Search

Osteosarcoma, the most common primary malignant tumour of bone, affects both children and adults. No fundamental biological differences between paediatric and adult osteosarcoma are known. Here, we apply multi‐region whole‐genome sequencing to an index case of a 4‐year‐old child whose aggressive tumour harboured high‐level, focal amplifications of MYC and CCNE1 connected by translocations. We reanalysed copy number readouts of 258 cases of high‐grade osteosarcoma from three different cohorts and identified a significant enrichment of focal MYC, but not CCNE1, amplifications in children. Furthermore, we identified four additional cases of MYC and CCNE1 coamplification, highlighting a rare driver event which warrants further investigation. Our findings indicate that amplification of the MYC oncogene is a major driver of childhood osteosarcoma, while CCNE1 appears recurrently amplified independent of age.

Background: Adult survivors of childhood osteosarcoma and Ewing sarcoma are at risk of developing therapy-related chronic health conditions. We characterized the cumulative burden of chronic conditions and health status of survivors of childhood bone sarcomas. Methods: Survivors (n = 207) treated between 1964 and 2002 underwent comprehensive clinical assessments (history/physical examination, laboratory analysis, and physical and neurocognitive testing) and were compared with community controls (n = 272). Health conditions were defined and graded according to a modified version of the NCI's Common Terminology Criteria for Adverse Events and the cumulative burden estimated. Results: Osteosarcoma and Ewing sarcoma survivors [median age 13.6 years at diagnosis (range 1.7–24.8); age at evaluation 36.6 years (20.7–66.4)] demonstrated an increased prevalence of cardiomyopathy (14.5%; P < 0.005) compared with controls. Nearly 30% of osteosarcoma survivors had evidence of hypertension. By age 35 years, osteosarcoma and Ewing sarcoma survivors had, on average, 12.0 (95% confidence interval, 10.2–14.2) and 10.6 (8.9–12.6) grade 1–4 conditions and 4.0 (3.2–5.1) and 3.5 (2.7–4.5) grade 3–4 conditions, respectively, compared with controls [3.3 (2.9–3.7) grade 1–4 and 0.9 (0.7–1.0) grade 3–4]. Both survivor cohorts exhibited impaired 6-minute walk test, walking efficiency, mobility, strength, and endurance (P < 0.0001). Accumulation of ≥4 grade 3–4 chronic conditions was associated with deficits in executive function [RR: osteosarcoma 1.6 (1.0–2.4), P = 0.049; Ewing sarcoma 2.0 (1.2–3.3), P = 0.01] and attention [RR: osteosarcoma 2.3 (1.2–4.2); P = 0.008]. Conclusions: Survivors of osteosarcoma and Ewing sarcoma experience a high cumulative burden of chronic health conditions, with impairments of physical function and neurocognition. Impact: Early intervention strategies may ameliorate the risk of comorbidities in bone sarcoma survivors.

The aim of the present study was to evaluate the efficiency and side effects of mifamurtide in childhood osteosarcoma (OS). In total, 477 doses of 2 mg/m intravenous (IV) mifamurtide, along with paracetamol as a premedication, were given to 15 patients with primary nonmetastatic OS after complete surgical resection and to 3 patients with progressive OS. The most common side effects encountered in the patients were chills and fever (17/18). These reactions were observed in 4 patients during the administration of each dose, in a single patient during the last administration, and in the remaining 12 patients during the first or initial 2 administrations. Headache, myalgia, and arthralgia were observed in 2 patients during each infusion. Headache was observed in 1 patient with additional hearing loss during the first 2 infusions. One patient had back pain occuring within the first infusion. Of the 15 patients with primary nonmetastatic OS and treated with the addition of mifamurtide to chemotherapy, 13 showed a complete remission, and 2 patients were still under treatment with a complete remission. Of 3 patients with progressive disease, 2 died while the disease progressed further in the third case over a 51-month period. The 3-year overall survival and event-free survival distributions were 87.5% (mean follow-up time, 46.12; 95% confidence interval, 37.79-52.45 mo) and 75.6% (mean follow-up time, 31.30; 95% confidence interval, 26.54-36.06 mo), respectively. We consider that mifamurtide therapy is a safe and well-tolerated agent in childhood OS.

Background Epiphyseal-preservation surgery for osteosarcoma is an alternative method which has been indicated carefully to selected patients. The tumor-devitalised autograft treated with liquid nitrogen procedure is one of the biological reconstruction method to reconstruct the defect after tumor excision. The limb length discrepancy is usually appeared in children with their growth after limb-sparing surgery. This study was aimed to investigated the growth of residual epiphysis following epiphyseal-preservation surgery for childhood osteosarcoma around the knee joint. Methods We retrospectively reviewed 12 patients with osteosarcoma who underwent epiphysis preserving tumor excision (8 in distal femur and 4 in proximal tibia) and reconstructed by using tumor-devitalized autograft treated with liquid nitrogen. The mean patient age was 11 (range, 6 to 14) years. The mean follow-up period were 63 (range, 41 to 90) months. Epiphysis transverse growth rate, epiphysis-width discrepancy (EWD) and collapse of epiphysis were evaluated by using pre- and post-operative whole standing leg radiographs. A retrospective chart review was performed to investigate functional outcome, complications and oncological status. Results The mean growth of epiphysis rate was 12.6% (range, 3.3 to 28.0%) of affected side and 12.7% (range, 3.8 to 28.9%) of contralateral side, mean EWD was 0.1 mm (range, − 1.0 to 1.7 mm), mean LLD was + 26.1 mm (range, + 1 to + 48 mm) and two patients with distal femoral reconstruction underwent limb lengthening of tibia. There was no collapse of the residual epiphysis. The mean MSTS score was 27.7 (range, 18 to 30). Conclusions Epiphysis transverse growth was not diminished, and there was absence of epiphyseal collapse even after epiphyseal-preservation surgery in this small series of childhood osteosarcoma around the knee. With careful assessment for epiphyseal tumor involvement, epiphyseal-preservation surgery shall be possible, and could be an alternative method worth considering.

While treatments for childhood osteosarcoma have improved, the overall survival for this common type of bone cancer have not changed for three decades and thus new targets for therapeutic development are needed. To identify tumor-related proteins in osteosarcoma, we used isobaric tags in a relative and absolute quantitation (iTRAQ) proteomic approach to analyze the differentially expressed proteins between osteosarcoma cells and human osteoblastic cells. Through clinical screening and functional evaluation, CCR4-NOT transcription complex subunit 1 (CNOT1) correlated to the growth of osteosarcoma cells. To date, the mechanisms and regulatory roles of CNOT1 in tumors, including osteosarcoma, remain largely elusive. Here, we present evidence that knockdown of CNOT1 inhibits the growth of osteosarcoma in vitro and in vivo. Mechanistically, we observed that CNOT1 interacted with LMNA (lamin A) and functioned as a positive regulator of this intermediate filament protein. The RNA-seq analysis revealed that CNOT1 depletion inhibited the Hedgehog signaling pathway in osteosarcoma cells. A rescue study showed that the decreased growth of osteosarcoma cells and inhibition of the Hedgehog signaling pathway by CNOT1 depletion were reversed by LMNA overexpression, indicating that the activity of CNOT1 was LMNA dependent. Notably, the CNOT1 expression was significantly associated with tumor recurrence, Enneking stage, and poor survival in patients with osteosarcoma. Examination of clinical samples confirmed that CNOT1 expression positively correlated with LMNA protein expression. Taken together, these results suggest that the CNOT1–LMNA–Hedgehog signaling pathway axis exerts an oncogenic role in osteosarcoma progression, which could be a potential target for gene therapy. This article is protected by copyright. All rights reserved.

Supplemental Digital Content is available in the text, Background: In pediatric tumors, immunotherapy exhibits less toxicity than chemotherapy and radiation. The current study aims to identify potential immune targets in immune-related genes of C-C motif chemokine ligand genes (CCLs) and C-C motif chemokine receptors (CCRs) in childhood osteosarcoma (OS) and to explore the underlying molecular mechanisms of childhood OS. Methods: Firstly, we identified immune-related genes in CCLs and CCRs, these genes were used for functional annotation and interaction analysis. Then, the prognostic value of these genes was evaluated using Kaplan-Meier analysis and multivariate COX regression model. And the potential relationship between risk score and immune infiltrating cells was identified. Finally, gene set enrichment analysis was used to determine the underlying molecular mechanism of OS. Immune-related genes in CCLs and CCRs are inextricably linked. Results: The results of survival analysis of these genes show that CCL5, CCL8, CCR4, and CCR5 are significantly associated with the prognosis of childhood OS. The combined effect survival analysis shows that the co-high expression of these 4 genes has a good prognosis for childhood OS. A prognostic signature model was constructed based on the 4 genes mentioned above, and the result of time-dependent receiver operating characteristic curves showed that this model was a good predictor of childhood OS 3- and 5-year prognosis. In addition, the risk score of the constructed prognostic signature model was closely related to immune infiltration. We also found that CCL5, CCL8, and CCR5 may affect the prognosis of OS through complex regulation among Toll-like receptor signaling pathway, mitogen-activated protein kinase (MAPK) family signaling cascade, and nuclear factor-kappaB pathway, whereas CCR4 affects the prognosis of OS by regulating eukaryotic translation. Conclusion: CCL5, CCL8, CCR4, and CCR5 are potential prognostic markers for the prognosis of childhood OS, and the underlying molecular mechanisms of childhood OS have been identified.

Purpose: Osteoporosis is currently receiving particular attention as a sequela in survivors of childhood osteosarcoma. The aim of this study was to evaluate bone mineral density (BMD) changes during methotrexate-based chemotherapy in children and adolescents with osteosarcoma. Methods: Nine patients with osteosarcoma were included in this retrospective study and compared with eight healthy controls. BMD of the lumbar spine and unaffected femur neck of patients was serially measured by dual-energy x-ray absorptiometry (DXA) before and just after chemotherapy and compared with controls. Results: Four patients (44%) showed decreased lumbar spine BMD and seven patients (78%) showed decreased femur neck BMD, while all controls showed increased lumbar and femur BMD (P=0.024 and P=0.023). The femur neck BMD z-scores decreased from −0.49±1.14 to −1.63±1.50 (P=0.032). At the end of therapy, five patients (56%) showed femur neck BMD z-scores below –2.0. Conclusion: The bone metabolism is disturbed during therapy in children with osteosarcoma, resulting in a reduced BMD with respect to healthy controls. Since a reduced BMD predisposes to osteoporosis, specific attention and therapeutic interventions should be considered.

Background: High-dose methotrexate (HD-MTX) is recognized as an efficient component of therapy against pediatric osteosarcoma in combination with other drugs such as cisplatin (CDP), carboplatin (CBDCA), doxorubicin (ADM), etoposide (VP-16) and ifosfamide (IFO). Objectives: To demonstrate the feasibility and effectiveness of the HD-MTX/CDP/DOX/VP-16/IFO [MTX(+)] protocol comparable to CDP/ADM/CBDCA/IFO [MTX(-)] for treating childhood osteosarcoma at Ramathibodi Hospital (1999-2014). Materials and Methods: A retrospective analysis was conducted of osteosarcoma patients aged less than 18 years treated with two chemotherapeutic regimens between 1999 and 2014. A total of 45 patients received the MTX(-) and 21 the MTX(+) protocol. Results: Overall limb-salvage and amputation rate were 12.9% and 77.7%, respectively. KaplanMeier analysis results for 3-year disease free survival (DFS) and overall survival (OS) regardless of treatment regimens were 43.4±6.0% and 53.2±6.1% respectively. The 3-year DFS and OS were improved significantly with the MTX(+) protocol compared to MTX(-) protocol (p=0.010 and p=0.009, log rank test) [69.8±10.5%, 79.8±9.1% for MTX(+) and 31.1±6.9%, 42.2±7.4% for MTX(-) protocol, respectively]. Patients with metastatic osteosarcoma treated with the MTX(+) protocol had statistically significant higher 3-year DFS and OS than those treated with the MTX(-) protocol (66.7±13.6% and 15.0±8.0% for 3-year DFS, p=0.010, 73.3±13.2% and 20±8.9% for 3-year OS, p=0.006, respectively). The independent risk factors for having inferior 3-year DFS and OS were poor histological response (tumor necrosis

miRNAs have been identified as key regulators of almost all cellular processes, therefore, their dysregulation is involved with several diseases, including cancer. miRNAs specifically related to the metastastic cascade are called metastamiRs and can be involved with different steps of this process, including loss of adhesion. Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor that often presents metastatic disease at diagnosis; therefore, a deeper study of adhesion-associated miRNAs could shed light on its pathophysiology. Online databases were used to select four miRNAs (miR-139; miR-181b; miR-584; miR-708) predicted or validated to target proteins related to adherent junctions and focal adhesion pathways, and their expression levels and possible associations with clinical features evaluated in primary OS samples. Our results showed downregulation of miR-139-5p and miR-708-5p in OS samples compared to non-neoplastic controls. Moreover, lower expression of miR-708-5p was associated with poor overall survival and higher expression of miR-181b-5p related to worst chemotherapy response (low HUVOS level). Based on these results, we selected miR-139-5p and miR-708-5p for further functional testing. Inducing the expression of miR-139-5p diminished the clonogenic capacity of the HOS cell line, while upregulation of miR-708-5p was related to a lower cellular adhesion. In summary, this work identified new signatures of microRNA dysregulation that may serve as useful prognostic markers in this aggressive pediatric bone tumor.

High-grade osteosarcomas are the most common primary malignant tumors of bone. With complete surgical resection and multi-agent chemotherapy up to 70% of patients with high-grade osteosarcomas and localized extremity tumors can become long-term survivors. The prognosis, however, is poor for patients with nonresectable, primary metastatic or relapsed disease. Outcome is essentially unchanged for three decades. Herein, we describe selected novel insights into the genomics, biology and immunology of the disease and discuss selected strategies, which hold promise to overcome the current stagnation in the therapeutic success in childhood osteosarcoma.

The purpose of this article is to report on the development, indication, and clinical outcome of extendible endoprostheses for the management of osteosarcomas in the skeletally immature patients after resection of major growth plates in conjunction with limb-salvage surgery. The first generation of extendible endoprostheses appeared in the late 1970s. They were invasive, and open lengthening procedures were required. Several subsequent modifications have yielded the endoprostheses capable of lengthening through less invasive methods to minimize the risk of complications. An extendible endoprosthesis should be applied for the skeletally immature patients when the estimated leg length discrepancy at skeletal maturity is expected to be more than 3 cm or when the arm length discrepancy will be more than 5 cm. Prosthetic reconstruction is well received emotionally and cosmetically. Furthermore, even if additional revision surgeries are required, extendible endoprostheses provide good functional outcome in skeletally immature children with osteosarcomas. However, the patients and their families must be carefully selected with an emphasis on motivation and acceptance, since rather frequent and substantial treatment during follow-up is inevitably required. In the future, improvements in the surgical techniques and endoprosthetic designs are needed to diminish the number of complications.

The purpose of this study was to examine the association between fluoride levels in public drinking water and childhood and adolescent osteosarcoma in Texas; to date, studies examining this relationship have been equivocal. Using areas with high and low naturally occurring fluoride, as well as areas with optimal fluoridation, we examined a wide range of fluoride levels in public drinking water. This was a population-based case–control study, with both cases and controls obtained from the Texas Cancer Registry. Eligible cases were Texas children and adolescents

We evaluate the incidence of second neoplasms in 86 patients with osteosarcoma (OS) of the extremities treated with different protocols of adjuvant chemotherapy. Three patients developed phyllodes tumors as the second neoplasm. One of these patients simultaneously developed a third cancer with therapy-related acute myeloid leukemia. The sites of primary OS were the tibia (2) and humerus (1). None had received prior radiotherapy before excision of phyllodes tumor. All the patients were female with a median age of 21.7 years at the time of presentation. As yet, that precise causation is unclear, but it can increase our understanding of carcinogenic processes, in general.

e22010 Background: There are only few data concerning efficiency and toxicity of mifamurtide in children with osteosarcoma (OS). The aim of this study was to evaluate efficiency and side effects of mifamurtide in childhood OS. Methods: We retrospectively analyzed the data of 18 patients with OS and who received mifamurtide between January 2012 and December 2016. Four hundred seventy seven doses of 2 mg/m2intravenous mifamurtide, along with paracetamol premedication were given in 15 patients with primary non-metastatic OS after complete surgical resection and 3 patients with progressive OS. Results: There were 11 males and 7 females, and the median age was 14 years (ranged, 9-18). The median follow-up time was 20 months (ranged, 7-51). The metaphyseal plates around the knee was the most frequent disease location with 94.4%. The median necrosis percentage was 94 (range, 35-100). All patients received Euromos protocol. The most common side effects were chills and fever (17/18). These reactions were observed in 4 patients during every administration, in only one patient at last administration and in the remaining 12 patients during first or first two administration. Headache, myalgia and arthralgia were observed in 2 patients during every infusion. In another one case, headache was observed during only first two infusions and he also hearing loss was developed (could be related CisPlatin) Back pain was observed in two patient during first infusion but one them suffered with severe back pain after few doses and stoped Mifamurtid. . Grade 3-4 neutropenia, trombocytopenia, abnormal liver enzymes and abnormal BUN and creatinin levels were not observed in patients who received mifamurtide alone after completion of chemotherapy. Of the 15 patients with primary non-metastatic OS treated with the addition of mifamurtide to chemotherapy, 13 showed complet remission for median 24 months (ranged,16-36) and 2 patients are still under treatment with complet remission. Of the 3 patients with progressive disease, 2 died and 1 had progressive disease for 51 months. Conclusions: Mifamurtide therapy is safe and well tolerated in childhood OS. Chills and fever were the major side effects, These events were transient and often no longer observed in subsequent administrations.

Differences in incidence and survival in osteosarcoma reports are considerable worldwide.This study describes the incidence and survival of patients with osteosarcoma in Argentina with data from the National Pediatric Cancer Registry (ROHA), and the impact of age, gender, stage, regional, and socioeconomic indicators on outcome.Pediatric patients with osteosarcoma reported to ROHA from 2000 through 2013 were analyzed, the annual age-standardized incidence rate (ASR) was calculated using the National Vital Statistics, and survival was estimated. The extended human development index (EHDI) for each reporting region was used as an indicator of socioeconomic status.There were 515 cases of osteosarcoma identified, yielding an ASR of 3.2/1,000,000 children (0-14 years old). The ASR did not vary significantly by year of diagnosis but ranged from 4.0/1,000,000 in the Cuyo/Western Central region to 2.7/1,000,000 in the northeast region (P0.000). The estimated 5-year survival rate was 45% (95% confidence interval [CI] 44-51%), with no difference by sex, diagnosis year, region, or EHDI score (P0.1 in all cases). Survival rate for localized disease was 52% (95% CI 45-57%) and for metastatic 22% (95% CI 15-30%).In Argentina, ASR of osteosarcoma is similar to that in high-income countries, but survival is lower in all regions. Future work will focus on identification and reduction of causes of preventable treatment failure.

In an 11-year-old boy with osteosarcoma in the proximal tibia (type iii), 2 cycles of dia chemotherapy (cisplatin, ifosfamide, doxorubicin) were administered preoperatively while epiphysiolysis was performed. Clinical response was determined to be complete by radiography and histopathology. Marginal excision was then performed with preservation of the proximal tibial epiphysis. Metaphyseal reconstruction was performed using distraction osteogenesis. Six cycles of dia chemotherapy were administered postoperatively. Twenty months later, the patient had developed no complications and experienced full bone healing, with no limb discrepancy. In selected adolescent patients with osteosarcoma, in whom the tumour is in full contact with the epiphysis, epiphyseal preservation by epiphysiolysis and reconstruction by distraction osteogenesis can provide an excellent outcome, resulting in a stable reconstruction that functionally restores the native limb.

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.

A 16-year-old Caucasian male was diagnosed with a primitive neuroectodermal tumor (PNET) five years following the diagnosis of nonmetastatic osteosarcoma of the left proximal humerus. The patient was initially treated with standard chemotherapy and limb salvage resection for osteosarcoma. Nine months after the completion of therapy, he developed lung metastases for which he underwent surgical resection and received additional chemotherapy. Almost five years after the osteosarcoma diagnosis, the patient was diagnosed with a supratentorial PNET, which represents the first known case reported in a patient with osteosarcoma.

Background: Surgical management of osteosarcoma of the limb in childhood often involves extensive surgery. Intervention ranges from local resection to amputation depending on the level and the extent of the disease process. However, where the disease is extensive the level of amputation may preclude effective prosthetic use. In these circumstances resection of the diseased segment of the limb, i.e. an intercalary amputation and reconstruction with rotation of the tibial component of the limb can provide function equivalent to a below-knee amputee. Methods: To examine the role of rotationplasty of the lower limb for childhood osteosarcoma of the femur, a retrospective study was carried out which examined the function of five patients who had been treated by a tibial rotationplasty. The records of two patients who had died from metastatic disease 2 and 4 years after surgery were examined. The three surviving patients were examined clinically and their clinical records and radiographs were reviewed. Results: Of the two patients who died from metastatic disease, neither had local recurrence of the tumour, neurovascular complications, late derotations or psychological problems. In the three patients who survived, there had been no local recurrence of tumour or other complication and each has an excellent level of activity with below-knee function using a rotationplasty prosthesis. Conclusions: For children with osteosarcoma of the femur and with extensive disease that precludes complete limb preservation, resection and tibial rotationplasty provides function far superior to a high above-knee amputation or a hip disarticulation without the risk of local recurrence.

Background: Osteosarcoma is the most common primary bone tumor in childhood and adolescence. Carboplatin, a platinum-derived agent, is used as neoadjuvant chemotherapy for pediatric osteosarcoma because of its anti-tumor activity and had low toxicity as compared to cisplatin. Objective: To determine demographic data, prognostic factors and outcome of childhood osteosarcoma treated with a carboplatin-based chemotherapeutic protocol at Chiang Mai University. Method: A retrospective analysis was conducted on 34 osteosarcoma patients aged less than 18 years and treated between 2003 and 2011. Results: Overall limb-salvage and amputation rates were 23.5% and 70.6%, respectively. With the mean follow-up time of 29.5 months (1.5-108.9), the Kaplan-Meier analysis for 3-year disease-free survival (DFS) and 3-year overall survival (OS) were 20.2±7.7% and 47.1±9.5% respectively. Patients who had initial pulmonary metastasis were at significantly greater risk for developing recurrence (p=0.02, OR=7; 1.2-40.1) and had a tendency to have lower 3-year OS compared to those without initial pulmonary metastasis (28.1±13%, 63.1±12.3%, respectively, p=0.202). On univariate analysis, age at diagnosis >14 years and patients who were declined surgery were significantly associated with lower 3-year OS (p=0.008 and

e22501Background: Treatment results of heavily pretreated refractory childhood osteosarcoma are not satisfactory. According to the data of different pilot trials progression-free survival (PFS) cur...

Importance This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma. Objective To examine neurocognitive, neurobehavioral, emotional, and quality-of-life outcomes in long-term survivors of childhood osteosarcoma. Design, Setting, and Participants Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls. Main Outcomes and Measures Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03. Results Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (−0.21 [95% CI, −0.32 to −0.10] vs 0.05 [95% CI, −0.13 to 0.23]; P = .01), attention (−0.78 [95% CI, −1.32 to −0.24] vs 0.24 [95% CI, −0.07 to 0.55]; P = .002), memory (−0.24 [95% CI, −0.48 to 0] vs 0.27 [95% CI, −0.08 to 0.62]; P = .01), and processing speed (−0.15 [95% CI, −0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03]; P P = .48), median clearance (estimate = −0.11; P = .76), and median/cumulative exposure (estimate = 0; P = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory ( t = 2.93; P = .006) and slower processing speed ( t = 3.03; P = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24; P = .05) and processing speed (estimate = 0.34; P = .005). Conclusions and Relevance Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.

Primary osteosarcoma of skull base is extremely rare. We present a case of primary osteosarcoma arising in greater wing of sphenoid in a child. Our patient had an incomplete excision after which he received adjuvant chemotherapy and radiotherapy. There was good response to adjuvant chemoradiotherapy and the patient is disease free at a follow-up of 18 months. Treatment of skull base osteosarcomas is difficult, as complete excision is often not possible. To the best of our knowledge, this is the first case of sphenoid wing osteosarcoma in childhood to be reported in literature.

General Aspects of Osteosarcoma.- The Epidemiology of Osteosarcoma.- The Etiology of Osteosarcoma.- Imaging Assessment of Osteosarcoma in Childhood and Adolescence: Diagnosis, Staging, and Evaluating Response to Chemotherapy.- Osteosarcoma Multidisciplinary Approach to the Management from the Pathologist's Perspective.- Conditions that Mimic Osteosarcoma.- Treatment.- Surgical Management of Primary Osteosarcoma.- The Role of Radiotherapy in Oseosarcoma.- Osteosarcoma Lung Metastases Detection and Principles of Multimodal Therapy.- Surgical Treatment of Pulmonary Metastases from Osteosarcoma in Pediatric and Adolescent Patients.- Non-Surgical Treatment of Pulmonary and Extra-pulmonary Metastases.- Review of the Past, Impact on the Future.- Adjuvant Chemotherapy in Osteosarcoma.- Osteosarcoma: Review of the Past, Impact on the Future. The American Experience.- Osteosarcoma: The European Osteosarcoma Intergroup (EOI) Perspective.- The Treatment of Nonmetastatic High Grade Osteosarcoma of the Extremity: Review of the Italian Rizzoli Experience. Impact on the Future.- Osteosarcoma: The COSS Experience.- Treatment of Osteosarcoma. The Scandinavian Sarcoma Group Experience.- Childhood Osteosarcoma: Multimodal Therapy in a Single-Institution Turkish Series.- International Collaboration is Feasible in Trials for Rare Conditions: The EURAMOS Experience.- Pediatric and Adult Osteosarcoma: Comparisons and Contrasts in Presentation and Therapy.- Supportive Care and Quality of Life.- The Role of Physical Therapy and Occupational Therapy in the Rehabilitation of Pediatric and Adolescent Patients with Osteosarcoma.- Caring for Children and Adolescents with Osteosarcoma: A Nursing Perspective.- Prosthetics for Pediatric and Adolescent Amputees.- Functional, Psychosocial and Professional Outcomes in Long-Term Survivors of Lower-Extremity Osteosarcomas: Amputation Versus Limb Salvage.- Research and Investigation: New and Innovative Strategies.- Bridging the Gap Between Experimental Animals and Humans in Osteosarcoma.- Is There a Role for Immunotherapy in Osteosarcoma?.- Molecular Classification of Osteosarcoma.- Current Concepts on the Molecular Biology of Osteosarcoma.- How the NOTCH Pathway Contributes to the Ability of Osteosarcoma Cells to Metastasize.- The Role of Fas/FasL in the Metastatic Potential of Osteosarcoma and Targeting this Pathway for the Treatment of Osteosarcoma Lung Metastases.- Bone Marrow Micrometastases Studied by an Immunomagnetic Isolation Procedure in Extremity Localized Non-metastatic Osteosarcoma Patients.- Strategies to Explore New Approaches in the Investigation and Treatment of Osteosarcoma.- History of Orthopedic Oncology in the United States.

Between January 1990 and December 2006, 123 patients or=90%) was significantly correlated with the 5-year EFS (31% vs. 67.6%, respectively, p=0.023) but not with OS (57.7% vs. 76.5%, respectively, p=0.13). The presence of metastases at diagnosis was found to be the most significant single characteristic influencing the outcome. The rate of histologically good response to preoperative chemotherapy was 64.5%, which is comparable with the 28-85% response rates given in the literature. Our results demonstrate that the combination of epirubicin, cisplatin, and ifosfamide is an active and reasonably well-tolerated regimen for childhood osteosarcoma.

Osteosarcomas (OS) are aggressive tumors of the bone and often have a poor prognosis. The tumors exhibit karyotypes with a high degree of complexity, which has made it difficult to determine whether any recurrent chromosomal aberrations characterize OS. To address inherent difficulties associated with classical cytogenetic analysis, comparative genomic hybridization (CGH) was applied to OS tissue. Forty-one pediatric OS specimens were analyzed by a CGH technique: 24 female and 17 male patients, with a median age of 12 years and 4 months. Chromosomal abnormalities were highly diverse and variable, including gains of chromosome 1p, 2p, 3q, 5q, 5p, and 6p and losses of 14q (50% in 14q11.2), 15q, and 16p. A high level of losses of chromosome 21 was present (26/41 cases; P = 0.008), most often loss of the 21q11.2 approximately 21 region. These novel findings in chromosome 21 of pediatric OS tumors suggest that specific sequences mapping to these chromosomal regions are likely to play a role in the development of OS.

The aim of this study was to assess early (15 min) and late (2 h) thallium-201 (Tl-201) uptake in children with osteosarcoma and to compare these findings with magnetic resonance imaging (MRI) and technetium-99m methylenediphosphonate (Tc-99m MDP), with emphasis on evaluating tumor viability before and after chemotherapy. Fifteen patients with biopsy-proven osteosarcoma received standard preoperative chemotheapy with a combination, of cisplatin, Adriamycin, and high-dose methotrexate. Their ages ranged between 7 and 18 years (median 14.5 years). All patients had Tl-201, Tc-99m MDP, and MRI studies. Thallium scintigraphy was performed at 15 min and 2 h after IV injection of 92 MBq of thallium. Thallium uptake ratio was calculated by dividing the count density of the lesion (L) by that of the controlateral normal (N) area. The percent reduction of Tl-201 uptake ratio (alteration ratio) was calculated by [100 x (prechemotheropy L/N - postchemotherapy L/N)/prechemotherapy L/N]. Pathologic changes were graded on the basis of % tumor necrosis as defined histologically. Scintigraphic comparisons demonstrated a high-degree of correlation with late Tl-201 alteration ratio and poor correlation with both early Tl-201 and Tc-99m MDP alteration ratios. Late Tl-201 images were superior to early Tl-201, Tc-99m MDP, and MRI in predicting tumor response to chemotherapy as determined by % tumor necrosis (p < .01). The authors found that late Tl-201 was an accurate test for evaluating the response to specific therapeutic regimens and it can be useful planning surgery or choosing alternative chemotherapeutic regimens.

Background The feasibility of distal femur epiphysis preservation through epiphyseal distraction by external fixator in childhood osteosarcoma was explored. Methods Between July 2007 and May 2011, 10 children who were suffering from distal femur osteosarcoma received epiphyseal distraction by external fixator, combined with tumor resection and repair with massive allograft bone to preserve the epiphysis of the distal femur and knee function. There were six male and four female patients, 9- to 14-years old (average 10.5 years old). The tumors were staged clinically according to the Enneking staging method: six cases were classified as stage in IIA and four cases as stage in IIB. All patients were diagnosed by biopsy, then received chemotherapy before and after surgery. All patients received tumor bone resection and the defects of the bone were repaired with massive allograft bone that was fixed by intramedullary nails; the distracted epiphysis and allograft bone were fixed with cancellous screws. Results All cases received follow-up from 15 to 56 months (average 38.5 months). There were no local recurrences. One case died of lung metastasis and one case had poor incision healing for rejection of allograft bone. According to the functional evaluation criteria of the International Society of Limb Salvage (ISOLS) after operation, five cases were rated excellent, four cases good and one case fair. The ratio of excellent or good was 90.0%. There was no statistically significant difference in length between the operated and the normal lower limbs during the last review. Conclusions Epiphyseal distraction by external fixator can result in satisfactory limb length and joint function for children with a malignant bone tumor.

This paper presented a case of an eight-year-old boy with osteosarcoma of the femur, in which the affected limb was reconstructed by the rotationplasty. Kotz firstly used the procedure for the treatment of the malignant bone tumor of the femur, which was reported in 1982.The operation was performed, following the Kotz's description. The postoperative course was uneventful, and functional recovery was satisfactory and rather quick. The patient never showed any psychiatric problem. Adjuvant chemotherapy was continued for a year, employing the combination of HD-MTX, ADR, CDDP. There was no local recurrence or distant metastasis for 13 months after the operation.Although its cosmetic result could be stressful for patients, the procedure offers many advantages as follows. The ability of reconstructed limb is functionally equal to below knee amputation and there is no complication of amputation neuroma. Compared with endoprosthetic replacement, there is no chance of prosthetic loosening and breakage. As growth persists in the operated limb, the problem of leg discrepancy can be avoided. In addition, radicality of the procedure is much safer than limb salvage operation.

The concept of salvage surgery in osteosarcoma is based on solid knowledge of the natural history of this disease. Unlike many other solid tumors, sarcomas manifest the peculiar characteristic of organ-restricted spread [1,2]. In most cases, lung metastases are the only site of distant relapse, occurring in 50–80% of osteosarcomas [1,3]. Although, if the cure rates for childhood osteosarcoma have dramatically improved over the last 20 years, lung metastases still remain a major cause of failure, occurring in 40–50% of patients [4] and being refractory to salvage chemotherapy [5, 6, 7]. A summary of the reported results of salvage surgery in osteosarcoma is given in Table 30-1 [8, 9, 10, 11, 12, 13, 14, 15].

The overall results of salvage surgery for lung metastases were evaluated on 174 consecutive patients with primary osteosarcoma below the age of 20, resected in Milan between 1970 and 1988. Seventy-two children treated in the years 1970-1981 were compared with 102 children treated in the years 1982-1988. In the latter period, adjuvant chemotherapy was replaced by neo-adjuvant programs and salvage surgery was applied systematically to all patients with resectable lung metastases through median sternotomy. During the last period, the overall 5 year survival improved significantly from 35% to 58% (P less than 0.001), while the disease free survival rose from 38% to 45% (median 15 vs. 33 months, P = 0.3). The proportion of patients with completely resected lung metastases rose from 17% (7/42) to 55% (27/49), without operative mortality, and the overall survival from detection of lung metastases (including unresected cases) improved from 0 to 28% at 5 years (P less than 0.001). The survival benefit was observed only in the group of children with resected metastases. These data indicate that systematic bilateral pulmonary resection, combined with neoadjuvant chemotherapy, has contributed to improve the final cure rate of childhood osteosarcoma.

10040 Background: Osteosarcoma is the most frequent bone tumor in children and adolescents. The aim of this study is to evaluate the demographic characteristics, therapy, and long term outcome of children with osteosarcoma in a single institution. Methods: Between January 1990 and December 2006, 94 children (53 male, 41 female) with a median age of 13 (5–16) years and a histopathologic diagnosis of osteosarcoma were treated with an institutional chemotherapy regimen comprising of 6 courses (3 pre-, 3 postoperatively) of epirubicin (90 mg/m2), cisplatin(100 mg/m2), and ifosfamide(2 g/m2 × 3 days) every 3 weeks. Results: The median follow-up time was 36 (2–219) months. 68 patients were alive at the time of analysis. 26 patients died; 20 of disease, 5 of toxicity, and 1 of second malignancy (acute myeloid leukemia). 90% of the patients had a limb salvage. 5 and 10 year OS for all patients were 64.7 % ( [95 % CI] 74.8–52.94 %) and 62.2 % (95 % CI 74.6–49.9 %), respectively. 5 and 10 year EFS for all patients was 51.8 % (95% CI 40.2–63.4 %). 5 and 10 year OS for nonmetastatic patients were 78.3 % (95% CI 66.9–89.7 %) and 75.1 %(95% CI 62.6–87.6), vs. 13.5 % 5 year OS for metastatic patients(95% CI 0–30.8 %) (p< 0.001). 5 and 10 year EFS for nonmetastatic patients was superior to those with metastatic disease [62.4 % (95% CI 49.9–79.9 %) vs. 6.9 % (95% CI 0–19.9 %)) (p No significant financial relationships to disclose.

A study is presented of the aetiology and results of treatment in a group of 125 proven osteosarcomas present in children under fifteen years of age. These cases have been collected from the records of one English and six European treatment centres. There is a slight male preponderance, but the striking aetiological feature is the very high proportion of tumours of the long bones of the limbs (96 per cent). The two and a half and five year disease-free survival rates were respectively 15 and 12 per cent, with a further 9 per cent still living, but under observation for less than two and a half years. Evidence of metastasis after two and a half years is very unusual, but no child with a tumour of an axial or girdle bone lived this length of time. Although the differences in the results of the different methods of treatment employed are not statistically valid, the largest number of long survivors had been treated by early amputation, which method also provided the lowest rate of local tumour recurrences. Reasons are discussed which indicate that prompt ablation is the treatment of choice, perhaps with certain advantages in the light of recent advances in adjuvant treatment. The past situation in connection with childhood osteosarcoma certainly provides strong support for immediate carefully designed clinical trials of the new adjuvant methods cited.

A rotation-plasty procedure was used in four children with osteosarcoma of the distal part of the femur. The results showed that this procedure, combined with en bloc wide excision of the proximal part of the tibia and the distal part of the femur including the knee joint, appears to be an adequate surgical treatment for osteosarcoma of the distal part of the femur in children. None of our patients to date had either clinical or radiographic evidence of local recurrence during follow-up periods of between twenty-seven and fifty-eight months. One patient, however, died of widespread metastatic disease. Despite postoperative adjuvant chemotherapy with high doses of methotrexate, there have been no problems with wound-healing and early fitting of a prosthesis was possible. Because of the success in preventing local recurrence in these four patients, we now generally employ this method in the surgical management of osteosarcoma of the distal part of the femur in children.

Methotrexate (MTX) has demonstrated significant activity against relapsed and metastatic osteosarcoma. However, there is little published data to indicate the appropriate dose for MTX when given as a component of a multidrug regimen for the treatment of osteosarcoma. Therefore, the investigators at the Childrens Cancer Study Group undertook a randomized clinical trial that compared Adriamycin and vincristine given with either high-dose methotrexate or moderate-dose methotrexate as postoperation chemotherapy in the treatment of childhood osteosarcoma. We report here the results for 166 patients with completely resected nonmetastatic disease of an extremity. The two therapies demonstrated equivalent disease-free survival (DFS). Further, no therapy prejudices survival after relapse. Approximately 38% of patients remain disease free 4 years after diagnosis. Two relapses occurred in patients free of disease at least 36 months after initiation of treatment. Some factors found by other investigators to be prognostic of poorer DFS, namely, male sex, primary tumor in the humerus or femur, and larger primary tumors, demonstrated similar though not statistically significant trends. The presence of spontaneous necrosis in the tumor sample from the definitive surgery was associated with poor prognosis for DFS. We postulate that this feature represents rapidly growing tumors with increased potential for metastases.

Cette technique, utilisee de plus en plus souvent comme alternative de l'amputation transfemorale ou de la desarticulation de la hanche apres resection d'une tumeur osseuse du membre inferieur, est detaillee. Une petite serie de cas est rapportee et commentee