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... Show moreBackground. 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. Show less
AIM Since the introduction of chemotherapy, survival in localised high-grade osteosarcoma has improved considerably. However, there is still no worldwide consensus on a standard chemotherapy... Show moreAIM Since the introduction of chemotherapy, survival in localised high-grade osteosarcoma has improved considerably. However, there is still no worldwide consensus on a standard chemotherapy approach. In this systematic review evidence for effectiveness of each single drug and the role of response guided salvage treatment of adjuvant chemotherapy are addressed, whereas in a meta-analysis the number of drugs in current protocols is considered. METHODS A systematic literature search for clinical studies in localised high-grade osteosarcoma was undertaken, including both randomised and non-randomised trials. Historical clinical studies from the pre-chemotherapy era were included for comparison purposes. RESULTS Nine historical studies showed a long-term survival of 16% after only local treatment. Fifty single agent phase II studies showed high response rates for adriamycin (A, 43%), ifosfamide (Ifo, 33%), methotrexate (M, 32%), cisplatin (P, 26%) but only 4% for etposide (E). In 19 neo-adjuvant studies the mean 5-year event free survival (EFS) was 48% for 2-drug regimens and 58% for ⩾3 drug regimens, with a 5-year overall survival (OAS) of 62% and 70%, respectively. Meta-analysis showed that ⩾3 drug regimens including methotrexate plus adriamycin plus cisplatin (plus ifosfamide) (MAP(Ifo)) had significant better outcome (EFS: HR=0.701 (95% confidence interval [95% CI]: 0.615-0.799); OAS: HR=0.792 (95% CI: 0.677-0.926) than 2-drug regimens, but there was no significant difference between MAP and MAPIfo (or plus etoposide). Salvage of poor responders by changing drugs, or intensifying treatment postoperatively has not proven to be useful in this analysis. CONCLUSION Meta-analysis in patients with localised high-grade osteosarcoma shows that 3-drug regimens, for example MAP are the most efficacious drug regimens. Show less
PURPOSE: To systematically review published studies comparing Quality of Life (QoL), functional ability and/or physical activity between different surgical interventions due to a malignant bone... Show morePURPOSE: To systematically review published studies comparing Quality of Life (QoL), functional ability and/or physical activity between different surgical interventions due to a malignant bone tumour of the leg. METHODS: A systematic literature search, covering the years 2000-2010 was performed using the PubMed, Embase, Web of science and Cochrane databases. Studies were included if they described and statistically compared QoL, functional ability and/or physical activity of at least two surgical interventions for lower extremity bone cancer. In addition, the methodological quality of the selected studies was evaluated by using a 24-point scale. Where appropriate, a qualitative analysis or meta-analysis was performed. RESULTS: The search strategy resulted in a list of 246 citations. Based on titles and abstracts 50 full-text articles were selected, of which 13 articles describing 12 studies, were finally included. Overall, the methodological quality of the studies was moderate. Studies were heterogeneous with respect to their categorisation of surgical interventions, average age of patients and average duration of follow-up. Overall, results regarding differences between ablative and limb-sparing surgery varied largely. Meta-analysis was considered to be not appropriate due to clinical heterogeneity, methodological differences and flaws. CONCLUSION: Twelve studies comparing the outcomes of QoL, functional ability and physical activity between limb-sparing and ablative surgery groups were identified, with an overall moderate methodological quality. Their largely varying outcomes suggest that no general conclusions on the advantage of either limb-sparing or ablative surgery in patients with malignant bone tumours of the lower extremity can be drawn. Show less
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... Show moreHigh-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. Show less
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... Show moreHigh-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. Show less
Gelderblom, H.; Jinks, R.C.; Sydes, M.; Bramwell, V.H.C.; Glabbeke, M. van; Grimer, R.J.; ... ; European Osteosarcoma Intergrp 2011
BACKGROUND Recurrence after osteosarcoma usually leads to death; thus prognostic factors for survival are of great importance. METHODS Between 1983 and 2002, the European Osteosarcoma Intergroup... Show moreBACKGROUND Recurrence after osteosarcoma usually leads to death; thus prognostic factors for survival are of great importance. METHODS Between 1983 and 2002, the European Osteosarcoma Intergroup accrued 1067 patients to 3 randomized controlled trials of pre- and post-operative chemotherapy for patients with resectable non-metastatic high-grade osteosarcoma of the extremity. Control treatment in all trials was doxorubicin 75 mg/m² and cisplatin 100mg/m². The comparators were additional high-dose methotrexate (BO02), T10-based multi-drug regimen (BO03) and G-CSF intensified-DC (BO06). Post-recurrence survival (PRS) was investigated on combined data with standard survival analysis methods. RESULTS Median recurrence-free survival was 31 months; 8 recurrences were reported more than 5 years after the diagnosis. In 564 patients with a recurrence (median 13 months post-randomisation), there was no difference in post-relapse survival between treatment arms. Patients whose disease recurred within 2 years after randomization had a worse prognosis than those recurring after 2 years. Patients with good initial histological response to pre-operative chemotherapy had a better overall survival after recurrence than poor responders. Local relapse was more often reported after limb-saving procedures (2 versus 8%; amputation versus limb-saving), independent of the primary tumour site. Site of first recurrence (local 20%, lung 62%, "other" 19%) affected survival, as patients recurring with non-lung distant metastases only or any combination of local relapse, lung metastases and non-lung metastases (=group "other") had significantly worse overall survival (local 39%, lung 19%, "other" 9% at 5 years). CONCLUSIONS These data describing a large series of patients with recurrent extremity osteosarcoma confirm the relationship between early recurrence and poor survival. There was better PRS in patients after good histological response to pre-operative chemotherapy, or with local-only recurrence. Show less
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... Show moreEwing 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 IFN gamma-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. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Show less
