Osteosarcoma: a Meta-Analysis and Review of the Literature

A Review Paper

Osteosarcoma: A Meta-Analysis and Review of the Literature

Jill C. Friebele, MD, Jeffrey Peck, MD, Xueliang Pan, PhD, Mahmoud Abdel-Rasoul, MS, MPH, and Joel L. Mayerson, MD

an overall annual incidence of 5.6 cases per million children Abstract under age 15 years.3-5 Peak incidence is in the second decade of Over the past 30 years, treatment advances and the life, and males are affected slightly more often than females.2,6 addition of neoadjuvant chemotherapy have led to im- The period of highest incidence coincides with the growth proved 5-year survival in patients with osteosarcoma. spurt of the long bones. Osteosarcoma preferentially affects More recent literature suggests the overall prognosis the metaphysis of long bones, the 3 main sites being distal remains highly variable, with little improvement since femur, tibia, and proximal humerus.2 the introduction of neoadjuvant chemotherapy. Tumor necrosis is an important predictor of patient progno- Historical Perspective sis. Necrosis of more than 90% correlates with overall For most of the 20th century, the 5-year survival rate for classic 7 survival (OS) approaching 75%. primary osteosarcoma was under 20%. In the 1970s, the first We reviewed the history of osteosarcoma treat- revolution in osteosarcoma treatment arrived with the intro- ment and survival and performed a meta-analysis of duction of adjuvant chemotherapy, which increased survival 8-10 the 2000–2011 literature. Forty articles were included rates to 50%. During this expansion of research, several in the study. Five-year OS was 63% (95% confidence chemotherapeutics (eg, vincristine, bleomycin, dactinomy- interval, 60%-66%) in studies that included patients cin) were discarded for poor effectiveness, and others (eg, with metastatic and nonmetastatic disease and 71% cisplatin, ifosfamide) were added to doxorubicin and metho- (95% confidence interval, 67%-76%) in studies that in- trexate, improving 5-year disease-free survival to about 70% cluded only patients with nonmetastatic disease. Fifty in patients with nonmetastatic osteosarcoma. In another sig- percent of the patients in the studies of those with non- nificant advance, adjuvant chemotherapy was supplemented with intensive preoperative chemotherapy, resulting in 5-year metastatic osteosarcoma achieved 90% necrosis on tumor-free survival that has ranged from 50% to 75% for high- histology. Five-year OS and number of patients achiev- grade osteosarcoma.5,11,12 Adding neoadjuvant chemotherapy ing 90% necrosis are consistent with previous reports. and histologic response has allowed for evaluation of surgical Research is needed to improve treatment regimens margins and early treatment of microscopic disease. Thus, and patient outcomes. effective limb-sparing procedures can be performed, and the incidence of amputation has decreased from 90% to between 10% and 20%.13,14 However, statistical improvements in sur- steosarcoma, a primary malignant tumor of the skel- vival associated with neoadjuvant treatment may simply delay eton, is characterized by direct formation of imma- time of recurrence and metastasis.15 In addition, though che- Oture bone or osteoid tissue by tumor cells. The World motherapy has improved survival in osteogenic sarcoma, many Health Organization histologic classification of bone tumors have written that this improvement appears to reflect mainly divides osteosarcoma into central and surface tumors and rec- the increase in the intensity of the chemotherapy used, which ognizes a number of subtypes within each group.1 The present also leads to a higher propensity for side effects.16 review refers only to the classic central high-grade primary Despite research and advances in chemotherapy regimens, osteosarcoma of bone, which represents about 90% of all os- the prognosis of patients with osteosarcoma remains highly teosarcoma cases. Classic osteosarcoma represents about 15% variable and often dismal. Mirabello and colleagues17 examined of all biopsy-analyzed primary bone tumors.1 It is the third osteosarcoma incidence and survival rates between 1973 and most common type of neoplasia, preceded by leukemia and 2004 and found that, with the introduction of neoadjuvant lymphoma among older children and adolescents aged 12 to 18 chemotherapy, survival rates improved significantly between years.2 High-grade primary osteosarcoma is the most common 1973 and 1983 and between 1984 and 1993, but there was primary skeletal tumor of childhood and adolescence, with little improvement between 1993 and 2004.

Authors’ Disclosure Statement: The authors report no actual or potential conflict of interest in relation to this article. www.amjorthopedics.com December 2015 The American Journal of Orthopedics® 547 Osteosarcoma: A Meta-Analysis and Review of the Literature

The long-term outcome for patients with metastatic disease coma are then at increased risk for chronic medical conditions is poor. Investigators have found that 11% to 20% of patients and adverse health status because of the osteosarcoma-related have pulmonary metastasis at initial diagnosis. About half of treatments.20 patients without pulmonary metastases develop them later in the disease course.18 Survival rates for patients with metastasis Prognostic Factors at initial presentation have ranged from 10% to 40%.19 Recur- It is important to understand and exploit the influences of rent disease still occurs in 30% to 40% of patients, and more different prognostic factors in treating patients with osteo- than 70% of them die of the tumor.15 The survivors of osteosar- sarcoma.7 These factors are important in establishing the best

Study Year Effect Size (95% CI) % Weighta Szendroi et al19 2000 0.73 (0.63, 0.83) 2.11 Bacci et al,14 long-term outcome 2000 0.75 (0.68, 0.81) 2.45 Bacci et al29 2000 0.70 (0.59, 0.81) 2.03 Bacci et al30 2001 0.71 (0.64, 0.78) 2.41 Bielack et al31 2002 0.65 (0.63, 0.68) 2.75 Hauben et al32 2002 0.53 (0.48, 0.58) 2.58 Scully et al33 2002 0.68 (0.59, 0.77) 2.24 Kager et al4 2003 0.29 (0.23, 0.35) 2.48 Wilkins et al34 2003 0.94 (0.88, 1.00) 2.49 Smeland et al35 2003 0.74 (0.66, 0.82) 2.31 Ozaki et al36 2003 0.27 (0.17, 0.38) 2.05 Bacci et al21 2004 0.62 (0.59, 0.65) 2.71 Longhi et al12 2004 0.49 (0.39, 0.58) 2.16 Mankin et al37 2004 0.68 (0.64, 0.72) 2.69 Kaste et al6 2004 0.76 (0.63, 0.88) 1.82 Donati et al38 2004 0.86 (0.73, 0.98) 1.89 Bacci et al40 2005 0.66 (0.63, 0.69) 2.73 Matsuo et al41 2005 0.30 (0.18, 0.42) 1.89 Kuhelj and Jereb42 2005 0.48 (0.37, 0.59) 1.97 Mialou et al43 2005 0.19 (0.11, 0.28) 2.24 Daecke et al44 2005 0.85 (0.73, 0.97) 1.93 Bacci et al,39 preadolescent group 2005 0.67 (0.62, 0.72) 2.57 Bacci et al,39 older group 2005 0.65 (0.62, 0.68) 2.74 Bacci et al15 2006 0.67 (0.64, 0.71) 2.70 Cho et al,45 preadolescents 2006 0.64 (0.48, 0.79) 1.59 Cho et al,45 adolescents 2006 0.59 (0.44, 0.73) 1.66 Petrilli et al,46 study III 2006 0.54 (0.45, 0.64) 2.16 Petrilli et al,46 study IV 2006 0.48 (0.39, 0.57) 2.22 Lee et al,48 maximal growth 2008 0.79 (0.74, 0.84) 2.58 Kim et al,47 growth patterns 2009 0.74 (0.69, 0.79) 2.62 Mirabello et al,17 younger group 2009 0.62 (0.59, 0.64) 2.75 Mirabello et al,17 older group 2009 0.59 (0.56, 0.62) 2.71 Wu et al49 2009 0.62 (0.56, 0.69) 2.44 Ayan et al50 2009 0.65 (0.55, 0.74) 2.15 Bruland et al51 2009 0.71 (0.67, 0.76) 2.60 Bielack et al52 2009 0.68 (0.66, 0.70) 2.77 Bispo and Camargo53 2009 0.55 (0.35, 0.75) 1.22 Hsieh et al,11 combined 2009 0.55 (0.44, 0.67) 1.95 Gonzalez-Billalabeitia et al54 2009 0.60 (0.48, 0.72) 1.93 Kong et al55 2009 0.73 (0.68, 0.77) 2.64 Kim et al56 2009 0.27 (0.10, 0.44) 1.45 Lee et al57 2009 0.76 (0.72, 0.81) 2.60 Kager et al18 2010 0.51 (0.32, 0.70) 1.30 Worch et al58 2010 0.67 (0.65, 0.69) 2.75 Overall (I2 = 93.4%, P < .001) — 0.63 (0.60, 0.66) 100.00

a Weights are from random effects analysis. 0 1

Figure 1. Five-year overall survival for studies that included patients with metastatic and nonmetastatic osteosarcoma is represented by black diamond. Gray box represents weight of study. Black bar represents 95% confidence interval. Each study’s weight (far right of graph) is based on number of patients included in study. Abbreviation: CI, confidence interval.

548 The American Journal of Orthopedics® December 2015 www.amjorthopedics.com J. C. Friebele et al treatment for the individual. Thus, more aggressive treatments provement over the past 20 years. The prognosis for younger can be started in patients with prognostic factors that pose a patients, patients with spinal disease, and patients with meta- higher risk of relapse.21 A number of clinical and pathologic static disease remains poor. Although some prognostic factors features (eg, tumor site, size, subtype; patient sex and age; high have been identified and shown to predict a good outcome, it alkaline phosphatase or high lactate dehydrogenase [LDH] val- seems few patients have these positive factors. In this article, ues; multidrug resistance; genetic variations) have prognostic we describe the literature review and meta-analysis we per- significance but often with contradictory results because of lack formed to better define recent survival trends for patients with of uniformity in patient analyses and methods.15 primary osteosarcoma. Survival for patients with primary osteosarcoma has been analyzed with respect to tumor size and location.7 Studies have Methods found higher survival rates for patients with smaller tumors The MEDLINE, PubMed, and Cochrane databases were (<10 cm) and more distal tumor locations.7 These superior searched for eligible studies published in English between survival rates may be the result of earlier detection of tumors 2000 and 2011—a decade of recently reported research. We ap- and more options for surgical resection of smaller, distal plied the search strategy [“osteosarcoma” OR “osteogenic sarcoma”] AND tumors. [“prognosis” OR “treatment” OR “survival”] and selected reports that Serum LDH levels have helped in risk stratification of pa- specifically addressed factors predicting survival in patients tients. High LDH often occurred at time of relapse, and relapse with osteosarcoma—reports that were limited to primary os- with high LDH correlated with poor prognosis. Meyers and teosarcoma of the pelvis or extremity and provided 5-year colleagues22 found that 5-year disease-free survival was 72% for overall survival (OS) data. Abstracts of the selected articles patients with normal LDH at presentation and 54% for patients were independently reviewed, and the inclusion and exclu- with elevated LDH at presentation. sion criteria were applied. We excluded basic science studies Several studies have shown that percentage of tumor necro- and those without pediatric patients, those without primary sis on histology is strongly correlated with good prognosis.21 osteosarcoma, those with periosteal or parosteal osteosarcoma, Most groups now define a good histologic response as less than and those that did not report 5-year OS data. 10% viable tumor cells at time of surgery, and a poor response as more than 10%.23 Results of the Pediatric Oncology Group Statistical Analysis (POG) protocol for localized osteosarcoma (POG 9351), or Number or proportion of patients (whichever was reported) Children’s Cancer Group (CCG) 7921, found 45% of patients with 5-year OS and number or proportion of patients with 90% had favorable responses (>90% necrosis) after preoperative necrosis were extracted from each study. For each trial, propor- chemotherapy.24 However, several clinicians have recently tion of patients with 5-year OS and 95% confidence intervals questioned this finding. (CIs) and proportion of patients achieving 90% necrosis and Overall, the prognosis for classic osteosarcoma of the ex- 95% CIs were determined. We also calculated proportion of tremity remains highly variable, and there has been little im- patients with 5-year OS and proportion of patients with 90%

Study Year Effect Size (95% CI) % Weighta Bacci et al,14 long-term outcome 2000 0.75 (0.68, 0.81) 6.54 Bacci et al29 2000 0.70 (0.59, 0.81) 5.22 Hauben et al32 2002 0.53 (0.48, 0.58) 6.98 Scully et al33 2002 0.68 (0.59, 0.77) 5.87 Wilkins et al34 2003 0.94 (0.88, 1.00) 6.68 Smeland et al35 2003 0.74 (0.66, 0.82) 6.09 Kaste et al6 2004 0.76 (0.63, 0.88) 4.60 Bacci et al39 2005 0.66 (0.63, 0.69) 7.49 Bacci et al15 2006 0.67 (0.64, 0.71) 7.39 Lee et al,48 maximal growth 2008 0.79 (0.74, 0.84) 6.96 Kim et al,47 growth patterns 2009 0.74 (0.69, 0.79) 7.10 Bruland et al51 2009 0.71 (0.67, 0.76) 7.03 Bispo and Camargo53 2009 0.55 (0.35, 0.75) 2.94 Gonzalez-Billalabeitia et al54 2009 0.60 (0.48, 0.72) 4.92 Kong et al55 2009 0.73 (0.68, 0.77) 7.16 Lee et al57 2009 0.76 (0.72, 0.81) 7.03 Overall (I2 = 89.4%, P < .001) — 0.71 (0.67, 0.76) 100.00

a Weights are from random effects analysis. 0 1

Figure 2. Five-year overall survival for studies that included only patients with nonmetastatic osteosarcoma. Abbreviation: CI, confidence interval.

www.amjorthopedics.com December 2015 The American Journal of Orthopedics® 549 Osteosarcoma: A Meta-Analysis and Review of the Literature

Study Year Effect Size (95% CI) % Weighta Szendroi et al19 2000 0.46 (0.35, 0.57) 2.96 Bacci et al,14 long-term outcome 2000 0.71 (0.64, 0.78) 3.30 Bacci et al29 2000 0.15 (0.07, 0.23) 3.20 Bielack et al31 2002 0.56 (0.53, 0.58) 3.51 Hauben et al32 2002 0.28 (0.23, 0.33) 3.43 Scully et al33 2002 0.38 (0.29, 0.47) 3.14 Kager et al4 2003 0.57 (0.51, 0.64) 3.31 Wilkins et al34 2003 0.87 (0.77, 0.97) 3.10 Smeland et al35 2003 0.58 (0.49, 0.67) 3.14 Ozaki et al36 2003 0.29 (0.18, 0.40) 3.00 Bacci et al21 2004 0.64 (0.61, 0.67) 3.49 Mankin et al37 2004 0.48 (0.44, 0.52) 3.47 Kaste et al6 2004 0.54 (0.39, 0.69) 2.63 Bacci et al40 2005 0.62 (0.59, 0.65) 3.50 Mialou et al43 2005 0.42 (0.31, 0.53) 2.99 Daecke et al44 2005 0.54 (0.37, 0.71) 2.45 Bacci et al,39 preadolescent group 2005 0.66 (0.61, 0.71) 3.40 Bacci et al,39 older group 2005 0.64 (0.61, 0.67) 3.51 Bacci et al15 2006 0.63 (0.60, 0.66) 3.48 Cho et al,45 preadolescents 2006 0.32 (0.17, 0.46) 2.65 Cho et al,45 adolescents 2006 0.28 (0.15, 0.41) 2.79 Petrilli et al,46 study III 2006 0.47 (0.37, 0.56) 3.11 Petrilli et al,46 study IV 2006 0.18 (0.11, 0.25) 3.31 Kim et al,47 growth patterns 2009 0.45 (0.39, 0.50) 3.40 Wu et al49 2009 0.40 (0.33, 0.47) 3.31 Ayan et al50 2009 0.64 (0.55, 0.74) 3.10 Hsieh et al,11 combined 2009 0.50 (0.38, 0.62) 2.93 Gonzalez-Billalabeitia et al54 2009 0.41 (0.29, 0.53) 2.91 Kong et al55 2009 0.43 (0.38, 0.47) 3.42 Kim et al56 2009 0.65 (0.47, 0.84) 2.34 Lee et al57 2009 0.48 (0.42, 0.54) 3.37 Kager et al18 2010 0.61 (0.43, 0.79) 2.33 Overall (I2 = 95.5%, P < .001) — 0.50 (0.45, 0.54) 100.00

a Weights are from random effects analysis. 0 1

Figure 3. Proportion of patients achieving 90% necrosis for studies that included patients with metastatic and nonmetastatic osteosarcoma. Abbreviation: CI, confidence interval.

Study Year Effect Size (95% CI) % Weighta Bacci et al,14 long-term outcome 2000 0.71 (0.64, 0.78) 7.81 Bacci et al29 2000 0.15 (0.07, 0.23) 7.64 Hauben et al32 2002 0.28 (0.23, 0.33) 8.02 Scully et al33 2002 0.38 (0.29, 0.47) 7.55 Wilkins et al34 2003 0.87 (0.77, 0.97) 7.49 Smeland et al35 2003 0.58 (0.49, 0.67) 7.55 Kaste et al6 2004 0.54 (0.39, 0.69) 6.64 Bacci et al40 2005 0.62 (0.59, 0.65) 8.13 Bacci et al15 2006 0.63 (0.60, 0.66) 8.10 Kim et al,47 growth patterns 2009 0.45 (0.39, 0.50) 7.97 Gonzalez-Billalabeitia et al54 2009 0.41 (0.29, 0.53) 7.16 Kong et al55 2009 0.43 (0.38, 0.47) 8.00 Lee et al57 2009 0.48 (0.42, 0.54) 7.93 Overall (I2 = 96.9%, P < .001) — 0.50 (0.41, 0.59) 100.00 aWeights are from random effects analysis. 0 1

Figure 4. Proportion of patients achieving 90% necrosis for studies that included only patients with nonmetastatic osteosarcoma. Ab- breviation: CI, confidence interval.

550 The American Journal of Orthopedics® December 2015 www.amjorthopedics.com J. C. Friebele et al necrosis with corresponding 95% CIs of studies that included all 29 included patients with metastatic and nonmetastatic patients with nonmetastatic disease. disease,4,6,11,14,15,18,19,21,29,31-36,37,39,40,43-47,49,50,54-57,59 and 13 included We assessed statistical heterogeneity among trials included only patients with nonmetastatic disease.6,14,15,29,32-35,40,47,54,55,57 in the meta-analysis using the Cochran Q test. Inconsistency Again, because of the known difference in prognosis between was quantified with theI 2 statistic, which estimates percent- patients with metastatic disease and patients with nonmeta- age of total across-studies variation caused by heterogeneity static disease, we performed separate analyses, one for the rather than chance.25 We considered I2 higher than 50% as combined dataset of all 29 studies (Figure 3) and the other indicating substantial heterogeneity. When substantial het- for the 13 nonmetastatic studies (Figure 4). Random-effects erogeneity was not found, the pooled estimate calculated on models showed 90% necrosis for 50% of patients in both the basis of the fixed-effects model was reported using the analyses: studies that included patients with metastatic and inverse variance method. When substantial heterogeneity was nonmetastatic disease (95% CI, 45%-54%; heterogeneity test, found, the pooled estimate calculated on the basis of a random- Q = 692.88; P < .001; I2 = 95.5%) and nonmetastatic studies effects model was reported using the DerSimonian and Laird26 (95% CI, 41%-59%; heterogeneity test, Q = 385.42; P < .001; method, which takes both within- and between-study varia- I2 = 96.9%). tions into account. We also performed a meta-regression analysis that in- Publication bias was assessed through funnel plots and with cluded necrosis as a continuous variable for both the Begg and Egger tests.27,28 Two-tailed P < .05 was considered overall dataset and the nonmetastatic dataset. Five-year statistically significant. All statistical analyses were performed OS was plotted against percentage of patients achiev- with Stata/SE Version 11.0 (StataCorp). ing 90% tumor necrosis for each study. The results are plotted in Figure 5 (combined dataset). Results No evidence of publication bias was detected for 5-year Our literature search yielded 597 articles. We cross-referenced OS or percentage necrosis for the analyses of the combined these articles with the MEDLINE, PubMed, and Cochrane search datasets by either Egger test or Begg test. For 5-year OS, results using the same keywords and discarded the duplicates. Ps were .21 (Egger) and .19 (Begg); for percentage necrosis, The abstracts of these articles were then reviewed in detail. The Ps were .10 (Egger) and .62 (Begg). In addition, no evidence 40 articles4,6,11,12,14,15,17-19,21,29-58 that met our study inclusion cri- of publication bias was detected for the analyses of the non- teria reported on studies that included patients with metastatic metastatic studies by either test. For 5-year OS, Ps were .55 and nonmetastatic osteosarcoma. Because of the significant (Egger) and .41 (Begg); for percentage necrosis, Ps were .42 difference in OS of patients with metastatic disease, we also (Egger) and .95 (Begg). analyzed articles that included only patients with nonmetastatic disease. Sixteen articles6,14,15,29,32-35,39,47,48,51,53,54,55,57 were included Discussion in the analysis of patients with nonmetastatic disease. Five-year OS was 63% (95% CI, 60%-66%) for studies that Figure 1 shows 5-year OS for each of the 40 studies. For included patients with metastatic and nonmetastatic osteosar- studies that compared survival of different groups of patients, coma and 71% (95% CI, 67%-76%) for studies that included the survival of each group is shown separately. For example, only patients with nonmetastatic osteosarcoma. These percent- Bacci and colleagues39 divided patients into adolescent and ages fall within the range found in the literature. Mankin and preadolescent groups and reported 5-year OS for each. In our colleagues37 reviewed 648 cases of patients with osteosarcoma analysis, we treated each group independently and reported treated at Massachusetts General Hospital in 2004; OS was their 5-year OS separately. For each study, 5-year OS, weight of study, and CI are included. Five-year OS ranged from 19% to 94%. Analysis was performed to determine 5-year OS for all studies based on weight given to each study. The ran- 100% dom-effects model used for this analysis (heterogeneity test, Q = 656.23; P < .001; I2 = 93.4%) showed 5-year OS of 63% 80% (95% CI, 60%-66%) for studies that included patients with metastatic and nonmetastatic osteosarcoma. 60% Figure 2 shows 5-year OS (range, 53%-94%) for each of the 16 studies that included only patients with non- 40% metastatic disease. The random-effects model used for 5-Year Overall Survival 5-Year this analysis (heterogeneity test, Q = 142.08; P < .001; 2 20% I = 89.4%) showed 5-year OS of 71% (95% CI, 67%-76%) for 20% 40% 60% 80% 100% studies that included only patients with nonmetastatic disease. Percentage of Patients Achieving 90% Tumor Necrosis We then examined percentage of patients achieving 90% necrosis on histology in each study. Several studies included Figure 5. Association of 5-year overall survival with proportion of in the OS analysis did not report percentage necrosis, leav- patients achieving 90% tumor necrosis in each study. ing 29 studies for the necrosis analysis. Of these 29 studies, www.amjorthopedics.com December 2015 The American Journal of Orthopedics® 551 Osteosarcoma: A Meta-Analysis and Review of the Literature

68%. In 2011, Sampo and colleagues60 reported 10-year OS of sity, Columbus, Ohio. Dr. Mayerson is Professor of Orthopaedics, 63% for patients with metastatic and nonmetastatic disease and Program Director for Orthopaedics Residency Program, College of Medicine, and Director of Sarcoma Services, Arthur James Cancer 73% for patients with local disease at presentation. Five-year Hospital, Ohio State University, Columbus, Ohio. OS rates in the literature are consistently about 70%. Ferrari Address correspondence to: Joel L. Mayerson, MD, Musculoskeletal and colleagues61 reported 5-year OS of 73% and 74% for 230 Oncology, Arthur James Cancer Hospital, Ohio State University, Prior patients treated with 2 different neoadjuvant chemotherapy Hall, Suite 725, 376 W. 10th Ave., Columbus, OH 43210 (tel, 614-293- 4420; fax, 614-293-3747; email, [email protected]). regimens between 2001 and 2006. The consistency in 5-year Am J Orthop. 2015;44(12):547-553. Copyright Frontline Medical OS suggests OS of pediatric patients with osteosarcoma has Communications Inc. 2015. All rights reserved. plateaued, and there has been no significant improvement in survival of patients with osteosarcoma over the past 30 years. References Histologic response to preoperative chemotherapy is 1. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma strongly associated with survival in pediatric osteosarcoma. and Ewing sarcoma. J Bone Joint Surg Am. 2000;82(5):667-674. 31 2. Cho WH, Song WS, Jeon DG, et al. Differential presentations, clinical Bielack and colleagues reported 5-year OS of 75% to 80% courses, and survivals of osteosarcomas of the proximal humerus over for patients who responded well to preoperative chemother- other extremity locations. Ann Surg Oncol. 2010;17(3):702-708. apy (>90% tumor necrosis) and 45% to 55% for patients who 3. Abate ME, Longhi A, Galletti S, Ferrari S, Bacci G. 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Bacci G, Longhi A, Ferrari S, et al. Prognostic significance of serum lactate Research Statistician, Center for Biostatistics, Ohio State Univer- dehydrogenase in osteosarcoma of the extremity: experience at Rizzoli on

552 The American Journal of Orthopedics® December 2015 www.amjorthopedics.com J. C. Friebele et al

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This paper will be judged for the Resident Writer’s Award.

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