Radiation therapy dose escalation achieves high rates of local control with tolerable toxicity profile in pediatric and young adult patients with Ewing sarcoma.

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

Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington's disease mice and innervate the striatum.

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

Reconstruction of Bony Defects With Motorized Intramedullary Nails After Tumor Resection.

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.

IKKß slows Huntington's disease progression in R6/1 mice.

Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKß, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington's disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKß on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKß phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKß to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKß knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKß in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKß knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKß is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKß is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKß may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

Total Hip Arthroplasty in Adolescents and Young Adults for Management of Advanced Corticosteroid-Induced Osteonecrosis Secondary to Treatment for Hematologic Malignancies.

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 < .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.

Team approach: Management of osteonecrosis in children with acute lymphoblastic leukemia.

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.

Whole-joint magnetic resonance imaging to assess osteonecrosis in pediatric patients with acute lymphoblastic lymphoma.

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.

Curative-intent radiotherapy for pediatric osteosarcoma: The St. Jude experience.

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.

Osteonecrosis of the Shoulders in Pediatric Patients Treated for Leukemia or Lymphoma: Single-Institutional Experience.

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.

Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma.

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.

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy.

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 (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.

Nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) in pediatric and young adult patients: Results from a prospective study using limited-margin radiotherapy.

BACKGROUND: Indications for and delivery of adjuvant therapies for pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) have been derived largely from adult studies; therefore, significant concern remains regarding radiation exposure to normal tissue. The authors report long-term treatment outcomes and toxicities for pediatric and young adult patients with high-grade NRSTS who were treated on a prospective trial using limited-margin radiotherapy. METHODS: Sixty-two patients (ages 3-22 years) with predominantly high-grade NRSTS requiring radiation were treated on a phase 2 institutional study of conformal external-beam radiotherapy and/or brachytherapy using a 1.5-cm to 2-cm anatomically constrained margin. The estimated cumulative incidence of local failure, Gray's method estimated cumulative incidence of local failure, Kaplan-Meier method estimated survival, competing-risk regression model determined predictors of disease outcome, and toxicity was reported according to CTCAE v2.0. RESULTS: At a median follow-up of 5.1 years (range, 0.2-10.9 years), 9 patients had experienced local failure. The 5-year overall cumulative incidence of local failure was 14.8% (95% confidence interval [CI], 7.2%-25%), and all but 1 local failure occurred outside the highest-dose irradiation volume. The 5-year Kaplan-Meier estimates for event-free and overall survival were 49.3% (95% CI, 36.3%-61.1%) and 67.9% (95% CI, 54.2%-78.3%), respectively. Multivariable analysis indicated that younger age was the only independent predictor of local recurrence (P = .004). The 5-year cumulative incidence of grade 3 or 4 late toxicity was 15% (95% CI, 7.2%-25.3%). CONCLUSIONS: The delivery of limited-margin radiotherapy using conformal external-beam radiotherapy or brachytherapy provides a high rate of local tumor control without an increase in marginal failures and with acceptable treatment-related morbidity. Cancer 2017;123:4419-29. © 2017 American Cancer Society.

Osteonecrosis is unrelated to hip anatomy in children with acute lymphoblastic leukemia.

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.

Prospective study of neuropathic pain after definitive surgery for extremity osteosarcoma in a pediatric population.

BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: 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.

Pathologic fracture in childhood and adolescent osteosarcoma: A single-institution experience.

PURPOSE: Pathologic fractures occur in 5-10% of pediatric osteosarcoma (OS) cases and have historically been considered a contraindication to limb salvage. Our purpose was to describe the radiographic features of pathologic fracture and examine its impact on local recurrence rates, functional outcomes, and overall survival. METHODS: We retrospectively analyzed patients at our institution from 1990 to 2015 with pathologic fracture at diagnosis or during neoadjuvant chemotherapy. We selected a control group of 50 OS patients of similar age and gender without pathologic fracture from 1990 to 2015. Functional outcomes were scored using Musculoskeletal Tumor Society criteria. Chi-square test was used for comparative analysis of groups. RESULTS: Thirty-six patients with 37 pathologic fractures form the study cohort. Of patients who received surgery, 18 of 34 patients with fracture underwent amputation compared to 8 of 48 patients in the nonfracture group (P = 0.007). Indications for amputation in fracture patients were tumor size (n = 7), neurovascular involvement (n = 6), and tumor progression during neoadjuvant chemotherapy (n = 5). Only one patient (2.9%) in the fracture group who underwent limb salvage suffered local recurrence. Of patients who received neoadjuvant chemotherapy, 25 of 34 fracture patients showed poor histological response compared to 24 of 47 nonfracture patients (P = 0.044). There was no statistically significant difference in overall survival (P = 0.96). Functional outcomes were significantly lower in fracture patients (median = 17.5) than nonfracture patients (median = 24) (P = 0.023). CONCLUSIONS: Radiographic features of pathologic fractures were highly variable in this population. Limb salvage surgery can be performed without increased risk of local recurrence. Patients with pathologic fracture suffer worse functional outcomes but no decrease in overall survival.

Influence of bony resection margins and surgicopathological factors on outcomes in limb-sparing surgery for extremity osteosarcoma.

BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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, and <0.0001, 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). CONCLUSION: 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.

Management of local recurrence of pediatric osteosarcoma following limb-sparing surgery.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Use of Vacuum-Assisted Closure to Reduce the Likelihood of Wound Complications After Limb-Sparing Resection of Pediatric Primary Bone Sarcomas of the Femur.

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.

Sequential emergence and contraction of epithelial subtypes in the prenatal human choroid plexus revealed by a stem cell model.

Despite the major roles of choroid plexus epithelial cells (CPECs) in brain homeostasis and repair, their developmental lineage and diversity remain undefined. In simplified differentiations from human pluripotent stem cells, derived CPECs (dCPECs) displayed canonical properties and dynamic multiciliated phenotypes that interacted with Aß uptake. Single dCPEC transcriptomes over time correlated well with human organoid and fetal CPECs, while pseudotemporal and cell cycle analyses highlighted the direct CPEC origin from neuroepithelial cells. In addition, time series analyses defined metabolic (type 1) and ciliogenic dCPECs (type 2) at early timepoints, followed by type 1 diversification into anabolic-secretory (type 1a) and catabolic-absorptive subtypes (type 1b) as type 2 cells contracted. These temporal patterns were then confirmed in independent derivations and mapped to prenatal stages using human tissues. In addition to defining the prenatal lineage of human CPECs, these findings suggest new dynamic models of ChP support for the developing human brain.