Domenico Andrea Campanacci

THE TREATMENT OF METASTASES IN THE APPENDICULAR SKELETON

Bone metastases from carcinomata are a medical and social issue. About one-half of all primary cancers tend to disseminate to the skeleton, which is the third most frequent site of metastatic spread after the lung and the liver. Epidemiological investigation has shown that of 1.2 million new cases of cancer each year in the USA, about 300 000 will eventually develop a bone metastasis. Tumours which have a predilection for dissemination to bone are those of the prostate (32%), breast (22%) and kidney (16%) followed by the lung and the thyroid. The sites most usually involved are, in order of frequency, the spine, pelvis, ribs, skull and proximal long bones. The treatment of bone metastases is usually palliative and aims to achieve adequate control of pain, to prevent and resolve compression of the cord in lesions of the spine and to anticipate or stabilise pathological fractures in the appendicular skeleton. In selected cases the complete resection of an isolated bone metastasis may improve the survival of the patient. The prognosis of patients with bone metastases is extremely variable depending on the site of the primary growth. During recent decades, the life expectancy of patients affected with metastatic carcinoma has improved considerably because of advances in chemotherapy, immunotherapy, hormonal treatment and radiotherapy. However, this improvement results in an increase in the population at risk of developing bone metastases or experiencing a pathological fracture. The reconstructive procedure requires greater reliability in order to avoid mechanical failure during prolonged survival of the patient. At present, the treatment of bone metastases may not follow any codified protocol. The patient may be treated by different specialists such as an orthopaedic surgeon, an oncologist or a radiotherapist without any rational guideline as to the indications for surgical treatment. We have recently introduced a new protocol for the treatment of bone metastases of the appendicular skeleton which describes guidelines for indications for surgery, the type of operation to be undertaken and the methods of reconstruction available. The aim is to offer adequate individual treatment to the patient, avoiding undertreatment or overtreatment, to achieve control of pain and to manage impending and pathological fractures so that the longer survival is associated with a better quality of life.

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.

Expression of transforming growth factor β isoforms in osteosarcoma variants: association of tgfβ1 with high-grade osteosarcomas

Studies on osteosarcoma cell lines point to the potential importance of transforming growth factor β (TGFβ) as an autocrine factor which controls the growth of human osteosarcomas. To define further the role of TGFβ isoforms in these neoplasms, a series of 27 osteosarcomas was studied using immunohistochemical, mRNA in situ hybridization, and reverse transcriptase‐polymerase chain reaction (RT‐PCR) techniques. All 14 central high‐grade osteosarcomas, two telangiectatic osteosarcomas, and one high‐grade surface osteosarcoma showed cytoplasmic immunoreactivity for TGFβ1, ‐2, and ‐3. The expression of TGFβ1 was moderate or diffuse in 14 cases (82·3 per cent), while low expression was detected in only three cases (17·7 per cent). For TGFβ2 and ‐3, only moderate or diffuse staining was observed. Low‐grade parosteal and periosteal osteosarcomas showed low or undetectable levels of TGFβ1, while TGFβ2 and ‐3 were moderately or diffusely expressed. Finally, three dedifferentiated parosteal osteosarcomas were diffusely positive for TGFβ1, ‐2, and ‐3 in the high‐grade component, while in the low‐grade component, available for analysis in two of these cases, TGFβ1 was demonstrated in a few neoplastic cells, and TGFβ2 and ‐3 maintained a diffuse distribution. Statistical analysis of these data showed that high‐grade osteosarcomas had a significantly higher expression of TGFβ1 than low‐grade osteosarcomas, while levels of TGFβ2 and ‐3 were comparable in the two groups (p<0·001; p=0·3; p=0·3, respectively; Fishers exact test). Similarly, mRNA levels of TGFβ1 detected by in situ hybridization were significantly higher (p=0·04, Fishers exact test) in high‐grade osteosarcoma variants, while no differences were found for TGFβ2 and ‐3 mRNA (p=1·0; p=0·2, respectively; Fishers exact test). In addition, mRNA analysis performed by RT‐PCR in seven cases (five high‐grade and two low‐grade osteosarcomas) confirmed the presence of high levels of TGFβ1 in high‐grade osteosarcomas, while low‐grade tumours had low or absent mRNA expression. In conclusion, this positive association suggests that TGFβ1 may be involved in determining the aggressive clinical behaviour of high‐grade osteosarcomas.

Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients.

BACKGROUND Enchondromatosis is characterized by the presence of multiple benign cartilage lesions in bone. While Ollier disease is typified by multiple enchondromas, in Maffucci syndrome these are associated with hemangiomas. Studies evaluating the predictive value of clinical symptoms for development of secondary chondrosarcoma and prognosis are lacking. This multi-institute study evaluates the clinical characteristics of patients, to get better insight on behavior and prognosis of these diseases. METHOD A retrospective study was conducted using clinical data of 144 Ollier and 17 Maffucci patients from 13 European centers and one national databank supplied by members of the European Musculoskeletal Oncology Society. RESULTS Patients had multiple enchondromas in the hands and feet only (group I, 18%), in long bones including scapula and pelvis only (group II, 39%), and in both small and long/flat bones (group III, 43%), respectively. The overall incidence of chondrosarcoma thus far is 40%. In group I, only 4 patients (15%) developed chondrosarcoma, in contrast to 27 patients (43%) in group II and 26 patients (46%) in group III, respectively. The risk of developing chondrosarcoma is increased when enchondromas are located in the pelvis (odds ratio, 3.8; p = 0.00l). CONCLUSIONS Overall incidence of development of chondrosarcoma is 40%, but may, due to age-dependency, increase when considered as a lifelong risk. Patients with enchondromas located in long bones or axial skeleton, especially the pelvis, have a seriously increased risk of developing chondrosarcoma, and are identified as the population that needs regular screening on early detection of malignant transformation.

Biological reconstruction after resection of bone tumours around the knee. Long term follow up.

We reviewed 25 patients who had undergone resection of a primary bone sarcoma which extended to within 5 cm of the knee with reconstruction by a combination of a free vascularised fibular graft and a massive allograft bone shell. The distal femur was affected in four patients and the proximal tibia in 21. Their mean age at the time of operation was 19.7 years (5 to 52) and the mean follow-up period 140 months (28 to 213). Three vascularised transfers failed. The mean time to union of the fibula was 5.6 months (3 to 10) and of the allograft 19.6 months (10 to 34). Full weight-bearing was allowed at a mean of 21.4 months (14 to 36). The mean functional score at final follow-up was 27.4 (18 to 30) using a modified 30-point Musculoskeletal Tumour Society rating system. The overall limb-salvage rate was 88%. The results of our study suggest that the combined use of a vascularised fibular graft and allograft is of value as a limb-salvage procedure for intercalary reconstruction after resection of bone tumours around the knee, especially in skeletally immature patients.

Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study.

BACKGROUND Mesenchymal chondrosarcoma (MCS) is a distinct, very rare sarcoma with little evidence supporting treatment recommendations. PATIENTS AND METHODS Specialist centres collaborated to report prognostic factors and outcome for 113 patients. RESULTS Median age was 30 years (range: 11-80), male/female ratio 1.1. Primary sites were extremities (40%), trunk (47%) and head and neck (13%), 41 arising primarily in soft tissue. Seventeen patients had metastases at diagnosis. Mean follow-up was 14.9 years (range: 1-34), median overall survival (OS) 17 years (95% confidence interval (CI): 10.3-28.6). Ninety-five of 96 patients with localised disease underwent surgery, 54 additionally received combination chemotherapy. Sixty-five of 95 patients are alive and 45 progression-free (5 local recurrence, 34 distant metastases, 11 combined). Median progression-free survival (PFS) and OS were 7 (95% CI: 3.03-10.96) and 20 (95% CI: 12.63-27.36) years respectively. Chemotherapy administration in patients with localised disease was associated with reduced risk of recurrence (P=0.046; hazard ratio (HR)=0.482 95% CI: 0.213-0.996) and death (P=0.004; HR=0.445 95% CI: 0.256-0.774). Clear resection margins predicted less frequent local recurrence (2% versus 27%; P=0.002). Primary site and origin did not influence survival. The absence of metastases at diagnosis was associated with a significantly better outcome (P<0.0001). Data on radiotherapy indications, dose and fractionation were insufficiently complete, to allow comment of its impact on outcomes. Median OS for patients with metastases at presentation was 3 years (95% CI: 0-4.25). CONCLUSIONS Prognosis in MCS varies considerably. Metastatic disease at diagnosis has the strongest impact on survival. Complete resection and adjuvant chemotherapy should be considered as standard of care for localised disease.

A Novel Recessive Mutation of Fibroblast Growth Factor-23 in Tumoral Calcinosis

BACKGROUND Tumoral calcinosis is a rare disease characterized by hyperphosphatemia due to hypophosphaturia and by ectopic calcifications. Phosphatonins are important hormones that regulate phosphorus homeostasis. Tumoral calcinosis is a rare congenital disorder in which the differential diagnosis from other syndromes associated with extraskeletal calcifications may be difficult. Mutations in the UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-3 (GALNT3) and fibroblast growth factor-23 (FGF23) genes have been described. Mutational analysis is important for the early recognition of the disorder, for prevention of its complications, and for family screening strategies. We examined two unrelated white patients affected by tumoral calcinosis. METHODS The first patient was a woman with a history of an ectopic calcification in the left shoulder. The second patient was a man with a history of an ectopic calcification in the right buttock. Routine biochemistry and FGF-23 assays were performed on serum samples. Genomic DNA was extracted from peripheral blood. The FGF23 and GALNT3 genes were analyzed by direct sequencing. RESULTS A new homozygous H41Q codon 41, C-->A transversion at position 123 (c.123C>A) in exon 1 of the FGF23 gene was evidenced in both patients. No mutation of the GALNT3 gene was detected in these patients. As determined by an ELISA assay, intact FGF-23 circulating protein was low in both patients. CONCLUSIONS This is the fourth mutation of the FGF23 gene described in subjects with tumoral calcinosis.

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.

Synovial chondromatosis in a lumbar apophyseal joint

Abstract A 31-year-old woman presented with painful swelling in the right paravertebral region that had been present for 2 years. Radiography and CT revealed an area of increased density due to multiple calcifications localized at the fourth lumbar vertebra. Histological examination revealed that the lesion consisted of nodules of hyaline cartilage, with focal areas of calcification, growing within synovial tissue.