Giovanni Beltrami

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.

Primary juxtacortical myoepithelioma/mixed tumor of the bone: a report of 3 cases with clinicopathologic, immunohistochemical, ultrastructural, and molecular characterization

We describe the clinicopathological, immunohistochemical, and molecular features of 3 primary juxtacortical myoepithelioma/mixed tumor of bone. The patients were 2 males (13 and 23 years of age) and a 15-year-old female. The juxtacortical lesions were all located in the femur, and were surgically removed, 2 with wide margins and one with marginal margins. This latter tumor recurred locally 18 months later. The 3 patients were free of disease at 6 to 17 months follow-up. Histologically, all lesions showed a prominent multinodular architecture, and were formed by epithelioid and stellate elements, organized in solid sheets, or embedded in myxoid or chondroid matrix. Areas of osteoid formation were also observed. One tumor had the appearance of classical mixed tumor, showing aspects of duct formation and focal squamous differentiation. Immunohistochemically, all cases were positive for cytokeratins, epithelial membrane antigen, and S100 protein. The expression of other myoepithelial markers, including p63, glial fibrillary acid protein and calponin was more limited. No rearrangement of Ewing sarcoma region 1 (EWSR1) and fused in sarcoma (FUS) genes was observed by fluorescent in situ hybridization. To our knowledge, this is the first report of primary myoepitheliomas of bone arising at juxtacortical sites. These lesions must be distinguished from other benign and malignant bone and cartilage-forming surface tumors, including periosteal chondroma and chondrosarcoma, juxtacortical chondromyxoid fibroma, and periosteal and paraosteal osteosarcoma. The clinicoradiologic presentation and their histological and immunohistochemical features are distinctive enough to allow the separation from these entities.

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.

Primary capillary hemangioblastoma of bone: report of a case arising in the sacrum.

Capillary hemangioblastoma (CHB) is a benign, highly vascularized tumor that generally occurs in the central nervous system either in the setting of von Hippel-Lindau (VHL) disease or, more often, as a solitary sporadic lesion that is increasingly recognized in extraneural sites. We present the case of a 72-year-old woman with low back pain and a well-demarcated lytic lesion of the sacrum, which at histological and ultrastructural examination was indistinguishable from central nervous system CHB. The patient had no signs of VHL disease and died of another cause with no evidence of disease 57 months after curettage of the lesion. To our knowledge, this is the second case of CHB reported to occur in bone.

Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization

Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.

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.