Primary High-grade Osteosarcoma Research Articles

Prediction of tumor response to neoadjuvant chemotherapy in high-grade osteosarcoma using clustering-based analysis of magnetic resonance imaging: an exploratory study.

To evaluate the ability of magnetic resonance imaging (MRI)-based clustering analysis to predict the pathological response to neoadjuvant chemotherapy (NACT) in patients with primary high-grade osteosarcoma. Twenty-two patients were included in this retrospective study. All patients underwent MRIs before and after NACT. The entire tumor volume was manually delineated on post-contrast T1-weighted images and subsegmented into three clusters using the K-means algorithm. Histogram-based parameters were calculated for each lesion. The response to NACT was obtained from the histopathological assessment of the tumor necrosis rate following resection. The Mann-Whitney test was used to compare poor and fair-to-good responders. The receiver operating characteristic curve was used to evaluate the diagnostic performance of the optimal parameters. At baseline, poor responders showed a significantly larger volume of cluster1 (Vol1) than fair-to-good responders (p = 0.038). After NACT, they exhibited a lower 10th percentile (P10) and kurtosis (p = 0.038 and 0.002, respectively). Vol1 at baseline and P10 after NACT had an AUC of 77% (95% CI 56-98%). The kurtosis after NACT had the best discriminative power, with an AUC of 89.7% (95% CI 75-100%). The MRI-based histogram and clustering analysis provided a good ability to differentiate between poor and fair-to-good responders before and after NACT. Further investigations using larger datasets are required to corroborate our findings.

Beyond 5-year survival. A report from the Cooperative Osteosarcoma Study Group (COSS).

Prognostic factors have been well described for osteosarcoma, but analyses evaluating the further course of long-term survivors are lacking. We used the large database of the Cooperative Osteosarcoma Study Group (COSS) to perform such an analysis. The COSS database 1980-04/2019 was searched for 5-year survivors of primary high-grade central osteosarcoma of the extremities or trunk. Identified patients were analyzed for their further survival outcomes, assessing potentially prognostic and predictive factors already evident at initial disease presentation and treatment as well as their disease course during the first 5 years of follow-up. Two thousand and nine former eligible patients were identified (median age at initial diagnosis 15.1 (2.5-63.0) years; male vs. female 1149 (57.2%) vs. 860 (42.8%); extremities vs. trunk 1927 (95.9%) vs. 82 (4.1%); extremity primaries <1/3 vs. ≥1/3 of the involved bone 997 (67.8%) vs. 474 (32.2%) (456 unknown); localized vs. primary metastatic 1881 (93.6%) vs. 128 (6.4%); osteosarcoma as a secondary malignancy 41/2009 (2.0%)). Therapy starting by chemotherapy versus primary surgery 1860 (92.6%) versus 149 (7.4%); definitive tumor surgery by limb salvage versus ablative 1347 (67.0%) versus 659 (1 no surgery, 2 unknown); tumor response to preoperative chemotherapy documented for 1765 (94.9%) patients receiving neoadjuvant chemotherapy, good (<10% viable tumor) versus poor 1130 (64.0%) versus 635 (36.0%), local radiotherapy documented for 19 (0.9%) tumors. Recurrence during preceding 5 years no versus yes 1681 (83.7%) versus 328 (16.3%). Median follow-up starting 5 years after initial diagnosis 6.1 (0.002-32.2) years; 1815 survivors and 194 deaths. Overall survival after another 5/10/15/20 years 91.7%/88.9%/85.8%/83.4% for all patients; 97.5%/95.2%/92.4%/89.9% if in remission years 1-5 versus 62.7%/57.3%/53.0%/51.2% if recurrence year 1-5 (p < 0.001). Significant predictors of survival for all patients age at diagnosis (p = 0.038), tumor site (p = 0.030), having experienced the osteosarcoma as secondary malignancy (p < 0.001), tumor response to preoperative chemotherapy (p = 0.002). Multivariate Cox regression testing possible for 1759 (87.6%) patients with complete dataset: Having had a recurrence in years 1-5 (p < 0.001), older age at diagnosis (p = 0.009), and osteosarcoma as secondary malignancy (p = 0.013) retained significance. Highly important predictors of death such as the extent of tumor response to chemotherapy no longer remain valid after 5-year survival. The individual history of malignancies and their outcomes seems to gain pivotal importance. This benchmark analysis clearly defined risk factors for the further course of 5-year survivors from osteosarcoma. It argues for large disease-oriented databases as well as for very long follow-up periods. Novel findings will most likely require innovative statistical models to analyze such cohorts.

Prognostic role of the recepteur d'origine nantais (RON) expression in primary high-grade osteosarcoma

BackgroundOsteosarcoma is a common primary malignant bone tumor susceptible to distant metastasis. The clinical outcome for patients remains poor due to the resistance to chemotherapy and lacking effective therapeutic targets. Recepteur d'origine nantais (RON), a transmembrane protein of the c-MET proto-oncogene family, has been reported to contribute to the malignant progression and bone metastasis in several tumors. The present study aimed to explore the prognostic significance of RON in primary high-grade osteosarcoma. MethodsImmunohistochemistry (IHC) and western blotting (WB) were used to investigate the protein expression of RON in 80 surgically resected specimens (50 high-grade osteosarcoma specimens and 30 non-neoplastic bone tissues) and 6 cell lines. The χ2 test or independent-sample Student's t-test was used to assess the significance of RON difference between osteosarcoma and non-neoplastic bone tissues. The χ2 test and Fisher's exact test were used to analyze the association of RON with the clinicopathological features of osteosarcoma patients. Kaplan–Meier method and Cox proportional hazards model were used to assess the significance of RON for the survival of osteosarcoma patients. ResultsThe results of IHC and WB observed significant overexpression of RON in osteosarcoma specimens (P < 0.001) and osteosarcoma cell lines. Moreover, immunohistochemical high expression of RON was associated with a poor response to chemotherapy (P = 0.032) as well as worse progression-free (P = 0.003) and overall (P < 0.001) survival of osteosarcoma patients. Multivariate analysis revealed that high expression of RON was independently associated with reduced progression-free (P = 0.027, HR = 2.31) and overall survival (P = 0.004, HR = 5.06) time of osteosarcoma patients. ConclusionsThe present study demonstrated that high expression of RON held independent value for unfavorable survival in primary high-grade osteosarcoma. Its potential role as a therapeutic target for osteosarcoma treatment deserves further research.

Impact of chemotherapy-induced necrosis on event-free and overall survival after preoperative MAP chemotherapy in patients with primary high-grade localized osteosarcoma.

To assess the correlation between the histological response to preoperative chemotherapy and event-free survival (EFS) or overall survival (OS) in patients with high-grade localized osteosarcoma. Out of 625 patients aged ≤ 40 years treated for primary high-grade osteosarcoma between 1997 and 2016, 232 patients without clinically detectable metastases at the time of diagnosis and treated with preoperative high-dose methotrexate, adriamycin and cisplatin (MAP) chemotherapy and surgery were included. Associations of chemotherapy-induced necrosis in the resected specimen and EFS or OS were assessed using Cox model and the Pearson's correlation coefficients (r). Time-dependent receiver operating characteristic analysis was applied to determine the optimal cut-off value of chemotherapy-induced necrosis for EFS and OS. OS was 74% (95% confidence interval (CI) 67 to 79) at five years. Median chemotherapy-induced necrosis was 85% (interquartile range (IQR) 50% to 97%). In multivariate Cox model, chemotherapy-induced necrosis was significantly associated with EFS and OS (hazard ratio (HR) = 0.99 (95% CI 0.98 to 0.99); p < 0.001 and HR = 0.98 (95% CI 0.97 to 0.99); p < 0.001, respectively). Positive correlation was observed between chemotherapy-induced necrosis and five-year EFS and five-year OS (r = 0.91; p < 0.001, and r = 0.85; p < 0.001, respectively). The optimal cut-off value of chemotherapy-induced necrosis for five-year EFS and five-year OS was 85% and 72%, respectively. Chemotherapy-induced necrosis in the resected specimen showed positive correlation with EFS and OS in patients with high-grade localized osteosarcoma after MAP chemotherapy. In our analysis, optimal cut-off values of MAP chemotherapy-induced necrosis in EFS and OS were lower than the commonly used 90%, suggesting the need for re-evaluation of the optimal cut-off value through larger, international collaborative research. Cite this article: Bone Joint J 2020;102-B(6):795-803.

Is Microscopic Vascular Invasion in Tumor Specimens Associated with Worse Prognosis in Patients with High-grade Localized Osteosarcoma?

Other than metastases at diagnosis and histological response to preoperative chemotherapy, there are few reliable predictors of survival in patients with osteosarcoma. Microscopic vascular invasion (MVI) has been identified in the resection specimens of patients with osteosarcoma. However, it is unknown whether the MVI in resected specimens is associated with worse overall survival and higher cumulative incidence of local recurrence or metastasis in a large cohort of patients younger than 40 years with high-grade localized osteosarcoma. (1) Is MVI associated with worse overall survival and higher cumulative incidence of events (local recurrence or metastasis) in patients younger than 40 years with high-grade localized osteosarcoma? (2) What clinical characteristics are associated with MVI in patients with high-grade localized osteosarcoma? A total of 625 patients younger than 40 years with primary high-grade osteosarcoma between 1997 and 2016 were identified in our oncology database. We included patients younger than 40 years with primary high-grade osteosarcoma who underwent definitive surgery and preoperative and postoperative chemotherapy. The minimum follow-up period was 2 years after treatment. Patients with the following were excluded: metastasis at initial presentation (21%, n = 133), progression with preoperative chemotherapy precluding definitive surgery (6%, n = 38), surgery at another unit (2%, n = 13), lost to follow-up before 2 years but not known to have died (3%, n = 18), and death related to complications of preoperative chemotherapy (1%, n = 4). A retrospective pathologic and record review was conducted in the remaining 419 patients. The median follow-up period was 5 years (interquartile range [IQR] 3 to 9 years). The overall survival of the entire group (n = 419) was 67% [95% CI 63 to 72] at 5 years. Of the 419 patients, 10% (41) had MVI in their resection specimens. The Kaplan-Meier method was used to estimate overall survival. The cumulative incidence of events captured the first event of either metastasis or local recurrence. This analysis was completed with a competing risk framework: deaths without evidence of local recurrence or metastasis were regarded as a competing event. Clinical and histological variables (sex, age, tumor site, tumor largest dimension, surgical margin, chemotherapy-induced necrosis, type of surgery, histologic type of tumor, type of chemotherapy regimen, pathologic fracture, and MVI) were evaluated using the log-rank test or Gray test in the univariate analyses and Cox proportional hazard model or Fine and Gray model in the multivariate analyses. After adjusting for other factors, multivariate analyses showed that the presence of MVI in resection specimens was associated with worse overall survival and higher cumulative incidence of event (hazard ratio 1.88 [95% CI 1.22 to 2.89]; p = 0.004 and HR 2.33 [95% CI 1.56 to 3.49]; p < 0.001, respectively). A subgroup analysis demonstrated that the relationship between MVI and survival applied only to patients with a poor response to chemotherapy (less than 90% necrosis; overall survival at 5 years, MVI [+] = 24% [95% CI 11 to 39] versus MVI [-] = 60% [95% CI 52 to 66]; p < 0.001 and cumulative incidence of events at 5 years, MVI [+] = 86% [95% CI 68 to 94] versus MVI [-] = 54% [95% CI 46 to 61]; p < 0.001). The MVI (+) group had a higher proportion of patients with a poor response to chemotherapy (85% [35 of 41] versus 53% [201 of 378]; p < 0.001), involved margins (15% [6 of 41] versus 5% [18 of 378]; p = 0.021), and limb-ablative surgery (37% [15 of 41] versus 21% [79 of 378]; p = 0.022) than the MVI (-) group did. MVI is associated with lower overall survival and higher cumulative incidence of local recurrence or metastasis, especially in patients with a poor histologic response to preoperative chemotherapy. Future studies in patients treated for osteosarcoma should consider this observation when planning new trials. Level III, therapeutic study.

Survival and prognostic factors at time of diagnosis in high-grade appendicular osteosarcoma: a 21 year single institution evaluation from east Denmark

Background: Survival of patients with high-grade osteosarcoma (HOS), the most common primary bone cancer, has not improved significantly the last 30 years and the disease remains a major challenge. The purpose of this study is to evaluate survival in relation to prognostic factors at time of diagnosis among patients diagnosed with primary appendicular HOS in East Denmark between 1990 and 2010.Material and methods: 101 patients (median age = 20 years, female/male ratio = 56/45) diagnosed with primary appendicular high-grade osteosarcoma between 1990 and 2010 were included in this study. Initially, 156 patients diagnosed with osteosarcoma between 1990 and 2010 were identified through the population based Regional Database of Pathology, which covers a population of approximately 2.7 million (east Denmark). 55 patients were excluded due to (A) tumor was low grade (n = 22), (B) located in axial skeleton (n = 18), (C) incorrect diagnosis (n = 11) or (D) biopsy represented a tumor relapse from a former primary osteosarcoma (n = 4). Overall survival was evaluated using the Kaplan–Meier survival analysis and log-rank test. Prognostic factors were analyzed using uni- and multivariate cox-regression method with variables scored equally in the model. p Values <.05 were considered statistically significant.Results: The probability of 5- and 10-year survival was 51% (95% CI: 41–61) and 46% (95% CI: 36–56), respectively. Metastatic stage at diagnosis and tumor size ≥10 cm measured radiologically at the largest diameter were independent prognostic factors for decreased survival with significant increased hazard-risks of 3.5 (95% CI: 1.9–6.5) and 1.97 (95% CI: 1.1–3.6), respectively.Discussion: In this single institution evaluation of primary appendicular HOS we found 5-and 10-year survival rates consistent with international standards for this patient group. Distant metastases and tumor size ≥10 cm at the time of diagnosis were independent prognostic factors for decreased survival in our cohort. These results underline the importance of awareness and early referral from the primary sector.

CORR Insights®: A Novel System for the Surgical Staging of Primary High-grade Osteosarcoma: The Birmingham Classification.

CORR Insights®: A Novel System for the Surgical Staging of Primary High-grade Osteosarcoma: The Birmingham Classification.

A Novel System for the Surgical Staging of Primary High-grade Osteosarcoma: The Birmingham Classification.

Chemotherapy response and surgical margins have been shown to be associated with the risk of local recurrence in patients with osteosarcoma. However, existing surgical staging systems fail to reflect the response to chemotherapy or define an appropriate safe metric distance from the tumor that will allow complete excision and closely predict the chance of disease recurrence. We therefore sought to review a group of patients with primary high-grade osteosarcoma treated with neoadjuvant chemotherapy and surgical resection and analyzed margins and chemotherapy response in terms of local recurrence. (1) What predictor or combination of predictors available to the clinician can be assessed that more reliably predict the likelihood of local recurrence? (2) Can we determine a better predictor of local recurrence-free survival than the currently applied system of surgical margins? (3) Can we determine a better predictor of overall survival than the currently applied system of surgical margins? This retrospective study included all patients with high-grade conventional osteosarcomas without metastasis at diagnosis treated at one center between 1997 and 2012 with preoperative chemotherapy followed by resection or amputation of the primary tumor who were younger than age 50 years with minimum 24-month followup for those still alive. A total of 389 participants matched the inclusion criteria. Univariate log-rank test and multivariate Cox analyses were undertaken to identify predictors of local recurrence-free survival (LRFS). The Birmingham classification was devised on the basis of two stems: the response to chemotherapy (good response = ≥ 90% necrosis; poor response = < 90% necrosis) and margins (< 2 mm or ≥ 2 mm). The 5-year overall survival rate was 67% (95% confidence interval [CI], 61%-71%) and 47 patients developed local recurrence (12%). Intralesional margins (hazard ratio [HR], 9.9; 95% CI, 1.2-82; p = 0.03 versus radical margin HR, 1) and a poor response to neoadjuvant chemotherapy (HR, 3.8; 95% CI, 1.7-8.4; p = 0.001 versus good response HR, 1) were independent risk factors for local recurrence (LR). The best predictor of LR, however, was a combination of margins ≤ 2 mm and a less than 90% necrosis response to chemotherapy (Birmingham 2b HR, 19.6; 95% CI, 2.6-144; p = 0.003 versus Birmingham 1a; margin >2 mm and more than 90% necrosis HR, 1). Two-stage Cox regression model and higher Harrell's C statistic demonstrate that the Birmingham classification was superior to the Musculoskeletal Tumor Society (MSTS) margin classification for predicting LR (Harrell's C statistic Birmingham classification 0.68, MSTS criteria 0.59). A difference in overall survival was seen between groups of the Birmingham classification (log-rank test p < 0.0001), whereas the MSTS margin system was not discriminatory (log-rank test p = 0.14). Based on these observations, we believe that a combination of the recording of surgical margins in millimeters and the response to neoadjuvant chemotherapy can more accurately predict the risk of local recurrence than the current MSTS system. A multicenter collaboration study initiated by the International Society of Limb Salvage is recommended to test the validity of the proposed classification and if these findings are confirmed, this classification system might be considered the standard practice in oncology centers treating patients with osteosarcomas and allow more effective communication of margin status for research. Level IV, prognostic study.

Improvement in High-Grade Osteosarcoma Survival: Results from 202 Patients Treated at a Single Institution in Taiwan.

The aim of this study was to compare survival before and after 2004 and define the prognostic factors for high-grade osteosarcomas beyond those of typical young patients with localized extremity disease.Few studies have reported the long-term treatment outcomes of high-grade osteosarcoma in Taiwan.A total of 202 patients with primary high-grade osteosarcoma who received primary chemotherapy at Taipei Veterans General Hospital between January 1995 and December 2011 were retrospectively evaluated and compared by period (1995–2003 vs 2004–2011). Patients of all ages and tumor sites and those following or not following controlled protocols were included in analysis of demographic, tumor-related, and treatment-related variables and survival.Overall survival and progression-free survival at 5 years were, respectively, 67.7% and 48% for all patients (n = 202), 77.3% and 57.1% for patients without metastasis (n = 157), and 33.9% and 14.8% for patients with metastasis (n = 45). The survival rates of patients treated after 2004 were significantly higher (by 13%–16%) compared with those of patients treated before 2004, with an accompanying 30% increase in histological good response rate (P = .002). Factors significantly contributing to inferior survival in univariate and multivariate analyses were diagnosis before 2004, metastasis at diagnosis, and being a noncandidate for a controlled treatment protocol.By comparison with the regimens used at our institution before 2004, the current results support the effectiveness of the post-2004 regimens, which consisted of substantially reduced cycles of high-dose methotrexate and a higher dosage of ifosfamide per cycle, cisplatin, and doxorubicin, for treating high-grade osteosarcoma in Asian patients.

Assessment of extent of surgical resection of primary high-grade osteosarcoma by treating institutions: A report from the Children's Oncology Group.

Complete surgical resection of primary tumors is critical for long-term control of high-grade osteosarcoma. Uniform assessment of the extent of surgical resection is important in clinical trials, though the accuracy of this reporting has been poorly studied. We conducted a retrospective cohort study of patients 5-40 years of age with newly diagnosed high-grade resectable osteosarcoma treated as part of the AOST0331 clinical trial at Children's Oncology Group institutions. The extent of surgical resection of the primary tumor was graded as wide or radical by the treating institution. Central assessment of the extent of resection by two orthopedic oncologists was compared with institutional assessment by reviewing pathology and operative reports. We included 956 patients who had data available for central review. The extent of resection reported by treating institutions was 536/956 (56%) radical and 420/956 (44%) wide. The extent of resection assessed by central review was 162/956 (17%) radical and 794/956 (83%) wide. The overall discordance rate for the cohort was 43%. Institutional reports of radical resection in high-grade osteosarcoma significantly over-estimate the proportion of patients undergoing radical resection. This highlights the need for centralized review and improved accuracy of reporting of the extent of resection. J. Surg. Oncol. 2016;113:351-354. © 2016 Wiley Periodicals, Inc.

Pathologic fracture does not influence local recurrence and survival in high‐grade extremity osteosarcoma with adequate surgical margins

The purpose of this study was to estimate the risk factors having relationships with pathologic fracture of osteosarcoma of extremities and to evaluate the role of limb salvage surgery in this group of patients. We retrospectively analyzed 28 consecutive cases of pathologic fracture of primary high-grade localized osteosarcoma of extremities between June 1, 2001 and June 30, 2009. All patients underwent limb salvage surgery and neo-adjuvant chemotherapy. They had a median age of 14 years (range, 6-30 years). The average follow-up time was 40.7 months (range, 9-108 months). Clinicopathological factors were analyzed in relation to pathologic fracture. Their recurrence and survival rates were compared to those in cohort of 171 osteosarcoma patients without pathologic fracture who underwent limb salvage surgery during the same period at the same institution. Less than 15 years, telangiectatic histological subtype, tumor located at the proximal humerus, and radiographical manifested as osteolytic features were risk factors in relation to pathologic fracture. The overall 3- and 5-year survival rates were 50.5% and 45.4%, respectively, in the fracture group, and were not significantly different from those in the control group (71.0% and 61.9%, respectively). Of all 28 fracture patients, 4 experienced local recurrences (14.2%) and 14 developed distant metastasis (50%), which were not significantly different from the rates in the control group (8.8% and 37.4%, respectively). Limb salvage surgery with adequate margins combined with neo-adjuvant chemotherapy for pathologic fracture of osteosarcoma did not seem to significantly increase the risk of local recurrence or distal metastasis.

Role of Neo-Adjuvant Chemotherapy in the Treatment of Osteosarcoma

Osteosarcoma is a tumour characterized by the production of osteoid by malignant cells. The incidence is approximately 1 to 3 million/year. The incidence is slightly higher in males. Onset can occur at any age; however, primary high grade osteosarcoma usually occurs in the second decade of life. Historically patients with osteosarcoma were treated with immediate wide or radical amputation. Despite the treatment, 80% patients with apparently isolated disease died of distant metastases. In recent years the number of patients with osteosarcoma of the limb treated by amputation + chemotherapy has increased. In our study, we divided the patients into two groups. One group (A) was treated with amputation + adjuvant chemotherapy. The other group (B) was treated with neo-adjuvant chemotherapy + amputation followed by adjuvant-chemotherapy. In our study, the margin negativity in post surgical specimen was significantly higher (P-value 0.0007) for the group treated with neo-adjuvant chemotherapy. Local recurrence in the group treated without neoadjuvant chemotherapy was significantly more (P-value 0.0005).The systemic recurrence at the end of 6 months was higher the group treated without neoadjuvant chemotherapy (P-value 0.0169).However systemic recurrence between 6 months -1 year and 1 year - 2 years were not significant(P-values 0.1501 and 0.4902). From the above figures it may be concluded that treatment with neo-adjuvant chemotherapy + amputation + adjuvant chemotherapy had definite advantages over upfront amputation + adjuvant chemotherapy.)

MRNA expression profiles of primary high-grade central osteosarcoma are preserved in cell lines and xenografts

BackgroundConventional high-grade osteosarcoma is a primary malignant bone tumor, which is most prevalent in adolescence. Survival rates of osteosarcoma patients have not improved significantly in the last 25 years. Aiming to increase this survival rate, a variety of model systems are used to study osteosarcomagenesis and to test new therapeutic agents. Such model systems are typically generated from an osteosarcoma primary tumor, but undergo many changes due to culturing or interactions with a different host species, which may result in differences in gene expression between primary tumor cells, and tumor cells from the model system. We aimed to investigate whether gene expression profiles of osteosarcoma cell lines and xenografts are still comparable to those of the primary tumor.MethodsWe performed genome-wide mRNA expression profiling on osteosarcoma biopsies (n = 76), cell lines (n = 13), and xenografts (n = 18). Osteosarcoma can be subdivided into several histological subtypes, of which osteoblastic, chondroblastic, and fibroblastic osteosarcoma are the most frequent ones. Using nearest shrunken centroids classification, we generated an expression signature that can predict the histological subtype of osteosarcoma biopsies.ResultsThe expression signature, which consisted of 24 probes encoding for 22 genes, predicted the histological subtype of osteosarcoma biopsies with a misclassification error of 15%. Histological subtypes of the two osteosarcoma model systems, i.e. osteosarcoma cell lines and xenografts, were predicted with similar misclassification error rates (15% and 11%, respectively).ConclusionsBased on the preservation of mRNA expression profiles that are characteristic for the histological subtype we propose that these model systems are representative for the primary tumor from which they are derived.

Methotrexate for high-grade osteosarcoma in children and young adults

The majority of the currently used treatment protocols for osteosarcoma are based on a combination of doxorubicin, cisplatin, methotrexate (MTX) and/or ifosfamide, of which MTX seems to be one of the most active drugs. However, in the literature, this has not been unambiguously proven. To compare the effectiveness of treatment including MTX with treatment without MTX for children and young adults (up to 21 years) with primary high-grade osteosarcoma. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 4, 2010), MEDLINE (1966 to January 2011) and EMBASE (1980 to January 2011). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of treatment including MTX with treatment without MTX in the treatment of paediatric high-grade osteosarcoma. Two reviewers independently performed the study selection. One reviewer performed the data extraction and quality assessment, which was checked by another reviewer. We could not identify any studies in which the only difference between the treatment groups was the use of MTX.We did identify a RCT comparing MTX with cisplatin (n=30 children). The risk of bias in this study was difficult to assess due to a lack of reporting. Survival could not be evaluated, but no evidence of a significant difference in response rate between the treatment groups was identified (RR=0.44; 95% CI 0.17 to 1.13; P=0.09). A significant difference in the occurrence of toxicities in favour of MTX was identified, but with regard to quality of life treatment with cisplatin seemed to give better results.For other combinations of treatment including and not including MTX no studies were identified. Since no RCTs or CCTs in which only the use of MTX differed between the treatment groups were identified, no definitive conclusions can be made about the effects on antitumour efficacy, toxicities and quality of life of the addition of MTX to treatment of children and young adults with primary high-grade osteosarcoma. The same is true for combinations of treatment including and not including MTX other than treatment with MTX versus treatment with cisplatin. Only 1 RCT comparing MTX with cisplatin treatment was available and therefore, no definitive conclusions can be made about the effectiveness of these agents in children and young adults with primary high-grade osteosarcoma. Furthermore, this study was performed in a different treatment era. Nowadays single agent treatment of osteosarcoma is considered inadequate. Based on the currently available evidence, we are not able to give recommendations for the use of MTX in clinical practice. More high quality research is needed.

5079 Role of paclitaxel in neoadjuvant chemotherapy in stage IIA-IIIA breast cancer

Purpose: Evaluate treatment and outcome of 20 patients with radioinduced osteosarcoma (RIO). Because of previous primary tumor treatment, RIO protocols were different from others we used for non-RIO.Patients and Methods: Between 1983 and 1998, we treated 20 RIO patients, ages 4–36 years (mean 16 years), with chemotherapy (two cycles before surgery, three postoperatively). The first preoperative cycle consisted of high-dose Methotrexate (HDMTX)/Cisplatinum (CDP)/Adriamycin (ADM) and the second of HDMTX/CDP/Ifosfamide (IFO). The three postoperative treatments were performed with cycles of MTX/CDP; IFO was used as single agent per cycle repeated three times.Results: Two patients received palliative treatment because their osteosarcoma remained unresectable after preoperative chemotherapy. The remaining 18 patients had surgery (7 amputations, 11 resections); histologic response to preoperative chemotherapy was good in 8 patients, poor in 10. At a mean follow-up of 11 years (range, 7–22 years), 9 patients remained continuously disease-free, 10 died from osteosarcoma and 1 died from a third neoplasm (myeloid acute leukemia). These results are not significantly different from those achieved in 754 patients with conventional osteosarcoma treated in the same period with protocols used for conventional treatment. However, this later group had an 18% 3-year event-free survival after treatment of relapse vs. 0% in the RIO group.Conclusion: Treated with neoadjuvant chemotherapy RIO seem to have an outcome that is not significantly different from that of comparable patients with conventional primary high grade osteosarcoma (5-year event-free survival: 40% vs. 60%, p = NS; 5-year overall survival 40% vs. 67%, p < 0.01).

Long-Term Management of Craniofacial Osteosarcoma

Primary osteosarcoma of the calvarium is rare. A 22-year-old female patient was admitted for a progressively enlarging, indurated mass under her scalp for 6 months. A computed tomographic scan revealed a 4 x 3 x 2-cm3 osteolytic lesion over the right parietal cortex with a sunburst appearance. The patient underwent en bloc tumor resection using bicortical parietal craniectomy with a 2-cm margin of normal bone, including the tightly adherent periosteum over the tumor. Immediate cranioplasty was performed with split-thickness autogenous calvarial bone grafts. Histopathologic examination showed the tumor to be a primary high-grade osteosarcoma of the skull. She received postoperative chemotherapy. She has recovered well and remains without any evidence of disease at her most recent, 8-year follow-up. The key to disease-free survival in treating primary osteosarcoma of the calvarium is complete surgical resection with immediate reconstruction followed by adjuvant chemotherapy.

Neoadjuvant Chemotherapy for Osteosarcoma of the Extremities in Preadolescent Patients

Medical records of 133 patients, 10 years old or younger with primary high-grade nonmetastatic osteosarcoma of the extremities treated at the Rizzoli Institute between 1983 and 1999 with neoadjuvant chemotherapy were reviewed and compared with those of 782 patients aged 11 to 40 years treated in the same period with the same chemotherapy protocols. In comparison to the older group, the younger group had more females, more patients with normal lactic dehydrogenase levels, and more non-limb-salvage procedures (amputation or rotationplasty). Five-year event-free and overall survivals were essentially the same in the two groups (63% and 71% vs. 60% and 70%) as were the patients rescued after relapse and presently event-free (18% vs. 20%). The authors conclude that there does not seem to be any indication to treat preadolescent primary high-grade nonmetastatic osteosarcoma patients by alternative and/or more aggressive therapies.

Osteosarcoma: What did we learn from the paediatric experience for adolescents and young adults?

Abstract The term ‘osteosarcoma’ (OS) defines a primary malignant tumour of bone, characterised by the production of osteoid tissue or immature bone by malignant proliferating sarcomatous cells. Due to the variable biological features of different osteosarcoma, several varieties are included in the osteosarcoma family, with different grades of malignancy (Table 1). Of these variables, high grade primary central os- teosarcoma is the most common form and accounts for more than 80% of cases. About 85% of these patients have tumours located in the extremities, and about 15–20% of patients are metastatic at diagnosis. This tumour represents 0.2% of all malignant tumours with an incidence of three new cases/year per million population, and the majority of cases are in children and adolescents younger than 20 years of age. There- fore, it is a very rare tumour and during the course of their activity, orthopaedic surgeons or medical oncologists see about one patient with this tumour every 5 years. Thus, the interest in osteosarcoma for these specialists is quite limited. From a cultural point of view, however, this is an important tumour: (1) for the oncologist, because most current strategies using adjuvant and neoadjuvant treatments in other more common tumours (for instance breast cancer) have been formulated on the basis of results obtained in osteosarcoma;(2)for the orthopaedic surgeon because some of the new methods of surgical reconstruction devised for osteosarcoma may also be used in other orthopaedic pathologies.The present report is limited to primary high grade osteosarcoma of the extremity and will consider separately different presentations (localised, metastatic at diagnosis, relapsed).

Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases

Evaluate treatment and outcome of 20 patients with radioinduced osteosarcoma (RIO). Because of previous primary tumor treatment, RIO protocols were different from others we used for non-RIO. Between 1983 and 1998, we treated 20 RIO patients, ages 4-36 years (mean 16 years), with chemotherapy (two cycles before surgery, three postoperatively). The first preoperative cycle consisted of high-dose Methotrexate (HDMTX)/Cisplatinum (CDP)/Adriamycin (ADM) and the second of HDMTX/CDP/Ifosfamide (IFO). The three postoperative treatments were performed with cycles of MTX/CDP; IFO was used as single agent per cycle repeated three times. Two patients received palliative treatment because their osteosarcoma remained unresectable after preoperative chemotherapy. The remaining 18 patients had surgery (7 amputations, 11 resections); histologic response to preoperative chemotherapy was good in 8 patients, poor in 10. At a mean follow-up of 11 years (range, 7-22 years), 9 patients remained continuously disease-free, 10 died from osteosarcoma and 1 died from a third neoplasm (myeloid acute leukemia). These results are not significantly different from those achieved in 754 patients with conventional osteosarcoma treated in the same period with protocols used for conventional treatment. However, this later group had an 18% 3-year event-free survival after treatment of relapse vs. 0% in the RIO group. Treated with neoadjuvant chemotherapy RIO seem to have an outcome that is not significantly different from that of comparable patients with conventional primary high grade osteosarcoma (5-year event-free survival: 40% vs. 60%, p = NS; 5-year overall survival 40% vs. 67%, p < 0.01).

HCDC4 variation in osteosarcoma

The hCDC4 gene (also known as Fbw7 or Archipelago) encodes an F-box protein that is responsible for targeting cyclin E for Skp1-cullin-F box protein (SCF) ubiquitination and proteosomal degradation. Disruption of this pathway has been associated with chromosomal instability and aneuploidy in several cancer cell lines and primary tumors. This study aimed to examine whether hCDC4 mutations contribute to aneuploidy in osteosarcoma. We analyzed 147 primary high-grade osteosarcoma specimens and 6 osteosarcoma cell lines. The protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) analysis with subsequent sequencing were performed to detect alterations of the hCDC4 gene. All specimens exhibited the same PTT pattern of normal bands with less intense common bands. Two shifts were detected by SSCP, and subsequent DNA analysis identified one in-frame three-base GAG (424-426) deletion and one silent nucleotide substitution (C1261T). We conclude that somatic hCDC4 mutations are infrequent in osteosarcoma, and are unlikely to play an important role in aneuploidy of this tumor.