Translation and preliminary validation of the English version of the DUX questionnaire for lower extremity bone tumor patients (Bt-DUX): a disease-specific measure for quality of life.

PURPOSE: To translate the Dutch DUX questionnaire for lower extremity bone tumor patients (Bt-DUX), a disease-specific quality of life (QoL) instrument, into the English (UK) language and preliminary validate the English version in patients who were treated for lower-extremity bone tumors. METHODS: Adaptation and translation process included forward translation, back-translation, and a review of the back-translation by an expert committee. Internal consistency and validity of the translated questionnaire were examined in a sample of adolescents treated for lower extremity osteosarcoma in the United Kingdom. Assessments included the Bt-DUX, the Toronto Extremity Salvage Score (TESS), the Short Form (SF)-36, and the TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL). RESULTS: Seventeen patients (7 ♂ and 10 ♀), median age 19.9 (range: 16-25) years completed the questionnaires. Mean Bt-DUX score was 38.8 (range: 23-78), with Cronbach's α being 0.95 domain-total correlations ranged between 0.84 and 0.93 (P < 0.01). Spearman's correlation coefficients between the Bt-DUX total and domain scores and corresponding TAAQOL and SF-36 scores were overall moderate to good and reaching statistical significance in a most cases. CONCLUSION: Preliminary evidence suggests that the English Bt-DUX translation is a valid disease-specific instrument for evaluating QoL of adolescents with lower extremity bone cancer.

Surgical technique: Tibia cortical strut autograft interposition arthrodesis after distal radius resection.

BACKGROUND: Distal radius reconstruction after en bloc tumor resection remains a surgical challenge. Although several surgical techniques, either reconstructing the wrist or achieving a stable arthrodesis, have been described, it is unclear to what degree these restore function. DESCRIPTION OF TECHNIQUE: We describe an updated technique making use of a tibia cortical strut autograft (TCSA) to perform a functional arthrodesis from the remaining radius to the first carpal row. This, in theory, could lead to less donor site morbidity while resulting in a stable but functional and pain-free arthrodesis of the wrist. METHODS: Between 1987 and 2010 we reconstructed the wrists of 17 patients using a TCSA arthrodesis (six primary and three revisions), seven with an osteoarticular allograft, three using an ulnar translocation, and one with a fibula autograft. Median age at diagnosis was 24 years (range, 9-58 years) and minimum followup was 2.7 years (median, 13.8 years; range, 2.7-24.5 years). Patients were evaluated using radiographs and clinical examination. We used Musculoskeletal Tumor Society (MSTS), Disabilities of the Arm, Shoulder, and Hand (DASH), and SF-36 questionnaires to assess function and quality of life. RESULTS: All TCSA reconstructions fused; one patient had a second surgery to expedite union with the carpal row. After osteoarticular allograft, five patients were revised (three to a TCSA) for nonunion, fracture, or joint collapse. ROM and grip strength were comparable in both AO and TCSA, all above 60% of the contralateral side. Median MSTS and DASH scores were 73% and 6, respectively, and did not differ between the groups. The SF-36 scores showed less pain after TCSA; otherwise, all patients presented with comparable function. CONCLUSIONS: TCSA wrist arthrodesis resulted in a functional and painless wrist reconstruction with a relatively low complication and donor site morbidity rate and comparable functional results as other techniques. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Hemiarthroplasties in young patients with osteonecrosis or a tumour of the proximal femur; an observational cohort study.

BACKGROUND: The failure scenario in total hip arthroplasty (THA), in younger patients, is dependent on the fixation and wear of the acetabular component. In selected cases, where endoprosthetic replacement of the femoral head is unavoidable for limb salvage or functional recovery, hemiarthroplasty can be chosen as an alternative. The purpose of this study is to evaluate hemiarthroplasty as treatment strategy for young patients with osteonecrosis or a tumour of the proximal femur. METHODS: Between 1985 and 2008, 42 hemiarthroplasties (unipolar and bipolar) were performed in patients younger than 65 years with osteonecrosis (n=13) or a tumour of the proximal femur (n=29). All patients were seen at yearly follow-up examination and evaluated. Revision or conversion to a THA was regarded as a failure of the implant. A Kaplan Meier analysis was performed. To determine significant differences between categorical groups, the Pearson chi-square test was used. In numerical groups the independent T-test and One-way ANOVA were used. RESULTS: After a mean follow-up of 7.1 years, failure of the hemiarthroplasty occurred 6 times. The Kaplan Meier survival analysis with conversion to THA or revision as endpoint of the bipolar hemiarthroplasties (n=38) shows a 96% survival at 15, and 60% at 20 years. In the unipolar type (n=4) we found a conversion rate of 50% within 3 years. CONCLUSIONS: Bipolar hemiarthroplasty is a reasonable alternative in a young patient with osteonecrosis or a tumour of the proximal femur as indication. Because of the high conversion rate after unipolar hemiarthroplasties, we would not recommend this type of prosthesis in the young patient.

A prospective study on quality of life and functional outcome in children and adolescents after malignant bone tumor surgery.

BACKGROUND: Few longitudinal data are available concerning quality of life (QoL) and functioning of young patients undergoing surgical procedures for malignant bone tumors around the knee joint. Aim of the present study was to evaluate patients' quality of life, functional ability, and physical activity during a 2-year postoperative period. METHODS: This prospective study included patients who underwent surgery for a malignant bone tumor around the knee joint between 2004 and 2008. Assessments were done at 3, 6, 9, 12, 18, and 24 months after surgery. QoL was measured with the TNO-AZL Children's or Adult's Quality of Life Questionnaires (TACQOL and TAAQOL), the Short Form-36 (SF-36) and Bone tumor (Bt)-DUX; functional ability with the Toronto Extremity Salvage Scale (TESS), the 6-minute walk test (6 MWT) and four functional performance tests; and physical activity with the Baecke questionnaire and the ActiLog® activity monitor. Statistical analysis included linear mixed model analysis. RESULTS: Forty-four patients (27 males, 17 females, mean age 14.9 (SD 4.8) years) were included, 27 (61%) underwent limb-salvage and 17 (39%) ablative surgery. Twenty patients were lost during the 2 years follow-up as a consequence of oncological complications. Over the first year, survivors showed significant improvement of QoL, functional ability and physical activity, except for the mental dimension of the SF-36 and the activity monitor results. Over the second year, these improvements were less pronounced. CONCLUSIONS: In the first 2 years after bone tumor surgery, survivors improved significantly with respect to QoL, functional ability, and physical activity levels.

Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression.

Ewing sarcoma is an aggressive round cell sarcoma with poor patient prognosis, particularly in cases of advanced-stage disease. Dynamic tumor-host immune interations within the tumor microenvironment may polarize in situ immune responses and shape tumor development and/or progression. To gain insight into the nature of tumour-host immune interactions within the Ewing sarcoma microenvironment, the presence and spatial distribution of infiltrating CD8(+) /CD4(+) T-lymphocytes were evaluated in therapy-naive Ewing sarcoma. Expression profiling of 40 different chemokines and several chemokine receptors was performed in therapy-naive tumours and cell lines by qPCR, immunohistochemistry, and flow cytometry. Considerable inter-tumour variation was observed regarding density, type, and distribution of infiltrating T-lymphocytes. Tumour-infiltrating T-cells contained significantly higher percentages of CD8(+) T-lymphocytes as compared to stroma-infiltrating cells, suggesting preferential migration of this T-cell type into tumour areas. Gene expression levels of several type 1-associated, pro-inflammatory chemokines (CXCR3- and CCR5-ligands CXCL9, CXCL10, and CCL5) correlated positively with infiltrating (CD8(+) ) T-lymphocyte numbers expressing corresponding chemokine receptors. Survival analyses demonstrated an impact of tumour-infiltrating, and not stroma-infiltrating, CD8(+) T-lymphocytes on tumour progression. At protein level, both tumour and stromal cells expressed the IFNγ-inducible chemokines CXCL9 and CXCL10. CCR5-ligand CCL5 was exclusively expressed by non-tumoural stromal/infiltrating cells. Together, our results indicate that an inflammatory immune microenvironment with high expression of type 1-associated chemokines may be critical for the recruitment of (CD8(+) ) T-lymphocytes expressing corresponding chemokine receptors. The observed impact of tumour-infiltrating (CD8(+) ) T-lymphocytes is consistent with a role for adaptive anti-tumour immunity in the prevention of Ewing sarcoma progression. Recognition of the merits and exploitation/induction of an inflammatory microenvironment may improve the efficacy of natural immune responses against, and (adoptive) immunotherapeutic approaches for, Ewing sarcoma.

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.

Chemotherapy-resistant osteosarcoma is highly susceptible to IL-15-activated allogeneic and autologous NK cells.

High-grade osteosarcoma occurs predominantly in adolescents and young adults and has an overall survival rate of about 60%, despite chemotherapy and surgery. Therefore, novel treatment modalities are needed to prevent or treat recurrent disease. Natural killer (NK) cells are lymphocytes with cytotoxic activity toward virus-infected or malignant cells. We explored the feasibility of autologous and allogeneic NK cell-mediated therapies for chemotherapy-resistant and chemotherapy-sensitive high-grade osteosarcoma. The expression by osteosarcoma cells of ligands for activating NK cell receptors was studied in vitro and in vivo, and their contribution to NK cell-mediated cytolysis was studied by specific antibody blockade. Chromium release cytotoxicity assays revealed chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines and osteosarcoma primary cultures to be sensitive to NK cell-mediated cytolysis. Cytolytic activity was strongly enhanced by IL-15 activation and was dependent on DNAM-1 and NKG2D pathways. Autologous and allogeneic activated NK cells lysed osteosarcoma primary cultures equally well. Osteosarcoma patient-derived NK cells were functionally and phenotypically unimpaired. In conclusion, osteosarcoma cells, including chemoresistant variants, are highly susceptible to lysis by IL-15-induced NK cells from both allogeneic and autologous origin. Our data support the exploitation of NK cells or NK cell-activating agents in patients with high-grade osteosarcoma.

Functional ability and physical activity in children and young adults after limb-salvage or ablative surgery for lower extremity bone tumors.

BACKGROUND: Aim of our study was to compare functional ability and physical activity in children and young adults who underwent surgery for a malignant bone tumor that was located around the knee. METHODS: This cross-sectional study included 82 patients aged 8-25 years with a follow-up of 1-5 years. The functional ability and the amount of physical activity were evaluated by means of questionnaires and objective instruments. RESULTS: Thirty nine patients underwent limb-salvage surgery (24 allograft and 15 endoprosthesis) and 43 underwent ablative surgery (27 amputations and 16 rotationplasty). Patients in the limb-salvage group were significantly older at the time of surgery than patients in the ablative group (mean age 15.2 years vs. 13.2 years, P = 0.03). Apart from significantly better scores for the timed up and down stairs and various walking activities in the limb-salvage group as compared to the ablative surgery group, no significant differences were seen for any of the outcome measures. CONCLUSIONS: One to 5 years after limb-salvage and ablative surgery due to a malignant bone tumor children and young adults do, apart from a few activities involving walking and climbing stairs, not differ with respect to overall functional ability and physical activity.

Proximal humerus reconstruction after tumour resection: biological versus endoprosthetic reconstruction.

The purpose of this study was to compare the outcome, complications and survival of the three most commonly used surgical reconstructions of the proximal humerus after transarticular tumour resection. Between 1985 and 2005, 38 consecutive proximal humeral reconstructions using allograft-prosthesis composite (n = 10), osteoarticular allograft (n = 13) or a modular tumour prosthesis (n = 14) were performed in our clinic. The mean follow-up was ten years (1-25). Of these, 27 were disease free at latest follow-up (mean 16.8 years) and ten had died of disease. The endoprosthetic group presented the smallest complication rate of 21% (n =1), compared to 40% (n = 4) in the allograft-prosthesis composite and 62% (n = 8) in the osteoarticular allograft group. Only one revision was performed in the endoprosthetic group, in a case of shoulder instability. Infection after revision (n = 3), pseudoarthrosis (n = 2), fracture of the allograft (n = 3) and shoulder instability (n = 4) were the major complications of allograft use in general. Kaplan-Meier analysis showed a significantly better implant survival for the endoprosthetic group (log-rank p = 0.002). At final follow-up the Musculoskeletal Tumour Society scores were an average of 72% for the allograft-prosthetic composite (n = 7, median follow-up 17 years), 76% for the osteoarticular allograft (n = 3, 19 years) and 77% for the endoprosthetic reconstruction (n = 10, 5 years) groups. An endoprosthetic reconstruction after transarticular proximal humeral resection resulted in the lowest complication rate, highest implant survival and comparable functional results when compared to allograft-prosthesis composite and osteoarticular allograft use. We believe that the surgical approach that best preserves the abductor mechanism and provides sufficient surgical exposure for tumour resection contributed to better functional results and glenohumeral stability in the endoprosthetic group.

Aberrant heparan sulfate proteoglycan localization, despite normal exostosin, in central chondrosarcoma.

The tumor suppressor genes EXT1 and EXT2 are involved in the formation of multiple osteochondromas, which can progress to become secondary peripheral chondrosarcomas. The most common chondrosarcoma subtype is primary central chondrosarcoma, which occurs in the medullar cavity of bone. The EXT1/EXT2 protein complex is involved in heparan sulfate proteoglycan (HSPG) biosynthesis, which is important for signal transduction of Indian hedgehog (IHH), WNT, and transforming growth factor (TGF)-beta. The role of EXT and its downstream targets in central chondrosarcomas is currently unknown. EXT1 and EXT2 were therefore evaluated in central chondrosarcomas at both the DNA and mRNA levels. Immunohistochemistry was used to assess HSPG (CD44v3 and SDC2), WNT (beta-catenin), and TGF-beta (PAI-1 and phosphorylated Smad2) signaling, whereas IHH signaling was studied both by quantitative polymerase chain reaction and in vitro. mRNA levels of both EXT1 and EXT2 were normal in central chondrosarcomas; genomic alterations were absent in these regions and in 30 other HSPG-related genes. Although HSPGs were aberrantly located (CD44v3 in the Golgi and SDC2 in cytoplasm and nucleus), this was not caused by mutation. WNT signaling negatively correlated with increasing histological grade, whereas TGF-beta positively correlated with increasing histological grade. IHH signaling was active, and inhibition decreased cell viability in one of six cell lines. Our data suggest that, despite normal EXT in central chondrosarcomas, HSPGs and HSPG-dependent signaling are affected in both central and peripheral chondrosarcomas.

Prognostic factors in pulmonary metastasized high-grade osteosarcoma.

INTRODUCTION: Resection of pulmonary metastases has previously been reported to improve outcome in high-grade osteosarcoma (OS) patients. Factors influencing survival in OS patients with pulmonary metastases are important for clinical decision making. METHODS: All 88 OS patients with pulmonary metastases either at diagnosis or during follow-up treated at the Leiden University Medical Center between January 1, 1990 and January 1, 2008 under the age of 40 were included in this study, including 79 cases of conventional, 8 cases of telangiectatic and 1 case of small cell OS. RESULTS: In total, 56 of 88 patients with pulmonary metastases were treated by metastasectomy. Resectability of pulmonary metastases was the main prognostic factor. In patients with primary non-metastatic OS, a longer relapse free interval to pulmonary metastases was significantly associated with better survival (P = 0.02). Independent risk factors determining worse survival after metastasectomy in multivariate analysis were male sex (P = 0.05), higher number of pulmonary nodules (P = 0.03), and non-necrotic metastases (P = 0.04). Whether surgery for recurrent pulmonary metastases was performed did not influence survival. Histological subtype of the primary tumor, histological response in the primary tumor after neo-adjuvant chemotherapy, occurrence of local relapse, local resection or amputation of the primary tumor and age at diagnosis did not influence outcome. CONCLUSION: This cohort of patients with detailed follow-up data enabled us to identify important risk factors determining survival in OS patients with pulmonary metastases. We demonstrate that after repeated metastasectomies, a subset of patients can be cured.

Quality of life in young patients after bone tumor surgery around the knee joint and comparison with healthy controls.

BACKGROUND: This study aimed to compare the health related quality of life (HRQoL) of children and adolescents after malignant bone tumor surgery of the leg with healthy controls. PROCEDURE: Patients between 8 and 25 years old were cross-sectional recruited. Patients under 16 years of age received the TNO (Netherlands Organization for Applied Scientific Research) and AZL (Leiden University Medical Center) Children's Quality of Life Questionnaire (TACQOL), patients aged 16 years and older received the TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL) and the Short Form-36 (SF-36). Three age- and sex-matched normative random samples, drawn from large, nationwide studies, were used for the comparison with healthy controls. Patients were interviewed regarding their most important problems related to the disease and its treatment. RESULTS: Eighty-one patients with a mean age of 16.9 years (SD 4.2) were included (41 female). Limb sparing surgery was executed in 38 patients, ablative surgery in 43 patients. In comparison with healthy controls, patients had significantly poorer HRQoL within the domains autonomy and motor function of the TACQOL, gross motor function, cognitive functioning, daily functioning and sexuality of the TAAQOL, and physical functioning, role physical, general health, and the physical and mental component summary scales of the SF-36. Patients reported limitations in physical activities, participation in sports, and cosmetic aspects as the most detrimental consequences of their disease and its treatment. CONCLUSION: In children and adolescents who underwent surgery for a malignant tumor of the leg physical, functioning was significantly impaired as compared to healthy controls.

Reduced human leukocyte antigen expression in advanced-stage Ewing sarcoma: implications for immune recognition.

Ewing sarcoma (EWS) is a tumour most commonly arising in bone, although on occasion in soft tissue, with a poor prognosis in patients with refractory or relapsed disease, despite multimodal therapy. Immunotherapeutic strategies based on tumour-reactive T and/or natural killer cells may improve the treatment of advanced-stage EWS. Since cellular immune recognition critically depends on human leukocyte antigen (HLA) expression, knowledge about HLA expression in EWS is crucial in the design of cellular immunotherapeutic strategies. Constitutive and IFNgamma-induced HLA class I expression was analysed in EWS cell lines (n = 6) by flow cytometry, using antibodies against both monomorphic and allele-specific antigens. Expression of antigen processing pathway components and beta-2 microglobulin (beta2m) was assessed by western blot. Expression of class II transactivator (CIITA), and its contribution to HLA class II expression, was evaluated by qRT-PCR, transduction assays, and flow cytometry. beta2m/HLA class I and class II expression was validated in EWS tumours (n = 67) by immunofluorescence. Complete or partial absence of HLA class I expression was observed in 79% of EWS tumours. Lung metastases consistently lacked HLA class I and sequential tumours demonstrated a tendency towards decreased expression upon disease progression. Together with absent or low constitutive expression levels of specific HLA class I loci and alleles, and differential induction of identical alleles by IFNgamma in different cell lines, these results may reflect the existence of an immune escape mechanism. Inducible expression of TAP-1/-2, tapasin, LMP-2/-7, and the beta2m/HLA class I complex by IFNgamma suggests that regulatory mechanisms are mainly responsible for heterogeneity in constitutive class I expression. EWSs lack IFNgamma-inducible HLA class II, due to lack of functional CIITA. The majority of EWS tumours, particularly if advanced-stage, exhibit complete or partial absence of both classes of HLA. This knowledge will be instrumental in the design of cellular immunotherapeutic strategies for advanced-stage EWS.

Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro.

Chondrosarcomas are highly resistant to conventional radiation and chemotherapy, and surgical removal is the only option for curative treatment. Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in cell cycle control: CDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c-MYC, which may point towards new therapeutic strategies. The pRb pathway was targeted using CDKN2A/p16 overexpressing vectors and shRNA against CDK4 in chondrosarcoma cell lines OUMS27, SW1353, and CH2879. Cell survival and proliferation were assessed. CDK4, MDM2 and c-MYC expression levels were investigated by qPCR and immunohistochemistry (IHC) in 34 fresh frozen and 90 FFPE samples of enchondroma and chondrosarcoma patients. On a subset of 29 high-grade chondrosarcomas IHC for cyclin D1, p21 and p53 was performed. The overexpression of CDKN2A/p16 and knockdown of CDK4 by shRNA in OUMS27, SW1353 and CH2879 resulted in a significant decrease in cell viability and proliferation and a decreased ability to form colonies in vitro. Expression of CDK4 and MDM2 was associated with high-grade chondrosarcoma both at the mRNA and protein level. Combining these results with the expression of cyclin D1 and the previously shown loss of CDKN2A/p16 expression show that the majority (96%; 28/29) of high-grade chondrosarcomas contain alterations in the pRb pathway. This suggests a role for the use of CDK4 inhibitors as a treatment of metastatic or inoperable high-grade chondrosarcoma.

A balanced t(5;17) (p15;q22-23) in chondroblastoma: frequency of the re-arrangement and analysis of the candidate genes.

BACKGROUND: Chondroblastoma is a benign cartilaginous tumour of bone that predominantly affects the epiphysis of long bones in young males. No recurrent chromosomal re-arrangements have so far been observed. METHODS: We identified an index case with a balanced translocation by Combined Binary Ratio-Fluorescent in situ Hybridisation (COBRA-FISH) karyotyping followed by breakpoint FISH mapping and array-Comparative Genomic Hybridisation (aCGH). Candidate region re-arrangement and candidate gene expression were subsequently investigated by interphase FISH and immunohistochemistry in another 14 cases. RESULTS: A balanced t(5;17)(p15;q22-23) was identified. In the index case, interphase FISH showed that the translocation was present only in mononucleated cells and was absent in the characteristic multinucleated giant cells. The t(5;17) translocation was not observed in the other cases studied. The breakpoint in 5p15 occurred close to the steroid reductase 5alpha1 (SRD5A1) gene. Expression of the protein was found in all cases tested. Similar expression was found for the sex steroid signalling-related molecules oestrogen receptor alpha and aromatase, while androgen receptors were only found in isolated cells in a few cases. The breakpoint in 17q22-23 was upstream of the carbonic anhydrase x (CA10) gene region and possibly involved gene-regulatory elements, which was indicated by the lack of CA10 protein expression in the index case. All other cases showed variable levels of CA10 expression, with low expression in three cases. CONCLUSION: We report a novel t(5;17)(p15;q22-23) translocation in chondroblastoma without involvement of any of the two chromosomal regions in other cases studied. Our results indicate that the characteristic multinucleated giant cells in chondroblastoma do not have the same clonal origin as the mononuclear population, as they do not harbour the same translocation. We therefore hypothesise that they might be either reactive or originate from a distinct neoplastic clone, although the occurrence of two distinct clones is unlikely. Impairment of the CA10 gene might be pathogenetically relevant, as low expression was found in four cases. Diffuse expression of SRD5A1 and sex steroid signalling-related molecules confirms their role in neoplastic chondrogenesis.

The Bt-DUX: development of a subjective measure of health-related quality of life in patients who underwent surgery for lower extremity malignant bone tumor.

BACKGROUND: To examine the practical applicability, internal consistency, and validity of the Bt-DUX, a disease-specific Health Related Quality of Life (HRQoL) instrument. The Bt-Dux was developed to examine patients' individual values of their life after a malignant bone tumor of the lower extremity at four domains (cosmetic, social, emotional, and functional). PROCEDURE: Patients were eligible for this cross-sectional, multicenter study if they underwent surgery for a malignant tumor of the leg in a period ranging between 12 and 60 months before the recruitment. Assessments included: Bt-DUX, Toronto Extremity Salvage Score (TESS) Short Form (SF)-36, TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL), and TNO-AZL Children's Quality of Life Questionnaire (TACQOL). RESULTS: Seventy-two patients (35 male, 37 female), mean age 17 (SD 4) years were included. Limb sparing surgery took place in 32 patients and ablative surgery in 40 patients. The Bt-DUX was completed in less than 5 min and easy to comprehend. The mean Bt-DUX score was 69.8 (SD 15.5), with Cronbach's alpha being 0.92. Domain-total correlations ranged between 0.84 and 0.88 (P < 0.01). Correlations between Bt-DUX Total score and TESS, SF-36 Physical and Mental Component Summary scales and selected TACQOL and TAAQOL scores were statistically significant (P < 0.05), except for the social scale of the TACQOL. The Bt-DUX was able to discriminate between patients with higher and lower TESS scores (P < 0.05). CONCLUSION: The Bt-DUX was found to be a practical and valid instrument. Its added value compared with existing HRQoL measures needs to be further established.

Dedifferentiated chondrosarcoma: prognostic factors and outcome from a European group.

BACKGROUND: Dedifferentiated chondrosarcoma has a very poor prognosis. Because of its rarity, there are few large studies of outcome which might identify potential prognostic factors. In particular there remains uncertainty about the value of chemotherapy for this condition. METHOD: A retrospective study was done using data supplied by members of the European Musculo Skeletal Oncology Society (EMSOS). We obtained data on 337 patients from nine European centres with this rare condition, with details on patients, treatment and outcome which were then analysed in an attempt to identify prognostic features. RESULTS: The median age was 59 years and there was a slight predominance of males (53%). The most common sites were the femur and pelvis. Twenty-nine percent of patients with a long bone tumour had a pathological fracture. 71 patients (21%) had metastases at the time of diagnosis and these patients had a median survival of 5 months with a 10% chance of survival at 2 years. For the 266 patients without metastases at diagnosis, 254 underwent surgery with 79% having limb salvage. Thirty-one percent of these 266 patients had chemotherapy with 47% of those under 60 receiving it. In this group of 266 patients, overall survival was 28% at 10 years and poor prognostic factors were the presence of a pathological fracture at diagnosis, a pelvic location and increasing age. Local recurrence and overall survival were related to inadequate margins of excision. We did not find that the histological subtype, size of the tumour or the use of chemotherapy significantly affected outcome. For all patients the overall survival was 24% at 5 years. CONCLUSIONS: The prognosis for patients with dedifferentiated chondrosarcoma remains dismal. Surgery with clear margins remains the principal treatment for this condition. Further use of chemotherapy should be within a trial or treatment protocol.

Detection and molecular cytogenetic characterization of a novel ring chromosome in a histological variant of Ewing sarcoma.

Ewing sarcoma/peripheral primitive neuro-ectodermal tumor (PNET) is a round-cell sarcoma that may show varying degrees of neuro-ectodermal differentiation. These tumors are identified by a characteristic round-cell morphology and immunohistochemical profile, as well as by specific translocations involving the EWS gene on chromosome 22 and the 3' portion of the E26 transformation-specific family of transcription factors. These translocations result in fusion proteins that act as aberrant transcription factors. The majority of Ewing sarcoma cases are characterized by a balanced t(11;22). Specific chromosomal abnormalities often correlate with distinct morphologic or phenotypic subtypes of tumors and play an important role in prognosis. Here we describe the molecular cytogenetic investigation of a case of Ewing sarcoma in the proximal humerus of a 39-year-old male using COBRA (combined binary ratio labelling) fluorescent in situ hybridization karyotyping, array comparative genomic hybridization, and EWS-gene specific fluorescence in situ hybridization. Multiple chromosomal aberrations were identified, including a der(22)r(20;22), resulting in an amplification of the proximal region of the EWS gene. This is the first time that both translocation and amplification involving the EWS gene and an unidentified gene are described. This case adds to the spectrum of both morphology and genetic rearrangements in Ewing sarcoma, and shows the importance of combined molecular cytogenetic approaches in identifying uncommon rearrangements in sarcomas.

Periosteal osteosarcoma--a European review of outcome.

Periosteal osteosarcoma is a rare primary malignant bone tumour. Treatment is by surgical excision, but controversy remains about the value of chemotherapy. The members of the European Musculo Skeletal Oncology Society (EMSOS) collaborated to produce a dataset of 119 patients. The predominant site for the tumour was the femur, followed by the tibia. All but 2 patients underwent surgery, with 9 requiring amputation and the others having limb salvage. A total of 81 patients had chemotherapy, of whom 50 had neoadjuvant chemotherapy. There was no standard chemotherapy regime, but all patients receiving chemotherapy were given doxorubicin combined with at least one other agent. The overall survival was 89% at 5 years and 83% at 10 years. Eight patients developed local recurrence, of whom 5 died. Survival was related to appearance of local recurrence (P < 0.0001) but no other single factor. The use of chemotherapy was not shown to be a prognostic factor, but was used in two-thirds of the patients in this study.

Phenol levels during intralesional curettage and local adjuvant treatment of benign and low-grade malignant bone tumours.

BACKGROUND: Phenol is widely used for years as local adjuvant treatment for bone tumours. Despite its use for a long time, no information is available about the local concentration of phenol that is achieved in an individual patient, and the most sufficient and safe procedure to wash out the phenol after using it as local adjuvant. QUESTIONS/PURPOSES: 1. What is the initial local concentration of phenol in the tissue of the cavity wall after the application of phenol? 2. How quickly is phenol 85% diluted by washing the bone cavity with ethanol 96% solution? 3. Is the degree and speed of dilution influenced by the size of the cavity? 4. How many times should the cavity be rinsed to obtain sufficient elimination of phenol? METHODS: A basic science study was performed at respectively 16 and 10 patients, treated by intralesional curettage and adjuvant therapy for low-grade central chondrosarcoma of bone. Test 1:in 16 patients ten samples were collected of the mixture of phenol and ethanol from the bone cavity. Test 2:in ten patients, two biopsy samples were taken from the cavity wall in the bone during surgery. RESULTS: Phenol concentrations had wide variety in different patients, but all decreased by rinsing with ethanol. CONCLUSIONS: Ethanol 96% is effective to wash out local applicated phenol, by rinsing the bone cavity six times. The local concentration of phenol diminishes to an acceptable concentration of 0.2%. This study provides new insights to safely further improve the surgical technique of intralesional treatment of bone tumours.