Purpose: Survivors of childhood lower extremity and pelvic osteosarcoma have a high burden of functional, strength, and range of motion (ROM) impairment. However, longitudinal trajectories of these outcomes have not been well studied. Methods: This longitudinal study included patients enrolled on an institutional therapeutic protocol with lower extremity or pelvic osteosarcoma. Functional assessments (functional mobility assessment, FMA) were performed at diagnosis, prior to surgery, 10-12 weeks post-surgery, end of therapy, and 6, 18, and 48 months post-therapy. Generalized mixed models were used to evaluate differences in FMA scores, strength, and ROM across time points. Results: The study included 35 patients (mean age 13.1 ± 3.4 years) with osteosarcoma of the lower extremity (n = 34) and pelvis (n = 1). The majority underwent a limb salvage procedure (74.3%). FMA scores were lowest at the pre-therapy time point (least squared (LS) mean 27.2, standard error (SE) 2.2) and highest at the 48-month follow-up time point (LS mean 48.4, SE 2.4, p-trend < 0.01). A large proportion of participants had scores indicating functional impairment throughout the study period including 80% of participants at the 48-month follow-up. Strength and ROM scores demonstrated similar trends in improvement over time; however, they remained below normative scores at long-term follow-up. Conclusions: A high burden of impairment in function, strength, and ROM persists among survivors of childhood lower extremity and pelvic osteosarcoma from diagnosis through long-term follow-up. Implications for Cancer Survivors: A lifelong focus on mitigating impairments in function, strength, and ROM is needed among survivors of childhood pelvic and lower extremity osteosarcoma.

Background: Despite success in treating childhood acute lymphoblastic leukemia and lymphoma (ALL), modern multiagent chemotherapy regimens containing high-dose corticosteroids can result in osteonecrosis afflicting survivors, frequently involving the knee. Thus, we describe the usage of fresh osteoarticular allograft (FOAG) to treat steroid-induced osteonecrosis of the femoral condyle in pediatric cancer survivors. We assessed the efficacy of FOAGs to heal necrotic bone, provide long-term pain relief, while retrospectively reviewing quality of life and functional status. Methods: We recorded patient demographics, pain, and functional scores preoperatively, postoperatively, and at the most recent follow-up, additional surgical procedures, and radiographic outcomes at each timepoint. Anatomic locations and sizes of the grafts were noted using operative reports and intraoperative photographs. Function and pain scores were collected by direct patient communication or through survey, with data scored using the KOOS (Knee Injury and Osteoarthritis Outcome Score), PROMIS (Patient-Reported Outcomes Measurement Information System), and CTCAE (Common Terminology Criteria for Adverse Events) scoring tools. Results: Eighteen patients, (12 females) over a period of 8 years, underwent the procedure. One patient was excluded due to death before 12 months follow-up. The average age at diagnosis of femoral condyle osteonecrosis was 14.5 years. The average age at the time of surgery was 18.5 years (range, 13 to 25 y). All patients had at least 16 months follow-up (average 60 mo; range 16 to 99 mo). Grafts ranged in size from 18 to 27.5 mm. All patients reported a return to normal function of the knees with KOOS scores approaching normal, PROMIS scores averaging 46, and CTCAE outcomes improving at an average of 34 months post-surgery. Two patients experienced a partial graft failure, which was repaired with new allografts. Conclusions: Although historical reviews indicated unsatisfactory results, our experience highlights the successful usage of FOAG for the management of patients treated for childhood leukemia who develop steroid-induced osteonecrosis of the femoral condyle. This procedure proved effective in managing pain and improving function and quality of life, with good bone ingrowth despite large necrotic lesions. Levels of Evidence: Therapeutic Level IV.

Study Aim: Patients with high-risk Ewing sarcoma (ES) have dismal outcomes despite aggressive multimodal therapy. This phase II, single-institution study evaluated the response rate to two up-front cycles of irinotecan, temozolomide, and temsirolimus (ITT) and assessed the tolerability of maintenance therapy following standard treatment in high-risk ES. Methods: Eligible patients had newly diagnosed high-risk ES (age ≥14 years old, metastatic disease, or primary pelvic tumor). The therapy included two cycles of window therapy (ITT) followed by interval-compressed chemotherapy (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) and maintenance therapy (cyclophosphamide, sorafenib, and bevacizumab). A two-stage sequential design was employed to assess a >50% WHO response (CR or PR) with 80% power. Patients who required emergent radiation were excluded from receiving window therapy. Results: Sixteen patients (median age 12.2 years; range 4.8–23.6 years) were enrolled (12 evaluable for overall response, 10 for primary tumor response). Only three achieved a PR to window therapy, leading to study closure. All evaluable patients demonstrated a decline in their primary tumor volume (mean decline: 32.5%, standard deviation: 17.6%, p-value: 0.0005) and SUV peak (mean decline: 49.9%, standard deviation: 21.1%, p-value: 0.002). Maintenance therapy was well tolerated, with only 2/13 patients discontinuing due to toxicity. Conclusions: ITT did not achieve the prespecified response rate of 50%, according to WHO criteria; however, all patients exhibited decreased volume and metabolic activity, highlighting the limitations of conventional response assessments. Maintenance therapy was feasible and well tolerated. Although limited by small sample size, heterogeneous disease presentations, and the absence of a control arm, this study supports further evaluation of ITT and a maintenance approach in larger, randomized trials for high-risk ES.

BACKGROUND:Limb-sparing surgery is the standard of care for primary bone tumors. However, such procedures are associated with high rates of wound complications, specifically in lower-extremity surgeries. Therefore, identifying and implementing interventions to minimize the likelihood of wound complications after limb-sparing resection of the lower extremity is crucial. METHODS:Patients who underwent limb-sparing osteosarcoma or Ewing sarcoma resection during a 7-year period at a single institution were retrospectively reviewed. Data were collected on 39 patients who underwent limb-sparing resection of the femur. Patient demographics, tumor characteristics, and perioperative and postoperative data were extracted and analyzed. Patients who underwent resection before April 2017 received conventional postoperative incision dressings. Starting in April 2017, patients received vacuum-assisted closure (VAC) with the 3 M™ Prevena VAC system after surgical closure. Eighteen patients received conventional postoperative incision dressing, and 21 received incisional wound VAC. A wound complication was defined as any Clavien-Dindo classification greater than 0 within a 28-day postoperative period. RESULTS:Patients who received postoperative incisional wound VAC had lower rates of wound complications than those who received conventional incision dressings (14% vs. 50%; p = 0.035). Additionally, patients in whom wound complications developed had a longer average hospital stay than those without wound complications (5 days vs. 4 days; p = 0.029). CONCLUSIONS:Wound complications prolong the hospital stay and can delay adjuvant chemotherapy for bone tumors. The use of postoperative incisional wound VAC is associated with less likelihood of wound complications and should be considered in any high-risk surgical closure. LEVEL OF EVIDENCE:Level III Treatment Study.

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

Motorized intramedullary lengthening nails allow for transport of a bone segment for limb lengthening, deformity correction, healing of nonunion, and intercalary distraction osteogenesis. Resection of tumors involving the bone can result in substantial defects that require reconstruction. Use of these nails allows for a biologic reconstruction with the incorporation of allograft or by distraction osteogenesis. Limb lengthening after an internal hemipelvectomy where the hip joint is resected can be performed to improve gait, decrease pain, and prevent the need for a custom shoe or shoe lift. Using these nails in compression aids the incorporation of intercalary allografts and prevents stress shielding and stress risers within the graft when compared with plating. It also allows for a subsequent lengthening of the limb using the same implant. Plate-assisted bone segment transport or the use of a bone transport nail allows for a true biologic reconstruction of an intercalary defect using distraction osteogenesis. These implants provide the orthopaedic oncologist with more options for reconstruction and the potential to improve the function and outcomes of their patients.

PDF file - 200K, Supplementary Table 1. Comparison of predictive performance for model parameterizations A, (B), and C (with IBW covariate) Supplemental Figure 1. The base structural bevacizumab model consisted of a two compartment model parameterized in terms of clearance from the central compartment and intercompartmental transfer to and from central and peripheral compartments. Supplemental Figure 2. Observed concentration-time data (filled diamonds) with simulations from individual posthoc parameter estimates (dashed lines; ~2 hrs step size) indicate that bevacizumab exhibits bi-exponential decay with a relatively rapid alpha phase and a prolonged beta terminal phase. Supplemental Figure 3. Visual predictive check of observed and model-predicted serum bevacizumab concentrations following 15 mg/kg dosing over a course of three occasions. The shaded region represents the 95% confidence interval of the Monte Carlo model simulations.

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: Patients with pediatric leukemia and sickle cell disease are at risk for developing osteonecrosis (ON), a disease that can result in pain, loss of function, and disability. Hip core decompression surgery is an option aimed to prevent femoral head collapse and avoid future arthroplasty. Objective: Describe functional outcomes and gait quality among a young population with hip ON before and after hip core decompression. Methods: Study included participants with hip ON secondary to treatment for hematologic malignancy or sickle cell disease, between 8 and 29 years of age, requiring hip core decompression surgery. At 1-year follow-up, 13 participants (9 male, median age of 17 years) completed the Functional Mobility Assessment (FMA), range of motion, and GAITRite testing. Results: The participants demonstrated improved mobility and endurance on the FMA at 1 year postoperatively compared with preoperatively, with higher scores for time on the Timed Up and Go (mean FMA score = 2.92 [SD = 1.32] vs 2.07 [SD = 1.70]), time on the Timed Up and Down Stairs (3.69 [0.85] vs 2.92 [1.66]), and 9-Minute Walk Test scores for distance walked (2.69 [0.63] vs 2.23 [0.93]) and heart rate (4.54 [0.66] vs 3.31 [1.38]). GAITRite analysis also showed improvements in many gait parameters at 1-year follow-up. Limitations: Cancer treatment complications other than ON could have contributed to results, not all eligible participants agreed to participate, and follow-up was only 1 year. Conclusions: Young patients with hip ON demonstrated improvements in functional mobility, endurance, and gait quality 1 year following hip core decompression.

We present a case of an infant with X-linked severe combined immunodeficiency (XSCID) and disseminated Bacille Calmette-Guérin (BCG) infection, who enrolled on our XSCID gene therapy trial, in which newly diagnosed patients receive lentiviral-transduced, gene-corrected CD34+ hematopoietic stem cells after low-dose, targeted busulfan conditioning (NCT01512888).1 The patient was reported in our initial publication (patient #6), and we herein describe in detail his clinical course that was complicated by disseminated BCG infection.

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 diagnosiswas 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 <.001). 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. (C) 2020 Elsevier Inc. All rights reserved.

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 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.

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.

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.

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.

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.