Rizzoli Institute Research Articles

Spine high-grade osteosarcoma in the era of radiotherapy with high-energy charged particles: A single institution retrospective analysis.

11532 Background: Limited are data on high-grade osteosarcoma occurring in the spine. Wide resection is recommended, but it is a difficult and high morbidity procedure in the spine. High-energy particle therapy has been recently used. The goal of this study was to examine treatment and outcome of patients with osteosarcoma in the mobile spine. Methods: Spine high grade osteosarcoma patients who underwent surgery at the Rizzoli Institute between 2009 and 2020 were identified. Treatment, outcome, and prognostic factors in patients treated in a single institution were examined. Results: Characteristics of the 20 patients (8 female; 12 male) included: median age, 39.7 years (range, 14-71 years), 5 (25%) with tumors in the cervical spine, 6 (30%) with tumors in the thoracic spine, and 9 with tumors in the lumbar spine (45%); 14 (70%) patients with localized disease and 6 (30%) with metastatic disease at the time of presentation. Nineteen patients (95%) underwent chemotherapy, the majority were treated with MAP (methotrexate, doxorubicin, cisplatin) regimen. In 12 patients undergoing preoperative chemotherapy (n = 11) or chemotherapy and radiotherapy (n = 1), the median tumor % necrosis was 20 (IQR 20 - 40), with none achieving a good histologic response (> 90%). All patients underwent surgery. Adequate surgical margins were achieved in 5 patients (25%). In patients with positive margins, radiotherapy was administered to 8 (40%) patients. Four patients with positive margins after resection received photon neoadjuvant or adjuvant therapy. Four patients received high-energy particles as adjuvant therapy after planned gross total excision. The median overall survival rate was 10.5 months (IQR 5.8 - 15.0) for patients with metastatic disease and 25.5 months (IQR 8.3 - 46.0) for patients with localized disease (P =.0501). Patients treated with planned intralesional gross total resection followed by adjuvant high-energy particle therapy had a significant higher disease-specific survival than patients with positive margins after resection with or without additional conventional radiotherapy (P =.023). Conclusions: Metastatic disease, is a poor prognostic factor for high grade osteosarcoma of the spine. Post-operative high-energy particle therapy improved overall survival in patients undergoing a planned gross total resection compared to intralesional resection in this series. Chemotherapy induced necrosis was low underscoring the need of more aggressive multidisciplinary approaches for these patients.

Electrochemotherapy Is Effective in the Treatment of Bone Metastases.

Bone metastases induce pain, risk of fracture, and neural compression, and reduced mobility and quality of life. Electrochemotherapy (ECT) is a minimally invasive local treatment based on a high-voltage electric pulse combined with an anticancer drug. Preclinical and clinical studies have supported the use of ECT in patients with metastatic bone disease, demonstrating that it does not damage the mineral structure of the bone and its regenerative capacity, and that is feasible and efficient for the treatment of bone metastases. Since 2009, 88 patients with bone metastasis have received ECT at the Rizzoli Institute. 2014 saw the start of a registry of patients with bone metastases treated with ECT, whose data are recorded in a shared database. We share the Rizzoli Institute experience of 38 patients treated with ECT for a bone metastasis, excluding patients not included in the registry (before 2014) and those treated with bone fixation. Mean follow-up was 2 months (1–52). Response to treatment using RECIST criteria was 29% objective responses, 59% stable disease, and 16% progressive disease. Using PERCIST, the response was 36% OR, 14% SD, and 50% PD with no significant differences between the two criteria. A significant decrease in pain and better quality of life was observed at FU.

Combined 3D analysis of lower-limb morphology and function in children with idiopathic equinovarus clubfoot: A preliminary study

IntroductionIn children treated for idiopathic equinovarus clubfoot (EVCF), the relation between morphologic defects on clinical examination and standard X-ray on the one hand and functional abnormalities on the other is difficult to objectify. The aim of the present study was to demonstrate the feasibility of combined 3D analysis of the foot and lower limb based on biplanar EOS radiographs and gait analysis. The study hypothesis was that this provides better understanding of abnormalities in form and function. MethodsTen children with unilateral EVCF and “very good” clinical results were included. They underwent gait analysis on the Rizzoli Institute multisegment foot model. Kinematic data were collected for the hip, knee, ankle and foot (hindfoot/midfoot, midfoot/forefoot and hindfoot/forefoot). Biplanar EOS radiographs were taken to determine anatomic landmarks and radiological parameters. ResultsComplete acquisition time was around 2hours per patient. No significant differences were found between EVCF and healthy feet except for calcaneal incidence, tibiocalcaneal angle and hindfoot/midfoot and hindfoot/forefoot inversion. DiscussionThe feasibility of the combined analysis was confirmed. There were no differences in range of motion, moment or power between EVCF and healthy feet in this series of patients with very good results. The functional results are related to radiological results within the normal range. The protocol provided anatomic and kinematic reference data. A larger-scale study could more objectively assess the contribution of EOS radiography using optoelectronic markers. Level of evidenceII, low-power prospective study.

Adjuvant and Neoadjuvant Chemotherapy for Osteosarcoma: A Historical Perspective.

Osteosarcoma was initially resistant to chemotherapy that worked for Ewing sarcoma and rhabdomyosarcoma as well as other chemotherapeutic agents available in the 1960s. In the early 1970s, responses of osteosarcoma to adriamycin were reported, and at about the same time, so were responses of osteosarcoma to high-dose methotrexate. These agents were introduced into adjuvant therapy due to the dire prognosis associated with apparently localized osteosarcoma. After initial questions regarding the role of chemotherapy delayed its uniform acceptance, there is now general agreement that chemotherapy is primarily responsible for the cure of patients with osteosarcoma when combined with surgical elimination of the primary tumor. Advances with combination chemotherapy later adding cisplatin and ifosfamide have improved ultimate survival. The history of the development of effective chemotherapy combinations at Memorial Sloan Kettering Cancer Center, UT MD Anderson Cancer Center, and the Rizzoli Institute are highlighted, and recent large cooperative group studies are reviewed in the context of those findings.

When neurosurgery and orthopedics were close in the past: Harvey Cushing and Vittorio Putti.

Harvey Cushing and Vittorio Putti are well-recognized medical authorities. The Italian orthopedic surgeon Vittorio Putti was an advocate of modern orthopedics and a scholar in orthopedic history. Putti was a frequent traveler and an esteemed lecturer, and a close friend of the American neurosurgeon, pathologist, and writer Dr. Harvey Cushing. Correspondence between the two can be found at the Yale Medical Historical Library, in New Haven, CT, and at the Rizzoli Institute in Bologna. A research was performed, which yielded an extensive documentation on the correspondence between the two surgeons. The research allowed to analyze and confirm the strong relationship between the two surgeons and highlighted their passion for collecting antique medical books. This paper is a tribute to two great surgeons in the history of medicine and aims at describing their personality and witnessing their great friendship through an unprecedented documentation. Both surgeons still live on through those who can continue to admire and study the fruit of their passion, as both men donated their precious collection of antique texts to public institutions, Putti to the Rizzoli Orthopedic Institute in Bologna, and Cushing to Yale University.

Wilhelm Schulthess, Pioneer in the Treatment of Spinal Deformities: The Testimony of the Rizzoli Orthopedic Institute.

: Wilhelm Schulthess was a pioneer in the treatment of spinal deformities. The Rizzoli Orthopedic Institute in Bologna, Italy, awarded him in 1911 for his work: "pathology and treatment of spinal deformities". In this paper the Swiss Clinician is remembered through the documentation still preserved at the Rizzoli institute.

Osteosarcoma follow-up: chest X-ray or computed tomography?

BackgroundIn patients with relapsed osteosarcoma, the surgical excision of all metastases, defined as second complete remission (CR-2), is the factor that mainly influences post-relapse survival (PRS). Currently a validated follow-up policy for osteosarcoma is not available, both chest X-ray and computed tomography (CT) are suggested for lung surveillance. The purpose of this study is to evaluate whether the type of imaging technique used for chest surveillance, chest X-ray or CT, influenced the rate of CR-2 and prognosis in patients with recurrent osteosarcoma.MethodsPatients up to 40 years with extremity osteosarcoma enrolled in consecutive clinical trials and treated at the Rizzoli Institute from 1986 to 2009 were identified. Only patients who had lung metastases alone as first pattern of recurrence were considered for the analysis. The rate of CR-2, overall survival (OS) and PRS were the end-points of the study.ResultsThe median follow-up was 47 months (1–300), 215 patients were eligible. Lung metastases were detected by chest X-ray in 100 (47%) patients, by CT in 112 (52%) and by symptoms in 3 (1%). CR-2 rate was 60% for patients followed by X-rays and 88% for those followed by CT (p < .0001). 5-year PRS was 30% (95% CI 21–39) in the X-ray group and 49% (95% CI 39–59) in the CT group (p = .0004). 5-year OS was 35% (95% CI 26–44) in the X-ray group and 60% (95% CI 51–70) in the CT group (p = .004).ConclusionsA follow-up strategy with chest CT leads to a higher rate of CR-2 and significantly improves PRS and OS in osteosarcoma, compared to chest X-ray.

The Masters of the Bolognese Orthopaedic School.

Bologna is one of the most ancient cradles of medical knowledge, as the city hosts one of the oldest medical faculties in the world. Among its best known institutions there is the Rizzoli Orthopaedic Institute, founded in the late nineteenth century, whose history is strictly connected with the evolution and development of the Italian orthopaedic practice of the last 120 years. The present manuscript acknowledges the main contributions by Francesco Rizzoli, Alessandro Codivilla and Vittorio Putti, who prompted the foundation and the international recognition of the Rizzoli Institute and the related Bolognese Orthopaedic School.

Prothèses totales de coude dans les tumeurs primitives et secondaires

BackgroundProstheses can be used in elbow reconstruction in both primary and metastatic lesions. Several authors have reported their experience with different types of implant, but not with modular prostheses. HypothesisLimb salvage using an elbow prosthesis is effective in obtaining good functional results and reliable local tumor control. Material and methodsForty-seven patients treated at the Rizzoli Institute for elbow neoplasm from 1990 to 2012 were evaluated. There were 30 primary tumors (64%), 24 bone tumors and 6 soft tissue sarcomas, and 17 bone metastases. Elbow reconstruction used a modular prosthesis in 25 patients and a standard prosthesis in 22. Reconstruction was primary in 30 patients and secondary in 17. ResultsAt last control, 15 (32%) were dead of disease (DOD) at a mean follow-up of 35months, 12 (25%) were alive with disease (AWD) at a mean follow-up of 29months, 19 (40%) showed no evidence of disease (NED) at a mean follow-up of 80months. Early complications were related to unexpected neurological damage, observed in 12 patients (25%): in 5 cases, the deficit resolved in a mean 6months; in the others, no or only partial recovery was observed. Two implants (4%) developed infection: 1 was treated with antibiotic therapy, and the other required implant revision. One implant showing cement extrusion was revised. In 3 patients (6%), radiography showed a radiolucent halo around the stem (2 humeral, 1 ulnar); no measures were taken, as the patients were completely asymptomatic at every follow-up. In 3 patients (6%), partial resorption of the allograft was observed on X-ray, but remained unchanged at last follow-up, without pain or functional impairment. Seven local recurrences (15%) were observed, at a mean 16months after surgery; 5 were treated by resection and/or radiotherapy, and 2 by amputation. Mean functional scores on MEPS and MSTS were respectively 84% and 22/30 (73%). ConclusionsElbow prostheses provided better function in primary than in metastatic tumor. Elbow prosthesis reconstruction after tumor resection is a viable option both for primary and secondary bone neoplasms. Type of studyTherapeutic. Level of evidenceIV, retrospective study.

Total elbow arthroplasty for primary and metastatic tumor

BackgroundProstheses can be used in elbow reconstruction in both primary and metastatic lesions. Several authors have reported their experience with different types of implant, but not with modular prostheses. HypothesisLimb salvage using an elbow prosthesis is effective in obtaining good functional results and reliable local tumor control. Material and methodsForty-seven patients treated at the Rizzoli Institute for elbow neoplasm from 1990 to 2012 were evaluated. There were 30 primary tumors (64%), 24 bone tumors and 6 soft tissue sarcomas, and 17 bone metastases. Elbow reconstruction used a modular prosthesis in 25 patients and a standard prosthesis in 22. Reconstruction was primary in 30 patients and secondary in 17. ResultsAt last control, 15 (32%) were dead of disease (DOD) at a mean follow-up of 35 months, 12 (25%) were alive with disease (AWD) at a mean follow-up of 29 months, 19 (40%) showed no evidence of disease (NED) at a mean follow-up of 80 months. Early complications were related to unexpected neurological damage, observed in 12 patients (25%): in 5 cases the deficit resolved in a mean 6 months; in the others, no or only partial recovery was observed. Two implants (4%) developed infection: 1 was treated with antibiotic therapy, and the other required implant revision. One implant showing cement extrusion was revised. In 3 patients (6%) radiography showed a radiolucent halo around the stem (2 humeral, 1 ulnar); no measures were taken, as the patients were completely asymptomatic at every follow-up. In 3 patients (6%) partial resorption of the allograft was observed on X-ray, but remained unchanged at last follow-up, without pain or functional impairment. Seven local recurrences (15%) were observed, at a mean of 16 months after surgery; 5 were treated by resection and/or radiotherapy, and 2 by amputation. Mean functional scores on MEPS and MSTS were respectively 84% and 22/30 (73%). ConclusionsElbow prostheses provided better function in primary than in metastatic tumor. Elbow prosthesis reconstruction after tumor resection is a viable option both for primary and secondary bone neoplasms. Type of studyTherapeutic. Level of evidenceIV, retrospective study.

Abstract 2946: Effects of two novel quinoline-based non-nucleoside DNA methyltransferase inhibitors against bone sarcomas

Abstract Introduction. Identification of new drugs against sarcomas still represents an urgent clinical need due to the rarity of these diseases. Aberrant DNA methylation of gene promoter regions is recognized to be highly involved in cancer and efforts have been made to synthesize non-nucleoside compounds that can effectively modulate gene expression, with bearable side effects. Two novel DNMT inhibitors (DNMTi), MC3353 and MC3343, were tested in Ewing sarcoma (EWS) and osteosarcoma (OS) cell lines to determine their effects on proliferation, apoptosis/necrosis induction, and cell differentiation. Methods and Results. We evaluated specificity on DNMTs inhibition of these compounds together with anticancer activities (cell growth inhibition, cell cycle perturbations, effects on programmed cell death) in a panel of EWS and OS cell lines. Cellular response to DNMTi treatment was assessed also at the molecular level by evaluation of key regulators of cell cycle and apoptosis. Effects on neural differentiation were assessed by β-III tubulin and heavy neurofilament modulation in Ewing sarcoma cells. Concurrently, effects on osteoblastic differentiation were carried out on Saos-2 OS cell line and evaluated by RT-PCR. Both inhibitors determined a significant inhibition of DNMTs activity. In vitro, MC3343 was found to slow cell proliferation by increasing the percentage of cells in G1 or G2/M phases, while MC3353 compound was unable to modulate cell cycle but induced an increase in cell death indicating a cytotoxic rather than a cytostatic effect. Modulation of key regulators of cell cycle and evaluation of PARP cleavage confirmed these results. Both DNMTi induced cell differentiation. In EWS, treatment significantly modulated the expression of neural markers (positivity to β-III tubulin; NF-H; neurite outgrowth). In OS cells, DNMTi increased both matrix mineralization and expression of genes specifically related to osteoblastogenesis. Conclusions. Non-nucleoside DNMTi may represent a possible new therapeutic approach to bone sarcoma. Grants from: Association for Cancer Research (IG2013_14049; to KS); 5 per mille contributions to Rizzoli Institute. FIRB RBFR10ZJQT, IIT-Sapienza Project, and FP7 Projects BLUEPRINT/282510 and A-ParaDDise/602080 to AM. CC is a recipient of a fellowship from the Associazione Onlus “il Pensatore: Matteo Amitrano” Citation Format: Maria Cristina Manara, Sergio Valente, Camilla Cristalli, Cristina Baricordi, Clemens Zwergel, Paola B Arimondo, Piero Picci, Antonello Mai, Katia Scotlandi. Effects of two novel quinoline-based non-nucleoside DNA methyltransferase inhibitors against bone sarcomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2946. doi:10.1158/1538-7445.AM2015-2946

MDM2 and CDK4 expression in periosteal osteosarcoma.

Periosteal osteosarcoma is defined by the World Health Organization as an intermediate-grade, malignant, cartilaginous, and bone-forming neoplasm arising on the surface of bone. Unlike other subtypes of osteosarcoma, no data have been published about mouse double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) expression. For this reason, we evaluated the molecular and immunohistochemical features of MDM2 and CDK4 in 27 cases relative to 20 patients with a diagnosis of periosteal osteosarcoma, surgically treated at the Rizzoli Institute between 1981 and 2014. When possible, these results were compared with the MDM2 amplification status as determined by fluorescence in situ hybridization (FISH). All but 1 case (26/27, 96.3%) were negative for MDM2 protein using immunohistochemistry both in primary and in recurrent periosteal osteosarcoma, whereas gene amplification of MDM2 was not detected in any tumor analyzed (10 cases). The positive immunohistochemical case shows a weak/moderate focal nuclear expression of MDM2 antibody in the prevalent cartilaginous component and in the spindle cells of peripheral fibroblastic areas associated with osteoid production in a primary periosteal osteosarcoma. CDK4 immunohistochemical expression was negative in all 27 cases. This retrospective analysis has demonstrated that MDM2 and CDK4 are very rarely expressed in primary and recurrent periosteal osteosarcomas and therefore do not appear to be molecules central to the control of cancer development, growth, and progression in periosteal osteosarcoma. Therefore, when compared with low-grade central and parosteal osteosarcomas, MDM2 and CDK4 markers cannot be used diagnostically to differentiate this subtype of osteosarcoma.

Prognostic significance of miR-34a in Ewing sarcoma is associated with cyclin D1 and ki-67 expression

At diagnosis, identification of reliable biological indicators of prognosis to allow stratification of patients according to different risks is an important but still unresolved aspect in the treatment of Ewing sarcoma (EWS) patients. This study aimed to explore the role of miR-34A expression on prognosis of EWS patients. Specimens from 109 patients with non-metastatic EWS treated at the Rizzoli Institute with neoadjuvant chemotherapy (protocols ISG/SSGIII, EW-1, EW-2, EW-REN2, EW-REN3, EW-PILOT) and 17 metastases were studied. Sixty-eight patients (62%) remained disease-free and 41 (38%) relapsed (median follow-up: 67 months, range 9-241 months). Expression of miR-34a and of some of its targets (cyclin D1, bcl-2, SIRT1 and YY1) was evaluated by qRT-PCR using TaqMan MicroRNA Assays and/or by immunohistochemistry on tissue microarrays from the same patients. High expression of miR-34a in localized tumors was significantly related to better event-free and overall survival (P = 0.004). Relevance of miR-34a was confirmed by using different calibrators (normal mesenchymal stem cells and different normal tissues). By multivariate Cox regression analysis, low miR-34a expression as well as nontotal necrosis and high levels of lactate dehydrogenase were all confirmed as independent risk factors associated with poor outcome. Expression of miR-34a was lower in metastases than in primary tumors. It inversely correlated with expression of cyclin D1 and Ki-67. By demonstrating its relationship with clinical outcome, we propose evaluation of miR-34a at diagnosis of EWS patients to allow early risk stratification. Validation of these results would nonetheless ultimately need a prospective assessment.

Outcome of advanced, unresectable conventional central chondrosarcoma.

For patients who have chondrosarcoma with unresectable disease, because of tumor location, tumor size, or extensive metastatic disease, treatment options are very limited because of their relative resistance to radiotherapy and chemotherapy. The overall survival of this patient population is poor; however, specific studies are lacking, and large series have not been published. Therefore, the authors conducted this retrospective, 2-center study to gain insight into the outcome of patients with advanced, unresectable, conventional central chondrosarcoma. All patients with unresectable conventional central chondrosarcoma who were diagnosed between January 1, 1980 and December 31, 2011 in 2 major European bone sarcoma centers (Rizzoli Institute, Bologna, Italy and Leiden University Medical Center, Leiden, the Netherlands) were selected. Relevant information was collected from the medical records at both centers. In total, 171 patients met the selection criteria. The overall survival rate for all patients was 48% at 1 year, 24% at 2 years, 12% at 3 years, 6% at 4 years, and 2% at 5 years. Patients with unresectable, locally advanced disease without distant metastases had a significantly better survival than patients with metastatic disease (P = .0014). Systemic treatment, consisting of either doxorubicin-based chemotherapy or the noncytotoxic drugs imatinib and sirolimus, improved survival significantly compared with no treatment (P = .0487). For patients who had locally advanced disease without metastases, radiotherapy was associated with a survival benefit (P = .0032). This study provides a standard for overall survival rates after a diagnosis of unresectable conventional central chondrosarcoma. Systemic treatment and radiotherapy may improve survival, although selection bias because of the retrospective nature of this study may have influenced the outcome. The poor survival underlines the need for new therapeutic options for this patient population. Cancer 2014;120:3159-3164. © 2014 American Cancer Society.

Giants of orthopaedic surgery: Carlos E. Ottolenghi MD (1904-1984).

Giants of orthopaedic surgery: Carlos E. Ottolenghi MD (1904-1984).

Preface

This year marks the 75th anniversary of the introduction to modern surgery of the revolutionary nail developed by Prof G. Kuntscher. His intuitions and studies as well as his techniques of closed intramedullary (IM) nailing of long bone fractures, continue to remain a pivotal cornerstone in orthopedic culture and practice. In Italy in the early 80s, the widespread use of IM nailing for mid-shaft femur or tibia fractures was relegated to major academic hospitals. The Rizzoli Institute in Bologna that I attended as an orthopedic resident was one of them, where innovative surgeons such as L. Gui and M. Campanacci were practicing. Bob D’ Ambrosia from New Orleans was always fascinated and interested with new techniques or implants. In the mid 80s he took me to Strasbourg, France to observe firsthand the results of the modified Kuntscher nail that Arsene Grosse had developed, the G-K nail. Subsequently, I exchanged Ilizarov’s know-how with nailing technique pearls in Memphis with Charlie Taylor, of the closed-section Russell-Taylor nail. Then I had the opportunity to learn the tip and tricks of IM nailing directly from the TIO Editor-in-Chief, Bruce Browner, in Houston, in the late 80s, working at Hermann Hospital. Dr Browner was introduced to the system by “Sig” Hansen from Seattle and subsequently mastered his experience at Shock Trauma in Baltimore with colleagues such as Brumback, Burgess, and Poka. Thus, not only I learned from the masters, but I have been a first-line spectator of historical changes in intramedullary stabilization of long bone fracture with reamed nails. Intramedullary nailing, truly one of my passions in orthopedic traumatology, remains a challenging art, an act of surgery that is performed daily on thousands of individuals all over the globe and where no single fracture is identical to the other. Major successions of changes and improvements have been made in nail design, metallurgy, and radiographic imaging. Still, preoperative planning, positioning of the patient and selection of treatment options continue to remain of paramount importance. This issue of Techniques in Orthopaedics contains the first of two parts dedicated to “Updates on Intramedullary Nailing.” I have selected some of the most comprehensive new aspects of intramedullary nailing, in traumatology as well as in reconstructive surgery. An international faculty shares it expertise, presenting new management approaches to help understanding and solving old problems, from limb lengthening to stabilization of femur, tibia, and femoral neck fractures. Articles that discuss up-to-date clinical evidence of compartment syndrome as well as original improved contemporary technical optional approach for tibia fractures are included. Contributions from Europe in the field of antibiotic-coated implants as well as the latest on lengthening over a nail are presented. A major thank you goes to Bruce Browner, who never ceases to impress me with his extraordinary, contagious enthusiasm about new projects. I hope that I have been able to pass it myself to some other young orthopedic trauma surgeon. This two-part TIO series is dedicated to all those whom I have lost and in particular to Mrs Florence L. Nathan: without her I would have not been where I am and a lot might have not been achieved.

Review of Foot Tumors Seen in a University Tumor Institute

Most tumors of the foot and ankle will be benign, and it has been easy for clinicians to underestimate the malignant potential of a given tumor. The purpose of our study was to gain insight into the incidence of different tumor types diagnosed in patients with tumors of the foot and/or ankle treated at the Rizzoli Institute from September 1990 to December 2007. Our series included 1170 patients and 1170 lesions, with an overall mean age at diagnosis of 43 (range 5 to 81) years. Overall, 870 lesions (74.36%) were nonmalignant and 300 (25.65%) were malignant. Soft tissue lesions were diagnosed in 189 patients (16.15%), of which 91 (48.15%) were nonmalignant (pseudotumors or benign). Bone lesions were diagnosed in 981 patients (83.85%), of which 779 (79.41%) were nonmalignant. Epidemiologic knowledge of foot abnormalities and clinical suspicion, an organized diagnostic method, and evidence-based treatment of musculoskeletal tumors are essential elements to obtaining optimal results in the treatment of malignant foot tumors.

MDM2 and CDK4 expression in periosteal osteosarcoma

Periosteal osteosarcoma is defined by World Health Organization as an intermediate-grade, malignant cartilage and bone forming neoplasm arising on the surface of bone. At difference to the other subtypes of osteosarcoma, in literature no data has been published about MDM2 and CDK4 expression. For this, we evaluate the immunohistochemistry expression of MDM2 and CDK4 to detect overexpression caused by gene amplification in 18 cases of periosteal osteosarcoma, surgically treated in Rizzoli Institute between 1981 and 2013. All but one case (17/18, 94.4%) were negative for MDM2 and CDK4 using immunohistochemistry. The positive case shows a strong nuclear expression of both antibodies in the prevalent cartilaginous component and in the spindle cells of peripheral fibroblastic areas associated with osteoid-producing. In conclusion, at difference to low grade central osteosarcoma and parosteal osteosarcomas, MDM2 and CDK4 are very rarely expressed in periosteal osteosarcoma and therefore do not appear to be a molecule central to the control of cancer development, growth and progression in periosteal osteosarcoma. These two markers can be used diagnostically to differentiate these subtypes of osteosarcoma and underline a different genetic pathway for the pathogenesis of this rare subtype of osteosarcoma. Periosteal osteosarcoma is defined by World Health Organization as an intermediate-grade, malignant cartilage and bone forming neoplasm arising on the surface of bone. At difference to the other subtypes of osteosarcoma, in literature no data has been published about MDM2 and CDK4 expression. For this, we evaluate the immunohistochemistry expression of MDM2 and CDK4 to detect overexpression caused by gene amplification in 18 cases of periosteal osteosarcoma, surgically treated in Rizzoli Institute between 1981 and 2013. All but one case (17/18, 94.4%) were negative for MDM2 and CDK4 using immunohistochemistry. The positive case shows a strong nuclear expression of both antibodies in the prevalent cartilaginous component and in the spindle cells of peripheral fibroblastic areas associated with osteoid-producing. In conclusion, at difference to low grade central osteosarcoma and parosteal osteosarcomas, MDM2 and CDK4 are very rarely expressed in periosteal osteosarcoma and therefore do not appear to be a molecule central to the control of cancer development, growth and progression in periosteal osteosarcoma. These two markers can be used diagnostically to differentiate these subtypes of osteosarcoma and underline a different genetic pathway for the pathogenesis of this rare subtype of osteosarcoma.

Osteoblastoma of the Sacrum

Retrospective case series. (1) To analyze clinical and radiographical characteristics, treatment, and outcome in patients with sacral osteoblastoma, (2) to evaluate progression-free survival and local recurrence rate, and (3) to identify prognostic factors. Osteoblastoma is a rare tumor that has been reported to affect the sacrum from 7% to 17%. Symptoms are various and the diagnosis is often delayed. From 1980 to 2010, 18 patients with sacral osteoblastoma (16 males and 2 females) were treated at Rizzoli Institute. Lesion involved S1 (2 cases), S1-S2 (3 cases), S2 (1 case), S2-S3 (1 case), S2-S4 (1 case), S3 (2 cases), S3-S4 (5 cases), S4 (1 case), and almost the entire sacrum in 2 cases. According to Enneking classification for benign bone tumors, 13 (72%) were diagnosed at stage 2 and 5 (28%) at stage 3. Mean tumor volume was 64 cm (range, 2-441 cm). Nine patients had preoperative magnetic resonance imaging. Five patients had a previous inadequate intralesional surgery elsewhere. Treatment consisted in intralesional surgery (16 cases), intralesional surgery and radiotherapy (1 case), and wide resection (1 case). Local adjuvants used were phenol (7 patients), cryocoagulation with "iceball" technique (1 case). Embolizations were performed in 7 patients. At a mean of 8.4 years (range, 1-28 yr), 15 patients (83%) remained continuously disease free, whereas 3 patients had local recurrence (17%). Progression-free survival was 87% at 5 years and 74% at 10 years. No statistical difference was found between patients who received or not local adjuvants (P = 1.254), older or younger than 20 years (P = 0.970), at stage 2 or 3 (P = 0.826), evaluated preoperatively with or without magnetic resonance imaging (P = 0.160), primarily treated versus patients with previous intralesional surgery elsewhere (P = 0.131). In our series, curettage was successful in most of the patients. Local adjuvants did not seem to reduce the risk of local recurrence when combined with intralesional surgery. 4.

Synovial sarcoma: Is chemotaxis important to tumor progression?

10571 Background: Synovial sarcoma (SS) is a rare and aggressive soft tissue tumor. In a first study (Palmerini E, Cancer 2009) we analyzed clinical prognostic factors in a retrospective series of 250 patients (pts) who were treated at Rizzoli Institute between 1976 and 2006. Stage, age, size, histology and use of radiotherapy influenced survival, whereas the role of chemotherapy was unproven. In the present study on the same patient population, in order to identify new prognostic factors and potential therapeutic targets, a panel of markers involved in chemotaxis and tumor growth were assessed. Methods: The expression of the chemokine receptor CXCR4 (a marker for chemotaxis which plays a critical roles in cancer progression) and the insulin-like growth factor receptor-1 (IGFR1) (a marker of growth activation ) were evaluated by IHC staining. Results: Tissue samples were available for the analysis in 88 patients (45 female and 43 male); median age was 37 years (range 11-63); size of the lesion was &gt; 5 cm in 60 patients (71%); histology was biphasic in 30 (34%) of patients. All pts underwent surgery, 56% of pts underwent adjuvant radiotherapy (RT) and 68% adjuvant chemotherapy. With a median follow-up of 6 years (1-30 years), the 5-year overall survival (OS) was 70% (60-81). A positive stain for IGFR1 was detected in 55 pts (62.5%), with expression in the nucleus in 21 pts. CXCR4 was expressed in 74 pts (84%), nuclear pattern in 31 pts. No relation between IGFR1 and CXCR4 expression and clinical variables was found. The 5-year OS was 63% (95%CI 41-85%) for pts with positive IGFR1/nuclear expression and 73% (95%CI 61-85%) p = 0.05, in pts with negative IGFR1/nuclear staining. Similarly, the 5-year OS was 47% (95%CI 27-66%) in patients with positive CXCR4/nuclear expression and 86% (95%CI 76-96%), p = 0.003, in negative cases. In a multivariate analysis including age, histology, size and use of RT, nuclear expression of IGFR1 and CXCR4 were confirmed statistically significant independent factor for OS. Conclusions: The nuclear expression of CXCR4 or IGFR1 negatively influences the survival in patients with SS. Further studies addressing the role of CXCR4 as a potential target in this high risk subgroup of SS patients are needed.