Surgical management of proximal femoral unicameral bone cyst in children.

Aims: The aim of this study is to evaluate the surgical treatment with the best healing rate for patients with proximal femoral unicameral bone cysts (UBCs) after initial surgery, and to determine which procedure has the lowest adverse event burden during follow-up. Methods: This multicentre retrospective study was conducted in 20 tertiary paediatric hospitals in France, Belgium, and Switzerland, and included patients aged < 16 years admitted for UBC treatment in the proximal femur from January 1995 to December 2017. UBCs were divided into seven groups based on the index treatment, which included elastic stable intramedullary nail (ESIN) insertion with or without percutaneous injection or grafting, percutaneous injection alone, curettage and grafting alone, and insertion of other orthopaedic hardware with or without curettage. Results: A total of 201 patients were included in the study. The mean age at diagnosis was 8.7 years (SD 3.9); 77% (n = 156) were male. The mean follow-up was 9.4 years (SD 3.9). ESIN insertion without complementary procedure had a 67% UBC healing rate after the first operation (vs 30% with percutaneous injection alone (p = 0.027), 43% with curettage and grafting (p = 0.064), and 21% with insertion of other hardware combined with curettage (p < 0.001) or 36% alone (p = 0.014)). ESIN insertion with percutaneous injection presented a 79% healing rate, higher than percutaneous injection alone (p = 0.017), curettage and grafting (p = 0.028), and insertion of other hardware combined with curettage (p < 0.001) or alone (p = 0.014). Patients who underwent ESIN insertion with curettage had a 53% healing rate, higher than insertion of other hardware combined with curettage (p = 0.009). The overall rate of postoperative complications was 25% and did not differ between groups (p = 0.228). A total of 32 limb length discrepancies were identified. Conclusion: ESIN insertion, either alone or combined with percutaneous injection or curettage and grafting, may offer higher healing rates than other operative procedures. Limb length discrepancy remains a major concern, and might be partly explained by the cyst's location and the consequence of surgery. Therefore, providing information about this risk is crucial.

Management and outcomes of adolescent and young adult sarcoma patients: results from the French nationwide database NETSARC.

BACKGROUND: The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. PATIENTS AND METHODS: NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15-30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. RESULTS: Among 3,227 patients aged 15-30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3-83.6) in AYA in RSC and 82.7% (95%CI 79.4-85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively). CONCLUSIONS: This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Best clinical management of tenosynovial giant cell tumour (TGCT): A consensus paper from the community of experts.

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein.

Intercalary allograft reconstruction following femoral tumour resection: mid- and long-term results and benefits of adding a vascularised fibula autograft.

PURPOSE: Bone healing in femoral reconstructions using intercalary allografts can be compromised in a tumour context. There is also a high revision rate for non-union, infection, and fractures in this context. The advantages and disadvantages of an associated vascularised fibula graft (VFG) are still a matter of debate. METHODS: In a multicentre study, we retrospectively analysed 46 allograft reconstructions, operated on between 1984 and 2017, of which 18 were associated with a VFG (VFG+) and 28 without (VFG-), with a minimum follow-up of 2 years. We determined the cumulative probability of bone union as well as the mid- and long-term revision risks for both categories by Kaplan-Meier survival analysis and a multivariate Cox model. We also compared the MSTS scores. RESULTS: Significant differences in favour of VFG+ reconstruction were observed in the survival analyses for the probability of bone union (log-rank, p = 0.017) and in mid- and long-term revisions (log-rank, p = 0.032). No significant difference was observed for the MSTS, with a mean MSTS of 27.6 in our overall cohort (p = 0.060). The multivariate Cox model confirmed that VFG+ was the main positive factor for bone union, and it identified irradiated allografts as a major risk factor for the occurrence of mid- and long-term revisions. CONCLUSION: Bone union was achieved earlier in both survival and Cox model analyses for the VFG+ group. It also reduced the mid- and long-term revision risk, except when an irradiated allograft was used. In case of a tumour, we thus recommend using VFG+ from a fresh-frozen allograft, as it appears to be a more reliable long-term option.

Brachytherapy for Pediatric Patients at Gustave Roussy Cancer Campus: A Model of International Cooperation for Highly Specialized Treatments.

PURPOSE: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. METHODS AND MATERIALS: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. RESULTS: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. CONCLUSIONS: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

Locally aggressive rarely metastazing tumors and low-grade sarcoma in children, adolescents and young adults: The benefits of a national network.

INTRODUCTION: Complete surgical resection constitutes the mainstay of treatment for locally aggressive, rarely metastazing tumor and low-grade soft tissue sarcomas (LAS). Local relapse is the most common tumor event, especially in the presence of positive margins (R1 margins). The aims of this study are to assess the impact of the national network on patient care and to evaluate the role of immediate re-excision in children, adolescents and young adults with incompletely resected LAS. METHODS: National retrospective multicenter study of all young patients (≤25 years) included in the Sarcoma "ConticaBase" treated for LAS between 2005 and 2017 for whom pathology/biology review was available via the national NETSARC + network. RESULTS: A total of 96 patients were identified (median age: 16 years). Tumors were localized in 99% of cases (1 N+ tumor). With a median follow-up of 4.7 years (range: 0.1-11.9), eight local relapses and two distant metastases were observed. No patient died. Overall 5-year event-free survival (EFS) was 90.4% [95%CI, 84.3-97]. Five year EFS for R1 patients (n = 51) with (n = 24) and without (n = 27) immediate re-excision was 90.5% [95%CI, 78.8-100.0] and 80.3% [95%CI, 64.7-99.9], respectively (p = 0.34). The 37 patients directly treated in a reference center more commonly had a diagnostic biopsy (78% vs. 21%; p < 0.001), more complete surgery (R0: 65% vs. 14%; p < 0.001) and less commonly underwent re-excision (16% vs. 54%; p < 0.001). CONCLUSIONS: This large series indicates that LAS are rare in young patients and have a favorable prognosis. Immediate management in reference centers is associated with better standard of care. The main tumor events are local relapses.

Long-term outcomes of non-invasive expandable endoprostheses for primary malignant tumors around the knee in skeletally-immature patients.

INTRODUCTION: Expandable endoprostheses are used to restore limb function and compensate for the sacrifice physis involved in carcinologic resection. Long-term outcomes of the last generation of knee "non-invasive" expandable endoprostheses are required. Objectives were to report on oncologic results of bone sarcoma resection around the knee with expandable endoprosthesis reconstruction and to compare the surgical outcomes of the "non-invasive" expandable endoprostheses used in our department. MATERIALS AND METHODS: Retrospective study that included all children with bone sarcoma around the knee that underwent tumor resection reconstructed with non-invasive expandable prosthesis. Phenix-Repiphysis was used from 1994 to 2008 followed by Stanmore JTS non-invasive from 2008 to 2016. Survival and complications were recorded. Functional outcomes included Musculoskeletal Tumor Society (MSTS) score, knee range of motion, lower limb discrepancy (LLD). RESULTS: Forty children (Sex Ratio = 1) aged a mean 8.8 years (range, 5.6-13.8) at surgery were included in the study. There were 36 osteosarcoma and 4 Ewing sarcoma that involved 33 distal femur and 7 proximal tibia. Cohort (n = 40) consisted of 28 Phenix-Repiphysis and 12 Stanmore with a mean follow-up of 9.8 ± 5.8 years and 6.1 ± 3.1 years, respectively. Postoperative infection rate was 7.5% in the cohort (3 Repiphysis). Functional results were significantly better in the Stanmore group with a mean MSTS of 87.6 ± 5.4% and knee flexion of 112 ± 38°. At last follow-up, implant survival was 100% in Stanmore group, whereas all living Phenix-Repiphysis were explanted. Mechanical failure was the primary cause for revision of Phenix-Repiphysis. Limb length equality was noted in 79% patients with Phenix-Repiphysis and 84% with Stanmore at last follow-up. CONCLUSION: Chemotherapy and limb-salvage surgery yield good oncologic outcomes. Expandable endoprostheses are effective in maintaining satisfactory function and lower limb equality. With improvements made in the last generation of "non-invasive" prostheses, implants' survival has been substantially lengthened.

Lower limb reconstruction for malignant bone tumours in children.

Malignant bone tumours of the lower limb represent the majority of cases in both osteosarcoma and Ewing sarcoma in the growth period. Surgical treatment represents a key element of treatment. Different localizations and age groups require a differentiated surgical approach. Life and limb salvage are first on the list of treatment goals, followed by functional and cosmetic considerations. This review article delivers and discusses current surgical treatment strategies and outcomes for lower limb malignant bone tumours in children.

Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment?

Biological and histopathological techniques identified osteoclasts and macrophages as targets of zoledronic acid (ZA), a therapeutic agent that was detrimental for patients in the French OS2006 trial. Conventional and multiplex immunohistochemistry of microenvironmental and OS cells were performed on biopsies of 124 OS2006 patients and 17 surgical ("OSNew") biopsies respectively. CSF-1R (common osteoclast/macrophage progenitor) and TRAP (osteoclast activity) levels in serum of 108 patients were correlated to response to chemotherapy and to prognosis. TRAP levels at surgery and at the end of the protocol were significantly lower in ZA+ than ZA- patients (padj = 0.0011; 0.0132). For ZA+-patients, an increase in the CSF-1R level between diagnosis and surgery and a high TRAP level in the serum at biopsy were associated with a better response to chemotherapy (p = 0.0091; p = 0.0251). At diagnosis, high CD163+ was associated with good prognosis, while low TRAP activity was associated with better overall survival in ZA- patients only. Multiplex immunohistochemistry demonstrated remarkable bipotent CD68+/CD163+ macrophages, homogeneously distributed throughout OS regions, aside osteoclasts (CD68+/CD163-) mostly residing in osteolytic territories and osteoid-matrix-associated CD68-/CD163+ macrophages. We demonstrate that ZA not only acts on harmful osteoclasts but also on protective macrophages, and hypothesize that the bipotent CD68+/CD163+ macrophages might present novel therapeutic targets.

[Musculoskeletal tumour surgery for adolescent and young-adult population: Collaboration between adult and pediatric surgeons is necessary]. / Collaboration pédiatre-adulte dans la chirurgie des tumeurs musculosquelettiques.

Orthopaedic surgery I has a key role on the medical pathway of adolescent and young-adult (AYA) patients with musculo-skeletal tumor from diagnosis, tumor resection, musculo-skeletal immediate or delayed reconstruction, to dealing with late complications and sequelae following reconstruction during childhood. Administrative authorizations, organization by health authorities as well as training courses are quite different for adult and pediatric surgery. However, surgery for musculo-skeletal tumors in AYA patients have neither adult nor pediatric specifities; resection-reconstruction rules and technics are the same for adult or pediatric patients, with nevertheless lower complication rate and more biologic reconstructions for the youngest, and more prosthetic reconstructions for the oldest. Late complications after bone and soft-tissue reconstructions in childhood and musculo-skeletal deformation after surgery and/or radiotherapy in childhood need the vision from "adult" orthopaedic teams for long and very long term success of the surgical project with a good knowledge of pediatric technics previously used. Thus, formal shared time and transition care are necessary between pediatric and adult surgical teams to prepare long-term follow-up of these childhood cancer survivors. Participation to the same specialized Multi-Disciplinary Board, scientific society gathering adult and pediatric surgeons, clinical trials with no age-limitation might help to erase barriers and to ease collaboration between adult and pediatric ortho-oncologic teams.

Clinical and radiological results of vascularized fibular epiphyseal transfer after bone tumor resection in children.

INTRODUCTION: Vascularized fibular proximal epiphyseal transfer associated to a diaphyseal segment is used to treat childhood epiphyseal defect. The aim of the present study was to analyze surgical technique and long-term clinical and radiological results. MATERIAL AND METHOD: Between 1997 and 2008, 7 patients with a mean age of 5.7 years (range, 2-8 years) were operated on for bone malignancy with vascularized fibular epiphyseal transfer: 5 Ewing sarcomas and 2 osteosarcomas, located in the proximal femur (n=3), proximal humerus (n=3) or distal radius (n=1). Mean transplant size was 13.8cm. Vascularization involved a single artery in 5 cases (3 peroneal, 2 anterior tibial) and both in 2 cases. Internal fixation used intramedullary nailing in 6 cases and screwed plate in 1. All patients underwent pre- and post-operative chemotherapy following French Pediatric Oncology Society (SFOP) protocols. RESULTS: Mean follow-up was 11 years (range, 3 years 11 months to >17 years). All patients were alive and in tumor remission. Reconstructed joint function was satisfactory in 85% of cases. Graft thickening indicated integration in all cases. The transferred cartilage had recovered growth in 4 cases. Complications comprised postoperative infection (n =1), consolidation defects (n = 2), fractures (n = 8), malalignment requiring surgical revision (n = 1), and spontaneously resolving common peroneal nerve palsies (n = 2). DISCUSSION: In young children, vascularized fibular epiphyseal transfer fills bone defect, reconstructs a functional joint and allows continued growth in the resected segment. Growth prostheses, in the authors' experience, always give poor results in this age-group, and fusion fails to address the growth problem. Patients should be informed about the risk of fracture, persisting over the long term. CONCLUSION: Vascularized fibular epiphyseal transfer is a difficult technique, subject to complications, but enables reconstruction of a bone segment involving the epiphysis in young children, conserving function and growth. LEVEL OF EVIDENCE: III, retrospective clinical study.

Expandable distal femur megaprosthesis: A European Musculoskeletal Oncology Society study on 299 cases.

BACKGROUND AND OBJECTIVES: Expandable distal femur prostheses have become more popular over the last decades, but scientific data is limited. METHODS: A retrospective study was performed, including cases treated between 1986 and 2019 in 15 European referral centers for bone sarcomas. RESULTS: A total of 299 cases were included. Average follow-up was 80 months (range, 8-287 months). Mean patient age was 10 years. Most (80%) of the implants were noninvasive growers and a fixed hinge knee was used more often (64%) than a rotating hinge. Most prosthetic designs showed good (>80%) implant survival at 10 years, but repeat surgery was required for 63% of the patients. The most frequent reason for revision procedure was the completion of lengthening potential. Noninvasive expandable implants showed less risk of infection compared to invasive growers (11.8% vs 22.9% at 10 years). No difference in aseptic loosening was found between cemented and uncemented stems. CONCLUSIONS: This study shows the increasing popularity of expandable distal femur prostheses, with overall good results for function and implant survival. However, repeat surgery is frequently required, especially in patients under the age of 10 years old. Infection is less frequent in noninvasive growers compared to implants that require invasive lengthening procedures.

Percutaneous alcohol-based sclerotherapy in aneurysmal bone cyst in children and adolescents.

INTRODUCTION: Aneurysmal bone cyst (ABC) is a benign bone lesion of childhood and adolescence. It can be locally aggressive, with risk of fracture. Management is controversial. The aim of the present study was to assess the efficacy, simplicity and tolerance of percutaneous alcohol-bases sclerotherapy in ABC. HYPOTHESIS: Alcohol-based sclerotherapy for ABC under radiographic control is safe and effective. MATERIAL AND METHODS: A single-center retrospective study for the period 2008-2016 included all of the 55 ABCs, in 54 patients, confirmed on pathology and treated by alcohol-based sclerotherapy under radiographic control. Mean age at diagnosis was 9.6 years. ABC involved the humerus in 30 cases (54%), tibia in 7 (13%) and femur in 5 (9%). Mean follow-up was 50.9 months (range, 16-117 months). Mean number of applications was 1.7 (range, 1-4). Results were assessed clinically (pain, return to sport, limb length and alignment, revision surgery) and radiologically. The main endpoint was lesion volume reduction. The secondary endpoint was failure, defined by open revision surgery or pain preventing return to a sports activity. RESULTS: Clinical progression was favorable in 36 patients (67%), and radiological progression in 45 (85%). Only 1 cyst required secondary resection. One patient experienced spontaneously resolving intraoperative bradycardia. Male gender and young age emerged as factors for poorer response. DISCUSSION: ABC management in children can be made difficult by lesion size, aggressiveness, location, proximity to the growth plate and small bone stock. Alcohol-based sclerotherapy is simple, reliable and effective in childhood ABC, and may be a first-line attitude, avoiding recourse to invasive surgery. LEVEL OF EVIDENCE: IV, retrospective study.

Difficulties of Management of Multiple Synchronous Bone Tumors in Li-Fraumeni Syndrome.

Li-Fraumeni syndrome is a rare inherited disease characterized by the early onset of multiple primary malignant tumors. Sarcomas account for more than 30% of all malignant tumors occurring at pediatric age. Furthermore, it was shown that the rates of second cancer were higher in childhood cancer survivors. We report the case of a patient with Li-Fraumeni syndrome who was referred to us with three synchronous skeletal tumors. This unique situation led to difficulties for the medical team regarding the diagnosis of malignancy and the surgical treatment to propose. The discovery of multiple lesions in the extension assessment underlines the usefulness of whole-body imaging for the follow-up of patients with germline TP53 mutations. Most recent guidelines now recommend annual whole-body MRI for screening for cancer patients carrying germline TP53. With this report, we aim to share our experience with this rare situation in order to improve care about these specific cases.

Assessment of resection margins in bone sarcoma treated by neoadjuvant chemotherapy: Literature review and guidelines of the bone group (GROUPOS) of the French sarcoma group and bone tumor study group (GSF-GETO/RESOS).

BACKGROUND: Standardized reports are essential to meeting the bone sarcoma reference center certification requirements of the French National Cancer Institute (INCa). The usual classifications of the Musculoskeletal Tumor Society (MSTS), the American Joint Committee on Cancer (AJCC/IUCC) TNM R classification and the American College of Pathologists, are inexact inasmuch as they fail to include chemotherapy impact on tumor cells in assessing surgical margins. This leads to inconsistent interpretation by teams managing bone sarcoma. The present literature analysis sought to assess the limitations of existing classifications for purposes of standardized reporting of the management of surgical specimens from patients with osteosarcoma or Ewing sarcoma receiving neoadjuvant chemotherapy, by addressing the following questions: 1) What is the prognostic value of margins and chemotherapy response in the classifications? 2) What are the histologic changes induced by chemotherapy, with what impact on interpretation of margins? METHOD: A PubMed literature analysis was performed, targeting the prognostic value of resection margin assessment, in September 2018. French bone pathology group (Groupe français des pathologistes osseux) and international guidelines on bone specimen management were referred to so as select items for a standardized report. Eight of the 523 articles retrieved met the study eligibility criteria. RESULTS: Minimal distance between tumor and surgical margin, with a>2mm threshold, seemed to be the optimal parameter for predicting local recurrence. Good chemotherapy response and appendicular skeletal location were associated with lower risk of local recurrence. None of the available classifications take into account the microscopic changes induced by chemotherapy in interpreting resection margins. DISCUSSION: To standardize practice, GROUPOS developed a standardized report for bone sarcoma specimens, considering the histopathologic changes in the tumor after neoadjuvant chemotherapy. The TNM R system was adapted and a threshold of>2mm was chosen as an acceptable limit to qualify surgical resection as safe (R0). R1 status (≤2mm) was subdivided into subgroups a, b and c, to include margin measurement in relation to the post-chemotherapy scar: R1a, resection within the scar; R1b, resection in healthy tissue,≤2mm from the scar and/or residual viable cells; and R1c, resection within the lesion in contact with viable cells or within coagulation necrosis areas. The GROUPOS members drew up this standardized report so as to ensure a common language, improving bone sarcoma management in specialized centers. Reliable data can thus be established for national and international multicenter studies. LEVEL OF EVIDENCE: IV.

Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study.

BACKGROUND: In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014. METHODS: Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate. RESULTS: 409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7-24.5), with 55 patients aged 18-25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51-62%) and overall survival 71% (66-76%). CONCLUSION: M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.

CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for the therapeutic stratification of osteosarcoma patients: An immunohistochemical analysis of the biopsies fromthe French OS2006 phase 3 trial.

The French phase 3 trial (OS 2006) testing zoledronic acid, an osteoclast inhibitor, with chemotherapy and surgery did not improve the outcome of patients with osteosarcoma (OS). To understand this unexpected result, the presence of infiltrating immune cells was investigated in 124 pre-therapeutic biopsies of patients enrolled in the trial. The percentage of CD68/CD163 tumor-infiltrating macrophages (TAMs), CD8+ lymphocytes, osteoclasts, and the PD1/PDL-1 checkpoint were assessed by immunohistochemistry. M1/M2 macrophage polarization was characterized by pSTAT1/CMAF staining. The expression of these biomarkers was correlated with clinical outcome. No statistical correlations were found with response to chemotherapy. High CD163 levels (>50% of cells per core; 43.8% of patients) were associated with CMAF nuclear expression and significantly correlated with better overall survival (p = 0.0025) and longer metastasis progression-free survival (MPFS, p = 0.0315) independently of metastatic status (p = 0.002). Only a trend was observed for patients with high CD68-positive cells (p = 0.0582). CD8+ staining was positive in >50% of cases with a median staining of 1%. Lower CD8+ levels were associated with metastatic disease at diagnosis and the presence of CD8-positive cells significantly correlated with improved overall survival in zoledronate-treated patients (p = 0.0415). PD1/PDL-1 staining was negative in >80% of cases and was not correlated with outcome. Finally, CD163-positive TAMs and CD8 positive cells are crucial prognostic biomarkers in OS, whereas PD1/PDL-1 checkpoint plays a minor role. For the first time, we described a correlation between CD8 positive cells and survival in zoledronate-treated patients. The immunohistochemical analysis of the microenvironment in biopsies may represent a novel tool for therapeutic stratification.

Long-term functional and radiological outcomes of allograft hip prosthesis composite. A fourteen -year follow-up study.

PURPOSE: Allograft hip composite prosthesis (APC) is a type of reconstruction after resection of the proximal femur. This study aimed to assess long-term outcomes after an APC reconstruction. MATERIALS AND METHODS: Forty-six patients were retrospectively included (14 revision total hip replacements, 30 primary malignant bone tumors, two metastasis). RESULTS: The mean length of femoral bone resection was 16.4 cm (7 to 27). With a mean follow-up of 14.7 years (6.3 to 32.6), Postel-Merle d'Aubigné score was 15.7 (8 to 21), Musculoskeletal Tumor Society score at 23.1 or 77% (15 to 29), and abductor strength at 3.4 (2 to 5). Allograft resorption was minor for 20 patients (44.4%), moderate for 13 patients (28.9%), and severe for 12 patients (26.7%). Host-allograft shaft bone fusion was achieved in 37 cases (84.1%). Trochanteric fracture occurred in 26 cases (59.1%). Length of femoral resection, allograft bone resorption, and trochanteric fracture did not have an effect on functional outcomes. At ten years follow-up, overall revision-free and femoral stem survivals were 54.1 ± 0.8% and 81.4 ± 0.6% respectively. No parameter evaluated influenced the survivorship. CONCLUSION: APC is a reliable reconstruction adapted for huge proximal femoral bone resections. Trochanteric fracture and allograft bone resorption do not seem to influence functional results. LEVEL OF EVIDENCE: Level IV.

Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Based on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma. METHODS: In this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18-25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18-25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223. FINDINGS: Between April 23, 2007, and March 11, 2014, 318 patients, median age 15·5 years (range 5·8-50·9), were enrolled from 40 French centres; of whom 158 were assigned to the control group (chemotherapy alone) and 160 to the zoledronate group, including 55 (17%) patients with definite metastases. The trial was stopped for futility after the second interim analysis. With a median follow-up of 3·9 years (IQR 2·7-5·1), 125 events occurred (55 in the control group and 70 in the with zoledronate group). Event-free survival at 3 years for all 315 randomly assigned patients was 60·3% (95% CI 64·5-65·9); 3-year event-free survival was 63·4% (55·2-70·9) for the control group and 57·1% (48·8-65·0) for the zoledronate group. The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group (hazard ratio [HR] 1·36 [95% CI 0·95-1·96]; p=0·094). No major increase in severe toxic effects of grade 3 or higher associated with zoledronate, barring expected hypocalcaemia (45 [29%] of 153 participants in the zoledronate group vs ten [6%] of 155 participants in the control group; p<0·0001) and hypophosphataemia (61 [40%] of 151 in the zoledronate group vs 26 [17%] of 156 in the control group; p<0·0001). No significant difference in orthopaedic complications was noted between the two groups (27 in the control group and 29 in the zoledronate group). Two treatment-related deaths were reported (one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion). INTERPRETATION: From the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data. FUNDING: French National Cancer Institute (INCa), Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l'Enfant.

[Secondary orthopaedic complications after childhood tumors of the musculoskeletal system]. / Les séquelles orthopédiques après tumeurs de l'appareil locomoteur.

BACKGROUND: Multidisciplinary care, modern care management, and medical progress have brought significant gains in modern survival rates for children and adolescents with tumors of the musculoskeletal system. OBSERVATIONS: The surgical approach must rest on the consideration of the long-term orthopedic sequelae likely to be caused by the elected treatment (limb amputation versus limb conservation - reconstruction choices), as well as by adjuvant therapies, such as chemotherapy or radiotherapy. Complications due to allograft reconstructions (infections, fractures, pseudoarthritis) occur within the range of 0 to 36 months. After 36 months, allograft longevity is fair, but 10 years later, 60% of grafts are likely to have failed and been removed. Joint prostheses have overall survival rates of 75% over 10 years, and 52% over 20 years. As for allografts, infectious complications occur within the first few years, while later prosthetic replacements are mostly due to mechanical causes. Assessing the long-term evolution of biological reconstructions proves a lot more challenging, due to the lack of hindsight and available information, except for vascularized fibula grafts, which show good long-term results. Numerous medical reviews have been published that address the quality of life of children treated for malignant tumors of the musculoskeletal system. They mostly consist in comparative studies between limb conservation and limb amputation, and point to similar results overall. Such data must be taken into account when deciding on a treatment for a child or an adolescent: quality of life, the function of the affected limb, the probable need for re-operation all encourage to favor reconstructions whenever they are possible, as they come closest to normal anatomy. CONCLUSION: Too frequently, medical knowledge remains fragmented among multiple disciplines, because of the difficulty of organizing follow-up over the very long-term. Progress can only be achieved by setting-up multidisciplinary care pathways between pediatric surgeons and surgeons treating adult patients.