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BACKGROUND AND OBJECTIVES We investigated the clinical significance of indeterminate pulmonary nodules (IPNs) in patients diagnosed with nonmetastatic, high-grade localized osteosarcoma. METHODS We retrospectively analyzed the clinical data of 364 patients with nonmetastatic, high-grade localized osteosarcoma. Based on pulmonary computed tomography findings at presentation, the patients were categorized into the no-nodules and the IPNs group and were further categorized into subgroups based on age (

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]; p0.001, 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]; p0.001 and cumulative incidence of events at 5 years, MVI [+] = 86% [95% CI 68 to 94] versus MVI [-] = 54% [95% CI 46 to 61]; p0.001). The MVI (+) group had a higher proportion of patients with a poor response to chemotherapy (85% [35 of 41] versus 53% [201 of 378]; p0.001), 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.

Purpose We aimed to determine the prognostic significance of lymphocyte counts and the lymphocytemonocyte ratio (LMR) in pediatric patients with osteosarcoma. Methods We retrospectively reviewed the medical records of 27 pediatric patients with localized extremity osteosarcoma, treated at the Korea Cancer Center Hospital between May 2002 and March 2016. Leukocyte counts and LMR before treatment and on day 14 (LMR14) of the first cisplatin-doxorubicin chemotherapy round were evaluated. Patients were dichotomized according to the median value of these parameters, and survival rates were compared. Results The median age of the 27 patients was 9.9 years (range, 3.2-14.1 years) and tumor sites were: distal femur (n=14), proximal humerus (n=7), proximal tibia (n=2), proximal fibula (n=2), and elsewhere (n=2). Patients were followed up on for a median of 76.4 months (range, 4.5-174.7 months), and 5-year overall (OS) and event-free survival (EFS) rates were 66.0%±9.8% and 60.9%±9.7%, respectively. Patients with a higher pretreatment lymphocyte count (≥2,320/μL) had better OS (90.9% vs. 46.2%, P=0.04) and EFS (83.9% vs. 38.5%, P=0.02). However, the day 14 lymphocyte count was not associated with survival. While no survival difference was observed between patients grouped according to pretreatment LMR (median value, 6.3), patients with a higher LMR14 (≥5) fared better than those with lower LMR14 (5-year OS: 83.3% vs. 46.3%, P=0.04). Conclusion Pretreatment lymphocyte count and LMR during chemotherapy had prognostic significance in pediatric osteosarcoma patients. Further studies involving larger cohorts are necessary to validate our findings.

Although hydrogel-based therapeutic agents have shown great potential for localized cancer treatments, the maximum tolerated dose (MTD) of these methods remains uncertain. To confirm this, doxorubicin (DOX) loaded PLGA-PEG-PLGA hydrogel was employed to investigate the MTD of DOX for localized osteosarcoma treatment. This hydrogel showed good injectable and biodegradable properties in vivo. And the drug remaining time was also obviously prolonged in the tumor site. Different doses of DOX (5.0, 15, 30 mg/kg) with/without hydrogel were adopted to the treatment of tumor-bearing mice. Despite both localized administrations of 5.0 mg/kg DOX showing no obvious systemic toxicity, this dose failed to control the persistent growth of tumors or prolong the survival time in comparison with the control groups. Localized administration of 30 mg/kg DOX showed a high efficacy for suppressing tumor growth, but exhibited obvious body weight losing at the same time. Correspondingly, the DOX-loaded hydrogel with the dose of 15 mg/kg achieved significantly improved anti-tumor efficacy and prolonged mean survival time compared with both the free DOX (15 mg/kg) and other control groups. Furthermore, during the whole therapeutic process, the mice showed no obvious body weight loss, major organs damage or death in this group. The MTD of DOX-loaded agent based on the PLGA-PEG-PLGA hydrogel gave a 2-fold increase compared to the MTD of free DOX (7.5 mg/kg, intravenous injection) for the mouse without significant systemic toxicity.

Background: Osteosarcoma is the most frequent bone cancer occurring in children and adolescents aged 10–20 years. Several prognostic factors have been identified by studies done at western centers. The aim of our study was to identify the prognostic factors in Tunisian patients in order to improve their management. Methods: We reviewed the data of localized limb osteosarcoma patients treated in Salah Azaïz Institute from January 1980 to December 2018. Patient’s treatment and survival variables were assessed. Patients received a neoadjuvant chemotherapy and underwent surgery in an expert center. They received afterward an adjuvant chemotherapy depending on the tumor necrosis assessed by Huvos. Results: Eighty-five patients were enrolled. Mean duration of follow-up was 30 months (range 1–297 months). Males were 1.6 times more frequent, median age was 17 (from 1 to 62 years). Conventional osteoblastic osteosarcoma was the most frequent histological subtype (77%). Median tumor size was 10 cm. Femoral location was the most frequent (60%). The overall average history of symptoms was 103 days (4 to 423 days). The 5-year overall-survival was 38% and the event free survival 32%. Tumor site, lactate dehydrogenase levels, high methotrexate levels at 24 h, clinical evaluation of the tumor perimeter, surgery type and delay of relapse were found to affect overall survival. Tumor site, Lactate dehydrogenase levels and clinical evaluation of the tumor perimeter affected the progression free survival. Conclusion: Demographic characteristics of Tunisian patients are mainly the same than worldwide. Femoral site, normal level of lactate dehydrogenase, a clinical response during neoadjuvant treatment, an R0 surgery, a delay of relapse over 2 years and Median H24 Methotrexate level superior to 4.4 µmol/l were associated with a better prognosis in our study.

Aims 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. Methods 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. Results 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. Conclusion 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.

Aim. To investigate prognostic factors in pediatric and young adult patients with localized osteosarcoma that could predict the development of subsequent pulmonary metastases and lead to an ability to risk-stratify therapy. We performed a systematic review of the literature published since January 1990 to establish common evidence-based prognostic factors. Methods. PubMed and Embase searches (Jan 1990–Aug 2018) were performed. Two reviewers independently selected papers for patients with localized osteosarcoma with subsequent metastatic development and then reviewed for quality of methods and prognostic factors. Results. Database searches yielded 216 unique results. After screening, 27 full-text articles were studied in depth, with 9 items fulfilling predetermined inclusion and exclusion criteria. Age, tumor location, tumor size/volume, and histologic response carried independent prognostic value in the majority of the studies. Conclusions. Several prognostic factors seemed to be consistent amongst the studies, but the heterogeneity and smaller sizes of the study populations made pooling of results difficult. Standardization of larger patient populations and consistent definitions/cutoffs for prognostic factors are needed to further assess for consistent prognostic factors and potential predictive models to be developed.

e22010 Background: Osteosarcoma is a malignant primitive bone tumor whose prognosis is not changed since 4 decades, after the introduction of neoadjuvant chemotherapy with Methotrexate, Cisplatin, Doxorubicine and Ifosfamide. Histologic response to preoperative chemotherapy is a significant prognostic factor. Huvos I (necrosis ≤ 50%) has worst prognosis . Previous studies reported a 3 years EFS of this Huvos I patients around 25% (Tsuda Y,2020). In order to evaluate if survival has changed in recent years in this unfavourable prognostic group we evaluated the outcome of osteosarcoma patients with Huvos I. Methods: from our Pathology archieves we retrieved all cases of localized osteosarcoma treated at Rizzoli with neoadjuvant chemotherapy who reported an histologic necrosis below or equal to 50% (Huvos I grade) after preoperative chemotherapy MAP (Ethical C. Approval 917/2020/Oss/IOR). Results: from 2003 to 2019 we had 70 cases of localized osteosarcoma with Huvos I necrosis after neoadjuvant chemotherapy ( MAP in 66 and MAPI in 4) evaluable. Median age 21,5 (3-70); M:F = 44:26. 10/70 had axial localization vs extremity(60), subhistotype distribution:46 osteoblastic,11 chondroblastic, 7 fibroblastic, 5 teleangectatic, one not classified. In 24 cases PgP was available(14 PgP positive). With a median follow up of 86.7 ms (IQR 41-136) 43/70 had already relapsed. The median EFS was 25 ms (95% CI 15-42) and the 3 yrs EFS was 40.6% (95% CI 29-52). The 3 yrs overall survival was 80% (95%CI 68-88) and median OS was not reached. Axial tumor site was associated with significant inferior EFS (P = .004). Conclusions: these data confirm the poor prognosis of patients with necrosis ≤50% and the need of new drugs to improve their survival in this sub-group.

11025 Background: We hypothesized that immune-infiltrates were associated with survival, and examined a primary osteosarcoma tissue microarrays (TMAs) to test this hypothesis. Methods: Biopsies of patients (pts) treated from 04/2001 to 11/2006 were analyzed. TMAs from representative areas were assembled. Clinical and pathological characteristics at diagnosis, expression of CD8, CD4, CD3, FOXP3, CD20, CD68/CD163 (tumor associated macrophage), Tia-1 (cytotoxic T cell), CD303 (plamacytoid dendritic cells: pDC), Arginase-1 (myeloid derived suppressor cells: MDSC), PD-1 on immuno-cells (IC), and PD-L1 both on tumor cells (TC) and IC were correlated with patients outcome. A TMA of surgical specimens of the same cases also was assembled, and chemotherapy-induced changes analysis is ongoing. Results: 86 pts identified. Median age: 16 (range 4-39); high LDH: 36/86; high serum alkaline phosphatase (SAP): 18/86. All pts underwent neoadjuvant chemotherapy and surgery. A good pathologic response (≥90% necrosis) was achieved by 45/86 pts. IHC results are displayed in the Table. With a median follow-up of 8 years (range 1-13), the 5-year overall survival (5-yr OS) was 74% (95% CI 64-85). Univariate analysis showed better 5-yr OS for: a) good responders (good 89% vs poor 57%, p=0.0001); b) pts with CD8/Tia1 tumoral infiltrates (+/+ 81% vs +/- 60% vs -/- 45% p=0.002); c) pts with normal SAP (normal 85% vs high 44%, p=0.04). A numerically lower 5-yr OS was found in PD-L1 (IC) positive (+ 58% vs - 77%, p=0.14) and CD163 negative (+ 81% vs - 56%, p=0.17) cases. After multivariate analysis, poor histologic response (p=0.007) and lack of CD8/Tia1 infiltration (p=0.02) were independently correlated with poorer survival. In the subset of CD8+ patients, poorer (p= 0.02) OS was observed for PD-L1 (IC) + cases. Conclusions: Our findings support the hypothesis that CD8/Tia1 (cytotoxic T cells) infiltrate in tumor microenvironment at diagnosis is associated with superior survival for patients with localized osteosarcoma, while PD-L1 expression is associated with poorer survival. [Table: see text]

Consensus has not been reached regarding the ability of pathologic fracture to predict local recurrence and survival in osteosarcoma. We aim to review the available evidence to examine the association between pathologic fracture and osteosarcoma prognosis. A comprehensive literature search for relevant studies published until March 2014 was performed using PubMed, Cochrane and Web of Science. The studies investigating pathologic fracture of osteosarcoma patients were systematically analyzed. The overall relative risk (RR) was estimated using a fixed-effect model or random-effect model according to heterogeneity between the trials. We included nine cohort studies involving 2,187 patients (311 with pathologic fracture and 1,876 without fracture) for the analysis of survival rate and local recurrence. Studies were assessed for quality using the Newcastle-Ottawa Assessment Scale. In the fixed-effects model, the meta-analysis showed that pathologic fracture in osteosarcoma patients predicted poor 3-year overall survival (OS) (RR=1.86, 95% CI: 1.37-2.53, p

To investigate the role of insulin-like growth factor-1 (IGF-1), in localized osteosarcoma, serum levels of IGF-1, IGFBP-2, and IGFBP-3 were measured in 224 similarly treated, newly diagnosed patients. We demonstrated that younger patients had lower concentrations of IGF-1 and IGFBP-3 compared to older (P

Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies.

Due to multiple factors, including their low incidence, heterogeneity and span of ages of affected patients, both osteosarcoma and Ewing’s sarcoma pose significant challenges to oncologists and patients. Despite these obstacles, significant progress has been made in the last 40 years in improving the survival of patients with localized osteosarcoma and Ewing’s sarcoma through multidisciplinary management. However, patients with primary refractory disease or disseminated disease fare poorly, emphasizing the need for novel therapies. Unfortunately, given their rarity, novel therapies for these tumors are difficult to rigorously trial. Current investigation is focused on identification of active targeted therapies in trials in patients with relapsed or refractory disease. Here we review the past, present and potential future clinical trials of systemic therapy in osteosarcoma and Ewing’s sarcoma.

Background The objective of this report was to estimate long-term outcome and prognostic factors in children and adolescents with osteosarcoma. A large group of osteosarcoma patients were analyzed at our national oncology center. Procedure To evaluate the efficacy of surgery and multiagent chemotherapy for treating osteosarcoma, we reviewed 122 cases (65 male, 57 female, mean age 13.8 ± 3.6 years) treated at the Second Department of Pediatrics in Budapest between 1988 and 2006. Demographic parameters, tumor-related and treatment-related variables, response, overall survival (OS) and event-free survival (EFS) were analyzed. Results The 5-year OS was 68% and 5-year EFS was 62%. OS of patients without metastasis was 79%, while OS with early metastasis was 17%. Survival of patients with amputation (n = 30) was not significantly different from patients with limb-salvage surgery (n = 82), but all patients without radical surgery died. Gender and histological classification had no prognostic significance. Patients with localized tumors in extremities had increased survival compared to patients with axial skeleton tumors (P = 0.013). Poor histological response to neoadjuvant chemotherapy (rate of survivor tumor cells >10%) was associated with decreased survival (P = 0.018). Patients under 14 years had better EFS than patients over 14 years (P = 0.008). Conclusions Our results demonstrate that younger patients with localized osteosarcoma of the extremities who receive limb-salvage surgery and chemotherapy have an excellent survival. Pediatr Blood Cancer 2011; 57: 415–422. © 2011 Wiley-Liss, Inc.

11525Background: Response to neoadjuvant chemotherapy correlates with a positive outcome in localized osteosarcoma patients. However, there are no reliable predictors of chemotherapy response. We i...

11524Background: Chemotherapy and surgery achieve a 5-year event-free survival of 60-70% in localized osteosarcoma (OS), but little additional progress has been made in recent decades. Clinical res...

The outcome of older osteosarcoma patients with multi-disciplinary management has not been clearly defined.We conducted a cohort (n=375) and a case-control (n=78) study on 26 older age patients (40-60 years) with localized osteosarcoma of extremity. In the case-control study, controls were matched for location and initial tumor volume.Compared to 349 younger patients, older age patients showed an osteolytic pattern on plain radiographs (P=0.05), fibroblastic subtype (P0.01), and poor histologic response (P=0.03). Multivariate analysis revealed that a large absolute tumor volume (P0.01), a tumor location in the proximal humerus (P=0.02), and a poor histologic response to preoperative chemotherapy (P0.01) independently predicted poorer metastasis-free survival. However, an older age showed marginal significance (P=0.09). A case-control study showed a higher proportion of the fibroblastic subtype and poor histologic response in the case group. Five-year metastasis-free survival rates for the 26 cases and 52 controls were 40.1+/-10.1% and 61.5+/-6.8%, respectively (P=0.02).Older age osteosarcoma patients showed an unfavorable histologic response to chemotherapy and lower survival than younger patients. Nevertheless, a further larger-scale study is required to confirm our observations.

Background Survival of osteosarcoma patients has reached a plateau with the addition of chemotherapy and in part predicted based on histologic response. Risk-adapted therapy might be an alternative approach. We aimed to identify risk groups using clinical variables available at time of diagnosis in order to better predict outcomes and form the basis for risk-adapted therapy. Methods This retrospective study analyzed 288 patients with high-grade osteosarcoma of their extremities. Clinicopathologic variables were analyzed to identify factors relevant to risk stratification. Results A risk assessment system was developed using age, maximal tumor length (MTL) and tumor location. Index scores were based on the sum total of factor scores, for each of the following: Age (years); “1” for ≥40 or 12–14 (female) or 13–15 (male), “0” for other ages; MTL (cm); “2” for ≥8, “1” for 6–8, “0” for ≤6; Tumor location; “1” for humerus, “0” for elsewhere. Index score 0 or 1 was assigned as low-risk, 2 as intermediate-risk, and 3 or 4 as high-risk. Of the 288 patients, 98 (34.0%) were designated as low-risk, 128 (44.4%) as intermediate-risk and 62 (21.6%) as high-risk. Risk group was related to histologic response and survival. While 63.3% of low-risk patients were good responders, only 43.0% and 33.9% of intermediate- and high-risk patients were good responders. Ten-year event-free survival (EFS) was 81.6 ± 3.9% for low-risk group, but 31.6 ± 6.0% for high-risk group. Conclusion We defined three risk groups that could be used as basis of risk-adapted therapy for osteosarcoma. Pediatr Blood Cancer 2009;52:340–345. © 2008 Wiley-Liss, Inc.

Background To evaluate the correlation between histologic response and size parameters, and to analyze the prognostic importance of size parameters on metastasis-free survival in localized osteosarcoma patients. Methods We retrospectively reviewed 331 patients with stage II osteosarcoma treated with surgery and chemotherapy. The tumor size parameters were measured and calculated based on MR images. The mean metastasis-free interval was 77.8 months (range, 3–205 months; median, 67 months). Results Tumor size is best defined by relative tumor plane (RTP). Patients with a large tumor (RTP>27.5 cm2/m2) had a significant correlation with poor histologic response and distal femoral tumor location. The independent prognostic factors for metastasis-free survival were American Joint Committee on Cancer (AJCC) stage, RTP, proximal humerus location, chondroblastic subtype, and poor histologic response. Conclusion The initial tumor size is closely related to histologic response and is an important prognostic factor in osteosarcoma. Tumor size is best represented by AJCC stage and RTP. These parameters may serve as a basis for risk-adapted therapy in combined stratification with histologic response. J. Surg. Oncol. 2008;97:456–461. © 2008 Wiley-Liss, Inc.

We assessed whether new parameter that considers both tumor volume change and necrosis rate predicts metastasis-free survival of localized osteosarcoma patients. We also evaluated relationship between tumor volume change and necrosis rate or metastasis-free survival.We retrospectively reviewed 151 patients with stage II osteosarcoma who were treated with surgery and neoadjuvant chemotherapy. The tumor volume change was measured and calculated based on pre- and postchemotherapy magnetic resonance images. The mean metastasis-free interval was 83.1 months. We calculated adjusted tumor necrosis rate as following formula: 100 - (100 - necrosis rate) x postchemotherapy/prechemotherapy tumor volume. Survival and logistic regression analyses were used to evaluate the correlation among size parameters, tumor necrosis rate and survival.The 5-year metastasis-free survival rate of 151 patients was 71.4% (95% CI, 67.7-75.1%). American Joint Committee on Cancer (AJCC) stage IIB (RR 2.27; 95% CI, 1.11-4.62; P = 0.025) and poor adjusted tumor necrosis rate (RR 2.02; 95% CI, 1.05-3.89; P = 0.035) independently correlated with metastasis-free survival period. Further, tumor volume change independently correlated with necrosis rate. Decreased tumor volume could predict good response, with sensitivity of 80.2%, specificity of 68.6%, and positive predictive value (PPV) of 74.7%. Increased or stable tumor volume could predict poor response, with sensitivity of 68.6%, specificity of 80.2%, and PPV of 75.0 %.The necrosis rate adjusted by the tumor volume change is an independent prognostic factor in osteosarcoma. This adjusted tumor necrosis rate may serve as a basis for risk-adapted therapy in combination with other prognostic factors.

To the Editor, We read the article by Wong and colleagues regarding the importance of surgical resection for postrelapse survival of patients with localized osteosarcoma with great interest. We would like to acknowledge some areas of the current study that require additional clarification from the authors. First, the authors may have predicted the relapse sites of the six patients in the study who did not receive surgery postrelapse (five in lung and one in heart). However, the patients with lung metastasis have poor survival outcomes compared to those with bone recurrence. The surgery group and nonsurgery group did not match well in the current study. Metastasis and aggressive tumors likely caused poor survival. Second, we found the title of the study, “Surgical Resection of Relapse May Improve Postrelapse Survival of Patients With Localized Osteosarcoma” confusing. Relapse is defined as local recurrence and metastasis. Wong et al. presented 15 patients with metastasis (ten in lung, four in bone, and one in heart) but no patient presented with local recurrence. It is unclear why the authors used the word “relapse” but not “metastasis” in the title of their study. Third, the authors cited the studies by Bacci G et al. [1], Bielack SS et al. [2], and Chou AJ et al. [3] in their Table 2 and Discussion section. The words “recurrence” or “recurrent” can be found in the titles of all three studies. We question whether “recurrence” has the same meaning as “metastasis” in those studies. If this was not the case, we find it inappropriate to make data comparisons between the current study and those reports cited in Table 2. Finally, we uncovered a few errors in the study. The authors wrote, “A second relapse occurred in four patients” but only three patients with a second relapse were shown in Table 1. In the Patients and Methods section, the authors stated, “The primary lesion involved the proximal tibia in six, the distal femur in four, and the proximal humerus in four patients.” However, we found only five distal femur patients in Table 1. In the Results section, we were puzzled by “disease relapsed at a median of 28 months (range, 0.7–12.6 months) from diagnosis.” Perhaps the authors meant years instead of months. We would like to thank Wong et al. for this paper. However, it would be more helpful if the authors clarified the above points.

Osteosarcoma is the most common primary tumor of bone. Approximately 2/3 of patients who present with localized osteosarcoma can be expected to be cured of their disease with surgery and routine chemotherapy. Only 1/3 of patients with metastases detectable at presentation will be cured. These survival trends have stagnated over the past 20 years using conventional chemotherapy. New agents need to be rationally investigated to strive for improvement in the survival of patients diagnosed with osteosarcoma. This manuscript will review the rationale for conventional chemotherapy used in the treatment of osteosarcoma, as well as agents in varying stages of development that may have promise for treatment in the future.

Despite numerous chemotherapy trials and the introduction of novel agents, survival in localized osteosarcoma, which plateaued in the mid-1980s, has been recalcitrant to our best efforts. The authors considered that a review of previous and current strategies that target survival might provide a direction for research efforts. Here, the focus is placed mainly on the reappraisal of previous mass chemotherapy trials and prognostic factors, in the hope of contriving a strategy to overcome the current stasis.

Anaphylactic/anaphylactoid reaction to methotrexate (MTX) is uncommon. It may occur with the first dose (non-allergic reactions) or after a previous exposure to the drug (allergic or specific reactions). Desensitization has been shown effective in children with allergic-type reactions permitting the continuation of high-dose methotrexate (HDMTX) therapy. We report the case of a child with localized osteosarcoma who developed an anaphylactoid reaction after a first HDMTX course. A desensitization protocol was successfully applied allowing the administration of four additional courses. In our experience, desensitization can be a safe and effective procedure in children with anaphylactoid reactions to HDMTX.

10540 Background: Data on outcome of localized Osteosarcoma (OS) treated with uniform protocol is limited from Asia. Methods: This is a single institutional review of patients treated between Jan 2...

목적: 본 연구는 수술 전 항암 약물 치료가 전이가 없는 골육종 환자의 생존율과 전이에 미치는 영향에 대해 알아보고자 하였다. 대상 및 방법: 1984년부터 2010년까지 사지에 발생한, 전이가 없는 원발성 골육종으로 수술적 절제술과 수술 후 항암 약물 치료를 시행한 30세 미만의 환자 225명을 후향적으로 분석하였다. 평...

In the surgical treatment of localized osteosarcoma of the extremities, limb-salvage procedures are currently used whenever wide surgical margins can be achieved [1, 2, 3]. The increased indications for conservative surgery in osteosarcoma rely mainly on accurate preoperative staging through diagnostic imaging tools and the use of adjuvant or neoadjuvant chemotherapy [1,2].

10514 Background: Neoadjuvant and adjuvant chemotherapy is now standard practice for patients who present with localized osteosarcoma. We present the long-term follow-up (>20years) for one of the original prospective randomized trials that compared adjuvant chemotherapy to no treatment in patients with high-grade operable osteosarcoma. Methods: The original study was performed at UCLA from 1981 to 1984. During this time, 59 patients with high-grade, operable, non-metastatic osteosarcoma were randomized to receive adjuvant chemotherapy (MSKCC T-10B protocol)(N=32; 24 men, 8 women, median age 15 yrs) vs. expectant management (N=27; 20 men, 7 women, median age 18 yrs). All patients received one neoadjuvant course of intra-arterial doxorubicin hydrochloride (90mg) and radiation (1750cGy). At a median follow-up of 2 years, there was a statistically significant improvement in both disease-free (55% vs. 20%, p20 years) follow-up. These results support the idea that early systemic treatment offers the best opportunity to cure patients with this high-risk malignancy. No significant financial relationships to disclose.

9527 Background: We conducted a collaborative protocol (twinning program) for newly diagnosed patients with localized osteosarcoma (OS 99) at SJCRH (sponsor) and CMH (partner site), a public tertiary-care pediatric hospital and bone tumor center in Santiago, Chile. Methods: CMH was selected as the partner site because Chile has a well developed public health system including free treatment for children with cancer. SJCRH trained and financially supported specialized personnel and provided oversight of study conduct and monitoring. The study was approved by the respective Human Subjects Protection Committees and a Data Safety Monitoring Board. Treatment comprised 12 cycles of chemotherapy (with growth factor support) given every 3 weeks for a total of 35 weeks and definitive surgery after 4 cycles of chemotherapy. Pathology studies and selected imaging studies were centrally reviewed at SJCRH. Patient costs were covered by the Chilean Ministry of Health and SJCRH except for sargramostim which was donated by Berlex Oncology. Patient care and study conduct were discussed in a multidisciplinary forum on a monthly basis. The two study teams maintained close communication through videoconferencing, and site visits. Results: Of the 72 eligible patients enrolled on study, 22 were treated in Santiago (2003–2006). Rare discrepancies in interpretation of diagnostic imaging and pathology studies were addressed in a timely manner. Preliminary results demonstrated similar patient outcomes and treatment tolerance at the two sites. Limb-salvage surgery was performed in 12 Chilean patients. Median per-patient costs were lower in Chile (US $80,000) than at SJCRH ($400,000). Conclusions: It is feasible, safe, and cost-effective to simultaneously treat pediatric patients with osteosarcoma on modern protocols, through well designed and rigorously monitored twinning programs that include countries with different level of resources. No significant financial relationships to disclose.

9521 Background: Based on the severe toxicity of high dose methotrexate (MTX) in adult patients, an alternative intensive chemotherapy (CT) was designed, associating doxorubicin, cisplatinum and ifosfamide in API-AI regimen. Promising results in 32 patients in a single institution study (Le Cesne ASCO 2004) led to a national multicenter phase II trial coordinated by the FSG of FNCLCC. Methods: Patients with a localized operable osteosarcoma were eligible. API-AI regimen consisted in 2 cycles every 28 days of doxorubicin 60 mg/m2 d1 and d15, cisplatinum 100 mg/m2 d1 and ifosfamide 5g/m2 d2 and d15, with equivalent dose of mesna and lenograstim after each course for 7 days. Good responders ≥95% necrosis (GR) received 2 postoperative API courses, and poor responders 2 d1 to d3 and ifosfamide 4 g/m2 d1 to d3. Results: From March 2001 to January 2004, 43 patients (male/female 28/15) with a median age of 23 years (range 17–50), were included. The median tumor size was 88 mm (13–280). All 43 patients received the preoperative API-AI regimen, with a dose intensity of ≥ 89% of the planned protocol. Toxicity was mainly haematological, with grade 3–4 sepsis, grade 4 neutropenia and thrombocytopenia observed in 12%, 79% and 49% of patients respectively. There was no severe renal and cardiac toxicity. All but 5 patients had a limb sparing surgery performed 77 days (median) after the first cycle (range 56–114 days). Intent to treat analysis showed 16/43 GR (37%). With a median follow-up of 36 months (25–48), the 2 year event-free and overall survival were 74% and 86% respectively. Conclusions: Despite the haematological toxicities, these results compare favorably with other previous induction CT schedules containing MTX in adults. A longer follow-up is required to evaluate the impact of this regimen on overall survival. No significant financial relationships to disclose.

9020 Background: High dose MTX in adult patients (pts) with LO is highly toxic. We have designed in 1995 an intensive protracted regimen without MTX (API-AI regimen) in LO Methods:. Preliminary res...

In March 1983, the Bone Tumor Center of the Istituto Ortopedico Rizzoli of Bologna, in collaboration with the Department of Pediatric Oncology of the University of Torino, and the 3rd Pediatric Clinic of the University of Bologna, started a new study of preoperative chemotherapy in patients with localized osteosarcoma of the extremities.