Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation.

Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of advanced GCTB. Since then, several reports have questioned the role of denosumab during occasional malignant transformation of GCTB. We report on three patients with H3F3A-mutated GCTBs, treated with denosumab. The tissue samples were analysed by histomorphology, immunohistochemistry, and in two instances by next generation panel sequencing of samples before and after treatment. One patient had a mutation of ARID2 in the recurrence of the GCTB under treatment with denosumab. One patient developed a pleomorphic sarcoma and one an osteoblastic osteosarcoma during treatment. Sequencing revealed a persisting H3F3A mutation in the osteosarcoma while the pleomorphic sarcoma lost the H3F3A mutation; however, a FGFR1 mutation, both in the recurrence and in the pleomorphic sarcoma persisted. In addition, the pleomorphic sarcoma showed an AKT2 and a NRAS mutation. These data are inconclusive concerning the role denosumab plays in the event of malignant progression/transformation of GCTB and point to diverging pathways of tumor progression of GCTB associated with this treatment.

Long-Term Clinical Outcomes of Intercalary Allograft Reconstruction for Lower-Extremity Bone Tumors.

BACKGROUND: Improved survival rates for patients with primary bone tumors of the extremities have increased the demand for reliable and durable reconstruction techniques. Some authors have stated that, after successful ingrowth, allografts are a durable long-term solution. This hypothesis is largely based on small studies with short-to-midterm follow-up. In order to determine the durability of intercalary allograft reconstructions in the lower extremities, we evaluated the long-term clinical outcomes at a minimum of 10 years. METHODS: All patients who received an intercalary allograft reconstruction in a lower extremity between 1980 and 2006 were included in this retrospective multicenter cohort study. One hundred and thirty-one patients with a median age of 19 years were included. Eighty-nine (68%) had a femoral reconstruction, and 42 (32%) had a tibial reconstruction. The most prevalent diagnoses were osteosarcoma (55%), Ewing sarcoma (17%), and chondrosarcoma (12%). The median follow-up was 14 years. A competing risk model was employed to estimate the cumulative incidences of mechanical failure and infection. Patient mortality or progression of the disease was used as a competing event. RESULTS: Nonunion occurred in 21 reconstructions (16%), after a median of 16 months, and was associated with intramedullary nail-only fixation (p < 0.01) and fixation with nonbridging plate(s) (p = 0.03). Allograft fracture occurred in 25 reconstructions (19%) after a median of 42 months (range, 4 days to 21.9 years). Thirteen (52%) of the allograft fractures occurred within 5 years; 8 (32%), between 5 and 10 years; and 4 (16%), at >10 years. With failure for mechanical reasons as the end point, the cumulative incidences of reconstruction failure at 5, 10, and 15 years were 9%, 14%, and 21%, respectively. CONCLUSIONS: Intercalary allograft reconstruction is an acceptable reconstructive option, mainly because of the absence of superior alternatives with a known track record. However, a considerable and continuing risk of mechanical complications should be taken into account. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Failure rates and functional results for intercalary femur reconstructions after tumour resection.

PURPOSE: To compare the results for patients treated with intercalary endoprosthetic replacement (EPR) or intercalary allograft reconstruction for diaphyseal tumours of the femur in terms of: (1) reconstruction failure rates; (2) cause of failure; (3) risk of amputation of the limb; and (4) functional result. METHODS: Patients with bone sarcomas of the femoral diaphysis, treated with en bloc resection and reconstructed with an intercalary EPR or allograft, were reviewed. A total of 107 patients were included in the study (36 EPR and 71 intercalary allograft reconstruction). No differences were found between the two groups in terms of follow-up, age, gender and the use of adjuvant chemotherapy. RESULTS: The probability of failure for intercalary EPR was 36% at 5 years and 22% for allograft at 5 years (p = 0.26). Mechanical failures were the most prevalent in both types of reconstruction. Aseptic loosening and implant fracture are the main cause in the EPR group. For intercalary allograft reconstructions, fracture followed by nonunion was the most common complication. Ten-year risk of amputation after failure for both reconstructions was 3%. There were no differences between the groups in terms of the mean Musculoskeletal Tumor Society score (27.4, range 16-30 vs. 27.6, range 17-30). CONCLUSIONS: We have demonstrated similar failure rates for both reconstructions. In both techniques, mechanical failure was the most common complication with a low rate of limb amputation and good functional results. LEVEL OF EVIDENCE: Level III, therapeutic study.

Modular prosthesis reconstruction after tumour resection, evaluation of failures and survival. / Reconstrucción con prótesis modulares posterior a una resección oncológica. Evaluación de los fracasos y análisis de la supervivencia.

OBJECTIVE: To analyze a series of patients with bone tumours reconstructed with modular prostheses and to evaluate: 1) Survival of the implant. 2) Causes of failure. 3) Complication rates. 4) Limb salvage overall survival. 5) Functional results and full weight bearing. MATERIALS AND METHODS: A retrospective study from longitudinally maintained oncology databases was undertaken. All patients with bone tumours reconstructed with endoprosthesis were analysed. A toal of 106patients matched the inclusion criteria. They were divided into groups: group 1, primary bone tumours; group 2, bone metastasis; group 3, osteoarticular allograft reconstruction revisions. The type of failures were classified according to Henderson et al. (2014) and functional results assessed by the Musculoskeletal Tumor Society (MSTS). Demographic analysis, survival and the differences between groups were recorded. RESULT: The mean follow-up of the patients was 68 months. Mean age was 43 years. Overall implant survival was 86.4% at 2 years (95% CI: 79-94) and 73% at 5 years (95% CI: 60-80). Nineteen patients (18%) developed a prosthetic failure. The limb salvage overall survival was 96% at 5 years (95% CI: 91-99). The mean functional results according to the MSTS was 24 and mean time to full weight bearing was 2.3 weeks. CONCLUSIONS: Limb conservation surgery and endosprosthetic reconstruction is a valid option for patients with bone tumours with failure rates similar to other reconstruction methods.

Proximal humerus chondrosarcoma.Long-term clinical and oncological outcomes. / Condrosarcoma de húmero proximal. Resultados clínicos y oncológicos a largo plazo.

INTRODUCTION: The proximal humerus is a common site for primary bone sarcomas, of which chondrosarcoma represents 15%. There are few reports about this select group of tumours. We set out to analyse a group of patients with proximal humerus chondrosarcoma treated with surgery and to assess their long term surgical and oncological outcomes. MATERIAL AND METHODS: A retrospective review was performed and all patients with a proximal humerus chondrosarcoma treated with surgery were included in the study. Overall survival and local recurrence rates were analyzed. Post-operative complications were recorded and limb salvage surgery failures classified according to the Henderson classification. RESULTS: 37 patients were included in the study. The median age was 46 years (SD: 15.6, range: 17-24), 24 (65%) were female and the mean follow-up was 8.5 years (SD: 6.4, range: 2 -26). Eighteen patients were classified as grade 1 (49%), 15 as grade 2 (40%), 2 as grade 3 (5%) and 2 dedifferentiated chondrosarcomas (5%). The 10-year overall survival was 94.5% and the 10-year event-free survival was 84.5%. Five patients developed local recurrences (13%) and none of them was grade 1. The reconstruction failure rate was 27% at 5 years and 34% at 10 years. There were no complications or local recurrence in patients treated with curettage. CONCLUSION: Proximal humerus chondrosarcoma presented high survival rates. Curettage and bone grafting is a safe procedure, with low risk of complications and local recurrence for grade 1 chondrosarcomas and should be the first indication for the proximal humerus. Reconstruction of the proximal humerus after a wide resection has a 5-year failure rate of 27% and 10-year failure rate of 34%.

In Vitro Comparative Study Between Conventional and Computer-Assisted Surgery Methods for Planning and Resection of Bone Sarcomas.

This poster aims to achieve an "in vitro" comparative study between three methods: 2D digital images planning and execution without navigation (freehand with ruler and caliper), 3D planning and execution without navigation (freehand with ruler and caliper) and 3D planning and execution guided with navigation. 3D planning and navigated procedures potentially improve sarcoma resection.

Structural allograft reconstruction of the foot and ankle after tumor resections.

BACKGROUND: Structural allografts have been used to correct deformities or to fill bone defects secondary to tumor excisions, trauma, osteochondral lesions, or intercalary arthrodesis. However, the quality of published evidence supporting the use of allograft transplantation in foot and ankle surgery has been reported as fair. The purpose of this study was to report the overall survival of structural allograft in the foot and ankle after tumor resection, and the survival according to the type of allograft and the complication rates in the medium to long term. MATERIALS AND METHODS: From January 1989 to June 2011, 44 structural allograft reconstructions of the foot and ankle were performed in 42 patients (28 men and 14 women) due to musculoskeletal tumor resections. Mean age at presentation was 27 years. Mean follow-up was 53 months. Demographic data, diagnosis, site of the neoplasm, operations performed, operative complications, outcomes after surgery, date of last follow-up evaluation, and local recurrences were reviewed for all patients. Regarding the type of 44 allograft reconstructions, 16 were hemicylindrical allografts (HA), 12 intercalary allografts (IA), 10 osteoarticular allografts (OA), and 6 were total calcaneal allograft (CA). RESULTS: The overall allograft survival rate, as calculated with the Kaplan-Meier method, at 5 and 10 years was 79 % (95 % CI 64-93 %). When allocated by type of allograft reconstruction the specific allograft survival at 5 and 10 years was: 83 % for CA, 80 % for HA, 77 % for OA, and 75 % for IA. The complications rate for this series was 36 % including: articular failure, local recurrence, infection, fracture and nonunion. CONCLUSION: This study showed that structural allograft reconstruction in the foot and ankle after tumor resection may be durable with a 79 % survival rate at 5 and 10 years. The two types of allografts that showed better survival rate were hemicylindrical allografts (80 %) and calcaneus allografts (83 %). The highest complication rates occurred after calcaneus allografts and osteoarticular allografts. LEVEL OF EVIDENCE: IV.

Oncologic and clinical outcomes in pelvic primary bone sarcomas treated with limb salvage surgery.

PURPOSE: We propose to study a group of patients with primary bone sarcoma of the pelvis treated with limb salvage surgery and analyze overall survival, local recurrence rates and functional outcomes. METHODS: A retrospective review was performed, and all patients diagnosed with pelvic primary bone sarcomas between 1990 and 2012 were analyzed. Patients treated with limb salvage surgery and with a minimum of 12-month follow-up for patients alive were included. The overall survival and the local recurrence rate were calculated for the assessment of oncological results. The associations with gender, age, histological grade, type of surgery, margins chemotherapy response and use of navigation were examined. RESULTS: Fifty-two patients were included in the study. The mean age was 37 years (range 10-82), and mean follow-up was 44 months (range 8-189). Forty-five (86 %) tumors were histologically classified as high-grade sarcomas, four (8 %) as low-grade sarcomas and three (6 %) as dedifferentiated sarcomas. Cancer-specific overall survival was 37.5 % for 5 years and 31 % for 10 years. Local recurrence rate was 30 %. High-grade tumors and chemotherapy necrosis below 90 % were negative prognosis factor. Postoperative complication rate was 34.5 % (n:18), being deep infection the most prevalent (n:13). Reconstruction of the pelvis after an oncology resection for primary pelvic sarcomas increased the incidence of complication significantly (p < 0.001). CONCLUSION: Primary bone sarcomas involving the pelvis are suggestive of a high-grade tumor and present poor oncologic outcomes. Pelvic reconstruction after a limb salvage surgery is associated with a high risk of complication. LEVEL OF EVIDENCE: Case series, Level IV.

Tratamiento quirúrgico de los tumores malignos y localmente agresivos del tercio proximal del peroné. Resultados oncológicos y evaluación funcional / Surgical treatment of locally aggressive and malignant tumors of the proximal third of the fibula. Oncology results and functional evaluation

Introducción. Los tumores óseos malignos o benignos localmente agresivos del tercio proximal del peroné son infrecuentes y generalmente su tratamiento es quirúrgico. Cuando se requiere una resección en bloque, la estabilidad de la rodilla puede comprometerse por afectación del complejo posterolateral. Material y métodos. Se analizaron 28 pacientes operados de manera consecutiva por un tumor óseo en el tercio proximal de peroné entre los años 1980 y 2006 (osteosarcoma: 9, TCG: 9, sarcoma de Ewing: 8 y condrosarcoma: 2). El 61% eran varones y la edad media fue de 21 años (rango: 8-60). El seguimiento promedio fue de 86 meses. El complejo posterolateral fue reinsertado a nivel de la metáfisis tibial. Los pacientes fueron evaluados funcionalmente con la escala Musculoskeletal Tumor Society (MSTS). Resultados. La supervivencia global fue del 89%, con un índice de recidiva local del 11% y un porcentaje de amputaciones secundarias del 6% a los 7 años de seguimiento promedio. El resultado promedio del MSTS fue del 93%. Cinco pacientes sufrieron secuelas neurológicas, 3 de tipo permanente. Ningún paciente sufrió inestabilidad subjetiva ni insuficiencia vascular. Conclusiones. La resección en bloque del peroné proximal en el tratamiento de los tumores óseos agresivos o malignos depara un buen control local de la enfermedad y una supervivencia a los 7 años, en los casos malignos, del 89%. La reinserción del complejo posterolateral a nivel tibial supone una buena estabilidad de la rodilla, sin secuelas funcionales a largo plazo (AU)

Introduction. Proximal fibula malignant and locally aggressive benign bone tumors are uncommon and usually treat by surgery. Bloc resection of the knee can compromise knee stability due to of the resection of the posterolateral ligament complex. Material and methods. We analyzed 28 consecutive patients treated for a proximal fibula bone tumor between 1980 and 2006 (osteosarcoma: 9, giant cell tumor: 9, Ewing sarcoma: 8 and chondrosarcoma: 2). Sixty-one percent were male and the median age was 21 years (range: 8-60). The mean follow-up was 86 months. The posterolateral complex was reinserted at tibial metaphyseal level. Patients were evaluated functionally using the Musculoskeletal Tumor Society scale (MSTS). Results. Overall survival rate was 89%, local recurrence rate was 11%, and secondary amputation rate was 6% at 7 years of median follow-up. The average MSTS score was 93%. Five patients had neurological complications. No patient experienced subjective instability or vascular insufficiency. Conclusions. Bloc resection of the proximal fibula for the treatment of aggressive or malignant primary bone tumors allowed us to obtain local tumor control, and overall survival rate for sarcomas of 89% at 7 years. The posterolateral ligament complex tibial reinsertion provided functional knee stability without major functional consequences in the medium term (AU)

[Surgical treatment of locally aggressive and malignant tumors of the proximal third of the fibula. Oncology results and functional evaluation]. / Tratamiento quirúrgico de los tumores malignos y localmente agresivos del tercio proximal del peroné. Resultados oncológicos y evaluación funcional.

INTRODUCTION: Proximal fibula malignant and locally aggressive benign bone tumors are uncommon and usually treat by surgery. Bloc resection of the knee can compromise knee stability due to of the resection of the posterolateral ligament complex. MATERIAL AND METHODS: We analyzed 28 consecutive patients treated for a proximal fibula bone tumor between 1980 and 2006 (osteosarcoma: 9, giant cell tumor: 9, Ewing sarcoma: 8 and chondrosarcoma: 2). Sixty-one percent were male and the median age was 21 years (range: 8-60). The mean follow-up was 86 months. The posterolateral complex was reinserted at tibial metaphyseal level. Patients were evaluated functionally using the Musculoskeletal Tumor Society scale (MSTS). RESULTS: Overall survival rate was 89%, local recurrence rate was 11%, and secondary amputation rate was 6% at 7 years of median follow-up. The average MSTS score was 93%. Five patients had neurological complications. No patient experienced subjective instability or vascular insufficiency. CONCLUSIONS: Bloc resection of the proximal fibula for the treatment of aggressive or malignant primary bone tumors allowed us to obtain local tumor control, and overall survival rate for sarcomas of 89% at 7 years. The posterolateral ligament complex tibial reinsertion provided functional knee stability without major functional consequences in the medium term.

[Survival and complications analysis of 97 patients with bone metastases treated surgically]. / Análisis de sobrevida y complicaciones en 97 pacientes con metástasis óseas tratados quirúrgicamente.

BACKGROUND: The purpose of this paper is to assess the survival and the different factors predisposing to increased local and overall complications in a group of patients treated surgically for bone metastases. MATERIAL AND METHODS: A total of 97 patients were included in our study, 45 females and 52 males. Mean age was 59 years (range 22-81) and the mean follow-up was 23 months (range 3-76). Were performed 104 surgical interventions. Patient survival was estimated with the Kaplan-Meier method. Complications, recurrences and the most significant factors were analyzed. RESULTS: Overall patient survival was 73% at one year, 47% at 2 years, and 6% at 5 years. Patient survival was greater in patients with a histologic diagnosis of metastatic renal cancer (p > 0.05) and a higher incidence of local relapses (p > 0.05). Intralesional surgery significantly affected the relapses. CONCLUSIONS: Patients with metastatic renal cancer had the greatest survival rate. However, they were associated with a higher rate of local relapses and postoperative failure.

Survivorship and radiographic analysis of knee osteoarticular allografts.

An evaluation of long-term survival and radiographic deterioration of 118 knee osteoarticular allografts in 114 patients was performed. Radiographic analysis was done according to the Musculoskeletal Tumor Society grading system. A failure was defined as when the allograft was removed during a revision procedure or amputation. Ten patients were lost to followup during the first 2 years after surgery. Eighteen patients without allograft failures died of complications related to the tumor. Twenty-six allografts failed because of infection (13 allografts), local recurrence (eight allografts), massive resorptions (three allografts) and fractures (two allografts). Sixty-four allografts still were in place at a mean of 98 months (range, 36-360 months) after implantation. The Kaplan-Meier 5-year survival rate for the knee osteoarticular allografts was 73% and the limb preservation rate was 93%. The mean radiographic score was 83%. Sixty-four percent of the allografts showed no radiologic changes or minor articular deterioration. Fourteen percent had narrowing of the joint space of more than 2 mm, and 22% had some form of subchondral bone collapse. Five patients required joint resurfacing to preserve the original allograft. Most of the allograft failures occurred during the first 4 years, and the allograft survival rate for the current series remained unchanged after 5 years.