Engineering Novel 3D Models to Recreate High-Grade Osteosarcoma and its Immune and Extracellular Matrix Microenvironment.

Osteosarcoma (OS) is the most common primary bone cancer, where the overall 5-year surviving rate is below 20% in resistant forms. Accelerating cures for those poor outcome patients remains a challenge. Nevertheless, several studies of agents targeting abnormal cancerous pathways have yielded disappointing results when translated into clinic because of the lack of accurate OS preclinical modeling. So, any effort to design preclinical drug testing may consider all inter-, intra-, and extra-tumoral heterogeneities throughout models mimicking extracellular and immune microenvironment. Therefore, the bioengineering of patient-derived models reproducing the OS heterogeneity, the interaction with tumor-associated macrophages (TAMs), and the modulation of oxygen concentrations additionally to recreation of bone scaffold is proposed here. Eight 2D preclinical models mimicking several OS clinical situations and their TAMs in hypoxic conditions are developed first and, subsequently, the paired 3D models faithfully preserving histological and biological characteristics are generated. It is possible to shape reproducibly M2-like macrophages cultured with all OS patient-derived cell lines in both dimensions. The final 3D models pooling all heterogeneity features are providing accurate proliferation and migration data to understand the mechanisms involved in OS and immune cells/biomatrix interactions and sustained such that engineered 3D preclinical systems will improve personalized medicine.

Together Intra-Tumor Hypoxia and Macrophagic Immunity Are Driven Worst Outcome in Pediatric High-Grade Osteosarcomas.

BACKGROUND: Osteosarcomas (OTS) represent the most common primary bone cancer diagnosed in adolescents and young adults. Despite remarkable advances, there are no objective molecular or imaging markers able to predict an OTS outcome at diagnosis. Focusing on biomarkers contributing broadly to treatment resistance, we examine the interplay between the tumor-associated macrophages and intra-tumor hypoxia. METHODS: Radiological and immunohistochemical (IHC) data were correlated with the outcome in a retrospective and monocentric cohort of 30 pediatric OTS. We studied hypoxic (pS6, phospho-mTor, HIF-1α and carbonic anhydrase IX (CAIX)) and macrophagic (CD68 and CD163) biomarkers. RESULTS: The imaging analyses were based on MRI manual volumetric measures on axial post-contrast T1 weighted images, where, for each tumor, we determined the necrotic volume and its ratio to the entire tumor volume. When they were above 50 cm3 and 20%, respectively, they correlated with a worse overall survival (p = 0.0072 and p = 0.0136, respectively) and event-free survival (p = 0.0059 and p = 0.0143, respectively). IHC assessments enable a significant statistical link between HIF-1α/CAIX hyper-expressions, CD68+ cells and a worse outcome, whereas activation of mTor pathway was linked to a better survival rate and CD163+ cells. CONCLUSIONS: This study evidenced the links between hypoxia and immunity in OTS, as their poor outcome may be related to a larger necrotic volume on diagnostic MRI and, in biopsies, to a specific IHC profile.

Anatomical fixation of tibial intercondylar eminence fractures in children using a threaded pin with an adjustable lock.

INTRODUCTION: Tibial intercondylar eminence fractures are a rare pathology causing anterior laxity of the knee, which requires anatomical reduction and a stable osteosynthesis. The aim of this study was to present the clinical results of reinsertion in anatomical position of these fractures, in the paediatric population, using a threaded pin with an adjustable lock. HYPOTHESIS: Our hypothesis was that the clinical results would be satisfactory and comparable to the literature. METHOD: This retrospective, monocentric study involved 34 consecutive patients with tibial intercondylar eminence fractures, divided into 55.9% with type 2, 35.2% with type 3, 8.8% with type 4 according to Meyers & McKeever, operated on between March 1999 and March 2018. Assessments were performed at a minimum follow-up of 1-year and included the Lysholm, subjective International Knee Documentation Committee (IKDC) and Tegner activity scores, and the measurement of anterior knee laxity by the KT1000. RESULTS: At the average follow-up of 8.8 years, 7 patients were lost to follow-up, 2 required anterior cruciate ligament reconstruction. Pathological residual laxity was present in 25% of cases and instability in 16%. The average Lysholm score was 93.1±9.8, the average subjective IKDC was 93.8±6.4 and the average Tegner score was 5.6±1.5. The average anterior laxity of the knee was 0.7±2.0mm. CONCLUSION: The anatomical reinsertion using a threaded pin with an adjustable lock for tibial intercondylar eminence fractures in a paediatric population provides good functional results and is comparable to the data in the literature. LEVEL OF EVIDENCE: IV; retrospective.

Functional outcome following closed reduction and percutaneous osteosynthesis of distal tibia articular fractures in children.

Closed reduction and percutaneous osteosynthesis is an alternative to the open procedure for articular fractures of distal tibia of children. 38 patients were retrospectively reviewed. The measured parameters were : the score of Gleizes and the discrepancies between preoperative radiographic and CT scan measurements and postoperative radiographs. A significant correlation was found between the gap and the step-off in preoperative radiographic and CT scan. A significant decrease of the gap and step-off displacement was noticed after surgery. The Gleizes scoring showed 35 good results, 2 average results and 1 poor result. Percutaneous fixation of ankle articular fractures in children is a simple and effective treatment giving similar results to open techniques while minimizing the risk of joint stiffness and healing complications. Growth complications are comparable with both techniques.

Outpatient paediatric arthroscopy: A retrospective study in 216 Patients.

BACKGROUND: Outpatient surgery is now widely performed in adults but remains rarely used for paediatric orthopaedic procedures. As with adult surgery, both the arthroscopic equipment and anaesthesia techniques have improved over the last few years. Arthroscopy is particularly well advanced at the knee but can also be used at other joints (hip, ankle, elbow, shoulder). The primary objective of this study was to evaluate the feasibility of outpatient paediatric arthroscopy. HYPOTHESIS: Arthroscopic surgery can be performed in children on an outpatient basis provided an appropriate care programme is applied. MATERIALS AND METHODS: This single-centre retrospective study included 216 patients aged 3.8 to 18 years who underwent outpatient arthroscopy (knee, n=170; ankle, n=22; elbow, n=12; shoulder, n=6; and hip, n=6). The decision to perform the procedure on an outpatient basis was made with the patient during the surgeon visit then confirmed during the anaesthesiologist visit. The main outcome measure was failure of outpatient arthroscopy defined as a need for standard inpatient admission. The secondary outcome measures were pain or sleep disturbances on the day after the procedure (as assessed during a telephone call), a need to see a physician during the first week after the procedure, and patient satisfaction. RESULTS: Of the 216 patients, 9 required overnight admission (4 because of vomiting, 4 because of pain, and 1 because of a malaise) and 2 patients were admitted elsewhere for postoperative pain then discharged within 24hours. Of the 160 patients who could be contacted on the day after the procedure, 141 (88%) said they had had a good night and 141 (88%) that they had little or no pain. Over 95% of patients were satisfied with their outpatient management. DISCUSSION: As with adults, arthroscopic surgery is an ideal indication for outpatient care in paediatric patients. Outpatient arthroscopic surgery is already widely used at the knee and is also suitable for other joints in the paediatric population. LEVEL OF EVIDENCE: IV, retrospective study.