Alexandre Rochwerger

Prognostic value of the Hippo pathway transcriptional coactivators YAP/TAZ and β1-integrin in conventional osteosarcoma

Introduction Currently, very few studies are available concerning the mammalian Hippo pathway in bone sarcomas. YAP/TAZ transcription co-activators are key downstream effectors of this pathway and may also have oncogenic properties. Additionally, recent in-vitro experiments showed that expression of β1-integrin promoted metastasis in osteosarcomas. This study investigated the expression of YAP/TAZ and β1-integrin in human osteosarcomas. Materials and methods We performed automated immunohistochemistry on tissue-microarrays (TMA) in which 69 conventional osteosarcomas biopsies performed prior to chemotherapy were embedded. Cellular localization and semi-quantitative analysis of each immunostain was performed using Immunoreactive Score (IRS) and correlated to clinico-pathological data. Results Cytoplasmic expression of β1-integrin was noted in 54/59 osteosarcomas (92%), with 33/59 cases (56%) displaying membranous staining. YAP/TAZ was expressed in 27/45 osteosarcomas (60%), with 14 cases (31%) showing cytoplasmic expression while 13 other cases (28%) displayed nuclear expression. No link was found between YAP/TAZ or β1-integrin expression and response to chemotherapy. In univariate analysis, YAP/TAZ immunoreactive score was pejoratively correlated with overall survival (p = 0.01). Expression of β1-integrin on cell membrane was also pejorative for OS (p = 0.045). In multivariate analysis, YAP/TAZ nuclear expression was an independent prognostic factor for PFS (p = 0.035). Conclusion this study indicates that β1-integrin and YAP/TAZ proteins are linked to prognosis and therefore could be therapeutic targets in conventional osteosarcomas.

Adjuvant treatment with zoledronic acid after extensive curettage for giant cell tumours of bone

BACKGROUND Giant cell tumours (GCT) of bone are benign neoplasms associated with a high rate of local recurrence after extensive intra-lesional curettage. Recently, understanding of the biological molecular availability of strong anti-osteoclastic drugs has suggested their potential value in reducing local recurrences after curettage. Through a phase II clinical trial, we investigated the effect of a short treatment with zoledronic acid (ZOL) after intra-lesional curettage of GCT, as well as local recurrence and tolerance of the treatment. METHODS AND PATIENTS Twenty-four patients were enrolled in a multicentre, phase 2 study. The patients were treated with extensive intra-lesional curettage followed by five courses of ZOL (4 mg IV every 3 weeks). The clinical and biological tolerance of each patient was assessed. Patients were reviewed clinically and by X-ray every 6 months until the end of the study (36 months). RESULTS Eighteen out of 20 patients reported side-effects with ZOL, mainly grade 1 and 2 effects. The local recurrence rate was 15%; three patients had a recurrence, one at 4 months (huge GCT of the sacrum), one at 24 months (patient who discontinued the treatment after the first course of ZOL), and one after the observational period, at 58 months. Finally, local relapse-free survival was 82 ± 9% at 60 months. CONCLUSION Short adjuvant treatments with ZOL after extensive intra-lesional curettage of GCT were associated with a low rate of recurrence but did not prevent local recurrence in this study. No serious general adverse effects were observed. More studies are needed to evaluate the potential benefit of medical bisphosphonate injections combined with intra-lesional curettage in the treatment of GCTB.

Amputation versus conservative treatment in severe open lower-limb fracture: a functional and quality-of-life study.

INTRODUCTION Severe lower-limb trauma is a major event in a patients life, and treatment is a challenge that has not been sufficiently studied. The main objective of the present study was to assess the difference in disability between amputees and patients who kept their leg after severe open lower-limb fracture. HYPOTHESIS The study hypothesis was that amputation allows better functional recovery and quality of life, in the same time-frame. MATERIALS AND METHODS All male and female patients aged over 18 years admitted to one of the trauma centers of Marseille (France) for major lower-limb trauma with Gustilo IIIb or IIIc fracture were included. Minimum follow-up was 2 years. Two groups were distinguished according to primary treatment: lower-limb salvage, or amputation. Rates of infection and of surgical revision, hospital stay, functional parameters (walking distance, standing, use of canes, running, jumping, driving, and physical and occupational activity) and quality of life (MOS SF-36 score) were compared between groups. RESULTS The conservative treatment group comprised 27 patients, and the amputation group 24. Rates of infection and of surgical revision and hospital stay were significantly lower in the amputation group (P<0.02). All functional parameters (except return to work) and overall quality of life were significantly better in the amputation group. There was no significant inter-group difference in MOS mental score. CONCLUSION In severe lower-limb trauma, amputation seems to give better functional and quality-of-life results. It did not, however, improve return to work, and was not better accepted psychologically than long and complex conservative management. LEVEL OF EVIDENCE IV, retrospective study.

Free antero-lateral thigh flap for total knee prosthesis coverage after infection complicating malignant tumour resection

BACKGROUND Infection is a common complication of major lower limb-sparing surgery with massive total knee prosthesis (MTKP) reconstruction after extensive tumour resection. When free tissue transfer is required to cover the prosthesis, musculo-cutaneous flaps are usually preferred based on proven efficacy when used in both one-stage and two-stage procedures. The use of a free fascio-cutaneous antero-lateral thigh (FC-ALT) flap in 3 patients with infected knee reconstructions is reported here. MATERIAL AND METHOD A retrospective study was performed of 3 patients in whom a free FC-ALT flap was used during a two-stage procedure to treat MTKP infection after femoral sarcoma resection. RESULTS Free FC-ALT flap transfer and exchange arthroplasty were successful in all 3 patients. Two years after the procedure, no patient had required amputation or experienced recurrent infection. CONCLUSION A free FC-ALT flap can provide adequate coverage of infected MTKP and deserves to be viewed as a valid alternative to free muscle flaps.

Does curettage–cement packing for treating giant cell tumors at the knee lead to osteoarthritis?

INTRODUCTION Giant cell tumors (GCTs) make up 15 to 20% of bone-related tumors in adults. They are often found around the knee in the metaphysis and epiphysis area, contacting the joint cartilage. The aims of our study were to evaluate the presence of early knee osteoarthritis (OA) in patients with GCTs in the knee area treated by curettage-cement packing, and to evaluate whether replacing subchondral bone with acrylic cement has an effect on the functional outcomes and quality of life. MATERIAL AND METHODS This was a retrospective study of all patients operated between 2000 and 2010 by the same specialized surgical team. Functional outcomes and quality of life were evaluated in each patient using the Knee Injury and Osteoarthritis Outcome (KOOS), the Musculoskeletal Tumor Society Score (MSTS) and the Short Form-36 (SF-36). The presence of OA was evaluated in a full radiological work-up comparing the operated knee with the healthy contralateral knee. Knee OA was defined as grade 3 or grade 4 radiographic findings based on the Kellgren and Lawrence classification, and a significant difference between the operated and contralateral knee. RESULTS Nineteen patients were included in this study. The average follow-up was 120 months (range 60-180). Four patients (21%) had radiographic KL-3 and one patient (5%) had KL-4. Eight patients (42%) had recurrence of the GCT. The distance between the tumor and cartilage, and the area of the subchondral bone invaded by the tumor appeared to contribute to OA progression. DISCUSSION Resection of GCTs around the knee by curettage-cement packing did not have an effect on development of OA. In the four patients who developed knee OA, the tumor was located less than 3mm from the joint cartilage and took up more than 90% of the epiphysis. Based on these observations, there seems to be a strong correlation between the development of knee OA and the small quantity of subchondral bone left after curettage. The functional outcomes and quality of life were similar no matter the knee OA grade in patients. Replacing subchondral bone by cement had no effect on quality of life in this study. LEVEL OF EVIDENCE IV (retrospective study).

Management of soft tissue tumors of the musculoskeletal system

A palpable mass in the musculoskeletal system is a common reason for consultation. The main issue is that a malignant tumor must not be missed. Inappropriate initial treatment can have direct consequences on the risk of local recurrence, the patients future function and life expectancy. A mass more than 5cm in diameter, a subfascial location and a recent increase in size are signs that should lead the physician to question whether the lesion is truly benign and to carry out diagnostic examinations. MRI is the gold standard imaging exam. Biopsy, which is now mainly percutaneous and imaging-guided, must be performed for any subfascial mass more than 5cm long or a smaller mass with a high risk of postoperative functional sequelae. Referring the patient to a specialized cancer center has direct benefits on the patients recurrence-free survival and reduces time lost during the diagnostic and treatment phases. For malignant tumors, surgical treatment requires resection margins that comply with cancer guidelines. Preservation of the limb and its function may require multidisciplinary reconstruction techniques. Pre- or post-operative radiation therapy or chemotherapy should be proposed only after discussion in a multidisciplinary team meeting.

Stratégie chirurgicale dans les tumeurs osseuses « du genou »

Distal femur and proximal tibia are the main localization of primary malignant bone tumor. Osteosarcoma and Ewing sarcoma are the most frequent. New techniques in imaging, recent development in chemotherapy protocols and surgery sharpening led to major improvement in their management, which allowed to minimize amputation ratio. The complexity of their treatment and their rarity imply the involvement of multidisciplinary approach, in terms of both surgical and medical points of view. After resection, total knee arthroplasty has become the gold standard of reconstruction in such localizations. It uses press fit against healthy bone, thanks to long centromedullar stems, because of major soft tissues resection due to carcinologic surgery rules. The incision is usually antero-medial and the main difficulty is mostly linked to the care of vascular and nervous systems and the extensor apparatus. The conservation (or not) of the latter modifies the surgical technique. Articular invasion will impose to perform a one-piece-articular resection, which will complicate the conservation of the extensor apparatus. There are lots of different techniques and prosthesis. Arthrodesis indications are seldom because prosthesis reconstructions have made proof of their efficacy and their longevity. Functional and oncologic results of this excision and reconstructive surgery are now clearly established. However, this represents complex and risky interventions which will often lead to secondary surgical revision because of the young age of patients and their functional demands. This can only stress the necessity of addressing patients to specialized, network-organized sarcoma teams.

Stratégie chirurgicale dans les tumeurs osseuses « du genou »Surgery in « around the knee » bone tumors

Distal femur and proximal tibia are the main localization of primary malignant bone tumor. Osteosarcoma and Ewing sarcoma are the most frequent. New techniques in imaging, recent development in chemotherapy protocols and surgery sharpening led to major improvement in their management, which allowed to minimize amputation ratio. The complexity of their treatment and their rarity imply the involvement of multidisciplinary approach, in terms of both surgical and medical points of view. After resection, total knee arthroplasty has become the gold standard of reconstruction in such localizations. It uses press fit against healthy bone, thanks to long centromedullar stems, because of major soft tissues resection due to carcinologic surgery rules. The incision is usually antero-medial and the main difficulty is mostly linked to the care of vascular and nervous systems and the extensor apparatus. The conservation (or not) of the latter modifies the surgical technique. Articular invasion will impose to perform a one-piece-articular resection, which will complicate the conservation of the extensor apparatus. There are lots of different techniques and prosthesis. Arthrodesis indications are seldom because prosthesis reconstructions have made proof of their efficacy and their longevity. Functional and oncologic results of this excision and reconstructive surgery are now clearly established. However, this represents complex and risky interventions which will often lead to secondary surgical revision because of the young age of patients and their functional demands. This can only stress the necessity of addressing patients to specialized, network-organized sarcoma teams.