (98%) by the third yearly scan. Knees were more frequently involved than hips; severity of osteonecrosis was greater in hips. Those who had pre-alloHCT osteonecrosis, two patients’ hips and six patients’ knees resolved completely; three patients’ osteonecrosis lesions regressed after alloHCT. On risk factor analysis, age at time of alloHCT (p=0.051) and osteonecrosis identified by MRs before alloHCT (p=0.001) were the primary risk factors. This analysis shows that preventive strategies for osteonecrosis in this population should focus on measures to minimize risk factors before alloHCT.

OBJECTIVE. Osteonecrosis in the growing population of childhood cancer survivors results from disease and treatment. Imagers must be knowledgeable about patient groups at risk for its development, patterns of involvement and potential implications. This review will focus on implications of this potentially life-altering toxicity.CONCLUSION. Childhood cancer survivors are at increased risk for developing osteonecrosis. Because osteonecrosis is often asymptomatic until late in the process, imaging is critical for its detection and characterization when interventions may be most effective to ameliorate its progression.

The standard treatment of osteosarcoma includes cisplatin and high-dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin-based regimens and caused less toxicity. To build on this experience, the authors conducted a multi-institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma.Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration-time curve of 8 mg/mL × min on Day 1) and ifosfamide (at a dose of 2.65 g/m(2) daily ×3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m(2) daily ×3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m(2) daily ×2 days) combined with ifosfamide or carboplatin.A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (90% tumor necrosis) to preoperative chemotherapy. The estimated 5-year event-free survival rate was 66.7% ± 7.0% for the OS99 trial compared with 66.0% ± 6.8% for the OS91 trial (P = .98). The estimated 5-year survival rate was 78.9% ± 6.3% for the OS99 trial and 74.5% ± 6.3% for the OS91 trial (P = .40).The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin-containing or HDMTX-containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX.

Osteonecrosis (ON) is a debilitating long-term complication of allogenic bone marrow transplantation (alloBMT) but may begin before alloBMT in some children because of their primary disease treatment. Therefore, to estimate the prevalence and associated risk factors for ON before alloBMT, we conducted a retrospective analysis of magnetic resonance (MR) studies of 118 children who underwent first alloBMT at our institution between December 2000 and September 2007. Of the 118 consecutive patients, 107 (90.7%) underwent prospective MR studies irrespective of symptoms (69 males; median age at alloBMT 12.9 years), and 11 underwent MR studies for symptoms. Amongst the 107 who had prospective imaging, 23 (21.5%) had ON; nearly 50% had at least 30% epiphyseal involvement. Knees were more frequently involved than were hips; severity of ON was greater in hips. ON prevalence before alloBMT was 23.72% when all 118 patients were included in the denominator. Risk factor analysis, limited to MR studies performed irrespective of symptoms, revealed female gender (P = 0.049) and age ≥10 years at the time of MR study (P = 0.03) as significant risk factors and primary diagnosis of lymphoid malignancies and aplastic anemia trended towards significance. ON prior to alloBMT is a common occurrence in children.

Mesoblastic nephroma is the most frequent renal tumor in newborns and young infants, and the cellular type is characterized by an ETV6-NTRK fusion, which constitutively activates the tropomyosin-related kinase (TRK) signaling pathway. Larotrectinib is a highly selective TRK inhibitor with activity in adult and pediatric patients who have TRK fusions. We present a rare case of a patient with mesoblastic nephroma metastatic to bone who had a dramatic response to larotrectinib.

Resurfacing hemiarthroplasties were performed to treat advanced osteonecrosis of 20 femoral heads in 14 patients (median age, 19.8 years; range, 15.1–27.4 years), treated for hematologic cancer in childhood or adolescence. Seven hips in five patients were revised to total hip arthroplasties (THA) because of pain; three of these showed radiographic loosening of the femoral head resurfacing component. The median time from resurfacing to revision was 2.4 years (range, 0.9–4.8 years). Marginal Cox-regression analysis, adjusting for correlations owing to bilateral involvement, showed positive association of revision-free survival of the prosthesis with patient’s age; time from resurfacing to the end of anticancer therapy, end of glucocorticosteroid therapy; percentage of joint space at the last radiograph; and size of the lesion has a negative association with revision-free survival. Because of this study’s exploratory nature, p values were not adjusted for the number of statistical comparisons. Among 14 patients, the probability of not requiring resurfacing prosthesis revision was 66% (SE, ±15%; 95% CI, 44%–100%) at 3 years. Osteonecrosis of the femoral head in young patients treated for hematologic cancer in childhood or adolescence poses a serious challenge to the orthopaedic surgeon. The data of this preliminary study suggest that in selected patients resurfacing hemiarthroplasty may delay the need for THA for 3–7 years. Level of Evidence: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

We reviewed the available literature and describe our own experience with management of femoral head osteonecrosis in patients with pediatric hematologic malignancies. Osteonecrosis has become a major complication lowering quality of life among survivors of pediatric leukemia and lymphoma. Periodic imaging during anticancer therapy allows for early detection of osteonecrosis. Most patients with greater than 30% femoral head involvement will require arthroplasty. More studies are desperately needed to find interventions for early stage osteonecrosis that would preserve the integrity of the articular surface. Bone-conserving surgeries are preferred in young patients in anticipation of multiple revisions needed during their expected lifespan.

Purpose Osteonecrosis of the capital femoral epiphysis is a significant late toxicity of treatment for childhood leukemia and lymphoma. We determined clinical and imaging risk factors predicting clinical joint outcomes of femoral head osteonecrosis in pediatric patients with leukemia or lymphoma. Patients and Methods We reviewed retrospectively medical records and magnetic resonance imaging scans of 80 patients with osteonecrosis of the capital femoral epiphysis. Logistic regression was used to examine relationships between risk factors and outcomes of joint surface collapse and arthroplasty. We used Kaplan-Meier survival curves to display the time to joint surface collapse and arthroplasty based on selected predictors. Results Median time between primary diagnosis and diagnosis of osteonecrosis of the hip was 1.7 years (range, 0.1 to 17.5 years). Twenty-three patients (29%) underwent arthroplasty in 36 hips at a mean of 1.3 years (range, 0.5 to 8.6 years) after diagnosis of osteonecrosis. Median age at time of first arthroplasty was 20.1 years (range, 15.1 to 35.4 years). Joint outcome of osteonecrosis was predicted solely by lesion size at diagnosis of osteonecrosis. The worst prognosis was associated with lesions occupying more than 30% of the femoral head volume; 80% of hips with these lesions collapsed within 2 years of diagnosis and 50% required arthroplasty. Conclusion Lesion size of osteonecrosis is the best predictor of clinical joint outcome of hip osteonecrosis in survivors of pediatric hematologic malignancy. Lesions occupying more than 30% of the femoral head have high likelihood of joint deterioration necessitating arthroplasty at a young age.

Neonatal soft-tissue tumors are rare and comprise a heterogeneous group of neoplasms with substantial histological diversity. Treatment options include careful observation, primary surgical resection or medical therapy. Although histologically benign, some neoplasms do exhibit an aggressive local behavior. The most common soft-tissue sarcomas in this age group include rhabdomyosarcoma, fibrosarcoma, malignant rhabdoid tumor and hemangiopericytoma. Prenatal diagnosis on routine ultrasound or in the context of a known predisposition syndrome is increasingly becoming more common. Management of neonatal tumors requires a multidisciplinary team that includes obstetricians, neonatologists, pediatric oncologists, pediatric surgical specialists and psychological support for the family members. Treatment is particularly challenging due to the difficulty in appropriate dosing of chemotherapeutic agents or the limitations of the use of radiation therapy. Although surgical treatment is predominant in this age group, close observation may be appropriate, since spontaneous regression has been reported for certain histological subtypes.

Background Comparison of functional mobility and quality of life is performed in patients with lower-extremity bone sarcoma following either amputation, limb-sparing surgery, or rotationplasty with four different types of outcome measures: (1) an objective functional mobility measure that requires patients to physically perform specific tasks, functional mobility assessment (FMA); (2) a clinician administered tool, Musculoskeletal Tumor Society Scale (MSTS); (3) a patient questionnaire, Toronto Extremity Salvage Scale (TESS); and (4) a health-related quality of life (HRQL) measure, Short Form-36 version 2 (SF-36v.2). Procedure This is a prospective multi-site study including 91 patients with lower-extremity bone sarcoma following amputation, limb-sparing surgery, or rotationplasty. One of three physical therapists administered the quality of life measure (SF-36v.2) as well as a battery of functional measures (FMA, MSTS, and TESS). Results Differences between patients who had amputation, limb-sparing surgery, or rotationplasty were consistently demonstrated by the FMA. Patients with limb sparing femur surgery performed better than those patients with an above the knee amputation but similarly to a small number of rotationplasty patients. Several of the more conventional self-report measures were shown to not have the discriminative capabilities of the FMA in these cohorts. Conclusion In adolescents with lower-extremity bone sarcoma, it may be advantageous to consider the use of a combination of outcome measures, including the FMA, for objective functional mobility assessment along with the TESS for a subjective measure of disability and the SF-36v.2 for a quality-of-life measure. Pediatr Blood Cancer 2007;49:964–969. © 2006 Wiley-Liss, Inc.

This aim of this study was to explore the relationship between MRI findings and clinical symptoms of knee osteonecrosis in children and to determine the significance of this relationship. Such information is important for early diagnosis of this frequent complication and for choosing an appropriate treatment strategy.Osteonecrotic lesion size and location were determined in a retrospective analysis of MR images of the knee obtained in our institution during the past 10 years. Association between MRI findings and clinical symptoms expressed by the knee scores was tested for a subgroup of our patient population who had clinical evaluation of the knees in the orthopedic clinic within 6 weeks of their MRI studies.In 80% of patients, osteonecrosis was bilateral. Lesions were distributed as follows: femur and tibia, 66% of the knees; femur alone, 26%; and tibia alone, 8%. Clinical symptoms of knee osteonecrosis were associated with lesions involving the articular surface of the distal femur, large lesions, and involvement of any part of the tibia. MR images showed milder osteonecrosis in patients who were less than 10 years old at the time of primary diagnosis.Osteonecrosis affecting the knees of children treated for leukemia and lymphoma is mostly asymptomatic. Children who are 10 years old or older have signs of more advanced osteonecrosis. Clinical symptoms often lag MRI presentation and may develop late in the course of the disease. Routine MRI evaluation is recommended for timely diagnosis of treatment-induced osteonecrosis.

The aim of this study was to determine whether a new MRI-based staging system for osteonecrosis of the knee in pediatric patients could be used with an acceptable level of intra- and interobserver agreement.We conducted a retrospective analysis of MRI studies of the knee performed in a single institution between April 1994 and July 2003. Knee osteonecrosis was identified in 168 children with a primary diagnosis of hematologic malignancy. This substantial number prompted us to design a staging system for use with pediatric patients. To assess interobserver reliability of two primary observers in using the system, they reviewed and interpreted the same 36 imaging studies of randomly chosen patients. For the assessment of intraobserver reproducibility, each observer rereviewed 16 studies. A senior observer coded potential causes of disagreement between the primary observers.Interobserver agreement was substantial: the kappa value was 0.66 (95% confidence interval [CI], 0.58-0.75) in locations where the observers had to record only the presence or absence of a lesion, and the weighted kappa value was 0.65 (95% CI, 0.59-0.72) in locations where they had to classify the extent of involvement. The presence of marrow edema, punctate foci of altered signal, and mottled marrow changes was associated with a higher level of disagreement between the primary observers.Our proposed classification system, developed specifically for use with MRI, was used with substantial intra- and interobserver agreement. We think its use can contribute to a standardized approach to the interpretation of MRI findings in pediatric osteonecrosis of the knee.

BACKGROUND. The outcome of patients with metastatic osteosarcoma treated in two consecutive trials from 1986 to 1997 was analyzed to evaluate the efficacy of carboplatin-based multiagent chemotherapy and to identify prognostic factors. The initial study (OS-86) used ifosfamide, cisplatin, doxorubicin, and high-dose methotrexate, and the subsequent study (OS-91) used the same agents at similar doses, but carboplatin was substituted for cisplatin. METHODS. Twelve patients (median age, 15.1 yrs) were treated in OS-86 for osteosarcoma metastatic to the lung only (11 patients) or bone only (I patient), and 17 patients (median age, 15.1 yrs) were treated in OS-91 for osteosarcoma metastatic to the lung only (12 patients), bone only (2 patients), lung and bone (2 patients), or other site (1 patient). RESULTS. Patients with metastatic disease enrolled in OS-86 and those with metastatic disease enrolled in OS-91 did not differ in terms of demographic features, histologic subtype, site of primary tumor, or site of metastases. There was a difference in survival according to treatment protocol (P = 0.054). All survivors (four of whom were enrolled in OS-86 and one of whom was enrolled in OS-91) had lung metastases only. Five-year survival estimates for patients with lung metastases only were 45.5 ± 13.7% (OS-86) and 8.3 ± 5.6% (OS-91) (P = 0.084). Unilateral lung metastases (P = 0.006), no more than three lung nodules (P = 0.014), and surgical remission (P = 0.001) were associated with improved survival probability. CONCLUSIONS. The poor outcome of patients with metastatic osteosarcoma treated in OS-91 justifies the use of cisplatin with its associated toxicity in patients with high-risk disease.

UNLABELLED We aimed to determine if the ankle is at risk for corticosteroid-induced osteonecrosis as a cause of pain in a cohort of childhood cancer survivors. We retrospectively reviewed magnetic resonance imaging scans of the ankle in patients treated at our institution between 1993 and 2003. Among the 15 patients who met study criteria, 20 of 30 (67%) ankles were involved. Older children had the highest incidence of the disease. The tibial metaphysis, epiphysis, and talus were the most frequent sites of osteonecrotic lesions. Ten patients were symptomatic with extended weightbearing activity. Surgery was required in four with continued amelioration of pain at last followup (17-44 months). As early detection and intervention lead to prevention of ankle morbidity, childhood cancer survivors would benefit from a prospective multi-institutional study that would provide understanding of ankle osteonecrosis and development of effective interventions. LEVEL OF EVIDENCE Prognostic study, Level II-1 (retrospective study).

A noninvasive expandable prosthesis for skeletally immature children after limb salvage surgery has been developed. Between 1998 and 2001, 18 Phenix prostheses were implanted in 15 pediatric patients who had been diagnosed and treated for osteosarcoma about the knee. Of the 15 original prostheses, 10 were implanted at the time of primary tumor resection and five were revisions from an endoprosthetic modular knee system. Sixty expansions of the 18 prostheses were done, with all but two done as outpatient procedures. An average 8.5 mm was obtained per lengthening (range, 1-30 mm). The average followup was 21.5 months (range, 12-33 months) and the latest Musculoskeletal Tumor Society functional scores averaged 90%. Eight revisions were required for stem fracture or loosening. There was one amputation because of a postoperative arterial thrombosis. The principle of the Phenix prosthesis involves storage of energy in a spring compressed by a locking system. Lengthening is achieved via exposure to an electromagnetic field that allows controlled release of the spring. This is a unique expandable custom prosthesis that offers many benefits in maintaining limb length equality in growing patients. Although the early experience is promising, additional data are required regarding the long-term structural integrity of the prosthesis. We are optimistic that this technology will prove beneficial, not only for patients with malignant bone tumors but in applications requiring serial limb length equalizations or for spinal deformities.

Limb salvage for management of osteosarcoma of the lower extremity has become the mainstay of treatment for patients with malignant bony and soft tissue tumors. The knee has become a special area of concern for the reconstructive surgeon due to the high rate of wound complications and difficulties of soft tissue reconstruction. With the availability of new prosthetic implants, the advancement of surgical soft tissue techniques and introduction of adjuvant and neoadjuvant chemotherapy, resection and reconstruction has become the standard approach for patients presenting to St. Jude Children's Research Hospital. The pediatric plastic surgeon's role usually requires handling of wound complications in these reconstructive procedures. This article will discuss the authors' approach to dealing with wound complications in this difficult patient population and their interaction with the orthopedic oncologic service in obtaining primary resection and soft tissue coverage.

Purpose Hip osteonecrosis frequently complicates treatment with glucocorticoids. When extensive (affecting ≥ 30% of the epiphyseal surface), 80% of joints collapse within 2 years, so interventions are needed to prevent this outcome. Patients and Methods This prospective cohort magnetic resonance imaging (MRI) screening study included all consecutive children treated for acute lymphoblastic leukemia on a single protocol. Hip MRI was performed at 6.5 and 9 months from diagnosis (early screening) and at completion of chemotherapy (final evaluation) to determine whether screening could identify extensive hip osteonecrosis before symptom development. Results Of 498 patients, 462 underwent screening MRI. Extensive asymptomatic osteonecrosis was identified by early screening in 26 patients (41 hips); another four patients (seven hips) were detected after the screening period, such that screening sensitivity was 84.1% and specificity was 99.4%. The number of joints screened to detect one lesion was 20.1 joints for all patients, 4.4 joints for patients older than 10 years, and 198 joints for patients ≤ 10 years old (P < .001). Of the 40 extensive lesions in patients older than 10 years, 19 required total hip arthroplasty and none improved. Of eight extensive lesions in younger patients, none required arthroplasty and four improved. Conclusion In patients age 10 years old or younger who require prolonged glucocorticoid therapy, screening for extensive hip osteonecrosis is unnecessary because their risk is low and lesions tend to heal. In children older than 10 years, early screening successfully identifies extensive asymptomatic lesions in patients who would be eligible for studies of interventions to prevent or delay joint collapse.

Complete resection of lung metastases improves survival in patients with osteosarcoma. We evaluated the long-term effect of metastasectomy on pulmonary function of patients treated for osteosarcoma during childhood.We reviewed the medical records of patients who had pulmonary function tests (PFTs) after metastasectomy for osteosarcoma. Patient, tumor, and treatment variables were abstracted along with PFTs. The PFTs were recorded as a percentage of predicted value and were classified as abnormal for forced vital capacity (FVC)80%, forced expiratory volume in 1 second (FEV1)80%, total lung capacity (TLC)75%, and single breath diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOcorr)75%.Twenty-one patients had PFTs performed during follow-up. Mean age at diagnosis of osteosarcoma was 13.2 ± 4.7 years (SD). Fifteen patients had a single thoracotomy, and 6 patients had ≥2 thoracotomies (range 2 to 6). Eighty lesions were resected. Nine patients had ≤2 lesions resected and 12 patients had2 lesions (range 3 to 12) resected. Mean time from the last surgical procedure to measurement of PFTs was 20.3 ± 9.0 years (SD). Total lung capacity was abnormal for 28.6%, DLCOcorr for 47.4%, FVC for 40%, and FEV1 for 47.6% of the cohort members. Individual PFTs were abnormal in 13.3% (TLC) to 46.7% (DLCOcorr) of patients who had 1 thoracotomy and in 50.0% (DLCOcorr) to 66.7% (FEV1, TLC) of patients with ≥2 thoracotomies. The number of thoracotomies was associated with abnormal TLC (p = 0.03).Patients who underwent pulmonary metastasectomy for osteosarcoma as children often had abnormal PFTs on long-term follow-up, but the reduction in lung volumes and DLCOcorr was relatively mild. Multiple thoracotomies predicted greater impairment of pulmonary function.

Purpose To determine the incidence, timing, and clinical significance of long-bone fractures in children with Ewing sarcoma family of tumors (ESFT). Patients and methods We retrospectively reviewed 93 consecutive cases of ESFT of the long bones seen at a single institution over the course of a 37-year period. Results Fracture occurred in 14 (15%) of 93 patients with long-bone ESFT, most commonly in the femur. Approximately 30% of patients with tumors of the femur had fractures at some point in the course of their disease. The incidence of fracture was highest among patients with tumors of the proximal third of the femur (50%); these fractures were usually present at the time of initial diagnosis. Nine (64%) of the 14 fractures occurred after the start of radiotherapy, and three of these were associated with either local recurrence or second malignancy. Conclusions Patients with femoral ESFT are at high-risk for fracture. If fractures occur after the completion of therapy, recurrence or second malignancy should be suspected.

In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5-2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.

Limb-sparing surgery for osteosarcoma requires taking wide bony resection margins while maximizing preservation of native bone and joint. However, the optimal bony margin and factors associated with recurrence and survival outcomes in these patients are not well established.We conducted a retrospective review of outcomes in children and adolescents with newly diagnosed osteosarcoma from 1986 to 2012, where bony resection margins for limb-sparing surgeries were decreased serially from 5 to 1.5 cm. The association between bony margins and other surgicopathological factors with survival and recurrence outcomes was determined.In 181 limb-sparing surgeries in 173 patients, planned and actual bony resection margins were not significantly associated with local recurrence-free survival (LRFS), event-free survival (EFS), and overall survival (OS)-at median 5.8 years follow-up, decreasing planned bony resection margins from 5 to 1.5 cm did not significantly decrease survival outcomes. Multivariable analysis showed that the presence of distant metastases at diagnosis was associated with decreased LRFS, EFS, and OS (P = 0.002, 0.005, and0.0001, respectively). Post-chemotherapy tumor necrosis ≤90% was associated with decreased EFS and OS (P = 0.001 and 0.022, respectively). Earlier years of treatment and pathologic fractures were associated with decreased OS only (P = 0.018 and 0.008, respectively); previous cancer history and male gender were associated with decreased EFS only (P = 0.043 and 0.023, respectively).We did not observe significant increase in adverse survival outcomes with reduction of longitudinal bony resection margins to 1.5 cm. Established prognostic factors, particularly histologic response to chemotherapy and metastases at diagnosis, remain relevant in limb-sparing patients. Pediatr Blood Cancer 2015;62:246-251. © 2014 Wiley Periodicals, Inc.

The optimal management of locally recurrent pediatric osteosarcoma is not established, especially after prior limb-sparing surgery. We describe our experience in the management of these patients and identify prognostic indicators of post-recurrence survival.We conducted a retrospective, single-institution review of patients with locally recurrent osteosarcoma after limb-salvage surgery who were treated between October 1989 and January 2012. The management of each recurrence was evaluated, and patient, disease, and treatment factors were correlated with post-recurrence survival (PRS).Of 200 patients who underwent limb-sparing procedures, 18 (9 %) had biopsy-proven local recurrence. Recurrences occurred in soft tissue in 15 patients (83.3 %). Six patients (33.3 %) were amenable to repeat limb-sparing surgery. Median time to local recurrence was 1.4 (range 0.6-10.4) years. Median PRS was 11.8 months (range 3.7 months-12.1 years). Post-recurrence survival was significantly associated with the length of resection margins and was longer when recurrent tumors were resected with margins of ≥1 cm, compared with subcentimeter or positive margins (P = 0.03). Median PRS was longer in patients who underwent amputations (2.44 years) than those who underwent repeat limb-sparing surgery (0.86 years), and in patients who had distant metastases resected (2.7 years) than those who did not (0.85 years); however, differences were not significant.Local management of recurrent osteosarcoma in a previously reconstructed limb is highly individualized. A sufficiently wide resection is important for local control of recurrences, independent of the type of surgery. Maintaining control of distant metastases may also contribute to improved survival.

Chemotherapy has improved the outcome of patients with newly diagnosed osteosarcoma, but its role in relapsed disease is unclear.We reviewed the records of all patients who were treated for relapsed high-grade osteosarcoma at our institution between 1970 and 2004. Postrelapse event-free survival (PREFS) and postrelapse survival (PRS) were estimated, and outcome comparisons were made using an exact log-rank test.The 10-year PREFS and PRS of the 110 patients were 11.8% ± 3.5% and 17.0% ± 4.3%, respectively. Metastasis at initial diagnosis (14%), and relapse in lung only (75%) were not significantly associated with PREFS or PRS. Time from initial diagnosis to first relapse (RL1) ≥18 months (43%), surgery at RL1 (76%), and ability to achieve second complete remission (CR2, 56%) were favorably associated with PREFS and PRS (P ≤ 0.0002). In patients without CR2, chemotherapy at RL1 was favorably associated with PREFS (P = 0.01) but not with PRS. In patients with lung relapse only, unilateral relapse and number of nodules ( ≤ 3) were associated with better PREFS and PRS (P ≤ 0.0005); no patients with bilateral relapse survived 10 years. The median PREFS after treatment with cisplatin, doxorubicin, methotrexate, and ifosfamide was 3.5 months (95% confidence interval, 2.1-5.2), and the median PRS was 8.2 months (95% confidence interval, 5.2-15.1).Late relapse, surgical resection, and unilateral involvement (in lung relapse only) favorably impact outcome after relapse. Surgery is essential for survival; chemotherapy may slow disease progression in patients without CR2. These data are useful for designing clinical trials that evaluate novel agents.

Osteonecrosis is a debilitating toxicity associated with acute lymphoblastic leukemia (ALL) treatment. A recent report associated interindividual differences in hip anatomy with the development of idiopathic osteonecrosis in adults. To evaluate the impact of hip anatomy on the development of therapy-related osteonecrosis, we retrospectively evaluated the femoral neck-shaft angle, femoral neck offset, and lateral center-edge angle using x-rays of 18 osteonecrosis cases and 46 control children treated for newly diagnosed ALL on a single protocol. Despite adequate statistical power, we found no association between hip anatomy and osteonecrosis. Investigation of other factors contributing to ALL-associated osteonecrosis is warranted.