Methods of biological reconstruction for bone sarcoma: indications and limits.

Therapy of bone sarcoma has dramatically changed over the past few decades. Several successful interdisciplinary treatment strategies have led to an increase of the survival rates from 20% to 60%-80%. Consequently new demands on the operative treatment of bone and soft tissue sarcoma have arisen. Nowadays limb salvage can be achieved in 80%-90% using tumour megaprostheses or biological reconstruction procedures. In this article we outline the indications and limitations of biological reconstruction procedures after bone tumour resection. We therefore introduce the different biological approaches such as free autologous bone grafting, reimplantation of extracorporeal devitalized autografts or distraction osteogenesis and summarize the currently available data on the individual procedures. Our analyses demonstrate a wide applicability of biological procedures in tumour situations. Although accompanied by considerable complications in the early postoperative phase, biological reconstructions clearly demonstrate the potential of having excellent long-term durability and functionality.

Intraoperative electron boost radiation followed by moderate doses of external beam radiotherapy in limb-sparing treatment of patients with extremity soft-tissue sarcoma.

PURPOSE: To analyze long-term prognosis and morbidity after limb-sparing treatment of patients with extremity soft-tissue sarcoma, with intraoperative electron boost radiotherapy (IOERT) followed by a moderate dose of external beam radiotherapy (EBRT). METHODS AND MATERIALS: A total of 153 patients who were treated in a single center from 1991 to 2004 were evaluated. Median IOERT dose was 15 Gy, mean EBRT dose 43 Gy (range, 40-50.4 Gy) in conventional fractionation (1.8-2 Gy). Median duration of follow-up was 33 months. Acute toxicity was assessed with Common Toxicity Criteria; late toxic effects were scored according to European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group criteria. RESULTS: Five-year overall survival and 5-year local control rates were 77% and 78%, respectively. Whereas tumor size, patient age, and EBRT dose did not significantly affect outcome, resection status and grading were significant for survival; resection status and IOERT dose were significant for local control. Extremity salvage until death or time of follow-up was achieved in 90% of our patients, 86% of whom showed excellent limb function without impairment in activities of daily life. Acute toxicity Grade 2-4 was observed in 23% and late toxicity Grade 2-4 in 17% of patients. CONCLUSIONS: Treatment with IOERT combined with moderate doses of external beam irradiation yields high local control and extremity preservation rates in resected extremity soft-tissue sarcoma.

Formation of a physiological reverse shoulder joint.

Congenital shoulder deformities are rarely seen in orthopaedic practice. Proximal humeral defects and glenoid hypoplasia have been reported separately in the literature. We present a case involving a 31-year-old woman having a cosmetic problem with her upper arm who was diagnosed with reverse shoulder joint deformity. This article presents the clinical, radiological and biomechanical findings of a physiological reverse shoulder joint. This is the first such reported case.

Ewing's sarcoma and primitive neuroectodermal tumor of hand and forearm. Experience of the Cooperative Ewing's Sarcoma Study Group.

PURPOSE: Because Ewing's sarcoma (EWS) is extremely rare in the hand and forearm, only limited data are available for planning treatment or predicting prognosis. METHODS: Data of 33 patients with EWS of the forearm or hand who were enrolled in studies of the German Association for Paediatric Oncology/Haematology and the European Intergroup Cooperative Ewing's Sarcoma Study Group were analyzed. Patients received neoadjuvant multi-agent chemotherapy according to the valid protocol. Local treatment consisted of surgery (n=7), radiotherapy (n=7), or a combination of both (n=19). RESULTS: The 5/10-year overall survival rate was 84.1% (95% CI: 71.2-96.9)/74.1% (95% CI: 56.8-91.5), and both 5/10-year event-free survival rate were 71.3% (95% CI: 55.4-87.1). Only one of seven patients with secondary metastases was in remission at the time of analysis. One patient with local recurrence and another with primary metastases died. Altogether, eight of 33 patients died of their disease. The event-free survival rate was 80.6% in patients with good response to chemotherapy and 33.3% in patients with poor response. Surgery in combination with radiotherapy achieved a higher survival rate compared with radiotherapy or surgery alone. One out of two patients with non-wide margins of resection died of disease. CONCLUSIONS: The results demonstrate a remarkably high survival rate for patients with EWS of the hand and forearm.

CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors: a multicenter validated retrospective study.

Osteosarcoma is the most common primary bone tumor characterized by juvenile onset, tumor heterogeneity, and early pulmonary metastasis. Therapeutic improvement stagnates since more than two decades. Unlike major malignancies, biomarkers as prognostic factors at time of diagnosis are missing. Disease rareness hampers study recruitment of patient numbers sufficient to outweigh tumor heterogeneity. Here, we analyzed in a multicenter cohort the osteosarcoma microenvironment to reduce effects of tumor cell heterogeneity. We hypothesized that quantitative ratios of intratumoral CD8+T-cells to FOXP3+T-cells (CD8+/FOXP3+-ratios) provide strong prognostic information when analyzed by whole-slide imaging in diagnostic biopsies. We followed recommendations-for-tumor-marker-prognostic-studies (REMARK). From 150 included cases, patients with complete treatment were identified and assigned to the discovery (diagnosis before 2004) or the validation cohort (diagnosis 2004-2012). Highly standardized immunohistochemistry of CD8+ and FOXP3+, which was validated by methylation-specific gene analysis, was performed followed by whole-slide analysis and clinical outcome correlations. We observed improved estimated survival in patients with CD8+/FOXP3+-ratios above the median (3.08) compared to patients with lower CD8+/FOXP3+-ratios (p = 0.000001). No patients with a CD8+/FOXP3+-ratio above the third quartile died within the observation period (median follow-up 69 mo). Multivariate analysis demonstrated independence from current prognostic factors including metastasis and response to neoadjuvant chemotherapy. Data from an independent validation cohort confirmed improved survival (p = 0.001) in patients with CD8+/FOXP3+-ratios above 3.08. Multivariate analysis proofed that this observation was also independent from prognostic factors at diagnosis within the validation cohort. Intratumoral CD8+/FOXP3+-ratio in pretreatment biopsies separates patients with prolonged survival from non-survivors in osteosarcoma.

The role of quantitative (18)F-FDG PET studies for the differentiation of malignant and benign bone lesions.

UNLABELLED: The role of quantitative (18)F-FDG PET studies for the differentiation of benign and malignant bone lesions is still an open question. METHODS: Our evaluation included 83 patients with 37 histologically proven malignancies and 46 benign lesions. Thirty-five of the 46 benign lesions were histologically confirmed. The (18)F-FDG studies were accomplished as a dynamic series for 60 min. Evaluation of the (18)F-FDG kinetics was performed using the following parameters: standardized uptake value (SUV), global influx (Ki), computation of the transport constants K1-k4 with consideration of the distribution volume (VB) according to a 2-tissue-compartment model, fractal dimension based on the box-counting procedure (parameter for the inhomogeneity of the tumors). RESULTS: The mean SUV, the vascular fraction VB, K1, and k3 were higher in malignant tumors compared with benign lesions (t test; P < 0.05). Although the (18)F-FDG SUV was helpful to differentiate benign and malignant tumors, there was some overlap, which limited the diagnostic accuracy. On the basis of the discriminant analysis, the SUV alone showed a sensitivity of only 54.05%, a specificity of 91.30%, and a diagnostic accuracy of 74.70%. The fractal dimension was superior and showed a sensitivity of 71.88%, a specificity of 81.58%, and an accuracy of 77.14%. The combination of SUV, fractal dimension, VB, K1-k4, and Ki revealed the best results with a sensitivity of 75.86%, a specificity of 97.22%, and an accuracy of 87.69%. Bayesian analysis showed true-positive results at the level of 0.8 for a low prevalence of disease (0.235) if the full kinetic data were used in the evaluation. CONCLUSION: (18)F-FDG PET has a high specificity for the exclusion of a malignant bone tumor. Evaluation of the full (18)F-FDG kinetics and the application of discriminant analysis are required and can be used prospectively to classify a bone lesion as malignant or benign.

18F-FDG kinetics and gene expression in giant cell tumors.

UNLABELLED: 18F-FDG kinetics were evaluated by use of compartment and noncompartment models of giant cell tumors. The kinetic data were compared with the gene expression data for a subgroup of patients. METHODS: Nineteen patients with giant cell tumors were examined with PET and 18F-FDG, and tracer kinetics were assessed quantitatively. A 2-compartment model, including the transport constants k1-k4 as well as the vascular fraction (VB) for 18F-FDG, was used for evaluation of the data. A noncompartment model was used to calculate the fractal dimension of the 18F-FDG time-activity curve to assess the heterogeneity of the tracer kinetics. Furthermore, tumor specimens obtained from 5 patients were assessed with gene chip technology (U95A), and these data were compared with the quantitative 18F-FDG data. RESULTS: The giant cell tumors showed generally enhanced 18F-FDG uptake 1 h after tracer application, with a mean 18F-FDG standardized uptake value (SUV) of 4.8 (range, 1.8-9.4). Quantitative evaluation of tracer kinetics showed a preferential increase for 18F-FDG transport, with a mean k1 of 0.340. The vascular fraction accounted for 35% of the tumor volume and was high compared with those for other tumors, such as soft-tissue sarcomas. 18F-FDG kinetics were heterogeneous, with a fractal dimension of 1.3. Gene chip analysis showed that the expression of 137 genes (1.1%) exceeded the median expression value of the reference gene, beta2-microglobulin. The highest expression was observed for the gene for the small, leucine-rich proteoglycan I (biglycan), which is important for bone cell differentiation and proliferative activity. Correlation analysis revealed an association of 18F-FDG data with the expression of several genes. Mainly genes related to angiogenesis were associated with the compartment parameters. The SUV at 56-60 min was correlated with the expression of vascular endothelial growth factor A (angiogenesis) and cell division cycle 2 protein (proliferation). CONCLUSION: Despite their classification as benign tumors, giant cell tumors have generally enhanced 18F-FDG uptake, mainly attributable to an enhanced vascular fraction and increased 18F-FDG transport. A comparison of gene chip data and 18F-FDG kinetic data showed a close association of quantitative 18F-FDG results and the expression of genes related to angiogenesis.

Reconstruction of the pelvic ring using an autologous free non-vascularized fibula graft in a patient with benign fibrous histiocytoma.

BACKGROUND: Benign fibrous histiocytomas (BFH) usually presents as a small benign lesion that predominantly occurs in the skin. Only few cases of BFH arising from bone have been reported, its occurrence in pelvic bones is even rarer. CASE PRESENTATION: A 34-year-old female presented with BFH at a rare anatomical location on both sides of the os ilium which was larger than earlier reported BFH of the bone. Surgical resection was performed successfully including resection of the inner pelvic ring and reconstruction of the linea terminalis using a non-vascularized fibular autograft. At 18 months after tumor resection and reconstruction of the pelvic ring, with interposition of a free vascularized fibula graft patient has an excellent clinical oncological and functional outcome. CONCLUSION: Non vascularized fibular autograft is a useful reconstructive procedure in select patients.

Lower limb salvage surgery with MUTARS endoprostheses: 2 to 7 year results.

The reconstruction of bone defects remains a challenge in orthopaedic oncology. Allogenic and autologous bone grafts, as well as megaprostheses are well-recognised methods for bone reconstruction. Modular, both cemented and cementless, endoprosthetic systems have become more popular to bridge defects of different sizes. The clinical and radiological results of 50 consecutive patients treated with MUTARS endoprostheses between 1995 and 2000 were evaluated in a prospective clinical study. The average follow-up was 46 months (25-86 months). Clinical evaluation showed good results with an average Enneking-Score of 72% (33-100%, SD +/- 19). Radiological evaluation showed various patterns of bone remodelling including extracortical bone bridging. Early symptomatic loosening occurred in 11 cases, necessitating revision surgery. In conclusion, the use of the MUTARS Endoprosthesis may be a valuable tool in the treatment of major bone defects in the lower limb, if the problems with the first-generation design can be solved.

Local recurrence of giant cell tumor of bone after intralesional treatment with and without adjuvant therapy.

BACKGROUND: The use of adjuvants after curettage has been well established for the treatment of giant cell tumor of bone. The purpose of this study was to analyze the rates of recurrence following different types of treatment as well as the influence of various factors of tumor presentation on those rates. METHODS: The data regarding benign giant cell tumors of the appendicular skeleton from ten bone tumor centers were evaluated. Axial and malignant tumors were excluded. The recurrence rates associated with the different treatment modalities were analyzed, and hazard ratios for a recurrence were calculated for multiple factors of tumor presentation. RESULTS: The study included 384 surgical procedures, involving 256 primary and 128 recurrent tumors. The mean duration of follow-up was 64.2 months. Wide excision was performed in seventy-eight cases (20.3%), and an intralesional procedure was done in 306 (79.7%). Of the intralesional procedures, 103 (33.7%) were performed without the use of adjuvants, 102 (33.3%) included filling with polymethylmethacrylate, seventy-four (24.2%) included polymethylmethacrylate filling after phenolization, and twenty-seven (8.8%) included use of local toxins. The overall recurrence rate after the intralesional procedures was 49% when no adjuvants had been used, 22% when polymethylmethacrylate only had been used as an adjuvant, 27% when polymethylmethacrylate had been used after phenolization, and 15% when phenol or other local toxins had been used (without polymethylmethacrylate). The highest rate of recurrence (36%) after curettage with adjuvants was associated with extracompartmental tumors. Recurrent tumors were not at increased risk for another recurrence, even when they were extracompartmental. The recurrence rate following curettage of a primary tumor without the use of adjuvants (55%) was higher than that following the same treatment of a recurrent tumor (39%) (p = 0.033). CONCLUSIONS: Use of polymethylmethacrylate as an adjuvant significantly reduces the recurrence rate following intralesional treatment of benign giant cell tumors, and it appears to be the therapy of choice for primary as well as recurrent giant cell tumors of bone. The significantly better results following treatment of recurrent tumors without adjuvants compared with the results of the same treatment of primary tumors were probably related to increased surgical thoroughness brought about by the surgeon's awareness of dealing with a riskier tumor.

Prognostic significance of drug-regulated genes in high-grade osteosarcoma.

About 25-45% of patients with high-grade osteosarcoma poorly respond to chemotherapy with an increased risk of relapse and the development of metastasis. Therefore, the aim of this study was the evaluation of the prognostic value of eight previously identified drug-regulated candidate genes on osteosarcoma therapy outcome. Gene expression of 8 candidate genes was analyzed in 35 formalin-fixed, paraffin-embedded, laser-microdissected osteosarcoma biopsies. The prognostic value of these genes was evaluated by the correlation of gene expression with therapy outcome, overall survival and event-free survival in univariate and multivariate analysis. Upon univariate analysis, the expression of MALAT-1, IMPDH2, FTL and RHOA significantly correlated with response to chemotherapy. Expression of all four genes was increased in the poor responder group. Upon multivariate analysis, IMPDH2 maintained its independent prognostic value (P=0.025). Concerning the overall survival of the patients, we observed a significant association with the expression of FTL, PHB, ATAD2, ACTN1 and RRM2 as well as lactate dehydrogenase serum levels. In the subgroups of patients with high expression of these genes and those with elevated lactate dehydrogenase levels, the mean overall survival was decreased 1.7-, 1.9-, 2.2-, 2.4-, 1.5- and 4.5-fold, respectively. Except RRM2, all genes and lactate dehydrogenase serum levels remained significant in the multivariate analysis. In addition, the event-free survival was significantly decreased in the subgroups of patients with high FTL, ATAD2 and IMPDH2 expression (1.8-, 6.3- and 2.4-fold, respectively). These data demonstrate that among the identified genes are valuable markers for the prediction of osteosarcoma therapy outcome. Especially IMPDH2 and FTL are promising candidates for the stratification of osteosarcoma patients into low- and high-risk groups. Owing to their involvement in drug action these genes may further be potential targets for the modulation of drug sensitivity.

Osteoid osteoma in an ex vivo animal model: temperature changes in surrounding soft tissue during CT-guided radiofrequency ablation.

PURPOSE: To assess temperature changes in the soft tissue surrounding bone during radiofrequency (RF) ablation of osteoid osteoma in an ex vivo animal model. MATERIALS AND METHODS: Intracortical cavities were created in fresh bovine long bone specimens obtained from a slaughterhouse as models for osteoid osteoma. Three groups of three specimens each were defined according to the thickness (1, 3, and 5 mm) of the cortical bone lamella separating the nidus from the periosteum. Three thermocouples were applied to the soft tissue surrounding the bone in defined distances (0, 5, and 10 mm) from the periosteum. Before RF ablation, the thickness of the cortical bone lamella was documented at computed tomography. Specimens were heated in a 37 degrees C basin. As soon as the measured temperature in the cavity of the specimen reached 35 degrees C, RF ablation was performed for 400 seconds, with a target temperature of 95 degrees C. During RF ablation, continuous measurements were performed simultaneously with digital thermometers. No simulation of vessel perfusion was used. The effect of the thickness of residual osseous lamella and the effect of the distance between the thermocouple and the periosteum were tested with an analysis of variance. Post hoc Bonferroni tests were performed. RESULTS: Mean maximum temperatures of 69.1 degrees, 51.3 degrees, and 42.5 degrees C for 1-mm lamella; 59.2 degrees, 46.5 degrees, and 41.1 degrees C for 3-mm lamella; and 50.6 degrees, 44.8 degrees, and 40.0 degrees C for 5-mm lamella were measured 0, 5, and 10 mm, respectively, from the periosteum. Significant temperature differences were shown with analysis of variance and post hoc tests for the three groups of bone lamella thickness and distance (P < .001). CONCLUSION: In the model of osteoid osteoma, the surrounding temperature (soft tissue) during RF ablation was shown to depend on the thickness of the cortical bone lamella and the distance from the periosteum.

Megaprostheses for the treatment of malignant bone tumours of the lower limbs.

Lower limb salvage surgery remains a challenge in orthopaedic oncology. Both cemented and cementless, modular, endoprosthetic systems are widely used to treat defects of different sizes. The systems have changed over the years, and each major orthopaedic company offers a modular tumour and revision system for the lower extremities. All systems have worse long-term results compared to conventional total hip or total knee systems. This is due to the large defects that need to be bridged with a more difficult fixation in the diapyhsis of the femur and tibia and a more complex restoration of joint biomechanics. This article summarises the results of several clinical studies with different systems. Newer systems without clinical follow-up are described. We previously reported a prospective study of 50 consecutive patients treated with the MUTARS endoprostheses. The follow-up was 2-7 years. Clinical evaluation showed good results compared to other systems. The review of the literature and our own results do not validate the support or favouring of one specific system. The surgeon should choose a system with which he/she is familiar and that provides the modularity needed intraoperatively to bridge any defect in the lower limbs.

Osteosarcoma of the hand and forearm: experience of the Cooperative Osteosarcoma Study Group.

BACKGROUND: Osteosarcoma is extremely rare in the hand and forearm. Therefore, only limited data are available for planning treatment or predicting the outcome and prognosis of osteosarcoma in the peripheral upper extremity. METHODS: Epidemiological, clinical, and histopathologic data were analyzed in 39 patients with osteosarcoma of the forearm or hand who were enrolled in studies of the Cooperative German-Austrian-Swiss Osteosarcoma Study Group from 1977 to December 2000. In patients with high-grade osteosarcoma, the treatment entailed surgical resection in combination with chemotherapy, whereas patients with low-grade osteosarcoma underwent only surgery. RESULTS: The 5-year overall survival rate among the 33 patients with high-grade central osteosarcoma of the distal upper extremity was 86.2% +/- 6.4%. The 5-year event-free survival rate was 65.4% +/- 9.6%. Five of the eight patients with secondary metastases were in remission at the time of analysis. Four patients died of their disease, and two patients died of chemotherapy-related complications. The mean overall survival rate was 88.0% +/- 6.5% in patients treated by wide or radical tumor resection and was 75.0% +/- 21.7% in patients with nonwide margins of resection. Whether amputation or local resection was performed had no significant influence on the prognosis. All six patients whose osteosarcoma was not classified as high-grade central osteosarcoma were in remission at the time of analysis. CONCLUSIONS: The results demonstrate a remarkably high survival rate for patients with high-grade osteosarcoma of the hand and forearm and confirm that multiagent chemotherapy in combination with wide excision is a highly effective treatment for this malignant tumor.

Results of limb-sparing surgery with vascular replacement for soft tissue sarcoma in the lower extremity.

OBJECTIVE: To evaluate limb-salvage surgery with vascular resection for lower extremity soft tissue sarcomas (STS) in adult patients and to classify blood vessel involvement. METHODS: Subjects were consecutive patients (median age, 56 years) who underwent vascular replacement during surgery of STS in the lower limb between January 1988 and December 2003. Blood vessel involvement by STS was classified as follows: type I, artery and vein; type II, artery only; type III, vein only; and type IV, neither artery nor vein (excluded from the analysis). Patient data were prospectively gathered in a computerized database. RESULTS: Twenty-one (9.9%) of 213 patients underwent vascular resections for lower limb STS. Besides 17 type I tumors (81.0%), 3 (14.3%) type II and 1 (4.7%) type III STS were diagnosed. Arterial reconstruction was performed for all type I and II tumors. Venous replacement in type I and III tumors was performed in 66.7% of patients. Autologous vein (n = 8) and synthetic (Dacron and expanded polytetrafluoroethylene; n = 12) bypasses were used with comparable frequency for arterial repair, whereas expanded polytetrafluoroethylene prostheses were implanted in veins. Morbidity was 57.2% (hematoma, thrombosis, and infection), and mortality was 5% (embolism). At a median follow-up of 34 months, the primary and secondary patency rates of arterial (venous) reconstructions were 58.3% (54.9%) and 78.3% (54.9%). Limb salvage was achieved in 94.1% of all cases. The 5-year local control rate and survival rate were 80.4% and 52%, respectively. We observed a 5-year metastasis-free survival rate of 37.7% and found vessel infiltration and higher tumor grade (low-grade vs intermediate grade and high grade tumors) to be negative prognostic factors at univariate and multivariate analysis. CONCLUSIONS: Long-term bypass patency rates, the high percentage of limb salvage, and the oncologic outcome underline the efficacy of en bloc resection of STS involving major vessels in the lower limb. Disease-specific morbidity must be anticipated. The classification of vascular involvement (type I to IV) is useful for surgical management.

Medial gastrocnemius muscle flap in limb-sparing surgery of malignant bone tumors of the proximal tibia: mid-term results in 25 patients.

Twenty-five patients in whom the medial head of the gastrocnemius muscle was transposed to cover defects in limb-sparing surgery of malignant bone tumors in the proximal tibia were evaluated prospectively in a tumor register. Surgical technique and mid-term clinical-functional results after a mean follow-up of 4 years 6 months are presented in this study. Twenty-four of the 25 gastrocnemius muscle flaps survived without complications. In 1 patient, infection and necrosis of the transposed muscle developed 10 days after surgery, requiring revisional muscle transposition. The total revision rate after primary tumor surgery was high (48%), but this had no impact on the viability of the transposed muscle flap. The mean Musculoskeletal Tumor Society score at follow-up was 75.1% (range, 20-97%) and the mean postoperative range of motion in the operated knee was 60 deg (range, 30-100 deg). Because of its easy, safe, and quick preparation, the medial gastrocnemius muscle flap is exceptionally valuable as a means of covering defects arising during the course of this extensive tumor surgery. It guarantees a high survival rate of the transposed muscle and supports vascularity of the skin flaps, helps to reestablish joint function and mobility by stabilization and reinforcement of the extensor mechanism, and provides protection against infection.