Guido Scoccianti

Prognostic factors and outcomes for osteosarcoma: an international collaboration

We aimed to evaluate the prognostic significance of traditional clinical predictors in osteosarcoma through an international collaboration of 10 teams of investigators (2680 patients) who participated. In multivariate models the mortality risk increased with older age, presence of metastatic disease at diagnosis, development of local recurrence when the patient was first seen, use of amputation instead of limb salvage/wide resection, employment of unusual treatments, use of chemotherapeutic regimens other than anthracycline and platinum and use of methotrexate. It was also influenced by the site of the tumour. The risk of metastasis increased when metastatic disease was present at the time the patient was first seen and also increased with use of amputation or unusual treatment combinations or chemotherapy regimens not including anthracycline and platinum. Local recurrence risk was higher in older patients, in those who had local recurrence when first seen and when no anthracycline and platinum were used in chemotherapy. Results were similar when limited to patients seen after 1990 and treated with surgery plus combination chemotherapy. This large-scale international collaboration identifies strong predictors of major clinical outcomes in osteosarcoma.

Ankle Arthrodesis with Bone Graft after Distal Tibia Resection for Bone Tumors

Background: Treatment of distal tibial tumors is challenging due to the scarce soft tissue coverage of this area. Ankle arthrodesis has proven to be an effective treatment in primary and post-traumatic joint arthritis, but few papers have addressed the feasibility and techniques of ankle arthrodesis in tumor surgery after long bone resections. Materials and Methods: Resection of the distal tibia and reconstruction by ankle fusion using non-vascularized structural bone grafts was performed in 8 patients affected by malignant (5 patients) or aggressive benign (3 patients) tumors. Resection length of the tibia ranged from 5 to 21 cm. Bone defects were reconstructed with cortical structural autografts (from contralateral tibia) or allografts or both, plus autologous bone chips. Fixation was accomplished by antegrade nailing (6 cases) or plating (2 cases). Results: All the arthrodesis successfully healed. At followup ranging from 23 to 113 months (average 53.5), all patients were alive. One local recurrence was observed with concomitant deep infection (a below-knee amputation was performed). Mean functional MSTS score of the seven available patients was 80.4% (range, 53 to 93). Conclusion: Resection of the distal tibia and arthrodesis of the ankle with non-vascularized structural bone grafts, combined with autologous bone chips, can be an effective procedure in bone tumor surgery with durable and satisfactory functional results. In shorter resections, autologous cortical structural grafts can be used; in longer resections, allograft structural bone grafts are needed. Level of Evidence: IV, Retrospective Case Study

Denosumab treated giant cell tumour of bone: A morphological, immunohistochemical and molecular analysis of a series

Aims Denosumab, a fully human monoclonal antibody directed against RANKL, has recently been introduced in the treatment strategy of giant cell tumour of bone (GCTB). Aim of this study was to investigate the phenotypical modifications induced by denosumab treatment in a series of 15 GCTB. Methods The tumours were characterised for histone 3.3 mutations, and studied immunohistochemically for the modifications of RANKL, RANK, SATB2 and RUNX2 expression, as well as of tumour proliferative activity and angiogenesis. Results Nine of 11 tumours investigated presented a histone 3.3 mutation in H3F3A, and 2 of these for which the analysis was carried out in pretreatment and post-treatment specimens showed the same mutation in both. Denosumab induced the disappearance of osteoclast-like giant cells, leaving residual spindle neoplastic cells arranged in a storiform pattern, with deposition of trabecular collagen matrix and osteoid, which tended to maturation in the peripheral portions of the lesion. RANK and RANKL expression was variable, with no significant variation after treatment. Moreover, we did not observe any significant modification of the expression of the osteoblastic markers SATB2 and RUNX2. Denosumab treatment determined a significant reduction of the proliferative index and of tumour angiogenesis (p=0.001, Wilcoxon rank-sum test). Conclusions These results indicate that denosumab induces a partial maturation towards the osteoblastic phenotype of the neoplastic cells of GCTB, with production of fibrous and osteoid matrix, but with minor immunophenotypical changes. Finally, we first report an antiangiogenic activity of denosumab in GCTB, possibly mediated by a RANKL-dependent pathway.

Total Calcanectomy and Reconstruction with Vascularized Iliac Bone Graft for Osteoblastoma: A Report of Two Cases:

Tumors affecting tarsal bones are a rare occurrence, accounting for approximately 1% of primary tumors of the skeleton,34 with the calcaneus being the most frequent site.6 Osteoblastoma occurrence in the bones of the foot is not infrequent, ranging from 3.4 to 11.1% of the cases in different series,5,18,33,34 with the talus most common followed by the calcaneus.5,6,33 Total excision of the calcaneus can be the treatment of choice in aggressive benign tumors and in selected cases of malignant tumors. Reconstruction of the heel after total calcanectomy is a challenging procedure and different techniques have been proposed. Due to the rarity of this condition, most of the reports in the literature involved a single case with no series reported. We describe two cases of aggressive osteoblastomas extensively affecting the calcaneus requiring total calcanectomy. In order to restore a functional weightbearing hindfoot after calcaneus excision, in both cases we performed a heel reconstruction by vascularized iliac crest graft fixed to the talus and the cuboid. Oncological, radiographic and functional results of these procedures at an average followup of 7 (range, 6.6 to 7.7) years are reported.

Modular Endoprostheses for Nonneoplastic Conditions: Midterm Complications and Survival

The use of modular endoprostheses is a viable option to manage both tumor resection and severe bone loss due to nonneoplastic conditions such as fracture sequelae, failed osteoarticular grafts, arthroplasty revisions, and periprosthetic fractures. We sought to investigate both midterm complications and failures occurred in 87 patients who underwent a megaprosthetic reconstruction in a nonneoplastic setting. After a mean follow-up of 58 (1–167) months, overall failure-free survival was 91.5% at 1 year, 80% at 2 years, 71.6% at 5 years, and 69.1% at 5 and 10 years. There was no significant difference in the survival rate according to the diagnosis at the index procedure (p = 0.921), nor to the reconstruction site (p = 0.402). The use of megaprostheses in a postneoplastic setting did not affect survival rate in comparison with endoprosthetic reconstruction of pure nonneoplastic conditions (p = 0.851). Perimegaprosthetic infection was the leading complication, occurring in 10 (11.5%) patients and implying a megaprosthetic revision in all but one case. Physicians should consider these results when discussing with patients desired outcomes of endoprosthetic reconstructions of a nonneoplastic disease.

Allograft-prosthetic composite versus megaprosthesis in the proximal tibia—What works best?

Modular megaprosthesis (MP) and allograft-prosthetic composite (APC) are the most commonly used reconstructions for large bone defects of the proximal tibia. The primary objective of this study was to compare the two different techniques in terms of failures and functional results. A total of 42 consecutive patients with a mean age of 39.6 years (range 15-81 years) who underwent a reconstruction of the proximal tibia between 2001 and 2012 were included. Twenty-three patients were given an MP, and 19 patients received an APC. There were nine reconstruction failures after an average follow-up of 62 months: five in the MP group and four in the APC group (p=0.957). The 10-year implant survival rate was 78.8% for the MP and 93.7% for the APC (p=0.224). There were no relevant differences between the two groups in functional results. Both MP and APC are valid and satisfactory reconstructive options for massive bone defects in the proximal tibia. In high-demanding patients with no further risk factors, an APC should be considered to provide the best possible functional result for the extensor mechanism.

Soft tissue sarcomas: new opportunity of treatment with PARP inhibitors?

AbstractBackgroundPoly(ADP-ribose) polymerases (PARP) are a large family of enzymes involved in several cellular processes, including DNA single-strand break repair via the base-excision repair pathway. PARP inhibitors exert antitumor activity by both catalytic PARP inhibition and PARP–DNA trapping, moreover PARP inhibition represents a potential synthetic lethal approach against cancers with specific DNA-repair defects. Soft tissue sarcoma (STSs) are a heterogeneous group of mesenchymal tumors with locally destructive growth, high risk of recurrence and distant metastasis. ObjectivesThe purpuse of this review is to provide an overview of the main preclinical and clinical data on use of PARPi in STSs and of effect and safety of combination of PARPi with irradiation. ResultsDue to numerous genomic alterations in STSs, the DNA damage response pathway can offer an interesting target for biologic therapy. Preclinical and clinical studies showed promising results, with the most robust evidences of PARPi efficacy obtained on Ewing sarcoma bearing EWS–FLI1 or EWS–ERG genomic fusions. The activity of PARP inhibitors resulted potentiated by chemotherapy and radiation. Although mechanisms of synergisms are not completely known, combination of radiation therapy and PARP inhibitors exerts antitumor effect by accumulation of unrepaired DNA damage, arrest in G2/M, activity both on oxic and hypoxic cells, reoxygenation by effect on vessels and promotion of senescence. Early trials have shown a good tolerance profile.ConclusionsThe use of PARP inhibitors in advanced stage STSs, alone or combined in multimodal treatments, is of great interest and warrants further investigations.

Soft tissue myxofibrosarcoma: A clinico-pathological analysis of a series of 75 patients with emphasis on the epithelioid variant.

The clinical course of soft tissue myxofibrosarcoma is characterized by a high incidence of recurrences and there is no agreement on how to identify patients at major risk. An epithelioid histological variant has been described, with a possible worse prognosis. We reviewed our series to identify prognostic factors and assess clinical significance of the epithelioid variant.

Modular megaprosthesis reconstruction for oncological and non-oncological resection of the elbow joint.

BACKGROUND Reconstruction of large bone defects around the elbow joint is surgically demanding due to sparse soft tissue coverage, complex biomechanics and the close proximity to neurovascular structures. Modular megaprostheses are established reconstruction tools for the elbow, but only small case series have been reported in the literature. METHODS Thirty-six patients who underwent reconstruction of the elbow joint with a modular megaprosthesis were reviewed retrospectively. In 31 patients (86.1%), elbow replacement was performed after resection of a bone tumour, whereas five non-oncological patients (13.9%) underwent surgery because of a previous failed elbow reconstruction. Functional outcome, rate of complications and oncological results were considered as primary endpoints. RESULTS The mean follow-up was 25 months. The average achieved Mayo Elbow Performance Score (MEPS) was 77.08 (range 40-95) and the average Musculoskeletal Tumor Society (MSTS) score was 22.9 (range 8-30). Six complications (16.7%) were observed: two radial palsies, one temporary radial nerve dysfunction, one ulnar palsy, one disassembling of the articular prosthesis component and one deep infection necessitating the only implant removal. The overall 5-year survival rate of the patients was poor (25.1%) because of rapid systemic progression of the oncological disease in patients with metastatic lesion. However, the 5-year survival rate of the implant was very satisfactory (93%). CONCLUSIONS Modular megaprosthesis is a reliable and effective reconstruction tool in large bone defects around the elbow joint. The complication rates are lower than seen in osteoarticular allografts and allograft-prosthesis composites while the functional outcome is equal. In palliative situations with metastatic disease involving the elbow, modular megaprosthesis enables rapid recovery and pain relief and preserves elbow function.

Treatment of Bone Metastases: Future Directions

Four main future directions in the treatment of bone metastases can likely be envisaged: fewer tumors in general population, fewer bone metastases in patients affected by tumors, less invasive therapies, and in selected cases highly invasive surgery also in metastatic patients who have been often banished to palliative treatment so far. Development and improvements of current techniques and introduction of new technological achievements are expected to improve actual therapeutic regimens. Nanotechnologies and a combination of diagnosis and treatment in the same time (theranostics) are likely to deeply change our approach to bone metastatic disease and, we hope, its results. New and less invasive surgical procedures are going to progressively decrease the surgical burden on most of the metastatic patients who will still need surgery, but at the same time, a growing number of these patients will undergo highly invasive surgery, due to the application of the criteria of primary tumor surgery also to metastatic patients, thanks to the improved survival. The future of the treatment of bone metastases will surely be a varied and variegated future, ranging from the use of extremely small devices, like nanoprobes, to the use of megaprostheses, and maybe also combinations of them. The clinician will have to be ready to manage a continuously growing range of therapeutic options and to have the capability to choose the right one for the specific patient.